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Venoarterial CO2 gradient
VENOARTERIAL C02 G R A D I E N T LL. TEBOUL, F. MICHARD, C. RICHARD
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Definitions
The venoarterial carbon dioxide (C02) tension (PCO~) gradient (zXPCO~) is the difference between PCO2 in mixed venous blood (PvC02) and the PCO2 in arterial blood (PaC02): APCO2 = PvC02 - PaCO~ PaC02 and PrO2 are partial pressures of the dissolved C02 in arterial and mixed venous blood respectively which represent only a fraction of arterial C02 content (CaC02) and mixed venous C02 content (CvCO~) respectively.
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C02 transport in the blood
• C02 is carried in the blood in three forms: dissolved, as bicarbonate and in combination with proteins as carbamino compounds. Because C02 is about 20 times more soluble than oxygen (O~), the dissolved form plays a more significant role in the normal carriage in the blood. -- Bicarbonate is formed in the blood by the following sequence: C02 + H20 *=* H~C03 *== H + + HC03where H20 is water, H2C03 is carbonic acid, H ÷ is hydrogen ion, HC03- is bicarbonate ion. The first reaction is very slow in plasma but fast within the red blood cell, because of the presence in this cell of carbonic anhydrase. The second reaction occurs rapidly within the red cell and does not need any enzyme. When the concentration of H ÷ and HC03- in the cells rises, HC03- diffuses out of the red blood cells into plasma but H ÷cannot diffuse eas-
fly because the cell membrane is relatively impermeable to cations. Some of the H ÷ liberated are bound to hemoglobin (Hb). H ÷ + HbO2 *:=* H - Hb + 02 This reaction occurs because reduced Hb is a better acceptor of H ÷ than the oxygenated Hb. In the peripheral venous blood, the loading of C02 is facilitated by the presence of reduced Hb (Haldane effect). -- Carbamino compounds are formed by the combination of CO~ with terminal amine groups of blood protein, especially the globin of Hb. Reduced Hb can load more C02 as carbamino compound than Hb0~. • A greater part of the C02 content (CC02) is in the form of bicarbonate. • The relationship between the PC02 and the total CC02 is curvilinear although much more linear than the 02 dissociation curve. Haematocrit, 02 saturation, temperature and pH influence the PCOJCCO~ content relationship [1, 2].
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Service de R6animation Medicale, H6pital de Bicetre, Facult6 de Medecine Paris-Sud, Le Kremlin Bic#tre. Correspondence to: Dr Jean-Louis Teboul, Service de R6animation M6dicale, H6pital de Bic6tre, 78, rue du G6neraI-Leclerc, 94275 Le Kremlin-Bic6tre cedex.
R6an. Urg., 1996, 5(2 bis), 204-211
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Determinants of venoarterial C02 gradient
The Fick equation applied to C02 indicates that the C02 excretion (equivalent to C02 production in a steady state) equals the product of cardiac output (CO) by the (CvC0~ - CaC02) gradient: VC02
= CO
. (CvC02
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CaC02).
Over the usual physiological range of CO~ contents, there is a relatively linear relationship between CCO~ and PCO~ so that by rearranging the Fick equation and substituting PC02 for CCO~, a modified Fick equation can be obtained: zXPC02 = kVCOJCO where k is assumed to be a constant. Therefore, z~PC02 would be linearly related to C02 production and inversely related to CO.
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Influence of C02 production on APC02
Aerobic C02 production At the cellular level, the aerobic CO~ generation is a normal terminal product of mitochondrial oxidative phosphorylation. Thus, under aerobic conditions CC02 in the effluent venous blood must be higher than in the afferent arterial blood. Under these normal conditions, the total C02 production (VC02) is directly related to global 02 consumption (V02). VC02 = R . V02, where'R is the respiratory quotient, that is not a constant but may vary between 0.7 and 1.0 with respect to the predominant energy source; for instance when lipids are the major fuel sources, R is close to 0.7 whereas under conditions of high carbohydrate intake R approaches 1.0. Therefore, the aerobic C02 production should augment either with increased oxidative metabolism or for a constant V02 when an equilibrated feeding regimen is replaced by a high carbohydrate intake regimen. Under both conditions, CvC0~ - CaC02 and APC02 should increase except if CO increases in the same extent. In normal subjects exhibiting 5 fold increases in V0~ and VC02 associated with a 2 fold increase in CO during a 50 Watt exercice, Hachamovitch et al. [3] had measured a significant increase in PvC02 from 41.7 ± 1.3 to 49.6 ±2 mmHg (p < 0.05) with unchanged PaC02, In these normal subjects, the aerobic production of C02 possibly accounted for the widening of APC02 during exercice.
Anaerobic C02 production When conditions of tissue hypoxia are present, an anaerobic production of C02 should occur. Two possible sources of C02 have been identified: buffering of excesses of H ÷ ions by HC03- ions and decarboxylation of metabolic intermediates [4]: under hypoxic conditions H ÷ ions are generated by two mechanisms: • excessive production of lactic acid owing to an acceleration of anaerobic glycolysis, since pyruvate is no longer cleared by the Krebs cycle. • hydrolysis of adenosine triphosphate (ATP) and of adenosine diphosphate (ADP) that occur in conditions of anaerobiosis. HC03- ions will then buffer H ÷ ions into the cell so that C02 will be generated. anaerobic decarboxylation of some substrats produced by intermediate metabolism such as cetoglutarate or oxaloacetate is a potential but minor source of anaerobic C02 production [4]. In hypoxic cells aerobic C02 production should be reduced but anaerobic C02 generation -- mostly -
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Venoarterial C02 g r a d i e n t - 2 0 5 -
through buffering of H ÷ ions generated in excess -should be markedly increased. Evidence of a significant anaerobic production of C02 in hypoxic organs is not so easy to bring. Indeed, the efferent venous blood flow can be sufficiently efficient to clear the CO~ producted under these circumstances of a marked drop in aerobic C02 production. Therefore, PC02 could be not augmented in the efferent vein and anaerobic C02 production not detected. However, if afferent and efferent blood flows are artificially stopped, hypoxia will ensue within the organ and the continued anaerobic C02 generation would then be detected by measuring either an increased PC02 in the organ itself or an increased PC02 in the stagnant efferent venous blood flow, and this despite a profound fall in aerobic C02 production. In experimental models of myocardial ischemia induced by ventricular fibrillation or prolonged coronary artery occlusion, striking elevations of PC02 consistent with anaerobic C02 production were measured in the myocardium or in the cardiac vein [5, 6]. In studies on patients undergoing mitral valve replacement, markedly increased myocardial PC0, has been measured during cross-clamping of the aorta after single dose cardioplegia [7]. Influence of CO on APC02 -- From the modified Pick equation, APC02 is inversely correlated to CO, so that for a given VC02, APC02 will increase in a proportion similar to that of the decrease in CO and conversely. Relevance of APC02 to vary with CO, under conditions of stable VC02, was supported by canine studies in which CO was gradually reduced, until V02 and presumably VC02 could no more be maintained [8-11]. In a protocol of progressive hemorrhage in anesthetized dogs, Bowles and Schlichtig [8] reported an elevation in APC02 from 4.2 ± 0.8 mmHg to 14.9 ± 1.2 mmHg following the reduction in CO from 1.9 ± 0.17 L/rain to 0.9 ± 0.04 L/rain during 02 supply independence, wherein V02 did not vary with 02 delivery (D02). In another model of progressive hemorrhage, Van der Linden et al. [9] also measured increases in APCO2 from 4.3 ± 1.3 to 12.9 ± 5.2 mmHg (p < 0.01) when CO was reduced from 4.7 ± 1.1 L/rain to 1.6 ± 0.3 L/rain (p < 0.01) while VO~ remained constant. Zhang and Vincent [10] also found thas as CO was gradually decreased during an experimental acute cardiac tamponade in anesthetized dogs, a progressive increase in APC02 had developed even in the initial period when VO~ and VCO2 were stable and lactic acidosis absent. Under these conditions of metabolic stability, APC02 had increased from 7.1 ± 4.6 mmHg to 17.5 ± 6.6 mmHg when CO had fell from 4.1 ± 1.0 L/min to 1.7 ± 0.6 L/rain. Groeneveld et al. [11] reported similar data in a model of reduction of CO secondary to incremental levels of PEEP applied in mechanically ventilated pigs. R~an. Urg., 1996, 5 ( 2 bis), 204-211
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Venoarterial C02 gradient
-- Elevation of APe02 following CO reduction, under conditions of stable COs production, can be explained by the C02 stagnation phenomenon. Because of the slowing of transit time, a greater than normal addition of C02 per unit of blood traversing the peripheral efferent microvessels tends to generate hypercapnia in the venous circulation. As long as pulmonary ventilation is adequate, as CO drops, a gradient will develop between PvC02 and PaC02. This concept of reduced CO-associated C02 stagnation is undoubtedly supported by studies that reported a progressive increased PvCO~ during reduction in CO, under conditions of constant VOs and maintained PaC02 by mechanical ventilation and anesthesia [8-11]. However, some authors [12, 13] have oberved in animals allowed to breathe spontaneously, increases in zXPC02 associated with CO reduction and V02 stability, that had resulted from a decrease in PaC02 but an unchanged PvC02. Indeed, under spontaneous breathing conditions, hyperventilation stimulated by reduced blood flow, may decrease PaC0s and then may limit the C02 stagnation-associated increase in PvC02 that would have occurred if PaC02 was not decreased. This underlines the usefulness of calculating APe02 rather than simply measuring PvC02, especially under conditions of spontaneous breathing.
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Clinical use of APC02
From the theoretical considerations and available data we have just reviewed, APe02 may be reasonably assumed to be inversely related to CO and directly related to C02 production. Also, two different modes of clinical use of APe02 have been proposed: either APCOs used as a marker of CO in relatively stable patients or APe02 used as a marker of tissue hypoxia in severely ill patients. Unfortunately, we will demonstrate below that neither of these modes of use should be really recommendable because complex interrelations between CO and aerobic as well as anaerobic C02 production often exist in critically ill patients. As we will see, this makes the bedside interpretation of APCO~ and of its changes particularly misleading. ,~PC02 as a marker of CO
-- Because of the inverse relationship between APe02 and CO, APe02 has been proposed to be used as a marker of CO or better as a marker of adequation of CO response to changes in 02 demand. Reliability of APCOs to reflect CO under conditions of relative hemodynamic stability has been underlined in animal [13] and clinical studies [14]. Rackow et al, [13] found that APC02 was significantly higher in rats exhibiting low CO but 02 supply independence after induction of severe sepsis than in R~an. Urg., 1996, 5 (2 bis), 204-211
septic rats receiving albumine to maintain a normal CO. In critically ill patients assumed to be hemodynamically stable, Durkin et al. [14] found that the mean value of APe02 in patients with cardiac index (CI) < 2.6 L/min/m 2 was higher than the mean value of APe02 of those with CI >f 2.6 L/min/m 2 (4.88 4- 0.40 mmHg vs 7.44 4- 0.63 mmHg). In a study in stable cardiac patients with normal lactate, an increase in CI with 10 t~g/kg/min dobutamine from 1.7 4- 0.4 L/min/m 2 to 2.4 4- 0.08 L/min/m 2 was associated with parallel decreases in APe02 from 9 4- 2 mmHg to 5 4- 3 mmHg, while VOs remained constant [15]. The findings of this latter study confirmed the reliability of APe02 changes to reflect CO changes in the range of low CO and stable metabolic conditions. It is likely but not proved that the normalization of APe02 under 10 t~g/kg/min of dobutamine infusion would mean that the level of CO achieved at this dose, although apparently still low, was in good adequation with global Os demand. -- Important limitations of the use of APe02 as a marker of CO and of its variations in critically ill patients have to be pointed out. • In a given patient, if VC02 varies simultaneously to CO changes, changes in APe02 do not obviously reflect changes in CO. This may occur under two circumstances: * in patients with tissue hypoxia in whom anaerobic COs generation is likely but aerobic C02 production is reduced. As we will see later, both aerobic C02 production and anaerobic C02 production may be influenced by changes in CO. * in patients without tissue hypoxia, but in whom treatment-induced changes in CO might be associated with treatment-induced changes in aerobic COs production. For instance, an augmentation of CO with a drug therapy having thermogenic effects may result in unchanged APe02. We have recently underlined this point, in a study performed in cardiac patients with low CO but without tissue hypoxia [15]. Administration of incremental doses of dobutamine (0, 5, 10 and 15 t~g/kg/min) had resulted in a doserelated elevation of CO, but in a biphasic APCOs response [15]: a first decrease until that dobutamine dose had reached 10 t~g/kg/min, then a slight increase at the highest dose, that likely had resulted from an increase in aerobic COs production due to thermogenie effects of the drug at this dose [16]. This was confirmed by the evolution of V02 which remained stable as long as the dose was raised up to 10 t~g/kg/ min but then significantly increased after that 15 t~g/ kg/min of dobutamine was infused [15]. In this study, APCOs would have been more useful than CO to titrate drug therapy. • For a given VCOs, an absolute change in CO in the lowest range of CO must result in greater changes in APe02 than it does in the highest range of CO. This is simply explained by the cur-
Venoarterial C02 gradient -
vilinearity of the relationships between APCO~ and CO. Indeed, according to the modified Fick equation: APC02 -- k (VCOJCO), for a constant VC02, APCO~ is linearly related to CO in low values of CO whereas there is a flattening of the APCOJCO relationships curve in high values of CO so that further elevation of CO will no more result in significant reduction in APC02. This mathematical lack of sensitivity of APC02 to reflect CO in the high range of CO does not necessarily mean that the use of APC02, in terms of adequation of CO response to 0~ demand must be rejected in high flow states. For instance, in sepsisrelated high flow states without profound tissue hypoxia where mixed venous O~ saturation (Sv0~) or 0~ extraction ratio would not be reliable markers of adequate CO because of both high flow and 02 extraction impairement, achievement of a normal APCO~ as a marker of adequate CO with 0~ demand could be used as a therapeutic goal. However, this hypothesis needs further confirmation. • The APCOJCO relationships will depend also on the level of VC02, so that a family of hyperbolic APCOJC0 relationships curves for various levels of VC0~ (isopleth VC02) can be drawn. Therefore, it is quite impossible to estimate an absolute value of CO from a APC02 measurement, or to deduce CO changes from APC0~ changes, even if VC02 is assumed to remain constant. • We previously assumed that the relationship between CC02 and PC02 is nearly linear and that the extrapolation of the Fick equation to the modified Fick equation is valid. In fact, this is not true in the highest range of CCO~ where APC02 changes are greater than zXCC0~ changes. Reduced pH and high
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02 saturation would further exaggerate disparities between CC02 and PC02 at high levels of CC02 (Fig. 1). Consequently, as during low flow states, CvC02 would be increased because of C02 stagnation, PvC02 would be particularly high so that for a given CO and VC02, APC02 would be of greater magnitude than previously assumed from the modified Fick equation. This phenomenon may be exaggerated by the fall in venous pH which constantly follows increased PvC02 and may be of further importance if metabolic acidosis coexist [3], or if Sv02 is high because of peripheral 0~ extraction impairement. Under these conditions, APC02 would markedly overestimate CvCO~ - CaC02 so that APCO~ changes would no longer reflect CO changes even for a stable aerobic VC02. Taken together, the limitations of using simply APC02 measurement as a marker of CO probably have accounted for the poor correlations -- even if significant -- between CO and APC02, which have been found in a number of experimental [13, 17, 18] or clinical studies [14, 19-21]. These findings suggest that although CO is probably the major factor influencing C02 gradient, APC02 cannot be so reliably used as a marker of CO in critically ill patients, especially in those assumed to have CO-associated VC02 changes. This does not mean that zXPC02 is less helpful than CO to assess global oxygenation. As pointed out earlier, under aerobic conditions, APC0~ might be particularly useful to assess adequacy of CO response to 0~ demand in patients with reduced blood flow, or perhaps even in patients with sepsis-related high flow states.
~6o
4o 3o n
2o
>81° 0
10
20 30 40 50 60 70 80 90 100 110 120 CARBON DIOXIDE PRESSURE mm Hg
Fig. 1. - - Relationship between C02 pressure (X axis) and C02 content
(Y axis). Note that well-oxygenated blood carries less C02 for the same PC02. R6an. Urg., 1996, 5 (2 bis), 204-211
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Venoarterial C02 gradient
APCO~ as a marker of tissue hypoxia
In cardiac arrest-resuscitated animal or patients, striking increases in APC0~ were reported [22-24]. These findings were ascribed to the reduced blood flow during resuscitation manoeuvers [22, 23] and to the development of anaerobic metabolism following cardiorespiratory arrest [24]. Adrogue et al. [24] also reported a venoarterial C0~ gradient greater in patients with circulatory failure, than in those without circulatory failure even with relatively low CO. From these observations, it was postulated that anaerobic C0~ production may play a major role in the widening C02 gradient under conditions of low flow states with tissue hypoxia. Thus some authors have proposed to use APC02 to detect tissue hypoxia or dysoxia in critically ill patients [8-10]. -- In fact, this is a much more complex issue than it appears, as confirmed by the existence of conflicting reports in the recent literature that require further explanations. Under conditions of tissue hypoxia, an anaerobic C02 production should occur, as pointed our earlier. However, the reduction in aerobic metabolism must decrease the aerobic C02 production. If the net resultant effect is a reduction in total C02 production as indicated by many studies [10-12], then APC0~ would decrease but not increase under conditions of normal or high blood flow. Indeed, the less produced C02 should be easily removed by a normal or elevated venous blood flow so that CvCO~ and PvC02 should decrease. -- To confirm this simple physiological hypothesis, one needs experimental studies in which cell hypoxia would be created by another mechanism than reducing blood flow, for instance hypoxemic hypoxia. To our knowledge, such studies, with analysis of APCO~ changes, do not exist in the literature. All studies that had addressed the issue of detecting tissue hypoxia by analysis of APC02, had used protocols of reducing blood flow. Yet, we have underlined earlier the key role of decreased CO in the widening of APC02, owing to a reduction in peripheral CO~ removal (CO~stagnation phenomenon) and this even in aerobic conditions. The presence of confounding variables in these studies would have resulted in some difficulties in interpreting results and in drawing definitive conclusions. • In a well done study, Zhang and Vincent [10] had analyzed the complex relationship between APC02 and CO by using a model of cardiac tamponade in anesthetized dogs. They concluded that APC02 can represent reliable parameters of tissue hypoxia. The authors compared the values of APCO~ and venoarterial pH gradients with that of blood lactate in their relationship to changes in VO~ and DO~ during an acute reduction in blood flow induced by cardiac tamponade. As mentioned above, they observed during the first period (02 supply independent R6an. Urg., 1996, 5(2 bis), 204-211 --
period) of reduction in CO from 4.1 4- 1.0 L/min to 1.7 4- 0.6 L/min, a slight increase in APC02 from 7.1 4- 4.6 mmHg to 17.5 4- 6.6 (p < 0.01), while a constant VC02 and end-tidal C02 tension (PETCO~) were measured. Below the critical level of DO~ (DO~ crit) where V02 cannot be maintained (0~ supply dependent period), the widening of APC02 was magnified by a further increase in PvC02 and a reduction in PaC02. Interestingly, below the level of DO2 crit VCO~ and PETC02 decreased, while lactate increased. The critical values of DO2 calculated for VOw, APC02 and lactate did not differ significantly. At the end of the study, APC02 was of 40.9 + 14.3 mmHg while CO was of 0.6 4- 0.3 L/rain. For the authors, the slight widening of APC02, until DO~ crit was reached, was obviously due to CO reduction (C02 stagnation) because VCO~ was unchanged, whereas the further reduction in CO (and DO~) during the 02 supply dependent period could have hardly accounted for the brisk increase in APCO~ observed. Also, the marked increase in APC02 during this phase was ascribed to combined effects of anaerobic CO~ production and reduced CO. It seems difficult to quite agree with this interpretation, because V02 and VC02 have been observed to decrease dramatically during this period so that the total CO~ production that venous blood flow had to remove, should have been dramatically reduced. Also, the brisk increase in APCO~ measured during this phase could not be due to an increase in production of C02 but rather to the predominant role played by the further reduction in CO, through C02 stagnation phenomenon, for the lowest range of CO. At least, two mechanisms can explain the predominant role of reduction in CO on APC02 under conditions of very low flow: First, the mathematical curvilinearity of the relationship between ACCO~ and CO (Fick equation), may explain the exaggerated APC02 increase for the lowest range of CO. In fact, this mathematical phenomenon is strong under conditions of maintained VC02, but attenuated here, because of gradual VC02 decreases simultaneously to CO decreases (gradual shift from a VCO~ isopleth to another one). Thus, in our point of view, this can play only for one part of the marked APC02 increase observed during this period. -- The other reason for the striking APC02 widening may be explained by the curvilinearity of the relationship between CvC02 and PvCO~ (Fig. 1), in that, even modest increases in CvCO~ (related to the preeceding mechanism), should result in exaggerated increases in APC02, especially under low venous pH conditions. One argument strongly supporting this interpretation is given by the data provided by Zhang and Vincent [10]: the product of APC02 by CO, an index of VC02, which remained constant during the O~ supply independent period, had fallen during the 02 --
s u p -
Venoarterial C02 gradientply dependent phase. It is not a surprising finding since the independently measured VC02 had also fallen [10]. However, this clearly indicates that the value of APCO~ achieved during the anaerobic phase was lower than the value which would have resulted from the same reduced CO under aerobic conditions! In other words, in the absence of tissue hypoxia, the same reduction in CO would have resulted in a more marked widening of APC02. Interestingly, the decrease in PaCOs that the authors observed along with severe reductions in CO had probably resulted from the fall in CO~ production [10]. Indeed, because alveolar dead space was observed to increase during the reduction in blood flow [10], PaCO~ would have rather increased if COs production had not fallen. From a physiological basis and from the data reported in the study of Zhang and Vincent [10], one can reasonably assume that in the presence of tissue hypoxia and reduced blood flow, increases in APCO~ are of lesser extent than in the presence of reduced blood flow but absence of tissue hypoxia. • The studies of Bowles et al. [8] and of Van der Linden et al. [9] also used a biphasic model of VOJDO~ relationship in anesthetized dogs. By producing a graded hemorrhage, they also found a brisk increase in APCO~ at the level of DOs crit. From the data presented in their studies, one could also demonstrate that, without the knowledge of the evolution of VOs, the APC02 changes measured while DO~ was above as well as below DO~ crit, would have been quite consistent with the sole reduction in CO associated with aerobic conditions. • Data and conclusions reported by Groeneveld et al. [11] quite agreed with our reasoning. These authors reduced DO2 by application of incremental levels of PEEP in pigs. They also found an hyperbolic response of APCOs to reduction in CO, but in the face of a reduced measured VCO~, they clearly concluded that during hypoperfusion and hypoxia, the increased APCO~ was caused by a greater reduction in tissue blood flow than in COs production, so that tissue COs removal was impaired [11]. Thus, from the analysis of available experimental data [8-11] it can be reasonably stated that in a given patient, a sudden increase in APCO~ should not be readily ascribed to the onset or to the worsening of hypoxia but rather to a further reduction in blood flow. Lack of sensitivity of APC02 to detect tissue hypoxia has been confirmed by clinical studies [19, 20, 25] and some experimental arguments [26]. • Some clinical studies have suggested that the reduced CO plays the key role in the widening of COs gradient observed under conditions of low blood flow with tissue hypoxia [19, 20]. Mecher et al. [19] found in patients with sepsis-related circulatory failure, that the subgroup of those with APC02 > 6 mmHg (mean 4- SEM = 9 4- 1 mmHg)had a -
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mean CI significantly lower than in the subgroup of those with APCOs ~< 6 mmHg (2.3 4- 0.2 L/min/m 2 vs 3.0 4- 0.2 L/min/m 2 respectively). Interestingly, the two subroups did not differ in terms of blood lactate (6 4- i mmol/1 vs 5.7 4- 1.1 mmol/1 respectively) and blood pressure (59 4- 3 mmHg and 63 44 mmHg), parameters which can be considered as associated with circulatory failure and tissue hypoxia. In others words, many patients of this study (18/37) had normal APCOs despite tissue hypoxia, probably because a high blood flow could have easily removed the COs produced at the periphery. In the subgroup of patients with high APCOs, fluid challenge had resulted in a decrease in APCO2 associated with an increase in CO. In contrast, no significant changes in CO and APCOs were observed in patients with normal APC02. Therefore, the authors reasonably concluded that in patients with septic shock, an increased APCO2 is associated with a reduced systemic flow. Bakker et al. [20] also demonstrated that in patients with septic shock, APCO~ was mostly related to CO. In their study including 64 patients with documented septic shock, 15 patients had DPC02 > 6 mmHg. These patients had a lower CI than the patients with normal APCO~ (2.9 4- 1.3 L/min/m 2 vs 4.3 4- 1.5 L/ min/m2). Moreover, opposite changes in APCO~ and in CO during the course of septic shock were observed [20]. Interestingly, patients with a high APC02 had similar VO~ and blood lactate than patients with a normal APC02. Although VCO~ and VOs were not measured directly these data suggest that difference in CO~ production in patients with septic shock did not substantially account for differences in APCOs [20]. Clearly, studies of Mecher et al. [19] and of Bakker et al. [20] have underlined the poor sensitivity of APCO2 to detect tissue hypoxia, since APCO2 was normal in most patients with sepsis-related circulatory shock except with those with low CO. • The poor sensitivity of APC02 as a marker of dysoxia was confirmed by the study of Wendon et al. [25] including patients with fulminant hepatic failure. Ten hypotensive patients were assumed to have significant tissue hypoxia, as they demonstrated an increase in V0s after prostacyclin infusion. During baseline, despite a likely tissue hypoxia, APCOs was low (less than 3 mmHg). This was probably explained by a low production of COs -- as postulated in view of the low V02 (119 ml/min/m 2) -- easily removed by the very high level of CO (CI = 5.4 L/min/ m2). These findings emphasize the fact, we have earlier postulated from physiological basis, that tissue hypoxia under conditions of high flow states should rather result in decreased than increased APCO2. • Otherwise, an additional argument in favor of the lack of sensitivity of APCO2 to detect tissue dysoxia, was recently brought by Schlichtig and Bowles [26]. From a complex but elegant reasoning, Rban. Urg., 1996, 5 ( 2 bis), 204-211
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VenoarterialC02 gradient
the authors demonstrated in dogs that portal venous PCO~ although elevated, might result only from aerobic oxidative phosphorlation while a progressive lethal cardiac tamponade had resulted in both reduction in intestine blood flow and striking elevation of mucosal PCO2 [26]. Mucosal PCO~ was measured indirectly with saline filled CO~-permeable Silastic balloon tonometers in the intestinal lumen. The more likely explanation is that the expanding tonometerportal vein PCO~ gradient with decreasing intestine flow represented anaerobic appearance of dissolved C02 in the mucosa with primarily aerobic PC02 appearance in muscularis and serosa. Thus it appeared that portal venous blood had reflected acid-base state of still well perfused tissues (as muscularis and serosa) and that these well perfused areas had produced principally aerobic C02. It was probable that mucosal anaerobically produced C02 could not be removed by flow because of the existence of hypoxic unperfused mucosal areas. Interestingly, this study demonstrated that: • a high portal venous PCO, (75 mmHg) and then mixed venous PCO2 can be only related to a reduction in blood flow in the presence of maintained aerobic CO~ production, even in near-zero flow conditions! • a high PvC0~ and then a high APC02 as global parameters could not detect localized organ hypoxia because of potential unperfusion of the dysoxic tissues; • the direct or indirect measurement of PC02 in a dysoxic organ could be of particular usefulness. -- While the poor sensitivity of APCO~ to detect tissue dysoxia appears now obvious from a theoretical reasoning and from clinical and experimental data, a few studies have brought the demonstration of a poor specificity of this parameter as a marker of hypoxia. To demonstrate that, one needs conditions where very high values of APCO~ can be measured in the absence of tissue hypoxia. Such conditions are not easy to find in some animal studies, where too marked reductions in blood flow had frequently resulted in tissue hypoxia [17, 18]. However, some experimental protocols have consisted in a graded reduction in CO and DO~, allowing to ensure a period of maintained VOw: also, in some studies high values of APCO~ 17.5 ± 6.6 mmHg (10); 14.4 4- 1.23 (8); 14 4- i mmHg (11); 12.9 4- 5.2 mmHg (9) have been found to coexist with aerobic conditions (0= supply independence period). In chronic cardiac patients where low CO may coexist without tissue hypoxia, high APCO~ values may coexist with aerobic conditions. Lenique et al. reported high values of APC02 in some cardiac patients with low CI and normal blood lactate who did not exhibit any VO~ supply dependency after DO~ was augmented by dobutamine infusion [15]. R6an. Urg., 1996, 5(2 bis), 204-211
In fact, such APC02 values like APCO2 values reported under aerobic conditions in animals [8-11] are relatively high in comparison with reported values of APC0~ in available clinical studies including patients with tissue hypoxia, in which arterial and mixed venous blood were sampled. We can conclude that: -- neither an increased APCO, nor a brisk increase in APC0~ can reliably detect onset or worsening of tissue hypoxia or dysoxia. Yet, although increased APCO~ or sudden increase in APCO2 may be encountered in aerobic conditions, they would then actually denote a too low blood flow in response to 0~ demand with short term subsequent risks of occurence of true tissue hypoxia. In this connection, using APC02 to assess hemodynamic status and to follow evolution under drug therapy cannot be rejected but needs further confirmation; --a normal APC02 does not exclude the presence of either a profound global tissue hypoxia when blood flow is maintained or a local hypoxia when hypoxic tissues are unperfused, This conclusion does not mean that anaerobic C02 production does not occur under conditions of tissue hypoxia, but rather that following APC02 changes is not the good way to detect anaerobic C02 production. Indirect evidence of anaerobic C02 production under conditions of tissue hypoxia have been brought by studies reporting, along with a decrease in DO2, decreases in V02 and VC02 (calculated from expired gas analysis) but with increased VCOJV02 ratio [11, 27]. Under these conditions, an increased VC02/V02 ratio indicates that VC02 is less reduced than V02 when tissue hypoxia occurs. In others words, this probably denotes the presence of anaerobic C02 generation in hypoxic tissue. The use of an increase in the respiratory quotient was recently proposed to detect global tissue hypoxia through detection of anaerobic C02 generation [27]. This could be perhaps the useful tool that one needs to detect global tissue hypoxia. Further confirmation is still required.
References [1] MCHARDY G.J.R. - - The relationship between the differences in pressure and content of carbon dioxide in arterial and venous blood. Clin. Sci., 1967, 32, 299-309. [2] DOUGLASA.R., JONES N.L., REED J.W. - - Calculation of whole blood CO2 content. J. AppL PhysioL, 1988, 65, 473-477. [3] HACHAMOVITCH R., BROWN H.V., RUBIN S.A. - - Respiratory and circulatory analysis of CO2 output during exercise in chronic heart failure. Circulation, 1991, 84, 605-612. [4] RANDAL H., COHEN J. - - Anaerobic CO2 production by dog kidney in vitro. Am. J. PhysioL, 1966, 211, 493-505. [5] VON PLANTA M., WElL M.H., GAZMURI R.J., BISERA J., RACKOW E.C. - - Myocardial acidosis associated with CO2 production during cardiac arrest and resuscitation. Circulation, 1989, 80, 684-692.
Venoarterial C02 g r a d i e n t -
[6] KETTEF., WElL M.H., GAZMURIR.J., BISERAJ., RACKOWE.C. -Intramyocardial hypercarbic acidosis during cardiac arrest and resuscitation. Crit. Care Med., 1993, 21, 901-906. [7] MACGOVERNG.J., FLAHERTYJ.T., KANTER K.R. et al. - - Assessment of myocardial protection during global ischemia with myocardial gas tension monitoring. Surgery, 1982, 92, 373-380. [8] E}OWLESS.A., SCHLICHTIGR., KRAMERD.J., KLIONSH.A. - - Arteriovenous pH and partial pressure of carbon dioxide detect critical oxygen delivery during progressive hemorrhage in dogs. J. Crit. Care, 1992, 7, 95-105. [9] VAN DER LINDEN P., RAUSIN I., DELTELLA. et aL - - Detection of tissue hypoxia by arteriovenous gradient for PCO2 and pH in anesthetized dogs during progressive hemorrhage. Anesth. Analg., 1995, 80, 269-275. [10] ZHANG H., VINCENT J.L. - - Arteriovenous differences in PCO2 and pH are good indicators of critical hypoperfusion. Am. Rev. Respir. Dis., 1993, 148, 867-871. [1 1] GROENEVELDA.B.J., VERMEIJC.G., THIJS L.G. - - Arterial and mixed venous blood acid-base balance during hypoperfusion with incremental positive end-expiratory pressure in the pig. Anesth. Analg., 1991, 73, 576-582. [12] MATHIAS D.W., CLIFFORD P.S., KLOPFENSTEIN S. - - Mixed venous blood gases are superior to arterial blood gases in assessing acid-base status and oxygenation during acute cardiac tamponade in dogs. Clin. Invest., 1988, 82, 833-838. [13] RACKOW E.C., ASTIZ M.E., MECHER C.E., WElL M.H. - - Increased venous-arterial carbon dioxide tension difference during severe sepsis in rats. Crit. Care Med., 1994, 22, 121-125. [14] DURKINa., GERGITSM.A., REED III J.F., FITZGIBBONSJ . - The relationship between the arteriovenous carbon dioxide gradient and cardiac index. J. Crit. Care, 1993, 8, 217-221. [15] LENIQUEF., TEBOUL J.L., BOUJDARIAR. et aL - - Usefulness on venoarterial CO2 tension gradient to adjust dobutamine dose in CHF patients. Am. Rev. Respir. Dis., 1993, 147, A621 (Abstract). [16] TEBOULJ.L., GRAINI L., BOUJDARIAR., BERTONC., RICHARDC. Cardiac index vs oxygen-derived parameters for ration-
[17] [18] [19] [20] [21] [22] [23]
[24] [25]
[26]
[27]
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amuse of dobutamine in patients with congestive heart failure. Chest, 1993, 103, 81-85. HAMALGYID.F.J., KENNEDYM., VARGA D. - - Hidden hypercapnia in hemorrhagic hypotension. Anesthesiology, 1970, 33, 594-601. DUCEYJ.P., LAMIELLEJ.M., GUELLERG.E. - - Arterial-venous carbon dioxide tension difference during severe hemorrhage and resuscitation. Crit. Care Med., 1992, 20, 518-522. MECHER C.E., RACKOW E.C., ASTIZ M.E., WElL M.H. - Venous hypercarbia associated with severe sepsis and systemic hypoperfusion. Crit. Care Med., 1990, 18, 585-589. BAKKERJ., VINCENTJ.L., GRISP., LEON M., COEFERNILSM., KAHN R . J . - - VenD-arterial carbon dioxide gradient in human septic shock. Chest, 1992, 101, 509-515. LIND L. - - VenD-arterial carbon dioxide and pH gradients and survival in critical illness. Eur. J. Clin. Invest., 1995, 25, 201-205. GRUNDLERW., WElL M.H., RACKOW E.C. - - Arteriovenous carbon dioxide and pH gradients during cardiac arrest. Circulation, 1986, 74, 1071-1074. WElL M.H., RACKOW E.C., TREVINO R., GRUNDLERW., FALK J.L., GRIFFELM.I. - - Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N. EngL J. Med., 1986, 315, 153-156. ADROGUEH.J., RASHAD N., GORIN A.B., YACOUBJ., MADIAS N.E. - - Assessing acid-base status in circulatory failure. N. Engl. J. Med., 1989, 320, 1312-1316. WENDONJ.A., HARRISONP.M., KEAYSR., GIMSONA.E., ALEXANDERG., WILLIAMSR. - - Arterial-venous pH differences and tissue hypoxia in patients with fulminant hepatic failure. Crit. Care Med., 1991, 19, 1362-1364. SCHLICHTIG R., BOWLES S.A. - - Distinguishing between aerobic and anaerobic appearance of dissolved CO2 in intestine during low flow. J. AppL Physiol., 1994, 76, 2443-2451. COHENI.L., SHEIKHF.M., PERKINSR.J., FEUSTELP.J., FOSTER E.D. - - Effect of hemorrhagic shock and reperfusion on the respiratory quotient in swine. Crit. Care Med., 1995, 23, 545-552.
mmm
R#an. Urg., 1996, 5 (2 bis), 204-211
•
Definitions
The venoarterial carbon dioxide (C02) tension (PCO~) gradient (zXPCO~) is the difference between PCO2 in mixed venous blood (PvC02) and the PCO2 in arterial blood (PaC02): APCO2 = PvC02 - PaCO~ PaC02 and PrO2 are partial pressures of the dissolved C02 in arterial and mixed venous blood respectively which represent only a fraction of arterial C02 content (CaC02) and mixed venous C02 content (CvCO~) respectively.
•
C02 transport in the blood
• C02 is carried in the blood in three forms: dissolved, as bicarbonate and in combination with proteins as carbamino compounds. Because C02 is about 20 times more soluble than oxygen (O~), the dissolved form plays a more significant role in the normal carriage in the blood. -- Bicarbonate is formed in the blood by the following sequence: C02 + H20 *=* H~C03 *== H + + HC03where H20 is water, H2C03 is carbonic acid, H ÷ is hydrogen ion, HC03- is bicarbonate ion. The first reaction is very slow in plasma but fast within the red blood cell, because of the presence in this cell of carbonic anhydrase. The second reaction occurs rapidly within the red cell and does not need any enzyme. When the concentration of H ÷ and HC03- in the cells rises, HC03- diffuses out of the red blood cells into plasma but H ÷cannot diffuse eas-
fly because the cell membrane is relatively impermeable to cations. Some of the H ÷ liberated are bound to hemoglobin (Hb). H ÷ + HbO2 *:=* H - Hb + 02 This reaction occurs because reduced Hb is a better acceptor of H ÷ than the oxygenated Hb. In the peripheral venous blood, the loading of C02 is facilitated by the presence of reduced Hb (Haldane effect). -- Carbamino compounds are formed by the combination of CO~ with terminal amine groups of blood protein, especially the globin of Hb. Reduced Hb can load more C02 as carbamino compound than Hb0~. • A greater part of the C02 content (CC02) is in the form of bicarbonate. • The relationship between the PC02 and the total CC02 is curvilinear although much more linear than the 02 dissociation curve. Haematocrit, 02 saturation, temperature and pH influence the PCOJCCO~ content relationship [1, 2].
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Service de R6animation Medicale, H6pital de Bicetre, Facult6 de Medecine Paris-Sud, Le Kremlin Bic#tre. Correspondence to: Dr Jean-Louis Teboul, Service de R6animation M6dicale, H6pital de Bic6tre, 78, rue du G6neraI-Leclerc, 94275 Le Kremlin-Bic6tre cedex.
R6an. Urg., 1996, 5(2 bis), 204-211
•
Determinants of venoarterial C02 gradient
The Fick equation applied to C02 indicates that the C02 excretion (equivalent to C02 production in a steady state) equals the product of cardiac output (CO) by the (CvC0~ - CaC02) gradient: VC02
= CO
. (CvC02
-
CaC02).
Over the usual physiological range of CO~ contents, there is a relatively linear relationship between CCO~ and PCO~ so that by rearranging the Fick equation and substituting PC02 for CCO~, a modified Fick equation can be obtained: zXPC02 = kVCOJCO where k is assumed to be a constant. Therefore, z~PC02 would be linearly related to C02 production and inversely related to CO.
.
Influence of C02 production on APC02
Aerobic C02 production At the cellular level, the aerobic CO~ generation is a normal terminal product of mitochondrial oxidative phosphorylation. Thus, under aerobic conditions CC02 in the effluent venous blood must be higher than in the afferent arterial blood. Under these normal conditions, the total C02 production (VC02) is directly related to global 02 consumption (V02). VC02 = R . V02, where'R is the respiratory quotient, that is not a constant but may vary between 0.7 and 1.0 with respect to the predominant energy source; for instance when lipids are the major fuel sources, R is close to 0.7 whereas under conditions of high carbohydrate intake R approaches 1.0. Therefore, the aerobic C02 production should augment either with increased oxidative metabolism or for a constant V02 when an equilibrated feeding regimen is replaced by a high carbohydrate intake regimen. Under both conditions, CvC0~ - CaC02 and APC02 should increase except if CO increases in the same extent. In normal subjects exhibiting 5 fold increases in V0~ and VC02 associated with a 2 fold increase in CO during a 50 Watt exercice, Hachamovitch et al. [3] had measured a significant increase in PvC02 from 41.7 ± 1.3 to 49.6 ±2 mmHg (p < 0.05) with unchanged PaC02, In these normal subjects, the aerobic production of C02 possibly accounted for the widening of APC02 during exercice.
Anaerobic C02 production When conditions of tissue hypoxia are present, an anaerobic production of C02 should occur. Two possible sources of C02 have been identified: buffering of excesses of H ÷ ions by HC03- ions and decarboxylation of metabolic intermediates [4]: under hypoxic conditions H ÷ ions are generated by two mechanisms: • excessive production of lactic acid owing to an acceleration of anaerobic glycolysis, since pyruvate is no longer cleared by the Krebs cycle. • hydrolysis of adenosine triphosphate (ATP) and of adenosine diphosphate (ADP) that occur in conditions of anaerobiosis. HC03- ions will then buffer H ÷ ions into the cell so that C02 will be generated. anaerobic decarboxylation of some substrats produced by intermediate metabolism such as cetoglutarate or oxaloacetate is a potential but minor source of anaerobic C02 production [4]. In hypoxic cells aerobic C02 production should be reduced but anaerobic C02 generation -- mostly -
-
-
-
Venoarterial C02 g r a d i e n t - 2 0 5 -
through buffering of H ÷ ions generated in excess -should be markedly increased. Evidence of a significant anaerobic production of C02 in hypoxic organs is not so easy to bring. Indeed, the efferent venous blood flow can be sufficiently efficient to clear the CO~ producted under these circumstances of a marked drop in aerobic C02 production. Therefore, PC02 could be not augmented in the efferent vein and anaerobic C02 production not detected. However, if afferent and efferent blood flows are artificially stopped, hypoxia will ensue within the organ and the continued anaerobic C02 generation would then be detected by measuring either an increased PC02 in the organ itself or an increased PC02 in the stagnant efferent venous blood flow, and this despite a profound fall in aerobic C02 production. In experimental models of myocardial ischemia induced by ventricular fibrillation or prolonged coronary artery occlusion, striking elevations of PC02 consistent with anaerobic C02 production were measured in the myocardium or in the cardiac vein [5, 6]. In studies on patients undergoing mitral valve replacement, markedly increased myocardial PC0, has been measured during cross-clamping of the aorta after single dose cardioplegia [7]. Influence of CO on APC02 -- From the modified Pick equation, APC02 is inversely correlated to CO, so that for a given VC02, APC02 will increase in a proportion similar to that of the decrease in CO and conversely. Relevance of APC02 to vary with CO, under conditions of stable VC02, was supported by canine studies in which CO was gradually reduced, until V02 and presumably VC02 could no more be maintained [8-11]. In a protocol of progressive hemorrhage in anesthetized dogs, Bowles and Schlichtig [8] reported an elevation in APC02 from 4.2 ± 0.8 mmHg to 14.9 ± 1.2 mmHg following the reduction in CO from 1.9 ± 0.17 L/rain to 0.9 ± 0.04 L/rain during 02 supply independence, wherein V02 did not vary with 02 delivery (D02). In another model of progressive hemorrhage, Van der Linden et al. [9] also measured increases in APCO2 from 4.3 ± 1.3 to 12.9 ± 5.2 mmHg (p < 0.01) when CO was reduced from 4.7 ± 1.1 L/rain to 1.6 ± 0.3 L/rain (p < 0.01) while VO~ remained constant. Zhang and Vincent [10] also found thas as CO was gradually decreased during an experimental acute cardiac tamponade in anesthetized dogs, a progressive increase in APC02 had developed even in the initial period when VO~ and VCO2 were stable and lactic acidosis absent. Under these conditions of metabolic stability, APC02 had increased from 7.1 ± 4.6 mmHg to 17.5 ± 6.6 mmHg when CO had fell from 4.1 ± 1.0 L/min to 1.7 ± 0.6 L/rain. Groeneveld et al. [11] reported similar data in a model of reduction of CO secondary to incremental levels of PEEP applied in mechanically ventilated pigs. R~an. Urg., 1996, 5 ( 2 bis), 204-211
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206
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Venoarterial C02 gradient
-- Elevation of APe02 following CO reduction, under conditions of stable COs production, can be explained by the C02 stagnation phenomenon. Because of the slowing of transit time, a greater than normal addition of C02 per unit of blood traversing the peripheral efferent microvessels tends to generate hypercapnia in the venous circulation. As long as pulmonary ventilation is adequate, as CO drops, a gradient will develop between PvC02 and PaC02. This concept of reduced CO-associated C02 stagnation is undoubtedly supported by studies that reported a progressive increased PvCO~ during reduction in CO, under conditions of constant VOs and maintained PaC02 by mechanical ventilation and anesthesia [8-11]. However, some authors [12, 13] have oberved in animals allowed to breathe spontaneously, increases in zXPC02 associated with CO reduction and V02 stability, that had resulted from a decrease in PaC02 but an unchanged PvC02. Indeed, under spontaneous breathing conditions, hyperventilation stimulated by reduced blood flow, may decrease PaC0s and then may limit the C02 stagnation-associated increase in PvC02 that would have occurred if PaC02 was not decreased. This underlines the usefulness of calculating APe02 rather than simply measuring PvC02, especially under conditions of spontaneous breathing.
•
Clinical use of APC02
From the theoretical considerations and available data we have just reviewed, APe02 may be reasonably assumed to be inversely related to CO and directly related to C02 production. Also, two different modes of clinical use of APe02 have been proposed: either APCOs used as a marker of CO in relatively stable patients or APe02 used as a marker of tissue hypoxia in severely ill patients. Unfortunately, we will demonstrate below that neither of these modes of use should be really recommendable because complex interrelations between CO and aerobic as well as anaerobic C02 production often exist in critically ill patients. As we will see, this makes the bedside interpretation of APCO~ and of its changes particularly misleading. ,~PC02 as a marker of CO
-- Because of the inverse relationship between APe02 and CO, APe02 has been proposed to be used as a marker of CO or better as a marker of adequation of CO response to changes in 02 demand. Reliability of APCOs to reflect CO under conditions of relative hemodynamic stability has been underlined in animal [13] and clinical studies [14]. Rackow et al, [13] found that APC02 was significantly higher in rats exhibiting low CO but 02 supply independence after induction of severe sepsis than in R~an. Urg., 1996, 5 (2 bis), 204-211
septic rats receiving albumine to maintain a normal CO. In critically ill patients assumed to be hemodynamically stable, Durkin et al. [14] found that the mean value of APe02 in patients with cardiac index (CI) < 2.6 L/min/m 2 was higher than the mean value of APe02 of those with CI >f 2.6 L/min/m 2 (4.88 4- 0.40 mmHg vs 7.44 4- 0.63 mmHg). In a study in stable cardiac patients with normal lactate, an increase in CI with 10 t~g/kg/min dobutamine from 1.7 4- 0.4 L/min/m 2 to 2.4 4- 0.08 L/min/m 2 was associated with parallel decreases in APe02 from 9 4- 2 mmHg to 5 4- 3 mmHg, while VOs remained constant [15]. The findings of this latter study confirmed the reliability of APe02 changes to reflect CO changes in the range of low CO and stable metabolic conditions. It is likely but not proved that the normalization of APe02 under 10 t~g/kg/min of dobutamine infusion would mean that the level of CO achieved at this dose, although apparently still low, was in good adequation with global Os demand. -- Important limitations of the use of APe02 as a marker of CO and of its variations in critically ill patients have to be pointed out. • In a given patient, if VC02 varies simultaneously to CO changes, changes in APe02 do not obviously reflect changes in CO. This may occur under two circumstances: * in patients with tissue hypoxia in whom anaerobic COs generation is likely but aerobic C02 production is reduced. As we will see later, both aerobic C02 production and anaerobic C02 production may be influenced by changes in CO. * in patients without tissue hypoxia, but in whom treatment-induced changes in CO might be associated with treatment-induced changes in aerobic COs production. For instance, an augmentation of CO with a drug therapy having thermogenic effects may result in unchanged APe02. We have recently underlined this point, in a study performed in cardiac patients with low CO but without tissue hypoxia [15]. Administration of incremental doses of dobutamine (0, 5, 10 and 15 t~g/kg/min) had resulted in a doserelated elevation of CO, but in a biphasic APCOs response [15]: a first decrease until that dobutamine dose had reached 10 t~g/kg/min, then a slight increase at the highest dose, that likely had resulted from an increase in aerobic COs production due to thermogenie effects of the drug at this dose [16]. This was confirmed by the evolution of V02 which remained stable as long as the dose was raised up to 10 t~g/kg/ min but then significantly increased after that 15 t~g/ kg/min of dobutamine was infused [15]. In this study, APCOs would have been more useful than CO to titrate drug therapy. • For a given VCOs, an absolute change in CO in the lowest range of CO must result in greater changes in APe02 than it does in the highest range of CO. This is simply explained by the cur-
Venoarterial C02 gradient -
vilinearity of the relationships between APCO~ and CO. Indeed, according to the modified Fick equation: APC02 -- k (VCOJCO), for a constant VC02, APCO~ is linearly related to CO in low values of CO whereas there is a flattening of the APCOJCO relationships curve in high values of CO so that further elevation of CO will no more result in significant reduction in APC02. This mathematical lack of sensitivity of APC02 to reflect CO in the high range of CO does not necessarily mean that the use of APC02, in terms of adequation of CO response to 0~ demand must be rejected in high flow states. For instance, in sepsisrelated high flow states without profound tissue hypoxia where mixed venous O~ saturation (Sv0~) or 0~ extraction ratio would not be reliable markers of adequate CO because of both high flow and 02 extraction impairement, achievement of a normal APCO~ as a marker of adequate CO with 0~ demand could be used as a therapeutic goal. However, this hypothesis needs further confirmation. • The APCOJCO relationships will depend also on the level of VC02, so that a family of hyperbolic APCOJC0 relationships curves for various levels of VC0~ (isopleth VC02) can be drawn. Therefore, it is quite impossible to estimate an absolute value of CO from a APC02 measurement, or to deduce CO changes from APC0~ changes, even if VC02 is assumed to remain constant. • We previously assumed that the relationship between CC02 and PC02 is nearly linear and that the extrapolation of the Fick equation to the modified Fick equation is valid. In fact, this is not true in the highest range of CCO~ where APC02 changes are greater than zXCC0~ changes. Reduced pH and high
207
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02 saturation would further exaggerate disparities between CC02 and PC02 at high levels of CC02 (Fig. 1). Consequently, as during low flow states, CvC02 would be increased because of C02 stagnation, PvC02 would be particularly high so that for a given CO and VC02, APC02 would be of greater magnitude than previously assumed from the modified Fick equation. This phenomenon may be exaggerated by the fall in venous pH which constantly follows increased PvC02 and may be of further importance if metabolic acidosis coexist [3], or if Sv02 is high because of peripheral 0~ extraction impairement. Under these conditions, APC02 would markedly overestimate CvCO~ - CaC02 so that APCO~ changes would no longer reflect CO changes even for a stable aerobic VC02. Taken together, the limitations of using simply APC02 measurement as a marker of CO probably have accounted for the poor correlations -- even if significant -- between CO and APC02, which have been found in a number of experimental [13, 17, 18] or clinical studies [14, 19-21]. These findings suggest that although CO is probably the major factor influencing C02 gradient, APC02 cannot be so reliably used as a marker of CO in critically ill patients, especially in those assumed to have CO-associated VC02 changes. This does not mean that zXPC02 is less helpful than CO to assess global oxygenation. As pointed out earlier, under aerobic conditions, APC0~ might be particularly useful to assess adequacy of CO response to 0~ demand in patients with reduced blood flow, or perhaps even in patients with sepsis-related high flow states.
~6o
4o 3o n
2o
>81° 0
10
20 30 40 50 60 70 80 90 100 110 120 CARBON DIOXIDE PRESSURE mm Hg
Fig. 1. - - Relationship between C02 pressure (X axis) and C02 content
(Y axis). Note that well-oxygenated blood carries less C02 for the same PC02. R6an. Urg., 1996, 5 (2 bis), 204-211
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2 0 8
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Venoarterial C02 gradient
APCO~ as a marker of tissue hypoxia
In cardiac arrest-resuscitated animal or patients, striking increases in APC0~ were reported [22-24]. These findings were ascribed to the reduced blood flow during resuscitation manoeuvers [22, 23] and to the development of anaerobic metabolism following cardiorespiratory arrest [24]. Adrogue et al. [24] also reported a venoarterial C0~ gradient greater in patients with circulatory failure, than in those without circulatory failure even with relatively low CO. From these observations, it was postulated that anaerobic C0~ production may play a major role in the widening C02 gradient under conditions of low flow states with tissue hypoxia. Thus some authors have proposed to use APC02 to detect tissue hypoxia or dysoxia in critically ill patients [8-10]. -- In fact, this is a much more complex issue than it appears, as confirmed by the existence of conflicting reports in the recent literature that require further explanations. Under conditions of tissue hypoxia, an anaerobic C02 production should occur, as pointed our earlier. However, the reduction in aerobic metabolism must decrease the aerobic C02 production. If the net resultant effect is a reduction in total C02 production as indicated by many studies [10-12], then APC0~ would decrease but not increase under conditions of normal or high blood flow. Indeed, the less produced C02 should be easily removed by a normal or elevated venous blood flow so that CvCO~ and PvC02 should decrease. -- To confirm this simple physiological hypothesis, one needs experimental studies in which cell hypoxia would be created by another mechanism than reducing blood flow, for instance hypoxemic hypoxia. To our knowledge, such studies, with analysis of APCO~ changes, do not exist in the literature. All studies that had addressed the issue of detecting tissue hypoxia by analysis of APC02, had used protocols of reducing blood flow. Yet, we have underlined earlier the key role of decreased CO in the widening of APC02, owing to a reduction in peripheral CO~ removal (CO~stagnation phenomenon) and this even in aerobic conditions. The presence of confounding variables in these studies would have resulted in some difficulties in interpreting results and in drawing definitive conclusions. • In a well done study, Zhang and Vincent [10] had analyzed the complex relationship between APC02 and CO by using a model of cardiac tamponade in anesthetized dogs. They concluded that APC02 can represent reliable parameters of tissue hypoxia. The authors compared the values of APCO~ and venoarterial pH gradients with that of blood lactate in their relationship to changes in VO~ and DO~ during an acute reduction in blood flow induced by cardiac tamponade. As mentioned above, they observed during the first period (02 supply independent R6an. Urg., 1996, 5(2 bis), 204-211 --
period) of reduction in CO from 4.1 4- 1.0 L/min to 1.7 4- 0.6 L/min, a slight increase in APC02 from 7.1 4- 4.6 mmHg to 17.5 4- 6.6 (p < 0.01), while a constant VC02 and end-tidal C02 tension (PETCO~) were measured. Below the critical level of DO~ (DO~ crit) where V02 cannot be maintained (0~ supply dependent period), the widening of APC02 was magnified by a further increase in PvC02 and a reduction in PaC02. Interestingly, below the level of DO2 crit VCO~ and PETC02 decreased, while lactate increased. The critical values of DO2 calculated for VOw, APC02 and lactate did not differ significantly. At the end of the study, APC02 was of 40.9 + 14.3 mmHg while CO was of 0.6 4- 0.3 L/rain. For the authors, the slight widening of APC02, until DO~ crit was reached, was obviously due to CO reduction (C02 stagnation) because VCO~ was unchanged, whereas the further reduction in CO (and DO~) during the 02 supply dependent period could have hardly accounted for the brisk increase in APCO~ observed. Also, the marked increase in APC02 during this phase was ascribed to combined effects of anaerobic CO~ production and reduced CO. It seems difficult to quite agree with this interpretation, because V02 and VC02 have been observed to decrease dramatically during this period so that the total CO~ production that venous blood flow had to remove, should have been dramatically reduced. Also, the brisk increase in APCO~ measured during this phase could not be due to an increase in production of C02 but rather to the predominant role played by the further reduction in CO, through C02 stagnation phenomenon, for the lowest range of CO. At least, two mechanisms can explain the predominant role of reduction in CO on APC02 under conditions of very low flow: First, the mathematical curvilinearity of the relationship between ACCO~ and CO (Fick equation), may explain the exaggerated APC02 increase for the lowest range of CO. In fact, this mathematical phenomenon is strong under conditions of maintained VC02, but attenuated here, because of gradual VC02 decreases simultaneously to CO decreases (gradual shift from a VCO~ isopleth to another one). Thus, in our point of view, this can play only for one part of the marked APC02 increase observed during this period. -- The other reason for the striking APC02 widening may be explained by the curvilinearity of the relationship between CvC02 and PvCO~ (Fig. 1), in that, even modest increases in CvCO~ (related to the preeceding mechanism), should result in exaggerated increases in APC02, especially under low venous pH conditions. One argument strongly supporting this interpretation is given by the data provided by Zhang and Vincent [10]: the product of APC02 by CO, an index of VC02, which remained constant during the O~ supply independent period, had fallen during the 02 --
s u p -
Venoarterial C02 gradientply dependent phase. It is not a surprising finding since the independently measured VC02 had also fallen [10]. However, this clearly indicates that the value of APCO~ achieved during the anaerobic phase was lower than the value which would have resulted from the same reduced CO under aerobic conditions! In other words, in the absence of tissue hypoxia, the same reduction in CO would have resulted in a more marked widening of APC02. Interestingly, the decrease in PaCOs that the authors observed along with severe reductions in CO had probably resulted from the fall in CO~ production [10]. Indeed, because alveolar dead space was observed to increase during the reduction in blood flow [10], PaCO~ would have rather increased if COs production had not fallen. From a physiological basis and from the data reported in the study of Zhang and Vincent [10], one can reasonably assume that in the presence of tissue hypoxia and reduced blood flow, increases in APCO~ are of lesser extent than in the presence of reduced blood flow but absence of tissue hypoxia. • The studies of Bowles et al. [8] and of Van der Linden et al. [9] also used a biphasic model of VOJDO~ relationship in anesthetized dogs. By producing a graded hemorrhage, they also found a brisk increase in APCO~ at the level of DOs crit. From the data presented in their studies, one could also demonstrate that, without the knowledge of the evolution of VOs, the APC02 changes measured while DO~ was above as well as below DO~ crit, would have been quite consistent with the sole reduction in CO associated with aerobic conditions. • Data and conclusions reported by Groeneveld et al. [11] quite agreed with our reasoning. These authors reduced DO2 by application of incremental levels of PEEP in pigs. They also found an hyperbolic response of APCOs to reduction in CO, but in the face of a reduced measured VCO~, they clearly concluded that during hypoperfusion and hypoxia, the increased APCO~ was caused by a greater reduction in tissue blood flow than in COs production, so that tissue COs removal was impaired [11]. Thus, from the analysis of available experimental data [8-11] it can be reasonably stated that in a given patient, a sudden increase in APCO~ should not be readily ascribed to the onset or to the worsening of hypoxia but rather to a further reduction in blood flow. Lack of sensitivity of APC02 to detect tissue hypoxia has been confirmed by clinical studies [19, 20, 25] and some experimental arguments [26]. • Some clinical studies have suggested that the reduced CO plays the key role in the widening of COs gradient observed under conditions of low blood flow with tissue hypoxia [19, 20]. Mecher et al. [19] found in patients with sepsis-related circulatory failure, that the subgroup of those with APC02 > 6 mmHg (mean 4- SEM = 9 4- 1 mmHg)had a -
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209 -
mean CI significantly lower than in the subgroup of those with APCOs ~< 6 mmHg (2.3 4- 0.2 L/min/m 2 vs 3.0 4- 0.2 L/min/m 2 respectively). Interestingly, the two subroups did not differ in terms of blood lactate (6 4- i mmol/1 vs 5.7 4- 1.1 mmol/1 respectively) and blood pressure (59 4- 3 mmHg and 63 44 mmHg), parameters which can be considered as associated with circulatory failure and tissue hypoxia. In others words, many patients of this study (18/37) had normal APCOs despite tissue hypoxia, probably because a high blood flow could have easily removed the COs produced at the periphery. In the subgroup of patients with high APCOs, fluid challenge had resulted in a decrease in APCO2 associated with an increase in CO. In contrast, no significant changes in CO and APCOs were observed in patients with normal APC02. Therefore, the authors reasonably concluded that in patients with septic shock, an increased APCO2 is associated with a reduced systemic flow. Bakker et al. [20] also demonstrated that in patients with septic shock, APCO~ was mostly related to CO. In their study including 64 patients with documented septic shock, 15 patients had DPC02 > 6 mmHg. These patients had a lower CI than the patients with normal APCO~ (2.9 4- 1.3 L/min/m 2 vs 4.3 4- 1.5 L/ min/m2). Moreover, opposite changes in APCO~ and in CO during the course of septic shock were observed [20]. Interestingly, patients with a high APC02 had similar VO~ and blood lactate than patients with a normal APC02. Although VCO~ and VOs were not measured directly these data suggest that difference in CO~ production in patients with septic shock did not substantially account for differences in APCOs [20]. Clearly, studies of Mecher et al. [19] and of Bakker et al. [20] have underlined the poor sensitivity of APCO2 to detect tissue hypoxia, since APCO2 was normal in most patients with sepsis-related circulatory shock except with those with low CO. • The poor sensitivity of APC02 as a marker of dysoxia was confirmed by the study of Wendon et al. [25] including patients with fulminant hepatic failure. Ten hypotensive patients were assumed to have significant tissue hypoxia, as they demonstrated an increase in V0s after prostacyclin infusion. During baseline, despite a likely tissue hypoxia, APCOs was low (less than 3 mmHg). This was probably explained by a low production of COs -- as postulated in view of the low V02 (119 ml/min/m 2) -- easily removed by the very high level of CO (CI = 5.4 L/min/ m2). These findings emphasize the fact, we have earlier postulated from physiological basis, that tissue hypoxia under conditions of high flow states should rather result in decreased than increased APCO2. • Otherwise, an additional argument in favor of the lack of sensitivity of APCO2 to detect tissue dysoxia, was recently brought by Schlichtig and Bowles [26]. From a complex but elegant reasoning, Rban. Urg., 1996, 5 ( 2 bis), 204-211
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2 1 0
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VenoarterialC02 gradient
the authors demonstrated in dogs that portal venous PCO~ although elevated, might result only from aerobic oxidative phosphorlation while a progressive lethal cardiac tamponade had resulted in both reduction in intestine blood flow and striking elevation of mucosal PCO2 [26]. Mucosal PCO~ was measured indirectly with saline filled CO~-permeable Silastic balloon tonometers in the intestinal lumen. The more likely explanation is that the expanding tonometerportal vein PCO~ gradient with decreasing intestine flow represented anaerobic appearance of dissolved C02 in the mucosa with primarily aerobic PC02 appearance in muscularis and serosa. Thus it appeared that portal venous blood had reflected acid-base state of still well perfused tissues (as muscularis and serosa) and that these well perfused areas had produced principally aerobic C02. It was probable that mucosal anaerobically produced C02 could not be removed by flow because of the existence of hypoxic unperfused mucosal areas. Interestingly, this study demonstrated that: • a high portal venous PCO, (75 mmHg) and then mixed venous PCO2 can be only related to a reduction in blood flow in the presence of maintained aerobic CO~ production, even in near-zero flow conditions! • a high PvC0~ and then a high APC02 as global parameters could not detect localized organ hypoxia because of potential unperfusion of the dysoxic tissues; • the direct or indirect measurement of PC02 in a dysoxic organ could be of particular usefulness. -- While the poor sensitivity of APCO~ to detect tissue dysoxia appears now obvious from a theoretical reasoning and from clinical and experimental data, a few studies have brought the demonstration of a poor specificity of this parameter as a marker of hypoxia. To demonstrate that, one needs conditions where very high values of APCO~ can be measured in the absence of tissue hypoxia. Such conditions are not easy to find in some animal studies, where too marked reductions in blood flow had frequently resulted in tissue hypoxia [17, 18]. However, some experimental protocols have consisted in a graded reduction in CO and DO~, allowing to ensure a period of maintained VOw: also, in some studies high values of APCO~ 17.5 ± 6.6 mmHg (10); 14.4 4- 1.23 (8); 14 4- i mmHg (11); 12.9 4- 5.2 mmHg (9) have been found to coexist with aerobic conditions (0= supply independence period). In chronic cardiac patients where low CO may coexist without tissue hypoxia, high APCO~ values may coexist with aerobic conditions. Lenique et al. reported high values of APC02 in some cardiac patients with low CI and normal blood lactate who did not exhibit any VO~ supply dependency after DO~ was augmented by dobutamine infusion [15]. R6an. Urg., 1996, 5(2 bis), 204-211
In fact, such APC02 values like APCO2 values reported under aerobic conditions in animals [8-11] are relatively high in comparison with reported values of APC0~ in available clinical studies including patients with tissue hypoxia, in which arterial and mixed venous blood were sampled. We can conclude that: -- neither an increased APCO, nor a brisk increase in APC0~ can reliably detect onset or worsening of tissue hypoxia or dysoxia. Yet, although increased APCO~ or sudden increase in APCO2 may be encountered in aerobic conditions, they would then actually denote a too low blood flow in response to 0~ demand with short term subsequent risks of occurence of true tissue hypoxia. In this connection, using APC02 to assess hemodynamic status and to follow evolution under drug therapy cannot be rejected but needs further confirmation; --a normal APC02 does not exclude the presence of either a profound global tissue hypoxia when blood flow is maintained or a local hypoxia when hypoxic tissues are unperfused, This conclusion does not mean that anaerobic C02 production does not occur under conditions of tissue hypoxia, but rather that following APC02 changes is not the good way to detect anaerobic C02 production. Indirect evidence of anaerobic C02 production under conditions of tissue hypoxia have been brought by studies reporting, along with a decrease in DO2, decreases in V02 and VC02 (calculated from expired gas analysis) but with increased VCOJV02 ratio [11, 27]. Under these conditions, an increased VC02/V02 ratio indicates that VC02 is less reduced than V02 when tissue hypoxia occurs. In others words, this probably denotes the presence of anaerobic C02 generation in hypoxic tissue. The use of an increase in the respiratory quotient was recently proposed to detect global tissue hypoxia through detection of anaerobic C02 generation [27]. This could be perhaps the useful tool that one needs to detect global tissue hypoxia. Further confirmation is still required.
References [1] MCHARDY G.J.R. - - The relationship between the differences in pressure and content of carbon dioxide in arterial and venous blood. Clin. Sci., 1967, 32, 299-309. [2] DOUGLASA.R., JONES N.L., REED J.W. - - Calculation of whole blood CO2 content. J. AppL PhysioL, 1988, 65, 473-477. [3] HACHAMOVITCH R., BROWN H.V., RUBIN S.A. - - Respiratory and circulatory analysis of CO2 output during exercise in chronic heart failure. Circulation, 1991, 84, 605-612. [4] RANDAL H., COHEN J. - - Anaerobic CO2 production by dog kidney in vitro. Am. J. PhysioL, 1966, 211, 493-505. [5] VON PLANTA M., WElL M.H., GAZMURI R.J., BISERA J., RACKOW E.C. - - Myocardial acidosis associated with CO2 production during cardiac arrest and resuscitation. Circulation, 1989, 80, 684-692.
Venoarterial C02 g r a d i e n t -
[6] KETTEF., WElL M.H., GAZMURIR.J., BISERAJ., RACKOWE.C. -Intramyocardial hypercarbic acidosis during cardiac arrest and resuscitation. Crit. Care Med., 1993, 21, 901-906. [7] MACGOVERNG.J., FLAHERTYJ.T., KANTER K.R. et al. - - Assessment of myocardial protection during global ischemia with myocardial gas tension monitoring. Surgery, 1982, 92, 373-380. [8] E}OWLESS.A., SCHLICHTIGR., KRAMERD.J., KLIONSH.A. - - Arteriovenous pH and partial pressure of carbon dioxide detect critical oxygen delivery during progressive hemorrhage in dogs. J. Crit. Care, 1992, 7, 95-105. [9] VAN DER LINDEN P., RAUSIN I., DELTELLA. et aL - - Detection of tissue hypoxia by arteriovenous gradient for PCO2 and pH in anesthetized dogs during progressive hemorrhage. Anesth. Analg., 1995, 80, 269-275. [10] ZHANG H., VINCENT J.L. - - Arteriovenous differences in PCO2 and pH are good indicators of critical hypoperfusion. Am. Rev. Respir. Dis., 1993, 148, 867-871. [1 1] GROENEVELDA.B.J., VERMEIJC.G., THIJS L.G. - - Arterial and mixed venous blood acid-base balance during hypoperfusion with incremental positive end-expiratory pressure in the pig. Anesth. Analg., 1991, 73, 576-582. [12] MATHIAS D.W., CLIFFORD P.S., KLOPFENSTEIN S. - - Mixed venous blood gases are superior to arterial blood gases in assessing acid-base status and oxygenation during acute cardiac tamponade in dogs. Clin. Invest., 1988, 82, 833-838. [13] RACKOW E.C., ASTIZ M.E., MECHER C.E., WElL M.H. - - Increased venous-arterial carbon dioxide tension difference during severe sepsis in rats. Crit. Care Med., 1994, 22, 121-125. [14] DURKINa., GERGITSM.A., REED III J.F., FITZGIBBONSJ . - The relationship between the arteriovenous carbon dioxide gradient and cardiac index. J. Crit. Care, 1993, 8, 217-221. [15] LENIQUEF., TEBOUL J.L., BOUJDARIAR. et aL - - Usefulness on venoarterial CO2 tension gradient to adjust dobutamine dose in CHF patients. Am. Rev. Respir. Dis., 1993, 147, A621 (Abstract). [16] TEBOULJ.L., GRAINI L., BOUJDARIAR., BERTONC., RICHARDC. Cardiac index vs oxygen-derived parameters for ration-
[17] [18] [19] [20] [21] [22] [23]
[24] [25]
[26]
[27]
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amuse of dobutamine in patients with congestive heart failure. Chest, 1993, 103, 81-85. HAMALGYID.F.J., KENNEDYM., VARGA D. - - Hidden hypercapnia in hemorrhagic hypotension. Anesthesiology, 1970, 33, 594-601. DUCEYJ.P., LAMIELLEJ.M., GUELLERG.E. - - Arterial-venous carbon dioxide tension difference during severe hemorrhage and resuscitation. Crit. Care Med., 1992, 20, 518-522. MECHER C.E., RACKOW E.C., ASTIZ M.E., WElL M.H. - Venous hypercarbia associated with severe sepsis and systemic hypoperfusion. Crit. Care Med., 1990, 18, 585-589. BAKKERJ., VINCENTJ.L., GRISP., LEON M., COEFERNILSM., KAHN R . J . - - VenD-arterial carbon dioxide gradient in human septic shock. Chest, 1992, 101, 509-515. LIND L. - - VenD-arterial carbon dioxide and pH gradients and survival in critical illness. Eur. J. Clin. Invest., 1995, 25, 201-205. GRUNDLERW., WElL M.H., RACKOW E.C. - - Arteriovenous carbon dioxide and pH gradients during cardiac arrest. Circulation, 1986, 74, 1071-1074. WElL M.H., RACKOW E.C., TREVINO R., GRUNDLERW., FALK J.L., GRIFFELM.I. - - Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N. EngL J. Med., 1986, 315, 153-156. ADROGUEH.J., RASHAD N., GORIN A.B., YACOUBJ., MADIAS N.E. - - Assessing acid-base status in circulatory failure. N. Engl. J. Med., 1989, 320, 1312-1316. WENDONJ.A., HARRISONP.M., KEAYSR., GIMSONA.E., ALEXANDERG., WILLIAMSR. - - Arterial-venous pH differences and tissue hypoxia in patients with fulminant hepatic failure. Crit. Care Med., 1991, 19, 1362-1364. SCHLICHTIG R., BOWLES S.A. - - Distinguishing between aerobic and anaerobic appearance of dissolved CO2 in intestine during low flow. J. AppL Physiol., 1994, 76, 2443-2451. COHENI.L., SHEIKHF.M., PERKINSR.J., FEUSTELP.J., FOSTER E.D. - - Effect of hemorrhagic shock and reperfusion on the respiratory quotient in swine. Crit. Care Med., 1995, 23, 545-552.
mmm
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