Non-Invasive Estimation of the Effective Pulmonary Blood Flow and Gas Exchange from Respiratory Analysis P. Christensen Introduction Monitoring of the effective pulmonary blood flow is important in the control of many intensive care therapies such as effect of drugs, optimization of PEEP level and ventilatory settings. A large number of methods have been developed for estimation of the effective pulmonary blood flow. However, only the indicator dilution combined with estimation of the pulmonary shunt have gained widespread use for clinical purposes. The drawback of the indicator dilution method is that it is an invasive method which require access to the pulmonary artery as well as a systemic artery. The increasing demands for noninvasive methods have led to the development of a number indirect methods of which the inert gas rebreathing method have gained most acceptance. Methods Based on Oxygen and Carbon Dioxide Breath-Holding Method During a breath-holding period the alveolar partial pressure of carbon dioxide increases to a plateau value above the true mixed venous partial pressure of carbon dioxide. The change in P A CO 2 during a breathholding period can be described by the following equation [1]: where SC0 2 is the slope of the carbon dioxide dissociation curve, P B the ambient pressure, VI the alveolar volume and V, the lung tissue volume. Q is the effective pulmonary blood flow and Py C0 2 is the true mixed venous partial pressure of carbon dioxide. Py C0 2 is estimated from several breath holding maneuvers of increasing length. There exists several modifications of the breath-holding method some of which demands inspiration of carbon dioxide (to ensure that equilibrium can be reached). The breath-holding techniques are rarely used today, because of advances in sensor technology and the required maneuvers. The breath- M. R. Pinsky (ed.), Applied Cardiovascular Physiology Springer-Verlag Berlin Heidelberg 1997
N on-invasive Estimation of the Effective Pulmonary Blood Flow 151 holding techniques are considerably more sensitive to inhomogeneity in the distribution in ventilation than the rebreathing techniques. Rebreathing Method The derivation of the effective pulmonary blood flow from a recording of the partial pressure of carbon dioxide is in principle identical to the breath-holding algorithms [2]. The rebreathing maneuver is simple to learn and well suited for exercise studies. Furthermore, the rebreathing method is less sensitive to breathby-breath variations in the emptying pattern of the lungs compared to the singlebreath and breathholding methods. The algorithm for estimation of the effective pulmonary blood flow is based on the indirect Fick principle: where Q is the effective pulmonary blood flow, VC02 the excretion rate of carbon dioxide. CvC0 2 and CaC02 are the content of carbon dioxide in the mixed venous blood and the arterial blood, respectively. Most modifications of the carbon dioxide rebreathing method use a mixture of carbon dioxide, oxygen and nitrogen. The carbon dioxide ensures the carbon dioxide equilibrium value is reached within the rebreathing period. From the recording of carbon dioxide during the rebreathing maneuver P vc02 is estimated using algorithms similar the equation described above (see Breath-holding method). P ac02 is estimated as the average of a number of end-tidal PC02 values recorded before the rebreathing maneuver. CaC02 and CvC02 are calculated from approximation of the carbon dioxide dissociation curves for arterial and venous blood, respectively. VC02 is often estimated from the mixed expired carbon dioxide concentration and a recording of the minute-volume. Thus, the simple rebreathing methods demand seperate maneuvers for calculation of P vc02, P ac02 and VC02. This has restricted the use of this method. One Step Rebreathing Method In 1976 Farhi et al. [3] reported at new rebreathing method that enabled determination of all variables needed to obtain cardiac output from a single rebreathing maneuver. This method takes into account that during a rebreathing maneuver readjustment of the lung tissue carbon dioxide content takes place. This problem is circumvented by hyperventilation during the rebreathing period. Thereby, causing an initial drop in PC02 and later during the rebreathing period reaching the initial PC02 level again, at this time T, the lung tissue content of carbon dioxide is identical to that at time o. The algorithm corrects for errors caused by changes in the rebreathing bag volume at time 0 and T.
152 P.Christensen where Q is the effective pulmonary blood flow, V rb (0) the initial rebreathing bag volume, p I the partial pressure that would result if the excess lung volume could be added to and mixed with the gas in the rebreathing bag, P rb (0) the partial pressure of carbon dioxide in the rebreathing bag at time O. P B is the barometric pressure, Peq is the equilibrium partial pressure of carbon dioxide. Ceq and Cc are the content of carbon dioxide in the mixed venous blood and in the pulmonary capillary blood. Farhi et al. (1976) showed that there is a systematic difference between the one step CO 2 rebreathing method and the acetylene method for estimation of cardiac output during both rest and exercise. This have been evaluated by Ohlson et al. [4] who found an acceptable correlation between the one step CO 2 rebteathing method and the direct Fick method. The Partial CO 2 Rebreathing Method In 1988 Capek and Roy [5] published a new CO2 method based on partial rebreathing through an additional deadspace during a 30 sec period. The technique utilizes a differential form of the Fick equation thereby avoiding the need to estimate the absolute value of the mixed venous partial pressure of carbon dioxide. The average end-tidal carbon dioxide partial pressure and carbon dioxide excretion are estimated. Next an instrumental dead space is added for a short period of time assuming that no recirculation of blood takes place. From recordings of volume displacements and PC02 the new "steady-state" carbon dioxide excretion and end-tidal partial pressure of carbon dioxide can be calculated. The recorded end-tidal carbon dioxide values are corrected for the alveolar dead space. The carbon dioxide partial pressures are used to estimate the content of carbon dioxide. The slope of the carbon dioxide binding curve is corrected for influence of hemoglobin and the partial pressure of carbon dioxide. From the above data the effective pulmonary blood flow can be estimated: where VC02 (1) and (2) are the carbon dioxide excretion before and at the end of the partial rebreathing period. Cal and Ca2 is the capillary blood content of carbon dioxide before and at the end of the partial rebreathing period. The method was compared to the thermal-dilution method in animal experiments. The results of the comparison showed that in 87% of the experiments the pulmonary capillary blood flow estimated by the partial rebreathing method was within 20% of the thermal-dilution values. Furthermore, the authors showed that the new method seems to be less sensitive to inhomogeneity in the distribution of ventilation/perfusion ratios. However, it should be noted that the method was evaluated using anaesthesized dogs during mechanical ventilation. Recently, Gama et al. [6] have published preliminary data of a study where the method have been successfully implemented in an intensive care environment. The advantage of the
Non-Invasive Estimation of the Effective Pulmonary Blood Flow 153 method is that the breathing pattern remain unchanged during the determination of the effective pulmonary blood flow. Single-Breath Method The single-breath method [7] for measurement of pulmonary blood flow has been the subject of numerous investigations during the past 30 years. The method is attractive due to its potential for providing noninvasive estimates of cardiac output on a breath by breath basis. The validity of the single-breath method is, however, debatable, because it depends on a number of assumptions that lack experimental verification. Furthermore, investigations comparing the singlebreath method with invasive cardiac output methods have given contradictory results. Finally, a theoretical study has demonstrated extreme sensitivity of the estimated pulmonary blood flow to small random errors in the data measured using the single-breath method. These results have discouraged the use of the single-breath method. The single-breath method estimates the pulmonary blood flow from the PC0 2 versus P0 2 curve recorded during a prolonged expiration. Analysis of a singlealveolus lung model shows that the pulmonary blood flow (Q), mixed venous PC0 2 (PvC0 2 ) and the rate of oxygen uptake (V0 2 ) are the only parameters that affect the PC0 2 versus P0 2 curve. If V0 2 is measured, the two other parameters (PBF and PvC0 2 ) can be determined by least squares curve fitting of the singlealveolus lung model to the experimental curve. The solution presented by Srinivasan [8] simplified the nonlinear data reduction procedure as the analytical expression for the PC0 2 versus P0 2 curve avoids the time consuming numerical integration procedures. This procedure is both theoretical and statistically ideal because it utilizes the expression for the PC0 2 versus P0 2 curve which can be derived from the alveolar model to fit the experimental data. This expression is: P0 2 = 1- PC0 2 _ K (P - PC0 2 /P B )(I -<x)/(j3 -<X) P B P B (a-pc0 2 /P B )(I-j3)/(j3-<x) (1) where P B is the barometric pressure and K, a and p are the parameters to be estimated by the nonlinear curve fitting procedure. The effective pulmonary blood flow is related to a, p and V0 2 by the following equation: where S is the slope of the CO 2 binding curve of blood. However, the results obtained with the single-breath method shows a reproducibility no better than 15% (coefficient of variation on repeated estimates of the effective pulmonary blood flow) even in well trained heathy test subjects [9].
154 P. Christensen Estimation of Effective Pulmonary Blood Flow Using Inert Gases Inert Gas Rebreathing Method The rebreathing method for estimation of effective pulmonary blood flow [10] is based on the Bornstein modification of the Fick principle. The rate of disappearance of inert gas from the lungs can be used to estimate effective pulmonary blood flow. In practice, a rebreathing bag is filled with a gas mixture containing an inert soluble gas (acetylene, freon-22 or nitrous oxide) and a poorly soluble gas (helium, argon or sulfur hexaphloride). Furthermore, if clsa is added to the gas mixture it will provide means to estimate the time at which the inert gas reaches the alveolar level of the airways and it also allows the diffusion capacity of the lungs to be estimated. The volume of the rebreathing bag has not been standardized, different investigators have used values ranging from 0.5-3.5 1. The gas mixture is rebreathed for a period that must be shorter than the recirculation time, during the rebreathing maneuver the concentrations of the gasses are measured by a mass spectrometer or a photoacustic gas analyser. Assuming complete gas mixing in the rebreathing system (rebreathing bag + lung) the disappearance curve for inert soluble was can be described by the expression: where Fx (to) and Fx (t) are the fractional concentration of inert solouble gas at the end of the first inspiration (to) and at time t. Q is the effective pulmonary blood flow, alfab and alfa t are the solubility coefficients of the inert soluble gas in blood and lung tissue, FRC is the functional residual capacity corresponding to the initial lung volume, Vrb is the initial volume in the rebreathing bag and V t the lung tissue volume. The effective pulmonary blood flow was calculated from the following expression: Q = Ax/alfab X ((FRC + Vrb) X 760/(PB -47) + (V t X alfa t)) where Ax is the slope of a semilogarithmic plot of the relative fractional concentrations of inert soluble gas (Fx (t)) and time. The rebreathing method have been used in large number of applications such as exercise study, effect of bronchodilatators, studies of regulation of the cardiovascular system. Recently, the inert gas rebreathing method have been used in several studies concerning evaluation of drug therapy and setting of artificiel ventilation in critically ill patients (both infants and adults) [11-13]. Furthermore, recent development in sensor technology [14], makes the method a promising tool for routine monitoring of the effective pulmonary blood flow in an intensive care environment.
Open Circuit Washin of Inert Gas Non-Invasive Estimation of the Effective Pulmonary Blood Flow 155 The open circuit method was published by Stout et al. in 1975 [15]. The method differs from the reb rea thing methods published earlier in several respects, 1) the method do not require steady-state conditions, 2) the blood flow can be determined despite changes in FRC, 3) calculation of effective pulmonary blood flow is independent of the lung tissue volume, 4) in principle the method is capable of measuring both the effetive pulmonary blood flow and cardiac output, thus enabling estimation of right-left shunt. The experimental procedure is simple the inspiration gas composition is changed to a gas mixture of an inert soluble gas, an inert insoluble gas, oxygen and balanced with nitrogen. This gas is inspired for a period of about 20 sec (assuming no recirculation during the measurement period). On Breath-by-Breath basis the inspired volume, expired volume, inert soluble gas uptake and end-tidal concentrations and blood flows are calculated. The physiological principle of the method is to estimated the uptake of the inert soluble gas during a non steady-state period with no recirculation, and correcting for incomplete mixing by an inert insoluble gas. The authors validated the method both theoretical and experimentally comparing with the direct Fick method. This comparison showed that the open circuit cardiac output was within ± 20% of the direct Fick cardiac output. However, the method is rather sensitive to random measurement errors and uneven distribution of ventilation, compared to the inert gas rebreathing method [16]. Inert Gas Single-Breath Breath-Holding Method Inert gas breath-holding methods for assesement of the effective pulmonary blood flow have required 2 or more breath-holding periods [17]. This has been a major drawback of the breath-holding method for estimation of acute changes in the effective pulmonary blood flow. Recently Kendrick et al. [18] have described a variant of the method which enables estimation of the effective pulmonary blood flow from a single breath-holding period (6 s-10 s). The breath-holding procedure is essential the same as for obtainment of carbon monoxide transfer factor and the algorithm is that described for the rebreathing method. Kendrick et al. found an acceptable agreement between the direct Fick method and the single-breath breath-holding method. The coefficient of variation of repeated estimates is appro 10%. Thus, as other single-breath methods the technique must be expected to be sensitive to uneven distribution of ventilation. Conclusion There is a growing interest for estimation of the effective pulmonary blood flow in critically ill patients. Recently, development in gas analyzer and computer tech-
156 P. Christensen: Non-Invasive Estimation of the Effective Pulmonary Blood Flow nology have made it possible to implement non invasive methods for estimation of the effective pulmonary blood flow based on analysis of gas exchange into the clinical environment. Of these the inert gas rebreathing method seems to be the most promising method. References 1. Farhi LE, Haab P (1967) Mixed venous blood gas tensions and cardiac output by "bloodless" methods; recent developments and appraisal. Respir Physiol2: 225-233 2. Butler J (1965) Measurement of cardiac output using soluble gases. In: Fenn WO, Rahn H (eds) Handbook of Physiology. Respiration. Am Physiol Soc, sect 3, vol II, chapt 62: 1489-1503 3. Farhi LE, Nesarajah MS, Olszowka AJ, Metildi LA, Ellis AK (1976) Cardiac output determination by simple one-step rebreathing technique. Respir Physiol 28: 141-159 4. Olhsson J, Wranne B (1986) Non-invasive assesment of cardiac output and stroke volume in patients during exercise: Evaluation of a CO 2-rebreathing method. Eur J Appl Physiol 55:538-544 5. Capek JM, Roy RJ (1988) Noninvasive Measurement of Cardiac Output Using Partial CO 2 Rebreathing. IEEE Trans Biomed Eng 35: 653-661 6. Gama de Abreu M, Ragaller M, Quintel M,Albrecht DM (1996) Non-invasive, Semi-Continuous Pulmonary Capillary Blood Flow Measurement by a Partial CO 2 Rebreathing Technique. Intensive Care Med 22 (Suppl 3) S 362 7. Kim TS, Rahn H, Farhi LE (1966) Estimation of true venous and arterial PCOz by gas analysis of a single breath. J Appl Physiol21: 1338-1344 8. Srinivasan R (1986) An analysis of estimation of pulmonary blood flow by the single-breath method. J Appl Physiol61: 198-209 9. Gronlund J, Christensen P, Hansen LG (1987) Single-breath - method for estimating pulmonary blood flow: Data reduction based on nonlinear curve fitting. Aviat Space Environ Med 58: 1097-1102 10. Sackner MA, Greeneltch D, Heiman MS, Epstein S, Atkins N (1975) Diffusing Capacity, Membrane Diffusing Capacity, Blood Volume, Pulmonary Tissue Volume, and Cardiac Output Measured by a Rebreathing Technique. Am Rev Respir Dis 111: 157-164 11. Bose CL, Lawson EE, Greene A, Mentz W, Friedman M (1986) Measurement of Cardiopulmonary Function in Ventilated Neonates with Respiratory Distress Syndrom Using Rebreathing Methodology. Pediatr Res 20: 316-320 12. Steinhart CM, Burch KD, Brudno S, Parker DH (1989) Noninvasive determination of effective (nonshunted) pulmonary blood flow in normal and injured lungs. Crit Care Med 17:349-353 13. Christensen P, Andersen PK (1996) Clinical applicability of a rebreathing method for noninvasive estimation of effective pulmonary blood flow. Intensive Care Med 22 (Suppl3) S 365 14. Clemens en P, Christensen P, Norsk P, Gronlund J (1994) A modified photo- and magnetoacoustic multigas analyzer applied in gas exchange measurements. J Appl Physiol 76: 2832-2839 15. Stout RL, Wessel HU, Paul MH (1975) Pulmonary blood flow determined by continuous analysis of pulmonary gas exchange. J Appl Physiol38: 913-918 16. Wendelboe Nielsen 0, Hansen S, Gronlund J (1994) Precision and accuracy of a noninvasive inert gas washin method for determination of cardiac output in men. J Appl Physiol 76 (4): 1560-1565 17. Cander L, Forster RE (1959) Determination of pulmonary parenchymal volume and pulmonary capillary blood flow in man. J Appl Physiol14: 541-555 18. Kendrick AH, Rozkovec A, Papouchado M, West J, Laszlo G (1989) Single-breath breathholding estimate of pulmonary blood flow in man: Comparison with direct Fick cardiac output. Clin Science 76:673-676