Transactions on Biomedicine and Health vol 2, 1995 WIT Press, www.witpress.

com, ISSN 1743-3525

A non-linear simulator of the human respiratory chemostat L. Chiari, G. Avanzolini, G. Gnudi, F. Grand! D E L . University of Bologna, V.le Risorgimento 2, ..S

Abstract A nonlinear dynamic model of oxygen and carbon dioxide exchange, transport and storage in the adult human is presented, which has satisfactory performances under different physiological conditions. The model includes three compartments related to lungs, tissues and brain, with a respiratory controller that adjusts alveolar ventilation and cardiac output in order to keep gas tensions close to their normal values. The model has been implemented in SIMULINK, a program for simulating nonlinear dynamic systems and able to facilitate model definition through block diagram manipulation and model analysis by means of a large range of built-in tools. It is shown that both dynamic and steady-state responses to a variety of respiratory forcings, including inhalation of high CO^ (hypercapnia) or low O% (hypoxia) gas mixtures, compare well with experimental data and represent an improvement on the responses provided by previous simulators. 1 Introduction Mathematical modelling of the respiratory system is not a new topic. The first quantitative formulation, restricted to steady-state responses, was made in 1945 [1] while the first dynamic analysis appeared in 1954 [ ] After these relatively simple models, the study of the 2. respiratory system has been refined and extended both in the plant description [ , ] and in the controller formulation [ , ] in order to 34 56 develop quantitative tools for testing hypotheses pri respiratory physiology and pathology. This paper presents a further work in this continuing process. It incorporates a new realistic model of acid-base chemical regulation [7] and includes physiological factors such as

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pulmonary shunt and dead space, having important effects on gas exchange and transport. In addition it is implemented through an advanced simulation tool which facilitates model definition and analysis [ ] In fact, block diagram language and sophisticated graphic 8. options enhance interactive capabilities while storage of simulated data supports successive elaborations such as sensitivity analysis, model complexity reduction and identification technique testing. 2 Model formulation The controlled system comprises lungs and all other tissues involved in gas exchange, transport and storage. In particular, brain tissue is treated as a third compartment, separate from other tissues, being seat of the central chemoreceptors, so that its local gas tensions play a special role in the chemical control. The controller adjusts continuously alveolar ventilation, V, and cardiac output, Q in order to keep the arterial tensions PaO2 and Paco.2, the arterial pH and the cerebrospinal pH close to their reference values. Equations and associated assumptions for each subsystem are presented below. A full list of the adopted symbols is given in the Appendix. 2.1 The Lungs Two equations are derived, which relate gas arterial concentrations and pressures in inspiratory air with venous concentrations. The fluctuations during the respiratory cycle are ignored, and the gas flow to the lungs and blood stream in the pulmonary capillaries is regarded as continuous and unidirectional. The lungs are regarded as a box with a constant volume equivalent to the Functional Residual Capacity and a uniform content. Alveolar gas tensions are assumed equal, at every time, to the gas tensions in the pulmonary capillaries, and explicitly include the pulmonary shunt. Using the foregoing assumptions, the mass balance for Og and CO% applied to the compartment including lungs and pulmonary capillaries, gives V, C,02 + 5~ PA02 =

PAC02 ~ Q\l ~ S)(CvC02 ~ QcO2 ) + ~ - " \PlCO2 ~ ^ACO2/ (2) " being P^j=P^\ j=o2,co2 and equal to the gas tensions in the expired air. The dependence of these gas tensions on the concentrations and the base content will be detailed in Section 2.3, while Pjj\j=o2,co2^e inputs for the system. Since a constant fraction, s, of the blood flow bypasses the ventilated alveoli and is not involved in the exchange process in the lungs, oxygen and carbon dioxide arterial content are the weighted sum of end-capillary and shunted venous blood content, as follows

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2.2 77ie Tissues Two relations are derived that bind the venous concentrations of Og and COg with the respective arterial concentrations and the metabolic rates in the tissue compartments. The two compartments are regarded as constant volume gas stores, homogeneous with respect to respiratory gas concentrations and tensions, where oxygen consumption and carbon dioxide production have a constant rate only influenced by metabolism but independent from gas levels. The mass balance equations for Og and CO% in the 'Brain' and 'Non-Brain' compartments can be expressed as follows

2
= Q z (Qo2 - Q,o2) - MCm2

(5)

(6)

(7) () 8

The brain compartment is assumed to be connected to a cerebrospinal fluid (CSF) reservoir through a membrane, permeable to respiratory gases only. In (5) and (7) the diffusion of these gases across the membrane is neglected being its relative contribution very small. Oxygen (and carbon dioxide) concentration in each compartment and in the respective venous blood can be related assuming the equality of partial pressures. Supposing the physically dissolved oxygen as the exclusive oxygen content of the compartment, venous partial pressure can be derived from the relation Ci02 ~ OC./02 ' Pi02 ~ OC,:o2 ' FviO2 \^/ while Cyio2 can be derived from P^o2 through the oxygen dissociation curve (15), being i=B,T and, respectively, vi=vb,vt. Likewise, C^<%>2 can be derived from P{co2 through the carbon dioxide dissociation curve described in eqn (16). For example, neglecting Bohr and Haldane effect and so considering the same CO% dissociation curve, 9, in tissue and blood, we have

Of course, if BBi~ BB^, i.e. the buffer base concentration in the compartment is almost the same as in blood draining it, then CviC02 = CiC02 \1 I/ It is interesting to note the possibility of considering BB as a further state variable to take into account the production and elimination of acids and bases in body fluids [ ] Venous blood leaving the brain 7.

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combines with venous blood flowing through other tissues to form mixed venous blood. The mixing laws take into account that circulation divides in fixed fractions to the 'Brain' and 'Non-Brain' compartments, being z the constant circulatory fraction to the 'NonBrain' compartment. Accordingly, we have CvO2 (1 Z)' CubO2 + Z ' CvtQ2 (12) CvCO2 (1 Z)' CvbCQ2 + Z ' CvtCO2 (13) Finally, mixed venous blood enters the lungs and completes the gas transport and exchange cycle. It is needed as an input to the controller a quantity introducing the role of CSF, such as P^co2- Since CO^ diffuses across the membrane with a speed proportional to the tension gradient, P^/co2 can be related to Pnco2 through the relationship PrsfCO2 ~~L' \ PfiCO2 ~ PcsfCO2 / (14) where k is the diffusion time constant across the CSF membrane. 2.3 Oxygen and carbon dioxide dissociation curves The relationships between gas tensions and concentrations are derived for blood and tissue compartments. Blood gases are chemically bound to hemoglobin, so that a dissociation curve has to be defined to relate their concentrations and tensions. As regards Og, we adopt a three straight-line segments dissociation curve as proposed by Longobardo [] 5 C,o2 = a + p-^o2 (15) This definition neglects the Bohr and Haldane effects. Alternatively, expressions explicitly incorporating hemoglobin content can be adopted. In the compartments the concentration of oxygen is simply taken from the partial pressure and solubility coefficient as stated by Henry's law and expressed in ( ) The dissociation curve for CO% is 9. derived through a recent model of buffer action in body fluids [7], based on a simple two-buffer description, in which a carbonic and a non-carbonic buffer (equivalent to a protein one) are effective. Total CC>2 is mainly determined by physically dissolved gas and bicarbonate, which is directly sensitive to possible disequilibria in acid-base balance. C.C02 = <?(P,c.o2, BB) = A-P,co2 + - + --r (16) where S = [BB + 2-(0.03-A)-P,co2 + 2-rY-8-r-BB (17) The same relation is valid for both the blood and tissue compartments. 2.4 The Controller The respiratory control system detects deviations from normal levels of Og and CO% partial pressures and adjusts alveolar ventilation and cardiac output in order to rapidly bring back gas pressures to normal values in a few minutes. The kidneys also

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intervene in the COg regulation by adjusting hydrogen ions filtration and bicarbonate resorption, but their action takes place very slowly, from several hours to few days, so that it is not taken it into account here. The respiratory control centres comprise several hierarchically linked controllers, processing many different inputs [9,10]. In spite of this complexity, the functionally important actions of the controller can be predicted, at a first instance, as functions of five variables: the arterial Og and CO% tensions, transduced by peripheral receptors; the CO% tension transduced by central receptors, PCCOZ, which is function of the gas level on the surface of the medulla, P^coz, and in the deep brain tissue, Pnco2 [11]; a neural drive component strictly related to metabolism, MRV, that plays an active role only during muscular activation, as in the case of exercise testing [ ] Pcco2 and MRV can be 6. calculated as follows (18)

]0

for c < 0

where d^ and k^ are constant referred to the central detecting system and c is an activation index that is non zero only when metabolic rates change. On the basis of Gray's multifactorial theory [ ] alveolar 1, ventilation can be expressed as . 2 2 ^ 2 + 0 2 2 0 + ^ ^ 2 + M^y-^R) for y > 0 0^0 .^^2 (0) for y<o where |Ll is a non-linear function describing the response of the arterial chemoreceptors to hypoxia, as defined in [ ] and the P'^ are time 3, delayed gas tensions. In particular, for the peripheral receptors an activation delay of 6 s (fast) is assumed, while central receptors have the time constant k (slow). As observed by Nielsen and Smith [12], after an apneic event, control is returned to eqn ( 0 only when Paco2 2) reaches a threshold level of 33 mmHg and the calculated ventilation exceeds 1.35 1/min. For the evaluation of minute ventilation, V#, dead space volume and respiratory frequency are required. The first can be calculated as a linear function of alveolar ventilation, the second through the procedure proposed by Otis [13], which minimizes the respiratory work. Cardiac output deviation from the normal value, Qp, depends upon the shifting of oxygen and carbon dioxide arterial blood tensions, as well as metabolic rates, from the normal range. Accordingly to [14], cardiac output can be given as (21)

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where function/is the sum of Chebyshev polynomials of the first kind that are non zero when PaO2 is lower than 95 mmHg and Paco2 exceeds 42 mmHg.

Figure 1. Block diagram of the Chemostat as implemented in SIMULINK

3 Simulation results The clear and friendly implementation of the respiratory chemostat, as obtained in a SIMULINK 1.3a workstation graphic window, is presented in Fig. 1. The three-compartment model includes 8 first order differential equations (1, 2, 5, 6, 7, 8, 14, 19). Nonlinearities are present, mainly due to the dissociation curve chosen for COg, which affect the relation between COg tensions and concentrations in eqn ( ) 2. Important nonlinearities are also induced by the controlling variables, V and Q that introduce indirect multiplying relations between state variables in all mass balance equations. Such a complex system was solved by a third order Runge-Kutta technique, offered in the SIMULINK simulation tools. The numerical method never generated instability in any test condition showing a general stability of the model. The test settings were obtained by changing the inspiratory gas

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fractions, with the aim of reproducing several forcings reported by literature. 3.1 Hypercapnia The dynamic behaviour predicted by the simulator for the main variables during 25 minutes of 5 % COg inhalation and subsequent recovery is given in fig. 2. The experiment is simulated increasing Pjco2 from zero to 0.05-(Pb-Pw), i.e. about 35 mmHg. The efficacy of the ventilatory control can be deduced by analysing the perturbed steady-state that is reached after the initial transient. From (2), ( ) ( ) (8) and (13), it is immediate to deduce that, if changes in 4, 7, ventilation are not effective, P&CO2 and consequently arterial tension strictly follow Pjco2- The swing in Paco2 (Fig. 2.a) is instead limited from 35 mmHg to about 7 mmHg by the contemporary increase in ventilation, that in the meanwhile becomes between three to four times its initial value (Fig. 2.c), as obtained also by Grodins [ ] 3. Similarly the increases in PBCO2 and Prco2 are restrained, as well. The increase in cardiac output (Fig. 2.d) depends only on the increase of PaC02 and is not affected by oxygen level, which remains over 95 mmHg (Fig. 2.b). During the first minute a rise of about 5 mmHg is registered in arterial CO% tension (Fig. 2.a), while V shows an initial rapid component so that about 35 % of the ventilatory response occurs (Fig. 2.c), with a value that is more than twice the initial one, in agreement with experimental observation [ 5 . This is the fast peripheral 1] chemoreceptor effect whereas the further and slower increase in these quantities can be ascribed to central receptors through the CSF. Pnco2 and Prco2 plots (Fig. 2.a) show the different time constants for the 'Brain' and 'Non-Brain' compartments, respectively of about 7/Q, and 45/Q minutes. In Fig. 2 it can be seen that ventilation acts as a shockabsorber towards the compartmental stores, that is the PBpPTj\j=O2,co2> which are smoothed with respect to the arterial quantities. Table I compares the main characteristics of the model response to experimental [16] and other simulated data [ , , ] for different CO% 346 intake fractions. It can be noted that both for 3 and 5% CO2 fractions the new model provides steady-state values which match fairly well the experimental data as well as the results from other simulators. For some variables (e.g. gas tensions) the accuracy of the model in reproducing reality is better than that, for example, provided by Grodins' simulator. The half-time off transient for ventilation states the very fast recovery that takes place once the input step is turned off while Paco2 goes back to its initial value after an undershoot, that is more accentuated the less is the fraction of inspired COg. For Paco2 (see Fig.2) and consequently V time courses, the off transient is faster than the on transient because the non linearity of the system decreases the time constant when the starting value of V increases. It can be

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seen that increasing carbon dioxide intake fraction an overshoot in the on front for Paco2 is present till a fraction of 3% (Table I) and gradually disappears, in contrast with data reported by Reynolds [16]. At the same time ventilatory response gets slower as Reynolds himself and Grodins [3] show. 3.2 Hypoxia The dynamic behaviour predicted by the simulator for the main variables during 10 minutes of 9% O% inhalation and subsequent recovery is shown in Fig. 3. The experiment is simulated decreasing PjQ2 from 149 mmHg to 0.09-(Pb-Pw), i.e. about 64 mmHg. The experiment follows a 2 minutes respiration of normal air, in which 21% oxygen is present. Without any control law, from (1), (3), ( ) (6) and (12), we can deduce that P^o2 decreases as P/O2, i.e. of 5, about 85 mmHg. From Fig. 3.b it can be seen, instead, that normal respiratory control limits the excursion of P^o2 to 65 mmHg. When the fraction of inspired oxygen is lowered from its normal value, PaO2 shows a sudden fall and heavily influences the cardiac output that rises to support the oxygen request by the tissues (Fig. 3.d). At the same time, blood flow to brain is increased: this leads, after a very slight depression in the first seconds, to a subsequent increase in ventilation (Fig. 3.c). The latter rises for the continuous fall in PaO2 and finally reduces Paco2 (Fig. 3.a). A ventilation overshoot in the on front is registered, before the system settles to a new steadystate in which both the gas tensions are lower than the normal values. In the off transient alveolar and arterial oxygen have a sudden increase so that ventilation is suddenly depressed and an apneic state is reached, still being the carbon dioxide tension, not enough to stimulate the respiratory centre. In the meanwhile the so called periodic breathing phenomenon appears and both the gas tensions return, oscillating, to their steady state (Fig.3.a,b). During apnea P^o2 and PaC02 increase. Paco2 finally reaches the threshold value in which ventilation is no more zero. The information flow during this experiment reproduces what happens during hypercapnia, but here a great part of the receptors involved are peripheral, and therefore fast, near the surface of the medulla rather than in central systemic arteries. It results in smaller transient times, as clearly appears comparing table II with table I. The same behaviour is correctly reproduced by the model. Table II compares the main characteristics of the model response to experimental [17] and other simulated data [ , , ] for different 346 COg intake fractions. It can be noted that the new model provides arterial partial pressures closer to experimental data with respect to Grodins model, though still too low. Moreover ventilation is in good agreement with experimental values.

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% COg PaQ2 [mmHg] PaC02 [mmHg] % Overshoot % Undershoot VE [1/min] Half-time On transient [s] Half-time Off transient [s]

Table I. Hypercapnia Simu lated data Experimental data Reynolds Grodins Saunders Fincham New Mod<:1 5 3er5 3er5 3er7 3er5 138.4 122erl42 122erl32 119crl31 126crl31.8 42er55 41.5er46.0 41.6er46.8 45.9 44.3er47.5 I7er0 47erO 24er20 54erl9 140er50 27cr54 12er44 11.3er20.2 11.4erl9.1 11.2crl7.4 19.62 64er93 43er24 42erl06 33er42 27er42 16erl5

%Og ?aC02 [mmHg] Pa02 [mmHg] VE [1/min] Half-time On transient [s] Half-time Off transient [s]

Table II. Hypoxia Simu lated data Experimental data Reynolds Grodins Saunders Fincham 8er9 7cr9 8 8er9 34.1er35.3 24er31 31.2er32.4 28.9 42.6er44.7 32er36 36.9er39.5 28.9 12.3er9.5 10.33 18erl2 9.7er9.0 174erl67 49er33 24er27 13er24

New Model 8er9 30.9er33.0 30.2er33.5 11.5erl0.1 23er22.8 2er3

4 Conclusions A nonlinear dynamic model of the physiological respiratory chemostat active on adult humans, based on three compartments and a feedback controller, has been described. The model gives a highly detailed description of the chemical buffer activity and has been implemented through the facilities of the SIMULINK graphical, menu-driven environment. Simulation results appear to agree closely with data measured in steady-state and only qualitatively with data measured in transients. In fact discrepancies were encountered in describing ventilatory dynamics, which results too fast with respect to data by other authors, both experimental and simulated. In particular the new model provides in every case better responses than Grodins model and in many aspects appears superior to Saunders model. Although the adopted controller is simplified, the responses of the present model are comparable to those reported by Fincham, who however does not enable to simulate metabolic disturbances in acid-base balance. For this reason it looks like a good instrument to accommodate a wide range of forcings and to interpret the physiological mechanisms underlying the regulation of ventilation.

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a) b)

^60f/- 0)

V V

P 'BCO2 z f ii 50
40 v^

^40 <?n

(
70

1
20 30 Time [min] c)

P %CO2

p 02
10 20 30 Time [min] d) 40

15

6.5

5.5

10

20 30 Time [min]

40

10

20 30 Time [min]

40

Figure 2. Gas tensions and controlling quantities in the simulated hypercapnia experiment
60

15

10 20 Time [min] c)

10 20 Time [min]

30

10 20 Time [min]

Figure 3. Gas tensions and controlling quantities in the simulated hypoxia experiment

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1. Gray, J.S. The multiple factor theory of respiratory regulation, Army Air Force School of Aviation Medicine, 1945, P. R. No 386 (1,2,3) 2. Grodins, F.S., Gray, J.S., Schroeder, R., Norins, A.L. & Jones, R.W. Respiratory responses to CC>2 inhalation. A theoretical study of a nonlinear biological regulator, J Appl Physiol, 1954,7:283-308 3. Grodins, F.S., Buell, J. & Bart, AJ. Mathematical analysis and digital simulation of the respiratory control system, / Appl Physiol, 1967, 22(2):260-276 4. Saunders, K., Bali, H. & Carson, E. A breathing model of the respiratory system: the controlled system, / theor Biol, 1980, 84:135-161 5. Longobardo, G.S., Cherniack, N.S. & Fishman, A.P. Cheyne-Stokes breathing produced by a model of the human respiratory system, /A^/fA^W, 1966, 21(6):1839-1846 6. Fincham, W.F. & Tehrani. F.T. A mathematical model of the human respiratory system, / Biomed Eng, 1983, 5:125-133 7. Chiari, L., Avanzolini, G., Grandi, F., Gnudi, G. A simple model of the chemical regulation of Acid-Base balance in blood, in Engineering Advances/94 (ed. N. Sheppard, M. Eden & G. Kantor), pp 1025-1026, froc. of fAf 76fA /nf. Con/i off/%? /EEEEM2S, Baltimore, Maryland, 1994 8. SIMULINK: user's guide, The Math Works Inc., 1992 9. Gray, J.S. Pulmonary ventilation and its physiological regulation, ed C.C. Thomas, Springfield, Illinois, 1950 lO.Widdicombe, J.G. Respiratory reflexes from the lungs, Brit Med Bull, 1963, 19:15-20 11.Mitchell, R.A., Loeschcke, H H , Massion, W.H. & Severinghaus, . . J.W. Respiratory responses mediated through superficial chemosensitive areas on the medulla, J Appl Physiol, 1963, 18:523-533 12.Nielsen, M. & Smith, H. Studies on the regulation of respiration in acute hypoxia, Ada Physiol Scand, 1952, 24:293-313 13.Otis, A.B., Fenn, W.O. & Rahn, H. Mechanics of breathing in man, /A^/fA^W, 1950, 2:592-607 14.Fincham, W.F. & Tehrani, F T On the regulation of cardiac . . output and cerebral blood flow, J Biomed Eng, 1983, 5:73-75 15.Lambertsen, C.J. Factors in the stimulation of respiration by carbon dioxide. In The regulation of human respiration, ed. D.J.C. Cunningham & B.B. Lloyd, pp 257-276, Blackwell, Oxford, 1963 16.Reynolds, W J , Milhorn, H T & Holloman, G.H. Transient . . . . ventilatory response to graded hypercapnia in man, / Appl Physiol, 1972,33:47-54 17.Reynolds, W.J. & Milhorn, H T Transient ventilatory response to . . hypoxia with and without controlled alveolar pCOg, / Appl Physiol, 1973,35:187-196

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Computer Simulations in Biomedicine Appendix. Model variables and parameters Unit Basal Value Definition Symbol 462 Buffer-Base mmoil BB Concentration of species j in Cu i-i-i district i End-Capillary i=e,j=O2,CO2 0.794/0.567 i=a,j=O2,CO2 Arterial 0.193/0.568 i=B,j=O2,CO2 Brain Compartment 9.59e-4/D.644 /2.0f-4/0.677 Tissue Compartment i=TJ=02,C02 i=vb,j=O2,CO2 Venous blood from Brain 0.778/0.644 i=vt,j=02,C02 Venous blood from Tissue 0.143/0.611 f=vj=02,C02 0.740/0.675 Mixed Venous Blood 0 Muscular activation index c Metabolic consumption lmin~* MC,o2 in Brain 0.050 i=B 0.275 in Tissue i=T Metabolic production 1 min'l Mf,c02 in Brain 0.050 i=B in Tissue i=T 0.782 Metabolic neural drive 0 MRV mmHg Tension of gas j in district i Pii Alveolar =A,j=O2,CO2 704.6/39.42 End-Capillary 704.6/J9.42 =gj=02,CO2 =a,j=O2,CO2 Arterial 96.54/39.68 Brain Compartment =B,j=02,C02 30.29/58.98 Tissue Compartment =T,j=02,C02 36.78/49.87 i=vb,j=O2,CO2 Venous blood from Brain 30.29/58.98 i=vt,j=O2,CO2 Venous blood from Tissue 36.78/49.87 Cerebrospinal Fluid 58.98 i=csfJ=C02 Central Receptors i=C,j=C02 58.97 Inspired Oxygen 749.2 P/02 0 Inspired Carbon Dioxide PlCO2 Cardiac Output 5 l-rnin' Q Alveolar Ventilation 4.206 l-rnin'^ v Minute Ventilation 6.327 l-miri'l VE 0.024 Solubility Coefficient l-l-l-atm-1 <BO2/U<TO2 min Neural drive dynamic 0.8 1 cm Depth of central receptor 75f-3 dcr min Diffusion time constant 5.33 k Lr Central receptor constant 5.766e3 min-cm'^-l'l *^cr Coefficient -0.2077 mmol 1' mmHg' A Coefficient 79.45 mmoll'^ r mmHg Barometric Pressure 760 Pb mmHg Water Vapour Pressure 47 PW Standard control point setup 20.79 R Pulmonary Shunt Fraction 0.024 s I Brain Volume 0.9 VB I End-Capillary Volume 0.7 Ve I Lung Volume at FRC 2.9 VFRC I Tissue Volume 38.74 VT Blood fraction to Tissue 0.8668 z