pharmacotherapy for mechanical circulatory support: a...

60 n The Annals of Pharmacotherapy n 2011 January, Volume 45 theannals.com

Orthotopic heart transplantation rep-resents the definitive, yet increas-

ingly difficult to acquire, therapeutic op-tion for end-stage heart failure. In 2008,a total of 2143 orthotopic heart transplan-tations were performed in the US, a 3%decline from the previous year. At the endof 2008, a total of 1684 patients were on awaiting list for orthotopic heart transplan-tation. The mortality for patients on thewaiting list was reported as 170 per 1000patient-years at risk, representing the high-est risk in all solid organ transplantations.Additionally, a major shift has occurredover the previous decade in the UnitedNetwork of Organ Sharing status at thetime of transplantation, with the majorityoccurring in patients listed as status 1A or1B (Table 1).1,2 This is likely reflective ofthe major advancements in mechanicalcirculatory support (MCS) over the latterportion of the previous decade.3 Indeed,the number of pump implants reportedto the Interagency Registry for Me-chanically Assisted Circulatory Sup-port (INTERMACS) database in 2008was far greater than the 18 months beforethat time, owing in large measure to en-hanced use of continuous-flow ventricularassist systems (VASs) (Figure 1).4

Pharmacotherapy for Mechanical Circulatory Support:

A Comprehensive Review

Christopher R Ensor, Christopher A Paciullo, William D Cahoon Jr, and Paul E Nolan Jr

Cardiology

Author information provided at end of text.

OBJECTIVE: To provide a comprehensive review of the pharmacotherapy asso-ciated with the provision of mechanical circulatory support (MCS) to patients withend-stage heart failure and guidance regarding the selection, assessment, andoptimization of drug therapy for this population.

DATA SOURCES: The MEDLINE/PubMed, EMBASE, and Cochrane databases weresearched from 1960 to July 2010 for articles published in English using the searchterms mechanical circulatory support, ventricular assist system, ventricular assistdevice, left ventricular assist device, right ventricular assist device, biventricularassist device, total artificial heart, pulsatile, positive displacement, axial, centrifugal,hemostasis, bleeding, hemodynamic, blood pressure, thrombosis, antithrombotictherapy, anticoagulant, antiplatelet, right ventricular failure, ventricular arrhythmia,anemia, arteriovenous malformation, stroke, infection, and clinical pharmacist.

STUDY SELECTION AND DATA EXTRACTION: All relevant original studies, meta-analyses, systematic reviews, guidelines, and reviews were assessed for inclu-sion. References from pertinent articles were examined for content not foundduring the initial search.

DATA SYNTHESIS: MCS has advanced significantly since the first left ventricularassist device was implanted in 1966. Further advancements in MCS technologythat occurred in the latter decade are changing the overall management of end-stage heart failure care and cardiac transplantation. These pumps allow forimproved bridge-to-transplant rates, enhanced survival, and quality of life. Phar-macotherapy associated with MCS devices may optimize the performance of thepumps and improve patient outcomes, as well as minimize morbidity related totheir adverse effects. This review highlights the knowledge needed to provideappropriate clinical pharmacy services for patients supported by MCS devices.

CONCLUSIONS: The HeartMate II clinical investigators called for the involvement ofpharmacists in MCS patient assessment and optimization. Pharmacotherapeuticmanagement of patients supported with MCS devices requires individualizedcare, with pharmacists as part of the team, based on the characteristics of eachpump and recipient.

KEY WORDS: antithrombotic therapy, clinical pharmacist, mechanical circulatorysupport.

Ann Pharmacother 2011;45:60-77.

Published Online, 4 Jan 2011, theannals.com, DOI 10.1345/aph.1P459

Development and Advancement of MCSTechnology

MCS technology has impoved greatly since implanta-tion of the first paracorporeal left ventricular assist device(LVAD) by Michael DeBakey in 1966.5 Today, there aremore than 20 VASs and total artificial hearts (TAHs) in de-velopment or clinical use worldwide (Table 2).6,7 Left ven-tricular assist systems (LVASs) may be categorized into 2technological series: positive-displacement pulsatilepumps and continuous-flow rotary pumps. Positive-dis-placement pulsatile pumps, such as the Thoratec Heart-Mate XVE, are full support systems; however, they are notlong-term solutions, as the XVE begins to break after ap-proximately 1 year of use. Continuous-flow rotary pumpscan be further divided into axial and centrifugal flow de-signs. The impeller of an axial-flow pump, such as theThoratec HeartMate II, in an analogous mechanism to anArchimedes screw, imparts kinetic energy onto blood as itpasses through the VAD housing. Centrifugal-flow pumpsmove blood using a water-wheel–like impeller design in ananalogous fashion to an electricity turbine at the base of adam.

LVASs today are smaller than ever; some are as light as93 g, such as the Micromed Heart Assist,5,8 and may becontained entirely within the thoracic cavity, such as theHeartWare HVAD.9 As pumps have become smaller, sohave the transcutaneous leads (driveline) used to deliverpower and data to the LVAD apparatus; some allow for aretroauricular lead placement, such as the Jarvik 2000,which may lower the risk of infectious sequelae.10 Thetransdermal energy transfer system, which eliminates thetranscutaneous lead and uses the skin as an electrical con-ductor, is the ideal driveline technology and has been used,

albeit only marginally successfully, in the Arrow (PennState) LionHeart VAD and the AbioCor Total ArtificialHeart.11,12

Until recently, TAH technology has only marginally ad-vanced over the first device, the Liotta TAH implanted byDenton Cooley in 1969.13 The most widely used TAH, theJarvik-7, now marketed as the CardioWest TAH-t,12,14-16 firstimplanted by William DeVries in 1982,17 represents an en-hancement of the Liotta technology. The CardioWest TAH-treplaces both native ventricles and all 4 cardiac valves with 2positive-displacement pulsatile ventricle housings.12,14-16 TheAbioCor TAH, a fully implantable rigid dyssynchronous pos-itive-displacement pulsatile pump, resulted in early setbacksin patient survival due to thrombosis, bleeding, and infec-tions, and is available in the US only under a humanitariandevice exemption.12 A promising pseudo-pulsatile continu-ous-flow TAH is in development and is currently being im-planted in nonhuman models.18

The shift in LVAD technology away from pulsatile sup-port began with the MicroMed DeBakey VAD, the first ofits kind used in humans, which uses a continuous axial-flow rotary pump design.8,19 Following the MicroMedDeBakey VAD was the Jarvik 2000, which also uses anaxial-flow design. Designed to be implanted via a sub-costal left-thoracotomy surgical approach with the outflowcannula anastamosed to the descending aorta, the Jarvik2000 offers surgical and size advantages over conventionalpulsatile pumps.20,21 Preliminary experience gained throughclinical use of both pumps assisted in the design and modi-fication of the most widely used LVAS in clinical practicetoday, the Thoratec HeartMate II (Figure 2).22

The HeartMate II LVAS uses a continuous axial-flowrotary pump design with a magnetically driven impellerthat rotates on 2 ball-and-cup bearings held in place by theinlet and outlet stators.23 It has been evaluated in 2 pivotaltrials, the bridge to transplantation (BTT) and destination

The Annals of Pharmacotherapy n 2011 January, Volume 45 n 61theannals.com

Table 1. United Network of Organ Sharing Status Definitions2

Status Criteria

1A 1. Mechanical circulatory support, 30 days of 1A time, or

2. Mechanical circulatory support-related complication, in-definitely, or

3. Intraaortic counterpulsation (balloon pump), or

4. Swan-Ganz catheter plus either 2 continuous infusion ino-tropes, or ≥0.5 µg/kg/min of milrinone, or ≥7.5 µg/kg/minof dobutamine alone.

1A(e) 1A may be acquired by exemption (e) for inpatients only if the above therapies are counterproductive, such as in end-stage restrictive cardiomyopathy.

1B Must meet 1 of the following criteria:

1. Mechanical circulatory support, indefinitely, or

2. 1 continuous infusion inotrope.

2 Actively listed patients who do not meet the above criteria.

7 Listed patients who are considered temporarily unsuitable for transplantation.

Figure 1. Proportion of continuous and pulsatile flow pump implants re-ported to the Interagency Registry for Mechanically Assisted CirculatorySupport (July 2006-December 2009).4

therapy (DT) studies, and was the first axial-flow pump tobe approved by the Food and Drug Administration for bothindications.24,25 The outcomes attributable to the HeartMateII are superior when compared with those of conventionalpulsatile pumps and optimal medical therapy (Figure 3).26

Survival in the HeartMate II BTT trial was 75% at 6months and 68% at 12 months.24 Survival in the HeartMateII DT trial was 68% at 12 months and 58% at 24 months.25

These results are in contrast to the survival outcomesachieved with the pulsatile HeartMate XVE (55% at 12months and 24% at 24 months) and even more so whencompared to medical management (<50% at 6 months,25% at 12 months, and 8% at 24 months), as described inthe REMATCH (Randomized Evaluation of MechanicalAssistance for the Treatment of Congestive Heart Failure)trial (Figure 3).26,27

The next generation of LVASs is the continuous cen-trifugal-flow rotary pumps. These pumps may offer advan-

tages over axial-flow technology.9 The HeartWare HVADimpeller is leavened in place and spun using opposingmagnetic charges, is lubricated with hydrodynamic thrustbearings, and uses a smaller driveline (diameter) than theHeartMate II. Theoretically, this pump has zero wear po-tential; as such, the MCS community is looking forward topublication of the device’s long-term durability statistics10

(see Addendum). There are 5 such pumps in developmentor clinical use today (Table 2).

Preoperative Preparation

Patient characteristics at the time of VAS implantationpredict postoperative morbidity and mortality. Globally,these characteristics are described by the 7 levels definedin the INTERMACS database (Table 3). As severity of ill-ness increases, the risk of mortality after VAS implant alsoincreases; accordingly, the highest risk is manifested in re-


CR Ensor et al.

Table 2. Mechanical Circulatory Support Devices in Clinical Use or Development Worldwide

Device Flow Mechanism Ventricular Support Clinical Use

Temporary support devices

Arteriovenous extracorporeal membranous oxygenation Continuous BiVAD (bypass) PC BTR

BVS5000 (AbioMed; Danvers, MA) Pulsatile (cylinder) BiVAD or SVAD PC BTR

Impella 2.5 and 5.0 (AbioMed) Axial LVAD BTR

CentriMag (Levitronix; Zurich, Switzerland) Centrifugal BiVAD or SVAD PC BTR

TandemHeart (CardiacAssist, Inc.; Pittsburgh, PA) Centrifugal BiVAD or SVAD BTR

Durable support devices

Positive displacement pumps

AB5000 (AbioMed) Pulsatile sac-type (ventricle) BiVAD or SVAD PC BTR; BTT

Excor (Berlin Heart; Berlin, Germany) Pulsatile sac-type BiVAD or SVAD BTT

MEDOS VAD (MEDOS Medizintechnik AG; Stolberg, Germany) Pulsatile sac-type BiVAD or SVAD EU only

Thoratec PVAD/IVAD (Thoratec Corp.; Pleasanton, CA) Pulsatile sac-type BiVAD or SVAD PC BTR; BTT

HeartMate XVE (Thoratec Corp.; Pleasanton, CA) Electric pusher plate LVAD BTT; DT

AbioCor (AbioMed) Pulsatile sac-type TAH DT (HDE)

CardioWest (SynCardia Systems, Inc.; Tucson, AZ) Pulsatile sac-type TAH-t BTT

Continuous-flow rotary pumps

Heart Assist 5 (Micromed Cardiovascular, Inc.; Houston, TX) Axial LVAD BTT (IDE)

HeartMate II (Thoratec Corp.) Axial LVAD BTT DT

Incor (Berlin Heart) Axial LVAD EU only

Jarvik 2000 (Jarvik Heart, Inc.; New York, NY) Axial LVAD BTT (IDE)

MVAD (HeartWare, Inc.; Miami Lakes, FL) Axial LVAD Nonhuman models

Synergy (CircuLite, Inc.; Saddle Brook, NJ) Axial LVAD EU only (CEM)

CorAide (Cleveland Clinic; Cleveland, OH) Centrifugal LVAD Nonhuman models

DuraHeart (Terumo Heart, Inc.; Grand Rapids, MI) Centrifugal LVAD BTT (IDE)

EVAHEART (Evaheart Medical USA, Inc.; Pittsburgh, PA) Centrifugal LVAD BTT (IDE)

HVAD (HeartWare, Inc.) Centrifugal LVAD BTT (IDE)

LevaCor VAD (World Heart, Inc.; Salt Lake City, UT) Centrifugal LVAD BTT (IDE)

CFTAH (Cleveland Clinic) Centrifugal, pseudo-pulsatile TAH Nonhuman models

BiVAD = biventricular assist device; BTR = bridge to recovery; BTT = bridge to transplantation; CEM = available only in the European Conformite Eu-ropéenne Mark approval trial; DT = destination therapy; EU = Europe; HDE = available in the US only by humanitarian device exemption; IDE = avail-able only in an investigational device exemption trial; LVAD = left ventricular assist device; PC = postcardiotomy; SVAD = single ventricular assistdevice; TAH = total artificial heart; TAH-t = temporary total artificial heart.

cipients characterized as INTERMACS level 1 (Figure4).4 Some preoperative factors are reversible in theweeks, days, and hours before surgery. Such variables in-clude the nutritional, hemodynamics and volume, hepaticand renal, coagulation, and infectious disease status of therecipient.

NUTRITIONAL STATUS

The nutritional status of the recipient both pre- andpostimplantation should be maximized to a serum prealbu-min level >15 mg/dL, ideally through enteral means. Aserum prealbumin level below this target 2 weeks afterVAS implantation has been associated with an increasedrisk of in-hospital mortality.28 Diets should be high-proteinand high-calorie to maximize albumin and immunoglobu-lin production and maintain intravascular oncotic pressure.Efforts to induce postoperative weight loss in the intensivecare unit (ICU) or within the first 2 weeks after VAS im-plantation, through fasting or underfeeding, should beavoided.

HEMODYNAMICS AND VOLUME MANAGEMENT

The effect of preimplant hemodynamic optimization iswell characterized by the mortality risk of VAS recipients inINTERMACS level 3 at the time of implantation (Table 3,Figure 4) compared to levels 2 and 4.4 It may be that theadded hemodynamic and vasodilatory properties of the in-otropes milrinone and dobutamine affect postimplantationsurvival.

Optimization of ventricular stroke work, particularly ofthe right ventricle, to ≥600 mm Hg•mL/m2 through use ofpulmonary and systemic vasodilators, may decrease the inci-dence of right ventricular failure after VAS implantation.29,30

Such medications often require the use of continuous or in-termittent filling pressure monitoring using a pulmonaryartery catheter (Swan-Ganz) in the preoperative period andinclude nitroglycerin, sodium nitroprusside, nesiritide, hy-dralazine, sildenafil, milrinone, and dobutamine.

Preimplant volume management is equallycritical in the prevention of right ventricular fail-ure, elimination of right ventricular assist device(RVAD) use, and minimization of bleeding dueto hepatic congestion. In the HeartMate II BTTtrial, independent predictors of right ventricularfailure included a central venous pressure(CVP)/pulmonary capillary wedge pressure(PCWP) ratio >0.63 and a serum blood urea ni-trogen (BUN) level >39 mg/dL.31 Additionally,preoperative uremia impacts the degree of post-operative bleeding due to platelet dysfunc-tion.32,33 Continuous renal replacement therapyserves to acutely lower BUN and may mitigatethe risk of uremic bleeding.

ANTIMICROBIAL PROPHYLAXIS

There are few data regarding the most ap-propriate perioperative antimicrobial prophy-laxis regimen for VAS implantation. The RE-

Pharmacotherapy for Mechanical Circulatory Support


Figure 3. Survival after implantation of a continuous-flow LVAD (HeartMate II) orpulsatile-flow LVAD (HeartMate XVE) in comparison to medical therapy in the Heart-Mate II DT and REMATCH trials. Reprinted with permission.26 LVAD = left ventricu-lar assist device.

Figure 2. Thoratec HeartMate II LVAS with the outflow graft anasta-mosed to the ascending aorta. Reprinted with permission.22 LVAS = leftventricular assist system. Color version available online.

MATCH trial required a 4-drug regimen consisting of intra-venous therapy with vancomycin 15 mg/kg twice daily, ri-fampin 600 mg daily, fluconazole 400 mg daily, and an an-tipseudomonal fluoroquinolone (eg, ciprofloxacin 400 mgevery 8 hours) for 48 hours after implantation.27 Many cen-ters have eliminated rifampin and use various β-lactams. Asurvey is ongoing to quantify the effectiveness of regimensused at HeartMate II centers in the US.

Postoperative Management

HEMOSTASIS

In the initial postoperative period, patients recoveringfrom VAS implantation are treated similarly to those whounderwent other cardiac surgical procedures. Followingdecannulation from cardiopulmonary bypass, completeheparin reversal with protamine is performed and bleedingbecomes the primary concern. Perioperative blood loss isone of the most serious and common adverse events fol-lowing VAS implantation, far outweighing the acute risk ofsystemic or pump thrombosis.25,34-38 Treatment of perioper-ative acute blood loss in patients with a VAS is similar tothat of other patients who undergo cardiac surgery, includ-ing measures such as administration of antifibrinolytics,blood products, and rarely, recombinant factors; however,important differences do exist.

Management of critical bleeding with blood componenttherapy is adjusted based on patient-specific characteristics.Selection of blood products will differ depending onwhether the goal of the VAS implant is DT or BTT. Allo-geneic packed red blood cell (PRBC), platelet, fresh frozenplasma, and cryoglobulin transfusions may result in al-losensitization (development of antibodies against donorhuman leukocyte antigens).36 Sensitized patients whose ulti-mate goal is transplantation have a limited donor pool,spend more time on the waiting list, and are at higher riskfor antibody-mediated rejection following transplantation.Limiting the amount of allogeneic transfusions is important

when treating blood loss in the BTT patient. AutologousPRBC transfusion, most often returned to the patient fromthe cell-saver intraoperative apparatus, does not induce anti-body sensitization and is preferred for the BTT patient. Useof leukocyte-reduced PRBCs is an alternative to autologousPRBC transfusion. Leukofiltration reduces the number ofwhite blood cells in a unit of blood product, thereby de-creasing the risk of human leukocyte antigen immunization.Use of leukocyte-reduced and blood-type (ABO) matchedplatelets may also prevent allosensitization in patients whoreceive large amounts of blood products.39

Off-label use of recombinant human factor VIIa (rFVIIa)in cardiac surgery is widely reported.40 Administration ofrFVIIa in cardiac surgery decreases PRBC transfusion andreoperation, but may increase the risk of serious throm-boembolic events such as stroke, bypass-graft loss, andmyocardial infarction.41 Use of rFVIIa after VAD implanthas been retrospectively reported.42-46 Despite reducingPRBC requirements, rFVIIa administration is associatedwith an increased risk of thromboembolism in patientssupported by a VAD. In a recent retrospective report on188 VAD implants over 2 years, 62 patients received rFVI-Ia for refractory bleeding during or immediately after VADimplantation.43 Thirty-two patients received a low dose(10-20 µg/kg) and 30 received a high dose (30-70 µg/kg).Compared with predose measurements, significant reduc-tions were observed in prothrombin time (PT, low dose15.3 vs 10.6 seconds, p = 0.002; high dose 14.6 vs 11.1seconds, p = 0.009) as well as activated partial thrombo-plastin time (aPTT, low dose 52.7 vs 37.7 seconds, p =0.001; high dose 67.3 vs 50.0 seconds, p = 0.02). Hemo-globin values rose significantly after administration in bothgroups (low dose 9.1 vs 10.5 g/dL, p = 0.0004; high-dose9.8 vs 11.0 g/dL, p = 0.02). The number of PRBC units,platelets, and fresh frozen plasma transfused decreased sig-nificantly after rFVIIa administration, regardless of doseused. Similar to other studies of rFVIIa, the rate of throm-boembolic events was higher in the high-dose (n = 11,36.7%) versus the low-dose (n = 3, 9.4%) group (p <0.001).41,47,48

Based on available data, rFVIIa use should be avoideduntil all identifiable coagulation abnormalities have beencorrected. If rFVIIa is necessary, it is important to find theminimum effective dose required to achieve hemostasis.Higher doses of rFVIIa increase the risk of thromboem-bolism and cost. Lower doses (10-20 µg/kg) are likely aseffective as higher doses and confer a lower risk of adverseevents.

DEVICE HEMODYNAMICS

VADs are preload-sensitive pumps. Positive displace-ment pulsatile pumps, such as the HeartMate XVE (automode), function optimally when the chamber fills during


CR Ensor et al.

Table 3. INTERMACS Patient Profile at the Time of VAS Implantation4

Level Description

1 Critical cardiogenic shock

2 Progressive decline (on inotropes)

3 Stable but inotrope-dependent

4 Recurrent advanced heart failure (off inotropes)

5 Exertion intolerant

6 Exertion limited

7 Advanced New York Heart Association Class III Heart Failure Symptoms

INTERMACS = Interagency Registry for Mechanically Assisted Cir-culatory Support; VAS = ventricular assist system.

native ventricular systole; continuous-flow rotary pumpsfill relatively evenly during both systole and diastole.49,50

There is some degree of enhanced filling of the continu-ous-flow rotary pumps during ventricular systole, which ismeasured by the difference in power requirements be-tween systole and diastole to maintain the fixed speed ofthe impeller and is quantified as the pulsatility index(HeartMate II).7 The pulsatility index at isolated times is acrude marker of pump preload; however, it also varies byimpeller speed and the degree of native ventricular func-tion and recovery. The trend in pulsatility index values canprovide a more meaningful measure of changes in pumppreload. Pump flow is a direct measure on pulsatilepumps such as the HeartMate XVE; conversely, it is a cal-culated number on the HeartMate II and is predominantlyreliant on impeller speed and power requirements for esti-mation. In HeartMate XVE support, a decline in pumpflow likely reflects a decline in circulating blood volume,whereas a similar decline in the HeartMate II can be a re-sult of multiple factors, making it a less-than-ideal markeron which to base volume assessments.7 The degree ofpreload sensitivity of the continuous axial-flow rotarypumps differs by pump design. In vitro, the Jarvik 2000appears variable in its degree of preload sensitivity,whereas the HeartMate II is more predictable in the samemodel.51 Traditional measures, such as CVP, PCWP, andclinical examination, as well as the appearance of the ven-tricles on echocardiography, should be used to guide vol-ume management. Pulsatile pumps are able to provide agreater degree of ventricular unloading than are continu-ous-flow rotary pumps, and patients supported with thelatter often require chronic diuretic therapy to maintaineuvolemia.

Unlike their pulsatile counterparts, which reliably deliv-er a set stroke volume with each ejection irrespective ofchanges in systemic vascular resistance, the continuous-flow rotary pumps are relatively afterload sensitive. Analo-gous to increased water pump strain and poor forward flowthrough a kinked garden hose, the continuous-flow rotarypump does not perform optimally in the setting of highsystemic vascular resistance. Medical management ofVAD -associated hypertension is similar to traditional med-ical therapies used in heart failure such as angiotensin con-verting enzyme (ACE) inhibitors and β-blockers.7,52,53 Ven-tricular unloading lowers renin and aldosterone but upreg-ulates the production of cardiac angiotensin stimulatingsympathetic tone; thus, ACE inhibitors may provide amechanistic advantage over other afterload-reducing thera-pies.53 Afterload-reducing therapies should be used to main-tain mean arterial pressure between 70 and 80 mm Hg.7,54

Due to continuous ventricular unloading by axial or cen-trifugal pumps, pulse pressure variation narrows and bloodflow becomes laminar as impeller speed is increased.Diastolic pressure rises in this scenario, necessitating the useof mean arterial pressure as the preferred measure of bloodpressure.54 Automated blood pressure cuffs and traditionalauscultation with a sphygmomanometer may fail to find sys-tolic and diastolic pressures. Use of an audio Doppler with asphygmomanometer is often the only way to determine meanarterial pressure in the absence of arterial cannulation.7

THROMBOSIS PROPHYLAXIS

Thromboelastography

Thromboelastography (TEG) evaluates the contribu-tions of clotting factors, fibrinolysis, platelets, anticoagu-

lants, and other blood elements to the dynamicsof the viscoelastic (clot-strengthening) propertiesof whole blood under low shear conditions fromthe beginning of coagulation through fibrinoly-sis.55 Thromboelastography is unlike convention-al clot-based assays such as aPTT and PT, whichuse citrated plasma activated with calcium and asurface activator such as kaolin or thromboplas-tin for the aPTT and PT, respectively, to measurethe contributions of selected clotting factors inthrombus formation.56 Neither the aPTT nor PTprovide information related to clot strength orstability, the effects of fibrinolysis, or the variedcontributions of circulating cells to clot forma-tion and stability.57

Thromboelastography uses whole blood as itsanalyte. The blood sample is most commonlycollected in tubes containing sodium citrate,which allows for a short delay of up to 30 min-utes following venipuncture before the bloodsample is processed. An aliquot of the blood



Figure 4. Proportion of VAS implantation by Interagency Registry for MechanicallyAssisted Circulatory Support (INTERMACS) patient profile and associated mortality risk(June 2006-March 2009). Percent mortality of the INTERMACS levels 4-7 are calcu-lated in aggregate.4

sample is then placed into the TEG analyzer and is recalcifiedto initiate clotting. Some laboratories used a factor XII activa-tor such as kaolin or a factor VII activator such as tissue fac-tor to accelerate clot formation.58-60

There are several standard parameters from the TEGtracing with which the clinician should become familiar(Figure 5). Reaction time represents initial fibrin clot forma-tion and can be prolonged by anticoagulants, clotting factordeficiencies, or endogenous clotting inhibitors.55,61 The firm-ing time represents attainment of a prespecified level of clotstrength that results from interaction of clotting factors withplatelets.55,61 Thus, firming time reflects the rate of clotstrengthening. Several factors, including anticoagulants,clotting factors (fibrinogen), platelet count and function, andhematocrit, influence firming time. The angle is the slope

formed from reaction time tangential to the diverging TEGtracing and is similar to firming time in that α represents therate of clot formation.55,61 The angle may be modified byclotting factor concentrations, platelet function, and, to alesser extent, by anticoagulants. Maximum amplitude ismeasured as the maximal vertical distance between the di-vergence of the TEG tracing and represents the maximalstrength of the clot.55,61 It is largely a marker of platelet andfibrinogen functionality. The coagulation index is a globalassessment of coagulation status.55,61 The coagulation indexis calculated from a multiple regression equation that usesthe measured TEG parameters R, firming time, angle, andmaximum amplitude. TEG is widely used in TAH supportand is gaining use in the postoperative management of pa-tients who have undergone VAD implantation.62-65 However,


CR Ensor et al.

Figure 5. TEG tracings of a patient supported by the CardioWest TAH-t. Thromboelastograph Panel A: untreated with heparinase. Panel B: treated withheparinase. At the time of these TEG tracings, the patient was being treated with heparin 1200 units/h, aspirin 81 mg daily, dipyridamole 400 mg every8 hours, and pentoxifylline 400 mg every 8 hours. Panel A suggests that the patient is normocoagulable with a coagulation index of 0.0. Panel B sug-gests that the patient is hypercoagulable in the absence of heparin with a CI of 2.0. Additional laboratory tests performed on this day included whiteblood cell count = 9,700/µL, hematocrit = 27.2%, platelet count = 462 × 106/L, and fibrinogen = 427 mg/dL. TEG was performed using recalcified cit-rated whole blood and a TEG Analyzer model no. 5000 (Haemonitics Corporation, Braintree, MA). CI = coagulation index; K = firming time; MA = max-imum amplitude; R = reaction time; TAH-t = temporary total artificial heart; TEG = thromboelastography.

each institution must determine its reference ranges for eachTEG parameter based on the practices of the individual co-agulation laboratory. Limitations of TEG are minor and in-clude availability of the analyzer and the technical expertiserequired to run the test.

Prophylaxis Regimen

After VAS implantation, a hypercoagulable state is ex-pressed that is dependent on pump design and patient char-acteristics. This hypercoagulable state consists of a complexinteraction of inflammation; contact- and tissue-factor–ini-

tiated coagulation; hyperfibrinogenemia; platelet activa-tion, which is frequently accompanied by thrombocytosis;endothelial cell activation; either hyper- or hypofibrinolysis;and hemolysis.4,66-69 Counterbalancing this multifactorial hy-percoagulable condition frequently requires an individualizedthromboprophylaxis regimen consisting of anticoagulants incombination with antiplatelet agents (Tables 4 and 5).7,62-65

Based on experience, we believe that in pumps requir-ing anticoagulants, dosing should be guided by TEG re-sults (Figure 5). The non–kaolin-activated TEG is moresensitive to heparin’s anticoagulant effects compared to



Table 5. Example Thromboprophylaxis Regimens and Dosing14

Initiation Monitoring TEG LTAStrategy Drug Dose Parameters Goal Parameters Effecta Effecta

Anticoagulation Heparin Start: 2-5 units/kg/h Start: day +1 when Normocoagulability TEG (R, K), fibrinogen, ↑ R, K Nonechest tube drainage by CI on TEG CBC, renal function, ↓ α<30 mL/h for 4 h blood stasis, bleeding

Bivalirudin Start: 0.005 mg/kg/h Start: day +1 when Above Above ↑ R, K NoneMaximum: 0.02 chest tube drainage mg/kg/h <30 mL/h for 4 h

Warfarin Start: 2-5 mg/day Start: day +2-5 Above Above plus: genomics, ↑ R, K Noneafter recovery of INR, drug interactions, ↓ α, MAhepatic function and hepatic function, with stable nutrition albumin, prealbumin,

vitamin K intake

Antiplatelet Aspirin Start: 81 mg/day Start: return to ICU Suppressed LTA ↓ α, MA ↓ AA, Maximum: 650 mg/day chest tube drainage platelet function: ADP,

<30 mL/h for 4 h AA: 20-40% EPIand if platelets≥50,000 × 106/L

Dipyridamole Start: 50 mg every 8 Start: day +1-5 if Normocoagulability TEG (α, MA), LTA, CBC, ↓ α, MA ↓ ADP,hours platelets ≥50,000 × by CI on TEG hepatic function, EPI

106/L Suppressed LTA bleedingplatelet function:ADP: 20-40%

Viscosity reduction Pentoxifylline Start: 200 mg every Start: only if FBG Normocoagulability TEG, FBG ↓ CI None8 hours >350 mg/dL by CI on TEG

Maximum: 400 mg FBG <350 mg/dLevery 8 hours

α = angle; AA = arachidonic acid; ADP = adenosine diphosphate; CBC = complete blood cell count; CI = coagulation index; EPI = epinephrine; FBG= fibrinogen; ICU = intensive care unit; INR = international normalized ratio; K = firming time; LTA = light transmittance aggregometry; MA = maxi-mum amplitude; R = reaction time; TEG = thromboelastography.aExpected.

Table 4. Selected Thromboprophylaxis Regimens by Device Type

HeartMate XVE HeartMate II Jarvik 2000 HeartWare HVAD CardioWestPulsatile-flow LVAS Axial-flow LVAS Axial-flow LVAS Centrifugal-flow LVAS Pulsatile TAH

Heparina – ± + ± +

Warfarin – + + + +

Aspirin + + + + +

Dipyridamole R R ± R ±

Pentoxifylline – – R – ±

LVAS = left ventricular assist system; R = rarely used by some centers in individualized situations; TAH = total artificial heart; – = not routinely used;± = used by some centers in individualized situations; + = used in nearly all situations.aMay substitute argatroban or bivalirudin for patients with suspected or known heparin-induced thrombocytopenia.

aPTT,70 thereby avoiding over-anticoagulation and in-creased risk for bleeding. In addition, reliance on arbitrarilyselected aPTT results may result either in greater incidenceof early hemorrhagic complications71 or hypercoagu-lability.72 The aliquot of the TEG blood sample to whichheparinase is added permits evaluation of both the underly-ing, nonheparinized coagulation status as well as the anti-coagulant effects of concurrent warfarin therapy.64 Giventhe early postimplant end-organ dysfunction and hemor-rhagic diathesis, initial heparin infusion rates should below, in the range of 2-5 units/kg/h, and titrated according todaily TEG results targeting a goal of normocoagulability asdetermined by the coagulation index.62-65 The direct throm-bin inhibitors argatroban73 and bivalirudin74 have been usedin lieu of heparin, especially in patients with a history ofheparin-induced thrombocytopenia. However, in vitrostudies suggest that currently available direct thrombin in-hibitors, although prolonging clot initiation similarly toheparin, are not as effective as heparin in attenuating clotpropagation and clot strength.75

Warfarin is most frequently used for long-term anticoag-ulation.7,64,65 It is generally recommended to overlap initia-tion of warfarin with ongoing parenteral anticoagulanttherapy.7,64,65,74,76 However, emerging evidence with theHeartMate II suggests that withholding postoperative hep-arin and starting de novo warfarin between the second andfifth postoperative day does not increase the risk of pump-related thrombosis and decreases the risk of bleeding.7,71

Initial dosing of warfarin in patients supported by a VASgenerally ranges from 2 to 5 mg/day, but should be alteredif necessary based on the patient’s hepatic and renal func-tion, age, weight, and nutritional status; concomitant use ofpotential interacting drugs; and the presence of infection.The international normalized ratio (INR) target for war-farin varies among devices. Recent recommendations forthe HeartMate II propose an INR range of between 1.5 and2.5.7 We suggest that the INR range should be individual-ized based on results of TEG-guided monitoring with thetarget INR range resulting in normocoagulability.64,65

Given the persistent platelet activation induced by a VAS,77

antiplatelet therapy is typically required.7,62-65 Aspirin is rec-ommended as first-line therapy; however, concomitant thera-py with dipyridamole may be needed in select cases.7,62-65

Postimplant aspirin hyporesponsiveness is not infrequent butusually resolves with an increase in dose.77 Nonetheless, as-pirin hyporesponsiveness can recur, in part, as a result of con-current elevations both in platelet count and fibrinogen.77

Dipyridamole, in a dose-related fashion when combined withaspirin, decreases both platelet aggregation and platelet adhe-siveness more than aspirin alone.78 The clinical use of titrateddoses of dipyridamole, in combination with aspirin, has re-sulted in a low incidence of embolic neurologic events in pa-tients who undergo implantation with the CardioWestTAH.62-64

As with anticoagulants, we believe that antiplatelet ther-apy should be individualized using TEG in conjunctionwith platelet count and fibrinogen.62-65,79 Careful monitor-ing of the patient’s overall clinical condition and concur-rent drug therapy is strongly recommended since condi-tions such as acquired von Willebrand factor deficiency,anemia, and uremia, as well as several nonantiplateletdrugs, may produce important measurable antiplatelet ef-fects or thrombocytopenia.80-83 Light transmittance aggre-gometry, using platelet-rich plasma, has been used to as-sess antiplatelet responsiveness in patients supported withthe CardioWest TAH.62-65 Multiple platelet agonists such asadenosine diphosphate, epinephrine, collagen, and arachi-donic acid can be used during the testing procedure. Dosesof aspirin and dipyridamole are adjusted as needed with agoal of suppressing adenosine diphosphate– and arachi-donic acid–induced platelet aggregation and preserving theresponse to collagen.62-65 Hyporesponsiveness to collagen-induced platelet aggregation has been reported as a signifi-cant risk factor for bleeding.84

Complications

While VAS devices have greatly advanced the manage-ment of end-stage heart failure, they also pose the risk ofmultiple complications that may adversely affect morbidityand mortality. A single-center, retrospective analysis of pa-tients receiving MCS devices found a cumulative adverseevent rate of 89.2% 60 days following implantation.85 Pa-tients in the device group of the REMATCH trial weremore than twice as likely as patients in the medical therapygroup to have a serious adverse event.86 Adverse events ex-perienced following VAD implantation cover a wide spec-trum and are dependent on pump design; the most com-monly reported include right ventricular failure, arrhyth-mias, anemias, bleeding, neurologic events, and infections.Thrombosis has become an increasingly uncommon ad-verse effect. Understanding the mechanisms behind VAS-associated complications may help to prevent their occur-rence, and prompt identification and management mightminimize their effects.

RIGHT VENTRICULAR FAILURE

Assessment of right ventricular function is critical inevaluation of possible VAD candidates, as postoperativeright ventricular failure, defined as the need for inotropicagents for >7 postoperative days or the addition of anRVAD, is associated with poor outcomes. Patients withpostimplant right ventricular failure requiring biventricularsupport have prolonged ICU stays, increased transfusionrequirements, a higher incidence of renal failure, and ahigher mortality rate than patients requiring single ventric-ular support.87,88 Commonly, patients with left sided heart


CR Ensor et al.

failure have a component of right ventricular dysfunctionrelated to increased left ventricular filling pressures andrightward septal shift. Right ventricular function will oftenimprove following the unloading of the left ventricle dur-ing LVAD support, and no further intervention is required.Other etiologies of right ventricular failure, such as pul-monary arterial hypertension, must be ruled out prior toplacement of the device, as these are not alleviated byLVAD support.

Despite meticulous screening, right ventricular failureoccurs following 13-30% of LVAD implants, dependingon device.31,89,90 There are a number of preoperative riskfactors for right ventricular failure after LVAD implanta-tion; the most common is preoperative right ventriculardysfunction.89,91-93 Additional risk factors that have beenidentified are low cardiac index, low right ventricularstroke work, high serum creatinine level, previous cardiacsurgery, and low systolic blood pressure.89 Notably, fewanalyses were performed with continuous-flow devices,and preliminary data showed a similar incidence but de-creased severity of right ventricular dysfunction after con-tinuous-flow device implant.94 In a post hoc analysis of theHeartMate II BTT trial, 13% of patients experienced rightheart failure defined as the need for an RVAD or extendedinotrope support.31 Risk factors for right heart failure in thispopulation were high central venous pressure, preoperativeventilator support, and high BUN.

There are 3 primary etiologies for right ventricular fail-ure following LVAD implantation. First, right ventricularmyocardial damage may be preexisting or may develop in-traoperatively due to inadequate cardioplegia or an intraop-erative myocardial infarction. Second, sudden unloading ofan overloaded left ventricle causes the intraventricular sep-tum to shift leftward, impacting right ventricular geometryand performance. Right ventricular failure due to leftwardseptal shift is often due to excessively high LVAD impellerspeed or the use of a pulsatile device. Lastly, patients mayhave preexisting pulmonary hypertension from chronicheart failure, valvular disease, or unknown etiologies. Pul-monary hypertension may be unmasked when filling pres-sures to the left ventricle are decreased, but pulmonarypressures remain elevated.

Perioperative use of vasopressor agents such as phenyl-ephrine, norepinephrine, and epinephrine may result in arise in pulmonary pressures, thereby increasing the workloadon the right side of the heart. Preferential use of vasopressinin this patient population may be warranted due to postcar-diotomy vasopressin deficiency and the lack of effects onthe pulmonary vasculature.95-97 Because optimal flow to thenewly implanted LVAD is dictated by right ventricular func-tion, immediate and effective treatment for right heart dys-function is paramount in the postoperative period. WhileRVAD support may be indicated in some patients, medicaltherapy with inotropes and pulmonary vasodilators is often

the first intervention. Most patients supported with a VADwill require early inotropic support postoperatively, with apreference for agents that cause pulmonary vasodilation inthe case of right ventricular failure (Table 6).98,99

Chronic heart failure–related elevations in left atrialpressure, pulmonary venous congestion, and alterations insympathetic tone lead to increases in pulmonary pressures.The L-arginine/nitric oxide (NO) pathway plays an impor-tant role in the regulation of pulmonary vascular tone.100

Cyclic guanosine monophosphate (cGMP) is the secondmessenger that mediates the pulmonary vasodilatory ef-fects of NO, which is inactivated by the phosphodiesterase(PDE) family of enzymes. In the lung, phosphodiesterasetype-5 (PDE-5) is the primary PDE enzyme responsiblefor metabolizing cGMP, but PDE-3 also contributes to va-sodilation.98 This system can be therapeutically manipulat-ed by providing inhaled NO, inhibiting the degradation ofNO by the PDE enzymes, or both, which results in in-creased NO concentrations at the level of the pulmonaryarteries, producing vasodilation.

Use of inhaled NO in cardiac surgery is well de-scribed.101 In addition to any preexisting pulmonary hyper-tension, cardiopulmonary bypass causes an increase in pul-monary vascular tone. Inhaled NO causes a local vasodila-tion, decreasing pulmonary vascular resistance whileimproving oxygenation. For patients with right ventricularfailure, the decrease in pulmonary vascular resistance im-proves right ventricular output. Unlike other pulmonaryvasodilators given systemically (milrinone, epoprostenol),NO does not cause a decrease in systemic vascular resis-tance. NO is inactivated by binding to hemoglobin, result-ing in methemoglobin. Methemoglobin does not carryoxygen, resulting in a leftward shift of the oxygen-hemo-globin dissociation curve, impairing the release of oxygenfrom hemoglobin. Methemoglobin concentrations shouldbe monitored closely during inhaled NO therapy.

The use of NO following pulsatile LVAD implantationhas been retrospectively evaluated.102-105 At doses of 10-40ppm, NO has been shown to decrease pulmonary arterypressure as well as increase LVAD output. Initiating NO



Table 6. Inotropes Used After VAS Implantation98,99

Agent Contractility Chronotropy SVR PVR

Dobutamine +++ + – – –

Dopamine +++ + ++ +

Epinephrine ++++ ++ +++ +

Isoproterenol ++++ ++++ – – – –a

Milrinone +++ + – – – – –

PVR = pulmonary vascular resistance; SVR = systemic vascular re-sistance; VAS = ventricular assist system; + = increase; – = decrease.aVasodilatory actions of isoproterenol are offset by increases in right ven-tricular output and an increase in pulmonary artery pressure is seen.

while weaning patients from cardiopulmonary bypass mayalleviate the need for RVAD placement.105 There have beenno reports of NO use following a continuous-flow LVADinsertion, but similar outcomes should be expected.

Due to the cost and toxicity of NO, alternative inhala-tion agents for pulmonary hypertension following cardiacsurgery have been evaluated.106 Prostacyclin (epoprostenol)is a potent pulmonary and systemic vasodilator when givenintravenously. However, when nebulized and given via in-halation, prostacyclin’s effects are limited to the pulmonaryvasculature.107 Prostacyclin exhibits a linear dose-responsecurve, with maximal effect achieved at approximately 50ng/kg/min. Prostacyclin decreases pulmonary artery pres-sures and increases cardiac output following cardiothoracicsurgery, including LVAD implantation.106 The efficacy ofinhaled prostacyclin, combined with its ease of administra-tion, low cost, and excellent safety profile, make it an at-tractive option for the treatment of right heart dysfunctionfollowing LVAD implantation.

Sildenafil causes pulmonary vasodilation via PDE-5 in-hibition in the pulmonary vasculature. In addition to thisdecrease in right ventricular afterload, sildenafil has beenfound to have inotropic effects in a hypertrophied rightventricle.108 This dual mechanism makes sildenafil an at-tractive option for treatment of right ventricular failure af-ter LVAD implantation.30,109 In the largest evaluation,sildenafil was studied in an open-label clinical trial of 58patients with an LVAD.30 All patients had improved PCWP(11.8 ± 2.0 mm Hg from baseline value of 23.2 ± 6.2mm Hg, p = NS) after LVAD implantation but unchangedPVR (5.65 ± 3.00 to 5.39 ± 1.78 Wood units, p= NS).Sildenafil was initiated in 26 patients and titrated to an av-erage dosage of 51.9 mg 3 times daily. A decrease in meanpulmonary artery pressure from 36.5 ± 8.6 to 24.3 ± 3.6mm Hg (p < 0.0001) was seen in sildenafil-treated patients,which corresponded to a decrease in PVR from 5.87 ± 1.93to 2.96 ± 0.92 (p < 0.001) Wood units. There were no sig-nificant changes in either variable from baseline in controlpatients. Additionally, systolic and diastolic function im-proved in the sildenafil group, with no serious adverse ef-fects. Based on available data, sildenafil is an appropriatechronic treatment for patients with LVAD and right ven-tricular dysfunction or high pulmonary artery pressuresthat compromise left ventricular filling. A starting dose of20 mg 3 times daily is appropriate, titrated to adequate pul-monary artery pressures via the continuous or intermittentuse of a pulmonary artery catheter.

VENTRICULAR ARRHYTHMIAS

Excessive unloading of the left or right ventricle mayexacerbate underlying electrical dysfunction of a myopath-ic heart.110-113 Ventricular suck-down (suction) events, thecomplete unloading of the ventricle resulting in intracardiac

tissue (typically the ventricular septum or valve leaflets)temporarily occluding the inflow cannula, in the setting ofcontinuous-flow rotary pump support, have been reportedto transiently increase the risk and induce episodes ofmonomorphic ventricular tachycardia.111 Since most ven-tricular arrhythmias tend to be monomorphic ventriculartachycardia, pharmacotherapy includes electrolyte opti-mization (potassium 4.5-5 mEq/L; magnesium >2 mg/dL),β-blockade, amiodarone, and the sodium channel blockersprocainamide, lidocaine, and mexilitine.113 Moreover, thenonuse of β-blockers has been strongly associated withventricular arrhythmias in the setting of VAD support (OR7.04, p = 0.001).114

ANEMIA

The reported incidence of anemia ranges widely due tovariability in patient population, device implanted, and defi-nition of anemia.115 A single-center, retrospective review ofpatients with LVAD found that anemia, defined as hemoglo-bin <12.0 g/dL, was an independent predictor of adverseoutcomes including mortality.115 The underlying mechanismof VAD -associated anemia has long been presumed to berelated to device-induced hemolysis.116,117 Hemolytic anemiais typically transient and responds well to decreases in revo-lutions per minute of the continuous-flow pumps.7

Additional research suggests that chronic systemic in-flammation from device implantation may result in an ane-mia of chronic disease.118 Inflammatory cytokines, releasedin response to blood contact with VAD surfaces, inhibiterythropoietin-induced erythrocyte maturation. Given theinhibition of erythrocyte maturation, interest in the use oferythropoietin-stimulating agents has risen.119-121

GASTROINTESTINAL BLEEDING

As with anemia, the incidence of gastrointestinal (GI)bleeding appears to depend on the type of device implanted.Rates of GI bleeding were 22-40% in recipients of continu-ous-flow devices as compared with 0-6.5% in those withpulsatile devices.122,123 Several theories seeking to explain thisdiscrepancy have been proposed, including arteriovenousmalformations and acquired von Willebrand disease.122,123

Narrow pulse pressures produced by nonpulsatile flow maypromote development of arteriovenous malformation.124

While arteriovenous malformations can remain asymptomat-ic, it has been hypothesized that platelet dysfunction from an-tithrombotic therapy and acquired von Willebrand disease in-crease vulnerability to GI bleeding.122,125 von Willebrand fac-tor promotes platelet adhesion and aggregation at the site ofvascular injury.125 Increased shear stress and flow accelerationfollowing VAD implantation result in loss of high-molecularweight von Willebrand factor multimers and impaired vonWillebrand factor function, consistent with acquired von


CR Ensor et al.

Willebrand disease.126-128 Proposed pharmacologic strategiesin continuous-flow LVAD patients with GI bleeding includelocalized sclerotherapy, antifibrinolytics such as tranexamicacid, and recombinant human factor VIII/von Willebrandfactor complexes (Humate-P, CSL Behring, King of Prussia,PA). Transient interruption of anticoagulation and reductionin pump speed to allow more pulsatile flow have also beenproposed.126

NEUROLOGIC EVENTS

In addition to increased risk of bleeding, VAD recipientsare at risk for strokes and transient ischemic attacks. Aswith other VAD complications, the reported incidence ofstroke varies, with estimates ranging from 3% to 47%.129

Strokes appear to occur most frequently soon after deviceimplantation, although overall risk increases with longerduration of VAD support.130 These events may affect de-vice outcomes, including heart transplantation and mortali-ty. A single case report exists describing the successful useof intraarterial thrombolysis for acute ischemic stroke in apatient supported by a Novacor LVAD.131 Thrombolysiscannot be widely recommended in this patient populationdue to a paucity of data regarding intracranial hemorrhageand systemic bleeding risk. Additionally, patients who ex-perience an ischemic stroke should not receive aggressiveanticoagulation due to the risk of hemorrhagic transfor-mation.132 With limited treatment options and a potential-ly significant impact on patient outcomes, prevention ofthrombotic events in patients supported by a VAD is es-sential. Compliance with the antithrombotic regimensmentioned previously, especially in the early period fol-lowing device implantation, can greatly reduce the risk ofthromboembolic events.

INFECTIONS

VAS support may also be complicated by infection,with occurrence rates ranging from 25% to 50%.133 Infec-tion is a major source of postimplantation morbidity andmortality and is associated with prolonged hospitalization,VAS malfunction, heart transplantation delay, need for sur-gical revision, and removal or exchange of the infected de-vice.134 Data from the REMATCH trial indicated that themortality rate of HeartMate XVE recipients experiencingsepsis may be 50% higher than in those without sepsis.135

Risk factors for infection in the VAS recipient populationinclude concomitant conditions that impair immune func-tion (eg, renal dysfunction, diabetes), malnutrition, urinaryand intravascular catheters, mechanical ventilation, and ad-vanced age. Device-specific factors, including delayedwound healing, larger VAS size, driveline exit-site trauma,and extended duration of support, also play a role. Onesuch device-specific factor is the induction of an aberrant

state of T-cell activation that leads to programmed cell deathamong CD4-bearing T-cells during HeartMate XVE sup-port. This is thought to be related to the textured fibril coat-ing on blood-contacting surfaces inside the XVE chamberand may predispose the acquisition of fungal VAS infec-tions.136

Infections occurring during VAS support may be sys-temic, such as bloodstream infections (BSIs), or localizedto the device itself. Several VAS components are suscepti-ble to infection, including the percutaneous driveline exitsite, the driveline tract, the device and its surroundingpocket, and the internal (blood-containing) components(Figure 6).137,138 Pathogens may be introduced by directcontamination during surgical implantation, via the drive-line or driveline exit site, or by hematogenous dissemina-tion from distant sources. The most common pathogens as-sociated with VAS infection include staphylococci, Entero-coccus spp., gram-negative bacilli such as Pseudomonasaeruginosa, and Candida spp.134,137

BSIs without evidence of device involvement may betreated as routine bacteremia. Empiric therapy should in-clude antimicrobials effective against common pathogensassociated with VAD support, including multidrug-resistantgram-negative rods, in accordance with local resistance pat-terns.133 Delineation of the origin of a BSI as arising from adevice versus a nondevice source is very difficult; thus,



Figure 6. Potential sites of infection of the HeartMate XVE LVAD.Reprinted with permission.38 A. Percutaneous lead (driveline) exit site.B. Driveline tract. C. External surfaces of pump and surrounding pumppocket. D. Internal blood-containing components (such as the inflow andoutflow tri-leaflet pericardial valves of the depicted HeartMate XVE). LVAD= left ventricular assist device.

clinical symptoms must also guide duration in addition totraditional pump evaluations. Device-related BSIs may bedefinitively established only through explant VADcultures.139 Device-related BSIs should be suspected in thepresence of septic emboli, new incompetence of pump in-flow or outflow valves (pulsatile pumps), or in patients withrecurrent or persistent BSIs.137,139 Device-related BSIs areoptimally treated with device explantation and/or changeoutand long-term (longer than 6 weeks) parenteral antimicro-bial therapy.137,139 As pump replacement in patients with de-vice-related BSIs may be technically challenging, UnitedNetwork of Organ Sharing grants 1A status for heart trans-plantation in transplant-eligible patients (Table 1).2 If devicesalvage is attempted, prolonged antimicrobial therapy (untildevice changeout or transplantation) may be necessary.140

Infections localized to the driveline or driveline exit sitecan often be treated with antimicrobial therapy, immobiliza-tion of the driveline, and local wound care.137 Optimal dura-tion of antimicrobial therapy is undefined and is dependenton the depth and degree of tissue involvement. Typically,driveline infections require prolonged treatment (4-6 weeks)with parenteral antimicrobials and may necessitate chronicsuppression. If, however, the infection tracks deeply alongthe driveline or involves the area of device implantation(pump pocket), excisional debridement and temporaryplacement of drains are often required. Pump pocket infec-tions are difficult to treat and frequently recur despite exten-sive debridement and protracted antimicrobial treatmentlonger than 6-12 weeks). Pump pockets are typically hypo-vascularized, which may result in subtherapeutic antimicro-bial deposition via the parenteral route. As a result, pocketdebridement, followed by localized administration of contin-uous antimicrobial irrigation via inflow and outflow drainsin the pump pocket, has been advocated.7 Insertion of poly-methylmethacrylate antimicrobial-impregnated beads hasalso been described in a few case reports.141-143 Ultimately,pump pocket infections may necessitate VAS changeout.

As VAS-associated infections are often difficult to treat,implementation of strategies to prevent infection is vital.These strategies include screening and treatment of nasalStaphylococcus aureus colonization, aseptic surgical tech-nique, optimization of host defenses through maintenanceof normoglycemia and nutritional support, perioperativeantimicrobial prophylaxis, and avoidance of trauma andmicrobial contamination at the driveline exit site.137,139

Technical advances in VAS design, such as the develop-ment of fully implantable devices, will further minimizeinfectious complications.

OTHER COMPLICATIONS

Additional VAS-associated complications include, but arenot limited to, renal and hepatic dysfunction and psychiatricdisorders. As these complications are associated with in-

creased morbidity and mortality, prevention, when possible,and optimal management are important aspects of patientcare. Knowledge of VAS-associated complications and theirunderlying mechanisms may help to prevent their occur-rence. With the increasing use of VAS therapy for end-stageheart failure, further research characterizing complicationsand their management will help optimize patient outcomes.

Role of the Clinical Pharmacist

The role of the clinical pharmacist in the care of subspe-cialty populations has been described in various forums.144-148

Use of MCS devices is a subspecialty of advanced heart fail-ure and cardiac transplantation.The HeartMate II clinical in-vestigators called for the involvement of a pharmacist in as-sessment and optimization of care for patients on MCS.7 Inan analogous fashion to solid organ transplantation, MCS pa-tients are closely followed by a team of care coordinators andspecialist physicians, including cardiac surgeons and heartfailure cardiologists. The clinical pharmacist is an integralpart of these teams at our institutions. Indeed, many of thelarger MCS centers in the US employ a clinical pharmacist intheir cardiac surgical ICU; however, if the MCS implantationgoes smoothly, the patient may spend less than 48 hours inthe ICU. As such, 2 of our institutions employ a longitudinalclinical specialist model with involvement in all intensities ofthe care of the MCS patient.

The clinical pharmacist can have a great impact on all ofthe topics discussed in this review through direct patientcare, protocol development, research activities, and patientand provider education. In particular, the clinical pharma-cist should be actively involved in preoperative optimiza-tion and postoperative blood product minimization toachieve surgical hemostasis. Pharmacist involvement inthis activity is critical to minimize allosensitization in theBTT patient. Conversely, the clinical pharmacist should beactively involved in the antithrombotic therapy of the pa-tient to minimize bleeding risk and prevent thrombosis. Anintimate understanding of the impact of pharmacothera-peutic options for hemodynamic support is critical forpump optimization. Likewise, antiarrhythmic drug therapymay be tailored based on the underlying electrical charac-teristics of the VAS, using the expertise of the clinicalpharmacist. Perioperative antimicrobial prophylaxis, infec-tion treatment, and chronic suppression are areas of steward-ship for pharmacists. Similar to care of patients with heartfailure, involvement in the educational process of the MCSpatient may enhance adherence to afterload reduction and thecomplicated thromboprophylaxis regimen and perhaps ex-tend time between readmissions to the hospital, although thishas not been evaluated in the VAS population.149

The International Society for Heart and Lung Transplan-tation (ISHLT) focuses on the basic and clinical sciencesfor the failing heart and lungs. The ISHLT is developing


CR Ensor et al.

consensus documents regarding definitions of disease andtreatment in the field of mechanical circulatory support.There is an ongoing effort by pharmacist members of theISHLT to develop a clinical pharmacy and pharmacologycouncil. Pharmacists seeking involvement and collabora-tion in this field should consider membership in the ISHLT.

Summary

Orthotopic heart transplantation alone cannot sustain theincreasing demand for advanced therapies for end-stageheart failure. MCS devices, such as VAS and TAH, pro-vide enhanced BTT success and extend the quality of lifefor these patients. Pharmacotherapy is necessary both be-fore and after implantation of an MCS device. Likewise,pharmacologic management of the adverse effects of MCSdevices may minimize the morbidity associated with thesepumps. The clinical pharmacist can contribute significantlyto management of MCS through direct patient care, proto-col development, research activities, and education of pa-tients and providers.

Addendum

Preliminary results of the ADVANCE BTT trial of theHeartWare HVAD were presented at the 2010 AmericanHeart Association scientific sessions. The results were en-couraging; at 6 months, 92% of patients (per protocol)were alive with their original device or had received atransplant. Moreover, at 1 year, 90.6% of all patients (in-tent-to-treat) who had received an implant or transplantwere alive.150

Christopher R Ensor PharmD BCPS, Clinical Specialist, Cardio-thoracic Transplantation and Mechanical Circulatory Support; Clin-ical Assistant Professor, School of Pharmacy, University of Mary-land; Department of Pharmacy, Comprehensive Transplant Center,The Johns Hopkins Hospital, Baltimore, MD Christopher A Paciullo PharmD BCPS, Clinical Pharmacy Spe-cialist, Cardiothoracic Surgery Critical Care, Department of Phar-macy, Emory University Hospital, Atlanta, GAWilliam D Cahoon Jr PharmD BCPS, Clinical Pharmacy Special-ist, Cardiology; Clinical Assistant Professor, School of Pharmacy,Virginia Commonwealth University, Virginia Commonwealth Uni-versity Health System; Department of Pharmacy, Medical Collegeof Virginia Hospitals, Richmond, VAPaul E Nolan Jr PharmD FCCP FASHP, Professor, College of Phar-macy, University of Arizona; Senior Clinical Scientist, The Universi-ty Medical Center, Tucson, AZCorrespondence: Dr Ensor, [email protected]/Online Access: www.theannals.com/cgi/reprint/aph.1P459

Financial Disclosure: Dr. Nolan has received research and trav-el support from Syncardia Systems, Inc.; research, travel support,and consulting honoraria from Abiomed, Inc.; and serves as a con-sultant for Micromed, Inc.

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Farmacoterapia Para la Asistencia Circulatoria Mecánica: unAnálisis Global

CR Ensor, CA Paciullo, WD Cahoon Jr, y PE Nolan Jr


EXTRACTO

OBJETIVO: Proporcionar un análisis global de la farmacoterapia asociadaa la asistencia circulatoria mecánica en pacientes con insuficienciacardiaca terminal y servir de guía para los farmacéuticos en cuanto a laselección, valoración, y optimización de la medicación para estapoblación.

FUENTES DE DATOS: Se consultaron las bases de datos MEDLINE/PubMed,EMBASE, y Cochrane buscando artículos escritos en lengua inglesadesde enero 1960 a julio 2010 utilizando los siguientes términos debúsqueda: asistencia circulatoria mecánica, sistema de asistenciaventricular, dispositivo de asistencia ventricular, dispositivo de asistenciaventricular izquierdo, dispositivo de asistencia ventricular derecho,dispositivo de asistencia biventricular, corazón artificial, pulsátil,desplazamiento positivo, axial, centrífugo, hemostasia, hemorragia,hemodinámico, presión arterial, trombosis, tratamiento antitrombótico,anticoagulante, antiplaquetario, insuficiencia ventricular derecha,arritmia ventricular, anemia, malformación arteriovenosa, ictus,infección, y farmacéutico clínico.


CR Ensor et al.

SELECCIÓN DEL ESTUDIO Y MÉTODO DE EXTRACCIÓN DE LA INFORMACIÓN: Seevaluaron para su inclusión todos los estudios originales relevantes,meta-análisis, estudios sistemáticos, directrices, y recapitulaciones. Seexaminaron las referencias de los artículos relevantes para buscarmaterial adicional que no se hubiera encontrado en la búsqueda inicial.

SÍNTESIS DE LOS DATOS: La asistencia circulatoria mecánica (ACM) haavanzado de forma significativa desde que se implantó el primerdispositivo de asistencia ventricular izquierda en 1966. Los avancesadicionales en la tecnología de ACM que tuvieron lugar en la últimadécada están cambiando el tratamiento global de la insuficienciacardiaca terminal y del transplante cardiaco. Estas bombas mejoran lastasas de puente para transplante, incrementan las tasas de supervivenciay mejoran la calidad de vida del paciente. La farmacoterapia asociada alos dispositivos de ACM puede servir para optimizar el rendimiento delas bombas y mejorar la respuesta del paciente, así como minimizar lamorbilidad asociada a sus efectos adversos. Este estudio destaca elconocimiento necesario para proporcionar los servicios de farmaciaclínica adecuados a pacientes con dispositivos de ACM.

CONCLUSIONES: Los pacientes con dispositivos de ACM representan unasubespecialidad dentro de la insuficiencia cardiaca avanzada y eltransplante cardiaco. Los investigadores clínicos del dispositivoHeartMate II pidieron la implicación de un farmacéutico en lavaloración y optimización de pacientes con dispositivos ACM, en unreciente estudio global. El manejo farmacoterapéutico de pacientes condispositivos ACM es muy especial y requiere una individualizaciónsegún las características de la bomba y del receptor.

Traducido por Violeta Lopez Sanchez

Revue de la Pharmacothérapie Pour le Support de la CirculationMécanique

CR Ensor, CA Paciullo, WD Cahoon Jr, et PE Nolan Jr


RÉSUMÉ

OBJECTIFS: Présenter une revue de la pharmacothérapie utilisée dans lesupport de la circulation mécanique chez les patients souffrantd’insuffisance cardiaque terminale et présenter des recommandationsaux pharmaciens vis-à-vis la sélection, l’évaluation et l’optimisation desmédicaments pour ces patients.

SOURCE DES DONNÉES: Les banques de données MEDLINE/PubMed,EMBASE, et Cochrane ont été utilisées pour rechercher les référencesen langue anglaise avec les mots-clés suivants: mechanical circulatorysupport, ventricular assist system, ventricular assist device, leftventricular assist device, right ventricular assist device, biventricularassist device, total artificial heart, pulsatile, positive displacement, axial,centrifugal, hemostasis, bleeding, hemodynamic, blood pressure,thrombosis, antithrombotic therapy, anticoagulant, antiplatelet, rightventricular failure, ventricular arrhythmia, anemia, arteriovenousmalformation, stroke, infection et clinical pharmacist.

SÉLECTION DES ÉTUDES ET EXTRACTION DES DONNÉES: Toutes les référencesoriginales, méta-analyses, revues systématiques, lignes directrices etarticles de revue ont été évalués. Les références d’articles pertinents ontété examinées pour identifier des références additionnelles.

SYNTHESE DES DONNÉES: Le support de la circulation mécanique (SCM) aévolué de façon dramatique depuis l’implantation du premier dispositifdans un ventricule en 1966. Les avancements durant la dernièredécennie ont changé la prise en charge de l’insuffisance cardiaqueterminale et de la transplantation cardiaque. Les pompes ont permisd’allonger le temps possible avant la transplantation, la survie, de mêmeque la qualité de vie. La pharmacothérapie impliquée dans le SCM peutservir à améliorer la performance des pompes et améliorer les résultatsde santé. Cette revue met en évidence les connaissances requises afin depouvoir offrir les services de pharmacie clinique aux patients ayant desdispositifs de circulation mécanique.

CONCLUSIONS: Les patients nécessitant un SCM représentent une sous-spécialité dans le traitement de l’insuffisance et transplantationcardiaque. De plus, les chercheurs de l’étude HeartMate II ont réclamél’implication des pharmaciens dans la prise en charge de ces patients. Lagestion de la pharmacothérapie des patients nécessitant du SCM estunique et requiert un traitement individualisé selon les caractéristiquesdu patient et du dispositif utilisé.

Traduit par Nicolas Paquette-Lamontagne



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