non invasive cardiac system (nicas) whole body electrical ...7 yusuke tanino et al. whole body...

Non Invasive Cardiac system (NICaS)

Whole Body Electrical Bio Impedance

Bio Impedance Technology

Study Review

January 2014

2

No. Article Subject Page 1 Cardiac Output Monitoring - Reviewing the Evidence on Four

Systems, Health DEVICES Vol. 42 No. 6 June 2013 NICaS

Validation 4

2 Yu Taniguchi et al. Noninvasive and Simple Assessmentof Caridac Output and Pulmonary Vascular Resistance With Whole-Body Impedance Cardiography Is Useful for Monitoring Patients With Pulmonary Hypertension, Circulation Journal, June 12,2012

NICaS Validation

15

3 SG Hall, J Garcia, DF Larson and R Smith. Cardiac power index: staging heart failure for mechanical circulatory support, Perfusion 2012 27:456-459

Cardiac Power Index Validation

22

4 JGF Cleland et al. Non invasive measurements of Cardiac Output 9CO) and Cardiac Power Index (CPI) by whole body bio impedance in patients with heart failure. A report from SICA-HF study 9FP7/2007-2013/241558). European Journal of Heart Failure Supplements (2012) 11

NICaS Validation

29

5 Yoseph Rozenman et al, Detection of left ventricular systolic dysfunction using a newly developed, laptop based, impedance cardiography index, International Journal of Cardiology Volume 149, Issue 2: 248-250, 2 June 2011

GGI Validation 30

6 Robert G. Turcott et al,Measurement Presision in the Optimization of Cardiac Resynchronization Therapy, Circulation Heart Failure 2010;3:395-404, February 22, 2010

ICD for CRT Optimization

Validation

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7 Yusuke Tanino et al. Whole Body Bioimpedance Monitoring for Outpatient Chronic Heart Failure Follow up, circulation Journal 73:1074-1079, June 2009

NICaS Validation

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8 Konstantin M. Heinroth et al, Impedance Cardiography: a useful and reliable tool in optimization of cardiac resynchronization devices. Europace (2007) 9, 744-750, 11 May 2007

ICD for CRT Optimization

Validation

50

9 Dorinna D. Mendoza et al. Cardiac Power Output predicts mortality across a broad spectrum of patients with acute cardiac disease. American heart Journal 153:366-370, March 2007

Cardiac Power Index Validation

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10 Oscar Luis Paredes et al. Impedance Cardiography for Cardiac Output Estimation - Riliable of Wrist-to-Ankle Electrical Configuration -. Circulation Journal 2007; 70: 1164-1168, September 2006

NICaS Validation

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11 G Cotter, A Schachner, L Sasson, H Dekel and Y Moshkovitz. Impedance cardiography revisited. Physiological Measurement 27 (2006) 817-827, July 2006

NICaS Validation

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12 Ronald D. Smith et al. Value of Noninvasive Hemodynamics to Achieve Blood Pressure Control in Hypertension Subjects. Hypertension 2006;47:771-777, Mar 6, 2006

ICD for Hypertension

Validation

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Table of Content

No. Article Classification Page

13 Marina Leitman et al. Non-invasive measurement of cardiac

output by Whole-body bio-impedance during dobutamin stress

echocardiography: Clinical implementations in patients with left

ventricular dysfunction and ischemia. The European Journal of

Heart Failure 8 (2006) 136-140

NICaS

Validation

86

14 W. Frank Peacock et al. Impact of Impedance Cardiography on

Diagnosis and Therapy of Emergent Dyspnea: The ED-IMPACT

Trial. Academic Emergency Medicine Vol. 13, No. 4:365-371, April

2006

ICD Validation

for ER

91

15 Hector O. Ventura, Sandra J. Taler and John E. Strobeck.

Hypertension as a Hemodynamic Disease: The Role of

Impedance Cardiography in Diagnostic, Prognostic and

Therapeutic Decision Making. American Journal of Hypertension

Vol. 18, No. 2, Part 2:26S-43S, February 2005

ICD Validation

for

Hypertension

98

16 Guillermo Torre-Amiot et al. Whole-Body Electrical Bio-

Impedance is accurate in Noninvasive Determination of Cardiac

Output: A Thermodilution controlled, Prospective, Double

Blinded Evaluation. European Journal of Heart Failure, June 2004

NICaS

Validation

116

17 Gad Cotter, Yaron Moshkovitz, Edo Kaluski, Amram J. Cohen,

Hilton Miller, Daniel Goor and Zvi Vered. Accurate, Noninvasive

Continuous Monitoring of Cardiac Output by Whole-Body

Electrical bioimpedance. CHEST 2004;125;1431-1440

NICaS

Validation

117

18 Gad Cotter et al. The role of cardiac power and systemic vascular

resistancein the pathophysiology and diagnosis of patients with

acute congestive heart failure. The European journal of Heart

Failure 5 (2003) 443-451

Cardiac Power

& Peripheral

Resistance

Validation

129

19 John E. Strobeck et al. Beyond the Four Quadrants: The Critical

and Emergong Role of Impedance Cardiography in Heart Failure.

Editorial, April 2004 Supplement 2

ICD Validation

for CHF

138

20 Amram J. Cohen. Non-invasive measurement of cardiac output

during coronary artery bypass grafting, European Journal of

Cardio-thoracic Surgery 14 (1998):64-69

NICaS

Validation

144

21 C. Gresham Bayne. Evaluation and management of the elderly

homebound patient with congestive heart failure

ICD Validation

for CHF

150

Table of Content, Cont’d

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) t'k*ffiam

GC WITH THE FLOWTHERMODILUTION USING A PULMONARY ARTERY CATHETER IS CONSIDERED THE GOLD STANDARD

IN MEASURING CARDIAC OUTPUT. HOWEVER. DRAWBACKS ASSOCIATED WITH THE TECHNIQUE HAVE

PROMPTED CLINICIANS TO SEEK LESS INVASIVE OPTIONS. BUT THESE ALTERNATIVES HAVE THEIR OWNLIMITATIONS. WE EXAMINE THE EVIDENCE ON FOUR DEVICES THAT MEASURE CARDIAC OUTPUT USINGMI N IMALLY INVASIVE AND NON INVASIVE TECH N IQU ES.

\Ieasuring a patient's cardiac output-the amountof blood pumped bv the heart per minute-can aidin diagnosing diseases of the cardiovascular systemand in managing high-risk patients (e.g., those suf-fering from burns, sepsis, or shock) and patientsundergoing maior surgicai procedures. The cardiacoutput value can be derived lrom heart rate andstroke volume (the amount of blood pumped br-the heart per beat) using the relationship

cordioc oulpul = stroke volume x heort roie

The uaditional approach to monitoring car-diac output is pulmonarv arterv catheterizationusing thermodilution as the measurement method..Florvever, the draw-backs associated with this tech-nique-including the risk of pulmonarr artervruprure aod air emboli5m-h21.g led clinicians roseek less invasive alternatives.

In our December 2009 issue, rve looked at somerninimallf invasive and noninvasive alternatives topulmonarl' arterv catheterization for cardiac outputmonitoring and revierved the evidence regardingdreir effectiveoe ss. This article setres as ao update tothat piece. We profiie four additional cardiac outputmonitoring svsterns and rer.'ierv the evidence

regarding their accuracv compared to other cardiacoutput monitodng techniques, particuiadr ther-modilution. \Y'e also examine evidence regardingimproved clinical outcomes with use of thesederrices.

\\:e look at the following s,rstems:

) ConMed Ecollt. The literarure s'e revierved didnot show the ECOII to be ao acceptable alter-native to the reference techniques; horvercr,nvo studies found that the monitor rvas usefulin predicting fluid responsir.eness in abdominaland cardiac surger\r patients. \I'hen the monitoris used in the ()R

"vith electrosurgical equip-

ment, interruptions in monitoring could occur.\\:e did flot 6od any sfudies addressing clinicaioutcomes.

F Edwords Llfesciences FloTroc sensor. Previousl,vreviewed literarure showed the FloTrac sensor tobe comparable to thermodilution in stable car-diac surgerv patients. Srudies on the latest gen-eration of the FIoTrac sensor, horvever, [oundthat the device may be less reliable than thermo-dilution in hemodynamicallv unstable patientssuch as those undergoing abdominal surgen'

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Reuiewing theEuideruce on FourCardiac OatputMonitoring Slstems

or iiver transplantation, those on vasopres-sor therapt', or those with sepsis. Tivo srudiesreported improved clinical outcomes (reducedcomplications and hospital length of star) rvhenthe FloTrac sensor was used to guide fluid management in abdominal surgerv patients.

) Edwords Llfesciences VolumeView sensor. TheYolumeYierv sensor is relativelv nerv; therefore,the evidence on it is limited. \Iore indepen-dent srudies on raried patient populations arerequired to determine its ef6cacr'. \\"e did not6nd anr studies ad&essing clinical outcomes.

) Nl Medicql NlCoS. SLx srudies examined in ourLiterarure review found that the NICaS is anacceptable aiternative to the reference tech-niques for cardiac output measurements in car-diac patients and heart lailure patieots. Tvuo ofthose studies found it to be more accurate thanthoracic impedance cardiographr. \V'e did not6nd anr- srudies addressing cl-inical outcomes.()f these s)'stems, only \I \Iedicalt \ICaS is

noninvasive; the remaining three svstems are coo-sidered minimallr- invasive.

r:'i lli ii.ji{} i.iri\:iY n:,i.'r ii:r"l' ::'i'r,iiiiVlf;}1}i i,tii'ii.}:LiTiaditionally, cardiac output is measured using a

technique knorvn as pulmonar,v arterl.- thermodilu-rion, *,hich incorporates the use of a pulmonarvarteq'catheter, or PlC. PuimonarY atterv thermo-dilution is considered the gold standard in cardiacoutput monitoriag. There are two basic versions oFthis technique: bolus and continuous. In bolus, orintermittent, thermodilution, a bolus of an iniectateat a knorvn temperature is infused into the blood-stream, and the change in temperarure caused bvthe iniectate is measured at some dorvnstream loca-tion using temperature sensors incorporated into a

PlC. ()ne dras'back to bolus thermodilution is thatit does not provide a cootiouous measurement of

UMDNS ierm- Monilors, Bedside, Cordioc OutputI2O-1741

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/guidance

cardrac output and therefore cannot detectrapid and sudden changes in the hemodr--namic starus oi high-risk pauents.

Continuous rhermodilution inroh'esmeasuring the change in the temperarureoi blood at a dorvnstream location afterintroducing a heating Elament upsream.Ti-picallr', the heating filament is placed inthe right tentricle and pou'ered on intermit-tenth', and blood tcmperarure is measured inthe pulmonarr arten-. The displaled cardiacoutput is an average of measurements takenovet three to slr minutes.

The use of a P,\C adds a degree oi riskto rhe technique: P-\Cs are both inrzsiveand associated with a number ol compli-cations, most of s,hich are related to theinsertion of the catheter; these .includepulmonarr- arterl rupfure, air embolism,and arrhr-thmias. --\dditionalh', evidenceregarding the efficacv o[ P-\Cs in improv-ing clinical outcomes is r'.'eak; therefore,this technique is being used on a smalland declining percentage of critical carepadenrs (Schrvann et al. 201 1, \\'heeleret aL.2006, Wiener et al. 2001).

The &arvbacks associated s'ith pulmonan-arterr thermodilution have spurred thedevelopment o[ less invasive alternativestbr monitoring cardiac outpttt. Thesealternatir-e technologies, although lessinvasi"'e than pulmonarv arterv thermodi-lution, have their orvn dtaw-backs, and theevidence regarding their usefulness canbe limited. 111 currentlv matketed cardiacoutput monitoring svstems fall into one ormore oF rhe follorving categories.

Aderiql woveform onolysis. This minimallvinvasive technique uses an arterial pres-sure lioe and is based on the principle thatchanges in arterial blood volume during a

cardiac clcle are accompanied br changesin pulse pressure. Stroke volume can bedetermined bv conrcrting the change inpulse pressure obtained from the arterialpressure rvaveform to a corresPofldingchange io blood volume. Pulsc pressurechanges that cortespond to a change in

LIMITATIONS OF THE LITERATURE

There ore limitotions to the published sludies we revievred, ond reoders should be core{ulvrhen drowing conclusions from our findings. One limitotion is intrinsic to fhe meosuremenl ofcordioc oulput: The occurocy o{ pulmonory oriery thermodilulion, the gold stondord method,is highly dependent on user technique. As o result, thermodilulion's resulis ore not olrvoysrelioble. This in lurn offects the ossessmenl of ollernoiive lechniques such os those used by lheproducts we review in this orticle: Becouse of ihe possible inoccurocies in ihe PAC meosure-menis thoiihe olternoii're techniques ore compored ogoinst, on olternotive is generolly con-sidered to be occurote even i{ there exists up fo o 3096 discreponcy (percentoge error) rvhencompored io the thermodllution re{erence meihod. This helps exploin the sometimes limitedond inconclusive noture of evidence regording the occurocy o{ lhe producis in this orticle.Thus, our review of the evidence olso took inio considerolion studies comporing the producisio other cordioc output moniioring techniques {e.g., vrhether ihe resulls from the two productscorrelote, or show ihe some irend).

Another limitotion o{ the siudies is thot, while they look oi the occurocy ond correloliono{ the cordioc output volue, ihey don't iypicolly provide ony insighi into lhe use o{ iheseoliernoiive iechniques in clinicol proctice {e.g., how often they ore used, ihe iype of theropiesthey guide, their clinicol outcomes). Thus, we recommenC thoi hospitois opply coution rvhenconsidering these devices for use.

blood volume are dependent on atterial [described under Electrical, belorv]) andcharacteristics such as aorric compliance the Edrvards Lifesciences FloTrac andand peripheral resistance. \'olumeYiet'.

Sr-stems using arterial rvar.elorm analr-sis often need to compensate for chaogesin individual arreial f aorac characteristicsthat might occr-rr during the measurementperiod, due either to phrsrologic changesor to changes associated rvith trcatment.\Iost devices compensate for thesechanges using an independent measureof stroke volume (e.g., thermodilution).Horvever, some devices don't use anvexternal calibration and instead use pro-prietan- algorithms that ftequenth- updatespeci6c calculation parameters based onthe patient's demographic and phvsiologicin[ormation.

Devices that use arterial rvar.eformanah sis might not be accurate in parienrsrvith certain arrhr-thrnias or arterial treepathologies (conditions that afFect theshape of the arterial pressure s'aveform)or in the presence of circulaton'assistdevrces such as intra-aortic balloon pumps.

Three of the s1'stems rve rer.ierved usethis technique: the Conlled EC()\I (rvluchuses a combination of afterial wavefofmanallsis and impedance catdiographl

Esopho geo I Dopp le n f his rninirnalir inr-asiveapproach uses Doppler ultrasound tech-niques to measure blood florv rn the aorta,and can be used in the absence of anr'peripl-reral or central line. In this technique,an ultrasonic rvaye is directed torvard theaorta. \Ieasurements are perlormed usingultrasouod probes that are inserted intodre esophagus and aimed at the aorta. Thefte<luencr- of the rvave reflected back b,v themoving blood cells (in t1-re aorta) is difierentilom the origrnallr uansmined ultrasound&equencl-; this shift in irequenci- can beused to obtain the velocin'of the bloodin the aorta. That velocin can be used tocalculate the distance traveled br- the bloodin the aorta during sr stole, knos'n as thestroke distance. The stroke distance is thenused to estimate stroke volume using thecross-secrional area of the aorta, lvhich isestimated usiog the panent! age, height, andrveight. This technique is rypicall,v used oninrubated patients.

Electricol. In this noninrzsive techoique,cardiac output is deriwed br applving anelecttical signal across certain areas of thebodr- (e.g., chest, ankle) using electrodes

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placed on the patient. Changes in theapplied signal are then measured duringeach cardiac cr-cle. ()bsen'ed changes inimpedance and phase shift can be relatedto changes in blood volume. Der,'ices usingthese techniques are n'picallr suscepribleto motion artilacts that might prove a hin-drance to continuous monitoring.

()ne o[ the more cornmon electricaltechniques is knorvn as impedance car-diograph,r' (ICG), u.'hich is based on tl'retheon that changes in blood tolume inthe aorta during each cardiac cvcle tesultin irnpedance changes that can be usedto estimate stroke volume. The imped-ance changes can be derived br measuringvoltage changes to ao applied electricalsignal. Traditionalh-, the ICG techniqueuses electrodes placed on the Patientt neckand chesr (knorvn as thoracic ICG). ()ne

PRODUCT REVIEWS

Pulmonarv arter't- thermodilution is consid-ered the goid standard for cardiac ourputmeasurement. Therefore, the tables thataccompanv our product reviervs comParcthe evidcnce on each product with theevidence on thermodilution. But becausecomparisons to other methods can alsobe use6;1 (see the box on page 180), rhediscussions in each revierv also take intoconsideration srudies comparing the prod-ucts to otier cardiac output techniques.

supplier. Coolled Corp. [101345], Utica,\Y (US-\); +1 (800) 4-18-6s06, +1 (31s)7 97 -831 5 ; g'rvs,. conmed.com

Procedure. f'he EC()]I (rvhich stands forEndotracheal Cardiac ()utput \Ionitor) isa minimallf inrasive srstem that measurescardiac output and other related hemodi--namic parameters using a combination o[trvo different techniques: ICG and arteriais.atetbrm analvsis. The monitor obtainsan impedance rvaveform rvith the ICG

drarvback o[ these locat-ions is the suscep-ubiliq' to noise: In addition to blood flow;the electrodes ma,r pick up other signalssuch as airflos, through the lungs. Twosvstems rc revierv use ICG: the ConlledEC()\I (rvhich uses a combi'ration of ICGand arterial r'"aveform anaitsis) and the \Ifledical \ICaS.Rebreothing. The noninvasive rebreathingtechnique is based on the principie thatintake or elirnination o[ a gas (as iodicatedbv the ditference in the concentration ofthe gas entering and exiring the lungs) isproportional to the amount of blood florvto the lungs that is invol't'ed in the gasexchange. The amount of gas consumed/produced is used as an indication of pul-monarv blood flos-, and in the absence ofsignificant intrapulmonan shunt (bloodflorv to thc lungs not invoh-ed in gas

excl.range) or intracardiac shunt QloodIlorv across the chambers ot the heart),pulmonan'blood flou'can be equated tosvstemic blood llorv or cardiac ourPut'Devices using this technique mal be inac-curate in patients with abnotmallr highintrapulmonarv or iotracardiac shttnts(rvhich can occur in thc presence oi somerespiratort or cardrac diseases).

Tronsthoro(ic echocordiogrophy. In trans-thoracic echocardiography, or TTE, anulrasound probe is placed on the chestto measure the Yelocifr o[ blood acrossthe aort-ic or pulmonan= vaive. This, com-bined s,ith the cross-sectional area oF thevalves, allot's calculation of ieft or rightstroke volume and cardiac output. Thisnoninvasive technique mar be inaccuratein patients u'ith r,alr.e and florv-patternabnormalities.

technique and uses this in conjunction,x.ith the arterial s,zr.elorm analrsis tech-nique to determine catdiac output.

The monitor consists of an endotrachealrube with a printed elecrrode arrat thatapplies the electrical signal required for ICG.The elecrode arrav consists of a singleelecuode at the proximal end of the rubeand slr electrodes at the distai eod. \\'henthe patient is innrbated, the distal eiectrodesare located adjacent to the ascending aorta,thus iacilitating aortic blood ilorv measure-ments. The electrode arrav also detectsthe R-rr,ar-e and uses the R-R interval roobtain l-reart rate measurements. ,lterialpressure data is obtained from an esistingarterial pressure Line and, in addition to car-diac output, facilitates estimation oi otherhemodvnamic pararneters such as s1'stemicvascular resistance and stroke volume rzria-tion (neit1-rer of u'hich can be obtained fromICG).;\t the beginning oF the procedure,the clinician must enter the patientt height,rveight, and age, rvhich are used along withthe measured ICG signal to estimate suokevolume. -\ccording to the vendor, since the

elecuodes are in such ciose proximifi'to theaorta, the EC()]I is less susceptible to noisecompared to traditional ICG methods.

clinicol uses, -\ccording to the vendor, thetrC()\I is used primarilv in the OR lorshort-term conLinuous morutoring andis indicated for use in patients rvho areexpected to be inrubated for 24 hours otless. .\lthough ICG technologr in general issusceptible to motion artilacts, this mav notbe an issue with this derice since inrubatedpatients in the ()R are also npicallv sedated.

Disposobles, The monitor requites a propri-etarr- disposable endotracheal rube.

t It.i :3

ConMed ECOM. (lmoge courtesy ofConMed.)

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) s"i'ton"

LITERATURE REVIEW: CONMED ECOM COMPARED TO THERMODILUTIONStudyBoll et ol. 2010

Gennort et ol.201 2 (conferenceobskoct)Mous et ol. 201 I

Moller-Sorensenet ol. 20'12

Von der Kleii et ol20 1 2 {conferenceobstroct)

40 cordioc surgerypotienls

I 4 cordioc surgerypotients

29 coronory orlerybyposs groft poiients

25 coronory orterybyposs groft potients

20 coronory orterybyposs grofi potienis

Bolus pulmonory orterylhermodilutionThermodilution.

Bolus pulmonory ortery ther-modilution ond tronsesopho-geol echocordiogrophy

Bolus pulmonory orterythermodilution

Pulmonory orlerythermodilution"

Polienlpopulolion Referencemethod OutcomesWith o percentoge error of 5O% ond o correlotion coe{ficient o{r : O.49, the h*o methods were not considered comporoble.With percenioge errors of 419'5 ond 5970 (bosed on orteriol Iinelccotion), the iwo methods were not considered comporoble.

The percentoge error wos 5070 compored to thermodilution ond48% compored to echocordicgrophy. However, lhe oulhors reportocceptoble trending of cordioc outpul.VVith percentoge errors ronging hom 37o/o to 45% bosed on pctientposilion, the ivro methods v/ere not considered comporoble. Thestudy olso reported poollrending of cordioc oulpul by the ECOMmonilor.

The obskoct reports poor correlotion (r = 0.23) beiween the ECOMmonilor ond lhe reference method in postoperolive potients.

- The obstroct does not speci{y whot lype of thermociilulion wos used.

'^ The obslrqcl does not specifo whelher lhe melhod of ihermodilulion used vros coniinuous or rnlermiilenl

Evidence. \\e revierved eight clinical srud-ies that compared the EC()\I monitor toother methods of cardiac output measure-ment. The srudies involved cardiac surgerrand abdominal surgerv patients, and thenumber of patients in the srudies rangedirom 12 to'10. In five of the eight snrdies,the ECOII monitor was compared to pul-monal\. arter\' thermodilution; these studresare outlined in the table on this page. Inthe remaining three srudies, the reierencemethods rvere transpulmonarr- thermodilu-tion (rvhich uses a central venous catheterrather than a P-\C) (F'ellahi er aL.201.2),esophageal Doppler fl orgensen er al. 2Ol2),and the FloTrac sensor @airamian et al.201 1; see our rerierv of this slstem belorv-).In addition, three ol the eight srudies(Bairamian et al. 2011, Gennart et aL.2012,\hn der Kieij et al. 201,2) rvere reported asconference abstracts onlr; therefore, therma\- not rePresent the 6nal results and con-clusions oi the srudies.

In all eight srudies, the authors con-cluded that the device \\,-as not comparableto the reference method. The evidenceregarding the monitort abilirl'to trendcardiac output is inconsistent, rvith onesrudv (\Iaus et al. 2011) reportiog goodtrending (based on the correlatjon benveen

182 x;arrg DEvtcEs JUNE2or3 ) w.xri.org

the EC()f t monitor and the referencetechniques) and rs'o studics (Jorgensener a|.2012, \Ioller-Soreosen et al. 2012)reporting poor trending. livo srudies(Bairamian et al. 20i 1, Fellahi et al. 2012)conclude that the techoique mav be usefulfor predicting fluid responsiveness (usingstroke volume rariation). Trvo other srud-ies @all et al. 2010, ]Ioller Sorensen et al.20i2) tbund that the EC()\I \i,as suscep-tible to interference from electrocauterr-equipment used during surgeries, leadingto intermittent loss of signal during elec-trosurger\' and somedmes several secondsafter electrosurger\- \'v?s discontinued.

\\b d-rd not 6nd anr studies ad&essingc[oical outcomes.

Supplier. Edrrards Li[esciences Corp.[374501], Irvine, C-\ (US.\); +1 (800) 124-

::f , ., (e-+e) 250-2500; rwwv.edrvards.

'.\lthough thc authrlrs usc rhe rcrm "clcctrocrutcn,"*cloelierc tlrc intcnt wrs "clcctrcsurgcn."

Procedure. The FloTrac sensor usesarterial rvaveflorm analrsis to estimatecontinuous cardiac output using the Flo-Trac algorithm. -\ccordiog to the vendor,the algorithm constantlv monitors rhe arte-rial pressure vaveform and compensatesfor changes tn arterial f aottic characteris-tics. The FloTrac sensor can be used witheither thc E\-1000 or thc \-igilco rnonitoroffered bv Eds'ards Lit'esciences.

The FloTrac sensor can be used onlvon patients rv-ho har.e an existing arterialline that can be connected to the sensor.The sensor has nvo output lines: ()ne isconnected to the arterial pressure cableof a bedside monitor, and the other isconnected to the E\-10o0/\'igileo moni-tor. The sensor, once connected, sendsarterial pressure rv'aveform informationto both monitors. The cardiac outputmonitor (either the E\'1000 or the \-igileo)uses this informat.ion in coniunction withpatient demographic information enteredbr the user (e.g., age, gender, height,rveighr) to esrimate cardiac output.

\\'e covered the FloTrac sensor in ourDecember 2009 Guidance -{.rticle. Sincethen, the vendor has updated the device'salgorithm. The hterarure review-ed in the

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LITERATURE REVIEW: EDWARDSSludy Potient populotionBioncofiore et ol. 2Ol I 2l liver tronsplontolion

potients

De Bocker et ol. 20,l I 58 septic potients

Morque ei ol. 201 3 18 seotic shock potienls

'l 9 septic shock potienis

28 liver tronsplontotionpotients

20 liver tronsplontotionpotients

Vosdev et o1.2012 38 coronory ortery bypossgroft poiients

LIFESCIENCES FLOTRAC COMPARED TO THERMODILUTIONReference method OulcomesBclus pulmonory ortery With o percentoge error o{ 37o/" ond o correlotion coelficientthermodilution of r = 0.65, lhe ogreement betueen the irvo methods vros noi

considered clinicoliy occeptoble.

Bclus ond continuous pulmo- \Vith o percentoge error ol 30.4o/o, the FloTroc sensorwosnory ortery thermodiluiion considered io be ot leosi os occurote os the reference methods

Continuous pulmonory ortery With on overoll percenloge error o{ 640/o, ihe iwo methodsihermodilution v/ere not considered comooroble.

With on overoll percentoge error ol 53o/o, the two methodsv/ere not considered comporoble. The oulhors conclude thotthe trending obility of the FloTroc sensor is foir.

Conlinuous pulmonory ortery Wilh o percenloge error ol 75o/o,the irvo melhods were nolther'modllution considered comporoble. The outnors olso report poor trending

of cordioc outpuf by ihe FloTroc sensor.

Slogt el ol. 20 I 3

Su et ol. 2012

Tsoi et ol. 20 I 2

Bclus pulmonory orterythermodilution

Bolus pulmonory orterythermodilution

Eclus pulmonory orierythermodiluiion

Wilh o percentoge error of 54.93o/o, ihe outhors report poorcorreiotion be,'ween the furo methods.

With percentoge errors of 2Ao/o ond 2296 depending on themonitoring site (rodiol vs. femorol), lhe turo melhods wereconsidered comporoble.

Fdwords Lifesciences FloTroc sensor.(lmoge courtesy of Edvrords Lifesciences.)

Evidence section belorv deals onlv rvith theperlormance oi the updated algorithm.

Glinicol uses. The Floftac sensor can beused for [ong-term continuous monitoringot- patients rvho are alreadv connected toan invasive blood pressure monitor rvithpreerisdng arterial iine access.

Disposobles. The srstem requires the pro-prietarr', disposable FloTrac sensor. It doesnot require anv proprietary catheters.

Evidenre. \\'e revierved 16 srudies publishedsince 2010 that compared the performanceot- the nerver generation oi the FloTracsensor with other cardiac output monitor-ing techoiques. Seven of the 16 srudies(see the table abor.e) compared the FloTracto pulmonarr- arter\- thermodilution, fourstudies compared it to uanspulmonarr'thermodilution, and the remaining 6r.ecompared it ro Doppler echocardiographr.The srudies invoived cardiac sutgerv, lir.ertransplantation, sepsis, and abdorninal sur-gery patients, and the number o[ patientsin the srudies ranged from i8 to 60.

In our previous revierq the earlier gen-eration of the FloTrac sensor',vas found

to be comparable to rhermodilution instable cardiac surgerr patients, and theone recent stud\- we rerierr-ed that lookedat cardiac surgerl patients (\hsdev et al.2012) reports that this is the case with thenerv version oF the FloTrac.

\Iost srudies on the nerver generauonoi the sensor examlned its performancein hemodlnamicallr unstable patientpopulations (e.g., septic patients, liver trans-plantadon patients). In 10 o[ the srudiesexamined in our current tevies', the authorsconclude that the latest generation of theFloTrac sensor is not compatable to therelerence techmques; patient populationsin these srudies include patients undergo-ing abdominai surgerl-, patients undergoingliver transplantauon, and patients under-going vasopressor therapr- (rvhich couldaffect arterial compliance). -\mong srudiescomparing FloTrac to thermodilution forpatients with sepsis, one srudr (De Backeret al. 2011) reported good accurao',rvhereas t$-o others (\Iarque et al. 2013,Slagt et al. 2013) reported a high petcentageerror. Tr'"'o srudies (Benes et al. 2010, \Iareret al. 2010) looked at patient outcomes

:j

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gaidance

rvhen the FloTrac sensor \\?s used forBuidmanagementduringmajorabdominal LIERATURE REVTEW: EDryARD5 LlFEsclENcEs voLUMEVtEWsurger'compared to,standard fluid man- coMpARED To THERMoDILUTIoNagemenr ePPfoacnes (usmg mean arrefralpi"..ur. and ..rrtr"l',,.rro,i. pressure ro Study Polient populotion Reference method Oulcomesguide therapr). Both srudies shotved that !^o1lo 9t ol, 5 potienls undergoing Bolus ond continu- lVith p-mentoge errors o[.49o/o

Ihe lcogth oi'rt^r ^.,d

incidence oI compLi- 39]^'J::1"-l liver tronsplonlolion :J-',!'lT:::J "'t"ry :ii !f i",*lT -':ilil"-dIcatrons decreased rvhen the FloTrac senior ence obstroct) thermodrlutron .olus ond conl'nuous fhermo-

dilution, the VolumeView wosrvas used. $ote that the f lar-er studr rvas nol considered comporoble lofunded br- Edtvards Littsciences.) the re{erence methods.

Supplier Edn'ards Lifesciences Corp.[374501], kvrne, C-\ pS-{); -l (800) -+24-

321 8, + I (949) 250-2500; t'rvrv.edr','ards.com

Procedure. The \blumeVierv sensor ispart of the \blume\ierv set and is usedin conlunction with the E\-1000 monitorfor continuous cardiac ourput morutor-ing. The sensor uses the arterial r'"'ar-eformanalrsis technique to estimate cont-inuouscardiac output, and the arterill s,-aveform isobtained using the \blumeYierv femoralcatheter. Horvever, uniike the FloTracsensor, s'hich does not use any exter-nal calibration, the YolumeYierv sensorrequires calibration using an externalcardiac outpur measurement. Tvpicallv,

Edwords Lifesciences VolumeView sensor.(lmoge courtesy of Edwords Lilesciences.)

calibration is recommended tbr arte-rial rvaveform analrsis techniques Forunstable or criticallv ill patients at definedintervals of time (can range from e'r'err30 minutes to everl eight hours based oopatient condition) or before undertak-ing anr therapeutic inten'endons. Thercndor offers the abilin-to perform trans-pulmonarv thermodilution' using the\blumeYierv set, and the resultiog cardiacoutput measurements can be used to peri-odicallr calibrate the YolumeView sensormeasurements.

The transpulmonan' thermodiiutiontechnique can also be used to obtain r-o1-ume measurements such as giobalend-diastolic volume, global ejection lrac-tion, and extra\ascular lung s,ater.

cllnicol uses. The YolumeVies, set can beused for long-term contjnuous monitoringof padents rvho have an existiag centralrenous linc.

Disposobles. The YolumeYierv set, rvhichinciudes the \blumeYiew sensor and the\blume\-ierv [emorai catheter.

Evidence. The evidence on the \blume-Yierv sensor is limited, since the dericervas introduced in 201 1 and is thereforerelativelr nes'. We onh- found nvo srudiesthat compared the YolumeYiew sensorrvith other cardiac outpur monitoring tech-niques in human patienrs. Costa er al.(2012) compared rhe cardiac outpur

- .\ salinc solutioo of kn()\\-o tcmpcriturc is injcctcdinto ao cxistinla ccntral rcnous cathctcr, end rhc chengcin rcmpcmturc of thc injcctatc is mcasured in thc [cmo,nl artcrr u:ing thc \irlumc\iicrv crtheter,

measurements from the YolumeYierv sen-sof to those obtained from pulmonarrarten- thermodilution rvith P^\Cs in fivepatients undergoing liver transplanra-tion (see the table above). lhe srudr-[ound that the \blumeYierv results rverenot comparable to the ralues obtainedfrom thermodilut-ion. This srudr. s,zs onlrrepotted as a conference abstract; thus, theresults reported mav not represent the 6nalresults and conclusions of the srudr. Theother studl', Kiefer ct al. (2012), comparedthe \blumeYierv sensor rvith aflother arte-rial s,'ar-e[orm analrsis technique that a]souses transpulmonarr. thermodi.lution forcalibration. This srudr rrzs performed on 72critjcallr ill patients and found that the Vol-umeYierv results *-ere comparable to thoseftom the reference method; note that thestudv $?s funded br Edrvards Lifesciences.

\\'e did not 6nd anv studies addressingcl-inical outcomes rvith this device.

supplier. \I \Iedical US-\ [457874], -\kron,{)H (US-\); +1 (800) 979-2904; rvrv*rnimedical.co.il

Procedure. The \ICaS (rvhich stands for\on Invasive Cardiac Svstem) consistsof a laptop aod one pair oF s'rist-ankleICG electrodes. The st'stem is based onthe ICG technique, rvhich is based on thetheorl that changes in the voltage oF anelectrical signal applied across an arcz ofthe bodr are due to changes in impedance(rvhich in rurn are associated *'ith changesin blood volume during each cardiac clcle).

ot

t*,

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Nl Medicol NlCoS. (lmqgg courtesy oINl Medicol.)

-\Iost cardiac output monitors that use thismodel measure changes in thoracic imped-ance wlth electrodes placed on the chest;horr,'e'r'eE the \ICaS monitor measures

impedance through nvo ICG electrodes-one on the patieot's $,rist and the other onthe contralateral ankle.

-{t the beginning of the procedure,the clinician must enter the patient'sgender, age, t'eight, and height. This datais used in conjunct-ion with the impedancedata obtained from the rvrist and ankleelectrodes to estimate stroke r.olume. Theelectrodes also provide heart rate and a

single-channel electrocardiogram (ECG).The ECG s.aveform, the impedance rvave-form, and the hemodi'namic parametersare all displared on the laptop. StandardECG electrodes are provided as an optionwith the monitor and can be used inaddition to the ICG eiectrodes to obtainthree-channel ECG.

Cllnicql uses. The ICG technologv is inher-entll suscept-ible to motion artifacts, andn picalh- patieots need to be still s'h.ilemeasuremeflts are being takeo.'fhus, thismonitoq like others that use the ICGmodel, is more suitable for spot-checkmeasurement of cardiac output andother hemodvnamic parameters than forcontinuous monitoring. -\nother issueto consider is that since this monitor islaptop-based, infection conftol risks mustbe taken into account, as the presence ofa kerboard complicates cleaning of thedevice. -\s a result, additional precautioas

(e.g., special ke1'board covers) ma,v beneeded, particularlv rvhen the device isused in the ()R.

Disposobles. One pair of rvrist-ankleelecuodes.

Evidence. \1'e reviewrd slx srudies comPar-ing cardiac ourput measurements fromthe \ICaS monitor with those ftom otherreference methods. Five of these stud-ies used thermodilution as the refetencemethod (see the table on this page), andthe remaining srudr' (Leitman et al. 2006)used Doppler echocardiographr'. ()ne ofthe srudies (Goor 2006) rvas reported asa conlerence abstract onlr; therefore, thereported findings mav represent onlr- pre-liminarr results and not the 6na1 resultsand conclusions o[ the srudr. The srudiesinvolved cardiac patients, and the numberof patients in the srudies ranged from35 to 122.

-\ll slr srudies found good correlationbetrveen the NICaS svstem and the refer-ence method. Tivo of the srudies (Cotteret al. 2006, Goor 2006) also comparedthoracic ICG, in addition to the \ICaSmonitor, to thermodilution for the samepatients, and Found the \ICaS svstem tobetter correlate with thermodilution.

\\:e did not Efld anv studres addressingclinical outcomes with this device.

LITERATUREStudyCoiter, Moshkovilz,et ol. 2004Cotter, Torre-Amiot,e1 ol. 2004Cotter et o]t.2006

Goor 2006 (con{erenceobsiroct)

Poredes et ol. 2006

Potient populotion122 cordioc potients

93 polienls wilh heorlfoilure43 cordioc potienis

46 cordioc polienls

35 cqrdioc potients

ihermodilulionThermodiluiion*

REVIEW: Nl MEDICAL NICAS COMPARED TO THERMODILUTION

Bolus pulmonory ortery lVilh o correlotion coefficient of r : 0.886, the two methodsthermodilution were considered comporoble.

Bolus pulmonory ortery With o correlotion coefficient o{ r = 0.8.l, the two methods were

Reference melhod Oulcomes

thermodilution considered comporoble

Bolus pulmonory ortery Vy'ith o correlotion coeflicieni oi r = 0.9. ihe two meihods wereconsidered comporoble.Wilh o percenioge error ol 2OYo, lhe two methods were consid-ered comporoble.

Bolus pulmonory ortery Wiih o percenioge error ol 19.95o/o ond o correloiion coefficieniihermodiluiion of r : 0.9], the iwo methods were considered comporoble.

' The obslroct does nol specify whot \pe of thermodilulion wos used.

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&!,,!:!{,c{"u,o,

RE FERENC ESISairemianJIr, RrxrkJI:, :\llard \IU, et al. (irmpan-

son of stnrkc trtlumc rariation obtained froman arrcrial prcssurc to cndorraclteal sensor svs-tcm. 2(111 .\nnual \[ccting of thc Internatir>nal-\ncsthcsia Rcsearch Socicq'; 201 1 \Ia1' 21 -2-l;\hncourcr (Oanada).

tlall'I'lt, (iulp l)(i, Patel \, cr al. (irmparison oftlrc cndotruchcal crrditc tlurput m<rnilor ltrthcrmodilution in canlirc surgcn plicnts.l (ttli,rlrird: I,b;; zlnt;th 2(llo ()cl.21(5):1(t2-6.

Bcncs J, Oh1'tn I, .Utmann I et al. Inrnropcradr cfltrid optimization using strokc r-olumc varia-tion in high risk surgical paticnts: results oIprospcctirc randomizcd srudt (n7 (-az2{)1{};l-1(3):Rl lll.

lliancofiorc G, Critchlcl'L.\, Lcc .\, ct al. Iilalua-tion of a ncs' sr>fru-arc tersitln of rhc lrlo l rac/Yigileo (r-crsion 3.1)2) and a comparison rvithprcr-ious data in cirdrotic paticnts undcrgo-ing fir-er trrnsplanr rurgc^-- /1n.ith -'lrulg2o11Sep;1 13(3):515-22.

Broch () ltcnnerJ, Clruencrvald ]I, ct al- -\ compad-son of third-gcncrarion scmi-inrasirc ilrrerialrvavcftrrm analvsis rrith rhermodilution inpatients undergoing coronatr surgcn'..\' Licttti/itlUbiltlurnul 21l2;2tt 12:15 lt)81. ll lpub2{)l 2 Jul 31 .l

Costa (1, Cccconct'l', Baron Q et al. Clrdiac out-put moniroring in cirilrotic paticnts: IiYl()(Xlr-crsus pulmonry arrerv catltctcr--prcliminarvdata fc<rn[crcncc abstractl. lt (rili;e! (qrt(onfirc tt. 32nd Intcrnational -svmPosiumon Inte nsivc Care and I'imcrgcncr \lcdrcineIlrussels llclgium. 2012; (irnlcrcncc Srarr(r-ar.pagings):20 1 2{)320-21}1 2(}S79. .\lso atailable:htg://ccfrrrum.com/contcnr/pdi/cc I 0ti26.pdi

(irrtcr G, Ikrshkoritz \ Kaluski Ii, ct al. -\ccunte,nonim-asir-e continuous monitoring of cadiacoutpur bv s'holc-bodv clectrical bioimpcdancc.Ur.,t 2001 .\pc I 25(-1): 1.13 I -'lt).

Cottcr (1, Schachncr -\, Sasson L, ct al- Impcdancc carditrgraphv retisitcd. I'l1itl -\l*ti 2(l(l(tScp;27(9):U1 7-27.

(lottcr (1,'lirrrc--\mot (], \tred Z, ct al. Wht>lc-bodv clcctrical bio-impedrncc is rccururcin non invasirc de tcrmination oI cardiacoutput: a tlrermodilution contnrllcd, PmsPec-tivc, d<rublc blind cr aluation. I lr.l I lurt I iil.\' upll 21ll.l;3(Supp);1 9. .\lso alailablc: httP;//cur j htiupp.oxtbrd journais.org/conrcnt/3/supplemcnt/ I9. l.extract.

Dc Backer I), \las G, -lan ,\, ct al. .\rtcrialpressurc-bascd canJiac output monitoring: a

mulriccntcr r alidation oI thc third-gcncrationstrfnvare in scptic Paricnrs. InlLn;irt (.are -\[td2t)1 1 Itb;37(2):233--11).

li(iltl Insriturc:I:ndotilcheal crrJirc ourpur mrtnirrr st stem(Oon\led (lorp.) tor dctermining carditc outputand strokc r-olume lcusrom product brict-1.(lustom I Iotlinc Se n-icc. 3)l2 l)ec -|.

lilo'I'mc scnsor Qidrvards Litlscicnccs, l.l.(-) ftrrnoninr-asilc cardiac output mrlnitoring lcustomproduct briefl. Cust()m I I()tlinc Scn ice. 201 2Dcc 6.

\oninr-asilc cardiac slstcm (\I \Icdical. Lrd)[<rr monitoring cardiac ()utPut lcustom pnrductbncf]. Custom I Iotlinc Scn-ice. 2012 l)ec 5.

Stra(l:r from thc hcart: undcrstanding cardilcourput monitr>ring tcchniques lguidancc erticlel.I kt lr h l) t ir i 2009 Dec;3ll(l 2):.3tt6--lt) l.YolumcYics set ([idrvards Litcscicnccs, I-1.(-)[r>r minimellt inr rsilc crrdilc output moninrring[custom producr brict-1. Cusrom I lorlinc -\cil'ice .

201-l I'eb 15.

l;cllahi-ll-, |ischer \l() Rebct () ct al. -\ comprrisonoI cndotracheal bioimpcdance cardi<>gr'rphrand transpulmonarr thcrmodilution in ctrdi:csurgcrv padcnrs.. | (.*di o lfuiit ; I L, : . lrc l l, 2111 2.\pr'26(?):217-22.

(]cnnart I;, lJeckcrs S, \trborgh O, et al. Impacrof;rrtcrial carhcrcr krcation tln thc accuritcr'of cardiac ourput proi-ided bl an cnd()trachcalbioimpcriancc dclice [c<>nfcrcncc abstr,rcrl. Cz7(rr, 2{)12; t(r(Suppl l).

(irxrr l) l'cripheral rersus thoracic impcdance c,rrdi-(Uriphr lconfcrcncc abstncrl. | ( ,trdiu, l iil 20{)6

.\ug; 12(6 Suppl):S5J-5.

J<trgcnscn I IK. llisg.rarJ.l, ()ilsm l. (-,'mp.rrison oibioimpcdance and ocsophagcal I)t>pplcr cerdiacoutput monitoring during abdomin:rl atlrtic sur-ger.t-. Cit (,an 20t2;16(SuPPl l).

Khs-aonimit B, Bhuralanontachai l{. Prcdicrion oiBuid rc-iponsircncss in scptic shock patienrs:comprring -strokc rrrlumc r trriarirtn br likilrac/Vigilur ancl rur(,mJtLd ptrlsc prcssurc r.triltion.I Lrr.l,,bttt.;l I tt ;io I ?{}1 2 treb;29(2) :6{_9.

Kre fcr \, I krtcr CK, \Iirn (i, et al. (llinicLrl v'rlida-rion of a nc$ the rm()dilution svstcm [<rr thcasscssment of crrdilc ourput rnd 11)lumctdcparamc tcrs. ( i t ( -a n 2tl 12 \ Iav 3{); I 6(3) :ll'9tt.

Kor,rkc \', \imada'I', \agata I I, ct al. 'liansicnthcmodvnamic change and xccurJc\'oI arrcrialblrxrd prcssurc-bascd cardi,rc ()utPut.. lrc'l,,lnd32ttl t .\ug;t 13(2):272-a.

Kusaka \', \irshit;rni K, Iric '1, ct irl. Clinical compari-s()n oi rn cchocardiograph-dcni-ed r-crsus pulsccounte r-dcrir'.d c.trdi.rc outpur mcxsurLmrnt in

abdominrl ?()rric xntutrsm surgcr.t. | (trdiotlttrt'l.

"t ; t .. I n, t h 2tt I 2 .\pr,26(2) :223' (,.

I-cirman \I, Suclre r t:, Kaluski l'1, ct al. \on-invasir c

mcasuremcnt of crrdirc ourput bv rvholc-bodrbi<>impedlncc during doburaminc strcss cclttt-crrdiogr.rpltr: clJnrc,rl implic.trioni ln Prticnt js ith Ic[t rrntricul;rr dtsfunction and ischaemia.I:Lr I I hnrt litil2t){)6 \lar;tt(2):13(r'l{}.

DO YOU HAVE A QUESTION ABOUT CARDIAC OUTPUTMONITORING?For exomple, ore you wondering . . .

) Whol fociors do I need to consider when purchosing o minimolly invosive or noninvos ve

cordioc output monilor?

) How widespreod is the use of cordioc outpui monitoring in clinicol proclice?

) Whot is lhe most estoblished olternotive technique in monitoring cordioc ouipui?You con get onswers to these ond couniless other quesiions through HD Advisor. Just

click the link in lhe top righi corner o{ your Heolth Devices home poge to occess your HDAdvisor doshboord ond storl your inquiry.

@ADVISORAsk the [xperts

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13 of 158.

\Ianluc S, (iros .\, (.himot L, et al- (:ardiac outpurmonitoring in scptic slrock: criluad()n oI thcthird gener:rrion l;krtrac-\'igilcoO. .l Qin,\lonil(,q nOil r 2( l l 3 .l 0n;27 (3):27 3 -().

\Iaus'I'^\I, llcbe r 13, llanks I).\, ct al- Oardiac outpurdcrcrmination lnrm cndorrirchcirllr mcasuredimpedancc cardiographv: cljnical evaluarion ofcndotrechcrl cardiac output monitor. / (,tnlilla-rn: V'r ii .' Ift t h 2ll I I ()ct;25(5):771)-5.

\Iarer,J, lloldt.J, \Icngisru .\\I, ct al. (loal-directcdinrrxrpcntire thcrapr bascd on eutocalibnrcdartcrirl prcssurc s alclorm analvsis rcduccs ho-.-pital stav in high-nsk surgical paticnts: r rand<>m-ized, controlled tnal. (. i r ( ut 2o ll ); 1 -t(1

) :l{ 1 tl.

\Icl.ean .\S, t luang S-f, Kot \I, ct al. Oomperison ofcardiac output measu(cmrnts in criticallr ill pa-ticnts: ljlo'I r,rc/\'igileo rs transrlroracic [)opplercclrocardi<rgrapll'. . lart,/h Iukr,il t Ltre 2O11

-[ul;39(.+):.i9{).tl.

\Icng I., 'l ran \P, .\lcxandcr IlS, cr al. 'l'hc impacrr>i phcnrlephrinc, cphcdrinc, and incrcascdprcload on third-generation Yigileo-likil rac andcsophagcal l)opplcr cardiac output mcasurc-mcnts. -. h c't h .. 1na13 2{) I I ( )cs1 1.3(-l):75 1 -7.

\Ictzcldcr S, Coburn \I, Iirics \1, er al. Performanccof cardiac output measurcmcnr de rir-cd fromartcrial prcssurc s'ar-efrrrm anah sis in prticntsrequirin.q high-dosc \f,s()prcss(rr thcnpl. IJr./;1 n *,th 2{l I I Jun-10(t(():77 G{1-1.

\ftrllcr-Sorcnsen I [, I hnsen KL, Ostcrgaard \1, ctal. Lack oi agrermcnt and trcnding abilin oi theendorrachcal cardiac outpur monitor comparcd

n'irh rhcrmodilurion. ;li/a ;1rut.;tLt.'iol .\',und 2012. \pr;5(r(-1) ;-133-{t).

\krnnct X, .\ngue I \,.lozn iak \1, ct al. 'l hird-gLncration I'kil'rac/\'igrlco docs not reliablrrrack changcs in cardiac outpur induccd bl nor-epincplrrine in cridcalll ill p^ticnts. Br.[ ,Arp]rilh2r) I 2 .\or;1 0tt(.l) :61 5-2?.

\lurdri Sll, I Iess JR, I lcss .\, ct el. Irocuscd rapidechocardiognphic cr-aluation r-crsus vascularcf,thcr-brsLd [*l ;rsscssmcnt oI c:rrdirc ourputxnd tuocri()n in criticallr' ill tnuma prticnts../' l)u r mt . l,u t c (.o rc .\' m3 2t) 12 \ Iav;72(5) : I I 58-6-1.

\lutoh 'I, Ishikarra'l', Kobalashi S, ct al. l)ertirr-mancc o I tlrird-gencrati<>n Irkiliac/\'igilc<rsrstcm during hrpcnlrnamic thcrrrpy lor deleledccrebral isciremia aticr subarachnoid hemor-rhage . .1ir4:i -\irrr, / Iilt 2lll?;3'99.

\ational I Icarr, I-ung, and l]lood Instinrte .\cutclle spiraron Distrcss Slntlromc (.\Rl)S) Clinical'lrials \cnrrrrk; \\'hcclcr .\l', llcrnard ()R, cr al.Pulmonan'artcfl' rrrsus ccntral \ cnous cathcterto lluidu rreatmrnt of lcutc lung injun: \ I:41 |.\lid 2{t{t6 \la1' 25;35"1(21):221.3-2-l

Parcdcs ()1., Shire-[, Shinkc'I, ct al. Impedancccardiograplrv [rrr cardiac output cstimarion: rcli-abilin oI rvrist-to-anklc elccrrodc conligurarion.(.ir:.1 ?0o6 Sup;7tt(9):l l6+fl.

Sclrl-ann \\I, I Iitlel Z, I krutl .\, ct al. I-ack ofeftectitcncss ol thc pulmonan' artcn' cath-crcr in cardiac :urgerr. .'luitb t7nQg2\l1l\or';l 1.j(5):99{-11){)2.

Slrrgt (i, de Lceurv \I.\, lScute J, ct al. (i:rrdiac otrtpurmcasured br unca[bratcd arteriai prcssurc s.avc-lorm analvsis br rcccntlr rclcased st>fnrare r-cr-sion 3.()2 r'crsus thcrmodilution in scptic shock.I Uin .\[uir (tn\ar 2013 .\pc27(2):l7l-7.

Su l](-,'t-.ai Yl', Chcn C\', ct al, (lardiac ()utput de-riled fiom artcrial pressurc q-ar-cfrrrm analvsis inpadcnrs undcrgoing lir-cr transplantation: i'alidiuoi r third-gcncrarion dcticc. 'l-ratpltnl Prut2ll12\Iar;$t(2):'12-l lt.

'lsai Yl; Su lXl, Lin (l(1, ct al. O;rrdirc ourput dcrii-tdtrom arrcrial prcssure t avciorm enallsis: r alidl-trrn oi tlrc rhir,.l-gcncr:tion sol-ro'rre in peticnrsundcrgoing r>rthotopic lir-er rransplantation.' l raulllail Pro: 2ll12 \Ier;-l-l(2):-1.33-7.

Van dcr Klcii S(-, Koolen B, (icrritse B, cr rr1. (-lini-cal cr:rluatir>n ot- a nes' cndotrachcal impcd-ince cardiogralhl mcthod. tlu,,/fu.,it 2l)12

.lul{t7 (7):729-33.

\ esdei- S, (-hauhan S, (ihoudhun \1, ct al. \rtcrixlpressure s ar-cfrrrm dcrir-cd cardiac output I;kr-'lrrc/\'igilco srstcm (third gcncration sofnvarc):comparison of nvo monitoring sitcs r-ith thctlrcrmr>dilution cardiac ourput../ (l)r -\Iqnit (.rm-

lrl 2012.\pr;26(2): 1 1 5-2t).

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Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

ulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance (PVR) because of pulmonary vascular re-

modeling. This leads to a decrease in cardiac output (CO) and ultimately death. Recently, targeted medical therapy for PAH patients with endothelin-receptor antagonists, phosphodies-terase-5 inhibitors, and prostacyclin analogs has been estab-lished,1 and the prognosis of PAH has improved.2 However, there is no universally accepted consensus on the treatment goals or follow-up strategy for PAH patients. Right heart cath-eterization (RHC) is not only the gold standard for the diagno-sis of PAH, but is also a useful tool for monitoring PAH, and is recommended 3–6 months after new treatments and in the case of clinical worsening.1 Hemodynamic monitoring with

RHC is predictive of survival and effective in a goal-oriented treatment strategy,3,4 and has been recommended by a recent guideline;1 however, there are some disadvantages in the reg-ular use of RHC as a follow-up procedure, especially with regard to invasiveness. Noninvasive and less complicated methods for monitoring hemodynamics are needed to manage patients with pulmonary hypertension (PH). Less invasive hemodynamic monitoring has recently been suggested as fea-sible in some situations.5 The Non-Invasive Cardiac System (NICaS; NI Medical, Hod-Hasharon, Israel) is a device for calculating CO noninvasively with whole-body impedance cardiography (ICGWB). The NICaS-derived CO (NI-CO) has been shown to be as reliable as the RHC-derived CO and is applicable for the noninvasive assessment of cardiac function

P

Received February 3, 2013; revised manuscript received May 1, 2013; accepted May 2, 2013; released online June 12, 2012 Time for primary review: 42 days

Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Y.T., N.E., K.M., K.N., H.K., H.T., T.S., K.H.); Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (N.E., K.N.), Japan

Mailing address: Noriaki Emoto, MD, PhD, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo-ku, Kobe 650-0017, Japan. E-mail: [email protected]

ISSN-1346-9843 doi: 10.1253/circj.CJ-13-0172All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Noninvasive and Simple Assessment of Cardiac Output and Pulmonary Vascular Resistance With Whole-Body

Impedance Cardiography Is Useful for Monitoring Patients With Pulmonary Hypertension

Yu Taniguchi, MD; Noriaki Emoto, MD, PhD; Kazuya Miyagawa, MD, PhD; Kazuhiko Nakayama, MD, PhD; Hiroto Kinutani, MD; Hidekazu Tanaka, MD, PhD;

Toshiro Shinke, MD, PhD; Ken-ichi Hirata, MD, PhD

Background: Right heart catheterization (RHC) is the gold standard for the diagnosis of pulmonary hypertension (PH) and a useful tool for monitoring PH. However, there are some disadvantages in the regular use of RHC because it is invasive. Noninvasive methods for monitoring hemodynamics are needed to manage patients with PH. In this study, we aimed to evaluate the reliability of noninvasive hemodynamic assessment with whole-body impedance cardiography (Non-Invasive Cardiac System [NICaS]) for PH.

Methods and Results: We investigated 65 consecutive patients undergoing RHC. Two-thirds of them had pulmo-nary arterial hypertension and one-third had chronic thromboembolic PH; 25% of the patients were receiving medi-cal therapy. Cardiac output (CO) was estimated by NICaS (NI-CO), thermodilution (TD-CO), and the Fick method (Fick-CO). There was a strong correlation between NI-CO and TD-CO (r=0.715, P<0.0001) and Fick-CO (r=0.653, P<0.0001). Noninvasive pulmonary vascular resistance (PVR) was estimated using a conventional invasive equation with NI-CO, mean pulmonary arterial pressure was calculated by echocardiographic measurement, and pulmonary capillary wedge pressure was estimated at 10 mmHg in all cases. NICaS-derived PVR was very strongly correlated with invasive PVR (TD-PVR: r=0.704, P<0.0001; Fick-PVR: r=0.702, P<0.0001).

Conclusions: Noninvasive measurement of CO and PVR using NICaS and echocardiography is a useful tool for the assessment of PH.

Key Words: Cardiac output; Noninvasive assessment; Pulmonary hypertension; Pulmonary vascular resistance; Whole-body impedance cardiography

Advance Publication by-J-STAGE

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sis, and dialysis, all of which interfere with the accurate mea-surement of impedance-derived CO with NICaS, as previ-ously described.6 Patients with elevated pulmonary capillary wedge pressure (PCWP >15 mmHg) on RHC were also ex-cluded; 5 patients were excluded because of the presence of an intra-cardiac shunt; 29 patients were reevaluated 3–6 months after new treatments or at clinical worsening.

HemodynamicsHemodynamic data were derived from standard RHC in all patients using a 6Fr Swan-Ganz catheter (Baxter Healthcare, Irvine, CA, USA). The catheter was introduced into the pul-monary artery under fluoroscopic guidance. Mean pulmonary arterial pressure (mPAP), systolic and end-diastolic pulmonary arterial pressure (sPAP and dPAP), mean right atrial pressure, and PCWP were measured. CO was measured using the fol-lowing techniques.

Thermodilution-Derived CO (TD-CO) A 5-ml bolus of iced 5% glucose solution was injected 5 times at the same rate. The results of 3 injections within 15% of their extreme disparity were averaged to derive the TD-CO value.

Modified Fick method (Fick-CO) Blood samples were ob-tained from systemic and pulmonary arteries. All samples were measured for oxygen saturation with the same device (Radi-ometer ABL 715, Copenhagen, Denmark).

NI-CO These measurements were performed simultane-ously with the measurement of TD-CO and Fick-CO during RHC. The measurement of NI-CO followed the method as previously reported:6 an alternating electrical current of 1.4 mA with a 30-kHz frequency is passed through the patient via 2 pairs of tetrapolar electrodes – 1 pair placed on the wrist above the radial pulse, and the other pair placed on the contralateral ankle above the posterior tibialis arterial pulse. If the arterial pulses in the legs are either absent or of poor quality, the sec-ond pair of electrodes is placed on the contralateral wrist.

The NICaS apparatus calculates the stroke volume (SV) by Frinerman’s formula:8

SV = dR/R × ρ × L2/Ri × (α + β)/β × KW × HF

where dR is the impedance change; R is the basal resistance; ρ is the blood electrical resistivity; L is the patient’s height; Ri is the corrected basal resistance according to sex and age; KW is a correction factor for weight according to ideal values; HF is the hydration factor, which takes into account the body water composition. α+β is equal to the ECG R-R wave interval

in patients with left-sided chronic heart failure,6,7 but its feasi-bility in patients with PH has not been evaluated. The purpose of this study was to evaluate the reliability of noninvasive measurement of CO and PVR with ICGWB in patients with PH.

Editorial p ????

MethodsThis study was approved by Kobe University Hospital Institu-tional Review Board and the patients provided written informed consent to participate.

PatientsWe enrolled 65 consecutive patients with known or suspected pulmonary hypertension hospitalized in Kobe University Hos-pital from April 2010 to August 2011. All patients who were scheduled for RHC without fulfilling one of the exclusion criteria were eligible for the study. The exclusion criteria in-cluded restlessness and/or unstable patient condition, severe aortic valve regurgitation and/or aortic stenosis, aortic aneu-rysm, heart rate >130 beats/min, intra- and extracardiac shunts, severe peripheral vascular disease, severe pitting edema, sep-

Table 1. Clinical Characteristics of All Patients at Initial Hospitalization

Age (years) 62±14

Female (%) 39 (65)　　　Diagnosis (%)

PAH 38 (63)　　　 IPAH 12 (20)　　　 CTD-PAH 24 (40)　　　 Po-PAH 2 (3)　　　 PH associated with respiratory disorders 3 (5)　　　 CTPH 20 (33)　　　WHO-fc (%)

1 1 (1.7)

2 22 (37.3)

3 32 (54.2)

4 4 (6.8)

Treatment (%) 25 (24)　　　 Bosentan 13 (22)　　　 Sildenafil 14 (23)　　　 Beraprost 10 (17)　　　Hemodynamic variables

sPAP (mmHg) 53.9±21.3

mPAP (mmHg) 31.7±12.0

RAP (mmHg) 3.7±4.2

PCWP (mmHg) 7.0±4.3

CO (TD) (L/min) 4.90±1.62

CO (Fick) (L/min) 3.92±2.08

PVR (TD) (dyn · s–1 · cm–5) 433±244

PVR (Fick) (dyn · s–1 · cm–5) 581±344

HR (beats/min) 73±11

CO, cardiac output; CTD-PAH, collagen tissue disease associ-ated PAH; CTEPH, chronic thromboembolic pulmonary hyperten-sion; HR, heart rate; IPAH, idiopathic PAH; mPAP, mean PAP; PAH, pulmonary arterial hypertension; Po-PAH, portal PAH; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; sPAP, systolic pulmonary arterial pressure; TD, thermodilution; WHO-fc, World Health Organization functional class.

Table 2. Hemodynamic Measurements

Parameter Value

TD-CO (L/min) 4.92±1.56

Fick-CO (L/min) 3.87±1.24

Echo-CO (L/min) 4.34±1.11

NI-CO (L/min) 4.40±1.32

TD-PVR (dyn · s–1 · cm–5) 446±249

Fick-PVR (dyn · s–1 · cm–5) 583±362

Echo-PVR (dyn · s–1 · cm–5) 660±363

NI-PVR (dyn · s–1 · cm–5) 544±316

Echo-CO, echocardiography-derived cardiac output; Echo-PVR, echocardiography-derived PVR; Fick-CO, cardiac output derived by the modified Fick method; Fick-PVR, PVR derived by modified Fick method; NI-CO, NICaS-derived cardiac output; NI-PVR, NICaS with echocardiography-derived PVR; PVR, pulmonary vascular resistance; TD-CO, thermodilution-derived cardiac output; TD-PVR, thermodilution-derived PVR.


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Noninvasive Assessment of PH

Measurement of PVRPVR (dyn · s–1 · cm–5) was calculated using RHC from the equa-tion:

PVR = 80 × (mPAP–PCWP)/COTD, Fick (TD-PVR, Fick-PVR).

PVR was also estimated noninvasively using a combination of NICaS and echocardiography, and by echocardiography alone.10 Echo-mPAP was calculated as Echo-sPAP×0.61+ 2 mmHg, as previously described,11 and noninvasive PVR was calculated as 80×(Echo-mPAP–PCWP)/COEcho, NI (Echo-PVR, NI-PVR). PCWP for the calculation of noninvasive PVR was estimated at 10 mmHg in all cases.10

Statistical AnalysisQuantitative data are presented as mean ± SD. The correlations

and β is the diastolic time interval. To calculate the CO, SV is multiplied by the heart rate. Because the NI-CO values are calculated every 20 s, the average of 3 measurements obtained consecutively during 60 s of monitoring is considered to be the NI-CO value for each individual case.

EchocardiographyEchocardiography was performed using a Vivid 5 system and a 3.5-MHz transducer (GE Vingmed Ultrasound AS, Horten, Norway). Two-dimensional Doppler examinations were per-formed in the usual manner. CO was measured by tracing the left ventricular ejection flow (Echo-CO). Echo-sPAP was es-timated from the peak velocity of the tricuspid regurgitation jet plus estimated right atrial pressure (Echo-RAP).9

Figure 1. Linear correlation analysis between TD-CO and NI-CO (A), Fick-CO and NI-CO (B), TD-CO and Fick-CO (C), TD-CO and Echo-CO (D), and Fick-CO and Echo-CO (E). TD-CO, thermodilution-derived cardiac output; NI-CO, NICaS-derived cardiac output; Fick-CO, cardiac output derived by the modified Fick method; Echo-CO, echocardiography-derived cardiac output.


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jects for TD-CO, Fick-CO, Echo-CO, and NI-CO were 4.92± 1.56 L/min, 3.87±1.24 L/min, 4.34±1.11 L/min, and 4.40± 1.32 L/min, respectively (Table 2). A significant and very strong correlation was observed between TD-CO and NI-CO (r=0.715, P<0.0001) and between TD-CO and Fick-CO (r= 0.795, P<0.0001) by 2-tailed Spearman’s rank correlation test (Figure 1). There was a strong correlation between Fick-CO and NI-CO (r=0.653, P<0.0001). However, the correlation between Echo-CO and TD-CO or Fick-CO was significant but not strong (r=0.512 or 0.461, P<0.0001, respectively). The differences between 2 measurements were plotted according to the Bland-Altman method (Figure 2). The mean bias and limits of agreement between TD-CO and NI-CO, Fick-CO and NI-CO, and TD-CO and Fick-CO were 0.50±1.08 (–1.61 to 2.61) L/min, and –0.54±1.04 (–2.57 to 1.49) L/min, and 1.02± 0.86 (–0.68 to 2.71) L/min, respectively. The limits of agree-ment between TD-CO and Echo-CO, and Fick-CO and Echo-CO were 0.64±1.33 (–1.97 to 3.26) L/min and –0.42±1.18 (–2.73 to 1.88) L/min, respectively. There was no clear differ-ence in the measurements of CO among the patients with id-iopathic PAH, collagen tissue disease associated PAH or CTEPH (Figure S1).

Comparison of Invasive and Noninvasive Measurement of mPAP and PVRThe mean values of all measurements of invasive mPAP and Echo-mPAP were 32.9±1.28 mmHg and 43.0±1.59 mmHg, re-spectively. There was a very strong correlation between inva-

among TD-CO, Fick-CO, Echo-CO, and NI-CO and between Echo-mPAP and mPAP measured by RHC (RHC-mPAP) were determined by calculating the Spearman’s rank corre-lation coefficient. P<0.05 was considered to be significant. Agreement between methods was analyzed by the Bland-Alt-man method.12 The limits of the agreement were expressed as the mean ± SD. The 95% confidence intervals (CIs) of the bias were also calculated. Receiver-operating characteristic (ROC) curves were generated for the detection of elevated PVR de-fined as > 240 dyn · s–1 · cm–5 (3 Wood units [WU]). The area under the curve (AUC), cut-off value, sensitivity, and specific-ity were estimated by the ROC curves. All statistical analyses were performed using GraphPad Prism version 5 (GraphPad Software, La Jolla, CA, USA).

ResultsThe baseline characteristics of all patients at initial hospital-ization are summarized in Table 1. Approximately two-thirds of the patients had PAH (World Health Organization [WHO] classification of PH group 1) and the other one-third of the patients had chronic thromboembolic PH (CTEPH: WHO group 4); 5% of the patients were classified as WHO group 3. At enrollment, 24% of the patients were receiving medical therapy.

Relationships Among ParametersThe mean CO values from all measurements in these sub-

Figure 2. Bland-Altman plots with mean difference (solid line) ±2SD (dotted line) comparing TD-CO and NI-CO (A), Fick-CO and NI-CO (B), TD-CO and Echo-CO (C), and Fick-CO and Echo-CO (D). TD-CO, thermodilution-derived cardiac output; NI-CO, NICaS-derived cardiac output; Fick-CO, cardiac output derived by the modified Fick method; Echo-CO, echocardiography-derived cardiac output; SD, standard deviation.


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and echocardiography. Kouzu et al showed that tricuspid re-gurgitant pressure gradient (TRPG)/right ventricular time-velocity integral (TVI) is reliable for the estimation of PVR.21 Although TRPG/TVI has been confirmed as a reliable method for estimating PVR,16 accurate measurement of TVI needs a skilled operator. Lindqvist et al reported the accuracy of a simple Doppler-derived measurement of PVR with the con-ventional invasive equation in patients with PH;10 however, their study excluded patients with severe tricuspid regurgita-tion, which causes inaccuracy in CO measurement using echo-cardiography. In the present study, we estimated PVR using the conventional invasive equation with the combination of NI-CO and Echo-mPAP. There was very strong correlation not only between invasive mPAP and Echo-mPAP, but also between invasive PVR and NI-PVR. Furthermore, a stronger correlation of PVR was found for the use of NI-CO compared with Echo-CO. The limits of agreements estimated by the Bland-Altman analysis were large, but comparable with previ-ous reports that showed the feasibility of PVR derived by echocardiography against invasive PVR.21,22 Furthermore, the high AUC, sensitivity, and specificity for NI-PVR to detect increased PVR >240 dyn · s–1 · cm–5 (3 WU) also indicates the reliability of noninvasive PVR assessment using NICaS.

In our study, the value for TD-CO was significantly higher than the CO values with other methods, including Fick-CO, and therefore, the value of TD-PVR was underestimated. This

sive mPAP and Echo-mPAP (r=0.703, P<0.0001; Figure 3A). The limits of agreement between invasive mPAP and Echo-mPAP were –9.63±10.2 (–29.6 to 10.4) mmHg (Figure 3B).

The mean values of all measurements of TD-PVR, Fick-PVR, Echo-PVR, and NI-PVR were 446±249 dyn · s–1 · cm–5, 583±362 dyn · s–1 · cm–5, 660±363 dyn · s–1 · cm–5, and 644±316 dyn · s–1 · cm–5, respectively (Table 2). There were significant and very strong correlations between TD-PVR and NI-PVR (r=0.704, P<0.0001), between Fick-PVR and NI-PVR (r=0.702, P<0.0001), and between TD-PVR and Fick-PVR (r=0.942, P<0.0001) (Figures 4A,D). However, the correlation between PVR measured by invasive methods and Echo-PVR was not as strong (r=0.602 or 0.603, P<0.0001, respectively; Figures 4G,J) as that between invasive methods and NI-PVR. Figure 4B and dyn · s–1 · cm–5 shows the Bland-Altman plots of the differences between TD-PVR, Fick-PVR, and NI-PVR. The limits of agreement between TD-PVR and NI-PVR, Fick-PVR and NI-PVR, and TD-PVR and Fick-PVR were –195±265 (–715 to 326) dyn · s–1 · cm–5, –35±325 (–673 to 603) dyn · s–1 · cm–5, and –135±164 (–457 to 187) dyn · s–1 · cm–5, respectively. The limits of agreement between TD-PVR and Echo-PVR, and Fick-PVR and Echo-PVR were –191±266 (–713 to 330) dyn · s–1 · cm–5, and –33±341 (–703 to 635) dyn · s–1 · cm–5, respectively (Figures 4H,K). The AUC for NI-PVR to detect increased PVR >240 dyn · s–1 · cm–5 (3 WU) against TD and Fick-PVR were 0.84 (95% CI, 0.72–0.96) and 0.92 (95% CI, 0.84–0.99), respectively (Figures 3C,F), and optimal cut-off values were 411 dyn · s–1 · cm–5 (sensitivity: 81.3%, specificity: 75%) and 400 dyn · s–1 · cm–5 (sensitivity: 80.3%, specificity: 100%), respectively. The AUC for Echo-PVR against TD and Fick-PVR were lower: 0.75 (95% CI, 0.57–0.92) and 0.83 (95% CI, 0.66–0.99) (Figures 4I,L) com-pared with that for NI-PVR against TD and Fick-PVR.

DiscussionWe report on the reliability of a noninvasive and simple meth-od of assessing CO and PVR using ICGWB in patients with PH. Previous reports have indicated the feasibility of hemody-namic assessment using various methods in comparison with RHC in a range of clinical settings;13 however, a reliable meth-od for the assessment of PH has not yet been established. In particular, there are few studies that have addressed the nonin-vasive assessment of hemodynamics in PH. Hemodynamic assessment using cardiac magnetic resonance or echocardiog-raphy have been shown to be reliable,10,14–17 but these methods require expensive equipment and trained operators. Thoracic impedance cardiography has been used for the measurement of CO noninvasively in PAH,18 and its reliability was shown to be compromised in cardiac patients in a meta-analysis.19

We demonstrated strong correlations among the NICaS, TD, and the Fick methods for the measurement of CO. Although the limits of agreement between NI-CO and TD-CO or Fick-CO estimated by the Bland-Altman approach were not small, they were acceptable when compared with previous reports.13 Therefore, we believe that NICaS can be a reliable tool for the noninvasive assessment of CO in PH. However, compared with NI-CO, the correlation between Echo-CO and TD-CO or Fick-CO was weaker and the limits of agreements were larger. The relative inaccuracy of CO measured by echocardiography was consistent with a previous report,20 and may be a conse-quence of using the Doppler method, severe tricuspid regurgi-tation, and operator-dependency.

We also demonstrated the feasibility of noninvasive and simple measurement of PVR using a combination of NICaS

Figure 3. Linear correlation analysis between RHC-mPAP and Echo-mPAP (A). Bland-Altman plots with mean difference (solid line) ±2SD (dotted line) comparing RHC-mPAP and Echo-mPAP (B). RHC, right heart catheterization; mPAP, mean pulmonary arterial pressure; Echo-mPAP, mPAP calcu-lated by echocardiography; SD, standard deviation.


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be determined appropriately. This may have resulted in bias in the measurement of NI-PVR. In our study, the Doppler param-eter needed in order to estimate NI-PVR was only TRPG, and there was no patient in whom we were unable to obtain that value. Second, we used the conventional invasive equation for estimating NI-PVR. We had to estimate PCWP at 10 mmHg in all cases as previously reported,10 which may also have re-

could be caused by overestimation of the value of TD-CO in the presence of low CO, consistent with previous reports.23

Study LimitationsThe main limitation of this study was the need to measure the Doppler parameter for estimating NI-PVR. Proper alignment of the ultrasound beam is crucial for the Doppler parameter to

Figure 4. Diagnostic reliability of NI-PVR compared with invasive PVR. Linear correlation analysis between TD-PVR and NI-PVR (A), Fick-PVR and NI-PVR (D), TD-PVR and Echo-PVR (G), and Fick-PVR and Echo-PVR (J). Bland-Altman plot with mean differ-ence (solid line) ±2SD (dotted line) comparing TD-PVR and NI-PVR (B), Fick-PVR and NI-PVR (E), TD-PVR and NI-PVR (H), and Fick-PVR and NI-PVR (K). Area under the receiver-operating characteristics curve with 95% confidence interval for NI-PVR and Echo-PVR to detect increased PVR (>240 dyn · s–1 · cm–5 [3 WU]) against TD-PVR (C,I) and Fick-PVR (F,L). PVR, pulmonary vascu-lar resistance; NI-PVR, NICaS with echocardiography-derived PVR; TD-PVR, thermodiluyion-derived PVR; Fick-PVR, PVR derived by the modified Fick method; Echo-PVR, echocardiography-derived PVR.


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8. Cohen AJ, Arnaudov D, Zabeeda D, Schultheis L, Lashinger J, Schachner A. Non-invasive measurement of cardiac output during coronary artery bypass grafting. Eur J Cardiothorac Surg 1998; 14: 64 – 69.

9. Yeo TC, Dujardin KS, Tei C, Mahoney DW, McGoon MD, Seward JB. Value of a Doppler-derived index combining systolic and dia-stolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol 1998; 81: 1157 – 1161.

10. Lindqvist P, Soderberg S, Gonzalez MC, Tossavainen E, Henein MY. Echocardiography based estimation of pulmonary vascular resistance in patients with pulmonary hypertension: A simultaneous Doppler echocardiography and cardiac catheterization study. Eur J Echocar-diogr 2011; 12: 961 – 966.

11. Chemla D, Castelain V, Humbert M, Hebert JL, Simonneau G, Lecarpentier Y, et al. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest 2004; 126: 1313 – 1317.

12. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 307 – 310.

13. Mantha S, Roizen MF, Fleisher LA, Thisted R, Foss J. Comparing methods of clinical measurement: Reporting standards for bland and altman analysis. Anesth Analg 2000; 90: 593 – 602.

14. Inaba T, Yao A, Nakao T, Hatano M, Maki H, Imamura T, et al. Volumetric and functional assessment of ventricles in pulmonary hypertension on 3-dimensional echocardiography. Circ J 2012; 77: 198 – 206.

15. Garcia-Alvarez A, Fernandez-Friera L, Mirelis JG, Sawit S, Nair A, Kallman J, et al. Non-invasive estimation of pulmonary vascular resis-tance with cardiac magnetic resonance. Eur Heart J 2011; 32: 2438 – 2445.

16. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method for noninvasive estimation of pulmonary vas-cular resistance. J Am Coll Cardiol 2003; 41: 1021 – 1027.

17. Kang KW, Chang HJ, Kim YJ, Choi BW, Lee HS, Yang WI, et al. Cardiac magnetic resonance imaging-derived pulmonary artery dis-tensibility index correlates with pulmonary artery stiffness and pre-dicts functional capacity in patients with pulmonary arterial hyper-tension. Circ J 2011; 75: 2244 – 2251.

18. Yung GL, Fedullo PF, Kinninger K, Johnson W, Channick RN. Com-parison of impedance cardiography to direct Fick and thermodilution cardiac output determination in pulmonary arterial hypertension. Con-gest Heart Fail 2004; 10: 7 – 10.

19. Raaijmakers E, Faes TJ, Scholten RJ, Goovaerts HG, Heethaar RM. A meta-analysis of published studies concerning the validity of tho-racic impedance cardiography. Ann NY Acad Sci 1999; 873: 121 – 127.

20. Fisher MR, Forfia PR, Chamera E, Housten-Harris T, Champion HC, Girgis RE, et al. Accuracy of Doppler echocardiography in the he-modynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med 2009; 179: 615 – 621.

21. Kouzu H, Nakatani S, Kyotani S, Kanzaki H, Nakanishi N, Kitakaze M. Noninvasive estimation of pulmonary vascular resistance by Dop-pler echocardiography in patients with pulmonary arterial hyperten-sion. Am J Cardiol 2009; 103: 872 – 876.

22. Selimovic N, Rundqvist B, Bergh CH, Andersson B, Petersson S, Johansson L, et al. Assessment of pulmonary vascular resistance by Doppler echocardiography in patients with pulmonary arterial hyper-tension. J Heart Lung Transplant 2007; 26: 927 – 934.

23. Tournadre JP, Chassard D, Muchada R. Overestimation of low car-diac output measured by thermodilution. Br J Anaesth 1997; 79: 514 – 516.

24. Kauppinen PK, Koobi T, Hyttinen J, Malmivuo J. Segmental com-position of whole-body impedance cardiogram estimated by com-puter simulations and clinical experiments. Clin Physiol 2000; 20: 106 – 113.

25. Taleb M, Khuder S, Tinkel J, Khouri SJ. The diagnostic accuracy of Doppler echocardiography in assessment of pulmonary artery systolic pressure: A meta-analysis. Echocardiography 2013; 30: 258 – 265.

Supplementary FilesSupplementary File 1

Figure S1. Linear correlation between NI-CO and TD-CO (A) or Fick-CO (B) in IPAH ( , red line), CTD-PAH ( , blue line) and CTEPH ( , green line).

Please find supplementary file(s);http://dx.doi.org/10.1253/circj.CJ-13-0172

sulted in the measurement of NI-PVR; however, in general, a wide variation in PCWP is not usually observed among pa-tients with PH. Third, because CO measurement using NICaS in patients with cardiac shunts is known to be unreliable,24 we excluded cases of PAH associated with cardiac shunts. Fourth, noninvasive estimation of CO and PVR with NICaS was fea-sible; however, there were some patients who had large diver-gence between NI-CO or NI-PVR and invasive CO or PVR. Further studies are needed to clarify the factors that lead to inaccurate measurements of CO and PVR. Fifth, in our study, the number of patients with WHO functional class 4 was small. Most patients were WHO functional class 2 or 3. The reliability of NICaS in patients with severe PH is to be exam-ined in future studies. Finally, the study sample size was rela-tively small and originated from a single center. We believe that a larger, multicenter study is needed to appropriately confirm the reliability of the method.

Although recent advances in treatment options and manage-ment have improved the outcomes for patients with PH, treat-ment goals and follow-up strategy are still not well defined. Hemodynamic monitoring with RHC is recommended in a goal-oriented treatment strategy for PH1 and is the gold stan-dard for the assessment of PAH; however, the invasiveness of RHC is a critical factoring its regular use as a follow-up pro-cedure. A noninvasive, accurate, and simple method is re-quired for the management of patients with PH. We have demonstrated noninvasive measurement of CO and PVR using only simple parameters. Echo-sPAP is needed to estimate PVR, but Echo-sPAP has been established as a simple, reli-able screening parameter for PH.25 This noninvasive, reliable, and simple assessment can be a useful tool for monitoring and managing patients with PH.

ConclusionNoninvasive measurement of CO and PVR using NICaS is as reliable as invasive RHC. This simple assessment could help physicians to manage their patients with PH.

DisclosuresNone.

References 1. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera

JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the Inter-national Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30: 2493 – 2537.

2. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 2012; 142: 448 – 456.

3. Fukumoto Y, Shimokawa H. Recent progress in the management of pulmonary hypertension. Circ J 2011; 75: 1801 – 1810.

4. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005; 26: 858 – 863.

5. Alhashemi JA, Cecconi M, Hofer CK. Cardiac output monitoring: An integrative perspective. Crit Care 2011; 15: 214.

6. Paredes OL, Shite J, Shinke T, Watanabe S, Otake H, Matsumoto D, et al. Impedance cardiography for cardiac output estimation: Reliabil-ity of wrist-to-ankle electrode configuration. Circ J 2006; 70: 1164 – 1168.

7. Tanino Y, Shite J, Paredes OL, Shinke T, Ogasawara D, Sawada T, et al. Whole body bioimpedance monitoring for outpatient chronic heart failure follow up. Circ J 2009; 73: 1074 – 1079.


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2012 27: 456 originally published online 13 June 2012PerfusionSG Hall, J Garcia, DF Larson and R Smith

Cardiac power index: staging heart failure for mechanical circulatory support

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Introduction

Cardiac power output is the hydraulic energy required by the heart to provide enough blood flow to the systemic circula-tion. Cardiac power output measured at exercise reflects the peak cardiac performance attainable by the heart. Comparing maximum cardiac power output with resting cardiac power output represents the heart’s cardiac reserve. In heart failure patients, cardiac reserve is severely limited.1 Patients performing exercise tests or positive inotrope infu-sion tests tend to show little difference in cardiac perfor-mance due to poor cardiac reserve. It has been demonstrated in several studies that heart failure patients with higher car-diac reserves have better survival rates. As heart failure pro-gresses in these patients, cardiac reserve continues to decline.2

Once cardiac performance can no longer be improved through inotropic drug therapy, heart failure patients may require mechanical circulatory support. Because end-organ damage is a predictor of poor prognosis in patients who receive mechanical circulatory support, it is important to implant devices before heart failure has become so severe that irreparable systemic damage has occurred. Symptomatic assessment, drug tolerance, and myocardial oxygen con-sumption are commonly used to determine the severity of heart failure, but are unable to provide all the informa-tion necessary to reflect true cardiac reserve. Myocardial oxygen consumption provides an indirect measurement of cardiac output; however, given that cardiac power output

incorporates cardiac output as well as systemic pressures, this distinguishes it as a rational marker of cardiac perfor-mance when compared to myocardial oxygen consump-tion. Cardiac power output has been used to assess cardiac performance and prognosis in cardiogenic shock and acute and chronic heart failure patients.3,4 The purpose of this study was to retrospectively analyze the application of car-diac power output to stage the severity of heart failure in patients who have received mechanical circulatory support.

Methods

Twenty-eight patients, twenty-four male and four female, with a history of heart failure were referred to the

Cardiac power index: staging heart failure for mechanical circulatory support

SG Hall, J Garcia, DF Larson and R Smith

AbstractCardiac power output has been shown to quantify cardiac reserve. Cardiac reserve is defined as the difference between basal and maximal cardiac performance. We compared cardiac power index to other commonly used hemodynamic parameters to validate its usefulness to stage heart failure patients and determine the optimal time for implantation of mechanical circulatory support. A retrospective study of twenty-eight heart failure patients implanted with mechanical circulatory support was analyzed at three levels of drug therapy. Subjects were further separated into two categories: survived versus deceased. Cardiac power index was the only statistically significant hemodynamic parameter that identified cardiac reserve (p<0.05) in this patient population. These results showed that a cardiac power index at or below 0.34 Watts/m2 resulted in increased mortality rate, ninety days post-implantation.Conclusion: Cardiac reserve was a determinant of post-device survival; therefore, these data suggest that device implanta-tion should occur prior to the 0.34 Watts/m2 threshold.

Keywordscardiac power output; cardiac reserve; mechanical circulatory support; hemodynamics; cardiac power index

Circulatory Sciences Graduate Perfusion Program, The University of Arizona, Tucson, Arizona, USA

Corresponding author:Doug F. Larson 4402 Arizona Health Sciences Center 1501 North Campbell Avenue Tucson, AZ 85724, USAEmail: [email protected]

Presented at the 33rd Annual Seminar of The American Academy of Cardiovascular Perfusion, New Orleans, Louisiana, 26-29 January 2012

27610.1177/0267659112450933Hall SG et al.Perfusion2012



Hall SG et al. 457

University of Arizona Medical Center for mechanical cir-culatory support. Patients were admitted due to increased heart failure symptoms or were medically transferred from outside institutions. The studied population con-sisted of New York Heart Association (NYHA) classes III and IV and American College of Cardiology (ACC-AHA) stages C and D. Patient data was taken from July 2008 to April 2011. Approval of the data review was granted by the University of Arizona Medical Center, Tucson and the Institutional Committee on Human Research.

Patient data was collected at three levels of drug ther-apy from right heart catheterizations, Swan-Ganz cathe-ters, and/or echocardiography exams. Hemodynamic data was initially collected when patients were first admit-ted to the intensive care unit and before they received ino-tropic drug therapy. Patients were then assessed when they were first placed on inotropic support. The initial inotropic dose was documented within four hours of administration. The most common inotropic drugs pre-scribed included one or more of the following: dobu-tamine, milrinone, and dopamine. Throughout the patients’ admission, medical management was adjusted based on declining heart function and/or drug tolerance. The third level of drug therapy assessed was considered the peak inotropic dose prescribed where current ino-tropic doses were increased or inotropic type was changed before the patients became non-responsive to medication and required mechanical circulatory support. Patients were further subdivided into two group: survived versus deceased. Patients in the survived group survived at least ninety days after receiving mechanical circulatory sup-port. The deceased group consisted of patients who died within ninety days of receiving mechanical circulatory support. Survival was assessed at ninety days to account for delayed organ failure due to prolonged hypoperfu-sion.

Six hemodynamic parameters were compared to assess the remaining cardiac reserve in the twenty-eight heart failure patients studied: heart rate(HR) – beats per minute (bpm); mean arterial pressure – mmHg, [(2 x diastolic) + systolic]/3; stroke volume – ml, (cardiac output(CO)/HR); ejection Fraction - %, (stroke volume (SV)/end-diastolic volume (EDV)) x 100; cardiac index (CI) - L/min/m2, [(HR x SV)/body surface area (BSA)]; and cardiac power index (CPI) - W/m2, [(MAP x CO) x 0.0022]/BSA.

Statistics

Statistical analysis was done using Data Analysis and Statistical Software Stata 11 (StataCorp LP, College Station, TX, USA). An independent two-sample t-test with unequal variance was used to identify if contractile reserve still existed in the failing heart. Mechanical circulatory support

hemodynamic standards were tested to determine which hemodynamic parameter gave a better representation of the remaining contractile reserve. All data are presented as mean ± SEM.

Results

Of the twenty-eight patients studied, twenty-one sur-vived and seven died within ninety days of receiving an implanted device. Six of the seven patients died from end-organ failure and one died from systemic inflamma-tory response syndrome within six months of receiving mechanical circulatory support. The twenty-one patients who survived ninety days from receiving mechanical cir-culatory support were classified as “destination therapy” or “bridge to transplant” patients.

Baseline hemodynamic values, seen in Table 1, indi-cated abnormal values for all subjects, with the exception of heart rate and mean arterial pressure. Baseline values were recorded as patients were on standard heart failure medications (ß-blocker, diuretics, angiotensin-converting-enzyme (ACE)-inhibitors, and angiotensin receptor blockers (ARBs)). The other hemodynamic parameters (ejection fraction, left ventricular stroke work index, car-diac output, cardiac index, and cardiac power) were all below healthy adult ranges. Table 2 displays documented mean inotropic therapy while patients were in the inten-sive care unit.

Heart rate and mean arterial pressure (Figure 1A & 1B) were not found to be statistically significant between the “survived” and “deceased” groups. Heart rate increased

Table 1. Baseline patient characteristics

Characteristic (n=28) Datum

Age (year) 53 ± 2.5BSA (m2) 2.0 ± 0.03HF Etiology Ischemic 13 (46%) Non-Ischemic 15 (54%)ICD 19 (68%)HR (BPM) 81 ± 7.5MAP (mmHg) 82 ± 4.6SVR (dyn·s/cm5) 1724 ± 197CVP (mmHg) 21 ± 2.1PCWP (mmHg) 29 ± 1.5LVSWI (g/m2/beat) 15 ± 1.92EF (%) 22 ± 3.5CO (L/min) 3.14 ± 0.3

Abbreviations. BSA: body surface area; ICD: implantable cardioverter de-fibrillator; HF: heart failure; HR: heart rate; MAP: mean arterial pressure; SVR: systemic vascular resistance; CVP: central venous pressure; PCWP: pulmonary capillary wedge pressure; LVSWI: left ventricular stroke work index; EF: ejection fraction; CO: cardiac output. Values are expressed as mean ± SEM or number (% within studied population).



458 Perfusion 27(6)

Table 2. Administered inotropes

Positive Inotrope Initial Dose (mcg/kg/min) Peak Dose (mcg/kg/min) P-value

Dobutamine 4.7 6.0 >0.05Milrinone 0.47 3.23 >0.05Dopamine 4.5 3.78 >0.05

Inotropic doses are expressed as mean values for the two levels of inotropic drug therapies studied.

in both the “survived” and “deceased” groups when com-pared across all three levels of drug therapy. Mean arterial pressure of the “deceased” group declined despite ino-tropic drug intervention. Those in the “survived” group maintained a consistent level of mean arterial pressure across all three levels of drug therapy.

Stroke volume was well below the healthy adult ranges (Figure 1D), but was not found to be statistically signifi-cant between the “survived” and “deceased” groups. Stroke volume did not increase in the “deceased” group after the initial inotropic drug therapy; however, when peak inotropic drug therapy was administered, stroke volume decreased. On the other hand, the “survived” group displayed an increase in stroke volume at each level of drug therapy.

Left ventricular ejection fraction (Figure 1C) derived from echocardiography was not significantly different between the “survived” or “deceased” groups. When placed on the initial inotropic treatment, both the “sur-vived” and “deceased” groups had an increased ejection fraction; however, the “deceased” was less (31.50 ± 7.5% to 22.76 ± 13.17 %). There was a large variance in the “deceased” group due to a select few having diastolic heart failure with preserved ejection fraction. Those with diastolic heart failure had poor cardiac performance, but because their chamber size was unchanged or even decreased despite ventricular wall thickening, the overall percentage of blood ejected from the heart with each contraction was still elevated due to a decrease in overall ventricular chamber size.

Cardiac output was used to calculate cardiac index in order to account for the distribution of blood across the body surface area. In Figure 1E, the “survived” and “deceased” patients presented with a cardiac index of 1.65 ± 0.83 and 1.52 ± 0.13 L/min/m2, respectively. With the initial inotropic treatment, the “survived” group’s cardiac index increased to 2.14 ± 0.54 L/min/m2, but remained constant with the peak inotropic treatment at 2.17 ± 0.47 L/min/m2. The “deceased” group displayed a moderate increase in cardiac index during the initial ino-tropic treatment (1.86 ± 0.62 L/min/m2), however, this decreased on peak inotropic support (1.69 ± 0.26 L/min/m2). Cardiac index was not a functional hemodynamic marker to identify if contractile reserve remained or whether it was able to detect survival outcomes between the survived and deceased groups.

Cardiac power output was used to calculate cardiac power index to adjust for blood volume distribution across the body surface area. The baseline administered inotropic dose increased cardiac power index, but revealed no statistical difference when compared to the deceased group (Figure 1F). When peak inotropic doses were administered, cardiac power index continued to decline in the deceased group, but was able to distin-guish the contractile reserve between the two groups. The mean cardiac power index of patients who survived was 0.34 ± 0.07 W/m2 at peak inotropic drug therapy. A cardiac power index below 0.34 W/m2 identified patients who did not survive ninety days past the implantation of mechanical circulatory support because all patients in the deceased group had a cardiac power index below 0.34 W/m2. Comparing cardiac power index between the survived and deceased groups showed significantly increased mortality rates once values fell below this point (p<0.05).

Discussion

Current hemodynamic guidelines use left ventricular ejection fraction and myocardial oxygen consumption as criteria to assess cardiac and systemic degeneration for possible mechanical circulatory support. As shown by Marmor et al., the present study demonstrates that ejec-tion fraction did not display any significant differences between the “survived” and “deceased” groups during maximal cardiac performance resulting from peak ino-tropic drug therapy.9 In addition, results from prior myocardial oxygen consumption studies on patients in end-stage heart failure have shown to be inconclusive when peak cardiac function was measured.3,10,11 Patients with NYHA classes III and IV symptoms are severely compromised when tested physically for myocardial oxy-gen consumption due to progressive muscle decon-ditioning, poor vascular circulation, compromised lung capacity, and anemia. Although ejection fraction and myocardial oxygen consumption tests have their respec-tive roles in measuring specific parameters of heart func-tion, they may not be completely reliable assessments of cardiac function in these severely compromised patients.

Right heart catheterization provides very useful infor-mation in gathering pressure and volume changes in spe-cific areas of the heart. This method requires that patients



Hall SG et al. 459

be placed in a supine position without simulating peak cardiac contractility. This is a significant limitation, as assessing heart function in this manner does not allow for measuring the difference between basal and maximal car-diac performance in order to determine true cardiac

reserve. Resting values alone do not provide a sufficient amount of information on cardiac performance in healthy versus diseased hearts; however, positive inotropic stimu-lation that achieves peak contractility is when diseased hearts can become distinguishable from healthy hearts.

Figure 1. Hemodynamic parameters of the survived and deceased.*Normal hemodynamic values are from reference numbers 5-8. Values are expressed as mean ± standard error of the mean. *p=0.009.



460 Perfusion 27(6)

With the limited physical and physiological abilities of this population, an effective method to assess true cardiac reserve is through the use of stress tests using inotropic drug infusion. This method has proven to be equivalent to results produced by maximal exercise tests.9,12 In severely compromised patients, this may be the only practical method to use in order to determine existing contractile energy. The current study used this concept by gathering data while patients were placed on initial ino-tropic support in order to stimulate the remaining con-tractile reserve, if any existed. As heart failure progressed in these patients and inotropic support was increased or altered, therapeutic saturation was met, eventually, due to the heart already functioning at its maximum contractile capacity. This indicated a lack of existing reserve in these patients, due to their basal cardiac performance equaling their maximum.

Cardiac power index was the only hemodynamic parameter that distinguished between the cardiac reserve of patients who survived ninety days post-implant versus those who died. Although invasive inotropic stimulation may not be the first choice to assess cardiac contractile reserve, measuring peak cardiac power index invasively may provide information on whether pharmacological support is still efficacious and if any contractile reserve still remains. Non-invasive methods to evaluate cardiac power output have been used for over five years and have been shown to effectively determine the severity of heart failure.3,8,10,13-16 With the availability of non-invasive equipment utilizing an inert gas re-breathing technique, patients in earlier stages of heart failure can be readily assessed for existing cardiac reserve.17 Cardiac power index can be a useful prognostic tool in order to deter-mine if cardiac reserve exists in these patients and when to intervene with pharmacological support or mechanical circulatory support before the systemic effects of heart failure become irreparable.

Limitations

Because this was a single-center study, our data were non-randomized and our cohort of patients was rela-tively small. Due to the novelty of the population, hav-ing a large number of subjects is a difficult limitation to overcome when performing studies on patients receiv-ing mechanical circulatory support. The variation in medical record charting between patients also limited the number of hemodynamic values that could be eval-uated. Subject data were collected either by right heart catheterizations, Swan-Ganz catheters, and/or echocar-diography exams, but these methods were inconsistent across the sample population. A future prospective study would be beneficial to reduce the lack of consis-tency between available subject data and their collection methods.

Conclusions

In conclusion, our data suggest that attaining cardiac index and mean arterial pressure, either invasively or non-invasively, and applying these values to the cardiac power index formula, can determine the severity of heart failure based on the heart’s maximal contractile reserve. Peak cardiac power index values may also be a useful tool to determine the appropriate therapeutic approach nec-essary for these patients. Cardiac power index has proven to recognize remaining contractile reserve in heart fail-ure patients in comparison to other commonly used hemodynamic parameters. In heart failure patients cate-gorized as NYHA classes III and IV or ACC-AHA stages C and D, a peak cardiac power index below 0.34 W/m2, with or without the use of drug therapy should immedi-ately be considered for implantation of mechanical cir-culatory support. Patients at or below a cardiac power index of 0.34 W/m2 have an increased incidence of mor-tality.

AcknowledgementThis study was supported the Steinbronn Heart Failure Research Award to DFL.

Conflict of Interest StatementNone declared.

References:

1. Williams SG, Barker D, Goldspink DF, Tan LB. A reap-praisal of concepts in heart failure: central role of cardiac power reserve. Arch Med Sci 2005; 1: 65–74.

2. Cotter G, Williams SG, Z Vered Z, Tan LB. Role of car-diac power in heart failure. Curr Opin Cardiol 2003; 18: 215–222.

3. Lang CC, Karlin P, Haythe J, Lim TK, Mancini DM. Peak cardiac power output, measured noninvasively is a pow-erful predictor of outcome in chronic heart failure. Circ Heart Fail 2009; 2: 33–38.

4. Cotter G, Moshkovitz Y, Kaluski E, et al. The role of car-diac power and systemic vascular resistance in the patho-physiology and diagnosis of patients with acute congestive heart failure. Eur J Heart Fail 2003; 5: 443–451.

5. Pfisterer ME, Battler A, Zaret BL. Range of normal values for left and right ventricular ejection fraction at rest and during exercise assessed by radionuclide angiocardiogra-phy. Eur Heart J 1985; 6: 647–655.

6. Mayer SA, Lin J, Homma S, et al. Myocardial injury and left ventricular performance after subarachnoid hemor-rhage. Stroke 1999; 30: 780–786.

7. Parry, Andrew. Inotropic drugs and their uses in critical care. Nurs Crit Care 2012; 17: 19–27.

8. Bromley PD, Hodges LD, Brodie DA. Physiological range of peak cardiac power output in healthy adults. Clin Physiol Funct Imaging 2006; 26: 240–246.

9. Marmor A, Jain D, Cohen LS, Nevo E, Wackers FJ, Zaret BL. Left ventricular peak power during exercise:



Hall SG et al. 461

a noninvasive approach for assessment of contractile reserve. J Nucl Med 1993; 34: 1877–1885.

10. Leitman M, Sucher E, Kaluski E, et al. Non-invasive meas-urement of cardiac output by whole-body bio-impedance during dobutamine stress echocardiography: clinical implications in patients with left ventricular dysfunction and ischaemia. Eur J Heart Fail 2006; 8: 136–140.

11. Wilson JR, Rayos G, Yeoh TK, Gothard P, Bak K. Dissociation between exertional symptoms and circula-tory function in patients with heart failure. Circulation 1995; 92: 47–53.

12. Marmor A, Schneeweiss A. Prognostic value of nonin-vasively obtained left ventricular contractile reserve in patients with severe heart failure. J Am Coll Cardiol 1997; 29: 422–428.

13. Jakovljevic DG, George RS, Donovan G, et al. Comparison of cardiac power output and exercise performance in patients with left ventricular assist devices, explanted

(recovered) patients, and those with moderate to severe heart failure. Am J Cardiol 2010; 105: 1780–1785.

14. Jakovljevic DG, Donovan G, Nunan D, et al. The effect of aerobic versus resistance exercise training on peak car-diac power output and physical functional capacity in patients with chronic heart failure. Int J Cardiol 2010; 145: 526–528.

15. Shelton RJ, Ingle L, Rigby AS, Witte KK, Cleland JG, Clark AL. Cardiac output does not limit submaximal exercise capacity in patients with chronic heart failure. Eur J Heart Fail 2010; 12: 983–989.

16. Nicholls D, O'Dochartaigh C, Riley M. Circulatory power--a new perspective on an old friend. Eur Heart J 2002; 23: 1242–1245.

17. Agostoni P, Cattadori G, Apostolo A, et al. Noninvasive measurement of cardiac output during exercise by inert gas rebreathing technique: a new tool for heart failure evaluation. J Am Coll Cardiol 2005; 46: 1779–1781.



Non invasive measurements of Cardiac Output (CO) and Cardiac Power Index (CPI) by whole body bio impedance in patients with heart failure. A report from SICA- HF study (FP7/2007-2013/241558) P Pellicori1, E Wright1, P Costanzo1, S Smith1, S Rimmer1, J Hobkirk1, A Torabi1, T Mabote1, J Warden1, JGF Cleland1, 1University of Hull, Department of Academic Cardiology - Hull - United Kingdom,

Objectives: Haemodynamic dysfunction is often used as part of the definition for heart failure (HF), predicts an adverse outcome and could be an important target for therapy but is rarely measured in routine practice, perhaps because simple, effective, inexpensive technology is lacking. We assessed the ability of whole body electrical bioimpedance to measure haemodynamics non-invasively.

Methods: Patients and controls enrolled in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA) were included in this analysis if in sinus rhythm. Stroke volume (SV), cardiac output (CO), cardiac power index (CPI) and total body water (TBW) were measured non-invasively using whole body bio-impedance (NICaS) after two minutes rest in the supine position. Results were compared amongst HF patients according to tercile of amino-terminal pro-brain natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF).

Results: The median age of the 51 patients with HF was 71 years (IQR:63--77), 15 were women (29%), median LVEF was 36% (IQR:29-44) and median body mass index (BMI) was 30kg/m2 (IQR:26-33). The median age of 15 control subjects was 66 years (IQR:56-75), 4 were women (27%) and median BMI was 29kg/m2(IQR:26-37). As expected, compared with controls, patients with HF had higher plasma NTproBNP, worse renal function, lower CPI (0.64±0.25w/m2 vs. 0.47±0.18w/m2;p< 0.01) but TBW was similar (47±9% vs. 46±8%;p=0.74).

Patients were divided into terciles of NTproBNP (lower and upper limits of the mid-tercile were 373 and 1063ng/L). Patients in the highest tercile of NTproBNP had lower BMI (32±5kg/m2 vs. 29±5kg/m2 vs.28±4kg/m2 respectively ; p=0.02), LVEF (42±5% vs. 37±9% vs. 29±8%; p<0.01), CPI (0.52±0.2w/m2 vs. 0.50±0.2w/m2vs. 0.38±0.1w/m2; p=0.04) and poorer renal function (Creatinine: 91±28μmol/l vs. 113±35μmol/l vs. 130±47μmol/l; p=0.02) and increased TBW (41±6% vs. 47±7% vs. 48±9%;p=0.02). No differences in CO or SV were found. In the lowest tercile of LVEF, SV (83±24ml vs. 67±23ml vs.58±9ml;p<0.01), CO (5.7±1.9l/min vs. 4.3±1.6l/min vs. 3.9±0.8l/min; p <0.01) and CPI (0.58±0.2W/m2 vs. 0.45± 0.2W/m2 vs. 0.38±0.1W/m2; p<0.01) were all significantly lower, but TBW was similar across terciles (43±6% vs. 46±7% vs. 48±9%; p= 0.28).

Conclusion: In patients with HF and sinus rhythm, whole body bio-impedance might be a useful method of monitoring the haemodynamic severity of heart failure that is quick, simple and inexpensive. Whether it is as or more useful than NTproBNP as a marker of outcome awaits the results of large long-term studies. (European Journal of Heart Failure Supplements ( 2012 ) 11 ( S1 ), S91)

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3

Letter to the Editor

Detection of left ventricular systolic dysfunction using a newly developed, laptopbased, impedance cardiographic index

Yoseph Rozenman a,⁎,1, Renee Rotzak a, Robert P. Patterson b,1

a Heart Institute, E. Wolfson Medical Center, Holon, Israel, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Israelb Medical School, University of Minnesota, USA

⁎ Corresponding author at: Cardiology Department, E5, Holon, 58100, Israel. Tel.: +972 3 5028404; fax: +97

E-mail address: [email protected] (Y. Rozenman1 Consultants of NI Medical Ltd.

0167-5273/$ – see front matter © 2011 Elsevier Irelanddoi:10.1016/j.ijcard.2011.02.029

Please cite this article as: Rozenman Y, eimpedance cardiographic index, Int J Cardi0 of 158.

a r t i c l e i n f o The regional ICG signal is obtained from 2 pairs of tetra-polar

Article history:
Received 8 February 2011Accepted 10 February 2011Available online xxxx
Keywords:Impedance CardiographyCongestive heart failureSystolic dysfunctionScreeningLaptop

electrodes: one on the wrist, above the radial artery, and the other onthe contra-lateral ankle above the posterior tibial artery. The detaileddescription of the system and measured parameters can be reviewedin previous publications [10–13]. The GGI is designed to assess thesystolic contractile function of the LV and is obtained from thefollowing formula:

GGI ¼ ΔR=R � α � HRðcorrectedÞ

where R is the basal impedance and ΔR is the change in impedance, αis the time to peak ΔR and HR is the heart rate. The GGI takes into

the result is a dimensionless index that reflects the systolic function of

Congestive heart failure (CHF) is a major cause of morbidity andmortality worldwide [1]. The development of left ventricular systolicdysfunction (LVSD) is amarker of poor prognosis. Mild reduction in EFprogresses with time and when EF gets to b40%, most patientsdevelop CHF and their prognosis is dismal [2,3]. Simple, cheaptechniques that will reliably detect mild reduction of the EF, typical forALVSD, will thus be of enormous value to reduce the occurrence ofCHF and cardiac mortality [3–7].

Impedance Cardiography (ICG) is a noninvasive method ofdetermining hemodynamic status and reliable estimates of myocar-dial contractility (and EF) can be obtained using indices based onsystolic time intervals [8–10]. We have recently developed an index—Granov Goor Index (GGI)—that combines time interval and imped-ance parameters in order to identify subjects with LVSD. The GGI isobtained from a regional ICG signal—measured using wrist and ankleelectrodes [10–13].

In this manuscript we determined the accuracy of GGI inidentifying subjects with LVSD (in a “training” cohort of 100individuals) and validated the findings in an additional cohort of201 subjects.

. Wolfson Medical Center, POB2 3 5028130.).

Ltd. All rights reserved.

t al, Detection of left ventriol (2011), doi:10.1016/j.ijcar

account both ΔR as an estimate of stroke volume and α as a timeinterval parameter. HR and R are used as normalization factors so that

the LV.The entire system (electrode, signal analysis and calculations) can

replace the CD ROM in a regular computer, transforming any laptopinto a simple diagnostic device—ideal for screening.

Echocardiography was performed using GE Vivid 7 (GE VingmedUltrasound A/S, Norway). EF was calculated using the biplaneSimpson's technique [14]. Echocardiography and ICG were performedon the same day.

Patients who were referred for screening echocardiography at theoutpatient clinic of the E. WolfsonMedical Center were considered forthis trial.

The study protocol conforms to the ethical guidelines of the 1975Declaration of Helsinki and was approved by the institution's humanresearch committee.

Optimal cutoff value for the GGI for detection of LVSD wasdetermined from the Receiver Operating Characteristic (ROC) curve ofthe training set. Sensitivity specificity and predictive accuracy of GGIto detect LVSD were determined using standard technique. Statisticalanalysis was performed using MedCalc® software (Broekstraat,Belgium version 9.5.2.0).

Tables 1 and 2 describe the demographic echocardiographic andICG results. The superiority of GGI in detecting LVSD is confirmedusing ROC curve analysis (Fig. 1). The area under curve (AUC) of ROCcurves of ΔR/R and α as predictors of LVSD were 0.84 and 0.75respectively, significantly lower (pb0.001) than the value for GGI(0.97 CI 0.92 to 0.99). For a GGI cutoff value of 10 the sensitivity,specificity positive and negative predictive values are 86%, 100%, 100%and 96% respectively.

cular systolic dysfunction using a newly developed, laptop based,d.2011.02.029

http://dx.doi.org/10.1016/j.ijcard.2011.02.029

mailto:[email protected]


http://www.sciencedirect.com/science/journal/01675273


Table 2Echocardiographic findings of subjects in the training and validation cohorts.

All Training cohort Validation cohort p

EchocardiographyLVEF (%) 56±9 55±9.6 57±9.2 NSLVEDD (cm) 4.8±0.6 4.9±0.6 4.8±0.6 NSLVESD (cm) 3.0±0.8 2.9 ±0.7 3.0±0.8 NSIVS (cm) 1.0±0.1 1.0 ±0.16 1.0±0.16 NSLVPW (cm) 1.0±0.1 1.0 ±0.1 1.0±0.8 NSLA diameter (cm) 3.8±0.6 3.8 ±0.55 3.8±0.6 NSMR (%) 27 27 26 NSLVH (%) 22 26 19 NSLA area (cm2) 18.9±5 18.5±4.9 19.0±5.0 NSDiastolic dysfunction (%) 19 14 20 NS

ICGCardiac index (l/m2) 3.5±0.8 3.5±0.9 3.6±0.75 NSStroke index (cc/m2) 50±9.3 50±9.5 49±9.2 NSTPR(dynes-sec-cm−5) 1299±341 1280±350 1308±337 NSGGI 11.6±2.3 11.6±2.6 11.6±2.1 NSGGI b10 (%) 17 18 16 NS

LVEDD and LVESD are left ventricular end diastolic and end systolic diameters. IVS andLVPW are LV septal and posterior wall thicknesses. MR—mitral regurgitation (minimalor mild), LVH—left ventricular hypertrophy, LA—left atrium and TPR—total peripheralresistance.

2 Y. Rozenman et al. / International Journal of Cardiology xxx (2011) xxx–xxx

Patients in the validation set were slightly older with a tendencyfor lower prevalence of smoking. Echocardiographic and ICG valueswere similar in these two sets of patients (Tables 1 and 2). A GGI cutoffof 10 was 89% sensitive and 96% specific for detection of LVSD,confirming the excellent results of the training set. Positive andnegative predictive values were 78% and 98% respectively.

False positives and false negatives of GGI as a predictor of EF areextremely rare (Fig. 2) reflecting the accuracy of GGI to detect LVSD.Careful observation of the data points suggests that rather than asimple correlation, the relation between EF and GGI is more like a stepfunction with a GGIb10 corresponding to a wide range of EFb55%while a GGI≥10 corresponds to varying levels of EF≥55%.

In this study we were able to demonstrate that a simple regionalimpedance based technology can reliably detect LVSD. Regional (ascompared to thoracic) ICG enables more accurate determination ofstroke volume and cardiac output [10–12]. The addition of α, a timeinterval parameter, with the resulting GGI adds significantly toaccuracy of this method to identify subjects with LVSD (increasingthe AUC from 0.84 to 0.97). Most importantly, also those at theasymptomatic stage of mild LVSD are accurately detected.

Some of the energy of the LV contraction produces forward bloodflow during systole, while a significant amount is briefly stored aspotential energy in the distended arteries—maintaining the forwardflow during diastole [15]. The information provided by α relates tothis stored energy while the ΔR is related to the stroke volume. Theincorporation of both these parameters into the GGI makes the GGI amore reliable index of the energy generated by the contraction of theLV. Time interval parameters were used in the past from the ICG curve(or its derivative) to try to estimate the EF. Despite significantcorrelation [9] the coefficient values (typically approximately 0.5) arenot high enough for clinical purpose. Thus accurate estimation of thevalue of EF is limited but, as we have showed, the GGI very accuratelydetermines whether the LVEF is normal or abnormal (step functionrather than simple correlation).

The natural history of patients with ALVSD is dismal [4]. Comparedwith those with normal LV, patients with ALVSD had 4–5-foldincrease risk of CHF and death. Early detection of ALVSD requires asearch for CAD as a possible etiology. When CAD is causing reversibledysfunction prompt revascularization is essential to improve out-come; preventing CHF and early arrhythmic death [16–19]. In thosewith irreversible ALVSD; further deterioration can be attenuated bythe use of appropriate drug therapy [3].

Since early intervention in subjects with ALVSD is beneficial,screening programs need to be implemented to identify theseindividuals. Echocardiography—the “gold standard” in the assessmentof LVSD—is impractical for general screening since it is very expensive.Thus an effective screening program should use an inexpensivediagnostic test (such as GGI) to identify those who are likely to haveALVSD.

Table 1Clinical characteristics of subjects in the training and validation cohorts.

All Trainingcohort

Validationcohort

p

Number 301 100 201Male (%) 56 65 52 NSAge (mean±SD) 63±9 60±10 64±11 P=0.0027BMI (kg/m2), (mean±SD) 28.2±3.5 28±4.5 28±4.4 NSHypertension (%) 44 41 44 NSDiabetes (%) 20 27 17 NSDyslipidemia (%) 51 57 48 NSSmoke (%) 20 28 16 Pb0.055Family history ofCAD (%)

52 58 49 NS

Asymptomatic CAD (%) 29 28 29 NS

BMI—body mass index.

Please cite this article as: Rozenman Y, et al, Detection of left ventriimpedance cardiographic index, Int J Cardiol (2011), doi:10.1016/j.ijcar31 of 158.

Even thoughwe excluded patients with symptoms of suggestive ofheart disease the decision to refer patients for echocardiographybiases the population so that data was not collected from the truetarget population—asymptomatic individuals with no prior history ofheart disease. However the likelihood that this will change theobserved relation between GGI and EF is small.

The GGI can accurately detect LVSD in subjects at risk (referred forechocardiography). The GGI can be easily obtained from regional ICGsignal using any laptop by replacing the CD ROM with the measuringhardware and software. This laptop based device is cheap and easy tooperate making it an attractive tool to screen for LVSD. Additionaltrials are required to prove the efficacy of this device in the targetpopulation of asymptomatic patients at risk.

Fig. 1. Receiver operating characteristic (ROC) curve of ΔR/R, α×HR and GGI asdiagnostic tests for LVSD (EFb55%).



Fig. 2. Scatter plot of EF vs. GGI demonstrating the diagnostic power GGI (with cutoff value of 10) to detect LVSD (EFb55%) (data from the entire cohort, n=301).

3Y. Rozenman et al. / International Journal of Cardiology xxx (2011) xxx–xxx

3

Acknowledgement

This study was supported by NI Medical Ltd. Israel.The authors of this manuscript have certified that they comply

with the Principles of Ethical Publishing in the International Journal ofCardiology [20].

References

[1] Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics: 2007update: a report from the American Heart Association Statistics Committee andStroke Statistics Subcommittee. Circulation 2007;115:e69–e171.

[2] Goldberg LR, Jessup M. Stage B heart failure: management of asymptomatic leftventricular systolic dysfunction. Circulation 2006;113:2851–60.

[3] Schocken DD, Benjamin EJ, Fonarow GC, et al. Prevention of heart failure: ascientific statement from the American Heart Association Councils on Epidemi-ology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High BloodPressure Research; Quality of Care and Outcomes Research InterdisciplinaryWorking Group; and Functional Genomics and Translational Biology Interdisci-plinary Working Group. Circulation 2008;117:2544–65.

[4] Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC, Vasan RS. Natural history ofasymptomatic left ventricular systolic dysfunction in the community. Circulation2003;108:977–82.

[5] Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett Jr JC.Plasma brain natriuretic peptide to detect preclinical ventricular systolic ordiastolic dysfunction: a community-based study. Circulation 2004;109:3176–81.

[6] McMurray JV, McDonagh TA, Davie AP, et al. Should we screen for asymptomaticleft ventricular dysfunction to prevent heart failure? Eur Heart J 1998;19:842–6.

[7] Galasko GI, Barnes SC, Collinson P, Lahiri A, Senior R. What is the most cost-effective strategy to screen for left ventricular systolic dysfunction: natriureticpeptides, the electrocardiogram, hand-held echocardiography, traditional echo-cardiography, or their combination? Euro Heart J 2006;27:193–200.

[8] Cotter G, Moshkovitz Y, Kaluski E, et al. Accurate, noninvasive continuousmonitoring of cardiac output by whole-body electrical bioimpedance. Chest2004;125:1431–40.

Please cite this article as: Rozenman Y, et al, Detection of left ventriimpedance cardiographic index, Int J Cardiol (2011), doi:10.1016/j.ijcar2 of 158.

[9] Feng S, Okuda N, Fujinami T, Takada K, Nakano S, Ohte N. Detection of impaired leftventricular function in coronary artery disease with acceleration index in the firstderivative of the transthoracic impedance change. Clin Cardiol 1988;11:843–7.

[10] Cotter G, Schachner A, Sasson L, Dekel H, Moshkovitz Y. Impedance cardiographyrevisited. Physiol Measures 2006;27:817–27.

[11] Paredes OL, Shite J, Shinke T, et al. Impedance cardiography for cardiac outputestimation. Reliability of wrist-to-ankle electrode configuration. Circ J 2006;70:1164–8.

[12] Goor DA, Frinerman E, Granov I, Patterson R. Peripheral versus thoracic impedancecardiography. J Cardiac Failure, Heart Failure Society of America (HFSA), 10thAnnual Scientific Meeting, September, 10–13; 2006. p. S54–5.

[13] Rozenman Y, Goor DA, Rotzak R. Progress report on non-invasive diagnosis ofasymptomatic left ventricular systolic dysfunction. Abstract J Card Fail 2009;15:68.

[14] Gottdiener JS, Bednarz J, Devereux RD, et al. American Society of Echocardiogra-phy: recommendations for use of echocardiography in clinical trials, a report fromthe American Society of Echocardiography's Nomenclature and StandardsCommittee and the task force on echocardiography in clinical trials. J Am SocEchocardiogr 2004;17:1086–119.

[15] Hardy CJ. Assessment of arterial elasticity by cardiovascular MRI. In: Kwong RY,Libby P, editors. Cardiovascular magnetic resonance imaging (contemporarycardiology). Totowa, New Jersey: Humana Press; 2008. p. 695–710.

[16] Gheorghiade M, Sopko G, De Luca, et al. Navigating the crossroads of coronaryartery disease and heart failure. Circulation 2006;114:1202–13.

[17] Pagano D, Lewis ME, Townend JN, Davies P, Camici PG, Bonser RS. Coronaryrevascularization for postischaemic heart failure: how myocardial viability affectssurvival. Heart 1999;82:684–8.

[18] Canty Jr JM, Suzuki G, Banas MD, Verheyen F, Borgers M, Fallavollita JA.Hibernating myocardium. Chronically adapted to ischemia but vulnerable tosudden death. Circ Res 2004;94:1142–9.

[19] Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing andimpact of revascularization on prognosis in patients with coronary artery diseaseand left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002;39:1151–8.

[20] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles.Int J Cardiol 2010;144:1–2.



and Euan A. AshleyRobert G. Turcott, Ronald M. Witteles, Paul J. Wang, Randall H. Vagelos, Michael B. Fowler

Measurement Precision in the Optimization of Cardiac Resynchronization Therapy

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Measurement Precision in the Optimization of CardiacResynchronization Therapy

Robert G. Turcott, MD, PhD; Ronald M. Witteles, MD, FACC;Paul J. Wang, MD; Randall H. Vagelos, MD, FACC;

Michael B. Fowler, MB, FRCP, FACC; Euan A. Ashley, MRCP, DPhil

Background—Cardiac resynchronization therapy improves morbidity and mortality in appropriately selected patients.Whether atrioventricular (AV) and interventricular (VV) pacing interval optimization confers further clinicalimprovement remains unclear. A variety of techniques are used to estimate optimum AV/VV intervals; however, theprecision of their estimates and the ramifications of an imprecise estimate have not been characterized previously.

Methods and Results—An objective methodology for quantifying the precision of estimated optimum AV/VV intervals wasdeveloped, allowing physiologic effects to be distinguished from measurement variability. Optimization using multipleconventional techniques was conducted in individual sessions with 20 patients. Measures of stroke volume and dyssynchronywere obtained using impedance cardiography and echocardiographic methods, specifically, aortic velocity-time integral,mitral velocity-time integral, A-wave truncation, and septal-posterior wall motion delay. Echocardiographic methods yieldedstatistically insignificant data in the majority of patients (62%–82%). In contrast, impedance cardiography yielded statisticallysignificant results in 84% and 75% of patients for AV and VV interval optimization, respectively. Individual casesdemonstrated that accepting a plausible but statistically insignificant estimated optimum AV or VV interval can result in worsecardiac function than default values.

Conclusions—Consideration of statistical significance is critical for validating clinical optimization data in individualpatients and for comparing competing optimization techniques. Accepting an estimated optimum without knowledge ofits precision can result in worse cardiac function than default settings and a misinterpretation of observed changes overtime. In this study, only impedance cardiography yielded statistically significant AV and VV interval optimization datain the majority of patients. (Circ Heart Fail. 2010;3:395-404.)

Key Words: cardiac resynchronization therapy � pacing optimization � AV delay � interventricular interval� echocardiography � impedance cardiography

Cardiac resynchronization therapy (CRT) decreases morbid-ity and mortality in populations with reduced cardiac

function and conduction abnormalities1–3; however, approxi-mately one third of these patients do not experience benefit.4Atrioventricular (AV) and interventricular (VV) pacing intervaloptimization improve hemodynamics acutely5–7 and may en-hance the response to CRT relative to default interval settingsamong both the traditional responder and nonresponder groups.To date, however, results of prospective randomized trials havebeen mixed.8–12

Clinical Perspective on p 404The clarification of fundamental issues in pacing interval

optimization is still at an early stage. For example, the extentto which optimum AV/VV intervals change with bodyposition and exertion remains unclear,13–16 and data assessingthe stability of optima over time have been inconsistent.17,18

Even the definitions of pacing intervals vary among manu-facturers, with identical programmed intervals correspondingto very different ventricular pace timing.19 Perhaps the mostimportant fundamental weakness is the lack of statistical toolsto quantitatively evaluate the significance of the measureddata and to characterize the precision of the estimatedoptimum AV/VV interval.11,20–22

In this study, we examined multiple commonly usedAV/VV interval optimization techniques. Central to ourapproach is the recognition that the underlying dependence ofcardiac function on AV/VV interval is obscured to somedegree by measurement noise and that the optimum intervalidentified by a given technique is in fact an estimation of thetrue physiologic optimum. The degree to which measuredoptimization data demonstrate a significant dependence onpacing interval and the precision of estimated optima wererigorously evaluated using new statistical tools based on

Received August 6, 2009; accepted January 20, 2010.From the Division of Cardiovascular Medicine and Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford,

Calif.Correspondence to Euan A. Ashley, MRCP, DPhil, Cardiomyopathy Center, Stanford University School of Medicine, Division of Cardiovascular

Medicine, Falk CVRC, 300 Pasteur Dr, MC5406, Stanford, CA 94305-5406. E-mail [email protected]© 2010 American Heart Association, Inc.Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.109.900076

395 by guest on December 9, 2013http://circheartfailure.ahajournals.org/Downloaded from 34 of 158.



bootstrapping, a computational approach that makes knowl-edge of the underlying statistical properties of the dataunnecessary.23

MethodsPatient SelectionData were obtained from consecutive patients referred for clinicalpacing interval optimization with institutional review board ap-proval. Patients with dual-chamber or biventricular pacemakers orimplantable cardioverter defibrillators were included without regardto underlying etiology (Table 1).

Optimization TechniquesAV/VV interval optimization was conducted using multiple tech-niques, as follows:

1. Noninvasive, beat-to-beat estimates of stroke volume (SV)were acquired continuously using impedance cardiography(ICG; BioZ, CardioDynamics, San Diego, Calif) (Figure1A).24–26 With ICG, changes in thoracic impedance are mea-sured using surface electrodes and then processed by a propri-etary algorithm to estimate SV and other hemodynamic pa-rameters. Each test interval was delivered for 60 seconds, withall beats recorded during the last 30 seconds included in theanalysis.

2. The remaining techniques were derived from echocardiogra-phy using a Philips iE33 System (Philips International B.V.,Amsterdam, The Netherlands). The aortic velocity-time inte-gral (A-VTI), which is directly proportional to SV, wasobtained by numerically integrating the ejection velocity en-velop obtained by continuous-wave Doppler directed in line

with aortic flow in the apical 5-chamber view (Figure 1B).20,21

For this and the other echocardiographic techniques, a 10- to20-second equilibration period followed each programmingchange. Data then were recorded over 1 to 2 respiratory cycles,with premature and postpremature beats excluded.

3. Mitral inflow velocity-time integral (M-VTI), which is directlyproportional to inflow volume, was obtained using pulsed-wave Doppler with the sample volume placed just apical to themitral leaflets in the apical 4-chamber view (Figure 1C).20,21

4. In contrast to the techniques described above, which attempt tocharacterize cardiac function by estimates of forward flow,septal-posterior wall-motion delay (SPWMD) provides anassessment of left ventricular (LV) mechanical synchrony.20

As shown in Figure 1D, the transducer signal was directedacross the septum and the posterior LV wall in the parasternallong-axis view. Color M-mode Doppler was used to highlightthe relative motion of the 2 walls, with minimum lag taken torepresent optimal ventricular synchrony.

5. A-wave truncation identifies the optimum AV delay as theshortest pacing interval that avoids truncation of the A-wave21

and is based on the same Doppler waveform as M-VTI. Figure1E shows an A-wave truncated at 150 milliseconds anduntruncated at 180 milliseconds.

Optimization techniques were compared in terms of their ability todetect underlying physiologic changes with pacing interval. Specif-ically, the statistical significance of the data was quantitativelyestimated, as described below. Because A-wave truncation yields abinary assessment at each test interval (A wave is or is nottruncated), it is not amenable to the analytic paradigm used for theother techniques. Therefore, for A-wave truncation, we report thenumber of times each of the 3 readers, blinded to other results, wasable to estimate an optimum pacing interval.

Summary statistics were obtained based on all patients referred forclinical optimization and, in addition, with hypertrophic cardiomy-opathy patients excluded. Because ICG allows a greater number ofdata points to be obtained compared with echocardiographic meth-ods, the AV interval optimization analysis was repeated for ICG datausing the same number of measurements that were obtained in thecorresponding A-VTI data set at each test interval.

Statistical MethodsA third-degree polynomial was fit to the data, and the location ofthe maximum was taken as the estimated optimum interval. ForSPWMD, the location of the minimum absolute value of thepolynomial was taken as the optimum. Use of a continuous function,such as a polynomial, allows interpolation between test intervals andaveraging both at and across test intervals provided that the numberof free parameters of the function is smaller than the number ofunique test intervals.

The test for statistical significance was based on the formulation ofthe alternative hypothesis that the measured data do not depend onpacing interval. The probability of obtaining the observed data underthis null hypothesis was estimated using bootstrapping.22,23 A teststatistic s was defined to be equal to the area bounded above by thebest-fitting polynomial and below by the minimum value of thepolynomial, as illustrated in Figure 2. The test statistic is not unique;other measures also would be acceptable if they possess the propertythat their value varies depending on how “physiological” theoptimization data are. Specifically, if an underlying physiologicoptimum exists, and if the range of test intervals was appropriatelyselected to span the optimum, then the test statistic should be largerthan what would be obtained under the null hypothesis in which thereis no dependence on pacing interval. The greater the difference incardiac function at the optimum pacing interval and the extreme ofthe test range, the greater the value of s. For each optimization dataset, 1000 surrogate bootstrapped data sets were generated by ran-domly selecting data points from the original data set with replace-ment and without regard to test interval. This process yieldssurrogate data sets with the same number of data points at each testinterval as the original but replaces the original mapping between

Table 1. Patient Demographics

Patient No. Age, y Sex EF Etiology

1 80 M 31 Ischemic

2 73 M 30 Ischemic

3 70 M 28 Ischemic

4 66 M 29 Idiopathic

5 62 M 42 Toxic

6 57 F 65 HCM*

7 55 F 70 HCM*

8 80 M 26 Ischemic, AS, MR

9 45 F 20 Toxic

10 71 M 25 MR

11 54 M 24 AS

12 57 F 23 MR†

13 54 M 27 Idiopathic

14 60 M 27 Ischemic

15 59 F 59 Idiopathic

16 75 M 33 Idiopathic‡

17 77 F 18 Idiopathic§

18 60 M 20 Ischemic

19 49 M 48 Ischemic, AV block

20 66 F 52 HCM

AS indicates aortic stenosis; EF, ejection fraction; HCM, hypertrophiccardiomyopathy; MR, mitral regurgitation.

*Dual-chamber device.†No LV capture.‡Frequent bigeminy.§No atrial lead.

396 Circ Heart Fail May 2010

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Figure 1. Raw optimization data. A, Impedance cardiography is measured noninvasively using surface electrodes and providesestimates of multiple hemodynamic parameters, including stroke volume (SV). B, Aortic velocity-time integral is measured withcontinuous-wave Doppler at the left ventricular outflow tract and is directly proportional to ejected SV. C, Mitral velocity-time inte-gral (M-VTI) is measured with pulsed-wave Doppler echocardiography and is directly proportional to inflow volume. D, Septal-posterior wall-motion delay is obtained using tissue Doppler imaging. The VV interval that minimizes the delay is taken as repre-senting optimum synchrony. E, A-wave truncation uses the same images as M-VTI to identify the pacing interval at which theA-wave becomes truncated by ventricular systole. The image shows the A-wave truncated when a 150-ms AV delay is used anduntruncated with a 180-ms AV delay.

Turcott et al Optimization of Cardiac Resynchronization Therapy 397




measured data and test interval with a random pairing. Eachsurrogate bootstrapped data set thus represents a single realization ofdata that would be observed under the null hypothesis whilepreserving the amplitude statistics of the original data. The teststatistic s� was calculated for each surrogate data set, and the fractionthat was greater than or equal to that of the original data estimates theprobability that a test statistic at least as large as that associated withthe original data would be observed under the null hypothesis. ForP�0.05, the null hypothesis was rejected, and the data wereinterpreted as demonstrating a statistically significant dependence onpacing interval.

The 95% CI of the estimated optimum pacing interval wasobtained by generating an additional 1000 bootstrapped data sets inwhich the original data were randomly selected with replacementwhile preserving the mapping to test interval. In this case, with themapping between test interval and measured data retained, thecollection of best-fitting polynomials of the bootstrapped data setsreflects the variability in the best-fitting polynomial of the originaldata that is attributable to the statistical variability in the measure-ments. The locations of the maxima of the surrogate data sets wereordered from smallest to largest, and the cutoff point of the smallest

and largest 2.5% of the surrogate optima were taken as the 95% CIof optimum estimated from the original data.

Assessment of A-VTI VariabilityThe variability of the measured A-VTI data was quantified bycalculating the average and SD over all measurements made at anAV delay of 120 ms, which by protocol were acquired over at least1 respiratory cycle at 4 different times during the recording session.To allow comparison with previously published values, a transfor-mation was derived that converts the coefficient of variation (definedas SD divided by mean) to the average difference of successivemeasurements. Specifically, �y�2CV�2/�, where �y is the averagedifference in successive measurements, and CV is the coefficient ofvariation. This result is based on the transformation yi��xi1�xi2�/�i,where the xi represents successive A-VTI measurements at a givenpacing interval in a given patient; yi, the normalized difference inA-VTI measures in a given patient, and the subscript i, patient-specific values. The derivation assumes that xi1 and xi2 are indepen-dently drawn from a Gaussian distribution whose mean �i and SD�i can vary among patients but whose coefficient of variation CViremains fixed for all patients, that is, CVi��i/�i�constant. Dataacquisition and device programming are summarized in Table 2.

Figure 2. Estimation of statistical significance using bootstrapping. Measures of cardiac function using impedance cardiography (ICG)and aortic velocity-time integral (A-VTI) recorded from the same patient at the same optimization session. A test statistic s is defined asthe area that is bounded above by the best-fitting polynomial and below by the minimum of the polynomial. The greater the differencein cardiac function at best and worst test intervals, the larger the value of s. Bootstrapping is used to obtain surrogate data sets (bot-tom) from the original data that preserve the amplitude statistics of the original data but lack the underlying dependence on cardiacfunction. The fraction p of bootstrapped tests statistics s� that exceed s reflects the likelihood that the observed data occur in theabsence of a dependence of cardiac function on test interval. Here, the ICG data are highly significant (P�0.001) and demonstrate aphysiologically plausible dependence on pacing interval. The data are well described by the continuous function despite the delivery oftest intervals in a random order and the relatively close spacing between test intervals. Furthermore, the 120-ms test interval delivered4 times over the course of data acquisition shows good repeatability compared with the range of SVs over all test intervals. In contrast,the A-VTI data are consistent with the null hypothesis: The large relative noise masks the underlying physiological dependence on pac-ing interval, and the location of the optimum identified by A-VTI is an artifact of the statistical variability. In this patient, accepting theoptimum identified by A-VTI would result in worse cardiac function than the default interval (120 milliseconds). Solid curve indicatesbest-fitting third-degree polynomial; X, location of estimated optimum pacing interval; horizontal line, 95% CI of estimated optimum. SVindicates stroke volume.





ResultsPatient demographics are presented in Table 1. Of the 20sequential, unique patients referred for clinical pacing opti-mization, 18 had biventricular pacemakers or implantablecardioverter defibrillators and 2 had dual-chamber devices.The LV lead in 1 patient failed to capture, and another patientwith chronic atrial fibrillation had a biventricular device

without an atrial lead. Patients who underwent AV delayoptimization were in sinus rhythm with the AV delay initiatedby an atrial sensed-event in all cases.

AV delay optimization data from a single patient arepresented in Figure 3. As with the ICG data shown here (leftpanel), when statistically significant data were obtained theytypically exhibited an inverted U appearance, indicating thatthe estimated optimum interval was in the interior of therange of test intervals. Statistically insignificant data typicallyhad a best-fitting polynomial that was flat relative to theintrinsic variability of the data.

The average and SD of the measured A-VTI data werecalculated over all beats (10 to 31, median 20) recorded fromeach patient during AV optimization at the 120-ms testinterval. The ranges of the per-patient average and SD of theA-VTI data were 6.7 to 56 cm and 0.73 to 5.1 cm, respec-tively. The median sample coefficient of variation was 0.075,which corresponds to an average normalized difference insuccessive measurements of �y�0.12, consistent with previ-ous reports of �y�0.1�0.1.27

The VV optimization data shown in Figure 4 are from thesame patient whose AV optimization results are presented inFigure 3. As with this individual, for most patients, VVoptimization yielded insignificant results more frequentlythan did AV optimization.

The number of statistically significant data sets is summa-rized in Table 3. For both AV and VV optimization, A-VTI,M-VTI, and SPWMD yielded data that were indistinguish-able from the null hypothesis (ie, failed to demonstrate astatistically significant dependence on pacing interval) themajority of the time. As shown in Table 3, this findingremained true whether patients with hypertrophic cardiomy-opathy were included or excluded from the analysis. ICG wassignificantly different from the null hypothesis 84% of thetime for AV delay optimization and 75% of the time for VVinterval optimization. Excluding patients with hypertrophiccardiomyopathy from the analysis, the null hypothesis couldbe rejected 81% and 75% of the time, respectively.

Table 2. Summary of Data Acquisition, Analysis, andPacemaker Programming

Data acquisition

AV and VV interval optimization were conducted independently, withsimultaneous biventricular pacing during AV optimization and an AVdelay of 120 ms during VV optimization

Data were recorded from each patient at a single session in thefollowing order: ICG (AV), ICG (VV), A-VTI (AV), M-VTI/A-Wave truncation(AV), A-VTI (VV), SPWMD (VV)

Consecutive beat-to-beat measures of cardiac function were recordedover at least 1 respiratory cycle

Test intervals were delivered in random order with 20–30 ms spacing

The 120 ms AV delay and 0 ms VV interval were repeated 4 times overthe duration of the recording to assess stability

Data Analysis

A 3rd degree polynomial was fit to the data, with the location of themaximum serving as the estimated optimum (For SPWMD, the optimumwas the location with the minimum absolute delay)

A P value reflecting the statistical significance of measured data wasobtained

The 95% CI of the estimated optimum was obtained

For A-wave truncation, the shortest AV delay that avoided A-wavetruncation was selected as optimum, and the fraction of patients forwhom an optimum could be determined was noted

Pacemaker Programming

The statistical significance, 95% CI, and physiologic plausibility of themeasured data were considered

The pacemaker was left at default settings (AV delay � 120 ms, VVinterval � 0 ms) for statistically insignificant data sets, wide 95% CIsthat included the default setting, or physiologically implausible data.Otherwise, the estimated optimum pacing interval was programmed.

Figure 3. AV delay optimization. Data were obtained from an individual patient at a single optimization session. Impedance cardiogra-phy (ICG) and aortic velocity-time integral (A-VTI) yielded statistically significant results, although the 95% CI of the estimated optimumwas much narrower for ICG than for A-VTI. Mitral velocity-time integral (M-VTI) data were not statistically significant. Solid curve indi-cates best-fitting third-degree polynomial; X, location of estimated optimum pacing interval; horizontal line, 95% CI of estimatedoptimum.





Among the statistically significant data sets, the optimumAV delay estimated by ICG differed from the default value(120 ms) by an average magnitude of 57 ms, and 63% of theestimates differed from default by at least 50 ms. Among thestatistically significant, ICG-derived VV interval data sets,estimated optima differed from the default value (0 ms) by anaverage of 52 ms, and 75% of the estimates differed by atleast 30 ms. Repeating the ICG AV interval optimizationanalysis using the same number of measurements at each testinterval as the A-VTI recordings continued to yield statisti-cally significant results in the majority of patients, with 81%of the reduced ICG data sets having P values �0.05.

An optimum AV delay could be estimated by 3 indepen-dent readers using A-wave truncation 69%, 75%, and 94% ofthe time. The estimates of each reader are compared with ICGresults in Table 4. The relationship between optima predictedby ICG and A-wave truncation was variable, with the Pearsoncorrelation coefficient ranging from 0.02 to 0.67 for the 3readers.

Although the analysis presented above is based on uniquepatient visits, 1 patient underwent both ICG and echocardio-graphic optimization on 2 separate occasions separated by 3.5months. As shown in Figure 5, in both cases ICG yieldedsimilar-appearing, statistically significant results. The esti-mates of the optimum pacing intervals were precise, withnarrow 95% CIs, and had good concordance, with 91 ms atthe first optimization and 67 ms 3.5 months later. In contrast,in neither optimization session did A-VTI yield statisticallysignificant results. The wide 95% CI of the initial A-VTIoptimum predicted that subsequent optimization attemptswould be unlikely to identify a similar optimum interval.

DiscussionIn this study, multiple clinically accepted AV and VV intervaloptimization techniques were used in single sessions in aheterogeneous group of 20 patients. For 62% to 86% ofpatients, A-VTI, M-VTI, and SPWMD yielded data that werestatistically indistinguishable from the null hypothesis; that is,

the majority of the time these measures yielded data that didnot show a significant dependence on AV or VV interval.With A-wave truncation, it was possible for 3 independentreaders to estimate an optimum AV delay 69%, 75%, and94% of the time. ICG performed better than the echocardi-ography methods, yielding statistically significant data 84%of the time for AV delay optimization and 75% of the time forVV interval optimization. Notably, the echocardiographytechniques tested here represent the most commonly usedapproaches to AV/VV interval optimization.28

In previous studies, SPWMD failed to predict a response toCRT,29,30 and interval optimization using A-VTI neitherimproved clinical outcomes12 nor yielded acute data that weredistinguishable from a negative control.31 The poor precisionof these techniques demonstrated in this study may accountfor the lack of clinical utility seen in the earlier work.

AV/VV interval optimization traditionally has been con-ducted without consideration of the intrinsic variability of themeasured data. Test intervals often are delivered in a nonran-dom order, sweeping systematically from one end of the testrange to the other, and the AV or VV interval associated withthe best average measure of cardiac function typically istaken at face value to represent the underlying physiologicoptimum.11,20 Although efficient, the traditional approach hasimportant drawbacks. A nonrandom order of test intervalsallows systematic error to be introduced into the measureddata in a way that cannot be subsequently corrected byaveraging (eg, with subtle drift of the Doppler angle over thecourse of data collection). Furthermore, without consideringthe intrinsic variability of the measured data, it is not possibleto characterize the precision of the estimated optimumAV/VV interval.

In the absence of knowledge about its precision, anestimated optimum AV/VV interval may in fact be spuriousand associated with worse cardiac function than thepopulation-derived, default setting (eg, a sensed AV delay of120 milliseconds) (Figures 2, 3, and 5). In addition, althoughmultiple studies have suggested that optimum pacing inter-

Figure 4. VV interval optimization. Data were obtained from the same patient and optimization session as those presented in Figure 3.Negative VV intervals indicate that the left ventricle is paced first, with extreme values corresponding to unichamber pacing. Excludingthe unichamber LV pacing from the septal-posterior wall-motion delay (SPWMD; VV��140 ms) would yield statistically significantresults, although the physiological plausibility of extremely early right ventricular pacing it predicts is questionable, especially in light ofthe insignificant results from impedance cardiography (ICG) and aortic velocity-time integral (A-VTI). Solid curve indicates best-fittingthird-degree polynomial; X, location of estimated optimum pacing interval; horizontal line, 95% CI of estimated optimum.





vals change over time,12,17,18 the lack of characterization ofthe precision of the estimated optima makes it impossible todetermine whether the observed change reflects changes inunderlying physiology or is simply due to statistical variabil-ity in measured data31 (Figure 5).

The fact that any optimization technique carries somedegree of imprecision requires caution when designing ran-domized prospective trials. Two electrogram-based optimiza-tion techniques sponsored by competing manufacturers arecurrently undergoing clinical trials. In 1 design,32 patients arerandomized to the experimental optimization technique or acontrol arm that may or may not include AV and VV intervaloptimization. If optimization is performed, it is conducted atthe physician’s discretion without a requirement to examinethe precision of the measured data, raising the possibility of aprogrammed AV or VV interval that yields worse cardiacfunction than population-derived default settings. By design,

the trial will not address the question of whether the experi-mental technique is superior to default settings. In contrast,another clinical trial33,34 uses a 3-arm design in which patientsare randomized to the experimental technique, a control armin which population-derived default settings are used, and aconventional optimization arm in which a specific optimiza-tion technique is uniformly used. This study design allowsdirect comparisons between the experimental technique andboth default settings and the specific conventional optimiza-tion method, and for comparison of the conventional tech-nique to default settings.

Statistical significance testing may provide a useful way toevaluate the quality of competing optimization techniques. Itavoids prespecifying a gold standard, and although demon-stration of improved clinical outcomes in well-designed trialsultimately is required, the approach presented here offers away to narrow the very wide field of plausible optimizationtechniques without the resource requirements of a prospectiveclinical trial.

Although a rigorous, quantitative analysis is desirable,statistical significance can be evaluated informally by plot-ting the measured data against pacing interval. With testintervals delivered in a random order, if the data exhibit theexpected inverted U shape and are tightly clustered about theoverall curve, then one can be confident that the estimation ofoptimum AV/VV interval is precise; repeating the process

Table 3. P Value Associated With Measured Optimization Data

AV Optimization VV Optimization

Patients ICG A-VTI M-VTI ICG A-VTI SPWMD

Individual patients

1 �0.001 0.03 0.03 �0.001 0.018 0.002

2 0.18 0.26 0.40 �0.001 0.51 0.25

3 �0.001 0.013 0.21 0.12 0.31 0.10

4 �0.001 0.001 0.007 0.72 0.12 0.003

5 0.09 0.37 0.50 �0.001 0.14 0.42

6 �0.001 0.68

7 �0.001 0.06

8 �0.001 0.24 0.05 �0.001 0.19 0.001

9 0.008 0.98 0.91 0.092 0.41 0.24

10 0.004 0.59 0.61 �0.001 0.007 0.57

11 �0.001 0.17 0.44 �0.001 0.73 0.93

12 0.016 0.04 0.17

13 0.023 0.50 0.44 0.054 0.41 0.054

14 �0.001 0.77 0.057 0.002 0.58 0.11

15 �0.001 0.003 0.14 0.006 0.073 0.24

16 0.051 0.05 0.16 0.002 0.061 0.081

17 �0.001 0.32 0.075

18 �0.001 �0.001

19 �0.001

20 �0.001 �0.001

All patients

Significant, n 16 6 3 12 2 3

Attempted, n 19 16 14 16 14 14

Significant, % 84 38 21 75 14 21

HCM excluded

Significant, n 13 6 3 12 2 3

Attempted, n 16 14 14 16 14 14

Significant, % 81 42 21 75 14 21

HCM indicates hypertrophic cardiopmyopathy; AV, atrioventricular; VV,interventricular; ICG, impedance cardiography; A-VTI, aortic velocity-timeintegral; M-VTI, mitral velocity-time integral; SPWMD, septal-posterior wall-motion delay.

Table 4. Estimated Optima: ICG and A-Wave Truncation

PatientNo.

ICG EstimatedOptima, ms

A-WaveTruncation, ms

Optimum 95% CI Reader 1 Reader 2 Reader 3

1 168 156 177 180 150 210

2 240 240 240 150 150 180

3 206 193 213 150 120 *

4 197 187 206 240 180 210

5 93 60 117 180 120 210

6 91 83 97 120 150 120

7 128 121 138

8 200 177 270 180 * 240

9 178 170 197 120 150 120

10 60 60 60 240 * *

11 60 60 60 150 120 120

12 60 60 60 180 * *

13 173 125 190 150 180 120

14 164 157 172 180 150 80

15 123 118 131 240 * *

16 218 30 248 * * 180

17

18 77 66 86

19 30 30 30 120 60 90

20 240 180 240

Percent interpretable was as follows: Reader 1, 94%; Reader 2, 69%;Reader 3, 75%. Correlation coefficients were as follows: Reader 1, 0.02;Reader 2, 0.67; Reader 3, 0.48.

*Reader indicated that A-wave truncation could not be reliably identified. ICGindicates impedance cardiography; CI, confidence interval.





likely would yield a similar result. On the other hand, if theplot is relatively flat compared with the intrinsic variability ofthe measured data, then the estimate of the underlyingoptimum is imprecise and heavily influenced by measure-ment variability. In this case, repeating the optimizationprocess likely would yield a very different estimated opti-mum AV/VV interval. The statistical tools used here alongwith plotting capability have been made available on theInternet.35

In the majority of patients examined in the present study,ICG generated precise estimates and A-wave truncationyielded data from which an optimum could be inferred,although often with significant interreader variability andmarginal correlation with the ICG-predicted optima. Notably,neither ICG nor A-wave truncation has been clinically vali-dated in prospective interval optimization studies. In addition,unanswered fundamental questions include whether the phys-iologic optimum interval evolves over time and whether itchanges between rest and exertion or between supine andupright posture. A study that compares estimated optimumintervals obtained at both supine rest and upright exertion inthe same patient, perhaps using motion-tolerant ICG, wouldadd important insight into these basic questions. In theabsence of such data and given the theoretical potentialbenefit of pacing optimization, our approach is to accept anestimated optimum interval if quantitative and qualitativeanalyses suggest that the estimate has good precision. Partic-ular attention should be paid to the effect of outliers and theoverall shape of the curve compared with the measurementvariability.

That ICG continued to yield statistically significant data inthe majority of patients, even when using an identical numberof data points as the A-VTI analysis, suggests that it has asuperior intrinsic signal-to-noise ratio and that the acquisitiontime can be substantially shortened from the 60 s per testinterval that was used in this study. The superior noiseproperties of ICG may be partly due to the automatic andobjective nature of data acquisition and analysis in contrast toA-VTI, which requires the sonographer to physically hold theprobe in a fixed position and the reader to manually demar-cate the envelope of the velocity waveform.

A wide variety of optimization techniques have beenadvocated, including multiple approaches to the assessmentof systolic function, diastolic function, and electrical andmechanical synchrony.9,19–21,24–26,30,36–40 Although each has arationale that is mechanistically plausible, consideration ofthe neurohormonal derangements of heart failure and thetherapeutic interventions that have been successful lead us toview SV and its surrogates as parameters that when optimizedare most likely to translate into clinical benefit. Specifically,it is now well established that ameliorating the effects ofsympathetic tone in these patients leads to improved clinicaloutcomes.41 For a given cardiac output, maximizing SVwould minimize sympathetic tone. Indeed, the effects on theneurohormonal system of increased mechanical efficiencymay contribute to the salutary effects of CRT, which remainsthe only contractility-enhancing intervention demonstrated toprolong life.42 Theoretical arguments may not account forimportant effects, however. For example, an increase in SV atthe expense of greater oxygen consumption may not benefit

Figure 5. Stability of estimated optimaover time. Impedance cardiography andaortic velocity-time integral wereobtained from the same patient at base-line and 3.5 months later. In this patient,the ICG data were highly significant, theappearance of the data on repeat opti-mization recapitulated the baseline data,the estimated optima were concordantbetween the 2 sessions, and the 95%CIs of the estimates were narrow. Incontrast, the A-VTI data did not show astatistically significant dependence onpacing interval, and the estimatedoptima were highly discordant betweenthe 2 optimization sessions. Acceptingthe A-VTI-estimated optima without aconsideration of their statistical signifi-cance or precision would lead to theerroneous conclusion that the optimumAV delay had changed in the intervening3.5 months.





the patient with ischemic heart failure. Ultimately, anyproposed optimization technique must be validated by ran-domized prospective trials with hard clinical end points, agoal which to date has not been frequently achieved.8–12

LimitationsThe study was based on a small and heterogeneous popula-tion comprising successive patients referred for clinical pac-ing interval optimization. Multiple conventional optimizationtechniques were examined for their ability to yield statisti-cally significant results. This property is necessary but notsufficient for improved clinical outcomes, which were notexamined in this study.

ConclusionsOptimization of AV and interventricular intervals in CRTrequires assessment of the variability of the measured data.Accepting an estimated optimum without considering itsprecision may result in worse cardiac function than defaultsettings in the individual patient and confound results inclinical trials. In the small, heterogeneous pacemaker popu-lation examined here, echocardiographic techniques yieldedstatistically insignificant data in the majority of patients. Incontrast, ICG yielded precise estimates of the optimum AVand VV interval in most patients. Further research is neces-sary to confirm these results, to validate the accuracy of theimpedance-predicted optima, and to demonstrate clinicalimprovement with pacing interval optimization compared topopulation-derived default settings.

Sources of FundingDr Turcott was supported by a Heart Failure Society of AmericaResearch Fellowship and by the National Library of Medicine(Biomedical Informatics Training Grant LM 07033). Dr Ashley wassupported by the National Institutes of Health (grant K08HL083914).

DisclosuresDr Witteles has received honoraria from Medtronic. Dr Wang hasreceived honoraria and research support from and has served as aconsultant or advisor to Boston Scientific, Medtronic, and St JudeMedical. Dr Fowler has received honoraria from Medtronic andBoston Scientific.

References1. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T,

Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM.Cardiac-resynchronization therapy with or without an implantable defi-brillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–2150.

2. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappen-berger L, Tavazzi L. The effect of cardiac resynchronization on morbidityand mortality in heart failure. N Engl J Med. 2005;352:1539–1549.

3. McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C,Dryden DM, Page RL, Hlatky MA, Rowe BH. Cardiac resynchronizationtherapy for patients with left ventricular systolic dysfunction: a systematicreview. J Am Med Assoc. 2007;297:2502–2514.

4. Yu CM, Wing-Hong Fung J, Zhang Q, Sanderson JE. Understandingnonresponders of cardiac resynchronization therapy—current and futureperspectives. J Cardiovasc Electrophysiol. 2005;16:1117–1124.

5. Breithardt OA, Stellbrink C, Franke A, Balta O, Diem BH, Bakker P,Sack S, Auricchio A, Pochet T, Salo R. Acute effects of cardiac resyn-chronization therapy on left ventricular Doppler indices in patients withcongestive heart failure. Am Heart J. 2002;143:34–44.

6. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, Klein H,Kramer A, Ding J, Salo R, Tockman B, Pochet T, Spinelli J. Effect ofpacing chamber and atrioventricular delay on acute systolic function ofpaced patients with congestive heart failure. Circulation. 1999;99:2993–3001.

7. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E.Improved left ventricular mechanics from acute VDD pacing in patients withdilated cardiomyopathy and ventricular conduction delay. Circulation. 1999;99:1567–1573.

8. Boriani G, Muller CP, Seidl KH, Grove R, Vogt J, Danschel W,Schuchert A, Djiane P, Biffi M, Becker T, Bailleul C, Trappe HJ.Randomized comparison of simultaneous biventricular stimulationversus optimized interventricular delay in cardiac resynchronizationtherapy: The Resynchronization for the HemodYnamic Treatment forHeart Failure Management II Implantable Cardioverter Defibrillator(RHYTHM II ICD) study. Am Heart J. 2006;151:1050–1058.

9. Morales MA, Startari U, Panchetti L, Rossi A, Piacenti M. Atrioven-tricular delay optimization by Doppler-derived left ventricular dP/dtimproves 6-month outcome of resynchronized patients. Pacing ClinElectrophysiol. 2006;29:564 –568.

10. Rao RK, Kumar UN, Schafer J, Viloria E, De Lurgio D, Foster E.Reduced ventricular volumes and improved systolic function with cardiacresynchronization therapy: a randomized trial comparing simultaneousbiventricular pacing, sequential biventricular pacing, and left ventricularpacing. Circulation. 2007;115:2136–2144.

11. Sawhney NS, Waggoner AD, Garhwal S, Chawla MK, Osborn J, FaddisMN. Randomized prospective trial of atrioventricular delay programmingfor cardiac resynchronization therapy. Heart Rhythm. 2004;1:562–567.

12. Boriani G, Biffi M, Muller CP, Seidl KH, Grove R, Vogt J, Danschel W,Schuchert A, Deharo JC, Becker T, Boulogne E, Trappe HJ. A pro-spective randomized evaluation of VV delay optimization in CRT-Drecipients: echocardiographic observations from the RHYTHM II ICDstudy. Pacing Clin Electrophysiol. 2009;32(suppl 1):S120–S125.

13. Ritter P, Daubert C, Mabo P, Descaves C, Gouffault J. Haemodynamicbenefit of a rate-adapted A-V delay in dual chamber pacing. Eur Heart J.1989;10:637–646.

14. Melzer C, Korber T, Theres H, Nienaber CA, Baumann G, Ismer B. Howcan the rate-adaptive atrioventricular delay be programmed in atrioven-tricular block pacing? Europace. 2007;9:319–324.

15. Scharf C, Li P, Muntwyler J, Chugh A, Oral H, Pelosi F, Morady F,Armstrong WF. Rate-dependent AV delay optimization in cardiac resyn-chronization therapy. Pacing Clin Electrophysiol. 2005;28:279–284.

16. Mehta D, Gilmour S, Ward DE, Camm AJ. Optimal atrioventricular delayat rest and during exercise in patients with dual chamber pacemakers: anon-invasive assessment by continuous wave Doppler. Br Heart J. 1989;61:161–166.

17. Zhang Q, Fung JW, Chan YS, Chan HC, Lin H, Chan S, Yu CM. The roleof repeating optimization of atrioventricular interval during interim andlong-term follow-up after cardiac resynchronization therapy. IntJ Cardiol. 2008;124:211–217.

18. Valzania C, Biffi M, Martignani C, Diemberger I, Bertini M, Ziacchi M,Bacchi L, Rocchi G, Rapezzi C, Branzi A, Boriani G. Cardiac resynchro-nization therapy: variations in echo-guided optimized atrioventricular andinterventricular delays during follow-up. Echocardiography. 2007;24:933–939.

19. Burri H, Sunthorn H, Shah D, Lerch R. Optimization of device pro-gramming for cardiac resynchronization therapy. Pacing Clin Electro-physiol. 2006;29:1416–1425.

20. Agler DA, Adams DB, Waggoner AD. Cardiac resynchronization therapyand the emerging role of echocardiography (part 2): the comprehensiveexamination. J Am Soc Echocardiogr. 2007;20:76–90.

21. Jansen AH, Bracke FA, van Dantzig JM, Meijer A, van der Voort PH,Aarnoudse W, van Gelder BM, Peels KH. Correlation of echo-Doppleroptimization of atrioventricular delay in cardiac resynchronizationtherapy with invasive hemodynamics in patients with heart failure sec-ondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol.2006;97:552–557.

22. Turcott RG, Ashley EA. Statistical methods for AV/VV optimization[abstract]. J Cardiac Failure. 2008;14:S65.

23. Efron B, Tibshirani R. Statistical data analysis in the computer age.Science. 1991;253:390–395.

24. Heinroth KM, Elster M, Nuding S, Schlegel F, Christoph A, Carter J,Buerke M, Werdan K. Impedance cardiography: a useful and reliable toolin optimization of cardiac resynchronization devices. Europace. 2007;9:744–750.





25. Braun MU, Schnabel A, Rauwolf T, Schulze M, Strasser RH. Impedancecardiography as a noninvasive technique for atrioventricular interval optimi-zation in cardiac resynchronization therapy. J Interv Card Electrophysiol.2005;13:223–229.

26. Tse HF, Yu C, Park E, Lau CP. Impedance cardiography for atrioven-tricular interval optimization during permanent left ventricular pacing.Pacing Clin Electrophysiol. 2003;26:189–191.

27. Zuber M, Toggweiler S, Quinn-Tate L, Brown L, Amkieh A, Erne P. Acomparison of acoustic cardiography and echocardiography for opti-mizing pacemaker settings in cardiac resynchronization therapy. PacingClin Electrophysiol. 2008;31:802–811.

28. Gras D, Gupta MS, Boulogne E, Guzzo L, Abraham WT. Optimization ofAV and VV delays in the real-world CRT patient population: an inter-national survey on current clinical practice. Pacing Clin Electrophysiol.2009;S236–S239.

29. Beshai JF, Grimm RA, Nagueh SF, Baker JH II, Beau SL, Greenberg SM,Pires LA, Tchou PJ. Cardiac-resynchronization therapy in heart failurewith narrow QRS complexes. N Engl J Med. 2007;357:2461–2471.

30. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J,Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J III, St JohnSutton M, De Sutter J, Murillo J. Results of the Predictors of Response toCRT (PROSPECT) trial. Circulation. 2008;117:2608–2616.

31. Turcott RG, Das AK, Ashley EA. Re: A prospective randomizedevaluation of VV delay optimization in CRT-D recipients: echocar-diographic observations from the RHYTHM II ICD study. Pacing ClinElectrophysiol. 2009;32:1360 –1361; author reply 1361–1362.

32. FREEDOM: A Frequent Optimization Study Using the QuickOptMethod. http://www.clinicaltrials.gov. Identifier: NCT00418314.Accessed January 2, 2010.

33. Stein KM, Ellenbogen KA, Gold MR, Lemke B, Lozano IF, Mittal S,Spinale FG, van Eyk JE, Waggoner AD, Meyer TE. SmartDelay

Determined AV Optimization: a comparison of AV delay methods usedin cardiac resynchronization therapy (SMART-AV): rationale and design.Pacing Clin Electrophysiol. 2010;33:54–63.

34. Comparison of AV Optimization Methods Used in Cardiac Resynchro-nization Therapy (CRT) (SMART-AV). http://www.clinicaltrials.gov.Identifier: NCT00677014. Accessed January 2, 2010.

35. Stanford University. Optimize CRT (Development Version) Available athttp://optimizecrt.stanford.edu. Accessed January 2, 2010.

36. Bertini M, Ziacchi M, Biffi M, Martignani C, Saporito D, Valzania C,Diemberger I, Cervi E, Frisoni J, Sangiorgi D, Branzi A, Boriani G.Interventricular delay interval optimization in cardiac resynchronizationtherapy guided by echocardiography versus guided by electrocardio-graphic QRS interval width. Am J Cardiol. 2008;102:1373–1377.

37. van Gelder BM, Meijer A, Bracke FA. The optimized V-V intervaldetermined by interventricular conduction times versus invasive mea-surement by LV dP/dt(max). J Cardiovasc Electrophysiol. 2008;19:939–944.

38. Burri H, Sunthorn H, Somsen A, Zaza S, Fleury E, Shah D, Righetti A.Optimizing sequential biventricular pacing using radionuclide ventricu-lography. Heart Rhythm. 2005;2:960–965.

39. Vidal B, Tamborero D, Mont L, Sitges M, Delgado V, Berruezo A,Diaz-Infante E, Tolosana JM, Pare C, Brugada J. Electrocardiographicoptimization of interventricular delay in cardiac resynchronizationtherapy: a simple method to optimize the device. J Cardiovasc Electro-physiol. 2007;18:1252–1257.

40. Turcott RG, Pavek TJ. Hemodynamic sensing using subcutaneous pho-toplethysmography. Am J Physiol Heart Circ Physiol. 2008;295:H2560–H2572.

41. Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heartfailure. A Bayesian meta-analysis. Ann Intern Med. 2001;134:550–560.

42. Kass DA. Rescuing a failing heart: putting on the squeeze. Nat Med.2009;15:24–25.

CLINICAL PERSPECTIVECardiac resynchronization therapy improves morbidity and mortality in appropriately selected patients. Whether furtherclinical benefit is possible with atrioventricular and interventricular pacing interval optimization remains unclear. Tools toassess the statistical significance of the measured optimization data have not been available previously. In the studyreported here, an objective methodology for quantifying the statistical precision of estimated optimum pacing intervals wasdeveloped and applied to a number of commonly used optimization techniques. Many of the techniques did not yieldstatistically significant data in a majority of patients referred for atrioventricular and interventricular interval optimization,a finding that raises questions about the ability of pacing interval optimization to enhance clinical outcomes. The datademonstrate that accepting an estimated optimum interval without consideration of its statistical significance can result inworse cardiac function than default settings and can lead to the erroneous conclusion that the physiological optimum haschanged over time. These results highlight the importance of evaluating the precision of measured data when conductingpacing interval optimization for the individual patient and when interpreting the results of clinical trials.





Circulation Journal Vol.73, June 2009

Circ J 2009; 73: 1074 – 1079

he growing geriatric population and increased number of survivors of acute heart failure have dramatically increased the number of outpatients with chronic

heart failure (CHF).1–2 Hemodynamic parameters, such as stroke volume (SV), cardiac output (CO), total systemic vascular resistance (TSVR), and plasma level of B-type natriuretic peptide (BNP) are thought to be important for predicting the long-term prognosis and guiding the optimal treatment of CHF.3–5 Until recently, hemodynamic parame-ters could only be obtained using the invasive thermodilu-tion method with a Swan–Ganz catheter placed in the pul-monary artery. A non-invasive and low-cost method for measuring hemodynamic parameters would be useful for the clinical assessment of CHF in an outpatient setting.

Several non-invasive technologies for measuring hemo-dynamics are now available. Non-Invasive Cardiac System (NICaS) (NI Medical; Hod-Hasharon, Israel) is a new device for calculating SV, CO, and TSVR utilizing whole body bioimpedance cardiography with electrodes placed on one wrist and on the contralateral ankle. We previously

established that NICaS-derived CO (NI-CO) is a reliable parameter when compared with thermodilution CO or mod-ified Fick CO6

The purpose of the present study was to evaluate the feasibility of using NICaS in outpatients with CHF and to assess whether NICaS-derived hemodynamic parameters in CHF are clinically significant by relating them to other con-ventional cardiovascular functional indices, and to assess the predictive accuracy of NICaS-derived parameters for CHF-related readmission.

MethodsPatient Selection and Exclusion Criteria

In the present study, patients who met the following cri-teria were enrolled: (1) hospitalized because of acute CHF; (2) had a stable condition after optimal medical therapy including diuretics, vasodilators, ACE-inhibitors; (3) had no renal dysfunction (defined as a creatinine value >2.0 mg/dl); and (4) had no significant severe valve diseases. The cardi-nal manifestations of heart failure were dyspnea and fatigue caused by cardiac dysfunction.

The study population comprised 68 CHF patients (56 men, 12 women, mean age 64.9±10.8 years); 20 patients were classified as New York Heart Association (NYHA) class I and 48 were NYHA class II patients (Table 1). The Institutional Ethics Committee of the Kobe University Hospital approved the study protocol and all patients pro-vided informed consent to participate in the study.

In most patients, CHF coexisted with multiple under-lying heart diseases, as shown in Table 1. Three patients

(Received September 8, 2008; revised manuscript received January 4, 2009; accepted January 20, 2009; released online April 16, 2009)Division of Cardiovascular Medicine, Department of Internal Medi-cine, Kobe University Graduate School of Medicine, Kobe, JapanConflict of Interest: none declaredMailing address: Junya Shite, MD, Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe Uni-versity Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: [email protected] rights are reserved to the Japanese Circulation Society. For permis-sions, please e-mail: [email protected]

Whole Body Bioimpedance Monitoring for Outpatient Chronic Heart Failure Follow up

Yusuke Tanino, MD; Junya Shite, MD; Oscar L Paredes, MD; Toshiro Shinke, MD; Daisuke Ogasawara, MD; Takahiro Sawada, MD; Hiroyuki Kawamori, MD;

Naoki Miyoshi, MD; Hiroki Kato, MD; Naoki Yoshino, MD; Ken-ichi Hirata, MD

Background: Although cardiac output index (CI), stroke volume index (SVI), and total systemic vascular resis-tance (TSVR) are important hemodynamic parameters for the prognosis of chronic heart failure (CHF), they are difficult to measure in an outpatient setting. Whole body bioimpedance monitoring using a Non-Invasive Cardiac System (NICaS) allows for easy, non-invasive estimation of these parameters. Here, whether NICaS-derived hemodynamic parameters are clinically significant was investigated by relating them to other conventional car-diovascular functional indices, and by evaluating their predictive accuracy for CHF readmission.Methods and Results: Study subjects of 68 patients with CHF were enrolled in the study immediately upon discharge from the hospital. NICaS-derived CI, -SVI, and -TSVR values obtained at an outpatient clinic were significantly related with left ventricular ejection fraction (LVEF) measured by echocardiography, serum B-type natriuretic peptide (BNP), and exercise tolerance. During the 100±98 days follow-up, 15 patients were readmitted to our hospital for CHF recurrence. Multivariate analysis indicated that LVEF, NICaS-derived CI, NICaS-derived SVI, and plasma BNP were significant indicators (receiver operating characteristic curve cut-off point, LVEF: 37%, NICaS-derived CI: 2.49 L · min–1 · m–2, NICaS-derived SVI: 27.2 ml/m2, plasma BNP: 344 pg/ml) for readmission.Conclusions: Hemodynamic parameters derived by NICaS are applicable for the non-invasive assessment of cardiac function in outpatient CHF follow up. (Circ J 2009; 73: 1074 – 1079)Key Words: Bioimpedance; Cardiac output; Congestive heart failure; Non-invasive cardiac monitoring system;

Prediction of readmission

T

ORIGINAL ARTICLE Heart Failure

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1075Bioimpedance Monitoring for Outpatient Heart Failure


had atrial fibrillation when CO was measured. In addition, 20 cases (29.4%) had a moderate degree of mitral valve regurgitation, 7 cases (10.3%) had a moderate degree of aortic valve regurgitation, and 1 case (1.5%) had moderate aortic valve stenosis. The cardiovascular medicines taken by the patients comprised: diuretics (n=44, 68.7%), digitalis (n=7, 10.9%), angiotensin-converting enzyme inhibitors (n= 28, 43.7%), angiotensin receptor blockers (n=42, 65.6%), beta blockers (n=53, 82.8%), nitrates (n=8, 12.5%), calcium channel blockers (n=13, 20.3%), and oral inotropic agents (n=10, 15.6%).

The exclusion criteria for the NICaS measurements included restlessness and/or unstable patient condition, severe aortic valve regurgitation and/or aortic stenosis, aortic aneurysm, heart rate above 130 beats/min, intra- and extra-cardiac shunts, severe peripheral vascular disease, severe pitting edema, sepsis, and dialysis, all of which inter-fere with the accurate measurement of impedance-derived SV,7 as previously described.

All patients were followed up at the outpatient clinic of the Cardiovascular Division of Kobe University hospital and had no walking disability. We measured the cardiac param-eters once the patients’ attented the outpatient department, which was the first routine visit to our hospital 1 month after discharge from the hospital for the first heart failure admis-sion. At the same visit, serum BNP levels were measured and a questionnaire about exercise tolerance was adminis-tered.

Cardiac Indicators Derived by NICaSTo measure NI-CO, an alternating electrical current of

1.4 mA with a 30 kHz frequency was passed through the patient via 2 pairs of tetrapolar electrodes, 1 pair placed on the wrist above the radial artery, and the other pair placed on the contralateral side above the posterior tibialis artery. If the arterial pulses were either absent or of poor quality, a second pair of electrodes was placed on the contralateral site. The NICaS apparatus calculated the SV using Tsoglin and Frinerman’s formula:8

SV = dR/R ×ρ× L2/Ri × (α+β)/β× KW × HFwhere dR is the change in impedance, R is the basal resis-tance, ρ is the blood electrical resistivity, L is the patient height, Ri is the corrected basal resistance according to gender and age,8–12 KW is a correction of weight according to ideal values,9–13 HF is a hydration factor that takes into account body water composition,11 α+β is equal to the ECG R–R wave interval, and β is the diastolic time interval.

Because the NI-CO results are calculated every 20 s, the average of 3 measurements obtained consecutively during 60 s of monitoring was considered to be the NI-CO value for each individual case. By using the NI-CO value, the fol-lowing parameters were calculated: NI-CO index (NI-CI = NI-CO/body surface area), SV index (NI-SVI = NI-CI/heart rate), and TSVR (NI-TSVR = Mean arterial pressure/CO*80 [dyne · s–1 · cm–5]).

Plasma BNP MeasurementsBlood samples were obtained from the patient in a resting

condition after NICaS measurement. The samples were drawn into plastic syringes, transferred to chilled siliconized disposable tubes containing aprotinin (1,000 kallikrein inac-tivator in units/ml; Ohkura Pharmaceutical, Kyoto, Japan) and ethylenediaminetetraacetic acid (1 mg/ml), immediately placed on ice, and then centrifuged at –48°C. An aliquot of

the plasma was immediately frozen at –80°C and thawed only once at the time of the assay, which was performed within 1 week. The plasma BNP concentration was measured using a specific immunoradiometric assay kit (Shionogi Co, Osaka, Japan), as previously reported.14

Echocardiography Measurement of the Ejection Fraction (EF) and the Ratio of Early-to-Atrial Filling of Transmitral Flow (E/A)

B-mode recordings were obtained with a commercially available instrument (SONOS 5500™; Agilent Technologies Inc, Palo Alto, CA, USA) operating at 2.5 MHz. Two-dimen-sional imaging examinations were performed in the standard manner from apical 4 and 2 chamber views, and the left ven-tricular (LV) EFs were measured from B-mode images according to the modified Simpson’s method. Also, pulsed-Doppler findings of transmitral flow were obtained to calcu-late the E/A.

Exercise Tolerance EstimationEach patient underwent a questionnaire-based interview

for the estimation of the exercise tolerance threshold (ET) according to a specific activity scale15

Statistical AnalysisMedCalc version 9.6 (MedCalc Software, Mariakerke,

Belgium) was used for data analysis. The quantitative data are expressed as mean ± SD. A Student’s t-test was used for descriptive statistics. The Mann–Whitney U-test was used for non-parametric data sets. A two-tailed Pearson’s corre-lation was used to compare the relationship between LVEF, log BNP, and NI-CI, NI-SVI, and NI-TSVR. Spearman’s coefficient of rank correlation (rho) was used to estimate the probability of correlations with ET. We used the multiple regression analysis in order to detect the predictors for CHF readmission, and also used receiver operating characteristic curve (ROC) analysis for BNP, NI-CI, NI-SVI, NI-TSVR, LVEF and ET to determine the thresholds between the read-mission group and the non-readmission group. A two-tailed P-value of less than 0.05 was considered to be significant.

ResultsRelationship Between NICaS-Derived Hemodynamic Parameters and LVEF, Plasma logBNP and ET

There were significant but weak correlations between LVEF and NI-CI (LVEF =22.70+5.21*NI-CI, r=0.3148, P= 0.0089), NI-SVI (LVEF =22.80+0.38*NI-SVI, r=0.3257, P=0.0067), NI-TSVR (LVEF =46.02–0.003*NI-TSVR, r= 0.2636, P=0.0298; Figure 1). There were significant mod-erate correlations between log BNP and NI-CI (log BNP =

Table 1. Patient Characteristics

No. of patients 68 Men 56 (82.4%) Women 12 (17.6%) Age (years) 64.9±10.8 NYHA I 20 (29.4%) NYHA II 48 (70.6%) Hypertension 8 (11.8%) Diabetes mellitus 17 (25.0%) Ischemic heart disease 18 (26.5%) Dilated cardiomyopathy 28 (41.2%)

NYHA, New York Heart Association classification

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Figure 1. Scatter plots showing the correlation between left ventricular ejection fraction (EF) and Non-Invasive Cardiac System (NICaS) derived cardiac output index (NI-CI) [A]; EF and NICaS derived stroke volume index (NI-SVI) [B], EF and NICaS derived total systemic vascular resistance (NI-TSVR) [C]. The 2-tailed Pearson’s correlation test (r) was used for the analyses.

Figure 2. Scatter plots showing the correlation between the logarithmic serum B-type natriuretic peptide (BNP) levels with NI-CI [A]; BNP and NI-SVI [B], BNP and NI-TSVR [C]. The 2-tailed Pearson’s correlation test (r) was used for the analyses. NI, non-invasive; CI, cardiac output index; SVI, stroke volume index; TSVR, total systemic vascular resistance.

y = 22.70 + 5.21 x r=0.3148 P=0.0089

1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

70

60

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NI-CI (L·min–1·m–2) NI-SVI (ml/m2)

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)

y = 22.80 + 0.38 x r=0.3257 P=0.0067

EF (%

)

10 20 30 40 50 60

70

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y = 46.02 – 0.003 x r=–0.2636 P=0.0298

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)

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BN

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g/m

l)

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10000

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Log(y) = 3.20 – 0.028 x r=–0.4737 P<0.0001

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1000 2000 3000 4000 5000 6000

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3.20–0.38*NI-CI, r=–0.4585, P=0.0001), NI-SVI (log BNP = 3.20–0.028*NI-SVI, r=–0.4737, P<0.0001), and NI-TSVR (log BNP =1.33+0.0003*NI-TSVR, r=0.4803, P<0.0001; Figure 2). There was a significant correlation between ET and NI-CI (rho =0.412, P=0.0025), NI-SVI (rho =0.575, P< 0.0001), and NI-TSVR (rho =–0.357, P=0.0087; Figure 3). There was no significant relationship between ET and E/A (Figure 4).

Predictive Factors for CHF ReadmissionDuring the 100±98 days (95%CI for the mean: 46–154)

follow-up, 15 patients were readmitted to our hospital because of CHF recurrence (readmission group) whereas 53 patients were not readmitted because of CHF recurrence (no-readmission group). There was a significant difference in NI-CI between the readmission and non-readmission groups (1.86±0.37 L · min–1 · m–2 vs 2.92±0.63 L · min–1 · m–2, P< 0.0001). Similarly, there were significant differences between groups in NI-SVI (24.2±7.9 ml · min–1 · m–2 vs 40.4 ml · min–1 · m–2, P<0.0001), NI-TSVR (3,786±1,162 dynes · cm–5 · m–2 vs 2,420±583 dynes · cm–5 · m–2, P=0.0007), LVEF (27.4±8.4% vs 39.3±11.7%, P=0.0005), ET (2.89–3.11 metabolic equiv-alents vs 5.00–7.00 metabolic equivalents in 95%CI for median, P<0.0001), and BNP (696.5 pg/ml [95%CI; 487.5–995.1] vs 98.1 pg/ml [95%CI; 69.8–138.1], P<0.0001). Receiver operator characteristic curves for sensitivity, spec-ificity, positive predictive value, and negative predictive value for readmission for each parameter are shown in Table 2. Multivariate analysis for readmission showed that LVEF measured by echocardiography, NI-CI, NI-SVI, and

plasma BNP were significant predictors of readmission (Table 3).

DiscussionWe have previously reported the reliability of NICaS-

derived hemodynamic parameters when compared with those obtained by the Swan–Ganz catheter. Overall, 2-tailed

Spearman’s coefficient of rank correlation (rho) = 0.412 P=0.0025

ET (M

ETs)

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Spearman’s coefficient of rank correlation (rho) = 0.575 P<0.0001

10 20 30 40 50 60

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ETs)

NI-SVI (ml/m2)

Spearman’s coefficient of rank correlation (rho) = –0.357 P=0.0087

1000 2000 3000 4000 5000 6000

10

9

8

7

6

5

4

3

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ET (M

ETs)


A B

C

Figure 3. Scatter plots showing the correlation between exercise tolerance threshold (ET) and NI-CI [A]; ET and NI-SVI [B], and ET and NI-TSVR [C]. Spearman’s coefficient of rank correlation test (rho) was used for analysis. NI, non-invasive; CI, cardiac output index; SVI, stroke volume index; TSVR, total systemic vascular resistance.

2 4 6 8 10

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Figure 4. Scatter plots showing the correlation between exercise tolerance threshold (ET) with E/A of transmitral flow derived by Doppler echocardiogram. Spearman’s coefficient of rank correlation test (rho) was used for analysis.

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Pearson’s correlation and Bland–Altman limits of agree-ment between NI-CO and thermodilution CO were r=0.91 and –1.06 and 0.68 L/min in 2SD and between NI-CO and Fick CO, r=0.80 and –1.52 and 0.88 L/min in 2SD, respec-tively.6 In the present study, NICaS-derived hemodynamic parameters were significantly correlated with LVEF, plasma log BNP, and ET. Furthermore, NICaS-derived CI and SVI were significant parameters for predicting the future recur-rence of heart failure. An NICaS-derived CI of less than 2.49 L · min–1 · m–2 had 100.0% sensitivity and 79.3% speci-ficity, and an NICaS-derived SVI of less than 27.2 ml · min–1 · m–2 had 80.0% sensitivity and 98.1% specificity. In the readmission group, no cases of a preserved EF greater than 55% were observed. ET was significantly worse in the readmission group than in the non-readmission group. The overall average EF was 36.68%, and the average EF was 27.40% in the readmission group and 39.30% in the non-readmission group. In this study, the NICaS-derived indices seem to be good predictors of readmission with CHF second to BNP.

Serum BNP levels can be a good surrogate indicator for the long-term prognosis of CHF patients.16 Logeart et al. reported that a serum BNP of more than 350 ng/L at pre-discharge predicted a worse prognosis in outpatients with CHF.17 According to our data, BNP had 93.3% sensitivity and 88.7% specificity for readmission when its cut-off value was 344 pg/ml, indicating that BNP had good predictive power. Thus, in the present study, NICaS did not have a decisive advantage over serum plasma BNP levels for pre-dicting readmission. In clinical use, however, NICaS has sufficient predictive power. BNP measurement requires a peripheral venous blood sample, but some patients might consider repeated blood sample collection an invasive pro-cedure. NICaS has the advantage of not being invasive because it only requires some electrodes to be placed on the patient’s skin, similar to an electrocardiogram. It is also

important that NICaS is compatible with the conventional hemodynamic indicators derived by the Swan–Ganz cathe-ter. Other hemodynamic indices including CI, SV are used when patients are in the intensive care unit. Once the patients are moved to the general ward, however, these indices are not readily available, although there are some limited modalities similar to echocardiography. Even when the patients are in the general ward or an outpatient department, the hemodynamic indices derived by NICaS can be easily taken and linked directly with the hemodynamic data derived by conventional methods. Therefore, another advantage of NICaS is that patient hemodynamic data obtained inside and outside the intensive care unit can be reported using the same scale, allowing for easy comparison.

According to the Ministry of Health, Labour, and Welfare in Japan, the number of outpatients with CHF has been increasing over the past several years.1–2 Recent studies have been initiated to better determine the actual prevalence of CHF in Japanese communities.18,19 Therefore, a less inva-sive method that is easier to use, sufficiently accurate, and inexpensive is needed to categorize CHF patients accord-ing to their disease severity or probability of readmission. The exercise tolerance test is a major index for estimating a patient’s practical cardiovascular performance, but there are a number of patients who cannot perform an exercise test because of their age, disability, or poor muscle con-ditioning. In such cases, an alternative evaluation standard of cardiovascular performance, such as NICaS, should be utilized.

Study LimitationsIt is widely believed that exercise capacity is related to

LV diastolic function20 but not to the LVEF, which in the present study was closely correlated to CI and SVI. We did not, however, find a significant relationship between E/A and ET. Also, in our study subjects, 3 patients were thought to have a purely diastolic dysfunction because they had a preserved EF of more than 55% and an E/A with the trans-mitral Doppler echocardiogram of less than 1 during their first visit to the outpatient department, and were not in the readmission group. Thus, in our study subjects, diastolic dysfunction did not have a significant effect, probably because of the small number of subjects used.

Although NICaS might be useful for estimating cardiac performance in patients who are not exercise tolerant or who have difficulty walking, it might not be reliable when applied to patients who match the exclusion criteria described above, including those with arteriosclerosis obliterans and severe pitting edema of the limbs.

Table 2. Receiver Operating Curve Analysis for Readmission

Sensitivity Specificit PPV NPV AUC Cut-off (%) (%) (%) (%)

BNP 93.3 88.7 70.0 97.9 0.95 344 pg/ml NI-CI 100 79.3 57.7 100 0.93 2.49 L · min–1 · m–2

NI-SVI 80 98.1 92.3 94.4 0.91 27.2 ml/m2

NI-TSVR 100 68.6 46.7 100 0.89 2,597 dyne · cm–5 · min–1

LVEF 86.6 64.2 40.6 94.4 0.80 37% ET 100 71.4 52.0 100 0.88 4 METs

PPV, positive predictive value; NPV, negative predictive value; AUC, area under curve; BNP, B-type natriuretic peptide; NI-CI, NICaS derived cardiac index; NI-SVI, NICaS derived stroke volume index; NI-TSVR, NICaS derived total systemic vascular resis-tance; LVEF, left ventricular ejection fraction; ET, exercise tolerance threshold.

Table 3. Multivariate Analysis for Factors of Readmission

OR (95% confidence interval P value

Age 1.0429 (0.9530–1.1414) 0.3611 Gender 0.3235 (0.0593–1.7647) 0.1923 LVEF 0.8918 (0.8205–0.9693) 0.007069 NI-CI 0.0318 (0.0023–0.4421) 0.01023 NI-SVI 0.8121 (0.6914–0.9540) 0.01129 BNP 1.0068 (1.0019–1.0117) 0.006053 Heart rate 1.0456 (0.9905–1.1038) 0.1064 SBP 1.0118 (0.9711–1.0542) 0.5750

OR, odds ratio; SBP, systolic blood pressure. Other abbreviations as in Table 2.

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ConclusionsNICaS-derived hemodynamic parameters obtained by

monitoring whole body bioimpedance are applicable for the non-invasive assessment of cardiac function for the follow up of outpatients with CHF.

References 1. Okamoto H, Tsutsui H. The epidemiology of heart failure in Japan.

Nihon Rinsho Extra Issue 2007; 913: 49 – 54. 2. Okamoto H, Kitabatake A. Epidemiology of heart failure in Japan.

Nihon Rinsho 2003; 61: 709 – 714. 3. Solomon SD, Anavekar N, Skali H, McMurray JJ, Swedberg K,

Yusuf S, et al. Influence of ejection fraction on cardiovascular out-comes in a broad spectrum of heart failure patients. Circulation 2005; 112: 3738 – 3744.

4. Koglin J, Pehlivanli S, Schwaiblmair M, Vogeser M, Cremer P, vonScheidt W. Role of brain natriuretic peptide in risk stratificationof patients with congestive heart failure. J Am Coll Cardiol 2001; 38: 1934 – 1941.

5. Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002; 105: 2392 – 2397.

6. Paredes OL, Shite J, Shinke T, Watanabe S, Otake H, Matsumoto D, et al. Impedance cardiography for cardiac output estimation: Reliabil-ity of wrist-to-ankle electrode configuration Circ J 2006; 70: 1164 – 1168.

7. Cotter G, Moshkovitz Y, Kaluski E, Kohen A, Miller H, Goor D, et al. Accurate, noninvasive continuous monitoring of cardiac output by whole-body electrical bioimpedance. Chest 2004; 125: 1431 – 1440.

8. Cohen AJ, Arnaudov D, Zabeeda D, Shultheis L, Lashinger J, Schachner A. Non-invasive measurement of cardiac output during coronary artery bypass grafting. Eur J Surg 1998; 14: 64 – 69.

9. Organ LW, Bradham GB, Gore DT, Lozier SL. Segmental bioelectrical impedance analysis: Theory and application of a new technique. J Appl Physiol 1994; 77: 98 – 112.

10. Lukaski H, Bolonchuk WW, Hall CB, Siders WA. Validation of tet-rapolar bioelectrical impedance method to assess human body com-position. J Appl Physiol 1986; 60: 1327 – 1332.

11. Hoffer EC, Meador CK, Simpson DC. A relationship between whole body impedance and total body water volume. Ann NY Acad Sci 1970; 170: 452 – 461.

12. Ward LC, Heitmann BL, Craid P, Stroud D, Azinge EC, Jebb S, et al. Association between ethnicity, body mass index, and bioelectrical impedance: Implications for the population specificity of prediction equations. Ann NY Acad Sci 2000; 904: 199 – 204.

13. Hamwi GT, Danowski TS. Changing dietary concepts in diabetes mellitus: Diagnosis and treatment. New York: American Diabetes Association; 1964; 73 – 78.

14. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, et al. Localization and mechanism of secretion of B-type natri-uretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994; 90: 195 – 203.

15. Sasayama S, Asanoi H, Ishizaka S, Miyagi K. Evaluation of functional capacity of patients with congestive heart failure. In: Yasuda H, Kawaguchi H, editors. New aspects in the treatment of failing heart. Tokyo: Springer-Verlag; 1992; 113 – 117.

16. Tsutamoto T, Wada A, Maeda K, Hisanaga T, Mabuchi N, Hayashi M, et al. Plasma brain natriuretic peptide level as a biochemical marker of morbidity and mortality in patients with asymptomatic or minimally symptomatic left ventricular dysfunction: Comparison with plasma angiotensin II and endothelin-1. Eur Heart J 1999; 20: 1799 – 1807.

17. Logeart D, Thabut G, Jourdain P, Chavelas C, Beyne P, Beauvais F. B-Type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol 2004; 43: 635 – 641.

18. Tsutsui H, Tsuchihashi-Makaya M, Kinugawa S, Goto D, Takeshita A; The JCARE-CARD Investigators. Clinical characteristics and outcome of hospitalized patients with heart failure in Japan. Circ J 2006; 70: 1617 – 1623.

19. Tsutsui H, Tsuchihashi-Makaya M, Kinugawa S, Goto D, Takeshita A; JCARE-GENERAL Investigators. Characteristics and outcomes of patients with heart failure in general practices and hospitals. Circ J 2007; 71: 449 – 454.

20. Parthenakis FI, Kanoupakis EM, Kochiadakis GE, Skalidis EI, Mezilis NE, Simantirakis EN. Left ventricular diastolic filling pattern pre-dicts cardiopulmonary determinants of functional capacity in patients with congestive heart failure. Am Heart J 2000; 140: 338 – 344.

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Impedance cardiography: a useful and reliable tool inoptimization of cardiac resynchronization devices

Konstantin M. Heinroth*, Marcel Elster, Sebastian Nuding, Frithjof Schlegel, Arnd Christoph,Justin Carter, Michael Buerke, and Karl Werdan

Department of Medicine III/Cardiology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40,06097 Halle (Saale), Germany

Received 18 October 2006; accepted after revision 7 April 2007; online publish-ahead-of-print 11 May 2007

Aims Optimizing cardiac resynchronization therapy (CRT) devices has become more complex sincemodification of both atrioventricular (AV) and interventricular (VV) stimulation intervals has become poss-ible. The current paper presents data from the routine use of impedance cardiography (IC)-based cardiacoutput (CO) measurements to guide the optimization of AV- and VV-interval timing of CRT devices.Methods and results Forty-six patients with heart failure (left ventricular ejection fraction ,35%, New YorkHeart Asociation (NYHA) III–IV) and left bundle branch block (.130 ms) in sinus rhythm were evaluated 3–5days after implantation of a CRT device by means of IC. CO was measured without pacing and with biven-tricular pacing using a standard protocol of VV- and AV-interval modification from 260 toþ60 ms and 80 to140 ms, respectively, in 20 ms steps. Mean CO without pacing was 3.66+ 0.85 L/min and significantlyincreased to 4.40+ 1.1 L/min (P , 0.05) with simultaneous biventricular pacing and an AV interval of120 ms. ‘Optimizing’ both VV and AV intervals further increased CO to 4.86+ 1.1 L/min (P , 0.05).Maximum CO was measured in most patients with left ventricular pre-excitation. The proportion of ‘non-responders’ to CRTwas reduced by 56% following AV- and VV-interval modification using IC guidance.Conclusion Modification of both AVand VV intervals in patients with a CRT device significantly improves COcompared with standard simultaneous biventricular pacing and no pacing. IC is a useful non-invasive tech-nique for guiding this modification. Marked variability of optimal AV and VV intervals between patientsrequires optimization of these intervals for each patient individually.

KEYWORDSCardiac resynchronization

therapy;

Non-invasive optimization;

Impedance cardiography

Introduction

Cardiac resynchronization therapy (CRT) has developed froman experimental method1 to an established adjunctivetreatment for patients with advanced heart failure. CRTaims to improve cardiac output (CO) by lessening the inter-and intra-ventricular conduction delay caused in part byleft bundle branch block (LBBB).2,3 CRTreduces clinical symp-toms of heart failure and hospitalization,4–6 improves haemo-dynamic parameters (including ventricular performance),7

and has been shown to reduce mortality.8–10 Acceptance ofthis therapy is reflected by its incorporation into currentguidelines for the management of heart failure.11,12

Successful CRT in any given patient depends upon manyvariables, such as the appropriate positioning of the LVlead,13–15 and also on achieving optimal biventricular stimu-lation timing.16,17 This latter variable has attracted particu-lar interest recently in an attempt to reduce the substantialproportion (20–30%) of patients who derive no apparentbenefit from CRT, despite meeting appropriate implantationcriteria and having had technically straightforward deviceimplantation (‘non-responders’).18

CRT devices have become significantly more complexrecently. Many now have the facility to programme differentatrioventricular (AV) and interventricular (VV) stimulationtiming intervals.19,20 Data exist to show that tailoringthese intervals to suit the patient in hand further improvesthe haemodynamic benefits brought by CRT. However, ques-tions remain as to which method of haemodynamic assess-ment is best for guiding the adjustment of the devicesettings to suit any given post-implant patient.

In the measurement of cardiac function, invasive methods(e.g. dp/dt estimation of contractility or the thermodilutionmethod for CO) are the gold standards but are not suitablefor routine use during routine follow-up of patients withimplanted CRT devices. Non-invasive methods used in opti-mizing device settings include echocardiographic tech-niques,21–24 radionucleotide ventriculography,25 fingerphotoplethysmography,26 and more recently, impedancecardiography (IC).6,27

IC is an established technique for haemodynamic assess-ment and is capable of calculating CO on a beat-to-beatbasis.28 It relies upon changes in impedance (resistance) tocurrent flow through the chest between strategicallyplaced electrodes. Given that most current takes the path

& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: [email protected]

* Corresponding author. Tel: þ49 345 557 2601; fax: þ49 345 557 2072.E-mail address: [email protected]

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of least resistance (principally the blood-filled aorta) andthat the impedance changes with blood flow, these variablescan be used to calculate CO. IC has been used in patientsreceiving dual chamber pacemakers29–31 and in the assess-ment of patients with heart failure.6,32–34 IC as a techniquemay supplement or even replace invasive measurements andDoppler echocardiography6,27,35 in the optimization ofimplanted CRT devices.This paper presents data from the routine use of IC in

optimizing CRT by adjusting AV and VV intervals to obtainmaximum CO in post-implant patients. To our knowledge,this is the first report on the combined manipulation ofAV- and VV-interval timing in biventricular pacing devicesusing IC.

Methods

Patient characteristics

Forty-six consecutive patients (37 males, 9 females, mean age63+ 9 years) with heart failure [left ventricular ejection fraction(LVEF) ,35%; NYHA III–IV], LBBB (.130 ms), and sinus rhythmwere evaluated 3–5 days after implantation of a CRT device.Baseline characteristics of study patients are detailed in Table 1.All patients had been receiving optimal (guideline compliant11,12)medical treatment for heart failure for at least 1 month beforedevice implantation. Evaluation of patients before CRT included12-lead surface ECG. Echocardiography was undertaken pre-implant, and post-CRT device optimization according to a standardtemplate was performed with a System FiVe (GE VingMed) machinecoupled to a 2.5 MHz transducer. In all patients, measurement ofleft ventricular (LV) dimensions, LVEF and evaluation for valvedisease, particularly mitral regurgitation was undertaken.Transmitral flow was assessed using pulsed wave Doppler imagingin the apical 4-chamber view. Coronary angiography was performedin patients who had not previously had this done or where patientshad symptoms of active coronary disease requiring further imaging.The echocardiography and coronary angiography form part of ourstandard patient ‘work-up’ for device implantation, but theseresults were not part of the prospectively chosen datasets gatheredfor the purpose of the study.

Device implantation

All patients received a CRT device in combination with acardioverter–defibrillator (Contak Renewal, Guidant, St. Paul, MN,USA) except one patient who received only a CRT device (ContakRenewal). Forty-five of the 46 CRT devices were implanted in ourcatheterization laboratory by a cardiologist and a cardiac surgeon.The other patient received a device with epicardial leads implantedduring surgical mitral valve reconstruction. Device implantation wassimilar in all cases. Initially the right ventricular (RV) lead wasplaced in the RV apex, then the coronary sinus lead was positionedusing the over-the-wire technique, and finally the right atrial leadwas implanted. The device was programmed in DDD-Mode with alower rate limit at 40–50 bpm, producing atrial synchronous

biventricular tracking of the intrinsic sinus rhythm (VAT-Mode).36

The AV interval was set at 120 ms as a standard value6 without LVor RV pre-excitation (VV interval ¼ 0). This ‘standard’ pacingset-up was kept from implantation until optimization.

Impedance cardiography

Optimization of biventricular pacing was performed using a com-mercially available system for IC (Task Force Monitor Systems,CNSystems, Graz, Austria) as described by Braun et al.6 Two electro-des were placed bilaterally to the inferior chest wall in combinationwith one electrode at the neck. Low-amplitude high-frequencycurrent was delivered via these surface electrodes, and transthor-acic impedance (resistance) to this current flow was measured.Changes in transthoracic impedance (mainly influenced by changesof systolic aortic blood flow) were measured by means of fouradditional surface electrodes: one pair placed bilaterally to thesternum and the second pair bilaterally to the abdomen. Cardiacoutput was calculated on a beat-to-beat basis from the trans-thoracic impedance signal.37 Figure 1 shows an example of the ICmeasurement acquired by the Task Force Monitor System.

Table 1 Patient characteristics

Patients 46Age (years) 63+ 9Gender (female/male) 9/37% CAD/% DCM 20/80QRS 187+ 26 msPQ 197+ 40 msLVEF 27+ 8%

Figure 1 Example of the impedance cardiography measurementacquired by the Task Force Monitor System. There are two pacedbeats and one beat without pacing. From top to bottom: lead IIfrom the surface ECG, blood pressure, and the first derivative dZ/dt of the impedance. DBP, diastolic blood pressure; SBP, systolicblood pressure; B, aortic valve opening; dZ/dt max, maximum ofthe first derivative of the impedance signal; X, aortic valve closure.

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Pacing study protocol

To optimize the CRT set-up, all patients were examined inthe supine position in a silent environment to reduce theimpact of sympathetic activation by external stimuli.A standard protocol involving a period of stabilization and

equilibration followed by VV-interval optimization and thenAV-interval optimization was employed in all patients.Pacemakers were programmed in a DDD-Mode with a lowerrate limit of 40 bpm to avoid effects of atrial pacing onthe AV interval.36 During data acquisition, telemetrybetween the implanted device and the programmer was dis-connected to prevent interference with the measurement ofimpedance. AV-interval values relate to the atrio-RV stimu-lation interval, and VV intervals relate to interventricularinterval with negative figures implying LV pre-excitation.The first stage of the pacing protocol was a period of

stabilization and equilibration. The baseline CO withoutpacing was recorded, and this was alternated three timeswith ‘standard’ simultaneous biventricular pacing with anAV interval of 120 ms for 50 s at each setting. Once consis-tent values for CO in both modes were confirmed, we pro-ceeded to the ‘optimization’ stage of the pacing protocol.With the AV interval fixed at 120 ms, VV intervals were

adjusted through a set of seven steps ranging from LV pre-excitation of 260 ms to an LV delay of þ60 ms in steps of20 ms (as reported previously38). The CO was recorded for50 s at each setting. Then, the VV interval was set at zerowhile the AV interval was adjusted from 80 to 140 ms step-wise in 20 ms increments. Again, CO at each setting wasrecorded. We found that 10 s were sufficient for stabilizationin values after any change in the stimulation set-up. Finally,the device was set at whichever combination of AV and VVintervals produced highest CO in that patient.We defined an increase in CO of greater than 10% above

baseline (i.e. without pacing) as a ‘positive response’ tobiventricular pacing, in keeping with data previously pub-lished.39 Where maximum CO was identified by IC to occurat very short AV intervals (i.e. A to RV or A to LV of,80 ms), an echocardiogram was performed to exclude atruncated A wave caused by atrial contraction againstclosed AV valves.

Statistics

All data are presented as means+ standard error. Statisticalanalysis was performed using multiple analysis of variance,Kruskall–Wallis test, and Fisher’s exact test to comparemore than two sets of data. For a comparison of two setsof data, a student’s t-test was performed. A P-value of, 0.05 was considered to be significant. Data was processedusing commercially available software (Statgraphics Plus forWindows).

Results

Cardiac resynchronization therapy

Forty-six CRT devices were successfully implanted, 45 by thetransvenous approach and 1 by the transthoracic approachduring surgical mitral valve repair. The LV lead was placedin a posterolateral (n ¼ 35) or an anterolateral (n ¼ 10)side branch. There were no complications.

There were no significant differences between the heartrates without pacing (75.1+ 10.7 bpm), with initial simul-taneous biventricular pacing (74.7+ 10.9 bpm), or opti-mized biventricular pacing (74.8+ 10.2 bpm, P . 0.05).Thus, results for CO obtained at each CRT set-up were unaf-fected by the heart rate.

Cardiac output without pacing vs. simultaneousbiventricular pacing vs. optimized biventricularpacing

The alternation between three cycles of no pacing with sim-ultaneous biventricular pacing during stabilization and equi-libration revealed (across all patients) a mean increase in COof 21.6+ 22.1% (P , 0.05) with pacing. The mean range(i.e. variation) between the three recordings (in eachpatient) without pacing was 10.1% and between the threerecordings with pacing was 11.8%.

Figure 2 shows data obtained for a typical patient atdifferent VV intervals with a fixed AV interval of 120 ms. Inthis patient, the maximum CO was measured during LV pre-excitation of 20 and 40 ms relative to RV stimulation. Still,earlier LV pre-excitation, simultaneous biventricularpacing, and RV pre-excitation resulted in a lower CO.

Data collected from all patients at each stimulation set-upwith VV optimization at a fixed AV interval of 120 ms andwith AV optimization at a VV interval set to zero areshown in Figure 3.

In detail, the maximum CO was achieved with the follow-ing VV intervals (when combined with an AV interval of120 ms): 260 ms in 15 pts, 240 ms in 6 pts, 220 ms in9 pts, +0 ms in 5 pts, þ20 ms in 2 pts, þ40 ms in 2 pts,and þ60 ms in 3 pts, so the majority of patients (30 of46 patients) achieved peak CO with LV pre-excitation. Theremaining four patients achieved maximum CO with simul-taneous biventricular pacing, two with an AV interval of80 ms, and two with an AV interval of 140 ms.

The combination of an AV interval of 120 ms and LVpre-excitation of 40 ms yielded the highest mean CO of

Figure 2 Cardiac output measured by impedance cardiography atdifferent ventriculo-ventricular intervals at an atrioventricularinterval of 120 ms in a representative patient. Optimum cardiacoutput was yielded at a left ventricular pre-excitation of 240 and220 ms.

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4.57+ 1.1 L/min. Similar values were obtained by LV pre-excitation of 20 and 60 ms (4.51+ 1.3 and 4.50+ 1.2 L/min, respectively). The optimal pacing set-up variedwidely from patient to patient. As a result of this variability,there was no significant difference in CO when the resultsfrom different AV and VV intervals were compared. Nosingle combination of AV and VV intervals could be recom-mended for application to the whole study population,because no single combination of intervals showed statisti-cally significant superiority over other combinations.For the population as a whole, when the CO obtained with

‘optimized’ biventricular pacing (i.e. the CO measured atwhichever AV and VV intervals produced the highest valuein that patient) is compared with the CO obtained with‘standard’ simultaneous biventricular pacing and comparedwith the CO obtained with no pacing, a statistically signifi-cant difference is seen (Figure 4). CO without pacingwas 3.66+ 0.85 L/min. CO increased to 4.40+ 1.1 L/min(P , 0.05) with simultaneous biventricular pacing using astandard AV interval of 120 ms.The mean increase in CO changing from no pacing to sim-

ultaneous biventricular pacing was 21.6+ 22.1%, P , 0.05).

‘Optimizing’ VV and AV intervals further increased the meanCO to 4.86+ 1.1 L/min. This corresponds to an increase inmean CO of 32.8% without pacing and an increase of 11.2%compared with simultaneous biventricular pacing, all threeset-ups resulting in significantly different CO (P , 0.05,Figure 4).Taking an increase in CO �10% as a definition of a positive

haemodynamic response to CRT,39 16 of the 46 patients(35%) were ‘non-responders’ with standard simultaneousbiventricular CRT. In five of these patients, CO with standardbiventricular pacing was lower than without any pacing. Themean CO in this group of 16 ‘non-responders’ (with standardsimultaneous biventricular CRT) was 100.8+ 4.9% (whereCO without pacing was 100%). After optimization, 9 ofthese 16 patients (who were ‘non-responders’ to standardsimultaneous biventricular CRT) experienced an increaseof �10% in CO to become ‘responders’. In this group ofnine patients, the mean CO increased significantly from101.3+ 3.6% to 121+ 5.1% (P � 0.05). In the seven patientswho failed to respond despite ‘optimization,’ the mean COwas 106.6+ 2.6% with optimized pacing. Nevertheless,after modification of AV and VV intervals to produce the

Figure 3 Cardiac output measured by impedance cardiography at different ventriculo-ventricular and atrioventricular intervals for allpatients. Data are presented as mean+ standard deviation. Maximum cardiac output was yielded at a left ventricular pre-excitation of240 ms and an atrioventricular interval of 120 ms.

Figure 4 Cardiac output measured by impedance cardiography without pacing, with simultaneous biventricular pacing (and an atrioventri-cular interval of 120 ms), and with ‘optimized’ biventricular pacing. Asterisk represents P ,0.05, simultaneous biventricular pacing vs. nopace; ash represents P ,0.05, optimized biventricular pacing vs. simultaneous biventricular pacing and vs. no pace.




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maximum CO, the number of haemodynamic ‘non-responders’ was reduced to 7 of the 46 patients, i.e. thenumber of non-responders was reduced by 56% (Figure 5).

Discussion

In the present study, we described the use of IC to guideoptimization of the AV and VV timing following CRT. To ourknowledge, this is the first report of both AV and VV manipu-lation using IC as a guide in CRToptimization. We found IC tobe simple to apply and capable of yielding rapid results in areliable and reproducible fashion. We found that theoptimal CRT-timing settings varied substantially betweenpatients underlining the need to optimize each patient’sdevice individually in order to gain most benefit fromdevice. Using this technique, we were able to significantlyimprove CO by manipulating both AV and VV intervals. Byoptimizing both settings, we were able to further improvethe CRT-related increase in CO in ‘responders’ and, further-more, could produce a significant increase in CO in patientswho, with ‘standard’ or simultaneous biventricular pacing,had demonstrated no increase in CO (‘non-responders’). Inpart, this reflects the importance of ‘electrical reposition-ing’ of the LV lead by VV-interval manipulation. Thus,using this technique, we were able to reduce the rate ofnon-responders to CRT by 56% (from 35 to 15%) by IC haemo-dynamic criteria.

Assessment of optimal biventricular stimulation:current methods

Although invasive measurements of CO and other par-ameters remain the ‘gold standard’ for the evaluation ofheamodynamics, they are not suitable for routine follow-upand optimization of CRT device settings because such inva-sive procedures are unpleasant for the patient and havepotentially serious complications.8,40

Most units favour non-invasive methods for the optimiza-tion of CRT devices. The use of echocardiographic tech-niques for this purpose has received more attention in theliterature, although there is no consensus as to which ofthe many echo-based parameters is the best surrogate forCO in the context of CRT optimization.

Mitral41 and aortic42 valve Doppler velocity time integrals(VTI) as well as several other24 echocardiographic para-meters have been assessed as an alternative to invasivemeasures and as a surrogate for CO in the optimization ofpacing devices. Recently, there has been promising datausing advanced tissue Doppler imaging techniques and real-time 3-D echo (particularly in selecting the optimal leadpositioning for biventricular pacing), but despite theseadvances, the echocardiographic lead optimization of CRTremains complex and time consuming. It requires an experi-enced operator and has significant problems relating toreproducibility and objectivity.

Impedance cardiography: a reliablealternative technique?

Several studies have demonstrated that IC is capable of pro-viding a reliable and accurate measurement of CO whencompared with invasive methods.28,32,43 The utility of IChas been shown in patients with decompensated cardiacfailure33 and in optimizing dual chamber pacemakers.44

A direct comparison of IC and echo techniques in optimizingAV intervals for pacemakers has been made in severalstudies30,31 with a recurring theme being that optimal AVintervals calculated by IC tend to be shorter than thoseobtained by echocardiography.45 Recently, Braun et al.6 pro-vided data using IC to guide the manipulation (primarily) ofAV intervals and showed that IC-based optimization is com-parable with transaortic VTI, but IC was felt to be more sen-sitive to small changes in CO and easier to apply.

Limitations of impedance cardiography

The limitations of IC was usefully reviewed by Kinderman.46

In a study of 14 patients with dual chamber pacemakers,data from IC overestimated CO if very short AV intervalswere programmed. This phenomenon seems to be attribu-table to a decrease in the thoracic impedance caused by aretrograde flow into the great thoracic veins induced byatrial contraction against closed AV valves. In these cases,optimization of AV interval solely according to the impe-dance signal would result in a truncated A wave of the trans-mitral flow, causing potentially deleterious effects. In ourstudy, if IC indicated that optimum CO was seen at morethan one AV or VV interval, the longer AV interval and theshorter VV interval were programmed. If IC indicatedoptimum CO at short AV intervals (below 80 ms), transmitralflow was checked by Doppler echocardiography to exclude atruncated A wave. Of the 46 patients in the present study,this echocardiographic ‘check’ was required in two,neither of whom required a lengthening of AV interval.

Importance of optimizing bothVV and AV intervals

The early generations of CRT devices enabled programmingof the AV interval only.

Figure 5 Comparison of the percentage of ‘non-responders’ tocardiac resynchronization therapy (definition see text) with simul-taneous biventricular pacing (with an atrioventricular interval of120 ms) vs. atrioventricular- and ventriculo-ventricular-intervaloptimized biventricular pacing according to the cardiac outputmeasured by impedance cardiography for the whole studypopulation.




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Prospective randomized trial data have shown thatAV-interval optimization not only improves the haemo-dynamic response to CRT, but also improves NYHA functionalclass and quality of life scores.47

The current generation of devices allows the manipulationof both AV and VV intervals.Since activation of the interventricular septum is mainly

influenced by the RV lead, modification of the VV intervalaffects not only inter-ventricular dyssynchrony, but alsointra-ventricular dyssynchrony of the LV. The capacity tomanipulate VV intervals may thus further improve thehaemodynamic response to CRT.There is increasing evidence that sequential biventricular

pacing is superior to simultaneous biventricular pacing inmany patients with a CRT device.Perego et al. examined the impact of sequential biventri-

cular pacing while invasively monitoring dp/dt in both ven-tricles simultaneously. Simultaneous ventricular pacingproduced an increase in dp/dt of 29% over baseline, butsequential pacing produced a significantly greater increaseof 35% (P , 0.01). The mean optimal VV interval was LV pre-excitation of 25 ms, and there was no detriment to RV func-tion.38 Similar findings were reported by van Gelder et al.20

This pattern of haemodynamic improvement with both AVand VV optimization has been verified using Doppler echo-cardiography,48 3-D echocardiography49 and radionuclideventriculography.25 The largest benefit is obtained in mostcases by LV pre-excitation. Our study is the first to validatethe previous data, showing the additional benefit of optimiz-ing both AV and VV intervals using IC as the method ofassessment.Where no facility for optimizing CRT devices in individual

patients exists, we would recommend an AV interval of120 ms and LV pre-excitation of 20–40 ms as empiricalintervals in CRT programming. However, due to significantheterogeneity between patients, we were unable to identifyany single set of AV and VV intervals as being superior andthus suitable for application to the whole CRT populationon an empirical basis. This variation between patients is tobe expected, since there is a substantial heterogeneitybetween patients of conduction pattern, ventricular size,scar tissue formation, ventricular function (especially withrespect to regional wall motion abnormalities) CRT lead pla-cement positions, and other variables. The facility to mani-pulate VV intervals in effect allows the operator to‘electrically reposition’ the LV lead to help overcome someof these variations to maximize the haemodynamic responseto the device.This work has been an early, descriptive study of the feasi-

bility of using IC to manipulate both AV and VV intervals inoptimizing CRT devices. Further work is required beforethis technique can enter mainstream use. For instance, inany given patient, since AV and VV intervals are likely tobe interdependent, the ideal IC protocol would test everyAV-interval setting against every VV-interval setting andvice versa. With current equipment, this would be impracti-cal. Another simpler method of combining these interdepen-dent values of AV and VV intervals would be to identify theoptimal VV interval (i.e. A to LV interval) and keeping thisfixed (rather than re-setting this to zero as our protocoldid), and then adjusting the AV (i.e. A to V interval) to iden-tify the optimal CO. We suspect that this method of com-bined optimization of AV and VV intervals by IC may yield

still higher CO values, and hence hopefully reduce thenumber of non-responders. Further studies are required.

Conclusions

The present paper is the first to report the utility of IC in theoptimization of both AV and VV intervals in biventricularpacemaker set-up in routine clinical practice. Using IC, wedemonstrated that manipulating both AV and VV intervalsis feasible and may result in a significant improvement inthe haemodynamic response to CRT compared with ‘stan-dard’ simultaneous biventricular pacing and no pacing. Theresults show the importance of optimizing CRT set-up ineach patient individually, since the variability betweenpatients’ means that no single set of intervals can be identi-fied as being suitable for all or even most patients.In our opinion, IC is a promizing method of CRT optimiz-

ation and may compare well with other techniques inroutine use. It carries less risk of complications than invasivetechniques and is more comfortable for the patient. Thevalidity and reliability of IC has now been reported byseveral authors.28,31–33,43 Notwithstanding its limitations,which include a tendency to relative CO overestimationand the potential for selecting inappropriately short AVintervals, IC has an emerging role in the optimization ofCRT parameters in routine clinical practice. Further workis required to make best use of IC derived data in combiningAV and VV intervals to ideally suit any given patient.

Conflict of interest: none declared.

References

1. Leclercq C, Cazeau S, Le BH, Ritter P, Mabo P, Gras D et al. Acute hemo-dynamic effects of biventricular DDD pacing in patients with end-stageheart failure. J Am Coll Cardiol 1998;32:1825–31.

2. Cohen TJ, Klein J. Cardiac resynchronization therapy for treatment ofchronic heart failure. J Invasive Cardiol 2002;14:48–53.

3. Cazeau S, Alonso C, Jauvert G, Lazarus A, Ritter P. Cardiac resynchroniza-tion therapy. Europace 2004;5(Suppl. 1):S42–8.

4. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E et al.Cardiac resynchronization in chronic heart failure. N Engl J Med2002;346:1845–53.

5. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C et al.Effects of multisite biventricular pacing in patients with heart failureand intraventricular conduction delay. N Engl J Med 2001;344:873–80.

6. Braun MU, Schnabel A, Rauwolf T, Schulze M, Strasser RH. Impedancecardiography as a noninvasive technique for atrioventricular intervaloptimization in cardiac resynchronization therapy. J Interv CardElectrophysiol 2005;13: 223–229.

7. Bakker PF, Meijburg HW, de Vries JW, Mower MM, Thomas AC, Hull MLet al. Biventricular pacing in end-stage heart failure improves functionalcapacity and left ventricular function. J Interv Card Electrophysiol 2000;4:395–404.

8. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De MT et al.Cardiac-resynchronization therapy with or without an implantable defi-brillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50.

9. Salukhe TV, Dimopoulos K, Francis D. Cardiac resynchronisation mayreduce all-cause mortality: meta-analysis of preliminary COMPANIONdata with CONTAK-CD, InSync ICD, MIRACLE and MUSTIC. Int J Cardiol2004;93:101–3.

10. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger Let al. The effect of cardiac resynchronization on morbidity and mortality inheart failure. N Engl J Med 2005;352:1539–49.

11. Hoppe UC, Bohm M, Dietz R, Hanrath P, Kroemer HK, Osterspey A et al.Guidelines for therapy of chronic heart failure. Z Kardiol 2005;94:488–509.




ownloaded from

55 of 158.


12. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and manage-ment of chronic heart failure in the adult: a report of the AmericanCollege of Cardiology/American Heart Association Task Force onPractice Guidelines (Writing Committee to Update the 2001 Guidelinesfor the Evaluation and Management of Heart Failure). J Am CollCardiol 2005;46:e1–82.

13. Butter C, Auricchio A, Stellbrink C, Fleck E, Ding J, Yu Y et al. Effect ofresynchronization therapy stimulation site on the systolic function ofheart failure patients. Circulation 2001;104:3026–9.

14. Gold MR, Auricchio A, Hummel JD, Giudici MC, Ding J, Tockman B et al.Comparison of stimulation sites within left ventricular veins on theacute hemodynamic effects of cardiac resynchronization therapy. HeartRhythm 2005;2:376–81.

15. Albertsen AE, Nielsen JC, Pedersen AK, Hansen PS, Jensen HK, MortensenPT. Left ventricular lead performance in cardiac resynchronizationtherapy: impact of lead localization and complications. Pacing ClinElectrophysiol 2005;28:483–8.

16. Auricchio A, Ding J, Spinelli JC, Kramer AP, Salo RW, Hoersch W et al.Cardiac resynchronization therapy restores optimal atrioventricularmechanical timing in heart failure patients with ventricular conductiondelay. J Am Coll Cardiol 2002;39:1163–9.

17. Doshi RN. Optimizing resynchronization therapy: can we increase thenumber of true responders? J Cardiovasc Electrophysiol 2005;16(Suppl.1):S48–51.

18. Birnie DH, Tang AS. The problem of non-response to cardiac resynchroni-zation therapy. Curr Opin Cardiol 2006;21:20–6.

19. O’Donnell D, Nadurata V, Hamer A, Kertes P, Mohammed W. Long-termvariations in optimal programming of cardiac resynchronization therapydevices. Pacing Clin Electrophysiol 2005;28(Suppl. 1):S24–6.

20. van Gelder BM, Bracke FA, Meijer A, Lakerveld LJ, Pijls NH. Effect of opti-mizing the VV interval on left ventricular contractility in cardiac resyn-chronization therapy. Am J Cardiol 2004;93:1500–3.

21. Breithardt OA, Sinha AM, Franke A, Hanrath P, Stellbrink C.Echocardiography in cardiac resynchronization therapy: identificationof suitable patients, follow-up and therapy optimization. Herz 2003;28:615–27.

22. Bax JJ, Ansalone G, Breithardt OA, Derumeaux G, Leclercq C, Schalij MJet al. Echocardiographic evaluation of cardiac resynchronizationtherapy: ready for routine clinical use? A critical appraisal. J Am CollCardiol 2004;44:1–9.

23. Lane RE, Chow AW, Chin D, Mayet J. Selection and optimisation of biven-tricular pacing: the role of echocardiography. Heart 2004;90(Suppl.6):vi10–6.

24. Melzer C, Knebel F, Ismer B, Bondke H, Nienhaber CA, Baumann G et al.Influence of the atrio-ventricular delay optimization on the intra left ven-tricular delay in Cardiac Resynchronization Therapy. CardiovascUltrasound 2006;4:5.

25. Burri H, Sunthorn H, Somsen A, Zaza S, Fleury E, Shah D et al. Optimizingsequential biventricular pacing using radionuclide ventriculography.Heart Rhythm 2005;2:960–5.

26. Butter C, Stellbrink C, Belalcazar A, Villalta D, Schlegl M, Sinha A et al.Cardiac resynchronization therapy optimization by finger plethysmogra-phy. Heart Rhythm 2004;1:568–75.

27. Tse HF, Yu C, Park E, Lau CP. Impedance cardiography for atrioventricularinterval optimization during permanent left ventricular pacing. PacingClin Electrophysiol 2003;26:189–91.

28. Fortin J, HabenbacherW, Heller A, Hacker A, Grullenberger R, Innerhofer Jet al.Non-invasive beat-to-beat cardiac outputmonitoring by an improvedmethod of transthoracic bioimpedance measurement. Comput Biol Med2006;36:1185–203.

29. Ovsyshcher I, Gross JN, Blumberg S, Furman S. Precision of impedancecardiography measurements of cardiac output in pacemaker patients.Pacing Clin Electrophysiol 1992;15:1923–6.

30. Kindermann M, Frohlig G, Doerr T, Schieffer H. Optimizing the AV delay inDDD pacemaker patients with high degree AV block: mitral valve Dopplerversus impedance cardiography. Pacing Clin Electrophysiol1997;20:2453–62.

31. Kolb HJ, Bohm U, Mende M, Neugebauer A, Pfeiffer D, Rother T. -Assessment of the optimal atrioventricular delay in patients with

dual-chamber pacemakers using impedance cardiography and Dopplerechocardiography. J Clin Basic Cardiol 1999;2:237–40.

32. Belardinelli R, Ciampani N, Costantini C, Blandini A, Purcaro A. -Comparison of impedance cardiography with thermodilution and directFick methods for noninvasive measurement of stroke volume andcardiac output during incremental exercise in patients with ischemic car-diomyopathy. Am J Cardiol 1996;77:1293–301.

33. Albert NM, Hail MD, Li J, Young JB. Equivalence of the bioimpedance andthermodilution methods in measuring cardiac output in hospitalizedpatients with advanced, decompensated chronic heart failure. Am JCrit Care 2004;13:469–79.

34. Adachi H, Hiratsuji T, Sakurai S, Tada H, Toyama T, Naito S et al.Impedance cardiography and quantitative tissue Doppler echocardiogra-phy for evaluating the effect of cardiac resynchronization therapy: acase report. J Cardiol 2003;42:37–42.

35. Santos JF, Caetano F, Parreira L, Madeira J, Cardoso P, Fonseca N et al.Tissue Doppler echocardiography for evaluation of patients with ventricu-lar resynchronization therapy. Rev Port Cardiol 2003;22:1363–71.

36. Bernheim A, Ammann P, Sticherling C, Burger P, Schaer B, Brunner-LaRocca HP et al. Right atrial pacing impairs cardiac function during resyn-chronization therapy: acute effects of DDD pacing compared to VDDpacing. J Am Coll Cardiol 2005;45:1482–7.

37. Ovsyshcher I, Furman S. Impedance cardiography for cardiac output esti-mation in pacemaker patients: review of the literature. Pacing ClinElectrophysiol 1993;16:1412–22.

38. Perego GB, Chianca R, Facchini M, Frattola A, Balla E, Zucchi S et al.Simultaneous vs. sequential biventricular pacing in dilated cardiomyopa-thy: an acute hemodynamic study. Eur J Heart Fail 2003;5:305–13.

39. Bleeker GB, Bax JJ, Fung JW, van der Wall EE, Zhang Q, Schalij MJ et al.Clinical versus echocardiographic parameters to assess response tocardiac resynchronization therapy. Am J Cardiol 2006;97:260–3.

40. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P et al. ThePacing Therapies for Congestive Heart Failure (PATH-CHF) study: ration-ale, design, and endpoints of a prospective randomized multicenterstudy. Am J Cardiol 1999;83:130D–5D.

41. Jansen AH, Bracke FA, van Dantzig JM, Meijer A, van der Voort PH,Aarnoudse W et al. Correlation of echo-Doppler optimization of atrioven-tricular delay in cardiac resynchronization therapy with invasive hemody-namics in patients with heart failure secondary to ischemic or idiopathicdilated cardiomyopathy. Am J Cardiol 2006;97:552–7.

42. Kerlan JE, Sawhney NS, Waggoner AD, Chawla MK, Garhwal S, Osborn JLet al. Prospective comparison of echocardiographic atrioventriculardelay optimization methods for cardiac resynchronization therapy.Heart Rhythm 2006;3:148–54.

43. Drazner MH, Thompson B, Rosenberg PB, Kaiser PA, Boehrer JD, BaldwinBJ et al. Comparison of impedance cardiography with invasive hemody-namic measurements in patients with heart failure secondary to ischemicor nonischemic cardiomyopathy. Am J Cardiol 2002;89:993–5.

44. Ovsyshcher I, Zimlichman R, Katz A, Bondy C, Furman S. Measurements ofcardiac output by impedance cardiography in pacemaker patients at rest:effects of various atrioventricular delays. J Am Coll Cardiol1993;21:761–7.

45. Santos JF, Parreira L, Madeira J, Fonseca N, Soares LN, Ines L. Non inva-sive hemodynamic monitorization for AV interval optimization in patientswith ventricular resynchronization therapy. Rev Port Cardiol2003;22:1091–8.

46. Kindermann M. Impedanzkardiograpie. HerzschrittmachertherElektrophysiol 2004;15:1102–9.

47. Sawhney NS, Waggoner AD, Garhwal S, Chawla MK, Osborn J, Faddis MN.Randomized prospective trial of atrioventricular delay programming forcardiac resynchronization therapy. Heart Rhythm 2004;1:562–7.

48. Riedlbauchova L, Kautzner J, Fridl P. Influence of different atrioventricu-lar and interventricular delays on cardiac output during cardiac resyn-chronization therapy. Pacing Clin Electrophysiol 2005;28(Suppl. 1):S19–23.

49. Sogaard P, Egeblad H, Pedersen AK, Kim WY, Kristensen BO, Hansen PSet al. Sequential versus simultaneous biventricular resynchronizationfor severe heart failure: evaluation by tissue Doppler imaging.Circulation 2002;106:2078–84.




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5

Cardiac power output predicts mortality across abroad spectrum of patients with acute cardiac diseaseDorinna D. Mendoza, MD, Howard A. Cooper, MD, and Julio A. Panza, MD Washington, DC

Background Cardiac power output (CPO) is a novel hemodynamic measurement that represents cardiacpumping ability. The prognostic value of CPO in a broad spectrum of patients with acute cardiac disease undergoingpulmonary artery catheterization (PAC) has not been examined.

Methods Consecutive patients with a primary cardiac diagnosis who were undergoing PAC in a single coronarycare unit were included. The relationship between initial CPO [(mean arterial pressure � cardiac output [CO])/451] andinhospital mortality was evaluated. CPO was analyzed both as a dichotomous variable (using a cutoff value previouslyestablished among patients with cardiogenic shock) and as a continuous variable.

Results Data were available for 349 patients. The mean CPO was 0.88 F 0.37 W. The inhospital mortality ratewas significantly higher among patients with a CPO V0.53 W (n = 53) compared with those with a CPO N0.53 W (n = 296)(49% vs 20%, P b .001). In separate multivariate analyses, both CPO and CO were associated with inhospital mortality.However, when both terms were included simultaneously, CPO remained strongly associated with mortality (odds ratio0.63, 95% CI 0.43-0.91, P = .01), whereas CO did not (odds ratio 1.05, 95% CI 0.75-1.48, P = .78).

Conclusions Cardiac power output is a strong, independent predictor of inhospital mortality in a broad spectrumof patients with primary cardiac disease undergoing PAC. (Am Heart J 2007;153:366270.)

Pulmonary artery catheterization (PAC) remains in

common usage in the coronary care unit (CCU) setting

despite questions regarding the use of this procedure in

critically ill patients.1-3 The decision to use PAC is based

on the concept that invasive hemodynamic measure-

ments provide a more precise understanding of the

status of the cardiovascular system, which in turn allows

close monitoring of the response to therapeutic inter-

ventions. However, traditional hemodynamic measure-

ments obtained from PAC, such as cardiac output (CO),

do not fully describe the fundamental state of the

cardiovascular system in the setting of severe illness.4 In

particular, because of its critical dependence on preload

and afterload, measured CO provides a limited estima-

tion of ventricular function.

Cardiac power output (CPO) is a novel hemodynamic

measure that is the product of simultaneously measured

CO and mean arterial pressure (MAP).4,5 By incorporating

both the pressure and flow domains of the cardiovascular

From the Division of Cardiology, Washington Hospital Center, Washington, DC.

This work was supported by the Cardiovascular Research Institute, Washington Hospital

Center, Washington, DC.

Submitted July 13, 2006; accepted November 21, 2006.

Reprint requests: Howard A. Cooper, MD, Division of Cardiology, Washington Hospital

Center, 110 Irving Street NW, Suite NA1103, Washington, DC 20010.

E-mail: [email protected]

0002-8703/$ - see front matter

n 2007, Mosby, Inc. All rights reserved.

doi:10.1016/j.ahj.2006.11.014

7 of 158.

system, CPO is an integrative measure of cardiac

hydraulic pumping ability. Cardiac power output has

been shown to be a powerful predictor of mortality in

patients with chronic heart failure (HF) and in those with

cardiogenic shock.6-8 Recently, a report from the SHOCK

Trial Registry found that CPO was the strongest inde-

pendent hemodynamic correlate of inhospital mortality

in patients with cardiogenic shock.4 We hypothesized

that CPO would provide important prognostic informa-

tion across a broad spectrum of patients with acute

cardiac disease. Accordingly, we analyzed the relation-

ship between CPO and short-term mortality in a consec-

utive series of patients undergoing PAC in a single CCU.

MethodsStudy design and data collection

The institutional review board for human research at the

Washington Hospital Center approved this research protocol.

Data were collected prospectively for consecutive patients

admitted to the CCU between October 2002 and February

2006. Based on all available information, the attending

physician determined the primary clinical diagnosis requiring

admission to the CCU. Patients with a noncardiac primary

diagnosis were excluded from this analysis. Persistent cardio-

genic shock was determined to be present by using conven-

tional clinical criteria of hypotension and signs of peripheral

hypoperfusion in the presence of pulmonary congestion that

did not rapidly resolve. Left ventricular ejection fraction (EF)

was visually estimated from 2-dimensional echocardiography

Table I. Primary diagnosis

Primary diagnosis (N = 349) No. of patients (%)

ST-segment elevation myocardial infarction 122 (35)Non–ST-segment elevation

myocardial infarction79 (23)

Ischemic cardiomyopathy 38 (11)Nonischemic cardiomyopathy 33 (9)Coronary atherosclerosis 17 (5)Unstable angina 16 (5)Cardiac arrest 15 (4)Acute myocarditis 4 (1)Hypertrophic cardiomyopathy 4 (1)Ventricular fibrillation 4 (1)Tako-Tsubo cardiomyopathy 3 (0.9)Aortic stenosis 2 (0.6)Atrial fibrillation 2 (0.6)Mitral regurgitation 2 (0.6)Mitral stenosis 2 (0.6)Pericardial tamponade 2 (0.6)Ventricular tachycardia 2 (0.6)Complete heart block 1 (0.3)Supraventricular tachycardia 1 (0.3)

American Heart Journal

Volume 153, Number 3Mendoza et al 367

58 o

obtained during the index admission, or from left ventricular

angiography (when available) if echocardiography was

not performed.

For each patient, the first set of hemodynamic measure-

ments obtained in the CCU was used for analysis. Measure-

ments included those made while receiving support with

inotropes and/or an intra-aortic balloon pump. Cardiac output

was measured by the thermodilution method, taking the

average of 3 to 5 readings. Mean arterial pressure was

determined by invasive arterial monitoring if available; other-

wise, automated sphygmomanometry was used. Cardiac

power output was calculated as MAP � CO H 451.4

Treatment decisions were made without specific regard to

CPO measurements.

Statistical considerationsPreviously, the SHOCK investigators determined that the

cutoff value of CPO that most accurately predicted inhospital

mortality in their patient cohort was 0.53 W.4 Accordingly, we

analyzed CPO both as a dichotomous variable (N0.53 W vs

V0.53 W) and as a continuous variable (per 0.2-W increments).

Baseline variables were compared using standard statistical

tests. The relationship between baseline variables and inhos-

pital mortality was assessed with univariate logistic regression

analysis. Multivariate logistic regression analysis was performed

to examine the independent relationship between CPO (as a

continuous variable) and inhospital mortality. A comprehen-

sive logistic regression model was constructed including the

following covariates: age, sex, race (white or nonwhite),

treated diabetes mellitus, current or recent smoking, chronic

renal failure requiring dialysis, prior coronary artery bypass

grafting, intra-aortic balloon counterpulsation, mechanical

ventilation, inotrope use, persistent cardiogenic shock, EF,

heart rate, central venous pressure, pulmonary capillary wedge

pressure, systemic vascular resistance, and CPO. A reduced

model was then created that included only those covariates

significantly associated with inhospital mortality. Cardiac

output was subsequently forced into this reduced model. A

2-sided P value less than .05 was considered to represent

statistical significance.

ResultsBaseline characteristics

Complete data were available for 349 patients. The

primary admission diagnoses are listed in Table I. The

most common diagnoses were acute myocardial infarc-

tion, cardiomyopathy, coronary atherosclerosis, and

unstable angina. Baseline patient characteristics and

hemodynamics are presented in Table II. The mean age

was 64 years, 59% were men, and 39% were of nonwhite

race. Patients had severe illness, as evidenced by the fact

that 50% required an intra-aortic balloon pump, 51%

required mechanical ventilation, and 55% required

intravenous inotropic support.

The CPO ranged from 0.17 to 2.48 W, with a mean of

0.88 F 0.37 W. Compared with patients with a CPO

N0.53 W (n = 296), patients with a CPO V0.53 W (n = 53)

were older (69 vs 63 years, P = .004) and more likely to

f 158.

be women (64% vs 34%, P b .001). As expected, those

with CPO V0.53 W had a lower MAP, CO, and cardiac

index, and a higher systemic vascular resistance (all

P b .001). Of note, the EF was similar among patients

with CPO N0.53 W and patients with CPO V0.53 W (31%

vs 28%, P = not significant).

OutcomesPatients with a CPO V0.53 W had a significantly higher

inhospital mortality rate than those with a CPO N0.53 W

(49% vs 20%, P b .001), corresponding to a positive

predictive value of 49% and a negative predictive value

of 80%. On univariate analysis, predictors of mortality

were age, diabetes mellitus, need for mechanical

ventilation, persistent cardiogenic shock, MAP, CO,

cardiac index, heart rate, central venous pressure, and

CPO (Table III). In the final reduced multivariate model,

CPO remained independently associated with a reduced

risk of inhospital mortality (odds ratio [OR] 0.65, 95% CI

0.54-0.78, P b .001) (Table IV). Other independent

predictors were heart rate ( P = .01), diabetes mellitus

( P = .02), and the need for mechanical ventilation

( P b .001). When CO was forced into this model, the

relationship between CPO and inhospital mortality was

not substantially altered (OR 0.63, 95% CI 0.43-0.91,

P = .01), whereas there was no significant relationship

between CO and mortality (OR 1.05, 95% CI 0.75-1.48,

P = .78).

Cardiogenic shockPersistent cardiogenic shock was diagnosed in

73 patients (21%). Mortality in patients with persistent

Table II. Baseline characteristics and initial hemodynamic measurements

Characteristic All patients (N = 349) CPO >0.53 (n = 296) CPO <_0.53 (n = 53) P

Age (y) 64 F 14 63 F 14 69 F 11 .004Male, n (%) 206 (59) 188 (64) 18 (34) b.001Nonwhite race, n (%) 135 (39) 113 (38) 22 (42) .65History of

Coronary artery bypass grafting, n (%) 61 (18) 51 (17) 10 (19) .77Percutaneous coronary intervention, n (%) 46 (13) 37 (13) 9 (17) .37Diabetes mellitus, n (%) 79 (23) 67 (23) 12 (23) 1.0Smoking, n (%) 27 (8) 25 (8) 2 (4) .40Chronic renal failure, n (%) 14 (4) 13 (4) 1 (2) .70

Intra-aortic balloon pump, n (%) 175 (50) 155 (52) 20 (38) .05Mechanical ventilation, n (%) 177 (51) 147 (50) 30 (57) .35Acute myocardial infarction, n (%) 201 (58) 175 (59) 26 (49) .17Persistent cardiogenic shock, n (%) 73 (21) 60 (20) 13 (25) .48Mean arterial pressure (mm Hg) 80 F 13 82 F 13 70 F 11 b.001Cardiac output (L/min) 4.9 F 1.8 5.2 F 1.7 2.8 F 0.7 b.001Cardiac index (L min�1 m�2) 2.5 F 0.8 2.6 F 0.8 1.6 F 0.4 b.001Systemic vascular resistance (dyne s/cm5) 1297 F 597 1207 F 535 1824 F 668 b.001Heart rate (beats/min) 88 F 19 90 F 18 86 F 19 .23Pulmonary capillary wedge pressure (mm Hg) 20 F 7 19 F 7 21 F 7 .15Central venous pressure (mm Hg) 13 F 7 12 F 5 15 F 12 .12Any inotrope, n (%) 193 (55) 161 (54) 32 (60) .42Ejection fraction (%) 30 F 13 31 F 13 28 F 12 .14

Table III. Univariate logistic regression results for inhospitalmortality

Variable OR (95% CI) P

Age 1.02 (1.00-1.04) .03Male sex 0.75 (0.46-1.22) .24Nonwhite race 0.74 (0.44-1.24) .25Prior coronary artery bypass grafting 1.15 (0.61-2.16) .66Prior percutaneous coronary intervention 1.13 (0.56-2.30) .73Diabetes mellitus 1.94 (1.12-3.36) .02Smoker 0.37 (0.11-1.27) .11Chronic renal failure 0.89 (0.23-3.14) .81Acute myocardial infarction 1.04 (0.63-1.71) .88Intra-aortic balloon pump 1.12 (0.69-1.84) .64Mechanical ventilation 4.30 (2.46-7.52) b.001Persistent cardiogenic shock 2.26 (1.29-3.94) .004Any inotrope 1.18 (0.72-1.93) .52MAP 0.96 (0.93-0.98) b.001CO 0.74 (0.63-0.88) b.001Cardiac index 0.47 (0.32-0.68) b.001Systemic vascular resistance 1.00 (1.00-1.00) .44Heart rate 1.01 (1.00-1.03) .03Pulmonary capillary wedge pressure 1.01 (0.98-1.05) .45Central venous pressure 1.05 (1.01-1.10) .01EF 1.00 (0.98-1.02) .98CPO 0.66 (0.55-0.79) b.001

Table IV. Multivariate logistic regression analysis forinhospital mortality

Variable OR (95% CI) P

CPO 0.65 (0.54-0.78) b.001Heart rate 1.02 (1.01-1.04) .01Diabetes mellitus 2.10 (1.13-3.89) .02Mechanical ventilation 3.76 (2.08-6.82) b.001


March 2007368 Mendoza et al

5

cardiogenic shock was higher than mortality among

patients without this condition (37% vs 21%, P b .001).

After excluding patients with persistent cardiogenic

shock, CPO remained independently associated with

inhospital mortality (OR 0.64, 95% CI 0.50 to 0.81,

P b .001).

9 of 158.

DiscussionTo our knowledge, the current study is the largest

reported analysis of CPO in a broad spectrum of

patients with critical cardiac illness undergoing PAC.

The major findings were the following: (1) inhospital

mortality was substantially higher in patients with a low

initial CPO, (2) CPO was independently associated with

inhospital mortality after controlling for important

covariates, and (3) the association between CPO and

inhospital mortality was stronger than that of the more

traditional CO.

Our findings suggest that measurement of CPO is

useful for risk stratification in patients with primary

cardiac disease undergoing PAC in the CCU setting.

CPO represents the rate of energy input that the

systemic vasculature receives from the heart, incorpo-

rating both pressure and flow domains of the cardio-

vascular system.4 It is therefore logical that such a

measure of cardiac pumping ability would predict

outcomes for patients with cardiogenic shock and

severe HF, as has been demonstrated previously.4,6-8


Volume 153, Number 3Mendoza et al 369

60 o

Our analysis extends these findings to a broader

spectrum of patients with critical cardiac illness,

including those with acute coronary syndromes, car-

diomyopathies of various etiologies, valvular heart

disease, cardiac arrhythmias, and complicated post–

percutaneous coronary intervention courses.

As expected, patients in our analysis had CPO values

considerably higher (mean 0.88 W) than those in a

more select group with acute myocardial infarction and

cardiogenic shock in the SHOCK trial registry (mean

0.62 W). Despite the substantial differences in patient

populations and absolute CPO values, however, the

relationship between CPO and inhospital mortality was

remarkably similar in the 2 analyses: an OR of 0.65 per

0.2-W increase in CPO in the current study compared

with an OR of 0.60 in the SHOCK trial registry.4

Furthermore, among the subset of our patients diag-

nosed with persistent cardiogenic shock (n = 73), the

positive and negative predictive values using a cutoff of

0.53 W were nearly identical in the 2 studies (62% vs

58% and 68% vs 71%, respectively). This concordance

of results suggests both that the relationship between

CPO and short-term mortality is consistent across a

broad spectrum of cardiac diagnoses and a wide range

of CPO values, and is reproducible across studies.

Cardiac power output is calculated from the more

familiar hemodynamic variables, CO and MAP. There-

fore, from a statistical standpoint, it cannot provide

additional prognostic information beyond that contained

within the 2 individual components. However, CPO

combines information from these 2 separate hemody-

namic axes (flow and pressure) into a single, easily

understandable variable that can potentially be targeted

for therapy. For this reason, the concept of CPO appears

to provide clinically useful information above and

beyond that provided by standard hemodynamic varia-

bles alone.

Recent studies have questioned the use of PAC in

guiding treatment in critically ill patients, including

patients with severe CHF.3,9-13 Possible explanations for

these negative results include complications related to

the PAC procedure itself (arrhythmias, infection);

misinterpretation of the obtained data; incorrect action

in response to even appropriately interpreted data; or

unanticipated deleterious effects of treatments imple-

mented in response to these data. In patients with

cardiac disease, treatments are typically targeted to the

CO (or cardiac index) and pulmonary capillary wedge

pressure. However, CO is a measure of cardiovascular

flow, not cardiac contractility, whereas pulmonary

capillary wedge pressure is a measure of intracardiac

pressure not directly representing cardiac perfor-

mance.1 Theoretically, therefore, CPO—a measure of

cardiac pumping ability—might be a more appropriate

target for medical therapy. In addition, CPO can be

simply and accurately determined noninvasively in most

f 158.

patients by using whole-body electrical bioimpedance

to determine CO, thereby eliminating any direct

complications of PAC.14,15 Clinical studies in which

noninvasively determined CPO is targeted for treatment

appear to be indicated.

Our study has several potential limitations. First, this

was a single-center retrospective analysis, subject to the

limitations inherent in such a study design. However,

measurements of CPO were not used by the CCU

physicians to make therapeutic decisions. Hence, we

are confident that the observed prognostic value of

CPO was not influenced by bias introduced from

knowledge of this information. Second, although we

attempted to control for important differences in

baseline characteristics between patients, residual con-

founding might remain. Third, we were unable to

distinguish between hemodynamic measurements made

with and without support from inotropes and/or an

intra-aortic balloon pump. Because both types of

interventions are likely to increase CPO, this might

affect the relationship between CPO and mortality.

However, this relationship was maintained after in-

cluding the use of these interventions in the multivar-

iate model. Indeed, the relationship between CPO and

mortality might be stronger in the absence of such

support measures. Finally, we must emphasize that our

findings demonstrate an association between CPO and

outcome without providing a direct assessment of

whether CPO should be used as a clinical end point for

therapeutic interventions.

ConclusionsCardiac power output is a novel and useful

prognostic tool in patients with acute cardiac disease

undergoing PAC in the CCU setting. Further studies

in which CPO is targeted for treatment appear to

be warranted.

References1. Connors Jr AF, Speroff T, Dawson NV, et al. The effectiveness of

right heart catheterization in the initial care of critically ill patients.SUPPORT Investigators. JAMA 1996;276:889 -97.

2. Dalen JE, Bone RC. Is it time to pull the pulmonary artery catheter?JAMA 1996;276:916-8.

3. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study ofcongestive heart failure and pulmonary artery catheterizationeffectiveness: the ESCAPE trial. JAMA 132005;294:1625 -33.

4. Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is thestrongest hemodynamic correlate of mortality in cardiogenic shock:a report from the SHOCK trial registry. J Am Coll Cardiol2004;44:340 -8.

5. Cotter G, Williams SG, Vered Z, et al. Role of cardiac power inheart failure. Curr Opin Cardiol 2003;18:215 -22.

6. Williams SG, Cooke GA, Wright DJ, et al. Peak exercise cardiacpower output; a direct indicator of cardiac function strongly


March 2007370 Mendoza et al

6

predictive of prognosis in chronic heart failure. Eur Heart J2001;22:1496-503.

7. Tan LB, Littler WA. Measurement of cardiac reserve in cardiogenicshock: implications for prognosis and management. Br Heart J1990;64:121 -8.

8. Tan LB. Cardiac pumping capability and prognosis in heart failure.Lancet 1986;2:1360 -3.

9. Sandham JD, Hull RD, Brant RF, et al. A randomized, controlled trialof the use of pulmonary-artery catheters in high-risk surgicalpatients. N Engl J Med 2003;348:5 -14.

10. Richard C, Warszawski J, Anguel N, et al. Early use of thepulmonary artery catheter and outcomes in patients with shock andacute respiratory distress syndrome: a randomized controlled trial.JAMA 2003;290:2713 -20.

11. Harvey S, Harrison DA, Singer M, et al. Assessment of the clinicaleffectiveness of pulmonary artery catheters in management of

1 of 158.

patients in intensive care (PAC-Man): a randomised controlled trial.Lancet 2005;366:472-7.

12. Rhodes A, Cusack RJ, Newman PJ, et al. Bennett ED. A randomised,controlled trial of the pulmonary artery catheter in critically illpatients. Intensive Care Med 2002;28:256 -64.

13. Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-arteryversus central venous catheter to guide treatment of acute lunginjury. N Engl J Med 2006;354:2213 -24.

14. Cotter G, Moshkovitz Y, Kaluski E, et al. Accurate, noninvasivecontinuous monitoring of cardiac output by whole-body electricalbioimpedance. Chest 2004;125:1431 -40.

15. Leitman M, Sucher E, Kaluski E, et al. Non-invasive measurement ofcardiac output by whole-body bio-impedance during dobutaminestress echocardiography: clinical implications in patients with leftventricular dysfunction and ischaemia. Eur J Heart Fail 2006;8:136 -40.

Circulation Journal Vol.70, September 2006

everal studies suggest the importance of cardiac poweroutput calculation, which is derived from cardiacoutput (CO) and mean blood pressure, to predict the

prognosis in heart failure patients not only in hospital butalso in the outpatient setting.1–3 CO measured by the ther-modilution method with a Swan-Ganz catheter placed inthe pulmonary artery has become one of the most widelyaccepted and used methods of monitor cardiac function,despite its certain limitations.1,3,4 A noninvasive and lowcost method for measuring CO would be relevant for thewidespread clinical use of cardiac power output.

Some noninvasive techniques of measuring CO have beenproposed over the past years. The indirect Fick method ofre-breathing carbon dioxide5,6 and Doppler flow measure-ment of the left ventricular outflow tract have been shownto be accurate;7 however, their applications require expen-sive equipments and trained operators. Other promisingresults have been observed with devices based on electricalbioimpedance technology,8 and 2 basic technologies ofimpedance cardiography (ICG) are currently in use. Thefirst is called whole-body ICG9,10 (ICGWB), which wasintroduced in 1948,11 in which the electrodes are placed onthe distal portion of the limbs. The second one is thoracic

ICG (ICGT), which was introduced in 1964, and the elec-trodes are placed on the root of the neck and on the lowerchest. When the CO is measured in subjects with healthyhearts, the results from both these technologies are usuallyreliable, but the reliability of CO measurements taken byICGT is compromised in patients with cardiac diseases.12–16

According to the Food and Drug Administration (FDA)standard of bio-equivalence,17 the disparity between 2 tech-

Circ J 2006; 70: 1164–1168

(Received March 30, 2006; revised manuscript received June 1,2006; accepted June 21, 2006)Division of Cardiovascular and Respiratory Medicine, Department ofInternal Medicine, Kobe University Graduate School of Medicine,Kobe, JapanMailing address: Junya Shite, MD, Division of Cardiovascular andRespiratory Medicine, Department of Internal Medicine, Kobe Uni-versity Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku,Kobe 650-0017, Japan. E-mail: [email protected]

Impedance Cardiography for Cardiac Output EstimationReliability of Wrist-to-Ankle Electrode Configuratio

Oscar Luis Paredes, MD; Junya Shite, MD; Toshiro Shinke, MD; Satoshi Watanabe, MD; Hiromasa Otake, MD; Daisuke Matsumoto, MD;

Yusuke Imuro, MD; Daisuke Ogasawara, MD; Takahiro Sawada, MD; Mitsuhiro Yokoyama, MD

Background Non-invasive measurement of cardiac output (CO) may become an important modality for thetreatment of heart failure. Among the several methods proposed, impedance cardiography (ICG) has gainedparticular attention. There are 2 basic technologies of ICG: thoracic and whole-body ICG whereby the electrodesare applied either to the chest or to the limbs. The present study is aimed to test the effectiveness of the Non-Invasive Cardiac System (NICaS), a new ICG device working with a wrist-to-ankle configurationMethods and Results To evaluate the reliability of NICaS derived CO (NI-CO), 50 CO measurements weretaken simultaneously with thermodilution (TD-CO) and modified Fick (Fick-CO) in 35 cardiac patients, with theTD-CO serving as the gold-standard for the evaluation. Overall, 2-tailed Pearson’s correlation and Bland-Altmanlimits of agreement between NI-CO and TD-CO were r=0.91 and –1.06 and 0.68L/min and between Fick-COand TD-CO, r=0.80 and –1.52 and 0.88L/min, respectively. Good correlation was observed in patients with load-ing conditions altered by nitroglycerin and also in patients with moderate valvular diseases.Conclusion Agreement between NI-CO and TD-CO is within the boundaries of the FDA guidelines of bio-equivalence. NI-CO is applicable for non-invasive assessment of cardiac function. (Circ J 2006; 70: 1164–1168)Key Words: Cardiac output; Impedance cardiography; Thermodilution method

S

Fig1. Schema of Non-Invasive Cardiac System, showing the imped-ance box, which is connected to the patient via proprietary electrodesand the computer that interprets the collected data. Three electrodesare applied to patient’s chest for the ECG monitor. One pair of imped-ance electrodes is applied to the left wrist and another pair to the rightankle (tetra polar mode).

62 of 158.

1165Wrist-to-Ankle Impedance for CO Measurement


nologies should not exceed the range of 20%. The purposeof this study was to evaluate the reliability and feasibility ofthe new Non-Invasive Cardiac System (NICaS: NI Medical,Hod-Hasharon, Israel), which calculates the CO by measur-ing ICG in a tetra polar mode, derived from electrodesplaced on one wrist and the contra-lateral ankle (Fig1).

MethodsThe Trial

This study prospectively enrolled 35 patients. The ther-modilution-derived CO (TD-CO) was measured using aSwan-Ganz catheter (Baxter Healthcare, Irvine, CA, USA),followed immediately by the modified Fick (Fick-CO) andwith the NICaS (NI-CO). In 15 subjects, a second round ofCO measurements was carried out using the 3 technologiesafter 2–4mg nitroglycerin injection into the arteries. Thus,a total of 50 comparative CO measurements were per-formed. The Institutional Ethics Committee of the KobeUniversity Hospital approved the study protocol and allpatients gave their consent.

Patient Selection and Exclusion CriteriaAll cardiac disease patients who were scheduled for

routine right heart catheterization or emergency proceduresthat required the deployment of a Swan Ganz catheter forcontinuous cardiac function monitoring were eligible forthe study, unless they fulfilled one of the exclusion criteria

The exclusion criteria for the NI-CO measurements in-cluded: restlessness and/or chaotic patient condition, severeaortic valve regurgitation and/or aortic stenosis, aorticaneurysm, heart rate above 130beats/min, intra- and extra-cardiac shunts, severe peripheral vascular disease, severepitting edema, sepsis and dialysis, all of which interferewith the proper measurements of impedance derived strokevolume.4

The study population comprised 35 patients (17 men, 18women, mean age 65.5±13.7 years). In most patients therewas coexistence of multiple underlying heart diseases,including hypertension (n=15), diabetes mellitus (n=13),coronary artery disease (n=21) and idiopathic dilated car-diomyopathy (n=3). Twelve patients presented with conges-tive heart failure (CHF) and 4 patients had atrial fibrillatiowhen CO was measured. In addition, our study subjectsincluded 7 cases of moderate degree of valve regurgitation(aortic regurgitation 2 cases, mitral regurgitation 4 cases,mild tricuspid regurgitation 1 case) and 7 cases of moderate

aortic valve stenosis.

Measuring COAll operators were unaware of the CO results obtained

by the various measuring techniques.TD-CO Right heart catheterization using a 6 or 8Fr

Swan-Ganz catheter was performed according to the stan-dard institutional protocol. The catheter was advanced tothe pulmonary artery under fluoroscopic guidance and veri-fied with the pressure waveforms registered on the poly-graph. TD-CO was measured 5 times by injecting 5 mlbolus of iced 9% saline solution at the same rate. There-after, the 3 results of the saline injections that were within15% of their extreme disparity were averaged for the TD-CO result.

Fick-CO For arterial oxygen saturation, blood sampleswere obtained from the arterial access sheath, and forvenous oxygen saturation, blood samples were withdrawnusing the distal edge lumen of the Swan-Ganz catheterplaced in the pulmonary artery. All samples were immedi-ately measured for oxygen saturation using the same device(Radiometer ABL 715, Copenhagen, Denmark).

NI-CO To measure the CO with the NICaS apparatus,an alternating electrical current of 1.4mA with a 30kHzfrequency is passed through the patient via 2 pairs oftetrapolar electrodes, one pair placed on the wrist above theradial pulse, and the other pair on the contralateral ankleabove the posterior tibialis arterial pulse. If the arterialpulses in the legs are either absent or of poor quality, thesecond pair of electrodes is placed on the contralateralwrist. The NICaS apparatus calculates the stroke volumeby Frinerman’s formula:18

Stroke volume=dR/R ×ρ× L2/Ri × (α+β)/β× KW×HFwhere dR is the impedance change, R is the basal resis-tance,ρis the blood electrical resistivity, L is the patient’sheight, Ri is the corrected basal resistance according togender and age,18–23 KW is a correction of weight accordingto ideal values,19–24 HF is the hydration factor, which takesinto account the body water composition,21 andα+β isequal to the ECG R–R wave interval, andβis the diastolictime interval.

Because the NI-CO results are calculated every 20s, theaverage of 3 measurements obtained consecutively during60s of monitoring was considered to be the NI-CO valuefor each individual case.

Table 1 Statistical Analysis of CO Measurements Performed by NI-CO and Indirect Fick-CO Compared With TD-CO

All measurements in 35 patients Measurements after NTG injection(n=50) (n=15)

NI-CO Fick-COTD- NI- Fick-

NI-CO Fick-COTD- NI- Fick-

vs vs vs vsTD-CO TD-CO

CO CO COTD-CO TD-CO

CO CO CO

Correlation 0.911a 0.801b 0.962a 0.822b

Bias (L/min) –0.18 –0.32 –0.15 –0.34 SD (L/min) 0.43 0.60 0.50 0.69Lower level of agreement (L/min) –1.06 –1.52 –1.16 –1.73 Upper level of agreement (L/min) 0.68 0.88 0.85 1.04Average CO ± SD (L/min) 4.18±1.01 4.36±1.03 4.05±0.89 3.59±0.76 3.85±0.85 3.67±0.79

Values are mean ± SD. Correlation was calculated using Pearson’s 2-tailed test.1ap<0.0001, 1bp<0.0001, 2ap<0.0001, 2bp=0.0001.CO, cardiac output; NI-CO, Non-Invasive Cardiac System derived CO; Fick-CO, modified Fick derived CO; TD-CO, thermodilution-derived CO; NTG, nitro-glycerine.

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Statistical AnalysisThe quantitative data are expressed as mean± SD. For de-

scriptive statistic, Student’s t-test was used. To compare theresults of NI-CO, Fick-CO and TD-CO, 2-tailed Pearson’scorrelation and the Bland-Altman25 limits of agreementwere used. The gold-standard for determining accuracy ofthe results was the TD-CO. Values of p<0.05 were consid-

ered to be significant

ResultsThe average values of CO in the study subjects for TD-

CO, NI-CO and Fick-CO were 4.18±1.01 L/min, 4.36±1.03L/min, and 4.05±0.89 L/min, respectively. There were

Fig3. [A] Bland-Altman scatter plot of difference against average of cardiac output (CO) results measured by Non-Invasive Cardiac System (NICaS) and thermodilution method. [B] Bland-Altman scatter plot of difference againstaverage of CO results measured by the modified Fick and thermodilution methods. NI-CO, NICaS derived CO; TD-CO,thermodilution-derived CO; Fick-CO, modified Fick derived CO

Fig2. Scatter plots of cardiac output (CO) showing the correlation between Non-Invasive Cardiac System (NICaS)derived CO (NI-CO) with thermodilution-derived CO (TD-CO) [A]; modified Fick derived CO (Fick-CO) with TD-CO[B] and NI-CO with Fick-CO [C]. The 2-tailed Pearson’s correlation test (r) was used for the analyses.

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no significant differences between the 3 groups (Table1).The overall results of the Pearson correlation analysis wereas follows: NI-CO vs TD-CO: r=0.91, p<0.0001; Fick-COvs TD-CO: r=0.80, p<0.0001 and NI-CO vs Fick-CO: r=0.85, p<0.0001 (Fig2). The Bland-Altman 2-standard devia-tion limit of agreement between the NI-CO and TD-COwas ±0.87 (–1.06 and 0.68) L/min, and the agreementbetween the Fick-CO and TD-CO was ±1.20 (–1.52 and0.88)L/min (Fig3). The calculated percentage of disparitybetween the NI-CO and TD-CO would thus be 19.95%(0.87L/min÷ 4.36L/min), which was less than that betweenFick-CO and TD-CO (29.63% [1.20L/min÷ 4.05L/min]).Nevertheless, there are 3 cases in this series in which thedisparity between the NI-CO and TD-CO was greater than20%, indicating that the disparity here is not equal, butclose to FDA bio-equivalence (Note that the mathematicalmodel of the FDA for determining bio-equivalence was notused here. Yet the simple model of limits of agreement,which was used, offers an acceptable appraisal of the goodinterrelationships between the 2 statistical approaches).

When we analyzed the subgroup of measurements be-fore and after nitroglycerine injection to alter vascular re-sistance, identical changes in CO were observed with theNI-CO and TD-CO (TD-CO: 4.42±1.00 L/min→ 3.59±0.76 L/min, NI-CO: 4.07±1.07 L/min→ 3.85±0.85 L/min(Fig 4)). The relation between NI-CO and TD-CO afternitroglycerine injection was r=0.96, p<0.0001, n=15. Allother statistical details are summarized in Table 1.

In the other subgroups of moderate degree of valvularregurgitation (n=7) and aortic valve stenosis (n=7), thecorrelation of NI-CO with TD-CO was r=0.92, p<0.0001,with a lower limit of agreement of –0.97L/min and upperlimit of agreement of 0.73L/min.

DiscussionAccording to Bland and Altman26 and Raaijmakers et

al,15 when averages of repeated measurement results areused to compare the performance of a new medical devicewith a gold-standard, there is an overestimation of the cor-relation coefficient. In the present investigation the prefera-ble single measurement design was used; namely, each testconsisted of a TD-CO measurement, followed immediatelyby a NI-CO and a Fick-CO measurement. In 20 patients,only 1 study was performed, whereas in the remaining 15patients 2 studies were done: before and after nitroglycer-ine injection. However, each of the second tests was con-ducted in the manner of an independent comparativemeasurement.

According to the definition of the FDA, if there is bio-equivalence between the gold-standard and a new technol-

ogy, all the comparative results should be within a range of20% disparity. Previous studies reported limits of agree-ment between ICGT-CO vs TD-CO of –2.2 to 2.2L/min atbest,27–29 ICGWB-CO (JR Medical-Tallinn, Estonia) vs TD-CO of –1.37 to 1.87L/min,10 and bipolar NI-CO vs TD-COof –1.25 to 1.30L/min (Table2).4 Based on these reports, it can be calculated that the disparity between ICGT-CO,ICGWB-CO, bipolar NI-CO vs TD-CO is 40%, 32.4% and26%, respectively. Our result for tetra polar NI-CO vs TD-CO (–1.06 to 0.68 L/min, disparity 20%) is better thanthose results. The reason for the better result with NICaSmay be related to the most upgraded calculation formula.

An important fringe benefit of this trial is the data pro-duced by the Fick-CO technology. This method, whichenjoys increasing popularity among practical cardiologists,is still considered controversial.30 According to the presentresults, the limits of agreement between Fick-CO and TD-CO are –1.52 and 0.88L/min (average ±1.20 L/min). In thepresence of a mean Fick-CO of 4.05L/min, the disparitybetween the 2 technologies is 30%, better than that of ICGTbut inferior to that of NI-CO.

Among the established exclusion criteria related to theuse of the NICaS are: severe aortic stenosis, in which theNI-CO is usually underestimated, and significant aortic re-gurgitation, in which the NI-CO tends to be overestimated.In the present trial, however, 7 cases of moderate aorticstenosis and 2 with mild – moderate aortic regurgitationwere involved, indicating that NICaS is applicable in casesof mild to moderate aortic valve disease.

From the 15 measurements that were obtained after nitro-glycerine injection, we observed a decrease in the mean CO

Fig4. Changes in cardiac output in 15 patients with repeated mea-surements, pre and post nitroglycerine (NTG) administration. Thegraph compares the results obtained by Non-Invasive Cardiac Systemderived cardiac output (NI-CO) and thermodilution-derived cardiacoutput (TD-CO). Values are mean ± SD.

Table 2 Summary of Previous Reports of the Accuracy of CO Measurements by ICG (ICGT-CO, ICGWB-CO, and NI-CO vs TD-CO)

Authors Method Condition Year publishedLimits of agreement between

ICG and TD (L/min)

Drazner M, et al27 ICGT CHF 2002 –2.2 to 2.2 Van De Water JM, et al28 ICGT CABG 2003 –2.36 to 1.99Leslie S J, et al29 ICGT CHF 2004 –2.2 to 2.2 Koobi T, et al10 ICGWB CABG 1997 –1.37 to 1.87Cotter G, et al4 ICGNICaS CABG, CHF 2004 1.25 to 1.30

Bipolar

Values are mean. ICG, impedance cardiography; ICGT, thoracic ICG; ICGWB, whole-body ICG; TD, thermodilution; CHF, congestive heart failure; CABG, coronary artery bypass graft; ICGNICaS, Non-Invasive Cardiac System ICG. Other abbreviations as in Table 1.

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levels. However, the accuracy of the results remained un-altered in NI-CO, which suggests that NICaS is also applic-able even when the arterial resistance has changed.

Clinical ImplicationsRecent studies have shown that the calculation of cardiac

power output (CO×mean arterial pressure) and systemicvascular resistance are important for the management ofvarious cardiac diseases.1–3 Cardiac power output was foundto be the strongest independent predictor of in-hospitalmortality in patients admitted with cardiogenic shock2 andis an important tool for assessing the clinical response todrug therapy. In addition, there is enough evidence thatambulatory monitoring of cardiac power would benefit pa-tients with CHF, resulting in better titration of medicationand possibly less readmission to hospital. By introducingNICaS apparatus, wide-spread clinical use of cardiacpower calculation would become feasible.

Conclusion and Limitations of NICaSThe present study indicates that NICaS performs at least

as accurately as the thermodilution method. However, thereliability of the NICaS method depends on an alignmentwith exclusion criteria. This allows for the use of NICaS inapproximately 80–85% of patients needing the examina-tion.

References1. Nohria A, Mielniczuk L, Warner L. Evaluation and monitoring of

patients with acute heart failure syndromes. Am J Cardiol 2005;96(Suppl): 32G–40G.

2. Fincke R, Hochman J, Lowe A, Menon V, Slater JN, Webb JG, et al(for the SHOCK investigators). Cardiac power is the strongest hemo-dynamic correlate of mortality in cardiogenic shock: A report fromthe SHOCK trial registry. J Am Coll Cardiol 2004; 40: 340–348.

3. Cotter G, Moshkovitz Y, Kaluski E, Milo O, Nobikov Y, SchneeweissA, et al. The role of cardiac power and systemic vascular resistancein the pathophysiology and diagnosis of patients with acute conges-tive heart failure. Eur J Heart Fail 2003; 5: 443–451.

4. Cotter G, Moshkovitz Y, Kaluski E, Kohen A, Miller H, Goor D, etal. Accurate, noninvasive continuous monitoring of cardiac output bywhole-body electrical bioimpedance. Chest 2004; 125: 1431–1440.

5. Haryadi DG, Orr JA, Kuck K, Mc James S, Westenskow DR. PartialCO2 rebreathing indirect Fick technique for non-invasive measure-ment of cardiac output. J Clin Monit Comput 2000; 16: 361–374.

6. Jover JL, SoroM, Belda FJ, Aguilar G, Caro P, Ferrandis R. Measure-ment of cardiac output after cardiac surgery: Validation of a partialcarbon dioxide rebreathing (NICO) system in comparison with con-tinuous thermodilution with a pulmonary artery catheter. Rev EspAnestesiol Reanim 2005; 52: 256–262 (in Spanish).

7. Turner MA. Doppler-based hemodynamic monitoring: A minimallyinvasive alternative. AACN Clin Issues 2003; 14: 220–231.

8. Moshkovitz Y, Kaluski E, Milo O, Vered Z, Cotter G. Recent devel-opments in cardiac output determination by bioimpedance: Compari-son with invasive cardiac output and potential cardiovascular applica-tions. Curr Opin Cardiol 2004; 19: 229–237.

9. Tischenko MI. Estimation of stroke volume by integral rheogram ofthe human body. Sechenov Phisiological J 1973; 59: 1216–1224 (inRussian).

10. Koobi T, Kaukinen S, Turjanmaa VM. Cardiac output can be reliablymeasured noninvasively after coronary artery bypass grafting opera-tion. Crit Care Med 1999; 27: 2206–2211.

11. Kedrov AA. An attempt to quantify assessment of the central andperipheral circulation by electrometrical method. Klin Med 1948; 26:32–51 (in Russian).

12. Patterson RP, Kubicek WG, Kinnen E, Witsoe DA, Noren G. Devel-opment of an electrical impedance plethysmography system to moni-tor cardiac output. Proceedings of the 1st Annual Rocky MountainsBioengineering Symposium 1964; 56–71.

13. Kubicek WG, Karnegis JN, Patterson RP, Witsoe DA, Mattson RH.Development and evaluation of an impedance cardiac output system.Aerosp Med 1966; 37: 1208–1212.

14. Kubicek WG, Kottke FJ, Ramos MU, Patterson RP, Witsol DA,Labree JW, et al. The Minnesota impedance cardiograph: Theory andapplications. Biomed Eng 1974; 9: 410–416.

15. Raaijmakers E, Faes ThJC, Scholten RJPM, Goovaerts HG, HeethaarR. A meta-analysis of published studies concerning the validity ofthoracic impedance cardiography. Ann NY Acad Sci 1999; 873: 121–134.

16. Handelsman H. Public health service reassessment: Measuring car-diac output by electrical bioimpedance. Health Technology Assess-ment Reports, US Dept Health and Human Services, Public Agencyfor Health Care Policy and Research 1991; 6: 1–13.

17. Guidance for Industry. Statistical approach to establishing bioequiv-alence: US department of health and human services. Food and DrugAdministration, Center For Drug Evaluation and Research (CDER)January 2001, BP.

18. Cohen AJ, Arnaudov D, Zabeeda D, Shultheis L, Lashinger J,Schachner A. Non-invasive measurement of cardiac output duringcoronary artery bypass grafting. Eur J Surg 1998; 14: 64–69.

19. Organ LW, Bradham GB, Gore DT, Lozier SL. Segmental bioelectri-cal impedance analysis: Theory and application of a new technique. JAppl Physiol 1994; 77: 98–112.

20. Lukaski H, Bolonchuk WW, Hall CB, Siders WA. Validation of tet-rapolar bioelectrical impedance method to assess human bodycomposition. J Appl Physiol 1986; 60: 1327–1332.

21. Hoffer EC, Meador CK, Simpson DC. A relationship between wholebody impedance and total body water volume. Ann NY Acad Sci1970; 170: 452–461.

22. Lamberts R, Visser KR, Zijlstra WG. Impedance cardiography.Assen, The Netherlands; Van Gorkum 1984; 21–94.

23. Ward LC, Heitmann BL, Craid P, Stroud D, Azinge EC, Jebb S, et al.Association between ethnicity, body mass index, and bioelectricalimpedance: Implications for the population specificity of predictionequations. Ann NY Acad Sci 2000; 904: 199–204.

24. Hamwi GT, Danowski TS. Changing dietary concepts in diabetesmellitus: Diagnosis and treatment. New York: American DiabetesAssociation 1964; 73–78.

25. Bland JM, Altman DG. Statistical methods for assessing agreementbetween two methods of clinical measurement. Lancet 1986; I: 307–310.

26. Bland JM, Altman DG. Correlation, regression and repeated data.BMJ 1994; 308: 896.

27. Drazner M, Thompson B, Rosenberg P, Kaiser PA, James MSN,Boehrer D, et al. Comparison of impedance cardiography with inva-sive hemodynamic measurements in patients with heart failure sec-ondary to ischemic or nonischemic cardiomyopathy. Am J Cardiol2002; 89: 993–995.

28. Van De Water JM, Miller TW, Vogel RL, Mount BE, Dalton ML.Impedance cardiography: The next vital sign technology? Chest2003; 123: 2028–2033.

29. Leslie S J, McKee S, Newby DE, Webb DJ, Denvir MA. Non-inva-sive measurement of cardiac output in patients with chronic heartfailure. Blood Press Monit 2004; 9: 277–280.

30. Dhingra VK, Fenwick JC, Walley KR, Chittock D, Ronco JJ. Lackof agreement between thermodilution and Fick cardiac output in criti-cally ill patients. Chest 2002; 122: 990–997.

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INSTITUTE OF PHYSICS PUBLISHING PHYSIOLOGICAL MEASUREMENT

Physiol. Meas. 27 (2006) 817–827 doi:10.1088/0967-3334/27/9/005

Impedance cardiography revisited

G Cotter1, A Schachner2, L Sasson2, H Dekel2 and Y Moshkovitz3

1 Divisions of Clinical Pharmacology and Cardiology, Duke University Medical Center, Durham,NC, USA2 Angela & Sami Sharnoon Cardiothoracic Surgery Department, Wolfson Medical Center, Israel3 Department of Cardiac Surgery, Assuta Hospital, Petah Tikva, Israel

E-mail: [email protected]

Received 7 February 2006, accepted for publication 9 June 2006Published 5 July 2006Online at stacks.iop.org/PM/27/817

AbstractPreviously reported comparisons between cardiac output (CO) results inpatients with cardiac conditions measured by thoracic impedance cardiography(TIC) versus thermodilution (TD) reveal upper and lower limits of agreementwith two standard deviations (2SD) of approximately ±2.2 l min−1, a 44%disparity between the two technologies. We show here that if the electrodesare placed on one wrist and on a contralateral ankle instead of on the chest, aconfiguratio designated as regional impedance cardiography (RIC), the 2SDlimit of agreement between RIC and TD is ±1.0 l min−1, approximately20% disparity between the two methods. To compare the performances ofthe TIC and RIC algorithms, the raw data of peripheral impedance changesyielded by RIC in 43 cardiac patients were used here for software processingand calculating the CO with the TIC algorithm. The 2SD between the TICand TD was ±1.7 l min−1, and after annexing the correcting factors of theRIC formula to the TIC formula, the disparity between TIC and TD furtherdeclined to ±1.25 l min−1. Conclusions: (1) in cardiac conditions, the RICtechnology is twice as accurate as TIC; (2) the advantage of RIC is the useof peripheral rather than thoracic impedance signals, supported by correctingfactors.

Keywords: cardiac output measurements, thoracic bioimpedance, whole-bodybioimpedance, impedance cardiography

Introduction

Three basic technologies are currently in use for impedance cardiography (ICG): (1) thethoracic ICG (TIC), where the electrodes are placed on the root of the neck and the lowerpart of the chest, being the dominant method in the market (Patterson et al 1964, Kubicek

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818 G Cotter et al

et al 1966, 1974); (2) the whole-body ICG (ICGWB), where four pairs of electrodes are used,one pair on each limb (Tischenko 1973, Koobi et al 1999); (3) the regional ICG (RIC), atechnology which is used by the NICaS (noninvasive cardiac system). In this technology,which is the subject of this report, only two pairs of electrodes are used, performing bestwhen placed on one wrist and on the contralateral ankle (Cohen et al 1998, Cotter et al 2004,Torre-Amione et al 2004).

Two comprehensive reviews of the literature on clinical experience in measuring thecardiac output (CO) by TIC determined that in patients with cardiac conditions the TIC-COresults are unreliable (Raaijmakers et al 1999, Handelsman 1991). According to Patterson(1985) and Wang et al (2001), a number of sources in the chest, such as the lungs, vena cava, andsystemic and pulmonary arterial vasculatures, generate systolic impedance reductions, whilethe heart generates signals of increased impedance. In addition to these multifarious sources of�Z,4 variations in the electrical conductivities between the sources of impedance changes andthe TIC electrodes (Kim et al 1988, Kauppinen et al 1998), and between the various impedancesources (Wtorek 2000) have been described. These model experimentations indicated thatthe thoracic �Z is not a reliable signal for calculation of the SV due to the multiple sourcesof dZ/dt (Kim et al 1988, Wang and Patterson 1995, Kauppinen et al 1998, Wtorek 2000),providing the explanations for the above-mentioned unsatisfactory clinical results obtained byTIC (Raaijmakers et al 1999, Handelsman 1991).

In this report, an attempt is made to defin the differences between the peripheral andthoracic impedance signals, and based on this, to explain the differences in the performanceof RIC and TIC.

As we are capable of saving raw data from the wrist–ankle (peripheral) impedancesignals, we were able to use the peripheral impedance waveforms and base impedance valuesto calculate stroke volumes, using various algorithms that have been associated with TICcalculations. This enabled us to prove that (1) the performance of RIC is twice as accurateas reported TIC results; (2) the reasons for this are as follows: (a) the impedance changeswhich are yielded by the limb electrodes are more suitable than the impedance changes ofthe thoracic electrodes for calculating the stroke volume and (b) the use of properly designedcoefficient improved the accuracy of the CO results by at least an additional 25%.

Methods

The data for this project were gathered from two patient series. In both, comparisons were madebetween cardiac output results measured by the NICaS versus thermodilution. One series,which was studied in hospital A, consisted of 30 patients who were studied immediately uponarrival at the ICU following an open heart operation. In 11 (36%), despite the intravenousadministration of adrenalin, cardiac index (CI) was lower than 2.5 l min−1 m−2. The secondseries included 13 cases of acute heart failure that were studied in hospital B. CI was lowerthan 2.5 l min−1 m−2 in seven (54%), and in the combined group of 43 cases of the twohospitals, it was lower than 2.5 l min−1 m−2 in 18 (43%).

The purpose of this study was to use peripheral impedance waveforms to calculate strokevolume by means of four different ICG algorithms and to compare each of these SV valueswith the thermodilution SV result.

Of the 55 and 31 studies conducted in hospitals A and B, respectively, raw data weresuccessfully retrieved from only the last 30 consecutive patients of hospital A and the last 13

4 In the ICGWB and RIC, where the impedance changes are depicted in the periphery, the impedance value isautomatically converted into the real parts (R0 and �R) of the measured impedance signals (Lamberts et al 1984).

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Impedance cardiography revisited 819

α

α+β

ECG

∆R

Figure 1. Unedited print of the ECG and �R waveforms to demonstrate the definition of α

and β.

consecutive cases of hospital B. It quickly became apparent that these 43 source data wereretrieved from only one of the two NICaS devices that were being used in the two hospitals. Thereason for this was that we did not realize that the software designed for source data retrievalwas not implemented in one of the two NICaS devices that were used interchangeably duringthese trials.

Measuring the CO

Thermodilution. The standard techniques for measuring the thermodilution CO (TDCO)used in these two hospitals have been reported elsewhere (Cotter et al 2004).

RIC (NICaS). To measure the CO with the NICaS (NICO), which is a tetrapolar device, twoelectrodes are placed on a wrist above the radial pulse and two on the contralateral ankle abovethe posterior tibialis arterial pulse. If the arterial pulses in the legs are either absent or of poorquality, the second pair of electrodes is placed on the contralateral wrist. The NICaS devicecalculates the SV by means of the following Frinerman formula5 (Cohen et al 1998):

SV = �RρL2(α + β)Kw × HFRRiβ

, (2)

where SV is the cardiac stroke volume (ml), �R is the resistance change during the cardiaccycle (�), R is the basal resistance (�), Ri is a corrected basal R (�), ρ is the blood electricalresistivity (� cm), L is the patient’s height (cm), Kw is a correcting factor for the body weight,HF is the hydration factor related to the body water composition and (α + β)/β is the ratioof the systolic time plus the diastolic time divided by the diastolic time of the �R waveform(figur 1).

5 The present formula is principally the same as the formula in Cohen et al (1998), but is written differently. Theoriginal formula was

SV = Hctcorr

Ksex× Kel × Kweight × IB × H 2

corr�R

R× (α + β)

β. (1)

The values of the hematocrit (Hct) and Na( (el) are now represented by ρ, which is the electrical resistivity of the blood.Ksex age, which affects the basal resistance (R), is now represented by Ri, and IB (index body) is now represented byHF (hydration factor). The correction of H 2 is no longer included in the formula, but in patients whose arms aredisproportionately long, the electrodes should be placed 5 cm proximally to their regular position.

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Definition and principles of the correcting coefficients of the Frinerman formula

The basic impedance part of Frinerman’s formula consists of the following Bonjer equation(1950):

SV = dRρL2

R2 , (3)

to which Frinerman’s correcting factors were added. These coefficient were designed toneutralize the individual effects of gender, age, body water composition and anthropomorphicvariabilities of each patient.

According to RIC studies, the basal R0 is higher in females than in males, a fact whichis in accordance with the literature (Organ et al 1994, Lukaski et al 1986, Hoffer et al 1970,Lamberts et al 1984, Ward et al 2000), and it tends to rise with age (Organ et al 1994).

Based on reported values of basal resistances related to sex and age (Organ et al 1994,Lukaski et al 1986, Ward et al 2000), a coefficien is calculated to determine an ideal valueof R0 for the studied patient. Ideal here means an ideal weight compared to height in healthycondition. By dividing the measured R0 of the patient by the calculated ideal R0, a correctingcoefficien is obtained. By multiplying the measured R by the correcting coefficient the Rivariable is determined and placed in the denominator of the formula.

Similarly, a correcting coefficien (Kw) for the body weight is calculated by dividing themeasured weight by the calculated weight according to Hamwi’s formula (1964) of idealweight. Kw is required for compensation of the reduced electrical conductance in the fat, andthis coefficien is placed in the numerator of the formula, affecting the value of �R. In a similarfashion, the hydration factor, HR, is calculated by the patient’s body water composition, andthis coefficien is placed in the numerator of the formula, either to reduce or to increase �R inover- or under-hydrated patients, respectively.

The variable (α + β)/β is based on the Windkessel principle (Frank 1926, Faes et al1999), where a distinction is made between the aortic infl w α, which is incurred by thesystolic left ventricular ejection, and the aortic outfl w (α + β), which extends throughout thecardiac cycle (figur 1).

Comparative calculation of CO by software simulation

The impedance raw data of the compiled 43 investigative patients were retrieved and theirCO were calculated by the following formulae: (1) Frinerman’s formula, as measured bythe NICaS; (2) Bonjer’s equation of 1950 (Bonjer 1950), which was expressed differently byPatterson’s f rst version of the TIC formula (Patterson et al 1964):

�V = ρ

(L

Z

)2

�Z; (4)

(3) Patterson’s formula of the f rst derivative (Patterson 1965):

SV = dZ

dt× T × ρ ×

(L

Z

)2

, (5)

where SV is the cardiac stroke volume (cm), dZ/dt is the peak of the f rst derivative of theimpedance change during systole (� s−1), T is the cardiac ejection time (s), L is the lengthbetween voltage pick-up electrodes (cm) and Z is the base impedance value (�), which is stillused by the TIC technology (Kubicek et al 1974); (4) a combined formula which includesPatterson’s equation together with Frinerman’s correcting factors (table 1, figure 2 and 3):

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1.0

3.0

5.0

7.0

9.0

11.0

1.0 3.0 5.0 7.0 9.0 11.0

TDCO (lit/min)

ICG

-CO

(lit/

min

)

Frinerman NICaS Bonjer

Kubicek-Patterson(first derivative) Kubicek & Frinerman Correcting Factors

Figure 2. Scatter plot comparing CO results calculated by four impedance algorithms versusthermodilution.

Table 1. Correlations and limits of agreement between four algorithms versus TD. Comparison offour different algorithms in 43 patients for measuring cardiac output (CO) of the same raw data:(a) Frinerman (NICaS); (b) Bonjer; (c) Patterson–Kubicek; (d) Patterson–Kubicek–Frinerman.Each of these was compared with thermodilution.

Frinerman Patterson– Patterson–Kubicek–TD NICaS Bonjer Kubicek Frinerman

Average CO (l min−1) 5.12 5.05 5.33 5.00 5.09SD 1.952 2.043 2.218 1.781 1.986Correlation with TD 0.969 0.841 0.897 0.950p value versus NICaSa – <0.001 <0.0005 0.33Bias −0.0698 0.2107 −0.1116 −0.0302SD of Bias 0.509 1.203 0.864 0.624LL agreement −1.088 −2.196 −1.840 −1.277UL agreement 0.949 2.617 1.617 1.217

SD = standard deviation; LL agreement = lower limit of agreement; UL agreement = upper limitof agreement.a Bonferroni adjusted p values for testing equality of correlation NICaS TD as compared with BonjerTD (<0.0001), Patterson–Kubicek TD (<0.0005), Patterson–Kubicek–Frinerman TD (0.33).

SV = dR × T

dt × R× ρ × L2(α + β)

Riβ× Kw × HF, (6)

where Frinerman’s �R was replaced by dZ/dt × T and (α + β)/β was deleted.

Patient selection

Restlessness, aortic insufficien y, abdominal aneurysm, heart rate above 130 beats min−1,arrhythmia with significan irregular heart rate, severe peripheral vascular disease, two or more

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(A) Frinerman

-3.0

-2.0

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Figure 3. Scatter plots of Bland–Altman difference-against-average of the CO results calculatedby the four impedance algorithms versus thermodilution results (based on table 1).

pitting edema and dialysis all interfere with the proper measurements of the SV; therefore, thispatient population, which amounts to 15% of the candidates, is a priori excluded from the ICGstudies. Also excluded are RIC measurements of the CO in thoracoabdominal operations, suchas esophagectomies and pancreatectomies, where plasma loss and heavy intravenous volumeloads due to significan bleeding undermine the stability of the basal R and the reliability ofthe CO results (Critchley et al 1996).

Statistical analysis

Thermodilution (TD) was used as the ‘gold standard’, and agreement between the four ICGformulae and TD was analyzed according to the Bland–Altman approach (Bland and Altman1986).

Results6

The results of the four algorithms revealed a rather similar average of the NICO in the rangeof 5 l min−1 (table 1). The Pearson correlation coefficient were r = 0.969, 0.841, 0.897 and0.950 with the formulae of Frinerman, Bonjer (1950), Patterson–Kubicek (Patterson 1965,Kubicek et al 1974) and the combined Patterson–Kubicek–Frinerman formula, respectively(table 1, figure 2 and 3). The Bland–Altman 2SD lower and upper limits of agreement withTD were −1.088 and 0.949, −2.196 and 2.617, −1.840 and 1.617, and −1.277 and 1.217,according to the same order of formulae as above (table 1, figur 3).

6 To calculate the SV with the Bonjer, Patterson–Kubicek and Patterson–Kubicek–Frinerman formulae, the raw dataof the 43 patients were e-mailed to Professor Robert Patterson, the inventor of the TIC technology (Patterson et al1964, Patterson 1965), who made these calculations at the University of Minnesota.

72 of 158.


Discussion

To compare the performance of the currently used TIC technology with RIC, we used threerecent reports representing TIC results in patients with chronic stable congestive heart failure,which revealed similar values (Drazner et al 2002, Van De Water et al 2003, Leslie et al 2004)and could serve as a paradigm of the performance of TIC in the presence of cardiac conditions.A relatively recent publication by Sageman et al (2002) could not be included here because(a) only CI values were provided, (b) these values are characteristic of patients with normalcardiac functions and (c) the patients’ CO results were averages of up to 20 measurements, anapproach which is not used clinically.

The average cardiac output in each of the three TIC series was in the range of 5 l min−1.Comparison in each series of the results with thermodilution (TD) revealed a Bland–Altmanlimit of agreement with a 2SD of approximately ±2.2 l min−1—a 44% deviation compared toTD (Drazner et al 2002, Van De Water et al 2003, Leslie et al 2004). Despite the fact that thepresent series did not include cases of chronic congestive heart failure, it is comparable withthe TIC studies because (a) the patients were actively managed for cardiac conditions, (b) aCI < 2.5 l min−1 m−2 was observed in 43% of the cases and (c) the average CO was in therange of 5 l min−1, as in the TIC paradigm.

When the Patterson–Kubicek algorithm was fed by impedance raw data yielded by theperipheral wrist–ankle rather than by thoracic electrodes, the disparity compared to TD was±1.7 l min−1, which is a 34% difference (figure 2 and 3). When the Patterson–Kubicekalgorithm was reinforced by the correcting factors of the NICaS formula and the peripheralraw data were used, there was a further decline in the disparity between ICG and TD to therange of ±1.25 l min−1, a 25% difference. This is almost as good as the 20% disparity betweenthe NICaS and the TD.

Judging by the 20% deviation between the NICaS and TD CO results, and by the 44%deviation between the reported TIC and TD CO results, it is evident that the accuracy of theNICaS is higher by a factor of more than 2, than the reported values of TIC (Raaijmakerset al 1999, Handelsman 1991, Drazner et al 2002, Van De Water et al 2003, Leslie et al 2004).

Moreover, according to the FDA standard of bioequivalence (Guidance for Industry 2001),the comparative results of new and gold-standard technologies should be contained within arange of 20% disparity. This 20% range is determined by the 10% repeatability rate of eachof the two methods. Judging by figur 3(A), the agreement between the NICaS and the TD isin very close proximity to the FDA standard bioequivalence.

About the validity of correcting coefficients

To appreciate the competence of the correcting factors, it is suffic to compare the CO resultsof Frinerman’s and Bonjer’s formulae (figure 3(A) and (B)). As stated earlier, the onlydifference between these two equations is the addition of Frinerman’s correcting factors toBonjer’s formula. Ri, for example, which is the corrected R0, may reach twice the value ofthe measured R0. Kw may increase the measured �R by up to 45%. The HF may eitherreduce or increase the value of �R by only slight to moderate degrees. Thus, it can bediscerned that when using Bonjer’s equation alone (figur 3(B)) the 2SD limits of agreementare approximately ±2.4 l min−1, and when Frinerman’s variables are added (figur 3(A)) the2SD limits of agreement are ±1.0 l min−1. There is a 20% disparity between the NICaS andthe TD, and a 45% improvement of Bonjer’s reinforced performance.

Similarly, annexing the Frinerman correcting coefficient to the TIC dZ/dt × Tformula dramatically improved the calculated CO results, from 2SD limits of agreement of

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824 G Cotter et al

approximately ±1.7 l min−1 (table 1, figur 3(C)) to 2SD limits of agreement of approximately±1.25 l min−1 (table 1, figur 3(D)).

It has been repeatedly shown by Hoffer et al (1970), Lukaski et al (1986), Organ et al(1994), Ward et al (2000) and others that the body is not a homogeneous conductor, and itsbasal resistance, and consequently the spatial distribution of conductivities, is a function ofthe body composition. It is also recognized that the two main factors which determine theimpedance variabilities are the percentages of body water and fat. As shown here, by using theRIC approach, the variabilities of age, sex, height and weight can be quantitated and translatedto the effective correcting coefficients

About the validity of the wrist–ankle electrodes

The most significan advantage of RIC in comparison to TIC is the use of the peripheralimpedance signal for calculation of the SV. According to Kauppinen et al (2000), 75% of theperipheral (RIC) impedance waveform is borne by the systolic blood volume pulsations ofthe arterial vasculature of the upper and lower limbs, and the remaining 25% arrives from thetrunk (thorax). Still, the sole source of the peripheral signal is generated by the blood volumepulse of the arterial vasculature.

It must be borne in mind that the aorta and its peripheral ramification comprise a singleanatomophysiological structure, and the pulse waveform, which evolves throughout its length,occurs almost at the same time. This is possible only because the velocity of the pulse wave isso rapid that the arterial expansion is completed before the termination of the left ventricularcontraction (Guyton and Hall 2000). The mean value of the pulse wave velocity (PWV) fromthe thorax to the calves is approximately 7–10 m s−1 (Guyton and Hall 2000).7 Similarly, theimpedance volume pulse travels at approximately the same rate as reported by Risacher et al(1995).

Thus, in accordance with the existing knowledge of the cardiac role in the formation ofthe pulse (McVeigh et al 2002), the RIC peripheral volumetric signal is borne throughout thelength of the arterial tree beginning with the left ventricular stroke volume ejection.

In contrast, the thoracic (TIC) waveform is generated by multiple sources, includingthe aorta, lungs, atria, vena cava and artifacts due to heart movements (Wang et al 2001,Kauppinen et al 1998, Wtorek 2000). In normal people, some studies have shown that TICgives reasonably reliable CO results (Raaijmakers et al 1999), but in the presence of cardiacconditions, distortions of the TIC waveforms were already observed in the earliest days of theemergence of this technology (Kubicek et al 1974). This is contrary to RIC, where we seevery few changes, if any, in the waveform shape incurred by the different cardiac conditions.

The immunity of the peripheral impedance waveform to the distorting influenc of cardiacconditions is reflecte by the results of the present study. The average disparity between TIC-CO and TD-CO measured in cardiac patients is 44%. In the present trial, the average disparitybetween TD-CO and ICG-CO, which was calculated by the combination of the TIC algorithmand a peripheral impedance waveform, was 34%. This 23% higher accuracy, which is obtainedby the standard TIC algorithm, can be attributed only to one factor, the reliance for calculationof the SV on the peripheral, rather than the thoracic, impedance signal.

The fact that the RIC region consists of only part of the whole body but can be usedto calculate the CO of the whole body is explained by the electrophysiological relationshipswhich exist between RIC and ICGWB. In the ICGWB technique, electrodes are placed on allfour limbs, and yet, despite the fact that the head which consumes 13% of the CO is not

7 Significan differences exist in these values, depending on the elasticity of the arterial vasculature.

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included in the electrical field the reliability of the CO results of this technology has beenvalidated (Tischenko 1973, Koobi et al 1999).

The common electrophysiological denominator of RIC and ICGWB is in that the samebasal R of a body that is measured by RIC is twice the value measured by ICGWB. Asmeasured in this series, and by and large as measured by others (Kauppinen et al 2000,Lukaski et al 1986, Organ et al 1994), the basal R of the region between the wrist and theankle is approximately 450 �.8 This, when the value of the basal R of ICGWB is in the rangeof 200–250 � (Tischenko 1973, Lamberts et al 1984, Kauppinen et al 2000). The 2:1 ratio ofthe basal R in RIC versus ICGWB is attributed to the fact that in ICGWB the two upper and thetwo lower limbs are measured in parallel. Consequently, the cross-sectional area of the limbsis twice as large in ICGWB, resulting in the reduction of the electrical resistance to one-half.Thus, it is the same physiological mechanism which facilitates the appropriate measurementof the total CO by ICGWB, which also holds for the exceptionally accurate RIC results.

Conclusions

The present CO results measured by the NICaS device indicate that, with regard to accuracyof measuring the CO, the RIC technology outperforms any other ICG technology, being twiceas accurate as TIC.

The peripheral systolic impedance changes are more reliable than the TIC impedancechanges for calculating the cardiac stroke volume.

The main disadvantage of the RIC technology is that in approximately 15% of the patientswho need the test, there are exclusion criteria which preclude the use of the NICaS, a problemwhich is also shared by other impedance technologies.

References

Bland J M and Altman D G 1986 Statistical methods for assessing agreement between two methods of clinicalmeasurement Lancet 1 307–10

Bonjer F H 1950 Circulatieonderzoek door Impedantiemeting Groningen, Drukkerij I, Oppenheim NVBonjer F H, Van Den Berg J W and Direden M N J 1952 The origin of the variations of body impedance occurring

during the cardiac cycle Circulation 6 415–20Cohen A J, Arnaudov D, Zabeeda D, Shultheis L, Lashinger J and Schachner A 1998 Non-invasive measurement of

cardiac output during coronary artery bypass grafting Eur. J. Cardiothorac. Surg. 14 64–9Cotter G, Moshkovitz Y, Kaluski E, Cohen A J, Miller H, Goor D A and Vered Z 2004 Accurate, noninvasive

continuous monitoring of cardiac output by whole-body electrical bioimpedance Chest 125 1431–40Critchley L A H, Leung D H Y and Short T G 1996 Abdominal surgery alters the calibration of bioimpedance cardiac

output Int. J. Clin. Monit. Comput. 13 1–8Drazner M, Thompson B, Rosenberg P, Kaiser P A, James M S N, Boehrer D, Baldwin B J, Dries D L and

Yancy C W 2002 Comparison of impedance cardiography with invasive hemodynamic measurements in patientswith heart failure secondary to ischemic or nonischemic cardiomyopathy Am. J. Cardiol. 89 993–5

Faes Th J C, Raaijmakers J H, Meijer H G, Goovaerts H G and Heethaar R M 1999 Towards a theoretical understandingof stroke volume estimation with impedance cardiography Ann. New York Acad. Sci. 873 128–34

Frank O 1926 Die Theorie der Pulswellen Z. Biol. 85 95–180Guidance for Industry Statistical Approach to Establishing Bioequivalence 2001 US Department of Health and Human

Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), BPGuyton A C and Hall J E 2000 Textbook of Medical Physiology 10th edn (Philadelphia, PA: WB Saunders)

8 It should be borne in mind that in females the electrical resistance between the wrist and the ankle is higher thanin males by 80–100 � (Organ et al 1994, Lukaski et al 1986, Hoffer et al 1970). Furthermore, there are differencesin the basal R values of different ethnic populations (Ward et al 2000), where different antropometric characteristicsexist. In the present series, the average basal R of the postoperative cases was lower by 100 � compared to thenon-operative cardiac patients, and this is attributed to the over-hydration induced during the surgery.

75 of 158.

http://dx.doi.org/10.1016/S1010-7940(98)00135-3

http://dx.doi.org/10.1378/chest.125.4.1431

http://dx.doi.org/10.1016/S0002-9149(02)02257-9

http://dx.doi.org/10.1111/j.1749-6632.1999.tb09459.x

826 G Cotter et al

Hamwi G T 1964 Therapy Changing Dietary Concepts in Diabetes Mellitus: Diagnosis and Treatmented T S Danowski (New York: American Diabetes Association) pp 73–8

Handelsman H 1991 Public health service reassessment: measuring cardiac output by electrical bioimpedance HealthTechnology Assessment Report 6 (US Dept Health and Human Services, Public Agency for Health Care Policyand Research) pp 1–13

Hoffer E C, Meador C K and Simpson D C 1970 A relationship between whole body impedance and total body watervolume Ann. New York Acad. Sci. 170 452–61

Kauppinen P K, Hyttinen J A and Malmivuo J A 1998 Sensitivity distributions of impedance cardiography using bandand spot electrodes analyzed by a three-dimensional computer model Am. Biomed. Eng. 26 694–702

Kauppinen P K, Koobi T, Hyttinen J and Malmivuo J 2000 Segmental composition of whole-body impedancecardiogram estimated by computer simulations and clinical experiment Clin. Physiol. 20 106–13

Kim D W, Baker L E, Pearce J A and Kim W K 1988 Origins of the impedance change in impedance cardiographyby a three-dimensional f nite element model IEEE Trans. Biomed. Eng. 35 12

Koobi T, Kaukinen S and Kauppinen P 2001 Comparison of methods of cardiac output measurements Crit. CareMed. 29 1092 (Letter to the Editor)

Koobi T, Kaukinen S and Turjanmaa V M 1999 Cardiac output can be reliably measured noninvasively after coronaryartery bypass grafting operation Crit. Care Med. 27 2206–11

Kubicek W G, Karnegis J N, Patterson R P, Witsoe D A and Mattson R H 1966 Development and evaluation of animpedance cardiac output system Aerospace Med. 37 1208–2

Kubicek W G, Kottke F J, Ramos M U, Patterson R P, Witsol D A, Labree J W, Remole W, Layman T E, Schoening Hand Garamela J T 1974 The Minnesota impedance cardiograph: theory and applications Biomed. Eng. 9 410–6

Lamberts R, Visser K R and Zijlstra W G 1984 Impedance Cardiography (Assen, The Netherlands: Van Gorkum)pp 21–94

Leslie S J, McKee S, Newby D E, Webb D J and Denvir M A 2004 Non-invasive measurement of cardiac output inpatients with chronic heart failure Blood Pressure Monit. 9 277–80

Lukaski H, Bolonchuk W W, Hall C B and Siders W A 1986 Validation of tetrapolar bioelectrical impedance methodto assess human body composition J. Appl. Physiol. 60 1327–32

McVeigh G E, Hamilton P K and Morgan D R 2002 Evaluation of mechanical arterial properties: clinical, experimentaland therapeutic aspects Clin. Sci. 102 51–67

Nyboer J 1950 Electrical impedance plethysmography: a physical and physiologic approach to peripheral vascularstudy Circulation 2 811–21

Organ L W, Bradham G B, Gore D T and Lozier S L 1994 Segmental bioelectrical impedance analysis: theory andapplication of a new technique J. Appl. Physiol. 77 98–112

Patterson R P 1965 Cardiac output determinations using impedance plethysmography MSc Thesis University ofMinnesota

Patterson R P 1985 Sources of thoracic cardiogenic electrical impedance signal as determined by a model Med. Biol.Eng. Comput. 23 411–7

Patterson R 1989 Body flui determinations using multiple impedance measurements IEEE Eng. Med. Biol. 8 16–9Patterson R P, Kubicek W G, Kinnen E, Witsoe D A and Noren G 1964 Development of an electrical impedance

plethysmography system to monitor cardiac output Proc. 1st Annual Rocky Mt Bioeng. Symp. pp 56–71Raaijmakers E, Faes Th J C, Scholten R J P M, Goovaerts H G and Heethaar R 1999 A meta-analysis of published

studies concerning the validity of thoracic impedance cardiography Ann. New York Acad. Sci. 873 121–34Risacher F, Jossinet J and Schmitt M 1995 Comparison of global and local pulse wave velocity in man measured by

multichannel impedance plethysmography Proc. 9th Int. Conf. on Electrical BioimpedanceSageman W S, Riffenburgh R H and Spiess B D 2002 Equivalence of bioimpedance and thermodilution in measuring

cardiac index after cardiac surgery J. Cardiothorac. Vasc. Anesth. 16 8–14Thomasset A 1962 Bioelectrical properties of tissue impedance measurements Lyon Med. 207 107–18Tischenko M I 1973 Estimation of stroke volume by integral rheogram of the human body Sechenov Physiol. J. 59

1216–24 (in Russian)Torre-Amione G et al 2004 Non-invasive measurement of cardiac output by whole-body electrical bioimpedance in

patients treated for acute heart failure: a prospective, double-blind comparison with thermodilution J. Am. Coll.Cardiol. 5 209A (abstract)

Van De Water J M, Miller T W, Vogel R L, Mount B E and Dalton M L 2003 Impedance cardiography—the nextvital sign technology? Chest 123 2028–33

Wang Y, Haynor D R and Kim Y 2001 A f nite-element study of the effects of electrode position on the measuredimpedance change in impedance cardiography IEEE Trans. Biomed. Eng. 48 1390–401

Wang L and Patterson L 1995 Multiple sources of the impedance cardiogram based on 3D f nite difference humanthorax models IEEE Trans. Biomed. Eng. 42 141–8

76 of 158.

http://dx.doi.org/10.1114/1.44

http://dx.doi.org/10.1046/j.1365-2281.2000.00234.x

http://dx.doi.org/10.1109/10.8683

http://dx.doi.org/10.1097/00126097-200410000-00008

http://dx.doi.org/10.1042/CS20010191

http://dx.doi.org/10.1109/51.32399

http://dx.doi.org/10.1111/j.1749-6632.1999.tb09458.x

http://dx.doi.org/10.1053/jcan.2002.29635

http://dx.doi.org/10.1378/chest.123.6.2028

http://dx.doi.org/10.1109/10.966598

http://dx.doi.org/10.1109/10.341826


Ward L C et al 2000 Association between ethnicity, body mass index, and bioelectrical impedance. Implications forthe population specificit of prediction equations Ann. New York Acad. Sci. 904 199–204

Wotton M J, Thomas B J, Cornish B H and Ward L C 2000 Comparison of whole body and segmental bioimpedancemethodologies for estimating total body water Ann. New York Acad. Sci. 904 181–6

Wtorek J 2000 Relations between components of impedance cardiogram analyzed by means of f nite element modeland sensitivity theorem Ann. Biomed. Eng. 28 1352–61

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http://dx.doi.org/10.1114/1.1327596

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72514Hypertension is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX

DOI: 10.1161/01.HYP.0000209642.11448.e0 2006;47;771-777; originally published online Mar 6, 2006; Hypertension

Study Group LevelsNoninvasive Hemodynamic Monitoring to Target Reduction of Blood Pressure

Ronald D. Smith, Pavel Levy, Carlos M. Ferrario and for the Consideration of Hypertensive Subjects

Value of Noninvasive Hemodynamics to Achieve Blood Pressure Control in

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Value of Noninvasive Hemodynamics to Achieve BloodPressure Control in Hypertensive Subjects

Ronald D. Smith, Pavel Levy, Carlos M. Ferrario; for the Consideration of NoninvasiveHemodynamic Monitoring to Target Reduction of Blood Pressure Levels Study Group

Abstract—Abnormal hemodynamics play a central role in the development and perpetuation of high blood pressure. Wehypothesized that hypertension therapy guided by noninvasive hemodynamics with impedance cardiography could aidprimary care physicians in reducing blood pressure more effectively. Uncontrolled hypertensive patients on 1 to 3medications were randomized by 3:2 ratio to either a standard arm or hemodynamic arm that used impedancecardiography (BioZ, CardioDynamics). Each patient completed 5 study visits with a 2-week washout period followedby 3 months of treatment. A total of 164 patients from 11 centers completed the study, 95 in the standard arm and 69in the hemodynamic arm. At baseline and after washout, there were no differences between arms in number ofmedications or demographic, blood pressure, or hemodynamic characteristics. Systolic blood pressure reductions in thehemodynamic arm were greater from baseline (19 mm Hg versus 11 mm Hg; P�0.01) and after washout (25 mm Hgversus 19 mm Hg; P�0.05). Diastolic blood pressure reductions were also greater in the hemodynamic arm frombaseline (12 mm Hg versus 5 mm Hg; P�0.001) and after washout (17 mm Hg versus 10 mm Hg; P�0.001). Thehemodynamic arm achieved goal blood pressure (�140/90 mm Hg) more frequently (77% versus 57%; P�0.01) anda more aggressive blood pressure level (�130/85 mm Hg) more frequently (55% versus 27%; P�0.0001). These studyresults indicate that antihypertensive therapy guided by impedance cardiography in uncontrolled hypertensive patientson �1 medications is more effective than standard care. (Hypertension. 2006;47:771-777.)

Key Words: hemodynamics � cardiac output � vascular resistance � hypertension, arterial� hypertension, essential � blood pressure

Approximately 65 million people in the United States1

and 1 billion people worldwide2 have hypertension; itis the most common reason adults visit US physicians.3Hypertension is a major public health concern, because itsignificantly increases risk of coronary artery disease,heart failure, renal disease, and stroke.4 In spite of majorpublic health and medical education efforts and availabilityof effective antihypertensive agents, blood pressure (BP) con-trol rates in the United States remain low, with only 31% ofhypertensives and 54% of those actively treated and takingmedications achieving BP �140/90 mm Hg.5 Why is BP controlsuch an elusive goal? The reasons are numerous and complex.However, inadequate pharmacological treatment remains themost common cause of uncontrolled BP in actively treatedpatients.6

Hypertension is a hemodynamic-related disorder. BP risesas the result of increased systemic vascular resistance (SVR),cardiac output (CO), fluid volume, or a combination of thesefactors.7,8 Consequently, antihypertensive agents lower BP byreducing SVR, CO, fluid volume, or combinations thereof.9

Previous authors hypothesized that hemodynamic informa-tion could help tailor therapy and subsequently improve BPcontrol.10 Invasive procedures for hemodynamic profiling arenot warranted in outpatient clinics, and noninvasive proce-dures, such as echocardiography, are costly and operatordependent.11

Impedance cardiography (ICG) has emerged as a reliablenoninvasive method to measure hemodynamics in physicianoffices. In a randomized, controlled trial, ICG-guided treat-ment improved BP control rates in resistant hypertensiontreated by hypertension specialists.12 We hypothesized thatICG-guided treatment could aid physicians in reducing BPmore effectively than standard care in a population ofuncontrolled hypertensive patients receiving 1 to 3 medica-tions in a primary care setting.

MethodsEligibilityMale and female patients (age range, 18 to 75 years) were eligible ifthey had a diagnosis of essential hypertension and were currently on

Received August 10, 2005; first decision August 29, 2005; revision accepted December 12, 2005.From the Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC.R.D.S. and C.M.F. received honorarium from CardioDynamics for consultation and speaker fees. Site investigators received study support from

CardioDynamics.Correspondence to Carlos Ferrario, Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Blvd,

Winston-Salem, NC 27157-1032. E-mail [email protected]© 2006 American Heart Association, Inc.Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000209642.11448.e0

771 by on June 11, 2011 hyper.ahajournals.orgDownloaded from 79 of 158.


1 to 3 antihypertensive medications with systolic BP of 140 to179 mm Hg and/or diastolic BP of 90 to 109 mm Hg. Patients wereexcluded if they were on �3 antihypertensive agents; had abnormallaboratory findings; or had history of heart failure, left ventricularejection fraction �40%, atrial fibrillation, severe valvular disease,cerebrovascular event within 3 months, severe renal disease, ne-phrotic syndrome, or cirrhosis. Patients in whom ICG might besubject to technical limitations were excluded (height �47 or �75inches or weight �66 or �341 pounds, presence of activatedminute-ventilation pacemaker, known hypersensitivity to sensor gelor adhesive, or skin lesion interfering with sensor placement).Patients who were enrolled and subsequently found to have not metthe inclusion/exclusion criteria were terminated and excluded fromanalysis. Therefore, this was not an intention-to-treat analysis. Thestudy was approved by an independent institutional review board,which adheres to the Declaration of Helsinki and US Code of FederalRegulations. These hypertensive outpatients provided written in-formed consent and had study procedures consistent with theprotocol (no. 20021400).

Hemodynamic Evaluation AssignmentEligible patients (N�164) underwent a 2-week washout period atwhich time all of the antihypertensive medications were discontinuedaccording to the manufacturer’s recommendations. After screeningand medication washout, each patient had 3 monthly office visits

(Figure 1). After the 2-week washout period, patients meetinginclusion/exclusion criteria were randomized in a 3:2 ratio to thestandard arm (n�95) or ICG-aided hemodynamic arm (n�69) usinga central telephone service and stratified by site. All of the physicianswere educated on the hemodynamic treatment strategy illustrated inFigure 2.

ProceduresBP determinations were made in the seated position using theoscillometric technique. ICG data were collected by trained techni-cians at each visit in all of the patients, but ICG findings were notrevealed in the standard arm to treating physicians or patients. ICGwas performed with patients in the supine position, resting for 5minutes before measurement (BioZ ICG Monitor, CardioDynamics).ICG involves the measurement of thoracic impedance throughplacement of 4 dual sensors, 2 on the neck and 2 on the chest.Electrical impedance changes are digitally processed to calculateCO, SVR, and thoracic fluid content (TFC).13 CO and SVR arenormalized for body size by indexing to each patient’s body sur-face area to obtain cardiac index (CI) and SVR index (SVRI). TFCis the inverse of baseline chest impedance, and any changes in TFCare directly proportional to total fluid (intravascular and extravascu-lar) changes.14 TFC has different normal ranges for each gender thatare displayed and printed for reference. The reproducibility of thisICG device in stable outpatients has been established,15 and accuracy

Figure 1. Study design comparing efficacy of standard arm vs hemodynamic arm treatment of high BP.

Figure 2. Suggested treatment strategy for hemodynamic arm; BB indicates � blocker; CAA, central acting agent; and VD, vasodilator.

772 Hypertension April 2006



has been validated versus invasive methods in patients with variouscardiovascular disorders.16,17

Outcome MeasuresPhysician investigators were instructed that the treatment goal was toreduce systolic and diastolic BP as low as they believed would bebeneficial to the patient and to achieve sustained BP �140/90 mm Hg. The primary study end points were reductions in systolicand diastolic BP from baseline and post-washout visit. Addi-tional study end points were achievement of: (1) goal BP �140/90 mm Hg, (2) more aggressive BP of �130/85 mm Hg, and (3) BPof �140/90 mm Hg with normal values of CI and SVRI. Normalrange for CI was defined as 2.5 to 4.2 L/min per m2 and for SVRI as1680 to 2580 dyne�s�m2/cm5. Isolated systolic hypertension wasdefined as systolic BP �140 mm Hg and diastolic BP �90 mm Hg.

InterventionsAfter randomization, therapy was initiated in all of the patients at thepost-washout visit, 2 weeks after screening. Physician investigatorsprescribed medications consistent with published guidelines, theirusual practice patterns, and patient clinical characteristics. In thehemodynamic arm, the treating physician was also encouraged to usea hemodynamic treatment strategy to guide therapeutic decisionsabout pharmacological agents and dosing (Figure 2).

Physicians could share ICG information with patients in thehemodynamic arm, and patients in both arms received education onthe importance of medication compliance, which was reinforced witha nurse telephone call midway between each study visit. Compliancewas assessed at each visit by asking patients to estimate thepercentage of prescribed pills they had taken over the previousmonth. Patients were considered compliant with the prescribedprotocol if pill count was �85% over the prior month.

Statistical AnalysisData from case report forms were collected by study coordinatorsand entered into a locked database. Statistical analysis was per-formed with SAS statistical analysis software, version 8.2. Contin-uous variables are expressed as mean�SD and categorical variablesas n (%). Differences in continuous variables between treatmentgroups were examined by the Student t test and by ANOVA and indiscrete variables using Fisher’s exact tests. Subgroup analysis wasperformed in subjects with isolated systolic hypertension, age �55years, and those receiving a thiazide diuretic. Additional evaluationof age-specific results was performed by a 2-way ANOVA forachievement of BP end points, in which treatment arm and dichot-omized age (�55 years) were included in the model. In combinationagents, each class and dosage was counted separately for analysis.Equivalency of defined daily doses for each class of medication wascalculated using World Health Organization criteria.18 Medicationchanges were evaluated in visits where such changes affected BP endpoints (visits 2 versus 1, 3 versus 2, and 4 versus 3). Medication classand dose were compared with the prior study visit, with any changein class or dose counted separately. Sample size was powered using5 mm Hg as the detectable difference between treatment groups witha type I error of 5% and type II error of 20%. The expectedheterogeneity in treatment approach for patients in the standard armwas offset by the greater number of patients randomized to thestandard arm. Although this approach increased the probability thatthe standard arm results would reflect actual practice patterns, itrequired a larger sample size to power the study.

ResultsEleven primary care centers participated in the study betweenNovember 2002 and November 2004. Of 262 patientsscreened, 184 were randomized. A total of 164 patients (95 inthe standard arm and 69 in the hemodynamic arm) completedthe study and were analyzed. There were 20 early termina-tions, including 2 who withdrew and 18 who were random-ized but were subsequently found not to have met BP

enrollment criteria (BP �140/90 mm Hg at screening) andwere removed as protocol violations. No reported adverseevents (minor or serious) were attributable to ICG.

There were no differences in the number of antihyperten-sive medications, patient demographic, clinical, BP, or ICGvariables at baseline or after washout (Table 1). At baseline,there were no differences in the percentage of patients in thestandard versus hemodynamic arm on 1 (42% versus 45%;P�0.05), 2 (48% versus 44%; P�0.05), or 3 (6% versus10%; P�0.05) medications. Baseline medication usage in the

TABLE 1. Patient Characteristics

Variable

StandardCare

(n�95)

HemodynamicCare

(n�69)P

Value

Age, y 54.5�9.4 55.2�9.2 ns

Body mass index, kg/m2 30.2�6.3 30.8�5.1 ns

Men 51 (53.4) 38 (55.1) ns

Ethnicity

White, non-Hispanic 75 (79.0) 53 (76.8) ns

White, Hispanic 7 (7.4) 5 (7.3) ns

Black 8 (8.4) 6 (8.7) ns

Asian 3 (3.2) 3 (4.4) ns

History

Type II diabetes mellitus 4 (4.2) 3 (4.4) ns

Ischemic heart disease 2 (2.1) 5 (7.3) ns

Hyperlipidemia 14 (14.7) 12 (17.4) ns

Baseline BP andhemodynamics

Systolic BP, mm Hg 147�9 148�12 ns

Diastolic BP, mm Hg 87�10 89�8 ns

Heart rate, bpm 75�12 74�13 ns

Cardiac index, L/min/m2 2.8�0.5 2.9�0.6 ns

Systemic vascularresistance index,dyne�s�m2/cm5

2933�576 2956�605 ns

Thoracic fluid content,/kOhm

28.6�4.9 28.0�4.8 ns

Isolated systolic hypertensionat baseline

46 (48.4) 31 (44.9) ns

Post-washout BP andhemodynamics

Systolic BP, mm Hg 156�13 155�13 ns

Diastolic BP, mm Hg 92�9 94�9 ns

Heart rate, bpm 79�12 78�14 ns

Cardiac index, L/min/m2 2.9�0.5 2.9�0.5 ns

Systemic vascularresistance index,dyne�s�m2/cm5

3083�630 3122�672 ns

Thoracic fluid content,/kOhm

29.1�5.0 28.4�4.3 ns

Medications

Total antihypertensivemedications

1.7�0.8 1.7�0.7 ns

Categorical variables expressed as n (%), continuous variables asmean�SD; ns indicates not significant.

Smith et al Noninvasive Hemodynamics and BP Control 773



standard versus hemodynamic arm was as follows: � blockers(2.1% versus 1.4%; P�0.05), angiotensin converting enzymeinhibitors (ACEI; 53.7% versus 47.8%; P�0.05), angiotensinII receptor blockers (ARB; 14.7% versus 29.0%; P�0.05), �blockers (23.2% versus 13.0%; P�0.05), calcium channelblockers (CCB; 33.7% versus 39.1%; P�0.05), central actingagents (0% versus 1.4%; P�0.05), diuretics (31.6% versus26.1%; P�0.05), and other vasodilators (0% versus 0%;P�0.05).

BP and ICG values at the final visit and their differences frombaseline and post-washout visits are shown in Table 2. SystolicBP reductions were greater in the hemodynamic arm frombaseline (19�17 versus 11�18 mm Hg; P�0.01) and post-washout (25�18 versus 19�17 mm Hg; P�0.05). DiastolicBP reductions were also greater in the hemodynamic armfrom baseline (12�11 versus 5�12 mm Hg; P�0.001) andpost-washout (17�12 versus 10�11 mm Hg; P�0.001).Final BP was lower in the hemodynamic arm (129/76�14/11versus 136/82�15/10 mm Hg; P�0.01). Figure 3 demon-strates that goal BP (�140/90 mm Hg) was achieved morefrequently in the hemodynamic arm (77% versus 57%;P�0.01), and the more aggressive BP (�130/85 mm Hg) wasalso achieved more often (55% versus 27%; P�0.0001).

Patients with isolated systolic hypertension in the hemo-dynamic arm (n�31) had greater systolic BP reductions from

baseline (22�16 versus 11�17 mm Hg; P�0.01) and post-washout (28�16 versus 18�16 mm Hg; P�0.05) than thosein the standard arm (n�46). Patients �55 years in thehemodynamic arm (n�33) had greater systolic BP reductionscompared with the standard arm (n�51) from baseline (21�17versus 11�20 mm Hg; P�0.05) and trended greater frompost-washout (26�20 versus 21�19 mm Hg; P�0.05). Diastol-ic BP reductions were also greater in those �55 yearsin the hemodynamic arm from baseline (13�11 versus4�12 mm Hg; P�0.001) and post-washout (16�11 versus10�12 mm Hg; P�0.05). In patients �55 years, goal BP(�140/90 mm Hg) was achieved more frequently in the hemo-dynamic arm (76% versus 53%; P�0.05), and the more aggres-sive BP (�130/85 mm Hg) was also achieved more often (58%versus 27%; P�0.01). ANOVA also indicated that age �55years had no effect on study end points (P�0.05).

SVRI was reduced to a greater extent in the hemodynamicarm than in the standard arm from baseline and post-washout.There were no significant differences between arms at thefinal visit for heart rate, CI, or TFC. However, the standardarm had a small but significant reduction in TFC frompost-washout to final. The percentage of patients achievingnormal hemodynamic values defined as simultaneously nor-mal values of BP, CI, and SVRI was 52% in the hemody-namic arm and 29% in the standard arm (P�0.01). Patients ineither arm who achieved BP �130/85 mm Hg had lowerSVRI (2646�592 versus 2855�606 dyne�s�m2/cm5; P�0.05)and lower CI (2.7�0.5 versus 2.9�0.5 L/min/m2; P�0.05) thanthose who did not achieve BP �130/85 mm Hg. Patients inthe hemodynamic arm who achieved BP �130/85 mm Hgtrended toward lower SVRI (2446�580 versus 2573�612dyne�s�m2/cm5; P�0.05) and higher CI (2.8�0.5 versus2.6�0.5 L/min/m2; P�0.05) than those in the standard carearm who achieved BP �130/85 mm Hg.

In the visit after medication washout, patients in thehemodynamic arm were more likely to be prescribed anACEI, ARB, or CCB (92.8% versus 80.0%; P�0.05). Over

TABLE 2. Final BP and Hemodynamic Values

Variable

StandardCare

(n�95)

HemodynamicCare

(n�69)P

Value

Systolic BP, mm Hg

Final 136�15 129�14 �0.01

� baseline to final �11�18 �19�17 �0.01

� post-washout to final �19�17 �25�18 �0.05

Diastolic BP, mm Hg

Final 82�10 76�11 �0.01



Heart rate, bpm

Final 77�13 76�11 ns

� baseline to final 1�12 2�13 ns

� post-washout to final �2�13 �2�13 ns

Cardiac index, L/min/m2

Final 2.9�0.5 2.9�0.5 ns

� baseline to final 0.1�0.5 0.0�0.5 ns

� post-washout to final 0.0�0.5 0.0�0.5 ns

Systemic vascular resistanceindex, dyne�s�m2/cm5

Final 2714�619 2523�581 �0.05



Thoracic fluid content, /kOhm

Final 27.8�4.1 28.2�4.9 ns

� baseline to final �0.8�3.6 0.1�3.0 ns

� post-washout to final �1.2�3.3 �0.2�2.7 �0.05

Variables expressed as mean�SD; ns indicates not significant.

Figure 3. Target BP achievement; with 95% CI; *P�0.01 vsstandard care, †P�0.0001 vs standard care.




the course of the study, patients in the hemodynamic armwere more likely to be prescribed an ACEI, ARB, or CCBwhen their SVRI was high, per the hemodynamic treatmentstrategy (78.3% versus 67.1%; P�0.05). However, therewere no differences in the other 2 treatments encouraged bythe hemodynamic treatment strategy, � blocker use based onhigh CI, or in diuretic use when TFC did not decrease inresponse to diuretic initiation or increase. Patients in thehemodynamic arm were more likely to avoid � blocker use orto have their � blocker reduced in the presence of low ornormal CI (85.4% versus 77.0%; P�0.05) as the hemody-namic strategy suggested. Direct vasodilators were not used,and, therefore, changes in vasodilator use in the presence ofnormal SVRI were not evaluated. Table 3 lists all of themedications at the final visit. Patients in the standard armwere on 2.0�0.8 medications compared with 2.1�0.9 for thehemodynamic arm (P�0.05). In the hemodynamic arm, ARBuse was higher (46.4% versus 30.5%; P�0.05), and ACEIuse was similar (49.3% versus 53.7%; P�0.05). However,the percentage of patients in the hemodynamic arm who wereprescribed either an ACEI or ARB was not significantlydifferent (87.0% versus 76.8%; P�0.05). There were nodifferences in the percentage of patients in the hemodynamiccare on 1 (25% versus 26%), 2 (48% versus 53%), 3 (19%versus 15%), 4 (9% versus 5%), or 5 (0% versus 1%)medications at the final visit (P�0.05 for all). There were agreater number of medication dose increases in the standardversus hemodynamic arm (3.6�1.3 versus 3.0�1.2; P�0.001),as well as a greater number of dose decreases (2.7�1.3 versus1.7�1.0; P�0.001). Medication class changes in the standardand hemodynamic arm were similar in both class initiation(1.0�0.9 versus 1.1�0.9; P�0.05) and removal (0.8�0.8 ver-sus 0.7�0.8; P�0.05).

Thiazide diuretic use at baseline was similar in the standardversus hemodynamic arm (28.4% versus 24.6%; P�0.05). Asimilar proportion of patients were prescribed thiazide diuret-ics at some point during the trial in both the standard and

hemodynamic arms (44.2% versus 40.2%; P�0.05), and usewas similar at the final visit (33.7% versus 34.8%; P�0.05).Medication doses were not different between arms except thatpatients in the standard arm were on higher doses of thiazidediuretics (18.9�8.3 versus 13.0�2.6 mg/day; P�0.01).There were no differences in the hemodynamic arm in thedosing of ACEIs (19.1 versus 19.1 mg/day; P�0.05), ARBs(93.9 versus 87.0 mg/day; P�0.05), � blockers (65.6 versus80.9 mg/day; P�0.05), or CCBs (7.9 versus 7.9 mg/day;P�0.05). The greater mean dose of thiazide diuretics wasbecause of a higher percentage of patients taking �25 mg/dayversus 12.5 mg/day in the standard arm (40.1% versus 8.3%;P�0.05). When the study end points were analyzed only forpatients on a thiazide diuretic in the final visit, patients inhemodynamic arm had greater decreases in systolic BP frombaseline (26�19 versus 8�17 mm Hg; P�0.001) and post-washout (36�17 versus 21�20 mm Hg; P�0.01) and greaterdecreases in diastolic BP from baseline (16�11 versus3�14 mm Hg; P�0.001) and post-washout (20�12 versus11�13 mm Hg; P�0.01). There were no differences inpatient-reported compliance between the standard and hemo-dynamic arm in visit 3 (96.8% versus 97.1%; P�0.05), 4(96.8% versus 98.6%; P�0.05), or 5 (100% versus 100%;P�0.05) or when these visits were combined (97.9% versus98.6%; P�0.05).

DiscussionOur results demonstrate that ICG-guided antihypertensivetreatment was more effective in reducing BP than standardtherapy and empiric selection of antihypertensive medica-tions. Patients in the 2 arms of our study were not signifi-cantly different at baseline, and each patient underwent amedication washout period to additionally equalize the 2groups. The 57% BP control rate in the standard arm wassubstantial and compared favorably to BP control rates oflong durations in large antihypertensive trials.19,20 However,the 77% BP control rate in the hemodynamic arm was evenmore impressive with an 8/7 mm Hg greater BP reductionfrom baseline and a 6/7 mm Hg greater BP reduction frompost-washout. As a result, patients in the hemodynamic armachieved goal BP of �140/90 mm Hg 35% more often (77%versus 57%) and the more aggressive level of BP control(�130/85 mm Hg) 104% more often (55 versus 27%) thanthose in the standard arm. The hemodynamic arm maintainedsuperiority in 3 key subgroups: patients who were older, onthiazide diuretics, or had isolated systolic hypertension.

Why did the hemodynamic arm achieve greater reductionsin BP and higher BP control rates than the standard arm? Thefundamental difference between the two arms was that patienttreatment in the hemodynamic arm was individualized andtargeted at the hemodynamic abnormality associated with theelevated BP. This approach led to greater reductions in SVRIin the hemodynamic arm, which allowed greater decreases inboth systolic and diastolic BP. The mechanistic and hemo-dynamically based improvement in BP was also demon-strated in patients achieving BP �130/85 mm Hg throughsignificantly lower SVRI and higher CI in both arms. Intheory, the larger drop in SVRI and BP levels in thehemodynamic arm could have occurred through use of more

TABLE 3. Final Antihypertensive Medications

AntihypertensiveMedication

StandardCare

(n�95)

HemodynamicCare

(n�69)P

Value

No. at final visit 2.0�0.8 2.1�0.9 ns

� Blocker 1 (1.0) 1 (1.4) ns

ACEI 51 (53.7) 34 (49.3) ns

ARB 29 (30.5) 32 (46.4) �0.05

� Blocker 18 (19.0) 6 (8.7) ns

Calcium channel blocker,dihydropyridine

36 (37.9) 28 (40.6) ns

Calcium channel blocker,nondihydropyridine

6 (6.3) 7 (10.1) ns

Central acting agent 0 (0.0) 1 (1.4) ns

Diuretic, thiazide 32 (33.7) 24 (34.8) ns

Diuretic, loop 1 (1.1) 0 (0.0) ns

Diuretic, potassium sparing 6 (6.3) 3 (4.3) ns

Vasodilator 0 (0.0) 0 (0.0) ns

Categorical variables expressed as n (%); ns indicates not significant.




medications, more effective medications, greater dosing in-tensity, more effective combination therapy, or better patientcompliance. Our study allowed full discretion by the physi-cian in choosing the agents, and a multitude of classes anddoses within classes were used. The study was not powered tofind small disparities in medication use, and most medicationdifferences did not reach statistical significance.

On the other hand, some differences are worth noting.Patients in the standard arm were more likely to experienceboth increases and decreases in their medication doses,whereas medication class changes were not different betweenarms. This result might have been expected, because treat-ment in the standard arm followed guidelines and usualpractice patterns in which a stepped approach to therapycontributes to a “trial-and-error” method of determiningwhether agents and doses are working. In the hemodynamicarm, the initial selection of antihypertensive medicationsappears to have been influenced by the hemodynamic data,because these patients were more likely to be prescribed avasodilating agent to reduce SVRI. Additionally, the hemo-dynamic treatment strategy influenced medication use whenSVRI was considered high, because patients in the hemody-namic arm were more likely to have received an ACEI, ARB,or CCB, as was suggested. The hemodynamic treatmentstrategy did not influence the prescription of � blockers in thepresence of high CI or in diuretic use in response to TFCchanges. However, �-blocker use was lower or reduced in thepresence of low or normal CI in the hemodynamic arm.Although the final number of antihypertensive medicationsgiven to patients in both arms of the study was similar,patients in the hemodynamic arm were more likely to beprescribed an ARB. However, when ACEI and ARB use wascombined into a single category (renin–angiotensin–aldoste-rone system inhibitors), the hemodynamic arm only trendedtoward greater use at the final visit (87.0% versus 76.8%).

Thiazide diuretic use increased during the study but waslower than in some pharmacological trials and what hyper-tension guidelines currently suggest. However, the percent-age of patients in both arms who were prescribed a thiazidediuretic at the final visit was very similar to the 35.6% usagethat was reported in recent analysis of over 25 000 hyperten-sive patients.21 The lower use of diuretics and � blockers alsofollows the previously recognized physician preference forother antihypertensive agents.22 Some might hypothesize thatgreater BP reductions could have been achieved in thestandard arm if diuretics were used more frequently. How-ever, when patients taking a thiazide diuretic were examinedas a subgroup, the hemodynamic arm maintained its superi-ority. Additionally, although the higher doses of thiazidediuretics in the standard arm may have contributed to agreater drop in TFC from the post-washout visit, they did notlead to better BP control.

Our study was not intended to evaluate whether a particularantihypertensive agent was more effective at reducing BPthan another. Rather, it was designed to determine whetherproviding hemodynamic data to the physician and patientcould more effectively reduce BP. Whether hemodynamicdata led to a more tailored approach to selection and moni-toring of antihypertensive agents or by other factors, it

resulted in greater reduction in BP and SVRI and better BPcontrol. Physicians cannot adequately estimate hemodynam-ics from routine clinical examination or BP measurements,23

because at similar levels of BP, SVR and CO can vary widely.Therefore, the addition of accurate, noninvasive, and readilyobtainable hemodynamic measurements is clinically relevant.

Importantly, the current study also showed that patients inthe hemodynamic arm were almost twice as likely to achieveBP control with normalization of both CI and SVRI. Im-provements in vascular resistance may result in greaterbenefits in reducing cardiovascular risk than improvement inBP alone,24 and differences in SVRI at the same BP mayexplain poorer prognosis for men versus women25 and blackversus nonblack patients.26 Hemodynamics are also known tochange with age. In older subjects, decreased arterial com-pliance and CI lead to increased SVRI, arterial BP, and pulsepressure.27 In spite of the expected differences in the hemo-dynamics of older patients, this study demonstrated thathemodynamically driven, individualized therapy was simi-larly effective regardless of age or existence of isolatedsystolic hypertension.

The use of ICG to achieve greater BP control offers thepotential for better short-term use of healthcare resources. Inaddition, the long-term benefits of even small levels of BPreduction are well known. A sustained BP reduction of4/3 mm Hg is expected to reduce stroke risk 23%, coronaryheart disease events 15%, heart failure 16%, and overallmortality 14%.28 Accordingly, a recent meta-analysis ofmajor hypertension trials reveals that an antihypertensiveagent is judged favorably when it produces mean BP im-provements versus placebo of only 3 or 4 mm Hg or versusanother antihypertensive agent of only 1 or 2 mm Hg.29

Previously, ICG has been used to profile hemodynamicvariability across BP values30 and to identify left ventriculardysfunction.31 Changes in ICG parameters have demonstratedthe hemodynamic effect of antihypertensive agents32,33 anddietary sodium.34 ICG-guided therapy has shown benefit in acase series,35 observational study,36 and a randomized trial inresistant hypertensive patients.12 In the randomized trial,ICG-guided therapy resulted in better final BP and greater BPcontrol. Similar to our study, that study showed no differ-ences in the number of medications between arms. In contrastto our study with lower diuretic doses and fewer medicationchanges in the hemodynamic arm, resistant hypertensionpatients receiving ICG-guided therapy had higher diureticdoses and more medication changes. The differences betweenthe studies might be expected because of the difference inpatients (severe hypertension on more medications versusmilder hypertension on fewer medications) and setting (spe-cialist versus generalist). However, in both studies, ICG-guided therapy led to more effective treatment as evidencedby better BP outcomes.

The conclusions of this study may be limited to its durationof 3 months. However, in pharmacological trials, short-termreductions in BP are typically sustained over longer periods.37

Another limitation may be in our use of patient-reportedmedication compliance. Without using automatic countingprocedures, our goal was to educate both arms equally and toreinforce patient compliance with follow-up phone calls.




Lastly, treatment differences in the hemodynamic arm do notimply superiority of one medication over another, because thestudy was not designed to evaluate this question.

PerspectivesThe results of this study indicate that ICG-guided antihyper-tensive therapy in uncontrolled hypertensive patients on 1 to3 antihypertensive medications is more effective than stan-dard care. This was evident by greater reductions in systolicand diastolic BP and by achieving a better level of BP control.Our study showed that, in clinical practice, inclusion of ICGhemodynamic assessment may improve BP control rates inpatients who are not controlled on initial therapy.

AcknowledgmentsConsideration of Noninvasive Hemodynamic Monitoring to TargetReduction of Blood Pressure Levels (CONTROL) Site Investigators:Fred E. Abbo, Douglas C. Beatty, Donald M. Brandon, Milan L.Brandon, Anthony V. Dallas, Jr, Lawrence Dinenberg, Mazhar ElAmir, Nigar Enayat, Neil W. Hirschenbein, Dorothy Lebeau, Ber-nard A. Michlin, John Millspaugh, Nell Nestor, Melissa Noble,Robin F. Spiering, Joseph Taylor, and Allen R. Walker. Statisticalsupport was provided by Gerard Smits and the study was sponsoredby CardioDynamics (San Diego, CA).

References1. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The

burden of adult hypertension in the United States 1999 to 2000: a risingtide. Hypertension. 2004;44:398–404.

2. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J.Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–223.

3. Chery DK, Woodwell DA. National Ambulatory Care Medical Survey:2000 summary. Advance Data. 2002;328:1–32.

4. American Heart Association. Heart Disease and Stroke Statistics —2004Update. Dallas, Texas: American Heart Association; 2003.

5. Wang Y, Wang QJ. The prevalence of prehypertension and hypertensionamong US adults according to the new joint national committee guidelines:new challenges of the old problem. Arch Intern Med. 2004;164:2126–2134.

6. Yakovlevitch M, Black HR. Resistant hypertension in a tertiary careclinic. Arch Intern Med. 1991;151:1786–1792.

7. Ferrario CM, Page IH. Current views concerning cardiac output in thegenesis of experimental hypertension. Circ Res. 1978;43:821–831.

8. Davidson RC, Ahmad S. Hemodynamic profiles in essential and sec-ondary hypertension. In: Izzo JL, Black HR, eds. Hypertension Primer.3rd ed. Dallas, TX: Council on High Blood Pressure Research, AmericanHeart Association; 2003:349–351.

9. Sullivan JM, Schoeneberger TE, Ratts ET, Palmer ET, Samaha JK,Mance CJ, Muirhead EE. Short-term therapy of severe hypertension.Hemodynamic correlates of the antihypertensive response in man. ArchIntern Med. 1979;139:1233–1239.

10. Egan B, Schmouder R. The importance of hemodynamic considerationsin essential hypertension. Am Heart J. 1988;116:594–599.

11. Northridge DB, Findlay IN, Wilson J, Henderson E, Dargie HJ. Non-invasive determination of cardiac output by Doppler echocardiographyand electrical bioimpedance. Br Heart J. 1990;63:93–97.

12. Taler SJ, Textor SC, Augustine JE. Resistant hypertension: Comparing he-modynamic management to specialist care. Hypertension. 2002;39:982–988.

13. Ventura HO, Taler SJ, Strobeck JE. Hypertension as a hemodynamicdisease: the role of impedance cardiography in diagnostic, prognostic, andtherapeutic decision making. Am J Hypertens. 2005;18:26S–43S.

14. Van De Water JM, Mount BE, Chandra KM, Mitchell BP, Woodruff TA,Dalton ML. TFC (thoracic fluid content): a new parameter for assessmentof changes in chest fluid volume. Am Surg. 2005;71:81–86.

15. Treister N, Wagner K, Jansen PR. Reproducibility of impedance cardi-ography parameters in outpatients with clinically stable coronary arterydisease. Am J Hypertens. 2005;18:44S–50S.

16. Van De Water JM, Miller TW. Impedance cardiography: the next vitalsign technology? Chest. 2003;123:2028–2033.

17. Yung G, Fedullo P, Kinninger K, Johnson W, Channick R. Comparisonof impedance cardiography to direct fick and thermodilution cardiac

output determination in pulmonary arterial hypertension. Congest HeartFail. 2004;10(2 suppl 2):7–10.

18. Defined Daily Dose (DDD) developed by the World Health Organizationfor use in drug utilization studies. WHO Collaborating Centre for DrugStatistics Methodology. Anatomical Therapeutic Chemical (ATC) Clas-sification Index With Defined Daily Doses (DDDs). Oslo, Norway: WHOCollaborating Centre; 2000.

19. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U,Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, LindholmLH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group.Cardiovascular morbidity and mortality in the Losartan Intervention forEndpoint reduction in hypertension study (LIFE): a randomised trialagainst atenolol. Lancet. 2002;359:995–1003.

20. ALLHAT Officers and Coordinators for the ALLHAT CollaborativeResearch Group. The Antihypertensive and Lipid-Lowering Treatment toPrevent Heart Attack Trial. Major outcomes in moderately hypercholes-terolemic, hypertensive patients randomized to pravastatin vs usual care:The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT-LLT). JAMA. 2002;288:2998–3007.

21. Singh H, Johnson ML. Prescribing patterns of diuretics in multi-drugantihypertensive regimens. J Clin Hypertens. 2005;7:81–87.

22. Ubel PA, Jepson C, Asch DA. Misperceptions about �-blockers anddiuretics: a national survey of primary care physicians. J Gen Intern Med.2003;18:1060–1061.

23. Connors AF, Dawson NV, Shaw PK, Montenegro HD, Nara AR, MartinL. Hemodynamic status in critically ill patients with and without acuteheart disease. Chest. 1990;98:1200–1206.

24. Fagard RH, Pardaens K, Staessen JA, Thijs L. Prognostic value ofinvasive hemodynamic measurements at rest and during exercise inhypertensive men. Hypertension. 1996;28:31–36.

25. Messerli FH, Garavaglia GE, Schmieder RE, Sundgaard-Riise K, NunezBD, Amodeo C. Disparate cardiovascular findings in men and womenwith essential hypertension. Ann Intern Med. 1987;107:158–161.

26. Hinderliter A, Blumenthal J, Waugh R, Chilukuri M, Sherwood A. Ethnicdifferences in left ventricular structure: Relations to hemodynamics anddiurnal blood pressure variation. Am J Hypertens. 2004;17:43–49.

27. Alfie J, Galarza C, Waisman G. Noninvasive hemodynamic assessment ofthe effect of mean arterial pressure on the amplitude of pulse pressure.Am J Hypertens. 2005;18:60S–64S.

28. Blood Pressure Lowering Treatment Trialists Collaboration. Effects ofdifferent blood-pressure-lowering regimens on major cardiovascularevents: results of prospectively-designed overviews of randomized trials.Lancet. 2003;362:1527–1545.

29. Williams B. Recent hypertension trials: implications and controversies.J Am Coll Cardiol. 2005;45:813–827.

30. Abdelhammed AI, Smith RD, Levy P, Smits GJ, Ferrario CM. Nonin-vasive hemodynamic profiles in hypertensive subjects. Am J Hypertens.2005;18:51S–59S.

31. Bhalla V, Isakson S, Bhalla MA, Lin JP, Clopton P, Gardetto N, MaiselAS. Diagnostic ability of B-type natriuretic peptide and impedance car-diography: testing to identify left ventricular dysfunction in hypertensivepatients. Am J Hypertens. 2005;18:73S–81S.

32. Mitchell A, Buhrmann S, Saez AO, Rushentsova U, Schafers RF, PhilippT, Nurnberger J. Clonidine lowers blood pressure by reducing vascularresistance and cardiac output in young, healthy males. Cardiovasc DrugsTher. 2005;19:49–55.

33. Breithaupt-Grogler K, Gerhardt G, Lehmann G, Notter T, Belz GG.Blood pressure and aortic elastic properties–verapamil SR/trandolaprilcompared to a metoprolol/hydrochlorothiazide combination therapy. IntJ Clin Pharmacol Ther. 1998;36:425–431.

34. Ashida T, Nishioeda Y, Kimura G, Kojima S, Kawamura M, Imanishi M,Abe H, Kawano Y, Yoshimi H, Yoshida K, Kuramochi M, Omae T.Effects of salt, prostaglandin, and captopril on vascular responsiveness inessential hypertension. Amer J Hypertens. 1989;2:640–642.

35. Sharman DL, Gomes CP, Rutherford JP. Improvement in blood pressurecontrol with impedance cardiograph-guided pharmacologic decisionmaking. Congest Heart Fail. 2004;10:54–58.

36. Sramek BB, Tichy JA, Hojerova M, Cervenka V. Normohemodynamicgoal-oriented antihypertensive therapy improves the outcome (abstract).Amer J Hypertens. 1996;9:141A.

37. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, HuaT, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B,Zanchetti A. VALUE trial group. Outcomes in hypertensive patients athigh cardiovascular risk treated with regimens based on valsartan oramlodipine: the VALUE randomised trial. Lancet. 2004;363:2022–2031.




www.elsevier.com/locate/heafai

86

The European Journal of Heart

Non-invasive measurement of cardiac output by whole-body

bio-impedance during dobutamine stress echocardiography: Clinical

implications in patients with left ventricular dysfunction and ischaemia

Marina Leitman a, Edgar Sucher a, Edo Kaluski a, Ruth Wolf a, Eli Peleg a, Yaron Moshkovitz b,

Olga Milo-Cotter a, Zvi Vered a, Gad Cotter c,*

aCardiology Department, Assaf-Harofeh Medical Center, IsraelbCardiac Surgical Department, Ramat-Marpe-Assuta Medical Center, Petah Tikva, Sackler School of Medicine, Tel-Aviv University, Israel

cDuke Clinical Research Institute, PO Box 17969, Durham NC, 27715, USA

Received 20 December 2004; accepted 30 June 2005

Available online 29 September 2005

Abstract

Objectives: To compare non-invasive determination of cardiac index (CI) by whole body electrical bioimpedance using the NICaS apparatus

and Doppler echocardiography, and the role of cardiac power index (Cpi) and total peripheral resistance index (TPRi) calculation during

dobutamine stress echocardiography (DSE).

Subjects and methods: We enrolled 60 consecutive patients undergoing DSE. Patients were prospectively divided into 3 groups: Group 1

(n =20): normal DSE (control). Group 2 (n =20): EF<40% without significant ischaemia. Group 3 (n =20): patients with significant

ischaemia on DSE. Measurements of CI were performed at the end of each stage of DSE by both echocardiographic left ventricular

outflow track flow and the NICaS apparatus, using whole-body bio-impedance. MAP was measured simultaneously and TPRi and Cpi

were calculated.

Results: The correlation between non-invasive CI as determined by NICaS and echocardiography was 0.81, although Echocardiographic

readings of CI were higher during administration of higher doses of dobutamine. Lower EF correlated with lower Cpi, especially stress

induced Cpi. Hence, patients with reduced EF (group 2) had a blunted increase in Cpi during stress. Patients with ischaemia (group 3) had a

blunted increase in Cpi as well as a decrease in Cpi and increase in TPRi during the last stages of DSE.

Conclusion: Measurement of CI by NICaS correlated well with Doppler derived CI. The calculation of Cpi and TPRi changes during

dobutamine stress may provide important clinical information.

D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Cardiac index; Cardiac power; Bioimpedance

1. Background and aims

Cardiac power index (Cpi) is the product of simulta-

neously measured cardiac index (CI) and mean arterial

blood pressure (MAP). Cpi increases — cardiac power

reserve during stress [1,2] or dobutamine administration

[3] was shown in previous studies to be an important

1388-9842/$ - see front matter D 2005 European Society of Cardiology. Publish

doi:10.1016/j.ejheart.2005.06.006

* Corresponding author. Duke Clinical Research Institute, 2400 Pratt

Street, Durham, 27715 NC, USA.

E-mail address: [email protected] (G. Cotter).

of 158.

measure of systolic cardiac contractile reserve, better than

VO2 and echocardiographic ejection fraction (EF).

Recently, Samejima et al. [4] demonstrated that CO

increase during stress using non-invasive CO determina-

tion with bioimpedance was correlated with stress induced

dyspnea.

The use of hemodynamic measures such as increase in

vascular resistance for the detection of ischaemia was

suggested almost a decade ago [5]. However, this research

avenue has not been pursued due to the lack of simple non-

invasive devices for CO measurement. Recently Weiss et al.

Failure 8 (2006) 136 – 140

ed by Elsevier B.V. All rights reserved.

Table 1

Baseline characteristics of patients in the three groups

Normal

DSE

Ischaemia

by DSE

EF<40% P value

N 20 20 20

Age (years) 59T10 59T17 54T20 0.6

Prior MI 25% 55% 90% 0.003

Hypertension 50% 75% 80% 0.12

Diabetes mellitus 25% 45% 50% 0.46

Hyperlipidaemia 35% 55% 40% 0.6

Prior smoking 30% 35% 30% 0.7

Family history of ischaemic

heart disease

30% 10% 10% 0.3

Medical therapy

Aspirin 75% 95% 85% 0.17

Beta-blockers 45% 75% 80% 0.03

ACEi/AT II antagonists 30% 55% 90% 0.04

Diuretics 10% 45% 90% 0.03

Statins 45% 80% 75% 0.1

Echocardiographic findings

Left ventricular EF (%) 57T6 50T11 28T7 <0.001

LVH 40% 50% 45% 0.78

EF: Ejection fraction, MI: Myocardial infarction, ACEi: Angiotensin

converting enzyme inhibitors, ATII antagonists — angiotensin II antago-

nists, LVH: Left ventricular hypertrophy.

R=0.81

NIC

as C

I

Echo CI0 2 4 6 8 10

10 9 8 7 6 5 4 3 2 1 0

Fig. 1. Correlation between Doppler echocardiography CI and NICaS CI

measurements. Horizontal axis — CI measured by echocardiography, L/

min/M2, Vertical axis: CI measured by NICaS, L/min/M2.

M. Leitman et al. / The European Journal of Heart Failure 8 (2006) 136–140 137

8

[6] demonstrated that in patients with significant ischaemia

during stress, CO increase by bio-impedance is lower than

in patients without ischaemia.

The NICaS apparatus uses whole body bio-impedance and

the Tsoglin–Frinerman formula for non-invasive determi-

nation of CI [7]. In short, a small electrical current is

transferred from the left wrist to the right foot, and the

impedance to its transit is detected (termed whole-body bio-

impedance). The instantaneous change in bio-impedance has

previously been shown to be related to the pulsatile changes

in the volume of the great arteries. The Tsoglin–Frinerman

formula uses this change in bio-impedance (DR) as well as

population based constants correcting for age, sex, weight

and body composition (electrolytes, haematocrit and changes

in baseline bio-impedance) to calculate the stroke volume

(SV). Thereafter by electrocardiographically measuring the

pulse rate it calculates cardiac output and CI. In a few recently

published studies [7–9], NICaS measurements of CI in

patients with various cardiac conditions showed good

reproducibility and correlated well with thermodilution

(R =0.8–0.9), with no bias and precision of approximately

0.6 L/min/M2.

The aim of the present study was two fold: first, to

compare CI measurements by NICaS and Doppler echocar-

diography over a wide range of values during dobutamine

stimulation and, secondly, to determine whether the non-

invasive continuous measurement of CI and MAP and

calculation of Cpi and TPRi changes during dobutamine

stress could be used for diagnosis of significant left

ventricular (LV) dysfunction or myocardial ischaemia as

determined by dobutamine stress echocardiography (DSE).

7 of 158.

2. Patients and methods

We enrolled 60 consecutive patients undergoing stand-

ard DSE using incremental dobutamine infusion from 10

to 40 Ag/min and atropine up to 1 mg as required to reach

the pre-determined target heart rate. Patients were recruited

in our outpatient clinic during a once weekly session. All

consecutive patients attending the clinic during that day for

the purpose of DSE were considered for the study. Patients

were divided into 3 groups: Group 1: Control. Normal

DSE, including baseline EF >40% and no significant

ischaemia, Group 2: LV systolic dysfunction as determined

by baseline echocardiographic EF <40% without signifi-

cant ischaemia and Group 3: Significant ischaemia as

determined by improvement of contractility during low-

dose dobutamine infusion followed by decreased contrac-

tility during high dose dobutamine infusion in at least one

non-infarcted myocardial segment.

Exclusion criteria were inability to achieve good

echocardiographic visualization, significant hypotensive or

hypertensive reactions or tachy or bradyarrhythmias during

dobutamine infusion and inability to reach the pre-deter-

mined heart rate.

2.1. Study protocol

DSE was performed according to a standard protocol by

2 DSE teams. NICaS CI was measured by one NICaS

operator. CI was determined by both echocardiographic left

ventricular outflow track (LVOT) diameter and flow

velocity as well as the NICaS apparatus. Operators

measuring CI by one method were blinded to the result

of the other method throughout the examination. There-

after, based on NICaS determined CI, we calculated Cpi

and total peripheral vascular resistance (TPRi) for each of

the above mentioned time-points. NICaS and Doppler

determined CI were not calculated during dobutamine

administration in 3 patients (5%) in whom it was judged by

3

2

1

0

-1

-2

-3

-4

-50 1 2 3 4 5 6 7 8 9D

iffer

ence

in C

I (Ec

ho D

oppl

er, N

ICaS

)

Mean CI (Echo Doppler; NICaS)

Fig. 2. Difference of CI measurements by Doppler echocardiography and NICaS vs. their mean (Bland and Altman analysis).

M. Leitman et al. / The European Journal of Heart Failure 8 (2006) 136–140138

88

the operator that LVOT obstruction occurred due to

dobutamine administration.

2.2. Study end-points

(1) The correlation between NICaS and Doppler echo-

cardiography derived CI and (2) the absolute and relative

changes in NICaS determined Cpi and TPRi during dobut-

amine stress in the 3 groups.

2.3. Statistical methods

All data is reported based on pre-determined group

allocations. To compare the baseline characteristics of the

groups we used the Student’s t-test to compare continuous

variables and the chi-square test to compare categorical

variables. Since the cardiac index and cardiac power

measurements were not normally distributed we used the

Spearman-rank test for comparison of NICaS and echo-

cardiographically determined CI and for comparison of

resting EF and Cpi during the different stages of DSE.

Since both NICaS and Doppler echocardiography are not

regarded as gold standard for CI determination, when

comparing the two methods we used the Bland and

Altman [10] recommendations and for each dobutamine

stage, as well as for the whole cohort, we determined bias

(mean difference between the 2 methods) and the limits of

agreement (precision) calculated as 2 SD of the bias.

Table 2

CI measurements obtained by Doppler echocardiography and NICaS during the d

Dobutamine infusion

rate

Mean NICaS-CI Mean echo-Doppl

Baseline 2.9T0.6 2.8T0.6

10 Ag/min 3.4T0.9 3.4T1.120 Ag/min 4.1T1.1 4.2T1.5

30 Ag/min 4.7T1.4 4.9T1.5

40 Ag/min 4.7T1.2 5.2T1.4

All measurements 3.9T1.3 4.1T1.5

of 158.

Analysis of variance with repeated measurements (time*

group) was used to compare changes in Cpi and TPRi

over time in the different groups. All P values <0.05

were considered significant.

3. Results

Sixty consecutive patients where enrolled in the 3

prospectively defined groups. The baseline characteristics

of the three groups are presented in Table 1. As expected,

patients differed with respect to baseline echocardio-

graphic EF, age and severity of background diseases.

The correlation between CI as determined by echocardio-

graphic LVOT area and mean flow velocity and the NICaS

apparatus was R =0.81 (Fig. 1). The Bland–Altman

distribution of CI measurements is depicted in Fig. 2. The

correlation was better for CI measurements at baseline and

during the infusion of dobutamine at doses of up to 20 Ag/min than for CI determinations during administration of

dobutamine at a rate of 30 and 40 Ag/min (Table 2, Fig. 2),

due to increasing bias (i.e., CI measurements by Doppler

echocardiography tending to be higher) and lower precision.

Therefore, the CI increase in the different stages of DSE was

similar by both techniques (Fig. 3). Again, a slight tendency

was observed for higher increase in the Doppler echocar-

diography determined CI during the last phase of dobut-

amine infusion.

ifferent DSE stages

er CI Spearman Rank

Correlation

Bias Precision

0.77 �0.06 0.39

0.81 0.04 0.71

0.87 0.16 0.8

0.81 0.24 1.16

0.62 0.49 1.18

0.81 0.17 0.9

5.5

5

4.5

4

3.5

3

2.50 10 20 30 40

Dobutamine dose (mcg/min)NICaS CI Echo-Doppler CI

CI (

Lite

r/min

/M2)

Fig. 3. Trend changes in CI during dobutamine infusion: Doppler

echocardiography vs. NICaS CI.

1.4

1.2

1

0.8

0.6

0.4

0.2

00 10 20 30 40

Dobutamine dose(mcg/min.)

Cpi

(wat

t/M2)

Normal DSE Ischaemia EF<40%

Fig. 4. Changes in Cpi during dobutamine infusion in the 3 groups.

M. Leitman et al. / The European Journal of Heart Failure 8 (2006) 136–140 139

8

We have observed a significant correlation between EF and

Cpi based both on echocardiographically determined CI and

on NICAS-CI (Table 3). Interestingly, and consistent with

previous studies [11], this correlation was better for stress

Cpi than for rest Cpi.

During dobutamine infusion, NICaS determined Cpi

increase was significantly different in the three groups

(Fig. 4). Cpi increase was smallest in the group of patients

with LV dysfunction followed by the group of patients

with significant ischaemia and highest in patients with

normal DSE ( p =0.002 comparing LV dysfunction with

normal DSE, p =0.03 comparing patients with ischaemia

with patients with normal DSE and p =0.02 comparing

patients with ischaemia to patients with LV dysfunction).

Baseline TPRi was significantly higher at baseline in the

LV systolic dysfunction group as compared to patients with

normal DSE (3120T1020 vs. 2450T940 dynes s M2,

p =0.04) however, during dobutamine stress it decreased

steeply in all 3 groups, to a similar degree.

A significant difference was observed in Cpi and TPRi

changes during the last phase of dobutamine infusion in

patients in the significant ischaemia group. As compared to

patients in the control as well as the systolic LV dysfunction

group, patients who were found by DSE to have significant

ischaemia had during the last phase of DES a significant

decrease in Cpi (�0.16T0.15 vs. +0.1T0.15 W/M2,

Table 3

Correlations between resting EF and Cpi by NICaS and echocardiography

during the different DSE stages

Dobutamine

infusion rate

Spearman Rank

Correlation between

resting EF and

echo-Doppler Cpi at

different DSE stages

Spearman Rank Correlation

between resting EF and

NICaS-Cpi at different

DSE stages

Baseline 0.44 0.44

10 Ag/min 0.56 0.39

20 Ag/min 0.61 0.54

30 Ag/min 0.58 0.53

40 Ag/min 0.59 0.45

All measurements 0.57 0.52

9 of 158.

p =0.0002) and increase in TPRi. (+279T636 vs. �59T169 dynes s M2, P=0.022).

No significant adverse events were recorded during the

dobutamine stress test.

4. Discussion

The results of the present study demonstrate that CI

determination by whole-body bio-impedance using the

NICaS device is correlated well with CI determination by

Doppler echocardiography. However, during infusion of

higher doses of dobutamine (�30 Ag/min), the correlation

became less accurate, mainly due to significant bias, i.e.

Doppler echocardiography CI measurements tended to be

significantly higher than NICaS readings.

In the overall cohort we found a correlation between

severity of LV dysfunction by resting EF and Cpi at rest and

especially Cpi during the dobutamine stress; i.e., the lower

the EF the lower the rest and peak DSE Cpi. Hence, in the

group of patients with reduced baseline EF (group 2), Cpi

increase during exercise was significantly blunted. This

finding is substantiated by the results of previous studies

showing that lower Cpi increase during stress (lower cardiac

power reserve) is correlated with poor outcome — although

this correlation was superior to the correlation of EF and

outcome. In the present study, the small number of patients

enrolled did not allow for outcome analysis, however, it is

possible that accurate non-invasive CI determination and

calculation of Cpi reserve by whole body bio-impedance

during stress may become a useful predictor of outcome in

patients with reduced left ventricular function.

The results of the present cohort, in concordance with

previous studies [5,6] show that during significant ischae-

mia, cardiac power tends to decrease and vascular resistance

increases. Again, such non invasive calculation may enable

an additional important indication for significant ischaemia

in addition to conventional signs on DSE.

Importantly, all haemodynamic data was obtained in the

present study using a simple non-invasive device. Although

M. Leitman et al. / The European Journal of Heart Failure 8 (2006) 136–140140

90

the size of the present cohort does not allow for far-reaching

conclusions, if these results are reproduced by additional,

larger studies, cardiac power and vascular resistance

changes could be used for non-invasive detection of left

ventricular dysfunction and ischaemia during simple stress

tests such as electrocardiographic exercise stress test or

mental stress test. Moreover, serial changes in these

measures may be useful for improving detection of

ischaemia in patients at home using telemedicine.

4.1. Study limitations

The study included a small, select group of patients

referred for DSE due to various symptoms. Hence, the

results require further confirmation in a larger study

including a non-selected group of outpatients.

5. Conclusion

The results of the present study suggest that a simple

stress test using dobutamine infusion and non-invasive

determination of CI by the NICaSi 2001 apparatus and

calculation of Cpi and TPRi can be used for easy out-patient

screening of patients for systolic LV dysfunction and

myocardial ischaemia.

References

[1] Williams SG, Cooke GA, Wright DJ, Parsons WJ, Riley RL, Marshall

P, et al. Peak exercise cardiac power output. A direct indicator of

of 158.

cardiac function strongly predictive of prognosis in chronic heart

failure. Eur Heart J 2001;22:1496–503.

[2] Cohen-Solal A, Tabet JY, Logeart D, Bourgoin P, Tokmakova M,

Dahan M. A non-invasively determined surrogate of cardiac power

(Fcirculatory power_) at peak exercise is a powerful prognostic factor

in chronic heart failure. Eur Heart J 2002;23:806–14.

[3] Marmor A, Schneeweiss A. Prognostic value of noninvasively

obtained left ventricular contractile reserve in patients with severe

heart failure. J Am Coll Cardiol 1997;29:422–8.

[4] Samejima H, Omiya K, Uno M, Inoue K, Tamura M, Itoh K, et al.

Relationship between impaired chronotropic response, cardiac output

during exercise, and exercise tolerance in patients with chronic heart

failure. Jpn Heart J 2003;44:515–25.

[5] Mohr R, Rath S, Meir O, Smolinsky A, Har-Zahav Y, Neufeld HN,

et al. Changes in systemic vascular resistance detected by the arterial

resistometer: preliminary report of a new method tested during

percutaneous transluminal coronary angioplasty. Circulation 1986;

74:780–5.

[6] Weiss SJ, Ernst AA, Godorov G, Diercks DB, Jergenson J, Kirk JD.

Bioimpedance-derived differences in cardiac physiology during

exercise stress testing in low-risk chest pain patients. South Med J

2003;96:1121–7.

[7] Cohen AJ, Arnaudov D, Zabeeda D, Schultheis L, Lashinger J,

Schachner A. Non-invasive measurement of cardiac output during

coronary artery bypass grafting. Eur J Cardiothorac Surg 1998;14:

64–9.

[8] Cotter G, Moshkovitz Y, Kaluski E, Cohen AJ, Miller M, Goor DA,

et al. Accurate, non-invasive continuous monitoring of cardiac output

by whole body electrical bio-impedance. Chest 2004;125:1431–40.

[9] Torre-Amione G, Cotter G, Kaluski E, Salah A, Milo O, Richter C,

et al. Non-invasive measurement of cardiac output by whole-body

electrical bioimpedance in patients treated for acute heart failure: a

prospective, double blind comparison with thermodilution. J Am

Coll Cardiol 2004;43:109 [abstract].

[10] Bland JM, Altman DG. Statistical methods for assessing agreement

between two methods of clinical measurement. Lancet 1986;1:307–10.

[11] Cotter G, Williams SG, Vered Z, Tan LB. The role of cardiac power in

heart failure. Curr Opin Cardiol 2003;18:215–22.

CLINICAL INVESTIGATIONS

Impact of Impedance Cardiography onDiagnosis and Therapy of EmergentDyspnea: The ED-IMPACT TrialW. Frank Peacock, MD, Richard L. Summers, MD, Jody Vogel, MD, Charles E. Emerman, MD

AbstractBackground: Dyspnea is one of the most common emergency department (ED) symptoms, but early diag-nosis and treatment are challenging because of multiple potential causes. Impedance cardiography (ICG) isa noninvasive method to measure hemodynamics that may assist in early ED decision making.

Objectives: To determine the rate of change in working diagnosis and initial treatment plan by adding ICGdata during the course of ED clinical evaluation of elder patients presenting with dyspnea.

Methods: The authors studied a convenience sample of dyspneic patients 65 years and older who werepresenting to the EDs of two urban academic centers. The attending emergency physician was initiallyblinded to the ICG data, which was collected by research staff not involved in patient care. At initial EDpresentation, after history and physical but before central lab or radiograph data were returned, the at-tending ED physician completed a case report form documenting diagnosis and treatment plan. The phy-sician then was shown the ICG data and the same information was again recorded. Pre- and post-ICGdifferences were analyzed.

Results: Eighty-nine patients were enrolled, with a mean age of 74.8 � 7.0 years; 52 (58%) were AfricanAmerican, 42 (47%) were male. Congestive heart failure and chronic obstructive pulmonary diseasewere the most common final diagnoses, occurring in 43 (48%), and 20 (22%), respectively. ICG datachanged the working diagnosis in 12 (13%; 95% CI = 7% to 22%) and medications administered in 35(39%; 95% CI = 29% to 50%).

Conclusions: Impedance cardiography data result in significant changes in ED physician diagnosis andtherapeutic plan during the evaluation of dyspneic patients 65 years and older.

ACADEMIC EMERGENCY MEDICINE 2006; 13:365–371 ª 2006 by the Society for Academic EmergencyMedicine

Keywords: dyspnea, hemodynamics, impedance cardiography, bioimpedance, cardiac output, systemicvascular resistance, noninvasive

Dyspnea is one of the most common emergencydepartment (ED) symptoms in older patients.1

Various conditions, including heart failure,chronic obstructive pulmonary disease, pneumonia, pul-monary embolus, and acute coronary syndromes, mayoccur alone or in combination in a given patient, adding

uncertainty to diagnosis and treatment. In patients withboth cardiac and pulmonary disease, the initial assess-ment and therapy in the ED are challenging.

Because cardiovascular disease, specifically decom-pensated heart failure (HF), is a relatively common causeof dyspnea in elders, an assessment of hemodynamics,

From the Department of Emergency Medicine, Cleveland Clinic

(WFP), Cleveland, OH; Department of Emergency Medicine,

University of Mississippi (RLS), Jackson, MS; Wayne State

University (JV), Detroit, MI; and Department of Emergency

Medicine, Case Western Reserve University (CEE), Cleveland, OH.

Received September 6, 2005; revision received November 7,

2005; accepted November 15, 2005.

Supported by GE Medical Systems (Milwaukee, WI), which

provided devices and disposables for this study, and by Cardio-

Dynamics (San Diego, CA), which provided a study grant for

support of research assistants. In addition, CardioDynamics

participated in the creation of the educational process for the par-

ticipating physicians before study commencement. The sponsor

had no role in data collection or statistical analyses, and the man-

uscript is the sole responsibility of the authors. W.F.P. and R.L.S.

received honoraria in 2003 for speaking for CardioDynamics.

Presented as a moderated poster at the American College of

Emergency Physicians Research Forum, October 2003.

Address for correspondence and reprints: W. Frank Peacock,

MD, The Cleveland Clinic Foundation, Department of Emer-

gency Medicine, Desk E-19, 9500 Euclid Avenue, Cleveland,

OH 44195. Fax: 216-445-4552; e-mail: [email protected].

ª 2006 by the Society for Academic Emergency Medicine ISSN 1069-6563

doi: 10.1197/j.aem.2005.11.078 PII ISSN 1069-6563583 365

91 of 158.


including cardiac output, systemic vascular resistance,and fluid status, may provide important informationand aid decision making beyond what is possible fromhistory and physical examination alone. Unfortunately,hemodynamic parameters cannot be accurately deter-mined by patient history or physical examination.2–5 Untilrecently, hemodynamic data could only be obtained bypulmonary artery catheterization. Because this invasiveprocedure is not practical in the ED, physicians typicallyare left to make diagnosis and treatment decisions with-out reliable information about a patient’s hemodynamicstatus.

Noninvasive hemodynamic monitoring by impedancecardiography (ICG) has been used in more than fourmillion patients. Cardiac output (CO) by ICG has beenshown to correlate well with CO obtained by invasivemethods in hospitalized patient populations with correla-tion coefficients for CO by ICG and thermodilution rang-ing from 0.76 to 0.89.6–10 ICG also has been used as analternative to invasive monitoring in the critical caresetting.11 In the ED setting, ICG has been studied for thedifferential diagnosis of dyspnea12–14 and the identificationof pulmonary edema15,16 and provides prognostic infor-mation about hospitalization costs and length of stay.17

ICG results are available within a few minutes, allowingmore rapid patient evaluation than that afforded byradiographic or laboratory studies.

Given the high rate of morbidity, mortality, and hospi-tal readmissions for patients with dyspnea and acute de-compensated HF, there is an urgent need to examinetechnologies that could lead to improvements in care inthe ED. The present study examines an aspect of thera-peutic efficacy18 as it relates to ICG and the acutely dysp-neic emergency patient, and not simply the performanceof ICG as a testing modality. Put into context, previousstudies of commonly used ED tools, such as pulse oxim-etry19,20 and B-type natriuretic peptide (BNP) testing,21

suggest that a 5% to 11% rate of change in diagnosis,or 10% rate of change in therapy, is clinically relevant.The effect of ICG-derived hemodynamics on diagnosisand treatment of dyspnea in the ED is not yet known.The purpose of this study was to determine the rate ofchange in diagnosis and therapy resulting from the avail-ability of ICG data during the initial evaluation of olderED patients presenting with dyspnea.

METHODS

Study DesignThis was a prospective study of dyspneic patients thatwas designed to determine the frequency of change inthe ED physician’s initial diagnosis and therapeutic planafter physician access to noninvasive ICG hemodynamicdata. The study was approved by each hospital’s institu-tional review board. All patients gave informed consentbefore enrollment in the study.

Study Setting and PopulationThe setting was two large urban academic EDs withexperience in using noninvasive hemodynamic monitor-ing. A convenience sample was obtained from patientsage 65 years or older who were presenting with a chiefcomplaint of dyspnea or symptoms of HF, as determined

by the ED physician. Because ICG is not currently recom-mended (per U.S. Food and Drug Administration guide-lines) for the diagnosis of acute coronary syndromes,including acute myocardial infarction (MI), patients wereexcluded if electrocardiogram (ECG) or serum markerswere positive for acute MI. Additional exclusions in-cluded the following: if ICG monitoring was not possiblebecause of inability to place electrodes, if the patient’sweight was greater than 341 pounds, or if the patienthad an activated minute ventilation pacemaker (whichuses an impedance signal). Also, although severe aorticregurgitation that could give a falsely elevated ICG COis rare and generally evident on ED evaluation, we ex-cluded those with aortic regurgitation by past history,and those with the typical diastolic murmur. Last, becausethe treatment and disposition actions for patients needingimmediate intubation and mechanical ventilation are gen-erally well defined from the emergency physician pointof view, and because it was our intent to study thediagnostically most challenging patients, those requiringurgent intubation and mechanical ventilation uponpresentation to the ED were excluded.

Study ProtocolProject coordinators screened candidates and an inde-pendent research nurse, not involved in the diagnosisor treatment of the patient, obtained hemodynamicdata. Hemodynamic data were collected by using theBioZ ICG monitor (CardioDynamics, San Diego, CA), ashas been described elsewhere.22 ICG data are obtainedby the following technique: four dual sensors (each sen-sor consisting of two electrodes) are placed on thepatient, as shown in Figure 1, on opposite sides of theneck at a level between the ears and shoulders and on ei-ther side of the chest in the mid-axillary line at the level ofthe xiphoid process. The outer electrodes in each sensortransmit a low-amplitude, high-frequency current (2.5mA, 70 kHZ), and the inner electrodes detect thoracicvoltage changes. Changes in voltage are used to calculatechanges in impedance (Z). Baseline, static impedance isindicative of chest fluid volume, and dynamic impedance

Figure 1. Front view of impedance cardiography method.

366 Peacock et al. � IMPEDANCE CARDIOGRAPHY IN EMERGENT DYSPNEA

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is affected by aortic blood volume and velocity. Beat-to-beat changes in thoracic impedance are processed tocalculate blood flow per heartbeat (stroke volume) andper minute (cardiac output). By using standard equations,other hemodynamic parameters, such as systemic vascu-lar resistance, are calculated. The reciprocal of baselinethoracic impedance can provide an index of intrathoracicfluid and is termed thoracic fluid content (TFC). TFC hasbeen used to identify intravascular and extravascularfluid changes23,24 and to titrate diuretic therapy.25

Before study initiation, participating physicians re-ceived instruction regarding the interpretation of thehemodynamic values obtained by the ICG device.Attending physicians, all of whom were board-certifiedor board-eligible in emergency medicine, were given adescription of ICG technology and hemodynamic param-eters provided on the ICG report, including definitionsand normal values for cardiac index (CI), resistance, tho-racic fluid content, and measures reflecting left ventricu-lar performance. This was performed at departmentalgrand rounds and at the monthly attending-physicianstaff meeting. Additional information was disseminatedin hardcopy by mailing and was duplicated by e-mail.The pathophysiology of HF and hemodynamic findingsmost suggestive of dyspnea caused by decompensatedHF (reduced CI, elevated systemic vascular resistance,and increased TFC) were described. The expected effectsof various medications on hemodynamic parameterswere discussed, including use of diuretics, vasodilators,and drugs affecting contractility. Additionally, physicianswere provided personal reference cards for use at theirdiscretion that detailed normative values for all ICGdata. Copies of the data card were also kept fixed to theICG device. These data were also shown at the time ofICG unblinding. For any given parameter, ICG data arepresented as a bar indicating the normal human range.The average result and the currently measured data pointthen are indicated on this bar, such that variations fromnormal are readily apparent.

All staff involved with patient care were blinded to theICG data until after the initial history and physical exam-ination by the attending physician. After the initial his-tory and physical exam, but before initiation of therapy(other than supplemental oxygen), and before obtainingany central laboratory or radiographic data, the attend-ing physician completed a case report form indicatinghis or her working diagnoses and short-term therapeuticplans. The physician was then immediately shown theICG hemodynamic data and was asked to complete thecase report form again, this time with consideration ofthe ICG data. All patient care then proceeded accordingto usual ED routine. Blood tests, including electrolytes,blood urea nitrogen (BUN), serum creatinine (Cr), andBNP levels, were obtained in the majority of cases.Although these data were not mandated as part of theprotocol, they were used in most cases to determine finalED diagnosis.

MeasuresThe two primary endpoints were 1) the rates of changein working diagnosis and 2) medical therapy after theaddition of ICG data to the physician’s initial clinicalassessment and therapeutic plan. In the cases in which

the diagnosis changed on the basis of ICG data, a com-parison to the final diagnosis was made to determinewhether the pre- or post-ICG diagnosis was more consis-tent with the final ED diagnosis. The final ED primary di-agnosis was defined as the principal diagnosis at the endof the ED visit after all diagnostic testing was completedand reviewed by the ED physician responsible for dispo-sition. A change in therapy was defined as the addition orsubtraction of a drug or procedure. Changing the dose ofa previously ordered drug was not considered a thera-peutic change. Adverse events were defined as cardiacarrest, intubation for respiratory failure, urgent cardio-version, or blood transfusion.

Data AnalysisThe size of the study was prospectively determined on thebasis of the number needed to detect a 5% rate of changein diagnosis or therapy. Given an alpha of 0.05 and a betaof 0.20, a sample size of 100 was needed to detect a statis-tically significant change. Data were analyzed by an inde-pendent statistician using SAS Software (Cary, NC).

Demographic data are reported descriptively. Continu-ous variables are reported as mean � standard deviation(SD). Rates of change were calculated by dividing thenumber of patients in whom diagnosis or therapeuticplan changed by the total number of patients and werereported as percentages. An analysis of variance wasperformed to assess for differences among vital signsand ICG parameters in the final diagnosis categories.

RESULTS

Eighty-nine patients, cared for by 31 ED staff physicians,were enrolled from December 2001 through July 2003and are included in the analysis. No adverse event,defined as cardiac arrest, intubation, cardioversion, orblood transfusion, occurred during the course of theED observation during this study.

The patient characteristics and vital signs are summa-rized in Table 1. The mean (�SD) age of the subjectswas 74.8 (�7.0) years. Fifty-eight percent of the patientswere African American, and 61% had a history of HF,

Table 1Patient Characteristics and Vital Signs

Patient Characteristic Value

Male, n (%) 42 (47)Ethnic background, n (%)

African American 52 (58)White 36 (41)Other 1 (1)

Medical history, n (%)History of heart failure 43 (48)History of chronic obstructive

pulmonary disease or asthma34 (38)

History of heart failure and COPD 11 (13)Vital signs (mean � SD)

Temperature (ºC) 36.5 � 0.7Respiratory rate (min�1) 22.2 � 5.1Heart rate (min�1) 84.6 � 18.8Systolic blood pressure (mm Hg) 145.6 � 29.3

N = 89.

ACAD EMERG MED � April 2006, Vol. 13, No. 4 � www.aemj.org 367

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including 13% with a history of both HF and chronic lungdisease. The prevalence of chronic lung disease, includ-ing asthma, was 38%. The average respiratory rate was22.2 (�5.1) min�1 with systolic BP and heart rate of145.5 (�29.3) mm Hg and 84.6 (�18.8) min�1, respectively.The hemodynamic values for the population as a wholeare listed in Table 2.

Patients could be categorized by final primary diagno-sis at the time of ED discharge or hospital admission intothree major groups: 1) HF (n = 43); 2) chronic obstructivepulmonary disease (COPD; 20); and 3) ‘‘other’’ (26). Theother group included other cardiovascular and lungconditions not included in the HF or COPD groups: atrialfibrillation (n = 4), bronchitis (4), hypertension (2), pneu-monia (2), pulmonary hypertension (2), anemia (1), influ-enza (1), lung cancer (1), palpitations (1), upperrespiratory infection (1), atypical chest pain (1), hypoxia(1), intra-abdominal abscess (1), non-cardiac shortnessof breath (1), pulmonary fibrosis (1), vertigo (1), and de-hydration (1).

Chest radiographs and ECG results were recorded bythe ED physician in 85 patients (96%). The various ECGand radiographic findings are summarized in Table 3.ECG findings were described as normal or nonspecificin the vast majority (82%), and the chest radiographwas normal or nondiagnostic in nearly half, with only16% showing either HF or upper zone redistributionconsistent with pulmonary venous congestion.

Diagnosis ChangesA summary of the rates of diagnosis and therapy changethat resulted from ICG data are presented in Figure 2.ICG data changed the working diagnosis in 12 (13%;95% CI = 7% to 22%). When diagnoses were categorizedas either cardiac or noncardiac, the post-ICG diagnosiswas the same as the final diagnosis in 8 of 12 patientsin whom ICG resulted in a change (67%, 95% CI = 35%to 90%). Of the four patients in whom a change in diag-nosis after ICG did not match the final ED diagnosis,one who was ultimately diagnosed with a cardiac causeof dyspnea had normal hemodynamic parameters, sug-gesting a pulmonary cause. In another patient, alteredhemodynamic parameters suggested cardiac dyspneathat was later attributed to an exacerbation of COPD.One patient with lung cancer had hemodynamic findingsconsistent with diastolic HF. Finally, one patient whoinitially was thought to have pulmonary dyspnea hadaltered hemodynamic findings that were believed to benondiagnostic by the evaluating physician; that patientwas ultimately treated for fluid overload and dischargedhome.

Results Grouped by Final DiagnosisA summary of the patient vital signs and hemodynamiccharacteristics grouped by final ED diagnosis is listedin Table 4. No diagnosis group had vital sign data thatwere significantly different from those of any othergroup (p = 0.1332). Of the hemodynamic parameters,cardiac index, systemic vascular resistance index, andthoracic fluid content had one diagnosis group thatdiffered significantly from the other two (p < 0.02). HFpatients had greater amounts of lung water, as reflectedby a mean TFC (38.5 � 12.3 kOhm�1) that was signifi-cantly higher than that of the other two diagnosis groups(30.0 � 6.17 and 30.4 � 5.6 for the COPD and othergroups, respectively). Patients with COPD had higherCI (3.08 � 0.57 vs. 2.39 � 0.56 and 2.48 � 0.65) and lowerSVR (1,361 � 407 vs. 1,772� 565 and 1,789 � 638) than didpatients in the HF or other groups, respectively.

Laboratory measurements, including electrolytes,BUN, Cr, WBC, Hgb, and BNP were analyzed byfinal diagnosis. Of the laboratory measurements, onlyBNP, measured in 72 patients, exhibited a statistically

Table 2Hemodynamic Values at Presentation

Hemodynamic Parameter Mean � SD Normal Range

Thoracic fluid content(kOhm�1)

34.2 � 10.4 30–50 (male)21–37 (female)

Systemic vascular resis-tance (dyne sec cm�5)

1,685 � 579 742–1,378

Cardiac index (L/min/m2) 2.6 � 0.6 2.5–4.2Stroke index (mL/m2) 31.8 � 10.1 35–65

N = 89.

Table 3Electrocardiographic and Chest Radiographic Findings

Parameter n (%)

Electrocardiographic findingsNormal, nonspecific, or ‘‘nondiagnostic ECG’’ 70 (82)Left ventricular hypertrophy 15 (18)Atrial fibrillation 11 (13)Prior myocardial infarction 8 (9)Left bundle branch block 3 (4)

Relevant chest radiography findingsNormal or no acute disease 42 (49)Increased cardiothoracic ratio (>0.5)

or cardiomegaly13 (15)

Pleural effusion 8 (9)Pulmonary edema or ‘‘heart failure’’ 8 (9)Upper zone redistribution 6 (7)Pulmonary infiltrate 5 (6)Atelectasis 2 (2)Hyperinflation 1 (1)

For each finding group, n = 85. Because of multiple findings, total for ECG

diagnoses is greater than 85.Figure 2. Category rate of change from pre-ICG to post-ICG

(mean values with 95% confidence intervals).


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significant difference (p < 0.0001) among the three diag-nosis groups. The HF group had a significantly highermean BNP level (940 pg/mL) than did the other diagnosisgroups (137 pg/mL, and 357 pg/mL for COPD and othergroups, respectively).

Treatment ChangesChanges in planned medication orders, occurring afterICG information was revealed (and without other inputto the treating physician), are shown in Table 5. Thirty-five patients (39%, 95% CI = 29% to 50%) had a total of54 changes in the medication plan after initial assessmentand review of ICG data. Use of diuretics most often wasaltered based on ICG findings, suggesting fluid overloador cardiac cause of dyspnea. When looking at medicationchanges by category of final diagnosis, there were 17medication changes in the 43 patients with a final diagno-sis of HF, 20 medication changes in the 20 patients with a

final diagnosis of COPD, and 17 medication changes inthe 26 patients in the other group. Twenty-three of 54(43%) medication changes that resulted from the avail-ability of hemodynamic information were changes inthe use of diuretics or bronchodilators.

DISCUSSION

In cases of elder dyspneic patients who may requireurgent treatment, the ED physician must assess status,formulate a working diagnosis, and institute therapy, inmany cases before all information is available. Hemo-dynamic information, which reflects the contribution ofthe cardiovascular system to the current presentation,may have an important impact on the process of care.Our results demonstrate that knowledge of ICG dataleads to a change of working primary diagnosis in 13%of elder patients presenting with dyspnea to the ED.When changes in diagnosis were made, they were con-sistent with the final diagnosis at time of ED dispositionin two-thirds of cases. In addition to changes in diagno-sis, ED physicians made medication changes on the basisof ICG-derived hemodynamic information in 39% ofcases. Finally, unlike vital signs, which were similar acrossthe various diagnostic groups, hemodynamic data variedbased on causes of dyspnea. These findings are consistentwith the hypothesis that hemodynamic information isrelevant and actionable in the ongoing evaluation andtreatment of such patients.

Patients presenting with dyspnea are commonly at riskfor exacerbation of either cardiac or pulmonary disease.Those with acute HF typically have reduced cardiacoutput and elevated vascular resistance. Those with apulmonary or other noncardiac cause of their dyspneatypically have normal cardiac output and hemodynamicparameters. Because the accuracy and reproducibilityof ICG have been validated in a variety of patient popula-tions and settings, it is not surprising that physiciansused this information to help guide diagnosis and treat-ment in dyspneic patients. Our finding of different valuesof hemodynamic parameters among the diagnostic groupsis consistent with this paradigm. The relatively high rateof change of diagnosis, when ICG-derived informationwas revealed to treating physicians, suggests acceptanceof the technical and diagnostic accuracy efficacies of thetest. Not only does the information result in altered diag-nosis, but the noninvasive hemodynamic data providedby ICG was applied by the physicians to therapeutic de-cision making, an indication of therapeutic efficacy, asdefined by Pearl.18 Thus, our results support the potentialvalue of such information and support a practical role forthis technology in the ED assessment of such patients.

Recently, BNP testing has been shown to be a usefulbedside tool to aid in diagnosis of patients presentingwith shortness of breath.26 However, despite the avail-ability of point-of-care laboratory testing, real-time diag-nosis and treatment can be delayed. In fact, one largetrial of cardiac markers found that even with point-of-care testing, the door-to-brain time (the time from EDarrival until cardiac marker results are available for thephysician to act upon) exceeded one hour.27 ICG dataare available within several minutes. And, unlike the he-modynamic information obtained by a pulmonary artery

Table 4Initial Vital Signs and Selected Hemodynamic Parameters byFinal Diagnosis

Final Diagnosis

Parameter

HeartFailure(n = 43)

ChronicObstructivePulmonary

Disease(n = 20)

Other(n = 26)

Temperature (ºC) 36.4 � 0.7 36.6 � 0.8 36.7 � 0.5Systolic blood

pressure (mm Hg)149.5 � 30.5 135.6 � 19.1 146.8 � 32.2

Diastolic bloodpressure (mm Hg)

80.2 � 18.0 75.7 � 13.0 78.5 � 21.2

Heart rate (min�1) 84.1 � 18.0 88.2 � 19.4 82.9 � 20.1Respiration rate (min�1) 22.1 � 5.7 23.8 � 3.8 21.0 � 4.6Thoracic fluid content

(kOhm�1)38.5 � 12.3* 30.0 � 6.17 30.4 � 5.6

Systemic vascularresistance (dynesec cm�5)

1,772 � 565 1,361 � 407* 1,789 � 638

Cardiac index(L/min/m2)

2.39 � 0.56 3.08 � 0.57* 2.48 � 0.65

Mean arterialpressure (mm Hg)

100.0 � 20.0 98.5 � 14.2 100.7 � 21.8

Stroke index (mL/m2) 29.7 � 9.9 36.3 � 9.7 31.6 � 10.0

Data are mean � SD.

* Different from other two categories, p < 0.02.

Table 5Therapeutic Changes Post- vs. Pre-ICG Listed by MedicationClass

Medication Class n (%) [95% CI]

Diuretics 12 (13) [7%–22%]Nitroglycerin 4 (4) [1%–11%]Bronchodilators 11 (12) [8%–24%]Steroids 6 (7) [3%–14%]Antibiotics 6 (7) [3%–14%]Anticoagulants 5 (6) [2%–13%]Other 10 (11) [6%–20%]

There were 54 total medication changes in 35 patients. Because of mul-

tiple therapeutic changes, total changes are greater than the number of

patients.


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catheter, performance of ICG is noninvasive and can bereadily accomplished in the ED without specialized train-ing and at minimal risk to the patient.

The magnitude of the changes in diagnosis and treat-ment resulting from ICG-derived hemodynamic datacan be compared with that from other technologiesthat are currently the standard of care in most EDs. His-torically, changes in therapy on the order of 5% to 11%appear to define utility of testing in the ED. In one study,Summers et al.19 reported that the ED physician assess-ment of patient severity of illness was changed by pulseoximetry in 3% of cases. Kosowky et al.,21 evaluatingBNP testing in patients older than 40 years of age, foundthat BNP data changed the diagnosis in 10%, and treat-ment in 11%, of cases. These trials suggest that the rateof change that resulted from ICG use in the present studywould be clinically significant in the ED environment.Moreover, ICG can be performed concurrently withexisting diagnostic and therapeutic strategies, such thatthe information is incremental in the decision-makingprocess.

The changes in ED decision making from esophagealDoppler results, a more invasive and less common formof cardiac output measurement, have been studied else-where.28 Those investigators found a change in man-agement decisions in 31% of cases. Our results show agreater change in therapy alone, perhaps because ofthe incremental information provided by systemic vascu-lar resistance and thoracic fluid content parameters.Although most ED physicians would not subject a patientto esophageal monitoring to obtain hemodynamic mea-surements, it is likely that many would consider thecollection of ICG data, which requires little more time orinconvenience than obtaining an electrocardiogram.We did not measure the time required to obtain ICGdata; however, in routine use, these data can be obtainedin about 3 to 5 minutes and require 30 to 60 secondsto interpret. Because ICG provides early and accuratedata, there is a potential for significant clinical impactfrom its use. We did not specifically study the financialeffects of ICG in this study or how it might have affectedlength of ED stay or hospital admission rate. However,at a procedural cost for each test of less than $20 andwith the cost of a day in intensive care at more than$1,000, the provision of ICG would be cost-effectiveeven if, for example, it reduced hospital length of stayby only one day for every 50 patients monitored.

LIMITATIONS

We acknowledge several limitations. This study evalu-ated the effect of ICG on working diagnosis and initialtreatment plan before the results of chest radiograph,ECG, or BNP level. Thus, it is impossible to gauge the rel-ative importance of the information obtained from ICGto that obtained by these other tests or to judge the addi-tional contribution of ICG for cases in which the resultsof other tests were available before performing ICG. Al-though blood work and various ancillary testing such aschest radiography are part of the complete ED evaluationof such patients, the results are generally not availablewithin the first few minutes of patient assessment. By de-sign, this study evaluated ICG’s effect on working diag-

nosis and therapy in a manner that would be consistentwith clinical practice in the ED, where patients present-ing with dyspnea might be evaluated with ICG eitherbefore or within minutes of the ED physician’s initialassessment. Furthermore, as seen in our study, the find-ings of ECGs and chest radiographs are often normal ornonspecific and may not provide significant diagnosticcertainty. Because ICG is not part of the diagnostic crite-ria for acute coronary syndromes, including acute MI, wedid exclude patients with evidence of myocardial necro-sis from analysis. Therefore, the role of ICG in providingpossible clues in the evaluation of patients with dyspneaas a manifestation of MI cannot be assessed by the pres-ent study.

Our study was also limited by the use of the final EDdiagnosis as the criterion standard for diagnostic cate-gorization. Although it is possible that this diagnosiswas incorrect or incomplete in some patients, this repre-sents the real-life diagnosis based on current evaluationstrategies during the patient’s ED visit. It is also possiblethat a physician had the right diagnosis and treatmentplan before reviewing ICG results and that ICG dataresulted in inappropriate therapies. A larger prospectiveoutcome-based study will be required to determine thepotential for this to occur.

In our study, ICG data were available and likely con-tributed to the final ED diagnosis, thereby introducingpossible bias. However, the goal of this study was notto assess technical accuracy of the technology, whichhas been evaluated in previous studies. In contrast, thisstudy was designed to assess whether physicians wouldincorporate early hemodynamic information into theprocess of formulating an initial working diagnosis andtreatment plan. In addition, the study design does not al-low us to draw conclusions about the sensitivity or spec-ificity of ICG criteria, or to compare diagnostic accuracyto other measures, such as BNP or chest radiography.The accuracy of the post-ICG diagnosis based on thesehemodynamic criteria could only be verified by a morestandardized diagnostic approach including cardiacimaging studies, blinded reviews of subsequent hospitalrecords with adjudication of discordant diagnoses, andlong-term follow-up, which were not within the scopeof the current study.

CONCLUSIONS

Knowledge of ICG data early in the ED evaluation of pa-tients older than 65 years of age presenting with dyspnearesults in significant changes in diagnosis and treatmentplan. Whether changes in diagnosis, diagnostic certainty,or therapy from ICG improve outcomes or are cost-effec-tive will require a prospective, randomized clinical trialwith longer periods of clinical follow-up.

The authors thank Gerard Smits, PhD, for his statistical assis-tance.

References

1. McCraig LF, Burt CW. National hospital ambulatorymedical care survey: 2001 emergency departmentsummary. Report from Centers for Disease Control


96 of 158.

and Prevention, National Center for Health Statistics.Advance Data Vital Health Stat. 2003; 335:18.

2. Eisenberg PR, Jaffe AS, Schuster DP. Clinical evalua-tion compared to pulmonary artery catheterization inthe hemodynamic assessment of critically ill patients.Crit Care Med. 1984; 12:549–53.

3. Speroff T, Connors AF Jr, Dawson NV. Lens modelanalysis of hemodynamic status in the critically ill.Med Decis Making. 1989; 9:243–52.

4. Neath SX, Lazio L, Guss DA. Utility of impedance car-diography to improve physician estimation of hemo-dynamic parameters in the emergency department.Congest Heart Fail. 2005; 11:17–20.

5. Van De Water JM, Dalton ML, Parish DC, Vogel RL,Beatty JC, Adeniyi SO. Cardiopulmonary assess-ment: is improvement needed? World J Surg. 2005;29(Suppl 1):S95–8.

6. Sageman WS, Riffenburgh RH, Spiess BD. Equiva-lence of bioimpedance and thermodilution in mea-suring cardiac index after cardiac surgery. JCardiothorac Vasc Anesth. 2002; 16:8–14.

7. Drazner M, Thompson B, Rosenberg P, Yancy C.Comparison of impedance cardiography with inva-sive hemodynamic measurements in patients withheart failure secondary to ischemic or nonischemiccardiomyopathy. Am J Cardiol. 2002; 89:993–5.

8. Van De Water JM, Miller TW. Impedance cardiogra-phy: the next vital sign technology? Chest. 2003; 123:2028–33.

9. Yung GL, Fedullo PF, Kinninger K, Johnson FW,Channick RN. Comparison of impedance cardiogra-phy to direct Fick and thermodilution cardiac outputdetermination in pulmonary arterial hypertension.Congest Heart Fail. 2004; 10(2 Suppl 2):7–10.

10. Albert NM, Hail MD, Li J, Young JB. Equivalence ofbioimpedance and thermodilution in measuring car-diac output in hospitalized patients with advanced,decompensated chronic heart failure. Am J CritCare. 2004; 3:469–79.

11. Silver M, Cianci P, Brennan S, Longeran-Thomas H,Ahmad F. Evaluation of impedance cardiography asan alternative to pulmonary artery catheterizationin critically ill patients. Congest Heart Fail. 2004; 10(2Suppl 2):17–21.

12. Springfield C, Sebat F, Johnson D, Lengle S, Sebat C.Utility of impedance cardiography to determinecardiac vs. noncardiac cause of dyspnea in theemergency department. Congest Heart Fail. 2004;10(2 Suppl 2):14–6.

13. Han J, Lindsell C, Tsurov B, Storrow A. The clinicalutility of impedance cardiography in diagnosing con-gestive heart failure in dyspneic emergency depart-ment patients [abstract]. Acad Emerg Med. 2002; 9:439–40.

14. Barcarse E, Kazanegra R, Chen A, Chiu A, CloptonP, Maisel A. Combination of B-type natriuretic pep-

tide levels and non-invasive hemodynamic parame-ters in diagnosing congestive heart failure in theemergency department. Congest Heart Fail. 2004;10:171–6.

15. Peacock WF, Albert NM, Kies P, White RD, EmermanCL. Bioimpedance monitoring: better than chestx-ray for predicting abnormal pulmonary fluid? Con-gest Heart Fail. 2000; 6(2):32–5.

16. Newman RB, Pierre H, Scardo J. Thoracic fluid con-ductivity in peripartum women with pulmonaryedema. Obstet Gynecol. 1999; 94:48–51.

17. Milzman D, Morrisey J, Pugh C, Napoli A, Gerace T,Fernandez E. Occult perfusion deficits in heart failurepatients: identification through noninvasive centralhemodynamic monitoring [abstract]. Crit Care Med.1999; 27:A88.

18. Pearl WS. A hierarchical outcomes approach to testassessment. Ann Emerg Med. 1999; 33:77–84.

19. Summers R, Anders R, Woodward L, Jenkins A, GalliR. Effect of routine pulse oximetry measurements onED triage classification. J Emerg Med. 1999; 16:5–7.

20. Mower WR, Sachs C, Nicklin EL, Safa P, Baraff LJ.Effect of routine emergency department triage pulseoximetry screening on medical management. Chest.1995; 108:1297–302.

21. Kosowsky JM, Weiner C, Morrissey JH. Impact ofB-type natriuretic peptide testing on medical deci-sion-making for older patients with dyspnea. AnnEmerg Med. 2003; 42:S11.

22. Summers R, Schoemaker W, Peacock WF, Ander D,Coleman T. Bench to bedside series: impedance car-diography (ICG). Acad Emerg Med. 2003; 10:669–80.

23. Luepker R, Michael JR, Warbasse JR. Transthoracicelectrical impedance: quantitative evaluation of anoninvasive measure of thoracic fluid volume. AmHeart J. 1973; 85:83–93.

24. Van de Water JM, Mount BE, Chandra KM, MitchellBP, Woodruff TA, Dalton ML. TFC (thoracic fluidcontent): a new parameter for assessment of changesin chest fluid volume. Am Surg. 2005; 71:81–6.

25. Taler SJ, Textor SC, Augustine JE. Resistant hyper-tension: comparing hemodynamic management tospecialist care. Hypertension. 2002; 39:982–8.

26. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapidmeasurement of B-type natriuretic peptide in theemergency diagnosis of heart failure. N Engl J Med.2002; 347:161–7.

27. Peacock WF, Roe MT, Chen AY, et al. Vein-to-braintime: an emergency department quality of caremarker for non-ST-segment elevation acute coro-nary syndrome [abstract]. Acad Emerg Med. 2004;11:569.

28. Urrunaga J, Rivers E, Mullen M, et al. Hemodynamicassessment of the critically ill: the clinician versusesophageal Doppler monitoring (EDM) [abstract].Acad Emerg Med. 2000; 7:587b.


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98

Featured Review Article

Hypertension as a Hemodynamic Disease: TheRole of Impedance Cardiography in Diagnostic,Prognostic, and Therapeutic Decision Making

Hector O. Ventura, Sandra J. Taler, and John E. Strobeck

AJH 2005; 18:26S–43S

Hypertension is the most common cardiovascular disease,affecting approximately 60 million Americans. Despite theimportance of this condition, only the minority of patientsare appropriately identifie and treated to reach recom-mended blood pressure (BP) goals. Although historicallydefine as an elevation of BP alone, hypertension is char-acterized by abnormalities of cardiac output, systemicvascular resistance, and arterial compliance. These hemo-dynamic aspects of hypertension have implications fordiagnosis, risk stratification and treatment. Impedancecardiography (ICG) has emerged as a unique and highly
accurate noninvasive tool that is used to assess hemody-
and Cabrini Medical Center (JES), New York, New York.

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namic parameters. Measurement of the various hemody-namic components using ICG in those with hypertensionallows more complete characterization of the condition, agreater ability to identify those at highest risk, and allowsmore effectively targeted drug management. This articlereviews the importance of hemodynamic factors in hyper-tension and the evolving role of ICG technology in theassessment and management of this important cardiovas-cular condition. Am J Hypertens 2005;18:26S–43S© 2005 American Journal of Hypertension, Ltd.

Key Words: Hypertension, hemodynamics, impedance
cardiography.
W hen functioning properly, the cardiovascularsystem provides normal blood flo to the var-ious tissues of the body under normal arterial

blood pressure (BP). Historically, BP is the most com-monly measured parameter of cardiovascular function. Hy-pertension–typically define by BP levels of 140/90 mm Hgand higher—leads to increased rates of coronary arterydisease, heart failure, renal disease, and stroke. Therefore,BP control is of paramount importance for both individualand public health considerations.

Blood pressure by itself is an incomplete indicator ofthe status of the cardiovascular system. Mean arterialpressure (MAP) is the product of two hemodynamic com-ponents: cardiac output (CO), the flo of blood pumpedby the heart each minute; and systemic vascular resistance(SVR), the force the left ventricle must overcome to expelblood into the systemic vasculature, also called total pe-ripheral resistance. Hypertension results from elevationsof CO, SVR, or both. Because “hemodynamics” literallyrefers to blood flow–relate parameters of the arterialsystem, CO and SVR are fundamental to obtaining greaterinsight into the pathophysiology of hypertension, and theycan help to guide diagnostic, prognostic, and therapeuticmanagement decisions. Thus, the hemodynamic model of

Received October 29, 2004. Accepted November 4, 2004.From the Ochsner Clinic Foundation (HOV), New Orleans,Loui-

siana; Mayo Clinic College of Medicine (SJT), Rochester, Minnesota;

hypertension has intrigued scientists and clinicians sincethe early part of the last century1 and has been reviewedextensively by leaders in the field 2–7

The hemodynamic components of BP, CO, and SVR,and other related parameters such as arterial complianceprovide insight into mechanisms of hypertension8 andhave implications for management of patients with thiscondition. Historically, most hemodynamic informationused in research has been obtained using invasive tech-niques, including arterial cannulation and placement of apulmonary artery catheter for the measurement of cardiacoutput and determination of SVR. However, invasive pro-cedures are not feasible in the routine care of patients withhypertension. Echocardiography provided early noninva-sive measurement of cardiac output, but it is costly andhighly operator dependent, and it is therefore impracticalfor frequent serial measurements in the clinical setting.Recent advancements in noninvasive hemodynamic mon-itoring with impedance cardiography (ICG) have beenachieved, elevating its role as a unique and valuable non-invasive tool for the assessment of hemodynamic status inpatients with hypertension.

This review describes the historical use of hemodynam-ics in hypertension and reveals the growing body of evi-

Address correspondence and reprint requests to Dr. Hector O.Ventura, Ochsner Clinic Foundation, 1514 Jefferson Highway, Room
3E419, New Orleans, LA 70121; e-mail: [email protected]
© 2005 by the American Journal of Hypertension, Ltd.Published by Elsevier Inc.

27SAJH–February 2005–VOL. 18, NO. 2, Part 2 HYPERTENSION AS A HEMODYNAMIC DISEASE

99

dence using noninvasive monitoring of hemodynamicswith ICG. The specifi role of hemodynamics in diagnos-tic, prognostic, and therapeutic decision making in thepatient with hypertension is reviewed in detail.

Hypertension: Definition andClinical PresentationHypertension is most commonly define as a systolic BP(SBP) of �140 mm Hg or a diastolic BP (DBP) of �90mm Hg. In patients at high risk for complications fromelevated BP levels, such as those with diabetes or chronicrenal disease, lower levels of BP (eg, �130/80 mm Hg)are recommended. Between BP levels of 115/75 mm Hgand 185/115 mm Hg, each 20–mm Hg increase in SBP or10–mm Hg increase in DBP doubles the risk of a cardio-vascular event.9 In recognition of this increase in risk fromlevels as low as 115/75 mm Hg, the Seventh Report of theJoint National Committee on Prevention, Detection, Eval-uation, and Treatment of High Blood Pressure (JNC 7)9

recently identifie “prehypertension” (define as a BP of120 to 139 / 80 to 89 mm Hg) as a significan potentialhealth problem associated with “increased risk for pro-gression to hypertension.” The JNC 7 recommended life-style modificatio for the management of prehypertension.Table 1 lists the stages of hypertension as define in theJNC 7 classification

Secondary hypertension results from an identifiablcause such as renal, adrenal, or vascular pathology. Incontrast, 90% of patients have no specifi identifiablcause of their BP elevation10 and are thus diagnosed withessential hypertension. Most patients with hypertensionare asymptomatic and do not show evidence of acutepathologic changes; their clinical presentation has beentermed “benign,” although their long-term risk of cardio-vascular complications is significantl greater than in nor-motensive persons without so-called benign hypertension.Severe elevation of BP, associated with papilledema onfundoscopic examination, is termed “malignant hyperten-sion.” Similar levels of BP elevation with congestive heartfailure, anginal symptoms, or other evidence for acceler-ated end-organ injury (but without papilledema) are

Table 1. JNC 7 Classification of blood pressure foradults �18 years of age

BP classification

SystolicBP

(mm Hg)

DiastolicBP

(mm Hg)

Normal �120 and �80Prehypertension 120–139 or 80–89Stage 1 hypertension 140–159 or 90–99Stage 2 hypertension �160 or �100

JNC � Joint National Committee on the Prevention, Detection, Eval-uation, and Treatment of High Blood Pressure.

termed “hypertensive urgencies” or “hypertensive emer-

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gencies.” The etiologies of hypertension (essential versussecondary) and the various clinical presentations (benign,malignant, unspecified and with or without associatedco-morbidities) are reflecte in the World Health Organi-zation’s International Classificatio of Diseases, NinthRevision (ICD-9), coding for hypertension (Table 2).

Hypertension: Magnitude of theProblemHypertension affects up to 60 million Americans and asmany as 1 billion persons worldwide; and it is the mostcommon reason that patients in the United States visit theirphysicians.9,11 The incidence of hypertension increasessignificantl with advancing age (Fig. 1), such that anormotensive adult in the United States 55 years of agestill has a 90% lifetime risk of developing hypertension.9In fact, the most common group with hypertension iscomprised of elderly patients with systolic hypertension.12

Although controlling BP levels reduces the incidence ofstroke and other cardiovascular complications, BP controlin the US is well below stated goals. For an individualpatient, this may be due to the lack of recognition of thecondition, failure to institute effective treatment, or the resultof a suboptimal long-term medical regimen (Table 3). Thereremains a substantial need for improvement in the effective-ness of hypertension treatment. As reported in JNC 7, only34% of adults aged 18 to 74 years with hypertension haveachieved BP control, despite a published goal of 50%. Inthe elderly population, BP control is even less successful:fewer than 20% of treated patients 70 years or more of ageattain BP levels of �140/90 mm Hg.9

Hypertension treatment commonly requires multiplemedications. “Refractory hypertension” has been defineas hypertension that is not controlled on two or moreantihypertensive medications.13 “Resistant hypertension”has been define by some as BP readings of �140/90 mmHg “despite an optimal two-drug regimen that has hadadequate time to work (at least 1 month since last drug ordosage adjustment).”14 As define by Gifford, resistanthypertension is the failure to reach goal BP in patients whoare adhering to full doses of an appropriate three-drugregimen that includes a diuretic.15 The JNC 7 recommendsa goal BP of �140/90 mm Hg for the general population,with the tighter goal of �130/80 mm Hg for persons withchronic renal disease or diabetes mellitus.

Hypertension substantially increases the incidence ofcardiovascular events, especially the risk of stroke. Wilk-ing et al,16 in data from the Framingham study, reported onthe prognostic significanc of systolic hypertension. Theyfound that for men and women, the relative risk of car-diovascular disease event adjusted for age was approxi-mately 2.5 times greater for persons with isolated systolichypertension compared with those with BP levels�140/95 mm Hg. Lower BP levels are thus associatedwith improved prognosis and decreased incidence of mor-
bidity and mortality. From pooled data of more than 60

n; u

28S AJH–February 2005–VOL. 18, NO. 2, Part 2HYPERTENSION AS A HEMODYNAMIC DISEASE

100

prospective studies and 1 million patients, Lewington et al17

report that 10–mm Hg reductions in systolic BP would beexpected to reduce stroke mortality by as much as 40%.

Table 2. International Classification of Diseases co

Essential hypertension401.0 Essential hypertension401.1 Benign essential hyper401.9 Unspecified essential h

Hypertensive heart disease402.00 Hypertensive heart dis402.01 Hypertensive heart dis402.10 Hypertensive heart dis402.11 Hypertensive heart dis402.90 Hypertensive heart dis402.91 Hypertensive heart dis

Hypertensive renal disease403.00 Hypertensive renal dise403.01 Hypertensive renal dise403.10 Hypertensive renal dise403.11 Hypertensive renal dise403.90 Hypertensive renal dise403.91 Hypertensive renal dise

Hypertensive heart andrenal disease

404.00 Hypertensive heart andheart failure or renal

404.01 Hypertensive heart and404.02 Hypertensive heart and404.03 Hypertensive heart and

and renal failure404.10 Hypertensive heart and

heart failure and ren404.11 Hypertensive heart and404.12 Hypertensive heart and404.13 Hypertensive heart and

and renal failure404.90 Hypertensive heart and

heart failure or renal404.91 Hypertensive heart and

failure404.92 Hypertensive heart and404.93 Hypertensive heart and

failure and renal failuSecondary hypertension

405.01 Secondary hypertensio405.09 Secondary hypertensio405.11 Secondary hypertensio405.09 Secondary hypertensio405.91 Secondary hypertensio405.99 Secondary hypertensio

FIG. 1 Prevalence of hypertension by age.

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Importantly, the authors note that even a 2–mm Hg reduc-tion in systolic BP is associated with a 10% lower deathrate from stroke. These reductions in risk apply all the wayto BP levels of 115/75 mm Hg. Thus, the failure to lowerBP even modestly in patients with hypertension is respon-sible for a significan number of preventable cardiovascu-lar events each year.

The financia implications of hypertension and hyper-tension management are substantial.18 The direct costs oftreating hypertension exceeded $37 billion in the year2003, and additional costs due to loss of productivity weremore than $13 billion (Table 4). Of the ten medical con-ditions evaluated for their effects on absenteeism from

for hypertension

lignantionrtension

; malignant; without congestive heart failure; malignant; with congestive heart failure; benign; without congestive heart failure; benign; with congestive heart failure; unspecified; without congestive heart failure; unspecified; with congestive heart failure

; malignant; without mention of renal failure; malignant; with renal failure; benign; without mention of renal failure; benign; with renal failure; unspecified; without mention of renal failure; unspecified; with renal failure

al disease; malignant; w/o mention of congestivereal disease; malignant; with congestive heart failureal disease; malignant; with renal failureal disease; malignant; with congestive heart failure

al disease; benign; w/o mention of congestiveilureal disease; benign; with congestive heart failureal disease; benign; with renal failureal disease; benign; with congestive heart failure

al disease; unspecified; w/o mention of congestivereal disease; unspecified; with congestive heart

al disease; unspecified; with renal failureal disease; unspecified; with congestive heart

alignant; renovascularalignant; otherenign; renovascularenign; othernspecified; renovascularnspecified; other

des

; Matensype

easeeaseeaseeaseeaseease

aseaseaseaseasease

renfailurenrenren

renal fa

renrenren

renfailuren

renren

re

n; mn; mn; bn; bn; u

work and loss of productivity, hypertension was the most


101

expensive—costing businesses an average of $392 pereligible employee per year.19 Improving the efficienc andeffectiveness of drug management in the hypertensivepopulation would likely reduce these costs in addition todecreasing morbidity and mortality associated with thecondition.

Hemodynamic MeasurementsUsing ICGThe historical use of BP without CO or SVR is, in part,because it has been impractical to estimate or measurethese parameters in most clinical settings. The assessmentof the hemodynamic components of hypertension fromclinical evaluation alone is unreliable. Even in patientswith acute conditions such as those requiring the emer-gency department or patients with decompensated conges-tive heart failure (in whom hemodynamic derangementsare greater than those in patients with essential hyperten-sion), clinicians are generally unable to estimate CO orSVR with accuracy.20,21

Echocardiography has been used to measure cardiacoutput and in some studies has demonstrated acceptablecorrelation with invasive techniques.22 However, in acomparison with ICG, echocardiography is considerablymore time consuming and technically demanding.23 In the

Table 3. Trends in awareness, treatment, and contto 74 years of age

NHANESII

(1976–1980)II

(1988

Awareness 51 7Treatment 31 5Control 10 2

NHANES � National Health and Nutrition Examination Survey.All numbers expressed as percentages.

Table 4. Direct and indirect costs attributable tohypertension

Type of costCost (in $

billion)

Direct costsInpatient 8.7Professional services 9.2Drugs and medical durables 17.8Home health care 1.5Total direct costs 37.2

Indirect costs of lost productivityRelated to morbidity 7.0Related to mortality 6.1Total indirect costs 13.1Total costs 50.3

Data are from Heart Disease and Stroke Statistics—2003 Update.American Heart Association; 2002.

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offic setting, CO is not generally reported by most phy-sicians interpreting echocardiograms in clinical practice.Thus, until recently, CO and SVR were commonly mea-sured only in the intensive care setting or catheterizationlaboratory setting using invasive means such as a pulmo-nary artery catheter.

In recent years, ICG has emerged as an accurate, safe,and inexpensive tool with which to measure hemodynamicparameters by noninvasive means. The procedure is mostcommonly performed in the physician offic setting bymedical assistants or nurses, requiring about 5 min tocomplete the test. Using four sets of paired sensors on theneck and chest, ICG measures the instantaneous change ofan electrical signal across the thoracic cavity (Fig. 2). Asthe changes of thoracic impedance during the cardiaccycle are most dependent on the changes in the size andthe blood volume of the thoracic aorta, ICG is able tocalculate the amount of blood ejected from the left ven-tricle (that is, the stroke volume [SV]). The product ofheart rate (HR) and SV yields CO. In addition, ICG-derived parameters related to the changes of thoracic im-pedance are indicative of aortic blood velocity andacceleration, and they correlate with measures of inotropicstate and cardiac performance. As flui is the best con-ductor of the electrical signal through the chest (when

f high blood pressure in adults with hypertension 18

91)III-2

(1991–1994) 1999–2000

68 7054 5927 34

FIG. 2 Measurement of impedance signal using four sets of paired

rol o

I-1–19

359

sensors. Sensors transmit and record electrical signal from whichmultiple hemodynamic parameters are derived.


102

compared with bone, air and fat, in particular), the totalthoracic impedance is inversely related to an index of fluitermed the “thoracic flui content” (TFC). Finally, using asimultaneous electrocardiographic recording, ICG mea-sures the pre-ejection period and LV ejection time—tim-ing intervals that relate to cardiac performance.

Representative simultaneous tracings of an electrocar-diogram, change in thoracic impedance (�Z), and firsderivative of impedance (dZ/dt) are shown in Fig. 3. Fromthe measured variables and from HR and mean BP deter-mined by oscillometry, SVR and other parameters arecalculated and displayed. An ICG test report is shown inFig. 4. A more detailed description of selected parametersis provided in Table 5.

Validation of Current ICGTechnologyPlacement of a pulmonary artery catheter is a costly pro-cedure requiring special training and expertise; and it isassociated with risks of bleeding, infection, and damage tovascular and other structures. Because of the risks inherentin invasive methods for measuring hemodynamics, studiescomparing ICG to invasive techniques of hemodynamicmeasurement are only available from populations withsignifican underlying cardiovascular conditions or situa-tions that justify the risks associated with pulmonary ar-tery catheter placement. In such clinical settings andpatient populations, multiple studies have shown that cur-rent ICG technology, using advanced data processing andmodeling techniques, yields data that are significantlmore accurate than those obtained with prior generationsof ICG devices.24 Five additional validation studies ofICG presented since 1998, 25–29 using refine ICG tech-nology (BioZ ICG Monitor, CardioDynamics, San Diego,CA), demonstrate the high correlation and accuracy avail-able with ICG when compared with invasive techniques(Table 6).

The ability to measure changes in hemodynamicparameters reliably in a given patient is critically im-portant from a clinical perspective, as the changes in

FIG. 3 Representative simultaneous tracings of electrocardiogram(ECG), thoracic impedance (�Z), and first-time derivative of imped-ance (dZ/dt), and dZ/dt waveforms. Fiducial points are identified onthe dZ/dt tracing from which various hemodynamic and parametersand timing intervals are derived.

serial measurements are the basis for evaluating pa-

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tients’ disease progression, response to therapy, andneed for further intervention. Thermodilution, using apulmonary artery catheter, has traditionally been thestandard to which ICG has been compared. Van DeWater et al24 assessed the relative reproducibility ofICG and thermodilution cardiac outputs in hospitalizedpatients in whom a pulmonary artery catheter wasplaced for hemodynamic monitoring after bypass sur-gery. Serial ICG measurements in a given patientshowed better reproducibility than serial CO measure-ments using thermodilution technique (Table 7). Theinvestigators concluded that current ICG technology hasadvanced such that ICG provides “a level of agreementthat is equivalent to thermodilution.” Their findingsupport the clinical utility of ICG for serial measure-ments in patients with cardiovascular disease.

In a stable group of patients in the outpatient setting,Verhoeve et al30 demonstrated a high reproducibility ofmeasurements performed on the same day and appropriatesensitivity for the physiologic variations expected fromday to day. The variation in the average of readings forCO, SVR, and thoracic flui content (TFC) ranged be-tween 3% and 7% for serial measurements 1 week apart.Figure 5 illustrates the high degree of correlation betweenstroke index measured on day 1 and then 1 week later in96 patients who were clinically stable.

The ICG technique is widely applicable, and reliableinformation can be obtained in minutes at virtually no

FIG. 4 Hemodynamic status report.


103

risk to the patient. However, ICG has some limitationsrelated to the technology and patient factors. AlthoughICG equations have demonstrated accuracy over a widerange of conditions and patient populations, ICG hasnot been evaluated extensively in patients �66 poundsor �342 pounds. Severe aortic insufficienc may affectICG reliability, but it has not been fully studied andvalidated in such patients. In addition, a few models ofpermanent pacemakers use impedance technology tomeasure minute ventilation. If the minute ventilationfunction is activated, the paced rate may increase be-cause of ICG signals31; therefore, patients with suchpacemakers must have the minute ventilation sensorfunction inactivated before ICG testing. In patients with

Table 5. Impedance cardiography variables

Impedance CardiographyVariable Un

Blood flowStroke volume mLStroke index mL/m2

Cardiac output L/minCardiac index L/min/m2

ResistanceSystemic vascular resistance dyne · secSystemic vascular resistance index dyne · sec

Contractility

Velocity index /1000/sec

Acceleration index /100/sec2

Pre ejection period msecLeft ventricular ejection time msecSystolic time ratio -

Cardiac workLeft cardiac work index kg · m/m2

Fluid statusThoracic fluid content /kOhm

BSA � body surface area; cm � centimeter; CVP � central venous� heart rate; ICG � impedance cardiography; MAP � mean arterialof 10 mmHg); R to R interval � 60/ heart rate: VEPT � volume of ecompliance.

Table 6. Validation studies of impedance cardiogra

Population AuthorRef Pa

HF in ICU Albert et al25

HF in catheterizationlaboratory Drazner et al26

Mechanical ventilation Ziegler et al27

Post-CABG Sageman et al28

Post-CABG Van De Water et al24

Pulmonary hypertension Yung et al29

CABG � coronary artery bypass surgery; CO � cardiac output; HF � hea

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atrial fibrillatio or frequent premature ventricular con-tractions, marked irregularity in heart rhythm can affectdata collection and analysis of wave forms.

Hemodynamic Parameters inHypertensionHypertension is the result of complex cardiac, renal, neu-rohormonal, and vascular mechanisms that are modulatedby both genetic and environmental factors.10,32 The inter-actions of these many factors result in endothelial dysfunc-tion and hemodynamic derangements of arterialcompliance, CO, and SVR. As noted earlier, MAP is theproduct of CO and SVR, and elevations of BP can result

Measurement/Calculation

VI � LVET � VEPT (Z MARC algorithm)SV/BSASV � HRCO/BSA

�5 [(MAP - CVP)/CO] � 80�5 · m2 [(MAP - CVP)/CI] � 80

1000 � first-time derivative of �Zmax/baseline impedance

100 � second-time derivative of�Zmax/baseline impedance

ECG Q wave to aortic valve openingAortic valve opening to closingPEP/LVET

(MAP - PCWP) � CI � 0.0144

1000 � 1/baseline impedance

ure (estimated value of 6 mmHg); ECG � electrocardiography; HRure; PCWP � pulmonary capilary wedge pressure (estimated valueically participating tissue; Z MARC � impedance modulating aortic

(ICG)

eter Comparison r Value Bias Precision

O ICG-TD 0.89 0.08 1.38

O ICG-Fick 0.73 0.74 1.1TD-Fick 0.81 0.75 0.95ICG-TD 0.76 0.03 1.1

O ICG-TD 0.89 �0.45 1.2I ICG-TD 0.92 0.07 0.40O ICG-TD 0.81 �0.17 1.09O ICG-Fick 0.84 �0.24 0.87

TD-Fick 0.89 0.19 0.76ICG-TD 0.80 �0.43 1.01

its

· cm· cm

presspresslectr

phy

ram

C

C

CCCC

rt failure; ICU � intensive care unit. TD � thermodilution;


104

from elevation of either or both of these hemodynamicparameters. Pulse pressure (PP), that is, the differencebetween systolic BP and diastolic BP, is determined by SVand total arterial compliance (TAC). Arterial complianceis a complex parameter that is most closely approximatedusing a complicated and sophisticated model (the three-element Windkessel model) that incorporates the ratio ofthe decay time constant to peripheral resistance.33,34 Truearterial compliance is thus tedious and time-consuming tomeasure and is not clinically useful. However, studieshave shown that arterial compliance can be reliably esti-mated as the ratio of SV to PP.34,35 Relationships amongthe hemodynamic parameters including PP, SV, MAP,CO, and SVR are shown in Fig. 6. The hemodynamics ofhypertension have been studied for decades, and previ-ously various aspects have been extensively re-viewed.3,36–39

Hemodynamics of Hypertension:Diagnostic ConsiderationsNumerous studies using either invasive or noninvasivetechniques have demonstrated that there are distinct he-modynamic subsets among various groups of patients withhypertension. Hemodynamic measurements allow the dif-ferentiation of patients with primarily elevated CO fromthose in which elevated SVR (signifying a vasoconstrictedstate) is the primary mechanism of their hypertension.

Table 7. Reproducibility of serial measurements:impedance cardiography (ICG) versus thermodilu-tion (TD)

ComparisonCorrelation(r value) SD (L/min)

TD 2 v TD 1 0.83 1.02TD 3 v TD 2 0.84 1.01TD 3 v TD 1 0.83 1.07ICG 2 v ICG 1 0.97 0.44ICG 3 v ICG 2 0.98 0.39ICG 3 v ICG 1 0.97 0.43

Adapted from Van De Water et al.24

FIG. 5 Reproducibility of stroke index (SI) measurements made 1week apart. Adapted from Verhoeve et al.30

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Moreover, hemodynamic measurements can elucidate therelative contributions of SV and arterial compliance toelevations in PP.

Invasive Hemodynamic andEchocardiographic Studies

In the Tecumseh, Michigan study, 40 patients were studiedusing echocardiographic techniques and investigatorsfound that 37% of patients with hypertension were “hy-perkinetic,” as define by increased cardiac index, HR,forearm blood flow and plasma norepinephrine levels.The distribution of cardiac index in this population studyis shown in Fig. 7. The wide distribution of cardiac indexvalues in these patients provides corroboration that hyper-tension represents a heterogeneous mix of various hemo-dynamic subsets.

In general, aging is associated with decreases in COand increases in SVR, as shown in Fig. 8. In young adults,hypertension may be more commonly associated withincreased CO, whereas in older adults it is more com-monly associated with elevated SVR. Lund-Johansen41

found a change in hemodynamic pattern in patients withborderline hypertension at 10 and 17 years of follow-up.There was a significan and progressive decrease in COover time, associated with an increase in SVR.

Age-related changes in hemodynamic status, as evi-denced by changes in arterial compliance, occur in patientswith hypertension even in the absence of changes in CO orSVR. Slotwiner et al42 used echocardiographic estimatesof cardiac output to study hemodynamic parameters in 272patients who were 25 to 80 years of age and had mildhypertension. These investigators found that in their studygroup, CO and SVR levels did not vary significantl withage. However, vascular stiffness, as reflecte by the ratioof PP to SV (the reciprocal of TAC) increased with age,which is possibly the mechanism for increased rates ofcardiovascular events in elderly individuals. Others havenoted that arterial stiffness exerts deleterious effects due toincreases in central aortic pressure—another hemody-namic mechanism that is key in the pathophysiology of

FIG. 6 Components of mean arterial pressure (MAP) and pulsepressure (PP). CO � cardiac output; SV � stroke volume; SVR �systemic vascular resistance.

hypertensive cardiovascular disease.43


105

Other factors besides age appear to predict generaltrends in the hemodynamic parameters in hypertensivepopulations. Hemodynamic parameters differ between hy-pertensive men and women. Messerli et al44 measured PP,CO, and SVR using invasive techniques in 200 subjects.Despite equal levels of arterial BP, women had significantly higher CO, PP, and lower SVR compared with men.Isometric exercise was associated with an increase inarterial pressure that was nearly 50% greater in men thanin women. The hemodynamic differences between menand women were confine to premenopausal women, sug-gesting that estrogens play a significan role in the cardio-vascular and hemodynamic responses in patients withhypertension. The mechanisms of hypertension seen withacute stressors, such as public speaking or mental arith-metic, also vary based on gender. Studies have shown thatmen and postmenopausal women have a more significanincrease in SVR in response to acute stressors, whereaspremenopausal women exhibit a hypertensive responsethat is due primarily to increases in CO. Some studies havesuggested that hypertension early in the course of diabetesand with obesity are associated with increased CO andrelatively normal SVR.45 Others have shown that theearliest hemodynamic abnormalities may be changes inarterial compliance.46 To a significan degree, hyperten-sion in patients on dialysis results from volume expansionand can be associated with signs of sympathetic stimula-tion such as increased HR and SV.

Impedance Cardiographic Studies

Impedance cardiography has been used to evaluate thehemodynamic parameters in normotensive individuals atdifferent ages and in various hypertensive populations. Ina study of 640 normal subjects evaluated as renal trans-plant donors, Taler et al47 found that increasing age wasassociated with increasing BP, increasing SVR, and de-creasing CO due to decreased SV. Hemodynamic changes

FIG. 7 Distribution of cardiac index values in Tecumseh, Michiganstudy. Cardiac index values for the hypertensive population show abimodal distribution. From Julius et al.40

with age were similar in men and women, although BP and

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CO were lower and HR and SVR were higher in women.Age-related changes included an increase in total thoracicimpedance, equivalent to a decrease in its reciprocal TFCand consistent with decreasing cardiopulmonary volumeor muscle mass or both.

In a study comparing hemodynamic variables betweenpre-menopausal and post-menopausal women, Hinderliteret al48 showed that post-menopausal women had lower COand higher SVR for any given BP level compared withpre-menopausal women. Importantly, these significanchanges in CO and SVR occurred without significanchanges in BP levels, suggesting that the hemodynamicparameters underlying BP provide more information thandoes MAP alone. This is also seen in data from a study byGalarza et al,49 in which, despite relatively stable DBPlevels in patients from the third to seventh decades of life,the investigators found significan increases in SVRI ofnearly 50% and decreases in cardiac index of 27%. Alfiet al50 used impedance techniques to show that elevationsin the difference between SBP and DBP (pulse pressure[PP]) occurred due to different hemodynamic mechanismsin men �30 years of age compared with those middle agedand older. In younger men, increased PP was associatedwith increases in stroke index, reflectin preserved hemo-dynamic load with normal arterial compliance. In contrast,after age 50 years, men showed increases in PP associatedwith decreases in stroke index, reflectin age-related de-creases in arterial compliance. Thus, BP readings alonedid not reflec the underlying hemodynamic differences ingroups with presumably different cardiovascular risk de-spite similar levels of MAP and PP. Gender differences areseen in impedance studies of the hypertensive response tocaffeine: men who show hypertensive responses to caf-feine increase their SVR, whereas women primarily in-crease SV and CO.51 Yu et al52 studied hemodynamicparameters in patients with different mood states. Findingsof correlation of CO and SVR—but not SBP, DBP, or

FIG. 8 Age-related changes in cardiac output and peripheral re-sistance. With increasing age, peripheral resistance rises in thehypertensive population and at higher levels it is associated with
decreasing cardiac output and ultimately congestive heart fail-ure.


106

MAP—with affective state is further evidence of the het-erogeneity of hemodynamic subsets within various groupsclinically identified

Hinderliter53 reported that African American men andwomen had increased SVR, decreased CO, and associatedLV remodeling compared with Caucasian men and womendespite similar BP readings. In normotensive AfricanAmericans, Calhoun et al54 postulated that vasoconstrictorresponses seen with mental stress and cold presser testingmay contribute to elevated SVR and the development ofhypertension.

These and other studies using ICG technology showthat within any given population SVR, CO, and TAC showsignifican variation. The heterogeneity of hemodynamicfinding within various cohorts is evidence that the spe-cifi hemodynamic status of an individual patient cannotreliably be predicted on the basis of age, gender, or ethnicbackground. Moreover, that hemodynamic values cannotbe identifie by BP levels or clinical assessment alonesupports the need for measurement of hemodynamic pa-rameters in individual patients with hypertension.

Hemodynamics of Hypertension:Prognostic ConsiderationsThe underlying hemodynamic abnormalities in hyperten-sion result in structural and functional changes in thecardiovascular system that adversely affect prognosis, ie,that increase risk of morbidity or mortality. Increases inhemodynamic measures such as SVR and reductions inarterial compliance provide prognostic information in ad-dition to that obtained by BP measurements alone.

Invasive Hemodynamic andEchocardiographic Studies

Elevated arterial BP is the result of increased arterialstiffness and increased SVR. This results in increased LVwall stress, the best measure of LV afterload. Using cath-eterization techniques, Fagard et al55 demonstrated thatSBP and SVR at rest and during exercise correlated with

Table 8. Improved predictive power of pulse pres-sure (PP) to stroke volume index ratio (SVIR) com-pared with pulse pressure alone*

Hazard rate,CV event

Hazard rate,mortality

PP 1.46 (0.91–2.35)† 1.65 (0.83–3.30)†PP to SVIR 1.79 (1.15–2.80)‡ 2.05 (1.15–3.65)‡

CV � cardiovascular.Values and 95% confidence intervals for 1-SD increase in the

variable of interest.Adapted from Fagard et al.56

* Adjusted for age, gender, mean arterial pressure, and heartrate; † P � NS; ‡ P � .01.

the risk of cardiovascular events and total mortality at an

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average of 16.2 years of follow-up. In this study, exerciseSVR—but not exercise BP—added prognostic value toparameters measured at rest, suggesting that hemodynamicvariables other than BP might have greater prognosticvalue.

A subsequent article56 reported the relationship betweenanother hemodynamic parameter, namely, the ratio of PP tostroke index (PP-to-SVi ratio), and outcomes in patientsfollowed for an average of 16.5 years. In this study, thePP-to-SVi ratio, that is, the reciprocal of TAC index, wasindependently associated with cardiovascular events or death.Each increase in PP-to-SVi ratio of 0.75 mm Hg/(mL/m2)was associated with a 79% increase in the risk of a cardio-vascular event (P � .01) and greater than double the risk ofall-cause mortality (P � .01). As shown in Table 8, theincreased hazard rates with PP-to-SVi ratio compared withPP alone demonstrates the additional predictive value whenthe hemodynamic parameter of flo (SVi) is added to thepressure measurement alone.

De Simone et al57 studied the effects of TAC on car-diovascular events over a 10-year period. They found thatrisks of fatal and total cardiovascular events were inde-pendently correlated with age, LV mass, and lower levelsof arterial compliance, define as decreasing values of themeasured ratio of echocardiographic SV to PP (SV/PP) tothat predicted from previously developed equations (%SV/PP). Moreover, consistent with the results of Fagard etal,56 the investigators found that systolic BP, mean BP, orPP alone (without including the flow-relate hemody-namic parameter of SV) were not independent predictorsof prognosis. After adjustment for age and LVH thereremained an independent effect of % SV/PP on cardiovas-cular endpoints at 10-year follow-up (Fig. 9). These in-vestigators found that hemodynamic parameters such asarterial compliance and percent predicted arterial compli-ance correlated better with changes in cardiac structure (ie,hypertrophy and remodeling) than did BP levels alone.

FIG. 9 Event-free survival based on predicted ratio of stroke vol-ume (SV) to pulse pressure (PP). Event-free survival is reduced in
hypertensive patients with reduced arterial compliance, as definedas a low predicted SV/PP ratio. From De Simone et al.57


107

Gender has long been known to affect prognosis inpatients with hypertension. In 1913, Janeway58 publishedthe observation that women with hypertension tended tohave a better prognosis than men. More recent studieshave suggested that this difference may be related todifferent hemodynamic substrates in men compared towomen with elevated BP levels. Messerli et al44 suggestedthat the disparate prognosis between men and womenmight be explained on the basis of differing hemodynamicmechanisms: “For any level of arterial pressure, totalperipheral resistance (and therefore the risk of hyperten-sive cardiovascular disease) was lower in women than inmen.”

The mechanism of the adverse prognosis from hyper-tension is in part related to structural changes in the heartthat result from elevated wall stress. Prolonged increasesin wall stress lead to left ventricular (LV) structuralchanges with relative increases in wall thickness, overallLV mass or both.59 In concentric remodeling, there is arelative increase in LV thickness without increase in over-all LV mass. This structural change appears to be relatedto increased pressure load but with relative decrease involume as evidenced by low normal CO (termed “volumeunderload”). Concentric left ventricular hypertrophy(LVH) is characterized by an increase in wall thicknesswith increase in LV mass or mass index and also resultsfrom pressure overload caused by long-term hypertension.Eccentric hypertrophy is define as increased LV massindex with preserved relative wall thickness and is asso-ciated with both pressure and volume overload. This pat-tern, a common result of the afterload and volumeexcesses in long-standing severe aortic insufficiency re-sults in spherical remodeling of the LV. Interestingly, inthis study of hypertensive individuals,59 both eccentrichypertrophy and concentric remodeling were more com-mon than the “classic” pattern of hypertensive heart dis-ease, namely, concentric LVH.

Nonetheless, LVH is a powerful predictor of cardiovas-cular risk and is independently associated with mortality inpatients with coronary artery disease.60–63 For example,Vakili et al63 reported on the pooled results of 20 pub-lished studies of LVH as define by electrocardiographicor echocardiographic criteria. They demonstrated aweighted mean relative risk of cardiovascular morbidityfrom LVH of 2.3, independent of all covariates analyzed.As reported by Ichkhan et al,64 LVH is associated withabnormalities of ventricular repolarization and at least atwofold increase in the risk of serious ventricular arrhyth-mias.

Hypertension results in abnormalities of endothelialfunction, affecting hemodynamic factors such as arterialcompliance. Gomez-Cerezo et al65 demonstrated impairedbrachial artery flow–mediate dilation, a common test ofendothelial function, in patients with sustained or labilehypertension. They found that flow-mediate dilation wasabnormal to a similar degree in patients with sustained
essential hypertension or “white-coat hypertension” but
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was normal in individuals with normal BP levels. Othershave evaluated measures of arterial compliance (or, alter-natively, arterial stiffness) using the measure of pulsewave velocity.66,67

Additional structural changes occuring at the level ofthe heart and blood vessel have prognostic significanc inpersons with hypertension, including vascular remodelingwith changes in lumen to wall thickness.68,69 Apoptosis, orprogrammed cell death, contributes to the vascularchanges (ie, remodeling) in hypertension. Inflammatioand fibrosi similarly contribute with the accumulation ofvarious components in the extracellular matrix such ascollagen and fibronectin Intengan and Schiffrin69 re-viewed the factors that result in arterial remodeling andaltered hemodynamic parameters in patients with hyper-tension.

Importantly, studies have shown that treatment withantihypertensive agents may result in regression of thestructural abnormalities caused by long-standing hyperten-sion and may result in improved prognosis.70–72 Mathewet al,70 reporting on data from the Heart Outcomes Pre-vention Evaluation (HOPE) study, demonstrated that treat-ment with the angiotensin-converting enzyme (ACE)inhibitor ramipril was associated with regression of LVHby electrocardiographic criteria compared with placebocontrol. That BP showed minimal difference between thetreatment and control groups is consistent with other stud-ies demonstrating improvement in overall hemodynamics(as shown by significan decreases in SVR and parallelincreases in CO) that are not evident from BP levels alone.Ofil et al,73 in an echocardiographic substudy of theSystolic Hypertension in the Elderly Program (SHEP),demonstrated partial regression of LVH in patients treatedwith a diuretic-based regimen for a minimum of 3 years. Ina meta-analysis of �1000 patients with serial echocardi-ography during treatment of essential hypertension, Ver-decchia et al74 demonstrated that patients whose LVHregressed during treatment had significantl fewer cardio-vascular events compared with those in whom LV massincreased, consistent with the hypothesis that improve-ments in hemodynamics correlate with improved progno-sis in patients with appropriately treated hypertension.

Impedance Cardiographic Studies

The ICG technique has been used to explore age-relatedchanges in hemodynamic variables and their correlationwith cardiovascular risk and the adverse prognosis. Thesestudies support previous finding that future risk in pa-tients with hypertension may not be reflecte in BP levelsalone. Alfi et al50 demonstrated that despite similar ele-vations in PP, younger men had preserved stroke index(and arterial compliance) compared with older men. Theyconcluded that preserved arterial compliance and cardiacpump function may explain the lack of prognostic signif-icance of elevated PP in younger men. These finding lend
further support to the value of the incremental information


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provided by the hemodynamic components of BP and PPlevels.

Hemodynamic differences have been demonstrated inpatients who have experienced complications of hyperten-sion compared with those with hypertension alone. In astudy of hemodynamic status in hypertensive patients withand without a history of stroke, Galarza et al75 found lowercardiac index and higher SVR index in those with historyof stroke. These differences occurred in the absence ofdifferences in BP or antihypertensive treatment, providinganother example of the unreliability of BP to reflec theseverity of underlying hemodynamic abnormalities.

Hemodynamics of Hypertension:Therapeutic ConsiderationsHypertension management includes hygienic measuressuch as sodium restriction and weight loss; and, in mostcases, it requires the use of one or more antihypertensiveagents. Antihypertensive medications exert their BP-low-ering effects by reductions in SVR or CO. Hemodynamiceffects can be used to classify antihypertensive agents,predict the response to antihypertensive therapy, and guideboth the initiation and titration of these agents.76–78

Just as interpretation and treatment of serum cholesterollevel improves when its components (HDL-cholesterol andLDL-cholesterol) are measured, hypertension may be betterdiagnosed and treated by examining its hemodynamic com-ponents (CO and SVR). As MAP is the product of CO andSVR, elevated mean BP results from elevated CO, SVR, orboth. As shown in Fig. 10, CO is the product of HR and SV.Stroke volume is determined in part by LV fillin (preload)and contractile (inotropic) state. Hypertension can thus resultfrom increases in SVR (vasoconstriction), HR (hyperchro-notropy), preload (hypervolemia), or contractility (hyperinot-ropy).

Invasive and Echocardiographic Studies

In a small group of men with severe hypertension, Sullivanet al79 studied the relationship between baseline hemody-

FIG. 10 Hemodynamic components of hypertension. BP � bloodpressure; CO � cardiac output; HR � heart rate; SV � stroke vol-ume; SVR � systemic vascular resistance.

namic status and the response to various antihypertensive

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agents that were randomly selected. Patients with elevatedSVR responded with decreases in SVR, and those withelevated CO had BP control associated with normalizationof CO.

Treatment targeted at the specifi hemodynamic causeof hypertension has predictable and appropriate results.Easterling et al80 studied noninvasive hemodynamic pa-rameters using Doppler echocardiography in 19 pregnanthypertensive women. Ten patients had elevated CO,whereas nine patients had elevated SVR, demonstratinghemodynamic heterogeneity within this apparently homo-geneous population. Patients with elevated CO weretreated with a �-blocker (atenolol) and those with elevatedSVR were treated with hydralazine, a vasodilator targetedat elevated SVR. Patients given hydralazine had dramaticimprovements in CO in association with decreases inSVR; those given atenolol for elevated CO had improve-ment in BP and normalization of CO. The investigatorssuggest that the failure of previous studies to show con-sistent results in the drug management of hypertension inpregnancy may have resulted from treating a heteroge-neous hemodynamic group with a single regimen. Theimplication of their study is that hemodynamically guidedtherapy would be expected to show more consistent resultsin hemodynamically diverse populations.

Differential effects of antihypertensive medications onhemodynamic variables may not be evident from changesin BP alone. Resnick and Lester81 studied the effects ofvarious BP medications on arterial compliance in patientsreferred to an outpatient practice specializing in hyperten-sion. The changes in compliance of the large arteries(capacitive compliance) and in smaller arteries (reflectivcompliance) were evaluated during treatment with ACEinhibitors, angiotensin-receptor blockers (ARBs), calciumchannel blockers (CCBs), and �-blockers. The researchersfound that despite similar changes in SBP, DBP, and PPduring treatment, there were improvements in arterialcompliance with ACE inhibitors, ARB, and CCB but notwith �-blockers. These researchers suggest that choosingmedications that have favorable effects on both BP andarterial compliance “might further enhance the potentialclinical benefi of drug therapy in hypertension.” Simi-larly, Zusman78 reported that despite similar degrees of BPreduction, the hemodynamic effects of the CCB nifedipinewere favorable when compared with the �-blocker ateno-lol, resulting in decreased SVR, increased CO and im-proved measures of LV contractility and diastolicfunction. Others have shown significantl different hemo-dynamic effects between various �-blockers such as be-tween metoprolol and carvedilol due to the �-adrenergicblocking properties of the latter.82

Studies suggest that most patients require multiplemedications to achieve BP control. In the Antihyperten-sive and Lipid-Lowering Treatment to Prevent Heart At-tack Trial (ALLHAT),83 a large randomized trialcomparing outcomes in patients treated with different
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on treatment at time of pre-randomization visit, althoughonly 27% had adequate BP control. After 5 years of treat-ment, 66% had achieved levels of BP �140/90 mm Hg. Ofthe participants whose hyptertension was controlled, 63%were on two or more medications, indicating that BPcontrol required combination therapy in the majority ofcases. Yakovlevitch and Black84 reviewed 436 charts toidentify 91 cases of resistant hypertension referred to theirhypertension clinic of a tertiary care center and evaluatedfor possible causes of resistance, including medicationnoncompliance, secondary causes of hypertension, druginteractions, and the appropriateness of the medical regi-men. They found that the most common cause of inade-quate BP control in the 91 patients identifie with resistanthypertension was an inappropriate medical regimen.

The hemodynamic responses of various classes of an-tihypertensive medications have been categorized in anextensive review of hypertension by Houston,85 and se-lected hemodynamic effects are summarized in Table 9.

Rationale for an ICG-GuidedApproach to AntihypertensiveTherapyThe foregoing discussion has presented data on the role ofhemodynamic information for diagnostic, prognostic, andtherapeutic decision making for patients with hyperten-sion. The use of ICG-derived hemodynamic information toimprove BP control requires accurate assessment of base-line hemodynamic state, creation of a therapeutic regimenbased on hemodynamic status, and timely measurement ofchanges in various hemodynamic parameters in responseto therapy.86 Studies have shown that it is very difficult—inot impossible—to make an accurate assessment of COand SVR at the bedside by physical examinationalone.20,21,87,88 Therefore, it is not likely to be possible touse physical examination to reliably identify baseline he-modynamic subsets or changes in hemodynamic status soas to optimize therapy.

Clinicians have used ICG in various patient care set-tings to assess its applicability in the assessment andtreatment of hypertension.89–95 As noted earlier here andin Fig. 7, there is significan hemodynamic heterogeneityamong individuals with hypertension, suggesting that BPlevel alone is not adequate to categorize patients intoclinically meaningful subgroups. De Divitiis et al91 usedICG to confir the presence of distinct hemodynamicprofile in patients with hypertension: 1) elevated CO inassociation with normal or nearly normal SVR, and 2)predominantly elevated SVR. Margulis et al96 evaluatedother hemodynamic parameters in untreated patients withhypertension. They found impairment of cardiac perfor-mance with decreased indices of contractility and evidencefor increased thoracic flui content, suggesting increasedwater content of the lungs or thoracic wall tissues.

Thoracic flui content, the reciprocal of total thoracic

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110

impedance, is strongly correlated with amount of flui inthe chest cavity, whether intravascular or extravascular. Inpatients undergoing thoracentesis, Petersen et al97 demon-strated a strong correlation between the volume of pleuralflui removed and the change in total thoracic impedance(correlation coefficient 0.97). In studies using lower-bodynegative pressure to create pooling of venous blood in thelower extremities, Ebert et al98 found a nearly perfectlinear correlation with changes in central venous pressureand changes in thoracic impedance. Thus, TFC has beenused to monitor changes in flui volume and guide diuretictherapy in patients with hypertension.

Linb et al89 reported that BP reductions resulted fromimprovements in baseline hemodynamic abnormalities;patients with elevated CO responded to targeted therapywith a �-blocker (propranolol), whereas those with ele-vated SVR responded to treatment with the vasodilatingCCB (nifedipine). Mattar et al99 showed that an intensiveregimen of diet and exercise resulted in improvements inhemodynamic parameters with substantial increases in COand decreases in SVR despite only modest changes inMAP. Moreover, the investigators speculated that failureof some hypertensive patients to show hemodynamic im-provement on serial ICG measures resulted from the in-appropriate choice of medications that were not targetedtoward the underlying hemodynamic abnormalities.

Hemodynamic parameters derived from ICG have beenused to evaluate the differential effects of medications inpatients with essential hypertension. In a study of theeffects of a cardioselective �-blocker compared with a�-blocker with intrinsic sympathomimetic activity, Toth etal100 studied 57 patients randomized to treatment witheither atenolol or pindolol for 12 weeks. Pindolol therapywas associated with a 12% decrease in SVR comparedwith minimal change with atenolol. Atenolol-related im-provement in BP resulted from decrease in HR and cardiacindex. Breithaupt-Grogler et al67 reported on the differen-tial hemodynamic effects of combination therapy withverapamil/trandolapril (Vera/Tran) compared with meto-prolol/hydrochlorothiazide (Meto/HCTZ) in 26 patientsafter 6 months of therapy. In addition to ICG-derived COand SVR, the authors measured carotidofemoral pulsewave velocity as a measure of arterial stiffness. The com-bination of CCB and ACE inhibitor (Vera/Tran) reduceddiastolic BP to a greater degree than Meto/HCTZ andlowered SVR by about 15% compared with minimalchange with the �-blocker/diuretic combination. Treat-ment with Meto/HCTZ was associated with a significanreduction in CO compared with baseline, which was notseen with Vera/Tran. However, pulse wave velocity de-creased with Vera/Tran but not with Meto/HCTZ, suggest-ing an improvement in the elastic properties of the aortawith the former drug regimen.

The ICG technique has been used to assess the hemo-dynamic effects of sodium restriction in a small group ofsubjects with mild hypertension.101 During sodium restric-
tion, ICG-derived measures of SV decreased in association
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with fall in diastolic BP. An increase in overall thoracicimpedance (the reciprocal of TFC) was consistent with adecrease in extracellular flui volume. In addition, ICGhas been used to explore the mechanisms of responses toACE inhibitors and prostaglandin inhibitors in patientswho are either salt sensitive or salt insensitive.102 Theseexamples illustrate the use of ICG in assessing the mech-anisms of BP elevation and the hemodynamic effects ofnonpharmacologic interventions in hypertension.

As noted above, antihypertensive medications ulti-mately act on one or more of the hemodynamic compo-nents that determine BP.79,80 Once the baselinehemodynamic status is known, an appropriate medicalregimen can be designed based on the expected hemody-namic effects of various medications. However, individualpatients vary in their responses to antihypertensive drugssuch that the actual hemodynamic effects and side effectscannot reliably be predicted. Therefore, empiric selectionof drug combinations based on their general hemodynamicactions as a class may not be successful in managing aspecifi patient, even if the baseline hemodynamic status isknown. The ICG technique is unique in that it can providenot only an accurate hemodynamic profil noninvasivelybut can guide therapy toward a drug regimen that is mostappropriate for the specifi patient based on serial mea-surements. Periodic measurements of hemodynamic statusallow the physician to monitor therapy when results aresuboptimal or unexpected. It is for these reasons that ICGhas emerged as a valuable tool in the evaluation andtreatment of patients with hypertension.

Outcome Studies Using ICG-Guided Therapy in HypertensionThe observation that hypertension is a hemodynamic dis-ease implies that measurement of hemodynamic parame-ters can be used to guide medication selection, to titratedose, and to evaluate efficac of the medical regimen.Several studies have used ICG to evaluate hemodynamicparameters and demonstrated that ICG-guided therapy im-proves BP control. Taler et al103 randomized 104 patientswith hypertension uncontrolled on two or more drugs to a3-month trial of ICG-guided therapy or standard therapydirected by a hypertension specialist. In this study, BPcontrol (define as achieving BP �140/90 mm Hg) oc-curred 70% more often in the ICG-guided group (Fig. 11).Use of ICG resulted in greater reductions in SVR indexand more intensive use of diuretic therapy, guided bylevels of TFC. According to the study investigators, mea-surement of hemodynamic and impedance parameters wasmore effective than clinical judgment alone in guidingselection of antihypertensive therapy patients resistant toempiric therapy.

Sharman et al104 studied a cohort of patients in theprimary care offic setting with drug-resistant hyperten-sion, define as systolic BP �140 mm Hg or diastolic BP
�90 mm Hg during treatment with two antihypertensive


111

medications. Patients were treated based on a publishedICG-guided treatment algorithm (Fig. 12) for an averageof 7 months. In this study, ICG resulted in BP control in57.1% of patients who were not controlled before the useof ICG-guided therapy. The average number of medica-tions increased from 2.0 at time of entry to 2.5 � 0.7 at theend of the study period. The observation that hemody-namic information derived from ICG resulted in BP con-trol with two medications in some patients and three ormore in others is consistent with both higher intensity andmore appropriate medical regimens. The investigatorsconcluded that ICG is safe and cost-effective and couldassist community-based physicians in treating uncon-trolled hypertension.

Sramek et al105 reported on a series of 322 patientswith hypertension uncontrolled despite previous ther-apy with two or more antihypertensive agents for peri-ods of 2 years or more. The researchers directed themanagement of hypertension at both control of BP andimprovement in underlying hemodynamic parametersincluding CO and SVR. At baseline, 16% of subjectshad significantl reduced CO (ie, were considered hy-podynamic) and approximately 19% were hyperdy-namic. In this large series of patients treated using theresults of ICG evaluation, so-called normodynamicgoal-oriented therapy controlled BP in 203 subjects(63%) within several weeks. The investigators highlightthe observation that ICG was able to identify medica-tions that were optimal and specifi for the individualpatients, resulting in an approach superior to the con-ventional “trial-and-error” method.

Additional Roles of ICG in PatientsWith HypertensionThe evidence cited above supports the use of ICG-derivedhemodynamic information in guiding the selection, initi-ation, titration, and evaluation of antihypertensive medi-

FIG. 11 Percentage of patients achieving blood pressure (BP)control using impedance cardiography (ICG)–guided therapycompared with non–ICG-guided therapy. Adapted from Taler etal.103

cation. However, patients and their physicians fail to

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achieve adequate BP control for reasons other than theresponses to specifi medications. Common barriers to BPcontrol include lack of awareness of the condition, inabil-ity to make necessary dietary and other lifestyle modifications, noncompliance with medications, complicatingfactors such as drug interactions, secondary causes ofhypertension, and comorbidities such as kidney disease.

Testing with ICG using currently available equipmentmay favorably affect each of these issues. Oscillometricmeasurements of BP, as with the most widely used ICGequipment, are more reliable and less operator dependentthan standard BP techniques. The accurate and reproduc-ible measures of CO and SVR identify patients with ab-normal hemodynamic states and may increase clinicalsuspicion and diagnostic sensitivity for those with border-line or prehypertensive BP readings. The ICG reports areuseful teaching tools for patients and may provide moti-vation for the dietary and other lifestyle changes that assistin BP control.

Changes in hemodynamic parameters may identify in-stances when patients stop their medications or when thereare complicating factors such as worsening renal functionor interactions with medications such as over-the-counternonsteroidal anti-inflammator drugs. As noted,103 an in-crease in one class of hypertensive agents may result incompensatory flui retention, leading to an increase inTFC as measured by ICG and the need for higher doses ofdiuretics. Similarly, flui retention resulting from the renaleffects of anti-inflammator medications may be recog-nized by changes in TFC. Importantly, ICG-derived mea-sures of cardiac performance, such as velocity index or

FIG. 12 Algorithm for hemodynamically guided therapy of hyper-tension. Adapted from Sharman et al105 and Taler et al.104 In thelatter study, postural changes in total body impedance (TBI), the
reciprocal of thoracic fluid content (TFC), were used as the criteriafor decisions reguarding fluid status.


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systolic time ratio, may be the initial signs of the devel-opment of LV dysfunction.106,107

Implications of Hemodynamicsand Future ConsiderationsIn addition to improving the diagnosis and therapy ofhypertension, hemodynamic measurements provide in-sights into other aspects of cardiovascular function. Forexample, studies have shown the importance of endothe-lial function in the development and progression of car-diovascular disease.108 Endothelial dysfunction, asmeasured by reduced flow-mediate arterial dilation, isassociated with abnormal hemodynamic measures, includ-ing elevated SVR.109 In the HOPE study,110 an ACEinhibitor—a drug that both lowers SVR and improvesendothelial function—reduced mortality from cardiovas-cular disease despite only minor effects on BP. Futurestudies will likely examine the significanc of elevatedSVR and arterial compliance in individuals with hyperten-sion or prehypertension and will correlate ICG-derivedhemodynamic parameters with other evolving markers ofincreased cardiovascular risk such as C-reactive protein,homocysteine level, and the metabolic syndrome.

The studies included in this supplement of the journal addto the growing body of literature that supports the accuracy,reliability, and clinical utility of ICG in diagnostic and prog-nostic assessment and therapeutic management of patientswith hypertension. The use of ICG has added significantl toour understanding of hypertension as a disease with bothhemodynamic causes and hemodynamic consequences. Justas congestive heart failure reflect abnormal flo or inappro-priate ventricular fillin pressures, hypertension occurs whenthere is abnormal flo or inappropriate vascular resistance orcompliance. When hypertension impairs LV performance(either systolic or diastolic), heart failure ensues. Althoughthese conditions often co-exist, in many cases hypertension isa step in a hemodynamic continuum that leads to furtherhemodynamic derangement and heart failure. It is believedthat future studies will confir recent finding that hemody-namic measurements in individual patients will improve di-agnosis, risk assessment, and treatment for these patients. It isalso possible that further exploration of the implications ofhypertension as a hemodynamic disease will lead to studiesdemonstrating that earlier detection and treatment of thehemodynamic components of hypertension may change thenatural history of this disease process.

References

1. Wiggers CJ: Hemodynamic changes in hypertension. Am Heart J1938;16:515–525.

2. Freis ED: Hemodynamics of hypertension. Physiol Rev 1960;40:27–54.

3. Freis ED: Studies in hemodynamics and hypertension. Hypertension
2001;38:1–5.
of 158.

4. Lund-Johansen P: Newer thinking on the hemodynamics of hyper-tension. Curr Opin Cardiol 1994;9:505–511.

5. Julius S: Autonomic nervous system dysregulation in human hyper-tension. Am J Cardiol 1991;67:3B–7B.

6. Susic D, Frohlich ED: Hypertension and the heart. Curr HypertensRep 2000;6:565–569.

7. Messerli FH, DeCarvalho JG, Christie B, Frohlich ED: Essentialhypertension in black and white subjects. Hemodynamic findingand flui volume state. Am J Med 1979;67:27–31.

8. Ventura H, Messerli FH, Oigman W, Suarez DH, Dreslinski GR,Dunn FG, Reisin E, Frohlich ED: Impaired systemic arterial com-pliance in borderline hypertension. Am Heart J 1984;108:132–136.

9. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ:The Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure. TheJNC 7 Report. J Am Med Assoc 2003;289:2560–2572.

10. Oparil S, Zaman MA, Calhoun DA: Pathogenesis of hypertension.Ann Intern Med 2003;139:761–776.

11. Schappert SM, Nelson C: National ambulatory medical care survey:1995–96 summary. Vital and health statistics, series 13, no. 142.Washington, DC: Government Printing Office November 1999.DHHS publication no. (PHS) 2000-1713.

12. Hyman DJ, Pavlik VN: Characteristics of patients with uncontrolledhypertension in the United States. N Engl J Med 2001;345:479–486.

13. Setaro JF, Black HR: Refractory hypertension. N Engl J Med1992;327:543–547.

14. Oparil S, Calhoun DA: Managing the patient with hard-to-controlhypertension. Am Fam Phys 1998;57:1007–1014.

15. Gifford RW Jr. Resistant hypertension: introduction and definitionsHypertension 1988;11(Suppl II):II-65–II-66.

16. Wilking SV, Belanger A, Kannel WB, D’Agostino RB, Steel K:Determinants of isolated systolic hypertension. J Am Med Assoc1988;260:3451–3455.

17. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R: Age-specifi relevance of usual blood pressure to vascular mortality: ameta-analysis of individual data for one million adults in 61 pro-spective studies. Lancet 2002;360:1903–1913.

18. Elliott WJ: The economic impact of hypertension. J Clin Hypertens2003;5(3 Suppl 2):3–13.

19. Goetzel RZ, Long SR, Ozminkowski RJ, Hawkins K, Wang S,Lynch W: Health, absence, disability, and presenteeism cost esti-mates of certain physical and mental health conditions affecting U.S.employers. J Occup Environ Med 2004;46:398–412.

20. Steingrub JS, Celoria G, Vickers-Lahti M, Teres D, Bria W: Ther-apeutic impact of pulmonary artery catheterization in a medical/surgical ICU. Chest 1991;99:1451–1455.

21. Connors AF, Dawson NV, Shaw PK, Montenegro HD, Nara AR,Martin L: Hemodynamic status in critically ill patients with andwithout acute heart disease. Chest 1990;98:1200–1206.

22. Hoit BD, Rashwan M, Watt C, Sahn DJ, Bhargava V: Calculatingcardiac output from transmitral volume flo using Doppler andM-mode echocardiography. Am J Cardiol 1988;62:131–135.

23. Northridge DB, Findlay IN, Wilson J, Henderson E, Dargie HJ:Non-invasive determination of cardiac output by Doppler echocar-diography and electrical bioimpedance. Br Heart J 1990;63:93–97.

24. Van De Water JM, Miller TW: Impedance cardiography: the nextvital sign technology? Chest 2003;123:2028–2033.

25. Albert N, Hail M, Li J, Young J: Equivalence of bioimpedance andthermodilution in measuring cardiac output and index in patientswith advanced, decompensated chronic heart failure hospitalized incritical care. Am J Crit Care 2004;13:469–479.

26. Drazner M, Thompson B, Rosenberg P, Kaiser PA, Boehrer JD,Baldwin BJ, Dries DL, Yancy CW: Comparison of impedancecardiography with invasive hemodynamic measurements in patientswith heart failure secondary to ischemic or nonischemic cardiomy-
opathy. Am J Cardiol 2002;89:993–995.


113

27. Ziegler D, Grotti L, Krucke G: Comparison of cardiac outputmeasurements by TEB vs. intermittent bolus thermodilution inmechanical ventilated patients (Abstract). Chest 1999;116:281S.

28. Sageman WS, Riffenburgh RH, Spiess BD: Equivalence of bioim-pedance and thermodilution in measuring cardiac index after cardiacsurgery. J Cardiothoracic Vasc Anesth 2002;16:8–14.

29. Yung, G, Fedullo P, Kinninger K, Johnson W, Channick R: Com-parison of impedance cardiography to direct Fick and thermodilu-tion cardiac output determination in pulmonary arterialhypertension. Congest Heart Fail 2004;10(Suppl 2):7–10.

30. Verhoeve PE, Cadwell CA, Tsadok S: Reproducibility of noninva-sive bioimpedance measurements of cardiac function (Abstract).J Card Fail 1998;4(Suppl):S3.

31. Aldrete AJ, Brown C, Daily J, Buerke V: Pacemaker malfunctiondue to microcurrent injection from a bioimpedance noninvasivecardiac output monitor. J Clin Monit 1995;11:131–133.

32. Frohlich ED: Local hemodynamic changes in hypertension. Insightsfor therapeutic preservation of target organs. Hypertension 2001;38:1388–1394.

33. Segers P, Brimioulle S, Stergiopulos N, Westerhof N, Naeije R,Maggiorini M, Verdonck P: Pulmonary arterial compliance in dogsand pigs: the three-element Windkessel model revisited. Am JPhysiol 199;277:H725–H731.

34. Randall OS, Westerhof N, van den Bos GC, Alexander B: Reliabil-ity of stroke volume to pulse pressure ratio for estimating anddetecting changes in arterial compliance. J Hypertens 1986;4(Suppl5):S293–S296.

35. Chemla D, Hebert J-L, Coirault C, Zamani K, Suard I, Colin P,Lecarpentier Y: Total arterial compliance estimated by stroke vol-ume-to-aortic pulse pressure ratio in humans. Am J Physiol 1998;274: (Heart Circ Physiol 43) H500–H505.

36. Egan B, Schmouder R: The importance of hemodynamic consider-ations in essential hypertension. Am Heart J 1988;116:594–599.

37. Izzo J: Arterial stiffness and the systolic hypertension syndrome.Curr Opin Cardiol 2004;19:341–352.

38. Guyton AC: The relationship of cardiac output and arterial pressurecontrol. Circulation 1981;64:1079–1088.

39. Fouad-Tarazi F, Izzo JL: Hemodynamic profile and responses, inIzzo JL, Black HR (eds): Hypertension Primer, : The Essentials ofHigh Blood Pressure. Council on High Blood Pressure Research(American Heart Association), Dallas, 1999, pp 115–117. SecondEdition

40. Julius S, Krause L, Schork NJ, Mejia AD, Jones KA, van de Ven C,Johnson EH, Sekkarie MA, Kjeldsen SE, Petrin J: Hyperkineticborderline hypertension in Tecumseh, Michigan. J Hypertens 1991;9:77–84.

41. Lund-Johansen P: Hemodynamic patterns in the natural history ofborderline hypertension. J Cardiovasc Pharm 1986;8(Suppl 5):S8–S14.

42. Slotwiner DJ, Devereux RB, Schwartz JE, Pickering TG, de SimoneG, Roman MJ: Relation of age to left ventricular function andsystemic hemodynamics in uncomplicated mild hypertension. Hy-pertension 2001;37:1404–1409.

43. Franklin SS: Blood pressure and cardiovascular disease: what re-mains to be achieved? J Hypertens 2001;19(Suppl 3):S3–S8.

44. Messerli FH, Garavaglia GE, Schmieder RE, Sundgaard-Riise K,Nunez BD, Amodeo C: Disparate cardiovascular finding in menand women with essential hypertension. Ann Intern Med 1987;107:158–161.

45. Davidson RC, Ahmad S: Hemodynamic profile in essential andsecondary hypertension, in Izzo JL, Black HR (eds): HypertensionPrimer: The Essentials of High Blood Pressure. Council on HighBlood Pressure Research (American Heart Association), Dallas,2003, pp 349–351. Third Edition

46. Romney JS, Lewanczuk RZ: Vascular compliance is reduced inthe early stages of type 1 diabetes. Diabetes Care 2001;24:2102–2106.

47. Taler S, Driscoll N, Tibor M, Sprau G, Augustine J, Larson T,

of 158.

Stegall M, Textor S: Changes in hemodynamic patterns with agein normotensive subjects (Abstract). Am J Hypertens 2004;17:373.

48. Hinderliter AL, Sherwood A, Blumenthal JA, Light KC, Girdler SS,McFetridge J, Johnson K, Waugh R: Changes in hemodynamics andleft ventricular structure after menopause. Am J Cardiol 2002;89:830–833.

49. Galarza CR, Alfi J, Waisman GD, Mayorga LM, Camera LA, delRio M, Vasvari F, Limansky R, Farias J, Tessler J, Camera MI:Diastolic pressure underestimates age-related hemodynamic impair-ment. Hypertension 1997;30:809–816.

50. Alfi J, Gabriel D, Waisman G, Camera MI: Contribution of strokevolume to the change in pulse pressure pattern with age. Hyperten-sion 1999;34:808–812.

51. Hartley TR, Lovallo WR,Whitsett TL: Cardiovascular effectsof caffeine in men and women. Am J Cardiol 2004;93:1022–1026.

52. Yu BH, Nelesen R, Ziegler MG, Dimsdale JE: Mood states andimpedance cardiography-derived hemodynamics. Ann Behav Med2001;23:21–25.

53. Hinderliter A, Blumenthal J, Waugh R, Chilukuri M, Sherwood A:Ethnic differences in left ventricular structure: relations to hemody-namics and diurnal blood pressure variation. Am J Hypertens 2004;17:43–49.

54. Calhoun DA, Mutinga ML, Collins AS, Wyss JM, Oparil S: Nor-motensive blacks have heightened sympathetic response to coldpressor test. Hypertension 1993;22:801–805.

55. Fagard RH, Pardaens K, Staessen JA, Thijs L: Prognostic value ofinvasive hemodynamic measurements at rest and during exercise inhypertensive men. Hypertension 1996;28:31–36.

56. Fagard RH, Pardaens K, Staessen JA, Thijs L: The pulse pres-sure-to-stroke index ratio predicts cardiovascular events anddeath in uncomplicated hypertension. J Am Coll Cardiol 2001;38:227–31.

57. de Simone G, Roman MJ, Koren MJ, Mensah GA, Ganau A,Devereux RB: Stroke volume/pulse pressure ratio and cardiovas-cular risk in arterial hypertension. Hypertension 1999;33:800 –805.

58. Janeway TC: A clinical study of hypertensive cardiovascular dis-ease. Arch Intern Med 1913;12:755–798.

59. Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG,Saba PS, Vargiu P, Simongini I, Laragh JH: Patterns of left ven-tricular hypertrophy and geometric remodeling in essential hyper-tension. J Am Coll Cardiol 1992;19:1550–1558.

60. Kahan T: The importance of left ventricular hypertrophy in humanhypertension. J Hypertens 1998;16(Suppl):S23–S29.

61. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Gattobigio R,Zampi I, Santucci A, Santucci C, Reboldi G, Porcellati C: Prognos-tic value of left ventricular mass and geometry in systemic hyper-tension with left ventricular hypertrophy. Am J Cardiol 1996;78:197–202.

62. Verdecchia P, Carini G, Circo A, Dovellini E, Giovannini E, Lom-bardo M, Solinas P, Gorini M, Maggioni AP: Left ventricular massand cardiovascular morbidity in essential hypertension: the MAVIstudy. J Am Coll Cardiol 2001;38:1829–1835.

63. Vakili BA, Okin PM, Devereux RB: Prognostic implications of leftventricular hypertrophy. Am Heart J 2001;141:334–341.

64. Ichkhan K, Molnar J, Somberg J: Relation of left ventricular massand QT dispersion in patients with systematic hypertension. Am JCardiol 1997;79:508–511.

65. Gomez-Cerezo J, Rios Blanco JJ, Suarez Garcia I, Moreno Anaya P,Garcia Raya P, Vazquez-Munoz E, Barbado Hernandez FJ: Nonin-vasive study of endothelial function in white coat hypertension.Hypertension 2002;40:304–309.

66. London GM, Cohn JN: Prognostic application of arterial stiffness:
task forces. Am J Hypertens 2002;15:754–758.


114

67. Breithaupt-Grogler K, Gerhardt G, Lehmann G, Notter T, Belz GG:Blood pressure and aortic elastic properties—verapamil SR/tran-dolapril compared to a metoprolol/hydrochlorothiazide combinationtherapy. Int J Clin Pharmacol Ther 1998;36:425–431.

68. Glasser SP: Hypertension syndrome and cardiovascular events.Postgrad Med 2001;110:29–35.

69. Intengan HD, Schiffrin EL: Vascular remodeling in hypertension:roles of apoptosis, inflammation and fibrosis Hypertension 2001;38:581–587.

70. Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, Bosch J,Sussex B, Probstfiel J, Yusuf S: Reduction of cardiovascular riskby regression of electrocardiographic markers of left ventricularhypertrophy by the angiotensin-converting enzyme inhibitorramipril. Circulation 2001;104:1615–1621.

71. Corea L, Bentivoglio M, Verdecchia P, Providenza M, Motolese M:Left ventricular hypertrophy regression in hypertensive patientstreated with metoprolol. Int J Pharmacol Ther Toxicol 1984;22:365–370.

72. Yoshitomi Y, Nishikimi T, Abe H, Nagata S, Kuramochi M, Mat-suoka H, Omae T: Left ventricular systolic and diastolic functionand mass before and after antihypertensive treatment in patientswith essential hypertension. Hypertens Res 1997;20:23–28.

73. Ofil EO, Cohen JD, St Vrain JA, Pearson A, Martin TJ, Uy ND,Castello R, Labovitz AJ: Effect of treatment of isolated systolichypertension on left ventricular mass. J Am Med Assoc 1998;279:778.

74. Verdecchia P, Angeli F, Borgioni C, Gattobigio R, de Simone G,Devereux RB, Porcellati C: Changes in cardiovascular risk byreduction of left ventricular mass in hypertension: a meta-analysis.Am J Hypertens 2003;16:895–899.

75. Galarza C, Alfi J, Waisman G, Burgos M, Zaniello G, del Rio M,Serra L, Toselli P, Vasvari F, Camera M: Severe systemic hemo-dynamic impairment in patients with stroke (Abstract). Am J Hy-pertens 1996;9(Suppl 1):172A.

76. Johns DW, Peach MJ: Factors that contribute to resistant forms ofhypertension. Pharmacological considerations. Hypertension 1988;11(Suppl II):II-88–II-95.

77. Tsukiyama H: Choice of antihypertensive agents in hemodynamicaspects to match pathophysiology and pharmacology in essentialhypertension. Jpn J Med 1989;28:261–264.

78. Zusman RM: Left ventricular function in hypertension. Relevanceto the selection of antihypertensive therapy. Am J Hypertens 1989;2:200S–206S.

79. Sullivan JM, Schoeneberger TE, Ratts ET, Palmer ET, Samaha JK,Mance CJ, Muirhead EE: Short-term therapy of severe hyperten-sion. Hemodynamic correlates of the antihypertensive response inman. Arch Intern Med 1979;139:1233–1239.

80. Easterling TR, Benedetti TJ, Schmucker BC, Carlson KL: Antihy-pertensive therapy in pregnancy directed by noninvasive hemody-namic monitoring. Am J Perinatol 1989;6:86–89.

81. Resnick LM, Lester MH: Differential effects of antihypertensivedrug therapy on arterial compliance. Am J Hypertens 2002;15:1096–1100.

82. Weber K, Bohmeke T, van der Does R, Taylor SH: Hemodynamicdifferences between metoprolol and carvedilol in hypertensive pa-tients. Am J Hypertens 1998;11:614–617.

83. ALLHAT Coordinators and Officers Major outcomes in high-riskhypertensive patients randomized to angiotensin-converting enzymeinhibitor or calcium channel blocker vs. diuretic. The Antihyperten-sive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT). J Am Med Assoc 2002;288:2981–2997.

84. Yakovlevitch M, Black HR: Resistant hypertension in a tertiary careclinic. Arch Intern Med 1991;151:1786–1792.

85. Houston MC: Hypertension strategies for therapeutic interven-tion and prevention of end-organ damage. Prim Care 1991;18:713–753.

86. Taler SJ, Augustine J, Textor SC: A hemodynamic approach to
resistant hypertension. Congest Heart Fail 2000;6:90–93.
of 158.

87. Bailey JM, Levy JH, Kopel MA: Relationship between clinicalevaluation of peripheral perfusion and global hemodynamics inadults after cardiac surgery. Crit Care Med 1990;18:1353–1356.

88. Tibby SM, Hatherill M, Marsh MJ, Murdoch IA: Clinicians’ abili-ties to estimate cardiac index in ventilated children and infants. ArchDis Child 1997;77:516–518.

89. Linb G, Eisenberg BM: Noninvasive techniques for evaluation ofheart function and hemodynamics in arterial hypertension. ActaCardiol 1990;45:133–139.

90. Abdelhamed AI, Levy P, Smith KS, Wilkins J, Smith R, FerrarioCM: Value of non-invasive hemodynamic measurements in hyper-tensive patients. Am J Hypertens 2002;15(Suppl 1):A89.

91. de Divitiis O, Di Somma S, Liguori V, Petitto M, Magnotta C,Ausiello M, Natale N, Brignoli M, Galderisi M: Effort blood pres-sure control in the course of antihypertensive treatment. Am J Med1989;87:(Suppl 3C)46S–56S.

92. Eliot RS: The dynamics of hypertension—an overview: presentpractices, new possibilities, and new approaches. Am Heart J 1988;116:583–589.

93. Taler SJ, Augustine J, Burnett JC, Textor SC: Hemodynamic andvolume changes during intensive treatment (Rx) for resistant hyper-tension (ResHTN) (Abstract). Am J Hypertens 2000;13:61A–62A.

94. Lang M: Noninvasive hemodynamic-driven care management.Achieving quality patient outcomes across a continuum of care.Cardiovasc Dis Manage 2001;71–73.

95. Vuurmans T, Boper P, Koomans H: Effects of endothelin-1 andendothelin-1 receptor blockade on cardiac output, aortic pressure,and pule wave velocity in humans. Hypertension 2003;41:1253–1258.

96. Margulis F, Dalton R, Killinger C, Pisarello J, Alvarez C: Decreasedmyocardial contractility and increased thoracic flui content de-tected by impedance cardiography in untreated hypertensive patients(Abstract). Am J Hypertens 1997;10(Suppl 1):55A.

97. Petersen JR, Jensen BV, Drabaek H, Viskum K, Mehlsen J: Elec-trical impedance measured changes in thoracic flui content duringthoracentesis. Clin Physiol 1994;14:459–466.

98. Ebert TJ, Smith JJ, Barney JA, Merrill DC, Smith GK: The use ofthoracic impedance for determining thoracic blood volume changesin man. Aviat Space Environ Med 1986;57:49–53.

99. Mattar JA, Salas CE, Bernstein DP, Lehr D, Bauer R: Hemody-namic changes after an intensive short-term exercise and nutritionprogram in hypertensive and obese patients with and without cor-onary disease. Arq Bras Cardiol 1990;54:307–312.

100. Toth PD, Demeter RJ, Woods, JR, Nyhuis AW, Judy WV:Comparison of the effects of pindolol and atenolol on hemody-namic function in systemic hypertension. Am J Cardiol 1988;62:413– 418.

101. Koga Y, Gillum RF, Kubicek WG: An impedance cardiographicstudy of the mechanism of blood pressure fall after moderate dietarysodium restriction. Jpn Heart J 1985;26:197–207.

102. Ashida T, Nishioeda Y, Kimura G, Kojima S, Kawamura M,Imanishi M, Abe H, Kawano Y, Yoshimi H, Yoshida K, Kuramo-chi M, Omae T: Effects of salt, prostaglandin, and captopril onvascular responsiveness in essential hypertension. Am J Hyper-tens 1989;2:640 – 642.

103. Taler SJ, Textor SC, Augustine JE: Resistant hypertension: com-paring hemodynamic management to specialist care. Hypertension2002;39:982–988.

104. Sharman DL, Gomes CP, Rutherford JP: Improvement in bloodpressure control with impedance cardiograph-guided pharmacologicdecision making. Congest Heart Fail 2004;10:54–58.

105. Sramek BB, Tichy JA, Hojerova M, Cervenka V: Normohemody-namic goal-oriented antihypertensive therapy improves the out-come. Am J Hypertens 1996;9:141A.

106. Parrott C, Burnham K, Quale C, Lewis D: Comparison of changes
in ejection fraction to changes in impedance cardiography cardiac


115

index and systolic time ratio. Congest Heart Fail 2004;10(2 Suppl2):11–13.

107. Thomson B, Drazner M, Dries D, Yancy C: Is impedance cardiog-raphy-derived systolic time ratio a useful method to determine leftventricular systolic dysfunction in heart failure (Abstract)? J CardFailure 2004;10(Suppl 4):S38.

108. Ross R: Atherosclerosis—an inflammator disease. N Engl J Med
1999;340:115–126.
of 158.

109. Panza JA: High-normal blood pressure—more “high” than “nor-mal.”N Engl J Med 2001;345:1337–1340.

110. Dagenais GR, Yusuf S, Bourassa MG, Yi Q, Bosch J, Lonn EM,Kouz S, Grover J: Effects of ramipril on coronary events in high-riskpersons: results of the Heart Outcomes Prevention EvaluationStudy. Circulation 2001;104:522–526.

111. Herrera-Acosta J, Perez-Grovas H, Fernandez M, Arriaga J: Enala-
pril in essential hypertension. Drugs 1985;30(Suppl 1):35–46.

European Journal of Heart Failure, June 2004 Whole-Body Electrical Bio-Impendance is accurate in Non Invasive Determination of Cardiac Output: A Thermodilution controlled, Prospective, Double Blind Evaluation. Guillermo Torre-Amiot1 MD, Gad Cotter2 MD, Zvi Vered2 MD, Edo Kaluski2 MD, Karl Stang3 MD. From Baylor College of Medicine, Houston, TX, USA (1), Assaf-Harofeh Medical Center, Israel (2) and Charite Campus, Berlin, Germany (3). Background: The NICaSTM is a novel non-invasive apparatus based on whole body electrical bio-impedance for simple non-invasive continuous CO determination. Patients and Methods: Patients were recruited while randomized in a study evaluating the efficacy of Tezosentan (a ET-A/B endothelin antagonist) in patients admitted due to acute heart failure (CHF). Patients were randomized after having been hospitalized due to acute heart failure with dyspnea at rest, CI < 2.5 L/min/m2 and PCWP ≥ 20 mmHg. Study Protocol: At baseline and during treatment with study drug at the pre-specified time points of 0.5,1,2,3,4 and 6 hours from randomization CO was determined by both thermodilution and the NICaSTM 2001 apparatus. At each time point CO was determined by thermodilution and NICaSTM 2001 apparatus by a two independed, blinded operators. Results: Out of 130 patients enrolled, in 93 CO was measured simultaneously by both methods at all the pre-determined time points. The overall Correlation between the two methods was R=0.81 (Figure). Precision and bias were 0.010.6 L/min. There was a difference between the two methods in cardiac output readings. When Mean CI (of both methods) was < 2 L/min/M2 CO readings were statistically significantly lower by NICaS while when CI was >3 L/min/M2, CO readings were statistically significantly higher by NICaS. We have calculated the cardiac power index (Cpi=CI* mean arterial pressure), and found that low Cpi (indicating reduced myocardial contractile reserve) was related to higher recurrent CHF. However, Cpi based on NICaS CI measurement (NICaS Cpi) was a better predictor of recurrent CHF then thermodilution Cpi (Th Cpi), due to less accurate prediction in patients with high Cpi.

Conclusions: NICaS is a novel accurate non-invasive method for CO determination. The results of the present study suggest that NICaS might be more accurate then thermodilution for CO determination due to the tendency of thermodilution to under estimate CO when high and over estimate it when low.

116 of 158.

DOI 10.1378/chest.125.4.1431 2004;125;1431-1440 Chest

Miller, Daniel Goor and Zvi Vered Gad Cotter, Yaron Moshkovitz, Edo Kaluski, Amram J. Cohen, Hilton

Electrical BioimpedanceWhole-BodyMonitoring of Cardiac Output by

Accurate, Noninvasive Continuous

http://chestjournals.org/cgi/content/abstract/125/4/1431and services can be found online on the World Wide Web at: The online version of this article, along with updated information

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2007Physicians. It has been published monthly since 1935. Copyright CHEST is the official journal of the American College of Chest

Copyright © 2004 by American College of Chest Physicians on April 4, 2007 chestjournals.orgDownloaded from 117 of 158.

http://chestjournals.org/cgi/content/abstract/125/4/1431

http://www.chestjournal.org

Accurate, Noninvasive ContinuousMonitoring of Cardiac Output by Whole-Body Electrical Bioimpedance*

Gad Cotter, MD; Yaron Moshkovitz, MD; Edo Kaluski, MD;Amram J. Cohen, MD, FCCP; Hilton Miller, MD†; Daniel Goor, MD; andZvi Vered, MD

Study objectives: Cardiac output (CO) is measured but sparingly due to limitations in its measure-ment technique (ie, right-heart catheterization). Yet, in recent years it has been suggested that COmay be of value in the diagnosis, risk stratification, and treatment titration of cardiac patients,especially those with congestive heart failure (CHF). We examine the use of a new noninvasive,continuous whole-body bioimpedance system (NICaS; NI Medical; Hod-Hasharon, Israel) for mea-suring CO. The aim of the present study was to test the validity of this noninvasive cardiac outputsystem/monitor (NICO) in a cohort of cardiac patients.Design: Prospective, double-blind comparison of the NICO and thermodilution CO determinations.Patients: We enrolled 122 patients in three different groups: during cardiac catheterization (n � 40);before, during, and after coronary bypass surgery (n � 51); and while being treated for acutecongestive heart failure (CHF) exacerbation (n � 31).Measurements and intervention: In all patients, CO measurements were obtained by two inde-pendent blinded operators. CO was measured by both techniques three times, and an average wasdetermined for each time point. CO was measured at one time point in patients undergo-ing coronary catheterization; before, during, and after bypass surgery in patients undergoingcoronary bypass surgery; and before and during vasodilator treatment in patients treated for acuteheart failure.Results: Overall, 418 paired CO measurements were obtained. The overall correlation between theNICO cardiac index (CI) and the thermodilution CI was r � 0.886, with a small bias (0.0009 � 0.684L) [mean � 2 SD], and this finding was consistent within each group of patients. Thermodilutionreadings were 15% higher than NICO when CI was < 1.5 L/min/m2, and 5% lower than NICO whenCI was > 3 L/min/m2. The NICO has also accurately detected CI changes during coronary bypassoperation and vasodilator administration for acute CHF.Conclusion: The results of the present study indicate that whole-body bioimpedance CO measure-ments obtained by the NICO are accurate in rapid, noninvasive measurement and the follow-up ofCO in a wide range of cardiac clinical situations. (CHEST 2004; 125:1431–1440)

Key words: cardiac function test; cardiac output; congestive heart failure

Abbreviations: CABG � coronary artery bypass graft; CHF � congestive heart failure; CI � cardiac index; CO � cardiacoutput; Cpi � cardiac power index; ISDN � isosorbide-dinitrate; MAP � mean arterial BP; NICO � noninvasive cardiacoutput system/monitor; SV � stroke volume; SVRi � systemic vascular resistance index; TEB � thoracic electrical bioim-pedance; WBEB � whole-body electrical bioimpedance

M easurement of cardiac output (CO) and the cal-culation of cardiac index (CI) has been used

selectively over the last 2 decades, mainly due to thefact that CI measurement requires the invasive proce-dure of right-heart catheterization and placement of aSwan-Ganz catheter (Baxter Healthcare; Irvine, CA).

Hence, the experience with its application for monitor-ing and risk stratification of cardiac patients is limited.

In recent years, however, evidence has accumu-lated to the effect that CI measurement and thecalculation of systemic vascular resistance index(SVRi) and cardiac power index (Cpi, the product of CI

clinical investigations in critical care

www.chestjournal.org CHEST / 125 / 4 / APRIL, 2004 1431



multiplied by mean arterial BP [MAP]) measuredsimultaneously might be instrumental in the monitor-ing and risk stratification of cardiac patients, especiallythose with acute and chronic congestive heart failure(CHF) and patients admitted with cardiogenic shock.1In cardiogenic shock, a recent analysis of the SHOCK(SHould We Emergently Revascularize Occluded Cor-onaries in Cardiogenic ShocK) registry data has shownCpi to be the strongest independent predictor ofin-hospital mortality,2 while in acute heart failure Cpiwas found to be an important tool for diagnosis and riskstratification.3,4 In patients with chronic CHF, a fewstudies5–7 have shown that noninvasive Cpi reserve (theincrease in Cpi during exercise or dobutamine stress) isthe strongest predictor of outcome (a better oxygenconsumption and echocardiographic ejection fraction)in such patients. Furthermore, changes in acute SVRimay be useful for early detection of myocardial isch-emia.8 Moreover, in two separate studies9–11 examiningthe efficacy of vasodilators in patients with acute CHF,medication was found to be effective mainly in patientswho were submitted to hemodynamic monitoring, im-plying that perhaps in order to be efficacious, vaso-dilator treatment should be monitored attentively toprevent overtreatment and undertreatment. In differ-ent studies,12,13 we have also demonstrated that carefultitration of vasodilator treatment administered for acuteheart failure and acute coronary syndromes is impor-tant to optimize its efficacy. In the present study,we evaluated the accuracy of a novel method of CImeasurement (whole-body electrical bioimpedance[WBEB]) in different cardiac clinical settings (duringcardiac catheterization and coronary artery bypass graft[CABG] surgery, and for monitoring patients withacute CHF) and over a wide range of CI values andseverity of left ventricular dysfunction.

Materials and Methods

Patient Populations

Group 1: Group 1 consisted of 40 patients with coronary arterydisease referred during March to July 1993 for left and right

cardiac catheterization based on conventional clinical indications.During the right-heart study, a pulmonary artery catheter wasintroduced under fluoroscopy; at a single time point, a pairedmeasurement of CI by a noninvasive cardiac output system/monitor (NICO) [NICaS; NI Medical; Hod-Hasharon, Israel]and by thermodilution was performed.

Group 2: Group 2 included 51 patients undergoing CABGoperations. The first 15 patients were studied at Wolfson MedicalCenter (Israel) during October to November 1994. The next 16patients were studied at Johns Hopkins Medical Center duringApril to May 1995. The remaining 20 patients were studied againat Wolfson Medical Center during August to October 1995. Aballoon-guided, Swan-Ganz catheter was introduced after theinduction of anesthesia, and five paired NICO CI and thermodi-lution CI measurements were obtained at specific operative andpostoperative stages: immediately prior to the skin incision; aftersternotomy; after pericardiotomy; 10 min after weaning from thepump; and immediately after arrival to the ICU. The resultsobtained from the first 31 cases of this series have already beenpublished.14

Group 3: Group 3 consisted of 31 patients admitted duringSeptember to December 2001 to the ICU of Assaf–HarofehMedical Center (Israel) because of an acute exacerbation ofCHF. Prior to admittance, they underwent a right-heart study inthe catheterization laboratory for the assessment of their cardiaccondition, and a Swan-Ganz catheter was inserted under fluoros-copy. CO measurement was begun on arrival to the ICU, wherethree baseline measurements were obtained, 15 min apart. In 17patients who required vasodilator therapy, four measurementswere obtained during the initiation and up-titration of IV isosor-bide-dinitrate (ISDN) treatment. In the 14 patients who did notrequire ISDN treatment, an additional (fourth) baseline mea-surement was obtained. All the studies were approved by thereview boards and the Helsinki committees of the varioushospitals. Consents for the studies were obtained from eachpatient.

Measuring CI

Thermodilution: In all three study groups, a No. 7F Swan-Ganzballoon flotation catheter was placed in the pulmonary artery. Ingroups 1 and 2, the Swan-Ganz catheter was introduced in thecatheterization room, and in group 2 on the operating table,following anesthesia. In the 16 patients of group 2 who werestudied at Johns Hopkins Medical Center, CO measures wereobtained by the 7010 Series Marquette (Marquette; Madison,WI). In the remaining 35 patients of group 2 studied at WolfsonMedical Center, and also in group 1 patients at the Tel AvivMedical Center (Israel), the Horizon 2000 (Mennen Medical;Rohovot, Israel) was used. In group 3, the CO was measured byMarquette 8000 Clinical Information Center 419897-015 (Mar-quette).

A volume of 10 mL of 5% dextrose at room temperature wasinjected in all patients via the proximal port. Temperaturechanges were measured via the distal port located in the pulmo-nary artery, ascertained by fluoroscopy, oxygen saturation, andwedge pressure measurements. In all patients, three CI measure-ments were obtained; when a � 15% disparity occurred betweenthe two extreme measurements, two further injections, or more,were administered until an average of three measurements withinthe 15% range was obtained.

NICO WBEB Technology

When transmitting a small electrical current through the body,an impedance to its transmission (restivity, R) is being measured.

*From the Cardiology Department (Drs. Cotter, Kaluski, andVered), Assaf–Harofeh Medical Center, Zerifin; the CardiacSurgery Department (Drs. Moshkovitz and Goor), Sackler Schoolof Medicine, Tel Aviv University, Tel Aviv; the Department ofCardiology (Dr. Miller), Sourasky Medical Center, Tel-Aviv; andthe Department of Cardiac Surgery (Dr. Miller), the EdithWolfson Medical Center, Holon, Israel.†Deceased.Manuscript received March 19, 2003; revision accepted Septem-ber 19, 2003.Reproduction of this article is prohibited without written permis-sion from the American College of Chest Physicians (e-mail:[email protected]).Correspondence to: Gad Cotter, MD, Cardiology Department,Assaf-Harofeh Medical Center, 70300, Zerifin, Israel; e-mail:[email protected]

1432 Clinical Investigations in Critical Care



This resistivity is called bioimpedance. According to Kirchov’slaw, electric current passes through conduits of higher conduc-tance (lowest resistivity). The resistivity of blood and plasma isthe lowest in the body (resistivity of blood is 150; plasma, 63;cardiac muscle, 750; lungs, 1,275; and fat, 2,500 ohm/cm).15

Thus, when an alternating current of 20 to 100 kHz is applied tothe body, it is primarily distributed via the extracellular fluid andthe blood. The changes in the body resistivity (�R) over time(milliseconds) are therefore related to the dynamic changes ofthe blood and plasma volume. This pertains particularly to thepassage of the stroke volume (SV) from the left ventricle intothe aorta and its branches. However, in the capillaries and in thevenous system the blood volume is relatively constant, becausethe flow in these vessels is not pulsatile. Consequently, eachsystolic increase in the aortic blood volume is associated with aproportional increase in the measurable conductance of thewhole body (Fig 1).16 Thus, for measuring the aortic SV by meansof its impedance change, Frinerman and Tsoglin developed thefollowing algorithm14:

SV �Hctcorr

Ksex, age� Kel � Kweight � IB �

H2corr �RR

��

�

in which the �R/R is corrected for hematocrit (Hctcorr), elec-trolytes (Kel), body composition (K sex, age), weight (Kweight),time characteristics (� � systolic time, � � diastolic time), andindex balance (IB), which measures the body water composition.

To collect patient signals, the NICO uses proprietary elec-trodes arranged in a wrist-to-ankle configuration (Fig 2); incertain conditions when this particular form is not applicable (aswith severe peripheral edema or severe peripheral vasculardisease), a wrist-to-wrist configuration is used. The precise

positioning of the NICO electrodes is not critical; an untrainedoperator can make the attachments. An alternating current of 30kHz, 1.4 mA is delivered through the two electrodes, and thebioimpedance and its fluctuations over time are measured. Inaddition, a standard three-lead ECG connection is made formeasuring the pulse rate. The other variables required for SV andCI calculation (age, gender, weight, height, hematocrit, electro-lytes) are introduced into the machine only at the start ofmonitoring. For measuring the CO, the SV is multiplied by theheart rate.

Although the idea of the WBEB was conceived and tested inthe Soviet Union in 1941,17 it remained dormant until re-cently. Meanwhile another bioimpedance approach for mea-suring the CO was initially introduced by Kubicek et al18 in theUnited States in 1966, and further refined in 1974.19 Hismethod is called thoracic electrical bioimpedance (TEB), andthe tools of this approach are commercially available. Notedhere are dissimilarities in the operation of the two technolo-gies. In the NICO, one electrode is applied to the wrist andthe other to the ankle; in TEB, a number of electrodes areplaced at the root of the neck and another set around the lowerpart of the chest cage. In WBEB, the SV is measured by theimpedance variation (�Z or �R) induced by the systolicvolume ejected into the aorta. In the original TEB formula of1966,18 the SV measurement was based on a similar principle.However, since when the electrodes are placed on the chest,the �Z wave could be hardly detected, Kubicek et al19 adoptedanother principle, whereby the SV measurement is based onthe depiction of the aortic systolic dp/dt (instantaneous pres-sure change over time) for calculation of the systolic bloodflow into the great arteries.

Figure 1. Recordings of the interrelation between impedance variations and hemodynamic parame-ters, according to Djordjevich and Sadove.16




Measuring CI by the NICO

For each CI determination, three NICO measurements wereobtained. Since the CO results that are displayed on the scope areupdated every 20 s, for the determination of the CI an averageCO is derived from a 60-s monitoring.

Statistical Methods

Agreement between the CI values of the NICO and thermodi-lution was evaluated in three ways: the mean CI values of theNICO and thermodilution were compared by a paired Student ttest; correlation between these values was evaluated by calculat-ing the Pearson correlation coefficient and by applying a linearregression model of the NICO on thermodilution; the differencesbetween the paired CI values of the NICO and thermodilutionwere plotted against the average CI values of both methods,instead of against thermodilution alone. This statistical methodwas recommended by Bland and Altman20 for evaluating a newdevice (NICaS) against an established method (thermodilution),which has its own inaccuracies. Bias was defined as the meandifference between the NICO CI and thermodilution CI values.Limits of agreement (precision) were calculated as bias � 2 SDof the differences between the NICO CI and thermodilution CIvalues. All three analyses were carried for the whole sample andfor each specific clinical group: cardiac catheterization patients(group 1), CABG patients (group 2), and CHF patients (group 3).

We have examined the differences between the CI determi-nation by the NICO and thermodilution at different CI readingsby classifying the readings into four subgroups according to themean CI levels: CI 1.5, CI � 1.5 and 2, and CI � 2 and 3,and CI � 3. CI readings by the NICO and thermodilution in eachgroup were compared using the paired Student t test andpresented as mean and SDs.

The sensitivity of the two methods (NICO and thermodilution)to a change in a specific medical condition was compared in theCABG group at five operative and postoperative stages. Avariance analysis with repeated measures (type of method andstage) was performed, followed by contrast analysis that com-pared successive stages. This analysis could be performed only forpatients with complete data at all the five stages. A similaranalysis was performed at seven time points in CHF patients whohad been treated with an IV vasodilatory drug. All statisticalanalyses were performed using the SAS System for Windows(version 8.01; SAS Institute; Cary, NC).

Results

No significant differences between the means ofNICO CI and thermodilution CI in the three clinicalgroups, as well as the whole cohort, were observed(Table 1). A significant, high correlation was foundbetween the NICO CI and the thermodilution CImeasurements: 0.886 in the whole cohort, and 0.881,0.902, and 0.851 in the catheterization, bypass sur-gery, and CHF groups, respectively. All correlationcoefficients were statistically significant (p 0.0001).

The results of applying linear regression models tothe data (Table 2, Fig 3) demonstrate similar modelsin the three clinical groups, as the intercepts andslopes of the regression lines are not significantlydifferent (intercepts, p � 0.2398; slopes, p � 0.2310).Figure 4 shows differences between CI values plot-ted against the average value of the two methodswith limits of agreement: two SDs from the meandifference.

Significant differences between the NICO CI andthermodilution CI were observed when comparingthe average CI of the four CI ranges (Table 3). WhenCI is 2 L/min/m2, the thermodilution CI readouts

Table 1—Comparison Between the Mean CI Values ofthe NICO and Thermodilution in the Three Clinical

Groups and in the Whole Cohort*

Group No.

ThermodilutionCI, L/min/m2

NICO CI,L/min/m2

p ValueMean SD Mean SD

Whole sample 418 2.39 0.70 2.38 0.73 NSCatheterization 40 2.81 0.72 2.81 0.68 NSCABG 208 2.33 0.72 2.31 0.77 NSCHF 170 2.35 0.63 2.38 0.66 NS

*NS � not significant.

Figure 2. Wrist-to-ankle configuration of the electrodes in WBEB. I � electric current; V � electricvoltage.




are significantly higher than the NICO CI; when CIis � 3 L/min/ m2, the thermodilution CI is lowerthan the NICO CI (Table 3). When CI was between2 L/min/m2 and 3 L/min/m2, there was a slightdifference of only 3.28% between the two methods,with a borderline significance (Table 3).

Twenty-five patients with CABG (subgroup A)had complete information of the NICO CI andthermodilution CI results at five operative and post-operative stages (Table 4, Fig 5, top). A further 26CABG patients (subgroup B) had incomplete data( 5 paired measurements for each patient), yieldingadditional 80 paired measurements (Table 4). Therewere time-related changes in the CI, and the NICOand the thermodilution followed these changesby producing similar results at each time point(p � 0.0035 and p � 0.0058, respectively; Fig 5,top). A contrast analysis, performed to compare theCO in successive stages of the measurements, found

that the difference between stage 3 and stage 4 wasstatistically significant according to the two measure-ments in subgroup A (NICO CI, p � 0.0135; ther-modilution CI, p � 0.002; Fig 5, top). In 17 of theCHF patients in group 3 who were treated withan IV vasodilator agent, and in whom the CI wasmeasured simultaneously at seven time points duringthe treatment, the total time trend was significant inthe NICO (p � 0.0056) but not significant in ther-modilution (Fig 5, bottom).

Discussion

In recent years it has been suggested that CO andMAP measurement and the calculation of CI, Cpi,and SVRi might be instrumental in the diagnosis,treatment titration, and risk stratification of cardiacpatients, especially those with CHF.7–10 However,

Table 2—Linear Regression Analysis, Bias, and Precision in the Three Clinical Groups and in the Whole Cohort

Sample Intercept Slope R2

Bias (Mean Between-Method Difference),

L/minPrecision (Mean � SD),

L/min

Whole 0.18 0.92 0.79 0.0009 0.6849 � 0.6831Catheterization 0.45 0.84 0.77 0.0040 0.7134 � 0.6393CABG 0.08 0.96 0.81 0.0247 0.6789 � 0.7331CHF 0.29 0.89 0.72 0.0271 0.684 � 0.692

Figure 3. Plot of CI values measured by the NICO and thermodilution.




CI has been measured only during invasive right-heart catheterization, which requires intensive careadmission and may be associated with complica-tions.21–23 Hence, CI was measured only rarely, andin the sickest patients. Therefore, a simple, reliable,noninvasive, and continuous method for CI mea-surement has become necessary in order to enableits application to cardiac patients with differentdegrees of medical severity and in diverse settings.

Currently there are four accepted methods fornoninvasive CO measurement. The Doppler echo-cardiogram obtained from the left ventricular out-flow track and CO2 rebreathing techniques havebeen shown to be accurate in measuring CI. Butthese methods are limited by the requirement forexpensive equipment and specialized personnel fortheir application and therefore are not simple to use,and moreover do not enable continuous measure-ments. Thoracic bioimpedance has been used in thelast decade for continuous CO measurement. Judg-

ing by the literature,24–26 as long as the heart func-tion is intact, TEB can be useful for monitoring thehemodynamic state in various clinical conditionssuch as trauma, massive surgery, sepsis, etc.24 Butwhen it comes to monitoring and managing patho-logic cardiac conditions TEB requires further im-provement.24–26

Thus far, eight groups of patients who submittedto CO measurements by WBEB have been reportedin six published articles. Kedrov,17 who was the first,compared the average CI measured by the WBEBin 57 subjects with normal hearts in published resultsof the Fick method, revealing 3.3 � 28% vs 3.31L/min/m2 (range, 2.4 to 4.2 L/min/m2), respectively.Tischenko27 compared the CI results measured byWBEB in three groups of subjects with normalhearts vs three standard methods. There were 31cases vs acetylen (r � 0.84), 28 cases vs thermodilu-tion (r � 0.95), and 28 cases vs Fick (r � 0.99).Using a modified Tischenko algorithm vs thermodi-

Figure 4. Differences between CI values (NICO vs thermodilution) plotted against the average valuesof the two methods.

Table 3—Differences Between the NICO CI and Thermodilution CI Within the CI Ranges

CI Ranges by NICO CIResults,

No.NICO CI,

MeanThermodilution

CI, MeanRelative

Difference, % Significance

1.5 30 1.278 � 0.16 1.515 � 0.35 12.99 0.00021.5 CI 2 98 1.749 � 0.14 1.876 � 0.33 4.65 0.00012 CI 3 220 2.433 � 0.28 2.392 � 0.40 3.28 0.0484CI � 3 70 3.594 � 0.57 3.449 � 0.64 5.44 0.0045




lution, Koobi et al28 obtained simultaneous measure-ments in 74 patients with coronary disease, reachinga bias between the two methods of 0.25 � 0.8 L/min(SD), where the limits of agreement (2 SD) were– 1.37 L/min and 1.897 L/min, respectively. Usingthe NICaS apparatus, Cohen et al14 compared itsperformance against thermodilution by measuringthe CO in patients undergoing CABG operations,with a correlation of r � 0.91. Thus, this six-clinicalseries, which included 274 subjects, revealed similarcorrelation coefficients between the comparedmethods, just as in the present series. Moreover, innone of these publications did the authors expressreservations about the performance of the WBEB.

There were, nonetheless, two publications inwhich no correlation was found between WBEB andthermodilution; in both instances, the underlyingclinical conditions are listed in the exclusion criteriaof the NICO. Lamberts et al29 compared the originalTischenko equation with dye dilution CO in 10patients, 4 of whom had significant aortic regurgita-tion and 1 had coarctation of the aorta. The NICOapparatus cannot measure the CO in such condi-tions.

Imhoff et al30 compared the NICO apparatusagainst thermodilution in 22 postpancreatectomy oresophagectomy patients. They were all managedpostoperatively by Swan-Ganz catheters for boostingthe oxygen delivery to 600 mL/min/m2 and the CI to4.5 L/min/m2. Hence, in these patients the radicalsurgical procedures were followed by massive inter-compartmental volume shifts due to IV administra-tion of up to 6 L per 24 h of crystalloids and plasma,often accompanied by massive peripheral edema. Insuch hemodynamic situations, the baseline imped-ance should properly become distorted, preventingan accurate measurement of the systolic impedancevariation.

In the present study, the agreement betweenNICO CI and thermodilution CI as tested by com-parisons of the means is highly significant. Thesimilarity between the means in the entire cohort as

well as in each diagnostic group, together with therelatively large sample size, further endorses thesignificance of the results.

The mean difference between the NICO andthermodilution in the entire sample range was0.0009 L/min (Table 2, Fig 4), ranging from 0.0040to 0.0271 L/min in the three diagnostic groups. Thisdisparity is smaller than the level of accuracy ofthermodilution, which is defined to a 15% range.31

Linear regression applied to the data revealed thatthe line slope was close to 1.00 in the entire samplerange and in each specific diagnostic group. Therewere no significant differences between the slopesand the intercepts of the three diagnostic groups.This indicates that the relation between the NICOand thermodilution is similar in all diagnostic groups.Following the recommendations of Bland and Alt-man,20 the differences between the two measure-ments were plotted against their means. This plotdemonstrates that the range of differences is similaralong the different values of the average.

Although the main purpose of this work was tocompare the performance of the NICO vs thermo-dilution, following the suggestion in previous stud-ies31–35 that thermodilution tends to overestimate CIwhen low and underestimate it when high, we havecompared the NICO CI and thermodilution CI inthe different CI ranges. The results of this analysishave shown that when the CI was 2 L/min/m2, thethermodilution results were higher than the NICOresults; when the CI was � 3 L/min/m2, the ther-modilution results were slightly lower than theNICO results (Table 3). As a consequence, thedifferences of the hemodynamic responses to vaso-dilation therapy may be better depicted by theNICO when compared with thermodilution (Fig 5,bottom).

The link between a low CI and a higher thermo-dilution readout, and between a higher CI with alow thermodilution readout, is also expressed in thestability of the range of differences along the differ-ent values of the average (Fig 4). Furthermore, the

Table 4—Trend Follow-up of the NICO CI and Thermodilution CI During the Five Operative andPostoperative Stages

Method

NICO CI Thermodilution CI

Subgroup A(n � 25)

Subgroups A � B(n � 51)

Subgroup B,(n � 26)

Subgroups A � B,(n � 51)

Mean SD Mean SD Mean SD Mean SD

1 2.28 0.87 2.25 0.83 2.22 0.69 2.22 0.672 2.09 0.58 2.09 0.57 2.14 0.57 2.14 0.523 2.17 0.62 2.26 0.69 2.15 0.68 2.22 0.704 2.72 0.79 2.54 0.81 2.80 0.74 2.61 0.775 2.56 0.74 2.46 0.85 2.61 0.83 2.53 0.87




almost identical results of thermodilution and theNICO observed in the CI 2 to 3 range (Table 3)yield a mutual endorsement of the technical opera-tions of the measuring devices by the two methods.It should also be noted that the two methods switchtheir interrelations at CI of approximately 2.5L/min/m2 (Fig 5, bottom), which is close to the lowerborder.

Limitations of the NICO

Diseases of the Aorta and Aortic Valve: The NICOmeasures the SV of the aorta and its derivatives(including the peripheral arteries). For determiningthe CO, SV is multiplied by the heart rate. Anyaberration in the hemodynamics of the aorta and itsderivatives may interfere with the proper function of

Figure 5. Top: Comparisons between the NICO CI and thermodilution CI at five operative andpostoperative stages. Bottom: NICO CI and thermodilution CI responses to vasodilating titrationtherapy in patients with acute CHF.




the NICO. In aortic insufficiency, the SV is patho-logically increased. Coarctation and significant aneu-rysms of the aorta and also severe peripheral arterialdisease may produce inaccurate readouts of the SV.

Significant (�3/�4) Peripheral Edema: In signif-icant edema, the baseline impedance of the body isoccasionally very low, currently interfering with theaccuracy of the results.

Shunts: Our experience with congenital heartdisease is limited, but we assume that since there isno complete separation between the two circulationsthe impedance technique may not be appropriate.

Restlessness: The impedance test requires a mo-tionless condition; in addition, restlessness is associ-ated with fluctuating activation of the sympatheticsystem, resulting in an unstable hemodynamic state.

Arrhythmias: In most cases, there is no interfer-ence with the CO measurement, although whenassociated with a heart rate � 150 beats/min or whenthere is a severe disarray of the complexes (ECG andSV), the results may become inaccurate, as may befor any technique measuring CO.

Resections: Major abdominal and thoracic surgicalresections, especially those that include major rapidshifts in fluid distribution between the intravascularand extravascular space.

Conclusions

In spite of these limitations, the NICO apparatusoffers a simple, noninvasive, reliable, and continuousmeasurement of CI in cardiac patients with particu-lar emphasis on CHF. This measurement combinedwith MAP measurement and the calculation of Cpiand SVRi is destined to become a safe, simple, rapid,noninvasive method for evaluating and treating pri-marily coronary patients sustaining chronic and acuteexacerbations of CHF.

References1 Cotter G, Williams SG, Vered Z, et al. The role of cardiac

power in heart failure. Curr Opin Cardiol 2003; 18:215–2222 Cotter G, Fincke R, Lowe A, et al. Hemodynamic parameters

in cardiogenic shock due to myocardial infarction: a reportfrom the SHOCK trial registry [abstract]. Circulation 2003;108:539

3 Cotter G, Moshkovitz Y, Milovanov O, et al. Acute heartfailure: a novel approach to its pathogenesis and treatment.Eur J Heart Fail 2002; 4:227–234

4 Cotter G, Moshkovitz Y, Kaluski E, et al. The role of cardiacpower and systemic vascular resistance in the pathophysiologyand diagnosis of patients with acute congestive heart failure.Eur J Heart Fail 2003; 5:443–451

5 Marmor A, Schneeweiss A. Prognostic value of noninvasivelyobtained left ventricular contractile reserve in patients withsevere heart failure. J Am Coll Cardiol 1997; 29:422–428

6 Williams SG, Cooke GA, Wright DJ, et al. Peak exercise

cardiac power output: a direct indicator of cardiac functionstrongly predictive of prognosis in chronic heart failure. EurHeart J 2001; 22:1496–1503

7 Cohen-Solal A, Tabet JY, Logeart D, et al. A non-invasivelydetermined surrogate of cardiac power (‘circulatory power’)at peak exercise is a powerful prognostic factor in chronicheart failure. Eur Heart J 2002; 23:806–814

8 Mohr R, Rath S, Meir O, et al. Changes in systemic vascularresistance detected by the arterial resistometer: preliminaryreport of a new method tested during percutaneous translu-minal coronary angioplasty. Circulation 1986; 74:780–785

9 Torre-Amione G, Young JB, Colucci ES, et al. Hemodynamicand clinical effects of tezosentan, an intravenous dual endo-thelin receptor antagonist, in patients hospitalized for acutedecompensated heart failure J Am Coll Cardiol 2003; 42:140–147

10 Teerlink JR, Massie BM, Cleland JG, et al, for the Ritz 1Investigators. A double-blind, parallel-group, multi-center,placebo-controlled study to investigate the efficacy and safetyof tezosentan in reducing symptoms in patients with acutedecompensated heart failure (RITZ 1) [abstract]. Circulation2001; 104:II-526

11 VMAC Investigators. Intravenous nesiritide vs nitroglycerinfor treatment of decompensated congestive heart failure: arandomized trial. JAMA 2002; 287:1531–1540

12 Cotter G, Faibel H, Barash P, et al. High-dose nitrates in theimmediate management of unstable angina: optimal dosage,route of administration, and therapeutic goals. Am J EmergMed 1998; 16:219–224

13 Kaluski E, Kobrin I, Zimlichman R, et al. RITZ-5: random-ized intravenous tezosentan (an endothelin ET-A/B antago-nist) for the treatment of pulmonary edema: a prospectiverandomized, multicenter, double-blind placebo controlledstudy. J Am Coll Cardiol 2003; 41:204–210

14 Cohen AJ, Arnaudov D, Zabeeda D, et al. Non-invasivemeasurement of cardiac output during coronary artery bypassgrafting. Eur J Cardiothorac Surg 1998; 14:64–69

15 Baker LE. Principles of impedance technique. IEEE EngMed Biol 1989; 3:11–15

16 Djordjevich L, Sadove MS. Basic principles of electrohaemo-dynamics. J Biomed Eng 1981; 3:25–33

17 Kedrov AA. An attempt of the quantify assessment of thecentral and peripheral circulation by electrometrical method.Klin Med 1948; 26:32–51

18 Kubicek WG, Karnegis JN, Patterson RP, et al. Developmentand evaluation of an impedance cardiac output system.Aerosp Med 1966; 37:1208–1212

19 Kubicek WG, Kottke FJ, Ramos MU, et al. The Minnesotaimpedance cardiograph: theory and applications. BiomedEng 1974; 9:410–416

20 Bland JM, Altman DG. Statistical methods for assessingagreement between two methods of clinical measurement.Lancet 1986; I:307–310

21 Robin ED, McCauley RF. Monitor wizards can be dangerous.Chest 1998; 114:1151–1153

22 Dalen JE, Bone RC. Is it time to pull the pulmonary arterycatheter? JAMA 1996; 276:916–918

23 Connors AF, Speroff T, Dawson NV, et al, for the SUPPORTinvestigators. The effectiveness of right heart catheterizationin the initial care of critically ill patients. JAMA 1996;276:889–897

24 Raaijmakers E, Faes ThJC, Scholten RJPM, et al. A meta-analysis of published studies concerning the validity of tho-racic impedance cardiography. Ann NY Acad Sci 1999;873:121–134




25 Patterson RP, Witsoe DA, From A. Impedance stroke volumecompared with dye and electromagnetic flowmeter valuesduring drug-induced inotropic and vascular changes in dogs.Ann N Y Acad Sci 1999; 873:143–148

26 Marik PE, Pendelton JE, Smith R. A comparison of hemo-dynamic parameters derived from transthoracic electricalbioimpedance with those parameters obtained by thermodi-lution and ventricular angiography. Crit Care Med 1997;25:1545–1550

27 Tischenko MI. Estimation of stroke volume by integralrheogram of the human body [in Russian]. Sechenov Phisio-logical J 1973; 59:1216–1224

28 Koobi T, Kaukinen S, Turjanmaa VM, et al. Whole-bodyimpedance cardiography in the measurement of cardiacoutput. Crit Care Med 1997; 25:779–785

29 Lamberts R, Visser KR, Zijlstra WG. Impedance cardiogra-phy. Assen, The Netherlands: Van Gorkum, 1984; 21–94

30 Imhoff M, Lehner JH, Lohelin D. Noninvasive whole-bodyelectrical bioimpedance cardiac output and invasive ther-

modilution cardiac output in high-risk surgical patients. CritCare Med 2000; 28:2812–2818

31 Davidson CJ, Fishman RF, Bonow RD. Cardiac catheteriza-tion. In: Branwald E, ed. Heart disease: a textbook ofcardiovascular medicine. 5th ed. Philadelphia, PA: W.B.Saunders Company, 1997; 192

32 van Grondelle A, Ditchey RV, Groves BM, et al. Thermodi-lution method overestimates low cardiac output in humans.Am J Physiol 1983; 245:690–692

33 Kohanna FH, Cunningham JN. Monitoring of cardiac outputby thermodilution after open-heart surgery. J Thorac Cardio-vasc Surg 1977; 73:451–457

34 Espersen K, Jensen EW, Rosenborg D, et al. Comparison ofcardiac output measurement techniques: thermodilution,Doppler, CO2-rebreathing and direct Fick method. ActaAnaesthesiol Scand 1995; 39:245–251

35 Nanas JN, Anastasiou-Nana MI, Sutton RB, et al. Compari-son of Fick and dye cardiac outputs during rest and exercisein 1,022 patients. Can J Cardiol 1986; 2:195–199




DOI 10.1378/chest.125.4.1431 2004;125;1431-1440 Chest

Daniel Goor and Zvi Vered Gad Cotter, Yaron Moshkovitz, Edo Kaluski, Amram J. Cohen, Hilton Miller,

Whole-Body Electrical BioimpedanceAccurate, Noninvasive Continuous Monitoring of Cardiac Output by

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The European Journal of Heart Failure 5 (2003) 443–451

1388-9842/03/$ - see front matter � 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.PII: S1388-9842 Ž03 .00100-4

The role of cardiac power and systemic vascular resistance in thepathophysiology and diagnosis of patients with acute congestive heart

failureGad Cotter *, Yaron Moshkovitz , Edo Kaluski , Olga Milo , Ylia Nobikov , Adam Schneeweiss ,a, b a a c a

Ricardo Krakover , Zvi Vereda a

Cardiology Department, Assaf-Harofeh Medical Center, 70300 Zerifin, Israela

Cardiac Surgery Department, Ramat-Marpe Hospital, Petah-Tikva, Israelb

Biostatistical Department, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer, Israelc

Received 16 August 2002; received in revised form 6 January 2003; accepted 21 January 2003

Abstract

Objective: Conventional hemodynamic indexes (cardiac index (CI), and pulmonary capillary wedge pressure) are of limitedvalue in the diagnosis and treatment of patients with acute congestive heart failure (CHF). Patients and methods: We measuredCI, wedge pressure, right atrial pressure (RAP) and mean arterial blood pressure (MAP) in 89 consecutive patients admitted dueto acute CHF (exacerbated systolic CHF, ns56; hypertensive crisis, ns5; pulmonary edema, ns11; and cardiogenic shock, ns17) and in two control groups. The two control groups were 11 patients with septic shock and 20 healthy volunteers. Systemicvascular resistance index (SVRi) was calculated as SVRis(MAPyRAP)yCI. Cardiac contractility was estimated by the cardiacpower index (Cpi), calculated as CI=MAP. Results and discussion: We found that CI-2.7 lyminym and wedge pressure )122

mmHg are found consistently in patients with acute CHF. However, these measures often overlapped in patients with differentacute CHF syndromes, while Cpi and SVRi permitted more accurate differentiation. Cpi was low in patients with exacerbatedsystolic CHF and extremely low in patients with cardiogenic shock, while SVRi was increased in patients with exacerbatedsystolic CHF and extremely high in patients with pulmonary edema. By using a two-dimensional presentation of Cpi vs. SVRiwe found that these clinical syndromes can be accurately characterized hemodynamically. The paired measurements of eachclinical group segregated into a specific region on the CpiySVRi diagnostic graph, that could be mathematically defined by astatistically significant line (Lambdas0.95). Therefore, measurement of SVRi and Cpi and their two-dimensional graphicrepresentation enables accurate hemodynamic diagnosis and follow-up of individual patients with acute CHF.� 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Cardiac power; Vascular resistance; Acute congestive heart failure

1. Introduction

Acute congestive heart failure (CHF) is a commondisease, accounting for over 700 000 annual admissionsto hospitals in the USA alone. We have recently sug-gested that this disease can be divided into four majorclinical syndromes w1x: (1) pulmonary edema, (2) car-diogenic shock, (3) hypertensive (HTN) crisis and (4)exacerbated systolic CHF. However, the diagnosis of

*Corresponding author. Tel.: q972-8-977-9778; fax: q972-8-977-9779.

E-mail address: [email protected] (G. Cotter).

these clinical syndromes of acute CHF may be difficult,due to an overlap in symptoms and signs among thedifferent syndromes as well as lack of objective criteriafor their diagnosis. For example, both cardiogenic shockand pulmonary edema patients present with severe cir-culatory and respiratory distress and in both cases CI islow and wedge pressure is high. However, these twoclinical syndromes have a completely different course(mortality rates at 1-month in the SHOCK study w2xwere approximately 60%, compared with a mortalityrate of approximately 10% for pulmonary edema patientsduring the first 30 days in the RITZ-5 study w3x). Inaddition, the pathophysiology of the two clinical syn-

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444 G. Cotter et al. / The European Journal of Heart Failure 5 (2003) 443–451

dromes is completely different and their treatment isalmost opposite. Moreover, even the diagnosis of acuteCHF is sometimes difficult, due to an overlap in signsand symptoms with those of acute exacerbations ofobstructive or restrictive lung diseases and the occasion-al difficulty in differentiation between septic and cardi-ogenic shock.

Measurement of invasive hemodynamic variables,including CI and pulmonary capillary wedge pressurehas been used in patients with acute decompensated andchronic compensated CHF, as well as cardiogenic shock,for more than two decades. However, despite extensiveexperience and numerous studies, no specific diagnosticcriteria or accurate cut-off points have been determinedw2,4–6x. In some studies, trends and changes in CI andwedge pressure have been used, however, no reproduc-ible criteria for diagnosis and follow-up could beestablished.

Cardiac power, an index of cardiac contractility, iscalculated based on the classical physical rule of fluids,i.e. powersflow=pressure, hence cardiac power index(Cpi) is the product of simultaneously measured meanarterial blood pressure (MAP) and cardiovascular flow(CI): CpisMAP=CI=0.0022 w1,7–9x. The units areWym . Cpi has been used extensively during recent2

years to evaluate patients with chronic and acute CHF.In three separate studies, Marmor and Schneeweiss w7x,Tan et al. w8x and Cohen-Solal et al. w9x have demon-strated that Cpi increases during exercise (cardiac powerreserve) and is the strongest predictor of outcome inpatients with chronic CHF, stronger than O consumption2

and echocardiographic ejection fraction. We have pre-viously demonstrated w1x that in patients with exacer-bated systolic CHF, baseline Cpi at admission is thestrongest predictor of short- and long-term outcome. Onthe other hand, the main event preceding recurrentworsening heart failure was a steep increase in SVRi.In a recent analysis, we have also found that Cpi atbaseline and during follow-up was the strongest predic-tor of outcome in a large cohort of cardiogenic shockpatients (unpublished data).

The main hypothesis of the present study was that inpatients with acute CHF, as Cpi decreases, SVRi shouldconcomitantly increase. Therefore, for each Cpi decreasethe SVRi increase may be adequate, too high or too lowand, thus, CpiySVRi coupling may characterize theclinical-hemodynamic state. Therefore, in the presentstudy, we examined in a two-dimensional representation,the relationship between changes in Cpi (pump work)and SVRi (resistance or work load) in the four clinicalsyndromes of acute CHF, (i.e. exacerbated systolic CHF,pulmonary edema, cardiogenic shock and HTN crisis),as well as in two control groups: (i.e. septic shock andnormal subjects).

2. Methods

2.1. Inclusion criteria

Hemodynamic data was obtained in all patients under-going right heart catheterization who were diagnosed bythe usual clinical criteria as having acute CHF. We alsoenrolled two control groups: these were 11 patients withseptic shock and 20 healthy volunteers.

2.2. Exclusion criteria

Significant valvular disease, significant brady- ortachy-arrhythmias or renal failure (creatinine )2.5 mgydl).

2.3. Clinical diagnosis criteria

2.3.1. Exacerbated systolic CHFPatients admitted due to signs and symptoms of

worsening CHF, who were in a stable clinical condition;not fulfilling the criteria for cardiogenic shock, pulmo-nary edema and HTN crisis and who had EF-35% onechocardiography. (The echocardiographic criteria wereused to ensure that the symptoms of dyspnea wereindeed due to acute CHF.)

2.3.2. Pulmonary edemaPatients admitted due to clinical symptoms and signs

of acute pulmonary congestion accompanied by findingsof lung edema on chest X-ray who had severe respiratorydistress accompanied by O saturation -90% in room2air by pulse oxymetery during the invasivemeasurements.

2.3.3. Cardiogenic shockSystolic blood pressure -100 mmHg for at least 1 h,

not responsive to percutaneous revascularization,mechanical ventilation, intra-aortic balloon-pump(IABP), IV fluid administration and dopamine of atleast 10 mgykgymin and accompanied by signs of endorgan hypoperfusion but not accompanied by fever)388 or a systemic inflammatory syndrome.

2.3.4. HTN crisisPatients with signs and symptoms of acute CHF

accompanied by high blood pressure (MAP)130mmHg during invasive measurements); not fulfilling thecriteria for pulmonary edema.

2.3.5. Septic shockSystolic blood pressure -100 mmHg accompanied

by fever )388, systemic inflammatory syndrome andsigns of end organ hypoperfusion for at least 3 h notresponsive to IV fluids and IV dopamine of at least 10mgykgymin. No evidence of an acute cardiac event.


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2.4. Assessment of hemodynamic variables

Prior to enrolment in this study all patients gavewritten informed consent. The study protocol wasapproved by the local ethics review board. In all patientsthe hemodynamic variables were obtained during rightheart catheterization using a Swan–Ganz catheter placedunder fluoroscopic guidance. All measurements wereobtained while patients were at least 30 s without IABPwhile on the same treatment used at the time the clinicaldiagnosis was made. Measurement of hemodynamicvariables was performed at least 6 h after the last intakeof an oral drug and 2 h after intravenous drug therapy.

CI was measured by thermodilution, using the meanof at least three consecutive measurements within arange of -15%. In normal subjects, right heart cathe-terization was not performed for ethical reasons. Thevalues used in this cohort were obtained by standardnoninvasive cuff blood pressure measurement and eval-uation of CI by the FDA approved NICaS� 2001, anoninvasive continuous cardiac output monitor w10x.Therefore, wedge pressure was not assessed in normalsubjects. Instead, we used standard values documentedin the literature w11x.

2.5. Calculation of hemodynamic variables

Cpi was determined as MAP=CI=0.0022 and SVRiwas determined as (MAPyright atrial pressure (RAP)yCI. As RAP was not measured in normal subjects, itwas estimated to be 10% of MAP w11x.

2.6. Echocardiographic evaluation

All patients underwent routine echocardiographicevaluation after initial stabilization. This included visualestimation of cardiac function, evaluation of valvularfunction and gross estimation of signs of diastolicdysfunction.

2.7. Statistical methods

The five clinical groups were compared with regardto all parameters using a one-way analysis of variance(ANOVA). Therafter, the Ryan–Einot–Gabriel–WelschMultiple Range Test was used for pair-wise comparisonsbetween the groups, while Dunnett’s t-test was used tocompare all groups to the healthy controls.

A one-sample t-test was performed to compare meanwedge pressure in each group to the wedge pressure ofnormal people (-12 mmHg).

In order to determine the usefulness of the hemodyn-amic parameters to discriminate between the clinicalsyndromes, ROC curves, derived from a logistic regres-sion model were applied to the data to determine the

best cut-off point for the various parameters, in termsof highest sensitivity and specificity.

2.8. CpiySVRi diagnostic graph

A classification rule was developed using secondorder discriminant analysis. The normality of the distri-bution of Cpi and SVRi was examined by the Wilk–Shapiro test. Due to the skewness of the data in somegroups, both variables (CPi and SVRi) were transformedinto log scale for better approximation to normality.Since the number of patients with HT crisis was smallthey were considered together with the exacerbatedsystolic CHF group. The classification used two steps.In the first step the rule separated three classes: septicshock, cardiogenic shock and a combined group, whichincluded the normal controls, compensated CHF andpulmonary edema patients (N–C–P). If, after the firststep the patient was defined as N–C–P, the secondclassification was used to differentiate between thenormal, exacerbated systolic CHF and pulmonary edemasubgroups.

All calculations were performed by SAS 6.12 (SASInstitute Inc., Cary, NC) using procedures FREQ,MEANS, GLM, DISCRIM, GPLOT.

Alfa level: 5%.

3. Results

Eighty-nine consecutive patients admitted due to acuteCHF and LV dysfunction (exacerbated systolic CHF,ns56; pulmonary edema, ns11; cardiogenic shock,ns17; and HTN crisis, ns5) as well as 11 patientswith septic shock and 20 healthy volunteers wereenrolled in the study. Baseline characteristics of thedifferent patient groups are presented in Table 1. Themean CI, wedge pressure, MAP, SVRi and Cpi accordingto clinical diagnosis are presented in Table 2.

3.1. Hemodynamic variables

3.1.1. Cardiac index (Fig. 1)The average values of CI were significantly lower in

patients with acute CHF and higher in patients withseptic shock. ROC analysis found a cut-off point ofCI-2.7 lyminym useful for the determination that a2

patient had acute CHF (sensitivitys1, specificitys0.99). However, values between 1.2 and 2.7 lyminym2

could be found in all patients with exacerbated systolicCHF and HTN crisis as well as 73% of patients withpulmonary edema and 47% of patients with cardiogenicshock. Moreover, the mean CI of patients with pulmo-nary edema and cardiogenic shock was found to bealmost identical (1.4"0.4 vs. 1.35"0.7 lyminym , Ps2

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Table 1Baseline characteristics of the five patient groups

Normal Septic Exacerbated Pulmonary Cardiogenicvolunters shock systolic CHF edema shock

Sex (male:female) 12:8 7:4 51:10 5:6 11:6Age (years) 60"8 55"11 69"10 73"12 67"11Weight (kg) 79"14 77"10 72"8 70"9 80"14Body surface area (m )2 1.92"0.22 1.91"0.23 1.88"0.21 1.81"0.24 1.92"0.24IHD (%) 0 18 79 73 100Previous MI 0 9 62 55 18EF (%) 55"3 46"9 27"5 41"10 24"6Diabetes mellitus (%) 20 73 66 66 53Current smokers (%) 60 55 36 44 53Hypertension (%) 50 45 56 88 71Hyperlipidemia (%) 65 73 66 66 53Baseline creatinine 135"75 124"55 144"81 110"47Medications for CHFDiuretic (%) 0 0 82 91 6Digoxin (%) 0 0 33 45 0ACE inhibitoryAII blocker (%) 0 9 95 91 29Beta-blocker (%) 0 9 62 55 24Nitrate (%) 0 0 41 55 0

IHD, ischemic heart disease; MI, myocardial infarction; EF, ejection fraction; CHF, congestive heart failure.

Table 2Baseline distribution of the various hemodynamic parameters in the six diagnosis groups presented as means and S.D.

Exacerbated Pulmonary Cardiogenic HTN Septic Normalsystolic CHF edema shock crisis shock

N 56 11 17 5 11 20SVRi 44.9"8.0 88.2"16.7 55.6"31.1 54.3"3.2 11.8"1.1 25.2"4.1Cpi 0.47"0.13 0.4"0.13 0.22"0.08 0.75"0.04 0.8"0.13 0.62"0.08Wedge 25.5"7.2 32.7"8.6 23.3"6.5 28.5"4.5 11.4"7.7 –MAP 101"18 131.4"12.7 72.2"11.3 150"10.5 68.2"5.4 87.9"8.85CI 2.06"0.33 1.37"0.32 1.42"0.64 2.24"0.37 5.2"0.5 3.2"0.36

The results of the ANOVA for comparisons between exacerbated systolic CHF (CHF), pulmonary edema(edema) and cardiogenic shock (shock) patientsParameter P-value for overall group P-value for paired comparisons (Ryan–Einot–Gabri-

el–Welsch multiple range test)groups comparison (ANOVA)CHF-edema CHF-shock Edema-shock

CI 0.0001 q qWedge 0.0037 q qSVRi 0.0001 q q qCPi 0.0001 q q

N, number of patients; SVRi, systemic vascular resistance index (wood m ); Cpi, cardiac power index (mmHg lyminym ); wedge, pulmonary2 2

capillary wedge pressure (mmHg); MAP, mean arterial blood pressure (mmHg); CI: cardiac index (lyminym ). q, Significant group difference.2

3.1.2. Mean arterial blood pressureBy virtue of their clinical definition, the average

values of MAP were higher in patients with HTN crisisand lower in those with septic and cardiogenic shock.However, large areas of overlap were found betweenpulmonary edema, HTN crisis and exacerbated systolicCHF (MAP)100 mmHg) and between exacerbatedsystolic CHF, cardiogenic shock and septic shock(MAP-100 mmHg).

3.1.3. Pulmonary capillary wedge pressure (Fig. 2)The mean wedge pressure was significantly higher in

patients with acute CHF and lower in patients with

septic shock. The analysis was based on normal valuesreported in the literature (-12 mmHg w8x) (Ps0.001).However, the overlap of wedge pressure in the differentacute CHF groups was extensive. Values between 12and 38 mmHg were found in 82, 64, 76 and 18% ofpatients with exacerbated systolic CHF, pulmonary ede-ma, cardiogenic shock and septic shock, respectively.

3.1.4. Cardiac power index (Fig. 3)Compared with the normal controls, the mean values

of Cpi were low in patients with exacerbated systolicCHF and pulmonary edema and extremely low in


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Fig. 1. CI (lyminym ) Box-plots (median and 25–75% percentile2

range) in patients with the different syndromes of acute CHF andpatients with septic shock and normal controls.

Fig. 3. Cpi (Wym ) Box-plots (median and 25–75% percentile range)2

in patients with the different syndromes of acute CHF and patientswith septic shock and normal controls.

Fig. 2. Pulmonary capillary wedge pressure (mmHg) Box-plots(median and 25–75% percentile range) in patients with the differentsyndromes of acute CHF and patients with septic shock and normalcontrols.

Fig. 4. Systemic vascular resistance index (SVRi) (wood m ) Box-2

plots (median and 25–75% percentile range) in patients with the dif-ferent syndromes of acute CHF and patients with septic shock andnormal controls.

patients with cardiogenic shock. However, some overlapwas encountered among the five groups.

3.1.5. Systemic vascular resistance index (Fig. 4)Average values of SVRi were significantly higher in

all patients with exacerbated systolic CHF, HTN crisisand extremely high in patients with pulmonary edema,but were lower in patients with septic shock. SVRi wasfound to be instrumental in the diagnosis of pulmonaryedema. All patients with this clinical syndrome hadSVRi)67 wood m , while SVRi values in all other2

patient groups, as well as in normal subjects, weresignificantly lower than this value.

3.2. CpiySVRi diagnostic graph (Fig. 5)

Since the number of patients with HTN crisis wassmall they were included in the exacerbated systolicCHF group. Distributions of SVRi and Cpi were highlyskewed. The normality of the distribution of Cpi andSVRi was assessed by the Wilk–Shapiro test. The resultsshowed that Cpi and SVRi distribution was not normalfor the normal volunteers (Ps0.03 for Cpi), the exac-erbated systolic CHF patients(Ps0.007 for Cpi and Ps0.04 for SVRi) and the cardiogenic shock patients(Ps0.016 for SVRi).

However, log(SVRi) and log(CPi) were normallydistributed (Psns for both Cpi and SVRi in all patientgroups). Therefore, for the analysis we used only log


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Fig. 5. Diagnostic graph for classification of the hemodynamic statusof patients with different syndromes of acute CHF.

Table 4Number of observations classified into the correct clinical group using log(SVRi) and log(CPi)

Group Cardiogenic Exacerbated Normal Pulmonary Septic Totalshock systolic CHF edema shock

Cardiogenic shock 15 2 0 0 0 17Exacerbated systolic CHF 0 60 1 0 0 61Normal 0 0 20 0 0 20Pulmonary edema 2 0 0 11 0 11Septic shock 0 0 0 0 11 11

Table 3Number of observations classified into the correct clinical group using log(Cpi) or log(SVRi) only

Group Cardiogenic Exacerbated Normal Pulmonary Septic Totalshock systolic CHF edema shock

(a) Number of observations classified into appropriate groups: classification using log(CPi) onlyCardiogenic Shock 13 4 0 0 0 17Exacerbated systolic CHF 1 44 14 0 2 61Normal 0 9 8 0 3 20Pulmonary edema 1 9 1 0 0 11Septic shock 0 0 3 0 8 11

(b) Number of observations classified into appropriate groups using log(SVRi) only

Cardiogenic shock 2 12 1 2 0 17Exacerbated systolic CHF 0 58 3 0 0 61Normal 0 3 17 0 0 20Pulmonary edema 2 0 0 9 0 11Septic shock 0 0 0 0 11 11

values. The distribution of the two log parameters (Cpiand SVRi) was different among the five groups, how-ever, none enabled separation of the groups (Table 3).These data suggested that separation may be possibleusing two-dimensional discriminant analysis. We usedclassical discriminant analysis for normal distributionswith unequal covariance matrices because the small

numbers of observations in two of the groups preventedus from using more flexible kernel functions.

Due to large variability of variances of the parametersin the five groups, we could not suppose equal covari-ance matrices in the groups. (The test of homogeneityof within covariance matrices gives Ps0.)

3.2.1. Classification ruleThe calculations leading to the classification rule and

CpiySVRi diagnostic graph are given in Appendix A.

3.2.2. Classification resultsThe results of the application of the classification rule

to the sample are presented in Table 4.

3.2.3. Performance of the classification ruleThe performance of a diagnostic procedure with only

two possible results and two classes of patients is usuallyexpressed using measures like positive (negative) pre-dictive value w12x or diagnostic odds ratio w13x. Formore complex tests with many outcomes and manyclasses of patients the overall performance may beexpressed through the difference between proportion oferroneously classified patients with and without usingthe test. This measure is usually called Lambda asym-metric (RNC), where R (rows) is the true group and C(column) is the group where the patient was classified.


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For our data Lambda (RNC)s0.95 (S.D. (Lambda)s0.03) which corresponds to three errors of classificationaccording to the classification rule, instead of 59 errorsof classification according to the prior probabilities.

4. Discussion

During the last decade the pathogenesis of CHF hasbecome clearer. The emphasis on cardiac performanceas the sole pathogenic mechanism of CHF has changedto a more comprehensive understanding of the impor-tance of the interaction between cardiac contractility,neurohormonal and inflammatory control mechanismsand vascular resistance. We have recently studied thetreatment of the acute CHF syndromes of pulmonaryedema and cardiogenic shock and have shown thattreatment modalities with significant vascular effect areeffective in improving the outcome of these patientsw14–16x. These findings substantiated our theory thatthe SVRi reaction to the decrease in Cpi determines thehemodynamic condition and clinical syndrome ofpatients with acute CHF.

4.1. Classical hemodynamic monitoring

CI is the most popular parameter used in invasivehemodynamic monitoring of patients with acute CHF.However, the results of the present study as well asprevious ones w2,4–6x show that CI measurements arenot sufficient for the diagnosis and treatment titration inpatients with acute CHF. This might be explained bythe fact that CI is actually a measure of cardiovascularflow. Hence, CI (flow) is determined by both cardiaccontractility and vascular resistance and, therefore, maychange dramatically when Cpi decreases but also witheven mild changes in SVRi. Pulmonary capillary wedgepressure is the second most popular hemodynamic var-iable used in hemodynamic monitoring, since it repre-sents the hydraulic pressure transmitted backwards tothe pulmonary circulation, and hence, is an importantdeterminant of pulmonary edema. However, wedge pres-sure cannot be used for the exact diagnosis of thedifferent clinical syndromes of acute CHF, due to theextent of overlapping values between patients withexacerbated systolic CHF, HTN crisis and even cardio-genic shock.

4.2. Cpi and SVRi and their role in patients with acuteCHF

Cpi as measured in the present study w1,8,9x is asimplified version of a previously described method ofmeasuring cardiac contractility w7x. This value is derivedfrom the entire cardiac cycle (instead of instantaneousmeasurements) and is the product of the mean pressureand flow. Cpi has been shown to be the best predictor

of outcome in chronic CHF patients w7–9x, exacerbatedsystolic CHF w1x and cardiogenic shock (unpublisheddata).

In the present study, we found that in patients withexacerbated systolic CHF either Cpi was decreased orSVRi was increased or both changes occurred. In aprevious study, we described the sequence of eventsleading to acute heart failure w1x. In most patients anacute CHF event starts with a progressive decrease incardiac contractility and power (Cpi). Thereafter, as Cpidecreases, neurohormonal vascular control mechanismsare activated and SVRi increases w1,17x. This increaseis a very important protective mechanism for tworeasons:

1. The increase in SVRi in the face of decreasedcontractility maintains blood pressure and the perfu-sion of vital organs.

2. This afterload increase (while within certain limits)may improve contractility (possibly through theGregg phenomenon w18x), which may account for the‘normal’ Cpi we observed in some patients withechocardiographically demonstrated systolicdysfunction.

However, SVRi increase in response to Cpi decreaseis not uniform. It can be appropriate (thus, leading to acompensated state), inappropriately low (thus, leadingto low blood pressure, forward hypoperfusion and car-diogenic shock) or inappropriately high (thus, inducingan extreme afterload mismatch leading to pulmonaryedema).

Indeed, in the present study, in patients who wereclinically diagnosed as cardiogenic shock, Cpi was foundto be extremely low, however, SVRi was only slightlyincreased. This imbalance between very low Cpi andinadequate increase in SVRi probably resulted in lowblood pressure and decreased perfusion pressure of vitalorgans including the heart. This decrease in coronaryperfusion might lead to decreased contractility inducinga vicious cycle of low contractility, low SVRi andreduced perfusion. For this reason, in a previous studyw15x we treated patients with cardiogenic shock, byshort-term administration of a peripheral vasoconstrictor(L-NMMA) with good clinical response.

On the other hand, in patients diagnosed as pulmonaryedema, despite what appears to be a similar clinicalpresentation (pulmonary congestion, clammy extremi-ties, low CI and high wedge pressure), the pathophy-siological findings as well as the treatment, are thecomplete opposite. In patients with pulmonary edema,we measured Cpi values similar to those in exacerbatedsystolic CHF, however, SVRi was markedly increased.These findings are collaborated by the study by Gandhiet al. w19x showing a dramatic increase in blood pressurein patients with pulmonary edema. We hypothesize thatthis increase in SVRi might be an inappropriate


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response, related to neurohormonal, endothelial andperhaps inflammatory activation w20,21x. This remark-able increase in SVRi induces an afterload mismatch,reducing CI and increasing intracardiac pressures,LVEDP and wedge pressure, resulting in the severecongestive symptoms of pulmonary edema. Therefore,as previously suggested w14,16,22,23x, vasodilator treat-ment is effective in the treatment of pulmonary edema.

4.3. Two-dimensional graphic representation of CpiySVRi and its use in the treatment of cardiogenic shockand pulmonary edema

In the present study, we found that when plotting ona two-dimensional graph the results of Cpi and SVRifor individual patients, each clinical group of patientscould be segregated into a specific area on the graphwhich could be bound by a mathematically defined line(Fig. 5). This graph enables exact clinical diagnosis ofmost (95%) patients with exacerbated systolic CHF,pulmonary edema, HTN crisis, cardiogenic shock andseptic shock. Of course, the boundaries on the graph aresomewhat arbitrary, since the definitions of the syn-dromes are as used by the medical community, andtherefore, arbitrary. However, this two-dimensional rep-resentation enables a better understanding of the patho-physiology of the different syndromes of acute CHF.

We believe that this new and simple diagnostic toolmay become useful for the initial evaluation of acutelydecompensated patients, while the clinical diagnosis hasnot yet been established and initiation of appropriatedisease-specific treatment is crucial. This might becomeeven more important with the advent of new devicesthat accurately measure CI noninvasively. The combi-nation of noninvasive MAP and CI measurement, Cpiand SVRi calculation and the two-dimensional CpiySVRi graph could enable improved diagnosis of patientseven in paramedic units and in emergency rooms.

Furthermore, this method may become an importanttool for monitoring the patients’ response to treatment.

4.4. Limitations

The results of the present study are based on arelatively small number of patients, and therefore, needconfirmation by prospectively evaluating a larger groupof patients with acute CHF. Also, the measurements inthe present study were performed by thermodilution,which has an inherent 10–15% deviation in measuringcardiac output. Finally, cardiac power calculations wereperformed using whole-cycle measurements (cardiacoutput and MAP). Although we recognize that thecardiovascular system operates in a pulsatile manner,cardiac power calculated according to the methodologyused in the present study has previously been shown tobe a useful measure of cardiac contractility and contrac-

tility reserve in chronic and acute CHF as well as incardiogenic shock.

Appendix A: Classification rule

Given a patient with measured values of SVRi andCpi, the classification may be performed either (A)through special calculations or (B) using the ‘Graph forclassification of CHF patients (CpiySVRi graph)’.(A) Classification using calculationsStep 1. Calculate three values v1, v2, v3 according to

the formulas below.

v1sLCPi2=21.54q2=LCPi=LSVRi=10.61qLSVRi2=59.44yLCPi=305.24yLSVRi=417.70q1408.89

2v2sLCPi =10.12q2=LCPi=LSVRi=5.67yLSVRi2=4.99yLCPi=135.81yLSVRi=90.11q482.61

v3sLCPi2=7.29qLCPi=LSVRi=2.57qLSVRi2=4.09yLCPi=97.41yLSVRi=58.22q368.16

Classify the patientinto the group ‘Septic shock’, if v1 is the smallest valueinto the group ‘Cardiogenic Shock’, if v2 is the smallestvalueif v3 is the smallest value go to step 2

Step 2. Calculate three values v4, v5, v6 according tothe formula below.

v4sLCPi2=6.45y2=LCPi=LSVRi=0.45qLSVRi2=16.01yLCPi=65.16yLSVRi=116.53q391.67v5sLCPi2=17.75q2=LCPi=LSVRi=26.56qLSVRi2=54.27yLCPi=420.26ySVRi=758.55q2775.78v6sLCPi2=32.95q2=LCPi=LSVRi=3.09qLSVRi2=19.72yLCPi=390.74yLSVRi=161.49q1355.57

Classify the patientinto the group ‘Exacerbated Systolic CHF’, if v4 is thesmallest value among v4, v5, v6 and LSVRi-log(67)into the group ‘Pulmonary Edema’, if v5 is the smallestvalue among v4, v5, v6 and LSVRi)log(67)into the group ‘Normal’, if v6 is the smallest valueamong v4, v5, v6

The value of SVRis67 was used to separate patientswith exacerbated systolic CHF from patients with pul-monary edema since the group of ‘pulmonary edema’was rather small and by classifying these patientsaccording to the usual rule we did not receive aseparating line for Cpi measures)250 Wym .2


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(B) Classification using the diagnostic graphPut the point (CPi, SVRi) on the diagnostic graph

Fig. 5 or point (LCPi, LSVRi) and classify the patientaccording to the area of the graph, where the point islocated.

References

w1x Cotter G, Moshkovitz Y, Milovanov O, et al. Acute congestiveheart failure: a novel approach to its pathogenesis and treat-ment. Eur J Heart Fail 2002;4:227 –34 (review).

w2x Menon V, White H, LeJemtel T, Webb JG, Sleeper LA,Hochman JS. The clinical profile of patients with suspectedcardiogenic shock due to predominant left ventricular failure:a report from the SHOCK Trial Registry. Should we emergentlyrevascularize occluded coronaries in cardiogenic shock? J AmColl Cardiol 2000;36:1071 –6.

w3x Kaluski E, Kobrin I, Zimlichman R, et al. RITZ-5: RandomizedIntravenous Tezosentan (an Endothelin ET-AyB Antagonist)for the treatment of pulmonary edema. A prospective random-ized, multicenter, double-blind placebo controlled study. J AmColl Cardiol 2003;41:204–10.

w4x Morley D, Brozena SC. Assessing risk by hemodynamic profilein patients awaiting cardiac transplantation. Am J Cardiol1994;73:379 –83.

w5x Anguita M, Arizon JM, Bueno G, et al. Clinical and hemodyn-amic predictors of survival in patients aged -65 years withsevere congestive heart failure secondary to ischemic or non-ischemic dilated cardiomyopathy. Am J Cardiol 1993;72:413 –7.

w6x Levine TB, Levine AB, Goldberg D, Narins B, Goldstein S,Lesch M. Reversal of end-stage heart failure is predicted bylong-term therapeutic response rather than initial hemodynamicand neurohormonal profile. J Heart Lung Transplant1996;15:297 –303.

w7x Marmor A, Schneeweiss A. Prognostic value of noninvasivelyobtained left ventricular contractile reserve in patients withsevere heart failure. J Am Coll Cardiol 1997;29:422 –8.

w8x Williams SG, Cooke GA, Wright DJ, et al. Peak exercisecardiac power output; a direct indicator of cardiac functionstrongly predictive of prognosis in chronic heart failure. EurHeart J 2001;22:1496 –503.

w9x Cohen-Solal A, Tabet JY, Logeart D, Bourgoin P, TokmakovaM, Dahan M. A non-invasively determined surrogate of cardiacpower (‘circulatory power’) at peak exercise is a powerfulprognostic factor in chronic heart failure. Eur Heart J2002;23:806 –14.

w10x Cohen JA, Arnaudov D, Zabeeda D, Schlthes L, Lashinger J,Schachner A. Non-invasive measurement of cardiac outputduring coronary artery bypass grafting. Eur J Card ThoracicSurg 1998;14:64 –9.

w11x Lange RA, Hillis LD. Cardiac catheterization and hemodyn-amic assessment. In: Topol EJ, Textbook of CardiovascularMedicine. page 1653.

w12x Sasieni PD. Statistical analysis of the performance of diagnostictests. Cytopathology 1999;10:73 –8 (invited review).

w13x Lijmer JG, Willen Mol B, Heisterkamp S, et al. Empiricalevidence of design related bias in studies of diagnostic tests. JAm Med Assoc 1999;282:1061 –6.

w14x Cotter G, Metzkor E, Kaluski E, et al. Randomised trial ofhigh-dose isosorbide dinitrate plus low-dose furosemide versushigh-dose furosemide plus low-dose isosorbide dinitrate insevere pulmonary oedema. Lancet 1998;351:389 –93.

w15x Cotter G, Kaluski E, Blatt A, et al. L-NMMA (a nitric oxidesynthase inhibitor) is effective in the treatment of cardiogenicshock. Circulation 2000;101:1358 –61.

w16x Sharon A, Shpirer I, Kaluski E, et al. High-dose intravenousisosorbide-dinitrate is safer and better than Bi-PAP ventilationcombined with conventional treatment for severe pulmonaryedema. J Am Coll Cardiol 2000;36:832 –7.

w17x Mohr R, Rath S, Meir O, et al. Changes in systemic vascularresistance detected by the arterial resistometer: preliminaryreport of a new method tested during percutaneous transluminalcoronary angioplasty. Circulation 1986;74:780 –5.

w18x Karunanithi MK, Young JA, Kalnins W, Kesteven S, Dip G,Feneley MP. Response of the intact canine left ventricle toincreased afterload and increased coronary perfusion pressurein the presence of coronary flow autoregulation. Circulation1999;100:1562 –8.

w19x Gandhi SK, Powers JC, Nomier AM, et al. The pathogenesisof acute pulmonary edema associated with hypertension. NewEngl J Med 2001;344:17 –22.

w20x Bank AJ, Lee PC, Kubo SH. Endothelial dysfunction in patientswith heart failure: relationship to disease severity. J Card Fail2000;6:29 –36.

w21x Milo O, Cotter G, Kaluski E, Blatt A, Krakover R, Vered Z,Hershkovitz A. Inflammatory and neurohormonal activation incardiogenic pulmonary edema: Implications on the pathogene-sis and outcome of acute ischemic versus non-ischemic acuteheart failure. Am J Cardiol (In Print).

w22x Northridge D. Furosamide or nitrates for acute heart failure?Lancet 1996;347:667 –8.

w23x Cotter G, Kaluski E, Moshkovitz Y, Milovanov O, KrakoverR, Vered Z. Pulmonary edema: new insights on pathogenesisand treatment. Curr Opin Card 2001;16:159 –63.


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editorial: emerging role of ICG in HF march . april 2004 . supplement 2 1

E D I T O R I A L

Beyond the Four Quadrants: The Critical and Emerging Role of Impedance Cardiography in Heart Failure

John E. Strobeck, MD, PhD;1 Marc A. Silver, MD,2 Co-Editors in ChiefFrom the Heart-Lung Center, Hawthorne, NJ;1 and the Department of Medicine and the Heart Failure Institute, Advocate Christ Medical Center, Oak Lawn, IL2

Address for correspondence: Marc A. Silver, MD, Advocate Christ Medical Center, 4440 West 95th Street, Suite 428 South, Oak Lawn, IL 60453-2600 E-mail: [email protected]

Heart failure (HF) is a disorder characterized by hemodynamic

abnormalities including a reduction in the heart’s ability to deliver oxygen-ated blood to the body. HF is also asso-ciated with important neurohormonal abnormalities, including activation of the renin-angiotensin-aldosterone and sympathetic nervous systems and their resulting effects on the heart and vascular endothelium. Our under-standing of the neurohormonal role in the progression of HF has greatly improved in the past 10 years,1 and many of the therapies that significant-ly improve the symptoms and progno-sis of patients with HF now target the underlying neurohormonal abnormali-ties. As shown in Figure 1, neurohor-monal activation can lead to progres-sion of hemodynamic abnormalities resulting in reduced cardiac output (CO); increased filling pressures; and ultimately worsening symptoms of fatigue, dyspnea, and decreased exer-cise tolerance. Although the neuro-hormonal mechanisms may cause pro-gression of the disease process, nearly all medications used in HF treatment have demonstrable effects on hemo-dynamics. Current acute HF treat-ment is aimed directly at stabilizing and improving a patient’s short-term hemodynamic condition; chronic HF treatments can alter short-term and improve long-term hemodynamics.

Specific hemodynamic measure-ments such as CO and systemic vascu-

lar resistance are generally obtained for only the most critically ill HF patients, in large part due to the risk, discom-fort, and cost of invasive procedures such as pulmonary artery catheter-ization.2 Nonetheless, understanding and measuring the factors that affect CO are central to the assessment, prognosis, and treatment of patients with HF. The four determinants of CO are the rate of the pump (heart rate), the volume of blood available to pump (preload), the pumping strength (contractility), and the force the heart must overcome to pump (afterload, generally approximated by systemic vascular resistance). Symptoms—physical findings like vital signs—and

laboratory findings such as blood tests and chest radiographs are imprecise measures of hemodynamic function. Unfortunately, they are the only data many clinicians have at their disposal when making important decisions in the care of patients with HF.

The direct cost of treating HF is esti-mated to be $56 billion per year in the United States3 and the number of HF patients in this country may reach 10 million by 2010.4 A significant portion of the cost of HF care is the high cost of hospitalizations for patients with acute decompensation. Through careful sur-veillance of patients with chronic HF using improved methods for measuring hemodynamic and neurohormonal

www.lejacq.com ID:3405

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60%

20%

Time

SecondaryDamage

Adrenergic System

RASX

X

HemodynamicsReduced cardiac output, increased filling pressures

SymptomsFatigue, dyspnea, decreased exercise tolerance

Figure 1. Neurohormonal activation and resultant hemodynamic and symptom changes. RAS=renin-angiotensin-aldo-sterone system

Figure 2. Clinical profiles in heart failure. PND=paroxysmal nocturnal dyspnea; JV=jugular vein; ACE=angiotensin-converting enzyme. Adapted from J Am Coll Cardiol. 2003;41(10):1797–1804.5

Congestion at Rest

LowPerfusion

at RestCL

A B

Warm & Dry Warm & Wet

Cold & Wet

(Complex)(Low Profile)

Congestion:Orthopnea/PND JV distension, Hepatomegaly, Edema, Rales, Abdominal-jugular reflex

Possible Evidence of Low Perfusion:Narrow pulse pressure, cool extremities, sleepy/obtunded, hypotension with ACE inhibitor, low serum sodium, renal/hepatic dysfunction

NO

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CHF-MarchApril-Suppl-04.indd 1 3/30/04 9:40:41 AM

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editorial: emerging role of ICG in HF march . april 2004 . supplement 22

status, primary care physicians and car-diologists may be able to intervene in a timely manner and prevent acute epi-sodes leading to hospitalization, major morbidity, or death.

Warner-Stevenson5 has developed and popularized the concept of categoriz-ing HF patients by hemodynamic sub-set based on perfusion with CO (warm vs. cold) and congestion with pulmo-nary artery wedge pressure (wet vs. dry). The four quadrants, representing the four hemodynamic classes, are shown in Figure 2. Studies have suggested that these profiles provide a useful framework to risk stratify patients with HF, pre-dict outcomes, and identify therapeutic

options. However, this framework is based on invasive pulmonary artery catheteriza-tion, with its requisite risk and cost, or on physical examination and patient history, which have been shown to lack sensitiv-ity and specificity, even in the hands of experienced clinicians.6 HF management using hemodynamic subsets could be substantially improved by the existence of more objective data with which to classify

patients and evaluate the effectiveness of subsequent pharmacologic and implant-able interventions.

Impedance cardiography (ICG) is a noninvasive method of determining hemodynamic status. In the past, studies questioned the reliability of ICG technol-ogy,7,8 leading some to conclude that the technology did not have value in clinical decision making. However, refinements in signal processing and CO algorithms have greatly improved the reliability of ICG technology. The latest generation of ICG devices (BioZ ICG Monitor, CardioDynamics, San Diego, CA; and BioZ ICG Module, GE Medical Systems Information Technologies, Milwaukee, WI) are both highly reproducible and accurate in a number of clinical settings, including HF.9–11 A recent search of the literature failed to show a single citation since US Food and Drug Administration 510(k) clearances of these particular devices that suggests they are not valid for clinical applications.

ICG is a form of plethysmography that utilizes changes in thoracic electri-cal impedance to estimate changes in blood volume in the aorta and changes in fluid volume in the thorax. As shown in Figures 3 and 4, the ICG procedure involves the placement of four dual

Table I. Impedance Cardiography ParametersPARAMETER ABBREVIATION MEASUREMENT/CALCULATION UNITS

FlowStroke volume SV VI × LVET × VEPT (Z MARC algorithm) mLStroke index SI SV/body surface area mL/m2

Cardiac output CO SV × heart rate L/minCardiac index CI CO/body surface area L/min/m2

ResistanceSystemic vascular resistance SVR ([MAP – CVP]/CO) × 80 dyne × s × cm-5

Systemic vascular resistance index SVRI ([MAP – CVP]/CI) × 80 dyne × s × cm-5 × m2

ContractilityPreejection period PEP ECG Q wave to aortic valve opening msLeft ventricular ejection time LVET Aortic valve opening to closing msSystolic time ratio STR PEP/LVET No unitsVelocity index VI First time derivativemax/baseline impedance /1000/sAcceleration index ACI Second time derivativemax/baseline impedance /100/s2

Left cardiac work index LCWI (MAP – PCWP) × CI × 0.0144 kg × m/m2

Fluid StatusThoracic fluid content TFC 1/baseline impedance /kOhm

VEPT=volume of electrically participating tissue; Z MARC=impedance modulating aortic compliance; CVP=central venous pressure (estimated value of 6 mm Hg); MAP=mean arterial pressure; ECG=electrocardiogram; PCWP=pulmonary capillary wedge pressure (estimated value of 10 mm Hg)

Figure 3. Front view of impedance cardiography method

Figure 4. Lateral view of impedance cardiography method


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sensors on a patient’s neck and chest. A low-amplitude, high-frequency alter-nating current is delivered from the four outer sensors and the four inner sensors detect instantaneous changes in voltage. As suggested by Ohm’s law, when a constant current is applied to the thorax, the changes in voltage are directly proportional to the changes in measured impedance. The overall tho-racic impedance, called base impedance (Z0) is the sum of the impedances of the components of the thorax, including fat, cardiac and skeletal muscle, lung and vascular tissue, bone, and air. Changes from Z0 occur due to changes in lung volumes with respiration and changes in the volume and velocity of blood in the great vessels during systole and dias-tole. The rapidly changing component of chest impedance (∆Z) is filtered to remove the respiratory variation, leaving the impedance changes due to ventricu-lar ejection. Figure 5 details the elements contributing to Z0 and ∆Z, and Figure 6 illustrates how the first derivative of the impedance waveform (∆Z/∆t) is used with an electrocardiogram to determine the beginning of electrical systole, aortic valve opening, maximal deflection of the ∆Z/∆t waveform, and the closing of the aortic valve. From these fiducial points, a variety of measured and calculated parameters (Table I) are continuously displayed on the ICG device screen for monitoring purposes, or in a printed report for review (Figure 7).

The hemodynamic parameters derived from ICG can aid in the diagnostic and prognostic evaluation of patients with HF. Using ICG, a clinician is able to evaluate direct or indirect measures of each of the four major determinants of CO (preload, afterload, contractility, and heart rate). Figure 8 is a conceptual dia-gram of CO and its determinants, ICG parameters associated with the determinants, and the effects of pharmacologic agent classes on each determinant. Due to greater accep-tance of ICG in clinical and research settings, clinicians are now able to use ICG-derived hemodynamic data to help decide when to initiate and

titrate these types of medications. A summary of applications of ICG in HF is presented in Table II, demonstrating its broad clinical applicability.

In this supplement to Congestive Heart Failure, we seek to further define the role of ICG through a series of original contributions. The study by

Table II. Summary of Impedance Cardiography Applications in Heart FailureAPPLICATION DESCRIPTION

Assessment and diagnostic

Establish baseline hemodynamicsTrend changes to gauge level of hemodynamic decompensationDetermine whether symptoms are due to hemodynamic deteriorationAid in differentiation of systolic vs. diastolic dysfunction

Prognostic Emergency department values predictive of length of stay and hospital charges

Improvements associated with improving NYHA class, quality-of-life measures

Abnormal values associated with mortalityTreatment Determine stability for initiation and up-titration of β-blocker and

ACE-inhibitor therapyAssist in selection of drug agents and dosingMeasure response to adjustments in therapyDetermine need and optimal selection/dosing of IV therapy

(dobutamine, milrinone, nesiritide)Optimize LVAD settings and wean patients from LVAD supportDetermine optimal pacemaker settings in patients with AV sequential

pacemakersDetect hemodynamic changes due to compensation, medication, and

diet complianceProvide an adjunct to post-transplant myocardial biopsies

NYHA=New York Heart Association; ACE=angiotensin-converting enzyme; LVAD=left ventricular assist deviceAdapted from Yancy C, Abraham W. Noninvasive hemodynamic monitoring in heart failure: utilization of impedance cardiography. Congest Heart Fail. 2003:9(5):241–250.

Figure 5. Contributing elements to thoracic impedance. Z0=baseline impedance; ∆Z=change in impedance Adapted from Osypka MJ, Bernstein DP. Electrophysiologic principles and theory of stroke volume determination by thoracic electrical bioimpedance. AACN Clin Issues. 1999;10(3):385–399.

Heart rate Preload

Afterload

Contractility

Pulmonaryartery

compliance

Strokevolume

Aorticcompliance

Age

Arterial bloodpressure

Pulmonaryartery

compliance

∆Z(Systole)

Specificresistanceof thorax

Noncardiogenic pulmonaryedema

Cardiogenic pulmonary edema

Thoracic fluid content

Exercise

Specificresistanceof blood

Hematocrit

Orientation of erythrocytes

Emphysema

Posture

Blood volume

Venous return

Myocardialcompliance

Z0

Intrinsiccontractility

Body anatomy/composition


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Yung et al. (p. 7) validates the accu-racy of ICG in patients with pulmonary hypertension by comparing ICG to both direct Fick method and thermodilution

CO. In doing so, the authors demon-strate the potential hazard of using thermodilution as the only reference standard for CO measurement. Parrott

et al. (p. 11) compare changes in ejec-tion fraction by echocardiography to changes in ICG parameters in estab-lished HF patients. Their findings dem-onstrate the ability of ICG to simply and cost-effectively identify changes in ventricular function. While pulmonary artery catheterization in patients with HF has been criticized and is largely unproven by clinical trial, an estimated 2 million such catheters are sold world-wide each year.12 Springfield et al. (p. 14) illustrate the role of ICG in the differential diagnosis of patients with dyspnea. Although B-type natriuretic peptide testing has gained wide atten-tion recently as an aid to diagnose HF in the emergency department,13 ICG may also have a diagnostic role and provides additional value because of its ability to identify appropriate therapeutic options and monitor the response to therapy in real time. Silver et al. (page 17) report on the abil-ity of ICG to replace pulmonary artery catheterization, which has tremendous cost implications for hospitals caring for such patients. Vijayaraghavan et al. (page 22) demonstrate the prognostic role of ICG in patients with chronic HF, and show strong association of ICG changes to changes in functional status and quality-of-life measures. Summers et al. (page 28) provide a series of case reports that illustrate ICG’s prac-tical role in the initiation and titra-tion of neurohormonal agents and their patient-specific hemodynamic effects.

This compilation of studies adds to the growing body of data supporting the role of ICG in the management of patients with HF. Within a year, the results of two multicenter trials studying key roles for ICG should be available: PRospective Evaluation and identifica-tion of Decompensation by Impedance Cardiography Test (PREDICT), con-ducted in patients with chronic HF; and the BioImpedance cardioGraphy (BIG) substudy of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE).14 PREDICT specifically addresses the ability of ICG-derived hemodynamic data to

Figure 6. Fiducial points derived from electrocardiogram (ECG) and impedance waveforms. ∆Z=change in impedance; ∆Z/∆t=first derivative of the impedance waveform; PEP=preejection period; LVET=left ventricular ejection time

ECG

∆Z

∆Z/∆t

Q =Start of ventricular depolarization

B =Opening of pulmonicand aortic valves

C =Maximal deflection of the ∆Z/ ∆ t

X =Closure of aortic valve

Y =Closure of pulmonicvalve

O =Mitral opening/rapid ventricular filling

Figure 7. Impedance cardiography hemodynamic status report (BioZ ICG Monitor, CardioDynamics, San Diego, CA)


141 of 158.


identify patients at risk for death, hos-pitalization, or emergency department visit. The BIG substudy will evaluate the diagnostic and prognostic role of ICG in both arms of a randomized, controlled trial in pulmonary artery catheter–hemodynamic-guided man-agement of patients admitted with an acute episode of HF.

There is now a compelling body of literature that demonstrates the validity of ICG using the most current technol-ogy. More and more studies have shown the value of ICG in clinical settings in addition to HF, including dyspnea,15 hypertension,16 and atrioventricular sequential pacemakers.17 The studies presented in this issue of Congestive Heart Failure further define the role of this valuable, noninvasive technology in clinical medicine. It is likely that these and other studies of ICG in HF will be used to refine our understanding and ability to assess patients and predict prognosis, expanding on the concept of the four quadrants presented in Figure 2. The impact of adding ICG hemo-dynamic data to the four quadrants is depicted in Figure 9. Knowledge of stroke index, cardiac index, systemic vascular resistance index, and chang-es in fluid with thoracic fluid content would likely provide more quantitative, objective, and sensitive measurements of hemodynamic factors, and has signifi-cant implications for the management of patients with HF.

Incorporating this model of assess-ment into a proposed therapeutic algo-rithm is shown in Figure 10. Ideally, a baseline measurement of ICG in addition to other standard clinical variables would be collected and uti-lized in combination to more precisely assess a patient’s perfusion, conges-tion, and vasoactive status. This assess-ment would lead to a categorization of the patient’s absolute or relative change in hemodynamic profile, facili-tating assessment of short-term risk for adverse HF-related events. The change in hemodynamic status and assessment

of higher risk may lead to increased clinical surveillance or a decision to intervene to prevent a negative patient outcome. In addition, ICG parameters may aid in the assessment of a stable, low-risk hemodynamic profile toward the initiation and up-titration of neuro-hormonal agents that are often under-prescribed but are known to improve event-free survival.

Note: This supplement to Congestive Heart Failure contains articles dealing with ICG. Readers are reminded that positive statements about the clinical utility of ICG, and the BioZ ICG Monitor in particular, are solely the opinions of the authors and do not represent an offi-cial endorsement by Congestive Heart Failure, its Editors or Editorial Board, or the Heart Failure Society of America.

Figure 9. Model for clinical profiles in heart failure utilizing impedance cardiogra-phy hemodynamic measurements

Congestion at Rest

LowPerfusion

at RestCL

A B

Warm & Dry Warm & Wet

Cold & Wet

(Complex)(Low Profile)

Role of impedance cardiography

1. Establish baseline cardiac index (CI), systemic vascular resistance index (SVRI) and thoracic fluid content (TFC)2. Monitor changes in CI to objectify perfusion assessment3. Monitor changes in TFC to objectify congestion assessment4. Monitor changes in SVRI to objectify vasoactive status

NO

NO YES

YESCold & Dry

TFC TFC

CI

CI

SVRISVRI

Figure 8. Pharmacologic agent effect on cardiac output determinants and imped-ance cardiography parameters. CO=cardiac output; CI=cardiac index; HR=heart rate; SV=stroke volume; SI=stroke index; ∆TFC=change in thoracic fluid content; SVR=systemic vascular resistance; SVRI=systemic vascular resistance index; VI=velocity index; PEP=preejection period; ACI=acceleration index; LVET=left ventricular ejection time; STR=systolic time ratio

REFERENCES 1 Packer M. How should physicians view heart

failure? The philosophical and physiological evolution of three conceptual models of the disease. Am J Cardiol. 1993;71(9):3C–11C.

2 ACC/AHA guidelines for the evaluation and management of chronic heart failure in the

Afterload(SVR/SVRI)

Cardiac output(CO/CI)

Heart rate(HR)

Strokevolume(SV/SI)

Preload(∆TFC)

Contractility(ACI, VI, PEP,

LVET, STR)

(-) Diuretics(+) Volume Expanders

(-) Vasodilators(+) Vasoconstrictors

(-) Negative Inotropes(+) Positive Inotropes

(-) Neg. Chronotropes(+) Pos. Chronotropes


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adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice. J Am Coll Cardiol. 2001;38(7):2101–2113.

3 O’Connell JB. The economic burden of heart fail-ure. Clin Cardiol. 2000;23(3 suppl):III6–III10.

4 Heart Disease and Stroke Statistics—2003 Update. Dallas, TX: American Heart Association; 2002.

5 Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admit-ted with heart failure. J Am Coll Cardiol. 2003;41(10):1797–1804.

6 Shah MR, Hasselblad V, Stinnett SS, et al. Hemodynamic profiles of advanced heart failure: association with clinical character-istics and long-term outcomes. J Card Fail. 2001;7(2):105–113.

7 Sageman WS, Amundson DE. Thoracic elec-trical bioimpedance measurement of cardiac output in postaortocoronary bypass patients. Crit Care Med. 1993;21(8):1139–1142.

8 Marik PE, Pendelton JE, Smith R. A compari-son of hemodynamic parameters derived from transthoracic electrical bioimpedance with those parameters obtained by thermodilution and ventricular angiography. Crit Care Med. 1997;25(9):1545–1550.

9 Greenberg BH, Hermann DD, Pranulis MF, et al. Reproducibility of impedance cardiog-raphy hemodynamic measures in clinically stable heart failure patients. Congest Heart Fail. 2000;6(2):74–80.

10 Drazner M, Thompson B, Rosenberg P, et al. Comparison of impedance cardiography with invasive hemodynamic measurements in patients with heart failure secondary to ischemic or nonischemic cardiomyopathy. Am J Cardiol. 2002;89(8):993–995.

11 Kazuhiko N, Kawasaki M, Kunihiko T. Usefulness of thoracic electrical bioimpedance cardiography: noninvasive monitoring of car-diac output. J Card Fail. 2003;9(suppl):S170.

12 Ginosar Y, Sprung CL. The Swan-Ganz cath-eter: twenty-five years of monitoring. Crit

Care Clin. 1996;12:771–776. 13 Mueller C, Scholer A, Laule-Kilian K, et al.

Use of B-type natriuretic peptide in the evalu-ation and management of acute dyspnea. N Engl J Med. 2004;350:647–654.

14 Shah MR, O’Connor CM, Sopko G, et al. Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE): design and rationale. Am Heart J. 2001;141(4):528–535.

15 Peacock F, Summers R, Emerman C. Emergent dyspnea impedance cardiography-aided assessment changes therapy: The ED IMPACT trial. Ann Emerg Med. 2003;42(4):S82.

16 Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic man-agement to specialist care. Hypertension. 2002;39:982–988.

17 Santos JF, Parreira L, Madeira J, et al. Noninvasive hemodynamic monitorization for AV interval optimization in patients with ven-tricular resynchronization therapy. Rev Port Cardiol. 2003;22(9):1091–1098.

Figure 10. Therapeutic algorithm for incorporating impedance cardiography (ICG) parameters into clinical assessment of heart failure. SI=stroke index; CI=cardiac index; TFC=thoracic fluid content; SVRI=systemic vascular resistance index; ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin-receptor blocker

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Non-invasive measurement of cardiac output duringcoronary artery bypass grafting

Amram J. Cohena,c,*, Dimitri Arnaudovb,c, Deeb Zabeedab,c,Lex Schultheisd, John Lashingere, Arie Schachnera,c

aDepartment of Cardiovascular Surgery, The Edith Wolfson Medical Center, Holon, 58100 IsraelbDepartment of Anesthesiology, The Edith Wolfson Medical Center, Holon, 58100 Israel

cSackler School of Medicine, Tel Aviv University, Tel Aviv, IsraeldDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Center, Baltimore, MD, USA

eDepartment of Cardiovascular Surgery, Johns Hopkins Medical Center, Baltimore, MD, USA

Received 18 November 1997; revised version received 23 March 1998; accepted 15 April 1998

Abstract

Objective: A new device, using whole body bioresistance measurements and a new equation for calculating stroke volume has beendeveloped. Using this equation, an attempt was made to correlate whole body bioresistance cardiac output with thermodilution cardiacoutput in patients undergoing coronary artery bypass grafting. Methods: Thirty-one adults undergoing elective coronary artery bypassgrafting were studied prospectively. Simultaneous paired cardiac output measurements by whole body bioresistance and thermodilutionwere made at fiv time points during coronary artery bypass grafting: in anesthetized patients before incision (T1), after sternotomy (T2),after opening the pericardium (T3), ten min post bypass (T4), and in the intensive care unit (T5). The patients had a mean of threethermodilution cardiac outputs compared with a mean of three bioimpedance measurements at each time point. The bias and precisionbetween the methods were calculated. Results: There was good correlation between bioresistance cardiac output (nCO) and thermodilutioncardiac output (ThCO) measurements in both groups for all recorded times. The patients’ mean ThCO and nCO, as well as bias andprecision between methods were calculated. Mean ThCOranged between 4.14 and 5.06 l/min; mean nCOranged between 4.12 and 4.97 l/min. Bias calculations ranged between −0.072 and 0.104 l/min. Precision (2 SD) calculations ranged between 0.873 and 1.228 l/min for95% confidenc intervals. Pearson’s correlation ranged from 0.919 to 0.938. Conclusions: Cardiac output measured with the new devicecorrelates well with the thermodilution measurements of cardiac output during and immediately following coronary artery bypass grafting.The overall agreement between the two methods was good. The new device is an accurate non-invasive method of measuring cardiac outputduring coronary artery bypass grafting. 1998 Elsevier Science B.V. All rights reserved

Keywords:Cardiac output; Cardiac surgery; Thermodilution; Electrical bioimpedance; Bioresistance; Hemodynamics

1. Introduction

Hemodynamic monitoring continues to be an integral partof peri- and postoperative care for patients undergoing car-diac surgery. Cardiac output (CO) is an important parameterin these measurements. To date, the clinical tool used tomeasure CO is the Swan–Ganz catheter using a thermodilu-tion technique. However, the procedure is invasive, expen-sive, and may lead to complications [1,2].

A number of attempts have been made to determine COin a non-invasive manner [3–6]. Using thoracic electricalbioimpedance techniques (TEB), moderate success has beenachieved in some clinical settings [3,4,6–8]. The techniquehas been unsuccessful when applied to patients undergoingcardiac surgery [9–11]. A new non-invasive cardiac systemdevice has been developed to utilize whole body bioresis-tance in a semi-empirical formula to determine the CO.Accuracy of the CO measurement using this device wasestablished comparing thermodilution CO (ThCO) forpatients undergoing right and left heart catheterization[12]. The purpose of this investigation was to compare the

European Journal of Cardio-thoracic Surgery 14 (1998) 64–69

1010-7940/98/$19.00 1998 Elsevier Science B.V. All rights reservedPII S1010-7940(98)00135-3

* Corresponding author. Tel.: +972 3 5028723; fax: +972 3 5028735.

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new technology for measuring cardiac output with thermo-dilution measured CO in patients undergoing coronaryartery bypass grafting (CABG).

2. Patients and methods

2.1. Patients

Thirty-one patients undergoing elective, primary CABGwere prospectively studied; 15 at Wolfson Medical Centerand 16 at Johns Hopkins University School of Medicine.Patients with aortic valve insufficien y, mitral and tricuspidregurgitation or cardiac shunt were not included. TheCABG was similar in both hospitals. All patients underwenta median sternotomy. Cardiopulmonary bypass was estab-lished using an aortic and single venous cannula. Diastolicarrest was achieved with cold sanguineous potassium cardi-oplegia in both antegrade and retrograde fashion. The inter-nal mammary artery was used to graft the left anteriorcoronary artery (LAD) in all cases, and saphenous veingrafts were used to bypass the other obstructed vessels.Proximal anastomoses were performed using a partialcross clamp. During the study, no patient had atrial fluttenor atrial fibrillation

2.2. Protocol

The study protocol was approved by Edith Wolfson andJohns Hopkins Institutional Review Boards. For eachpatient demographic and clinical data was tabulated. Ineach patient, CO measurements were taken at fiv differenttime intervals during the procedure; after induction ofanesthesia but before incision (T1), after sternotomy (T2),after creation of a pericardial pocket (T3), ten min afterweaning from bypass (T4), and immediately after arrivalin the intensive care unit (T5).

At each time interval, three adequate thermodilution mea-surements were made. All measurements were made at endexpiration during the respiratory cycle. Thirty-one patientsunderwent 155 thermodilution CO measurements. Nineteenwere excluded because of 10% variation between the mea-surements. Simultaneously, three bioresistance measure-ments were taken at each interval, and their average wasconsidered the bioresistance CO.

Each bioresistance measurement took 20 s. Since thesemeasurements were continuous, there was no time betweenmeasurements such that to achieve an average bioresistanceCO measurement took 1 min.

2.3. Thermodilution method

At both hospitals seven French true size thermodilutioncatheters (Baxter Healthcare, Irvine, CA) were inserted inthe operating room after induction of anesthesia. Theproper location of the thermodilution catheter was con-

f rmed by hemodynamic measurements and by post-operative chest roentgenograms. The pulmonary arterycatheter was connected to a thermodilution cardiac outputmonitor (‘Horizon 2000’, Mennen Medical, Israel was usedat Wolfson Medical Center, and 7010 Series Marquette,Madison, WI at Johns Hopkins Institutions). Ten millilitersof room temperature 5% dextrose solution was injectedmanually at end-expiration by an experienced anes-thesiologist who was unaware of the bioresistance COresults.

2.4. Whole body resistance method

NICaSy 2001, a non-invasive cardiac system device(NICaSy 2001, Teledyne-NIM, LLC, North Andover,MA, 510K, certificat number K942227), was utilized formeasuring bioresistance CO. Two proprietary designed,NICaSy disposable electrodes (510K, certificat numberK972002) were applied to each wrist, and were then con-nected to the non-invasive cardiac system device. The sys-tem passed an AC current 30 kHz and 1.4 mA through thewhole body. It then measured the resistive portion of thebioimpedance. Since the electrodes were placed on the dis-tal aspect of the extremities, the current passed through allmajor arteries and veins of the systemic circulation. Assuch, the system measured the bioresistance of the systemiccirculation and allowed calculation of the stroke volume.

In 1992, Tsoglin and Frinerman and developed a newsemi-empirical formula for calculating the stroke volume(SV) [13].

SV=Hctcorr

Ksex, age× kel × Kweight × IB ×

H2corrDR

R×

a + b

b

where Kel is a coefficien related to blood electrolytes,Kweight is a ratio of a patient’s weight to ideal weight, IBis the index balance equal to the ratio of the measuredextracellular flui (as measured from the baseline impe-dance) to the expected extracellular flui volume, HCTcorris a hematocrit correction factor proportional to measuredhematocrit, Ksex,age is a coefficien depending upon apatient’s sex and age, H is a patient’s height, DR is theincremental change of the resistive portion of the bioimpe-dance, R is the baseline whole body bioresistance anda + b/b is the ratio of the sum of the systole time plusdiastole time divided by the diastole time derived fromthe fin structure of the varying portion of the bioresistance.

Using whole body resistance measurements and theabove formula, SVwas calculated and converted to CO.

2.4.1. Statistical analysisThe correlation between methods at each time point was

evaluated by Pearson’s correlation coeff cient and simplelinear regression. The degree of agreement between meth-ods at each time point was evaluated by calculation of thebias (mean between-method difference) and precision(mean bias ±2 SD) [14].

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3. Results

Thirty-one patients were evaluated in the study. Demo-graphic and clinical data are shown in Table 1. The agree-ment between the average CO measured by bioresistanceversus thermodilution is shown in Table 2. The plot of theregression analysis and difference versus mean for all mea-surements at all times in the 31 patients is shown in Fig.1a,b. There was good correlation between ThCOand nCOranges of cardiac output during all phases of CABG and theimmediate postoperative period.

4. Discussion

The initial attempt to obtain CO by measuring the strokevolume (SV) through thoracic electrical bioimpedance(TEB) was performed by Kubicek [15] at the National Aero-nautics Space Agency (NASA) where he introduced theequation that became the basis for bioimpedance cardiogra-phy:

SV= r((dZ=dt)) × ((L2T))=(Z20 )

where SV is related to the resistivity of blood (r), dZ/dt isthe firs peak of the derivative of the bioimpedance curve, Lis the distance between the electrodes, Z0 is the mean timeaveraged thoracic bioimpedance and T is the ventricularejection fraction.

The equation was modif ed by Bernstein [16] to:

SV= VEPT × (( dZ=dt)=Z0)T

where VEPT is a coeff cient that represents the volume ofelectrically participating tissue. Using this equation, limitedclinical success has been achieved in determining CO usingbioimpedance techniques. Correlation to thermodilutiontechniques have been achieved in healthy volunteers,patients undergoing operations without cardiopulmonarybypass, patients undergoing procedures in the cardiaccatheterization laboratory, and small numbers of intensivecare unit patients [3,4,7,17–20].

This equation has been problematic due to diff culties inaccurately computing VEPT, and its application becomesimpractical in a patient undergoing rapid hemodynamicchanges. Furthermore, determination of VEPTis dependentupon the accurate placement of electrodes, which is notalways possible during open heart surgery. In addition,this equation still depends upon the firs derivative of thebioimpedance curve, which is a rapidly fluctuatin factor.As a result, attempts to correlate bioimpedance CO in thepatient with thermodilution techniques during CABG havebeen unsuccessful [9,10].

In addition to practical problems, there is a conceptualproblem in applying TEB to measure stroke volume. TEBmeasurements of the bioimpedance includes both systemicand pulmonary circulations. The two circulations cannot beseparated by measurements and variation in proportion ofthese circulation will lead to inaccurate measurements of SV[21,22]. This will not happen in whole body bioresistancemeasurements where the systemic circulation dominates themeasurement and reflect LV SV.

The physiological and physical basis of bioimpedancehas been studied by many authors [23–25]. However, thevariation between different tissues and their complex struc-tures make it difficu t to model their electrical behavior. Interms of bioresistance, the body may be divided into the‘blood compartment’ and ‘tissue compartment’. In the

Table 1Patient demographic and clinical data

Wolfson MedicalCenter

Johns HopkinsMedical Center

Males (N) 11 13Females (N) 4 3Average age (years) 63.26 ± 9.94 64.2 ± 9.37Minimum age (years) 46 51Maximum age (years) 79 81Average weight (kg) 73.13 ± 14.74 87.14 ± 13.29Minimum weight (kg) 42 59Maximum weight (kg) 102 108Average height (cm) 166.3 ± 10.4 176.92 ± 8.96Minimum height (cm) 140 160Maximum height (cm) 183 185Temperature (°C)a 26.8 ± 0.77 25.56 ± 0.403Number of vessels bypassed 3.33 ± 0.96 2.55 ± 0.73Diabetes (%) 46.67 18.75Hypertension (%) 53.33 56.25

aLowest temperature during the operation.

Table 2Agreement of CO by NICaS and thermodilution measurements (n = 31)

Time MeanThCO

MeannCO

R/R2 Regressionslopea

SEE y intercept Bias (mean between-method difference)(l/min)

Precision mean ± 2SD (l/min)

After anesthesia 4.19 4.19 0.93/0.86 1.128 0.328 −0.529 0.0086 −1.113–1.131After sternotomy 4.14 4.12 0.92/0.85 0.898 0.185 0.404 −0.019 −0.863–0.823After pericardiotomy 4.14 4.24 0.93/0.86 0.915 0.326 0.456 0.104 −1.015–1.223Immediately after bypass 5.06 4.97 0.92/0.85 0.967 0.367 0.324 −0.0483 −1.234–1.138ICU admission 4.71 4.62 0.94/0.88 0.891 0.306 0.424 −0.072 −1.156–1.012

SEE, standard error of the estimate; ICU, intensive care unit.ay, cardiac output by NICaS 2001 bioimpedance; x, cardiac output by thermodilution.

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‘blood compartment’, conductivity is high and therefore acurrent introduced into the body will travel primarily in thiscompartment. The resistance changes in this compartmentas the blood volume varies in the great arteries due to pul-satile flow In the ‘tissue compartment’, there is less signif-

icant current flo and constant resistance. In eachindividual, the resistance in the ‘tissue compartment’ isdetermined by the patient’s height, lean body weight (mus-cle) to fat ratio, sex, age, body build, extracellular fluivolume, and electrolytes. In the ‘blood compartment’, the

Fig. 1. (a) Linear regression analysis comparing bioresistance measured cardiac output with thermodilution cardiac output for all averaged measurements inthe study. (b) Mean difference between bioresistance measured cardiac output and thermodilution cardiac output for all averaged measurements in the study.


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resistance is determined by hematocrit, electrolytes and thepulsatile blood volume changes within the system. To mea-sure SV, the pulsatile changes within the blood compartmentand baseline bioresistance must be measured accurately andall other factors must be accounted for with appropriatecorrection factors. The measurement of whole body biore-sistance allows for the accurate measurement of pulsatilechanges and baseline resistance, and the proposed correc-tion factors allow for the accurate calculation of the sys-temic bioresistance with which accurate LV SV can becalculated.

The method utilized in this study has been proven accu-rate in patients undergoing catheterization [12]. It was alsoshown to be accurate in a pilot study in patients under-going CABG [26]. Compared with previous attempts tocorrelate bioresistance with SV, the equation has majoradvantages.

1. The equation does not depend on rapidly fluct atingtime derivatives of bioimpedance.

2. The equation uses empirically derived coeffici nts thatare obtained from laboratory values and simultaneouslymeasured bioimpedance values instead of the artifi ialand difficu t to approximate VEPT.

3. The precise placement of the electrodes is not a criticalfactor.

4. The NICaSy electrode arrangement is optimal to mea-sure the left ventricular SV.

5. The respiration has almost no effect on the NICaSy COmeasurements in real time.

The new methodology showed good correlation betweenthermodilution and bioresistance CO during all phases ofCABG and the immediate postoperative period in two inde-pendent hospital populations. Correlation was good in allranges, including low cardiac output. This fact is importantsince patients undergoing CABG frequently have low car-diac output. This was even true in the immediate post car-diopulmonary bypass period where changes in the patients’volume status, temperature, blood electrolytes and hemody-namics are changing rapidly. Such a correlation would beimpossible using previous techniques.

The new device has certain limitations. First, it cannotmeasure CO while using diathermy. Second, the device issensitive to movement so that the patient cannot be manipu-lated while the CO is being measured. These two factorsrequire that the operation stop for the 20–30 s required tomeasure CO. Finally, the device measuresSVand multipliesit by heart rate to measure CO. Arrythmias in which theheart rate varies signific ntly will result in a non-represen-tative measurement of CO.

In summary, a new device using a semi-empirical equa-tion relating SV to changes in the resistive portion of thepatients’ bioresistance has been developed. Informationabout specif c patient data, blood components and bodyhabitus inserted into the analytical software has signific ntlyimproved the ability to calculate SVfrom the bioresistance

data. The device allows accurate, easy to obtain, non-inva-sive CO during cardiac surgery. Within the above statedlimitations, we have confir ed the validity of the new biore-sistance methodology in 31 patients who underwent CABG.Bioresistance measured cardiac output correlated well withThCOduring the CABG procedure and the immediate post-operative period.

Acknowledgements

This paper was prepared in consultation with DiklahGeva who prepared the statistical calculations, and withthe technical assistance of Sally Esakov.

References

[1] Mermel LA, Maki DG. Infectious complications of Swan–Ganzpulmonary artery catheters: pathogenesis, epidemiology, prevention,and management. Am J Respir Crit Care Med 1994;149:1020–1036.

[2] Choh JH, Khazei AH, Ihm HJ, Thatcher WC, Batty PR. Catheterinduced pulmonary arterial perforation during open heart surgery. JCardiovasc Surg (Torino) 1994;35:61–64.

[3] Denniston JC, Maher JT, Reeves JT, Cruz JC, Cymerman A, GroverRF. Measurement of cardiac output by electrical impedance at restand during exercise. J Appl Physiol 1976;42:91–95.

[4] Smith SA, Russell AE, West MJ, Chalmers J. Automated non-inva-sive measurement of cardiac output: comparison of electrical bioim-pedance and carbon dioxide rebreathing techniques. Br Heart J1988;59:292–298.

[5] Reybrouck T, Fagard R. Assessment of cardiac output at rest andduring exercise by a carbon dioxide rebreathing method. Eur Heart J1990;11 (suppl I ):21–25.

[6] Belardinelli R, Ciampani N, Costantini C, Blandini A, Purcaro A.Comparison of impedance cardiography with thermodilution anddirect Fick methods for non-invasive measurement of stroke volumeand cardiac output during incremental exercise in patients withischemic cardiomyopathy. Am J Cardiol 1996;77:1293–1301.

[7] White SW, Quail AW, DeLeeuw PW, Traugott FM, Brown WJ,Porges WL, Cottee DB. Impedance cardiography for cardiac outputmeasurement: an evaluation of accuracy and limitation. Eur Heart J1990;11 (Suppl ):79–92.

[8] Teo KK, Hetherington MD, Haennel R, Greenwood PV, Rossall RE,Kappagoda T. Cardiac output measured by impedance cardiographyduring maximal exercise tests. Cardiovasc Res 1985;19:737–743.

[9] Sageman WS, Amundson DE. Thoracic electrical bioimpedancemeasurement of cardiac output in postaortocoronary bypasspatients. Crit Care Med 1993;21 (8 ):1139–1142.

[10] Clarke DE, Raffi TA. Thoracic electrical bioimpedance measure-ment of cardiac output – not ready for prime time. Crit Care Med1993;21 (8 ):1111–1112.

[11] Thomas AN, Ryan J, Doran BR, Pollard BJ. Bioimpedance versusthermodilution cardiac output measurement: the Bomed NCCOM3after coronary bypass surgery. Intensive Care Med 1991;17 (7):383–386.

[12] Miller HI, Frinerman E, Tsoglin A, Frinerman A, Rosenschein U,Keren G, Roth A, Laniado S. Non-invasive bioimpedance measure-ment of cardiac output: a validation study (Abstr). Second Confer-ence of the Israel Heart Society, 1993:58.

[13] Tsoglin, A., Frinerman, E, N.I. Medical, Ltd. Non-invasive methodand device for collecting measurements representing body activity

68 A.J. Cohen et al. / European Journal of Cardio-thoracic Surgery 14 (1998) 64–69

148 of 158.

and determining cardiorespiratory parameters of the human bodybased upon the measurements collected. US Patent No. 5,469,859,Nov. 28 1995.

[14] Bland, J.M., Altman, D.G. Statistical methods for assessing agree-ment between two methods of clinical measurement. Lancet1986;Feb 8–1(8476):307–310.

[15] Kubicek WG, Patterson RP, Witsoe DA. Impedance cardiography asa non-invasive method of monitoring cardiac function and otherparameters of the cardiovascular system. Ann NY Acad Sci1970;170:724–729.

[16] Bernstein DP. A new stroke volume equation for thoracic electricalbioimpedance: theory and rationale. Crit Care Med 1986;14:904–909.

[17] Donovan KD, Dobb GJ, Woods WP, Hockings BE. Comparison oftransthoracic electrical impedance and thermodilution methods formeasuring cardiac output. Crit Care Med 1986;14:1038–1044.

[18] Salandin V, Zussa C, Risica G, Michielon P, Paccagnella A, CipolottiG, Simini G. Comparison of cardiac output estimates by thoracicelectrical bioimpedance, thermodilution and Flick methods. CritCare Med 1988;16:1157–1158.

[19] Thomas SHL. Impedance cardiography using Sramek-Bernsteinmethod: accuracy and variability at rest and during exercise. Br JClin Pharmacacol 1992;34:467–476.

[20] Wong DH, Onishi R, Tremper KK, Reeves C, Zaccari J, Wong AB,Miller JB, Cordero V, Davidson J. Thoracic bioimpedance and Dop-pler cardiac output measurement: learning curve and interobserverreproducibility. Crit Care Med 1989;17:1194–1198.

[21] Fuller HP. Evaluation of left ventricular function by impedance car-diography: a review. Prog Cardiovasc Dis 1994;36:267–273.

[22] Patterson RP. Sources of the thoracic cardiogenic electrical impe-dance signal as determined by a model. Med Biol Eng Comput1985;23:41–417.

[23] Karnegis JN, Kubicek WG. Physiological correlates of the cardiacthoracic impedance waveform. Am Heart J 1970;79:519–523.

[24] Sakamoto K, Muto K, Kanai H, Iizuka M. Problems of impedancecardiography. Med Biol Eng Comput 1979;17:697–709.

[25] Paul E, Marik MD, Judy E. A comparison of hemodynamic para-meters divided from transthoracic electrical bioimpedance with thoseparameters obtained by thermodilution and ventricular angiography.Crit Care Med 1997;25:1545–1550.

[26] Cohen A, Frinerman E, Katz M, Ezra S, Dotan A, Weissberg A,Schachner A. Validity of bioimpedance hemodynamic measurementsduring coronary artery bypass grafting (CABG) (Abstr). J CardiovascDiag Proc 1996;13:57.


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EVALUATION AND MANAGEMENT OF THE ELDERLY HOMEBOUND

PATIENT WITH CONGESTIVE HEART FAILURE

C. Gresham Bayne MD BACKGROUND: The frail elderly patient population is characterized not only by age demographics, but by the inadequacy of the office-based medical model to meet their needs when they can no longer reach the physician’s office on a regular basis. In addition, we are often called to see the new patient with presenting symptoms of heart failure precipitated by one of many proximate causes. Congestive Heart Failure (CHF) is the leading cause for hospitalization after the age of 65. There are one million admissions for CHF annually with 80% of the patients over 65 years of age. CHF is the most costly DRG in the United States with annual costs exceeding $10 billion. The incidence and prevalence of CHF are rising in the population with prevalence doubling each decade after age 45. The one year survival for Class III and IV CHF elder patients is still only about 60%. The best objector predictor for survival has been the cardiothoracic ratio on standard chest Xray. There is a close and perhaps causative relationship between hypertension and CHF in the elderly due to the complex neurohormonal reflexes involved (see below). As people age the cardiovascular system normally increases its electrical impedance, has lowered beta-adrenergic responsiveness, alters its myocardial energy metabolism, with the heart usually showing impaired diastolic relaxation and compliance. The net effect is a marked reduction in the cardiovascular reserve. PRECIPITATING EVENTS: These precipitating events must be evaluated first, before the patient’s failure can be addressed. The most common of these is the failure to take their medications due to financial, social, or cognitive problems. Despite the medication failure, the benefit might be afforded us to switch them to the more acceptable geriatric approach to congestive heart failure than has often been the case in the past. Briefly stated, the philosophy of treatment has changed dramatically in past years from a diuretic-based ramp-up to the primary use of ACE inhibitors and other afterload reducers. This modern approach will be discussed more fully later. Other precipitating factors common to our population include anemia, hyperthyroidism, infection, new onset arrhythmias such as atrial fibrillation, change in diet, silent myocardial infarction, worsening valvular disease, inappropriate use of the sodium-retaining NSAIDS, and environmental changes such as increased ambient humidity or temperature, and stress. Obviously, these historical and clinical factors must be evaluated in perspective. The absence of a readily available medical records and EKG/Xray documentation mandates the use of appropriate technology when patients present with symptoms suggestive of failure. Even in non-acute settings, the ability to have local physicians copy

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and send forward medical records is so remote, it should not be anticipated that a chart is forthcoming. In fact, many of the patients will be well-served by an entirely new approach to their clinical symptoms, especially those on multiple medications. Obviously, precipitating causes should be addressed before redirecting the primary interest in care to the failure itself. PHYSIOLOGY REVIEW: The function of the heart is to pump arterialized blood forward under sufficient pressure to meet the peripheral tissue metabolic needs. Given adequate oxygenation and a normal hemoglobin, the cardiac output, defined as the pulse times the stroke volume, should pump enough blood to prevent angina (ischemia to the heart), cold knee caps (ischemia to the skin), oliguria or azotemia (ischemia to the kidney) and confusion (ischemia to the brain). Thus, a quick iSTAT and pulse oximetry is required to rule out azotemia, hypoxemia, and a metabolic acidosis demonstrated by the base deficit. Even a venous sample with a normal base excess is adequate to prove the absence of a low perfusion state. NOTE that the above definition of inadequate cardiac output (CO) did NOT mention the blood pressure at all! In fact, the only time hypotension is an emergency for bedbound patients is when the diastolic pressure is below 60 mmHg and the patient experiences angina or failure symptoms. Since coronary arterial blood flow is 85% during diastole, the aortic root pressure is critical in determining myocardial perfusion. Thus, in the emergency room, some patients in shock with angina find that dopamine is the best analgesic! To evaluate the failing heart, one needs to think in terms of myocardial efficiency, NOT blood pressure. Efficiency of the heart is measure in terms of Oxygen Demand by the heart as balanced against the Stroke Work Index. We will first address the Oxygen Demand, which is determined by five factors, of which only three are clinically relevant: the pulse, the mean arterial pressure and the wall tension index (as measured by the CXR assessment of cardiomegaly). Myocardial oxygen demand is linearly increased as the pulse increases over 100, dramatically increased by mean arterial pressure (usually estimated by a value one-third the distance between the diastolic and systolic pressures), and increases despite the same cardiac output with increases in the left ventricular end-diastolic volume (cardiomegaly). Thus, the patient with a pulse of 110, a blood pressure of 140/100 and cardiomegaly on CXR is demanding much more oxygen for their heart than a patient of normal heart size and vital signs. When the presenting symptoms include angina, the approach to failure is first to treat the increased demand by using nitrates or nifedipine to lower the MAP, slow the pulse, and vasodilate the coronary arteries. Once stabilized, the failure may be addressed.

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Stroke Work Index (SWI) is a complicated clinical measurement requiring the use of a pulmonary arterial catheter, but can be thought of in clinical terms quite simply. Remember, the heart does not have to create higher than normal pressures to increase its cardiac output (CO) if the peripheral vascular resistance (PVR) is reduced. The SWI is calculated basically by multiplying the cardiac output times the PVR. The human heart is a very efficient flow generator, but a very inefficient pressure generator. Thus, oxygen demand to increase cardiac output is efficiently handled, but requirements for hypertension are disastrous. It is important to note that the failing heart may, due to its inefficiencies and maladaptive neurohumoral reflexes, simply increase the blood pressure without generating much increase in the CO. Thus, hypertension is the enemy of both ischemic heart disease and congestive heart failure. The physiological changes in the elderly which occur in the chronic state of heart failure are numerous and complex. They include:

1. Increased renin levels, which increases the conversion of Angiotension I to Angiotension II, the most potent vasoconstrictor known

2. Increased renin levels promoting the kidney to increase aldosterone leading to increased retention of sodium and water

3. Increased adrenergic background tone by the adrenal cortex with elevated circulating norepinephrine levels and inappropriate hypertension

4. Decreased levels of adenyl cyclase leading to decreased levels of cyclic AMP which can lead to lower protein kinase, calcium entry levels and calcium re-uptake by the myofibrils

The net result is a chronic “fight or flight” background level of physiologic stress which ultimately leads to cardiac failure. I think of my elderly patients as on an endogenous catecholamine drip producing more hypertension than forward flow. Since it is unlikely that the patient will ever be “normal,” it is useful to think in terms of therapy to maximize forward blood flow at the lowest physiologic cost. TREATMENT PRINCIPLES: To maximize the cardiac output, we typically intervene with the three major forces we can easily effect with medication: Preload, Contractility, and Afterload. Preload: The hypovolemic patient may be in shock or hypotensive simply because of fluid depletion. This is often easily discerned by the history, physical and iSTAT testing, but often problematic in the bedbound, demented patient. The hypervolemic patient is often much harder to evaluate, since chronic rales, interstial lung disease, emphysematous changes, obesity, patient intolerance to the exam, may all affect our confidence level. Therefore, some simple in-home testing may be useful. The CXR showing cardiomegaly is strong support for a chronic hypervolemic state and elevated left ventricular filling pressures. The presence of LVH or left ventricular strain pattern in the EKG (R waves in V5 and V6 add up to more that 25mv) is often associated with overload.

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A final test, done only in the normotensive or hyptertensive patient, is the so-called “Chatterjee” test when one monitors the pulse before and after a single dose of sublingual nitroglycerine. Since NTG predictably lowers the pulmonary capillary wedge pressure (PCWP) (left ventricular filling pressure), the hypervolemic patient will NOT have a tachycardic change in pulse with NTG. The normal or hypovolemic patient will increase their pulse by 10% or more. Thus, the absence of tachycardia in response to NTG is de facto evidence of increase PCWP and indicates the need for (temporary) diuresis. The use of nitrates alone to control preload and subsequent CHF symptoms is complicated by the tolerance that all patients develop for the longer acting versions. The use of nitrates in the elderly is most often useful on the acute housecall when the patient has suddenly decompensated and has hypertension in addition to the symptoms of CHF. One must be cautious in the home when using nitrates to be able to place the patient in recumbency before administration, as the “nitrate syncope” syndrome is much more likely in our patients. The use of diuretics has been the mainstay of treatment for both hypertension and failure for some forty years, despite the fact that diuretics have yet to be shown in controlled prospective clinical trials to increase survival rates. Currently, some 35-40% of all seniors over the age of 65 are taking a diuretic in some form. However, cumulative studies are now overwhelming in their condemnation of the indiscriminate application of either loop or thiazide diuretics due to the following known side effects:

1. 60% of all toxic drug reactions are due to diuretics in the elderly 2. diuretics are the most common drug reaction requiring hospitalization 3. both types cause increased serum cholesterol, although subsequent cardiac

disease is unproven 4. both cause increased uric acid levels with subsequent tophaceous gout 5. both cause glucose intolerance in Type 2 prone patients, and the instigation of

Type 2 diabetes is NOT reversible by stopping the diuretic (bumex less than lasix)

6. both cause deafness, even in chronic oral dosing regimes (bumex less than lasix)

7. both cause decreased calcium absorption and worsen osteoporosis (loop worse than thiazides)

8. both cause behavioral risks with incontinence in the female, urinary retention in the male

9. both can lead to hyperkalemia in the elderly as well as hypokalemia 10. both can cause severe hyponatremia in the elderly

Thus, the use of diuretics is now considered second or third line therapy, after more contemporary treatment for both hypertension and/or failure has failed. Contractility: The state of inotropy of the heart in failure patients is compromised by many of the maladaptive neurohormonal changes discussed above as well as the loss of cardiac tissue from current ischemic heart disease and past infarcts. Unfortunately, the

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use of phosphodiesterase inhibitors in the elderly to increase inotropy has been clinically unsuccessful and the use of adrenergic agents such as dopamine and dolbutamine requires monitoring and infusion therapy along with the hassles of an intravenous. Early studies on NY Stage IV CHF patients on home dobutrex drips have prolonged life but at a significant cost on the quality of life. What we have learned in the ICU from the two adrenergic agents in most common use today is important. Whereas, dopamine causes a more potent increase in inotropy and blood pressure, it has little or no effect on PCWP, increases ventricular irritability, and requires much more care. Dolbutamine, on the other hand, not only has less toxicity at the same cardiac output, but lowers the PCWP dramatically, thereby restoring the normal cardiac anatomy and reducing myocardial oxygen demand. To reduce the oxygen demand of the heart, the eighties and early nineties saw an increase in the use of beta blockers even in failure patients. Unfortunately, the use of beta blockers to control hypertension in the elderly involves much more toxicity, and (other than post MI) has shown to increase mortality due to side effects, including an increase in cholesterol for all age groups. The use of digoxin remains controversial in patients without the need for rate control in atrial fibrillation. Although digoxin is the oldest and most proven inotropic agent, and the only one which does so while decreasing the wall tension index (cardiomegaly), its toxicity and need for periodic serum measurements makes it of much more problematic in the demented, homebound elderly CHF patient. A NEJM study in 1997 on Class II or III CHF patients showed no change in mortality with digoxin therapy in addition to ACE inhibition (see below), but a significant improvement in functional status and decrease in hospital days. Most patients with an ejection fraction of over 45% will do well on digoxin alone for control of symptoms of CHF. Obviously, the ability to measure directly an improvement in cardiac output with digitalis would allow better patient selection in the future. Suffice to say, patients with cardiomegaly and/or a S3 gallop should have a trial on digoxin alone before using multiple drug regimes. Finally, no one argues about the use of digoxin to control rapid ventricular response in the patient with atrial fibrillation. Afterload: If the SWI can be reduced by reducing the MAP, one might be able to both increase the forward flow of blood (CO) as well as decrease the myocardial oxygen demand. This would be the best of both worlds! Indeed, we now know that peripheral vasodilatation has less morbidity and better survival rates with better functional status than conventional beta blocker/diuretic regimes. The geriatric meetings are replete with studies confirming the observation that the ACE inhibitors by themselves can often control hypertension and should be used for patients with risk of CHF (such as LVH or cardiomegaly on CXR), and especially diabetics even when they are asymptomatic.

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By using ACE inhibition at lower doses beginning at night, one can often avoid orthostatic hypotension and preserve the peripheral vasomotor reflexes so important to prevent side effects. Many patients can be converted from 2-4 older medications (digoxin, lasix, KCL, tenormin) to a single dose of benzapril 10 mg hs. Titrating the benzapril up to 80 mg daily may control the blood pressure while relieving the symptoms of failure as well. The therapeutic effects must be evaluated by the patient’s subjective reports of exercise tolerance or orthopnea, as well as objective weights. If CHF is to be controlled on ACE inhibitors alone, the patient will lose weight on it. In addition, the Cooperative North Scandinavian Enalapril Survival Study showed that ACE inhibition improves symptoms and exercise tolerance, while affording significant survival benefits among patient with severe CHF. These agents not only decrease afterload, but preload as well, and deter activation of the neuroendocrine system leading to reduced risk of hypertensive episodes, stress reduction, less fluid retention, and perhaps less arrhythmogenicity. Before reverting back to the diuretics which some patients simply must have, adding a calcium channel blocker in angina patients or alpha receptor blockade may be useful to improve inotropy by increasing coronary blood flow and further decreasing the peripheral vascular resistance. In addition, the newer calcium-channel blockers such as amlodipine have been shown to increase end-diastolic ventricular relaxation, promoting ventricular filling and increasing stroke volume at the same filling pressures. Once the afterload is under control, the SWI is decreased enough to usually require no further therapy requirements for heart failure. Of course, if you cannot know the cardiac output, you cannot calculate afterload, so using BP as a surrogate if fraught with undertreatment biases. Should further therapy be required, a diuretic may be cautiously introduced since their effect is additive to both ACE inhibition and calcium channel blockade. What has been lacking in both the critical care and outpatient arenas is an ability to know the systemic vascular resistance. Thus, we are still basing our clinical decisions on non-physiological parameters: i.e., mean arterial pressure. Although MAP may be a useful guideline for stroke prevention, many patients with borderline /low cardiac outputs have normotension while their SVR is markedly elevated. We cannot know this without measurement of the cardiac output, which heretofore has been invasive and expensive with the pulmonary arterial catheter. The advent of non-invasive, inexpensive cardiac impedance studies in the outpatient and other settings has opened up a dramatic opportunity to not only titrate therapies toward maximum lowering of the SVR to improve cardiac output, but also to titrate therapies both acutely and chronically toward the best cardiac efficiency factors, since impedance can track the pre-ejection period and minimize isovolumetric contraction time. The Use of Cardiac Impedance in the Home-Bound Patient Background: For over twenty-five years it has been possible to provide a non-invasive monitoring system capable of measuring the trends in cardiac output, stroke volume,

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ejection fraction and total intra-thoracic fluid. Since the chest is essentially a box containing a variable amount of non-conducting air in the lungs and airways, and a variable amount of salt water in tissue and blood, measuring the resistance to the flow of electricity through the chest should correlate to fluctuations in air and/or fluid. In fact, this measurement, known as impedance, can easily be measured across the chest by a series of paired electrodes placed on the neck and lateral chest wall. The static values measured on an insensitive scale correlate to Total Fluid Content or TFC of the chest and will change over time with things like pleural effusions, extravascular lung water, and congestive heart failure. Using a very sensitive scale, one can see alterations in impedance conforming to the pumping action of the heart during each systole. Since the heart pumps blood out of the chest once the aortic valve opens, the velocity of this pumping action can be calculated from the first derivative of impedance or dZ/dT. The peak value of dZ/dT correlates closely with the stroke volume (SV) of each heartbeat. Since the cardiac output is easily calculated by multiplying the SV time heart rate, one can watch online as therapies affect the cardiac output. In the 1960’s impedance research was done primarily in Israel where engineers were best in signal acquisition technology or Russia, where cognitive strengths were focused on complex algorithms to reduce the signal noise from motion or respiratory artifact. Recently, a combination of these talents has come together to produce an FDA-approved non-invasive, whole-body impedance measurement which has the distinct advantage of not having to undress female patients (electrodes are placed on two extremities). There continues to be controversy over which is “best,” trans-thoracic or whole body impedance. In addition, there remains argument over which proprietary algorithm should be used. Proponents of the Sramek Equation believe selecting the single best systole for detailed examination and reporting is superior to averaging data from many systolic waveforms during a one minute sample (for example) analyzed by the Kubicek Equation. The second derivative of impedance varies with the acceleration of the blood as it exits the left ventricle and correlates closely with the inotropic state of the heart. Since electrodes can easily sense the EKG tracing of a patient, one can pinpoint the R wave and measure the time between the initiation of systole and the time when the aortic valve opens, sensed as the onset of the acceleration of blood or the second derivative of impedance. This period is called the PEP or Pre-Injection Period, a time when the heart is maximally consuming oxygen during systole, but doing no useful work, since no bloodflow has yet occurred in the aorta. The longer the PEP, the more inefficient the heart is for any given cardiac output. Examples of clinical conditions which prolong the opening of the aortic valve or PEP are hypertension, myocardial dyskinesis, ventricular aneurysm, and aortic stenosis. Finding the maximum cardiac output for the minimum PEP has now become routine in setting time intervals for two channel pacemakers. Since the closing of the aortic valve is also marked by an abrupt deceleration of blood flow in the aorta, one can use impedance to mark the closure of the aortic valve. Thus, the LVET, or Left Ventricular Ejection Time, when the left ventricle is actually pumping

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blood, can now be tracked with non-invasive monitoring. More importantly, it turns out that clinical studies of patients with heart disease, including mitral valve disease and atrial fibrillation, have shown an extremely close inverse correlation of the left ventricular ejection fraction and the PEP/LVET ratio. Clinical Significance in the Home Bound Patient: Many patients over the age of 80 are not only homebound, but extremely demented and frail. Not only do they have a high prevalence of congestive heart failure, the number one cause of death in the elderly, but they cannot get to the cardiologist for appropriate studies. Even if they could, they cannot tolerate a treadmill or other means of evaluating their heart. For those that can make it to the cardiologists office, Medicare policy limits payment for the gold standard of doppler ultrasound to annual usage in most cases. Thus, the reality is that the homebound patient is usually not followed objectively in the management of their cardiac function during therapeutic changes directed at blood pressure or congestive heart failure. It is clear now that afterload and CHF control are critical to maximizing both the lifespan and the functional status of these patients. Unfortunately, we have not had access to objective measurements for any of our therapies in the home. For instance, it is generally agreed that ACE inhibition therapy should be maximized to a physiologic endpoint, but daily weights, clinical exam, and pulse oximetry are late findings and too non-specific with too many covariables to give us confidence. The use of cardiac impedance as a non-invasive static and dynamic monitoring system to document cardiac function in the home represents a break-through technology allowing us to pursue better quality of care for these patients. Using the priniciple of transthoracic bioimpedance, intensivists and surgeons have known for over a decade that cardiac output and ejection fractions can be monitored with as much reliability as thermodilution Swan-Ganz catheter measurements. Not only is the data correlated with direct Fick measurements as well as thermodilution, the bioimpedance measurements show less inter-operator variability and higher reproducibility for trend analysis with a given patient. In summary, the use of FDA-approved portable bioimpedance devices (paid by Medicare at about $40/test), such as the (www.cardiodynamics.com ), the HemoSapiens (www.hemosapiens.com) or NIMedical (www.ni-medical.com) offers another step forward in low-cost, comprehensive testing and monitoring of patients outside of the hospital environment: whether in the home, the outpatient clinic, or the physician’s office. It is likely that the ease of use and higher physiological parameters measured will make this monitoring a mainstay for both future cardiologists and housecall physicians, although the high capital costs of machines and low per-test reimbursement have limited growth in the fee-for-service sector.

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http://www.cardiodynamics.com/

http://www.hemosapiens.com/

http://www.ni-medical.com/

Examples of theoretical usage of non-invasive measurement of trans-thoracic impedance in the homebound patient: 1. Evaluation of the new patient in heart failure 2. Weaning CHF patients off their high-dose beta-blockers and calcium

channel/diuretic therapies 3. Titrating to the maximum dose of ACEI/ARB consistent with renal

impairment 4. Monitoring diuretic therapies in the bedbound patient or others that

cannot be weighed 5. Adjustment of pacemaker rate settings for maximum cardiac output in

marginal patients 6. Titrate hypertensive therapies to the point of maximum cardiac

efficiency 7. Evaluate the patient with frequent PVCs, AF or other arrhythmia

affecting output 8. Evaluate starting or stopping of digoxin therapy 9. Safety in rapid rehydration or transfusion therapy at home 10. Monitoring the terminal patient remotely to aid the family in planning,

etc. 11. Monitoring patient compliance with dietary restrictions or fluid

hydration overnight 12. Use in pharmcologic stress test for IHD evaluations in the bedbound

patient 13. Monitoring of pleural effusions over time or during thoracentesis 14. Screening for CHF in patients with poor histories and weakness 15. Evaluate Cyclosporine or EPO-induced hypertension 16. Short term stabilization of the patient in pulmonary edema

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non invasive cardiac system (nicas) whole body electrical ...7 yusuke tanino et al. whole body...

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