NEW METABOLIC LUNG SIMULATOR:DEVELOPMENT, DESCRIPTION, AND VALIDATIONAbraham Rosenbaum, MD, Christopher Kirby, BSc , Peter

H. Breen, MD, FRCPC

The authors present the development, critical details, and validationof a practical metabolic lung simulator, to generate a wide range ofaccurate, adjustable, and stable reference values of CO2 productionand O2 consumption, for development, calibration, and validationof indirect calorimetry methodology and clinical monitors.

From the Department of Anesthesiology UCI Medical Center,University of California, Irvine, Building 53, Room 227, 101The City Drive South, Orange, CA 92868, USA.

Received 9 August 2006. Accepted for publication 25 October2006.

Address correspondence to Peter H. Breen, MD, FRCPC,Department of Anesthesiology UCI Medical Center, University ofCalifornia, Irvine, Building 53, Room 227, 101 The City DriveSouth, Orange, CA 92868, USA.E-mail: pbreen@uci.edu

Rosenbaum A, Kirby C, Breen PH. New metabolic lung simulator:

Development, description, and validation.

J Clin Monit Comput 2007; 21:71–82

ABSTRACT. Objective. Indirect calorimetry, the determination

of airway carbon dioxide elimination ðVCO2Þ and oxygen uptake

ðVO2Þ, can be used to non-invasively detect non-steady state

perturbations of gas kinetics and mirror tissue metabolism.

Validation of monitoring instruments in patients is difficult

because there is no standard reference measurement, a wide range

of physiologic values is required, and steady state is difficult to

achieve and confirm. We present the development, critical details,

and validation of a practical bench setup of a metabolic lung

simulator, to generate a wide range of accurate, adjustable, and

stable reference values of VCO2and VO2

, for development,

calibration, and validation of indirect calorimetry methodology

and clinical monitors. Methods. We utilized a metered alcohol

combustion system, which allowed safe, precise, and adjustable

delivery of ethanol to a specially designed wick system to

stoichiometrically generate reference VCO2and VO2

. Gas was

pumped through a circular circuit between the separate metabolic

chamber andmechanical lung, topreservebasic featuresofmammalian

gas kinetics, including a physiologic ventilation waveform and the

ability to induce non-steady state changes. Accurate and precise

generation of VCO2and VO2

were validated against separate

measurements of gas flow and gas fractions in a collection bag.

Results. For volume control ventilation, average error for VCO2and

VO2was )0.16%±1.77 and 1.68%±3.95, respectively. For pressure

control ventilation, average error for VCO2and VO2

was

0.90%±2.48% and 4.86%±2.21% respectively. Low values of

measured ethanol vapor and carbon monoxide supported complete

and pure combustion. Conclusions. The comprehensive

description details the solutions to many problems, to help future

investigations of metabolic gas exchange and contribute to improved

patient monitoring during anesthesia and critical care medicine.

KEY WORDS. oxygen uptake, oxygen consumption, respiratory

quotient, respiratory exchange ratio, indirect calorimetry, non-

steady state.

INTRODUCTION

Medicine in the 21st century is embracing non-invasivemonitoring [1, 2]. To that goal, the assessment of bodymetabolism by indirect calorimetry (respiratory gas ex-change measurement at the airway opening) is establishinga foothold in critical care medicine and anesthesia. Indi-rect calorimetry is used for the assessment of noninvasivemetabolic gas exchange in intensive care medicine [3, 4],including the assessment of metabolic expenditure and thetitration of nutritional support [5].

In most clinical indirect calorimetry systems, the mea-surement of airway carbon dioxide elimination ð _VCO2

Þ isgiven by

Journal of Clinical Monitoring and Computing (2007) 21:71–82

DOI: 10.1007/s10877-006-9058-4 � Springer 2007

_VCO2¼ _VE � F�ECO2

; ð1Þ

where _VE is the expired ventilation and F�ECO2is the mixed

expired CO2 (assumes the absence of CO2 in inspiredgas). By utilizing the Haldane transformation [5, 6] duringsteady state, which invokes conservation of the inert gasnitrogen ð _VI � FIN2

¼ _VE � F�EN2Þ, airway oxygen uptake

ð _VO2Þ is given by

_VO2¼ _VEðFIO2

� F�EN2=FIN2

� F�EO2Þ ð2Þ

where I denotes inspiration [6].The measurement of mixed expired gas fractions may be

obtained through the use of a mixing chamber (bymixer)[7, 8, 9] interposed in the expired limb of the ventilationcircuit, or a gas collection bag [4] or a mixing chamberattached to the exhaust port of a ventilator [4, 5, 10].

The development, testing, and validation of indirectcalorimetry clinical measuring systems require a reliable invitro metabolic lung simulator for several reasons. First,there are no available, accurate reference standard mea-surements of _VCO2

and _VO2in critical care medicine or

during anesthesia care. Second, in patients, it is difficult toboth maintain and confirm the presence of steady state,which is mandatory for validation data collections [11].Third, the metabolic lung simulator can quickly andaccurately generate a wide range of _VCO2

and _VO2values,

which would be impossible in patient studies. A thoroughsearch of the literature did not yield a detailed description ofa practical metabolic lung simulator capable of quicklygenerating a wide range of adjustable, accurate, and stablevalues of _VCO2

and _VO2over a wide array of tidal volume

and respiratory frequency. A further design requirementwas the coupling of a mechanical lung and metabolic en-gine, in order to hydraulically model mammalian gas ex-change.

This paper details the solutions to many technicalproblems which we overcame in order to attain an accu-rate and stable metabolic lung simulator, which must havethe capability to measure and resolve a few milliliters of O2

or CO2 out of many hundred milliliters of tidal volume.Using separate and independent measurements of gas flowand gas fractions in a collection bag, we validated themetabolic lung simulator, so that the system can serve as areliable reference standard for studies of indirect calorim-etry.

MATERIALS AND METHODS

Overview

A mechanical lung was connected through a circular cir-cuit to an airtight, rigid metabolic chamber (Figure 1). Aprecision infusion pump and custom burner providedmetered ethanol combustion in the chamber, which wasadhered to the bottom of a large, flat, open container. Tapwater constantly flowed through a port into the containerand flowed out of a second port into a sink drain, forminga constant temperature (T) water jacket around themetabolic chamber. An occlusive roller pump generatedconstant gas flow (5 L/min) between the metabolicchamber and the mechanical lung. The metabolic

COLLECTIONBAGROLLER

PUMP

O2

AIR

BYMIXER

INSPIRATION VALVE

EXPIRATION VALVE

PNEUMO-TACHOMETER

HUMIDITY and T SENSOR

VENTILATOR

BAFFLESYRINGE PUMP + CUSTOM ALCOHOL BURNER

EXHAUSTPORT

WATERBATH METABOLIC

CHAMBER

HEAT SHIELD

MECHANICALLUNG

Fig. 1. Metabolic lung simulator. The mechanical lung was connected to the rigid wall metabolic chamber through a circular circuit. An occlusive roller pumpdrove gas flow through the circuit at 5 L/min. A precision syringe pump delivered an adjustable, metered flow of ethanol to the custom burner assembly insidethe metabolic chamber. The metabolic chamber was maintained at constant temperature in a cooling water bath. A gas collection bag (Douglas bag) [5, 7, 10]was attached to the exhaust port of the ventilator. Airway flow was measured by the pneumotachometer. Airway humidity and temperature (T) were measuredby the fast-response airway sensor [14]. Reprinted with permission from Anesthesiology 2004; 100: 1427–37.

72 Journal of Clinical Monitoring and Computing

lung simulator was validated against separate measurementsof gas flow and gas fractions measured in a collectionbag. The practical absence of measured ethanol vaporand carbon monoxide supported complete and purecombustion of ethanol. The lung simulator was venti-lated with a clinical ventilator (Servo Ventilator 900C,Sweden).

Mechanical lung and metabolic chamber

A commercial mechanical lung (Dual Adult TTL, Model1600, Michigan Instruments, Inc., Grand Rapids, MI) [8,9, 12, 13], designed for ventilator testing, generated nor-mal respiratory compliance (C, 40 ml/cm H2O) and air-way resistance (R, 5 cm H2O � L�1 � s�1), to facilitate aphysiologic ventilation waveform. Adjustment of springson the mechanical lung bellows and insertion of resistanceelements into the airway system permitted independentregulation of C and R, respectively. In order, theY-junction of the ventilation circuit was connected to thepneumotachometer adapter (Capnomac Ultima, DatexMedical Instruments, Instrumentarium Corp., Helsinki,Finland), the fast-response humidity and temperaturesensor [14], and a 50 cm tube leading to the mechanicallung.These latter three components composed the ana-tomical dead space of the mechanical lung, determined bythe Bohr calculation to be 150 ml. End-expiratory volume(EEV) was 920 ml. Depending on the alcohol infusion andcombustion rate, the mechanical lung was ventilated withtidal volumes (VT) of 250–1000 ml and respiratory fre-quencies ( f ) of 7–14 breaths per minute, to achieve an

end-tidal PCO2ðPETCO2

Þ of about 40 mmHg. We alsotested the system with pressure control ventilation sincethe high initial flow could stress the measurement.

We used an occlusion roller pump (15 mm ID tubing;Precision Blood Pump, COBE Perfusion system, Lake-wood, CO) to generate a circular gas flow from themechanical lung to the metabolic chamber, composed of a5.7 L pressure cooker. The pressure cooker�s relief valvewas disabled and converted to a tube connector to thelung chamber. The emergency release valve of the cookerwas sealed. (Emergency pressure relief was served byplastic tubing separation at a connector).

Although the pump was designed for liquids, the rollerhead could be adjusted to occlude the tubing and provideconstant, unidirectional, and measurable gas flow. The gaswas pumped from the mechanical lung into the metabolicchamber (rather than the reverse direction), in order toslightly pressurize the metabolic chamber and minimizetidal volume incursion from the mechanical lung. Inaddition, this direction of gas flow allowed the pressureoscillations, generated by rotation of the roller pump

head, to cause less aberration of the expiratory flow airwaywaveform. Before each study, the roller pump waschecked for occlusion by observing implosion of the inlettube when it was occluded (i.e. roller pump suctioned allof the gas out of the tube).

Alcohol combustion system to generate CO2 production

and O2 consumption

A high precision, continuous flow, screw-type syringepump (Syringe Pump A-99, Razel Scientific InstrumentsInc., Stanford, CT) was utilized to drive a 60 ml syringe(Becton Dickinson & Co., Franklin Lakes, NJ), whichdelivered an adjustable, metered flow of ethanol to theburner assembly inside the metabolic chamber (Table 1).The ethanol flow rate from the syringe pump was vali-dated, in a separate procedure, by liquid ethanol collectionand gravimetric analysis over time.

To provide a stable flame, we designed and constructeda custom alcohol burner. The syringe pump was con-nected to a 20 cm 1/8" OD copper tube, which termi-nated in an elbow brass fitting (Swagelok Co. Cleveland,OH). This fitting held the 1/8" cotton wick (PM ResearchInc. Wellsville, NY). At low ethanol infusion rates, a baffleprotected the small flame from being extinguished.

The alcohol was pure ethanol (Gold Shield Alcohol,proof 200, Hayward, CA). Oxygen was consumed andCO2 and water were produced, facilitating simple andaccurate reference values of _VCO2

and _VO2(see Equations

3–6). In contrast, combustion of unpurified alcohol sig-nificantly complicated the calculations [15].

The combustion of ethanol [10, 16, 17] was given bythe equation:

C2H5OHþ 3O2 ! 2CO2 þ 3H2O ð3Þ

so that the respiratory quotient, RQ (= _VCO2= _VO2

) was2/3 (0.667). For a given minute volume delivery (ml/min) of liquid ethanol (Q),

Molesethanol ¼ q �Q=MW ; ð4Þ

where q was the density of ethanol (0.7893 g/ml) [18, 19]at syringe T (25 �C) and MW was the molecular weightof ethanol (46.069 g/mole).

Avogadro�s law states that one mole of a gas has avolume of 22,414 ml STPD (standard temperature andpressure, dry). Accordingly,

_VCO2ðml/min, STPDÞ ¼ Molesethanol � 2 � 22; 414; ð5Þ

and

_VO2ðml/min, STPDÞ ¼ Molesethanol � 3 � 22; 414: ð6Þ

Rosenbaum et al.: New Metabolic Lung Simulator 73

Mixed expired gas fractions (Figure 1, Equations 1 and 2)must also be measured dry. In clinical monitors (includ-ing our Capnomac Ultima), water permeable tubing(Nafion�), in the gas sampling system upstream from themeasurement cuvette, allowed measurement of dry gasfractions [4].

Cooling system

In order to maintain safe and stable temperature, weplaced the metabolic chamber inside a 30 L water bath(aluminum pot). Temperature-controlled tap waterflowed (about 2,000 ml/min) into the water bath (24 �C),enveloped the metabolic chamber, and drained out of thewater bath at the same flow rate. The water bath level wasmaintained at 2.5 cm above the top of the metabolicchamber. To prevent floating in the water bath, themetabolic chamber was cemented (via epoxy glue) to thebottom of the cooling bath pot. Inside the metabolicchamber, a heat shield dissipated heat away from the lidand the outflow PVC tube.

Leakage

Achieving a leak-proof system was a technicallydemanding and detailed oriented task. Regular tubingcomponents, such as standard connectors and rubberO-rings, were utilized as much as possible. An alternativemethod to connect tubing was via a small caliber PVCtube that fit tightly inside a larger caliber tube. A brassadapter connected the PVC tubes to the pressure cooker.

Plumber�s putty was used successfully to seal small leaksaround connections to the metabolic chamber. Plumber�sputty remained malleable and maintained a seal evenwhen immersed in water. Before each study, we con-firmed the absence of leaks by pressurizing the metaboliclung simulator system to 40 cm H2O. Given the normalC of 40 ml/cm H2O of the metabolic lung, the lungbellows increased to about 1.6 L. The resolution of thevolume scale of the lung bellows was 20 ml. Therefore,any descent of the inflated mechanical lung, observed overseveral minutes, enabled the detection of a leak. Thespraying of soapy water was the most reliable and simplestmethod to pinpoint leaks, heralded by the extensive for-mation of bubbles. In addition, any leaks from the met-abolic chamber generated a steady stream of bubbles in thecooling water bath.

Airway Flow Validation

We validated the airway flow pneumotachometer airwayadapter (D-LiteTM) and monitor (Capnomac Ultima) withthe manufacturer�s U-shaped water-displacement refer-ence spirometer, incorporating both adult and pediatricchambers. The ventilator delivered VT sequentiallythrough the pneumotachometer and through an endo-tracheal tube into the spirometer. Pneomotachometerflow was integrated with respect to time to generatedmeasured VT, which was compared to the spirometervalue. Each VT was averaged over six consecutive breaths.This validation procedure was repeated over a range of 11different VT (250–1200 ml). The entire experiment was

Table 1. Stoichiometric generation of CO2 production ð _VCO2Þ and O2 consumption ð _VO2

Þ by ethanol combustion in the metabolic chamber:effects of incomplete combustion to carbon monoxide (measured CO) or non-combustion (measured ethanol vapor)

Ethanol liquid infusion CO Ethanol vapor Total % errors

ml/min Stoichiometric ppm % Error ppm % Error

_VCO2

(ml/min)

_VO2

(ml/min)

_VCO2_VO2

_VCO2or

_VO2

_VCO2_VO2

0.087 66.8 100.2 40.2 0.30 0.10 40.2 0.60 0.90 0.70

0.173 132.9 199.3 10 0.04 0.01 55.3 0.42 0.45 0.43

0.260 199.7 299.5 10 0.03 0.01 199 1.00 1.02 1.00

0.347 266.5 399.8 10 0.02 0.01 1008 3.78 3.80 3.79

0.433 332.6 498.8 10 0.02 0.01 1653 4.97 4.99 4.98

Average error 0.08 0.03 2.15 2.23 2.18

SD 0.12 0.04 2.08 2.03 2.06

1.96Æ SD 0.24 0.08 4.08 3.97 4.04

The combustion of each infusion rate of liquid ethanol results in the stoichiometric generation of _VCO2and _VO2

. Measured CO in themetabolic chamber resulted from incomplete combustion of ethanol. Measured ethanol vapor resulted from unburned liquid ethanol. Thesevalues of incomplete combustion or non-combustion of ethanol generate calculated expected errors in _VCO2

and _VO2(see Appendix,

Equations, 14, 17, and 18). ppm, parts per million; SD, standard deviation.

74 Journal of Clinical Monitoring and Computing

repeated four times. For VT of 250 ml, we used thepediatric chamber of the calibrating spirometer and thepediatric pneumotachometer airway cuvette (Pedi-LiteTM).

_VO2and _VCO2

validation

After reaching steady state, a non-diffusing gas collectionbag (Hans Rudolph Inc, Kansas, MO), was connected tothe ventilator exhaust port, to collect approximately 10–15 consecutive exhaled VT. The collection bag wasmanually agitated to achieve a homogeneous gas mix-ture. The side-stream sampling gas analyzer (CapnomacUltima) measured mixed gas fractions (FICO2

, FIO2, F�ECO2

and F�EO2) by directing a stopcock first to sampling tubing

attached to the inspiratory limb and then to samplingtubing connected to the exhaust gas collection bag(expiration). Inspired and expired gases were each sam-pled over a period of 60 s. Prior to the exhaust gascollection, the bag was emptied by suction to avoid gasdilution. Airway pressure and flow ( _V, pneumotach-ometry) were measured. Airway temperature (T) andhumidity ðPH2OÞ were measured with the fast responseairway sensor [14].

Conversion of _V to STPD conditions [6] proceeded by:

_VSTPD ¼ _VATPS � ð½PTOT � PH2O�=PTOTÞ� ð273=½273þ T �Þ � ðPTOT=760Þ ð7Þ

where airway _V was measured at ambient temperature,pressure, and saturation conditions (ATPS), PTOT wasambient barometric pressure plus airway pressure, andPH2O was the water vapor partial pressure. Equation 7converted ambient temperature, pressure, and saturation(ATPS) to STPD [6] by removing volume expansion dueto water vapor (second term on right side of equation), byremoving volume expansion due to thermal changesabove 0 �C (third term), and by removing volume changedue to a pressure variation from 760 mm Hg (fourthterm). Airway _VCO2

and _VO2were then calculated

according to Equations 1 and 2, respectively.

Validation of complete combustion

In Table 1, the combustion of each infusion rate of liquidethanol resulted in the stoichiometric generation of _VCO2

and _VO2. Appendix 1 describes how measured CO in the

metabolic chamber resulted from incomplete combustionof ethanol. Measured ethanol vapor resulted fromunburned liquid ethanol. These values of incompletecombustion or unburned ethanol generated calculatedexpected errors in _VCO2

and _VO2(see Appendix 1,

Equations, 12, 15, and 16).

Data acquisition and analysis

All data signals were continuously captured (100 Hz) byan analog-to-digital (A/D) acquisition PC card (DAQcard700, National instruments, Austin, TX) installed in anotebook computer. The digital data acquisition systemwas driven by a custom program (Delphi Pascal, BorlandInternational, Scotts Valley, CA) written by our computersupport specialist (David Chien) and one author (PHB).

Statistical analysis

Airway _VCO2and _VO2

were compared to the stoichi-ometric values generated by ethanol combustion by leastsquares linear regression (slope, Y-intercept, and coeffi-cient of determination, R2) and by the Limits of Agree-ment technique described by Bland and Altman [20, 21].We developed a spreadsheet program (Excel spreadsheet,Microsoft Corp., Redmond, WA) to automate calcula-tions of _VCO2

and _VO2. Computer programs assisted sta-

tistical analysis (Medcalc, Medcalc Software, Mariakerke,Belgium), and graphical presentation (SigmaPlot 8.0,SPSS, Chicago, IL).

RESULTS

Airway flow validation

The upper panel of Figure 2 depicts the excellent linearcorrelation between volume measured by airway flow-meter (pneumotachometry) versus volume measured bywater-displacement spirometer (n = 44, slope = 0.99,Y-intercept = 5.66, and R2 = 0.996). The average error(±SD) was 0.56 ± 3.59%. In the Bland–Altman analysis[20](middle panel), the difference between flowmeter andspirometer volumes was plotted against the mean of thetwo values. Limits of agreement (LOA) were)0.09 ± 41.12 ml. Note that the difference betweenflowmeter and spirometer volumes increased as the meanvalue increased along the X-axis. Accordingly, the Bland–Altman ratio plot [21] was invoked in the lower panel.The ratio of flowmeter V-to-spirometer V was plottedagainst the mean of the two values. The ratio LOA were1.006 ± 0.070, which represents an error of 0.6 ± 7.0%.

_VCO2and _VO2

validation

Table 2 displays the measurements of _VCO2and _VO2

usingexhaled airway flow, inspired gas fractions, and expiredgas fractions in the exhaust gas collection, compared to thestoichiometric reference values of _VCO2

and _VO2gener-

Rosenbaum et al.: New Metabolic Lung Simulator 75

ated by five infusion rates of ethanol into the metaboliccombustion chamber. The range of _VCO2

was 67 to334 ml/min and the range of _VO2

was 100–500 ml/min.Average (±SD) errors for _VCO2

and _VO2were

)0.16% ± 1.77% and 1.68% ± 3.95%, respectively. Aver-age RQ was 0.655 ± 0.021.

In Figure 3, the upper left panel displays the excellentlinear regression between _VCO2

measured by expired gas

collection versus the values generated by stoichiometriccombustion of ethanol. Slope (m) was 1.00, Y-intercept (b)was )0.89, and R2 was 0.996. In the Bland–Altman analysis[20] (left middle panel), the difference between gas collec-tion _VCO2

and stoichiometric _VCO2was plotted against the

mean of the two values. Limits of Agreement (LOA) were)0.29 ± 11.19 ml/min. Note that the difference betweengas collection _VCO2

and stoichiometric _VCO2increased as

the mean value increased along the X-axis. Accordingly,the Bland–Altman ratio plot [21] was invoked in the leftlower panel. The ratio of gas collection _VCO2

-to-stoichi-ometric _VCO2

was plotted against the mean of the twovalues. The ratio LOA (mean � 1:96� SD) were0.998 ± 0.043, which represented an error of)0.2% ± 4.3%.

The right panels of Figure 3 display the similar data forthe comparison of _VO2

measured by expired gas collectionversus the values generated by stoichiometric combustionof ethanol. Linear regression (upper right panel) yieldedslope of 1.00, Y-intercept of 4.09, and R2 of 0.988. Thedifferences LOA (right, middle panel) were3.19 ± 30.14 ml/min. The ratio LOA (mean �1:96� SD)was 1.017 ± 0.088, which represented an error of1.7% ± 8.8%.

We also tested the measurement with pressure controlventilation, over peak inspiratory pressure range of 16–24 cmH2O. Average error (±SD) for _VCO2

and _VO2was

0.90% ± 2.48% and 4.86% ± 2.21% respectively. Linearregression analysis showed R2, slope and intercept of0.998, 0.98 and 5.35 for _VCO2

and 0.999, 1.03 and 5.30for _VO2

, respectively.Figure 4 demonstrates typical flow ( _V), pressure (P),

and volume (V) over three breaths, as captured from themetabolic lung simulator during pressure control venti-lation (lower panel) and volume control ventilation (up-per panel). Alcohol infusion rate was set for _VCO2

and _VO2

of 333.5 and 500.5 ml/min in both instances.

(Flowmeter V + Spirometer V)/2 (mL)0 200 400 600 800 1000 1200 1400 1600

Flo

wm

eter

V -

Spi

rom

eter

V (

mL)

-60

-40

-20

0

20

40

60

Spirometer V (mL)0 200 400 600 800 1000 1200 1400

Flo

wm

eter

V (

mL)

0

200

400

600

800

1000

1200

1400

m = 0.99b = 5.66

R2= 0.996

(Flowmeter V + Spirometer V)/2 (mL)0 200 400 600 800 1000 1200 1400

Flo

wm

eter

V /

Spi

rom

eter

V

0.90

0.95

1.00

1.05

1.10

1.15

1.01

1.08

0.94

1.96 SD

Mean

-1.96 SD

1.96 SD

Mean

-1.96 SD

41.0

-0.1

-41.2

Fig. 2. Validation of airway flow measurement. The Upper panel displaysthe linear regression of the volume (V) measured by the airway flowmeter(integration of pneumotachometer flow over expired time) versus V measuredby water-displacement spirometer (Datex-Ohmeda, InstrumentariumCorp., Helsinki, Finland) over a tidal volume range of 200–1200 ml(n = 44). m, slope; b, Y-intercept; R2, coefficient of determination. Theaverage error (±SD) was 0.56± 3.59%. In the Bland–Altman analysis[20] (Middle Panel), the difference between flowmeter V and spirometer Vwas plotted against the mean of the two values. Limits of agreement (LOA)were )0.09 ± 41.12 ml. Note that the difference between flowmeter V andspirometer V increased as the mean value increased along the X-axis.Accordingly, the Bland–Altman ratio plot [21] was invoked in the LowerPanel. The ratio of flowmeter V-to-spirometer V was plotted against themean of the two values. The ratio LOA were 1.006±0.070, which rep-resents an error of 0.6 ± 7.0%.

b

76 Journal of Clinical Monitoring and Computing

Purity of combustion (Table 1)

The average error in _VCO2or _VO2

due to incompletecombustion of ethanol to CO was less than 0.1% (seeAppendix 1). The average error in _VCO2

or _VO2due to

unburned ethanol was 2.2%. Ethanol evaporation wasmore pronounced at higher ethanol infusion rates.

DISCUSSION

We have previously provided a brief overview of themetabolic lung simulator [22]. In this paper we havepresented a practical, detailed description of the meta-bolic lung simulator, which generated a wide range ofaccurate, adjustable, and stable reference values of _VCO2

and _VO2, for development, calibration, and validation of

indirect calorimetry methodology and monitors. Com-pared to the expired gas collection method, errors for_VCO2

were )0.2% ± 4.3% and errors for _VO2were

1.7% ± 8.8% (Figure 3). In the gas collection method tomeasure _VCO2

and _VO2, an airway pneumotachometry

flow measurement was utilized in order to incorporatecontinuous conversion of flow (and volume) to STPDconditions, using the fast-response airway sensor oftemperature and humidity (14). Without conversion toSTPD conditions, the errors in airway _VCO2

and _VO2

increased by 8.71% ± 4.19% and 10.45% ± 6.25%,respectively. The airway pneumotachometry flowmeasurement was separately validated against a waterdisplacement spirometer (Figure 2). This validation ofairway flow can help separate errors in gas flow from

Table 2. Measurements of airway CO2 elimination ð _VCO2Þ and O2 uptake ð _VO2

Þ using exhaled airway flow, inspired gas fractions, andmixed expired gas fractions in the exhaust gas collection, compared to the stoichiometric reference values of _VCO2

and _VO2generated by

combustion of five infusion rates of ethanol in the metabolic chamber

_VCO2(ml/min) _VO2

(ml/min) R

Stoichiometric

(ethanol combustion)

Expired flow and

gas collection

Error (%) Stoichiometric

(ethanol combustion)

Expired flow

and gas collection

Error (%)

333.5 351.8 5.49 500.3 540.8 8.10 0.651

266.8 262.5 )1.63 400.2 410.1 2.48 0.640

200.1 200.8 0.34 300.2 317.6 5.81 0.632

133.4 135.7 1.69 200.1 200.5 0.22 0.676

66.7 66.9 0.34 100.1 104.4 4.33 0.641

333.5 330.5 )0.91 500.3 514.0 2.75 0.643

266.8 269.0 0.84 400.2 400.4 0.06 0.672

200.1 199.1 )0.52 300.2 308.8 2.88 0.645

133.4 133.9 0.35 200.1 210.5 5.22 0.636

66.7 67.0 0.43 100.1 107.0 6.91 0.626

333.5 330.4 )0.94 500.3 487.4 )2.58 0.678

266.8 257.0 )3.67 400.2 383.5 )4.18 0.670

200.1 199.3 )0.42 300.2 303.0 0.94 0.658

133.4 134.2 0.63 200.1 213.7 6.78 0.628

66.7 66.4 )0.42 100.1 102.7 2.58 0.647

333.5 333.3 )0.06 500.3 496.7 )0.70 0.671

266.8 264.0 )1.04 400.2 375.7 )6.13 0.703

200.1 196.9 )1.61 300.2 287.6 )4.18 0.685

133.4 131.1 )1.72 200.1 200.1 0.01 0.655

66.7 66.5 )0.31 100.1 102.4 2.25 0.650

Average -0.16 1.68 0.655

SD 1.77 3.95 0.021

1.96Æ SD 3.46 7.75 0.041

Each value represents the average of five consecutive measurements. Four experiments, on separate days, are shown. R, respiratory exchangeratio (= _VCO2

= _VO2Þ.

Rosenbaum et al.: New Metabolic Lung Simulator 77

errors in gas fraction measurements during analysis ofindirect calorimetry measurements.

We also tested the system with pressure control modesince the high initial inspiratory flow might stress the mea-surement. Average error and linear regression were excellentsimilar to the volume controlled ventilation mode. Figure 4demonstrates how the metabolic lung simulator generatedphysiologic respiratory waveforms for both volume controlventilation and pressure control ventilation.

We present the combustion of metered liquid ethanolto stoichiometrically consume O2 and produce CO2 as anaccurate reference standard for generation of _VO2

and_VCO2

. With absence of gas leaks in the metabolic lungsimulator, the only potential pitfalls were incompletecombustion of ethanol to CO or evaporation (and

non-combustion) of ethanol. Table 1 presents the mea-surements of CO and unburned ethanol vapor in themetabolic chamber, which generated calculated expectederrors in _VCO2

and _VO2(see Appendix 1, Equations, 12,

15, and 16). The average error in _VCO2or _VO2

due toincomplete combustion of ethanol to CO was negligible(<0.1%). The average error in _VCO2

or _VO2due to un-

burned ethanol was only 2.2%. Thus, the accuracy of themetabolic chamber was not significantly affected by eitherunburned or incomplete combustion of ethanol.

The design of our metabolic lung simulator encompassedbasic features of mammalian gas kinetics [9, 12], not foundin other metabolic engines. In our system, the mechanicallung and the metabolic chamber were connected in a cir-cular circuit controlled by an occlusion roller pump. This

0 100 200 300 400 500-20

-10

0

10

20

0 100 200 300 400 500

. VC

O2R

atio

0.92

0.96

1.00

1.04

1.08

..VCO2 Average (mL/min) VO2 Average (mL/min)

0 100 200 300 400 500 600 700

. VO

2Rat

io

0.85

0.90

0.95

1.00

1.05

1.10

1.151.96 SD

Mean

-1.96 SD

1.02

1.11

0.93

1.96 SD

1.96 SD

Mean

Mean

-1.96 SD

-1.96 SD-0.3

10.9

-11.5

1.00

0.96

0 100 200 300 400 500 600 700

-40

-20

0

20

40

60

1.96 SD

Mean

-1.96 SD

33.3

3.2

-27.0

VO2 Average (mL/min).V

CO

2Diff

eren

ce (

mL/

min

)

. VO

2Diff

eren

ce (

mL/

min

).

VCO2 Average (mL/min).

.VO2 Stoichiometry (mL/min)

0 100 200 300 400 500 6000

100

200

300

400

500

600

m= 1.00b= 4.09R2= 0.988

.VCO2 Stoichiometry (mL/min)

0 100 200 300 400. VC

O2 C

olle

ctio

n B

ag (

mL/

min

)

. VC

O2 C

olle

ctio

n B

ag (

mL/

min

)

0

100

200

300

400

m= 1.00b= -0.89R2= 0.996

1.04

Fig. 3. Validation of _VCO2and _VO2

. The upper left panel displays the linear regression between _VCO2measured by expired gas collection versus the values

generated by stoichiometric combustion of ethanol. m, slope; b, Y-intercept; and R2, coefficient of determination. In the Bland–Altman analysis [20] (leftmiddle panel), the difference between gas collection _VCO2

and stoichiometric _VCO2was plotted against the mean of the two values. Limits of Agreement (LOA)

were )0.29 ± 11.19 ml/min. The Bland–Altman ratio plot (21) was invoked in the left lower panel. The ratio of gas collection _VCO2-to-stoichiometric

_VCO2was plotted against the mean of the two values. The ratio LOA (mean ± 1.96 Æ SD) were 0.998 ± 0.043, which represented an error of

)0.2% ± 4.3%. The right panels display similar data for the comparison of _VO2measured by expired gas collection versus the values generated by

stoichiometric combustion of ethanol. Linear regression is depicted in the upper right panel. The differences LOA (right middle panel) were 3.19±30.14 ml/min. The ratio LOA (right lower panel) were 1.017 ± 0.088, which represented an error of 1.7% ± 8.8%.

78 Journal of Clinical Monitoring and Computing

design allowed for physiologic gas flow waveforms duringmechanical ventilation, with independent control of airwayresistance and respiratory system compliance. The systemdesign permits the introduction of non-steady state per-turbations (e.g. change in ethanol combustion rate or anabrupt decrease in roller pump flow rate) to address the

magnitude of effects of non-equilibrium states on the air-way measurements of indirect calorimetry.

We now present a review and comparison of previousimplementations of metabolic engines. Some workershave invoked the combustion of a precise volume ofalcohol [10, 18], but steady state could not be supported.Other researchers have delineated the limitations of astandard alcohol burner incorporating a wick [16, 23].Our previous studies have also demonstrated that thecapillary action drawing alcohol flow up the wick wasneither stable nor easily adjustable [13]. Our study is thefirst to implement a wick burner supplied by alcoholdelivered from a precision infusion pump. The wickburner in our design was widely exposed in the metabolicchamber. This exposure facilitated gas mixing and pre-vented the collection of the products of ethanol com-bustion (CO2 and H2O) around the wick burner, whichin turn could result in incomplete combustion or extin-guishment of the flame. The wide exposure of the wickburner also facilitated cooling via convection to preventalcohol evaporation [18, 23, 25] instead of combustionand also supported a wide range of ethanol combustionrates [26]. The wick burner precluded the need to usecomplicated and expensive combustion units [16]. Theabsence of carbon deposits supported the completecombustion of ethanol [15].

Instead of burning liquid alcohol, we [9, 12] and otherinvestigators [4, 15, 23, 27] have used the combustion ofbutane gas. However, this method requires a precisionflowmeter, which must be calibrated for butane gas andcapable of measuring a low gas flow range (11–57 ml/min)[15]. Butane gas flows must be converted to STPD con-ditions, requiring the measurement of gas T at the butaneflowmeter and a supply tank of dry butane gas (see below).Alternatively, the butane tank was weighed [23] and thegravimetric change in butane over time was converted toSTPD ml per min. Other novel but impractical systemshave included the sublimation of CO2 gas from dry ice orthe gravimetric change of burning steel wool [25].

Another common approach to generate _VCO2and _VO2

was the metered infusion of CO2 and N2, respectively,into the metabolic chamber. The N2 diluted O2 in thechamber to effectively create _VO2

. Measurement of CO2

and N2 gases was by mass or flow. The gravimetricweighing of gas tanks [18, 26] was clumsy, requiring anaccurate scale capable of measuring small weight changesof gas in a heavy cylinder. Measurement of gas flows [27]require precise flow-controllers, and accurate flowmeters[23, 25, 29, 30] which should be validated with high res-olution spirometers, such as a rolling seal O-ring spirom-eter [23] or a mercury seal O-ring spirometer [31]. A waterseal spirometer can add water vapor volume to the gas flowto be measured, which invoked complex calculations to

0 5 10 15 20

-50

0

0

0

Time (seconds)

V.

V (

L/m

in)

.

Time (seconds)0 5 10 15 20

-50

0

50

V (

mL)

0

500

1000

P

(cm

H2O

)

02040 Pressure Control Ventilation

50500

1000

2040

P

(cm

H2O

)

V (

mL)

Volume Control Ventilation

P

V

P

V

V

.

V (

L/m

in)

.

Fig. 4. Typical flow ( _VÞ, pressure (P), and volume (V) over 3 breaths,generated by the metabolic lung simulator during pressure control ventilation(lower panel) and volume control ventilation (upper panel). Alcohol infusionrate was set for _VCO2

and _VO2of 333.5 and 500.5 ml/min in both

instances. During pressure control ventilation, in order to maintain PETCO2

of 40 mmHg, peak inspiratory pressure and respiratory rate were set to24 cmH2O and 10 breath/min, respectively. During volume control ven-tilation, volume and respiratory rate were set to 1000 ml and 10 breath/min, respectively. Compared to volume control ventilation, pressure controlventilation generated higher inspiratory flow rate. This figure shows that themetabolic lung simulator generated physiological respiratory waveforms.

Rosenbaum et al.: New Metabolic Lung Simulator 79

convert gas flows to STPD conditions. This problem isencountered also with the H2 combustion methods, usedto demonstrate _VO2

by generation of water [32].Compared to both the non-combustion metabolic

chamber systems and combustion of butane gas, a keyadvantage of liquid alcohol combustion was that thestoichiometric calculations of _VCO2

and _VO2(Equations

3–6) do not involve measurement of gas flows, do not involvecomplex STPD correction procedures, and instead de-pend only on an accurate delivered flow of liquid ethanolat known T. The combustion of liquid ethanol alsogenerated a constant, known RQ of 0.667 (Eq. 3),independent of ethanol delivery flow and rate of com-bustion [25, 28]. Even in the case of ethanol evaporation(see above), RQ would not deviate from 0.667. Theknowledge of fixed RQ helped to assess problems withthe metabolic chamber [4]. For example, if RQ wascorrect, leakage in the system was unlikely.

Most studies were performed using an FIO2of 60% (FIN2

= 40%), since most patients in the critical care environ-ment are ventilated with oxygen fractions at or belowthis level. At higher FIO2

, the accuracy of airway flowand gas fraction measurement of _VO2

degrades as thefraction of nitrogen increases in the respiratory gas (Eq. 2)[4, 15, 24]. We did not test the metabolic lung simulatorwith FIO2

above 80% to avoid risk of acceleratedcombustion.

Conservation of the inert gas, nitrogen (Haldanetransformation), allows determination of the volume dif-ference between inspiration and expiration due to dif-ferences in inspired and expired T and humidity [6].Classical respiratory physiology emphasizes that steadystate is mandatory for the nitrogen conservation principle[11]. Equilibrium before a measurement was also man-datory so that _VCO2

and _VO2were equal in the metabolic

chamber and the mechanical lung. This requirement forsteady state, during validation experiments, cannot beover-stated. Criteria for steady state were stable values ofend-tidal PCO2

, FIO2, and FETO2

. Depending on themagnitude of changes to the system, especially the ethanolinfusion rate, the attainment of steady state would requirebetween 15 and 60 min.

Any leak in the metabolic lung simulator critically af-fected the reference standards of _VCO2

and _VO2. For

example, a 60 ml/min leak out of the system, from thetube transporting gas from the chamber back to the lung,can cause an error of 10%, given an expected _VO2

of300 ml/min and Fo2 of leakage gas equal to 0.5. Leaks inthe metabolic lung simulator had systematic effects on thelinear regression correlation of airway measurements of_VCO2

and _VO2versus the stoichiometric values. For

example, a tiny hole in the metabolic chamber, whose gaspressure was always higher than ambient pressure, caused

gas leakage out of the system, which masqueraded asadditional O2 consumption. Because the gas leak ratevaried with system pressure, there were variable effects onslope and intercept. However, during the presence ofleaks there was still strong correlation between the airwayand stoichiometric values (values of coefficient of deter-mination, R2, near unity) of _VCO2

and _VO2.

A critical feature of the mechanical lung design was themaintenance of precise end-expired volume (EEV, i.e.‘‘functional residual capacity’’) by two springs that re-turned the bellows firmly to a metal stop to define end-expiration. Any variation in EEV would perturb steadystate balance and equality of gas exchange between themetabolic and lung chambers. In the literature, manymetabolic engines lacked precise control of EEV [15,16, 27]. Our mechanical lung model (Dual Adult TTL)had two separate bellows systems. To minimize potentialfor leaks, only one bellow was used. The metabolicchamber was part of the EEV, so that the use of a rigidwall chamber allowed for the maintenance of a stableEEV.

We found that the smaller 5.7 L pressure cooker pro-vided a well-mixed metabolic chamber, without the needfor an internal fan. The small volume of the chamber alsofacilitated the reaching of steady state conditions within15–20 min. In addition, the small volume of the meta-bolic chamber minimized the incursion of tidal volumefrom the mechanical lung into the metabolic chamber,due to gas compliance. For example, at an end-inspiratorypressure of 15 cm H2O and a large metabolic chambervolume of 25 L, 363 ml from the mechanical lung wouldflow through the right connecting tube (Figure 1) intothe metabolic chamber.

The pressure cooker had several other advantages. Itsaluminum wall allowed for excellent heat transformation,so that the metabolic chamber�s temperature could beeasily controlled by the water bath. The pressure cookerimproved the safety of the system, especially during highFIO2

conditions, when compared to plastic chambers. Thepressure cooker also facilitated a leak-proof system since,by design, the container was airtight.

In conclusion, we have presented critical elements of apractical metabolic lung simulator, to generate a widerange of accurate, adjustable, and stable reference values of_VCO2

and _VO2, for the development, calibration, and

validation of indirect calorimetry methodology andmonitors. Attention to detail in this study was essentialand rewarding.

The authors thank David Chien, BSc for assistance in the

development of the metabolic lung simulator and Heike Howard,

MSc, Danny Botros, BSc, and Ben Kavoossi, BSc for assistance with

80 Journal of Clinical Monitoring and Computing

the measurements of carbon monoxide and ethanol vapor. The

authors also thank Jeffrey C. Milliken, MD, W. Lane Parker, CCP,

and Berend J. Ages, CCP, Division of Cardio-Thoracic Surgery, for

provision of and consultation for the precision occlusion roller

pump. Funding: Full support by National Heart Lung and Blood

grant R01 HL-42637 (P.I.: PH Breen). Additional partial support

from the Department of Anesthesiology, University of California-

Irvine and National Center for Research Resources grant M01

RR00827.

APPENDIX 1

Measurement of Ethanol Vapor and Carbon Monoxide in the

Metabolic Chamber: effects of non-combustion and incomplete

combustion of ethanol

A gas composition testing apparatus (Accuro, DragerSafety, AG & Co. KGaA, Lubeck, Germany) was uti-lized in conjunction with an appropriate gas detectiontube. For the detection of ethanol vapor, an ethanoldetection tube was utilized (Drager Tube 8101613alcohol 25/a). For the detection of carbon monoxide(CO), both a CO pre-Tube (CH 24101 Drager CarbonPre-Tube) and a CO tube (Drager tube CH 19701Carbon Monoxide 8a) were utilized. The Carbon Pre-Tube was needed to remove high petrohydrocarbonvapor (i.e. any ethanol vapor).

The presence of either CO or ethanol was determinedby a color change in the gas detection tube. The colorchange for ethanol (orange to brownish-black) resultedfrom the chemical reaction of ethanol with chromium(VI) to produce chromium (III).

CH3OHþ CrVIþ ! CrIIIþ ð8Þ

The color change (yellow to pale brown) for CO resultedfrom the chemical reaction of CO with iodide pentoxideto produce iodine and CO2.

5COþ I2O5 ! I2 þ 5CO2 ð9Þ

To conduct the measurements, the manufacturer-pro-vided pump was manually actuated 10 times over 2 minto aspirate gas from the metabolic chamber through thetesting tube. A color change of the tube composite indi-cated the presence of the test compound (ethanol or CO).The length of the color change was multiplied by factor F,which corrected for barometric pressure, to generatemeasurements in parts per million (ppm). Detection andmeasurement of ethanol and CO were conducted duringall five ethanol combustion rates ( _VO2

range of 100.10 to500.25 ml/min) (Table 1).

The amount of ethanol or CO gas produced (ml/min)was calculated by

_VETHANOL or CO ¼ ðFETHANOL or CO=106Þ � _VCIRCUIT

ð10Þ

where F was fraction or concentration (ppm) and_VCIRCUIT was the gas flow through the metabolic chamber(5,000 ml/min). Then, dividing by the molar gas volume,the moles of ethanol or CO produced per min was

MoleETHANOL VAPOR or CO=min ¼ðFETHANOL VAPOR or CO=106Þ � _VCIRCUIT=22; 414: ð11Þ

The effect of unburned ethanol on the percent error ofreference _VCO2

and _VO2was given by

Percent error of _VCO2or _VO2

¼100 �Mole=minETHANOL VAPOR=

Mole=minETHANOL LIQUID INFUSED ð12Þ

If incomplete combustion of ethanol occurs, CO canbe produced without CO2,

C2H5OHþ 2O2 ! 0CO2 þ 3H2Oþ 2CO ð13Þ

or the incomplete combustion of ethanol can produceboth CO and CO2,

C2H5OHþ 212O2 ! CO2 þ 3H2Oþ CO: ð14Þ

Compared to the complete combustion of ethanol toCO2,

C2H5OHþ 3O2 ! 2CO2 þ 3H2O; ð3Þ

any incomplete combustion (whether Equation 13 or 14)that produces 1 mole of CO will result in a 1 mole decreaseof CO2 and 1/2 mole decrease of O2. Equation 3also indicates that the complete combustion of ethanolproduces two moles of CO2 and consumes three moles ofO2. Then,

Percent error of _VCO2¼

100 �Mole/minCO=

ðMole/minETHANOL LIQUID INFUSED � 2Þ; ð15Þand

Percent error of _VO2¼

100 � ðMole/minCO � 1=2Þ=ðMole/minETHANOL LIQUID INFUSED � 3Þ ð16Þ

Table 1 reports the detection of minimal ethanol vaporand CO in the metabolic chamber, resulting in calculated

Rosenbaum et al.: New Metabolic Lung Simulator 81

insignificant errors of the generation of reference _VCO2

and _VO2.

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