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Ann Thorac Surg 1999;67:1320-1327
© 1999 The Society of Thoracic Surgeons
a Department of Cardiac Surgery, University of Milan, Centro Cardiologico, Fondazione I Monzino IRCCS, Milan, Italy
Accepted for publication November 12, 1998.
Address reprint requests to Dr Parolari, Department of Cardiac Surgery, University of Milan, Centro Cardiologico, Fondazione I Monzino IRCCS, Via Parea, 4, 20138, Milano, Italy
e-mail: corallo{at}imiucca.csi.unimi.it
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Abstract |
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Methods. One hundred one patients were studied during cooling, hypothermia, and rewarming. Oxygen consumption, DO2, hemodynamics, and DO2crit were measured at these times.
Results. There was a direct linear relation between DO2 and VO2 during all three times. No relation between VO2 and hemodynamics was detected during cooling; during hypothermia, an inverse linear relation with peripheral arterial resistance was found. Finally, during rewarming, there was a direct relation with pump flow rate, and an inverse relation with arterial pressure and arterial resistance. The same relations among the variables were found at delivery levels above or below DO2crit.
Conclusions. During cardiopulmonary bypass there is a direct linear relation between DO2 and VO2; the relations with hemodynamic variables depend on the phases of cardiopulmonary bypass. This suggests that increasing delivery levels may recruit and perfuse more vascular beds, and higher delivery levels are advisable during perfusion. During rewarming and hypothermia, lower arterial resistances are also desirable to optimize VO2.
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Introduction |
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There is little agreement in the literature about the main determinants of VO2 during CPB, except for the role of temperature in reducing the metabolic activity of the body [1, 3]. Many studies, performed both on animals and in humans, reached some controversial conclusions about the relations between VO2 and oxygen delivery (DO2) [2, 4–8], and between VO2 and hemodynamic variables during clinical CPB [5, 7, 9].
The present study was designed to study the relations between VO2, DO2, and hemodynamics in a clinical perfusion setting, during a moderately hypothermic CPB performed with a nonpulsatile roller pump and the use of the 
-stat acid–base management in adults.
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Material and methods |
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Intraoperative management
Patient management during and after operation was essentially the same. All patients received standard moderate dose fentanyl and benzodiazepine anesthesia, which was induced by the administration of sodium thiopental, fentanil, succinilcholine, and pancuronium bromide.
After the induction of anesthesia, all the patients underwent orotracheal intubation and intermittent positive pressure ventilation, which was supplemented with oxygen and isoflurane when indicated. Bolus doses of fentanil, sodium thiopental, diazepam, and pancuronium bromide were given when necessary; sodium nitroprusside or intravenous nitroglycerin were administered when mean arterial pressure was 95 mm Hg or less, before, during, and after CPB [7]; hypovolemia was corrected with an infusion of polygelatine, with an hematocrit < 20% as transfusion trigger. Hemodynamic variables were monitored with an arterial pressure catheter and a pulmonary artery catheter inserted, respectively, into the right radial artery and the right internal jugular vein. Rectal and cervical esophageal probes were used for temperature monitoring; additional probes were positioned in the arterial and venous port of the pump oxygenator. A nonpulsatile roller pump (CAPS HLM, Stockert Instruments Inc, Munich, Germany) and hollow-fiber oxygenators (Monolith, Sorin Biomedica, Saluggia, Italy) were used in all patients.
Each operation was performed with moderate systemic hypothermia (28 to 30°C) and hemodilution. Blood flow during CPB was maintained at 2.4 L · min-1 · m-2 at normothermia and at 2 L · min-1 · m-2 at hypothermia; acid–base equilibrium was maintained by the -stat method and serial determination of the blood gases was performed using an IL-813 blood gas analyzer, and oxygen saturation and hemoglobin concentration were measured with the use of an IL-282 cooxymeter (Instrumentation Laboratories Inc, Lexington, MA); hematocrit was measured with centrifugation. Acid–base and blood gas results were those of the in vitro blood gas analyzer measured at 37°C and uncorrected for patient temperature.
Blood sampling and data collection
Blood samples have been collected at the following times: (1) cooling: 10 minutes after starting CPB (average esophageal temperature 31° ± 1.7°C); (2) hypothermia: at least 10 minutes after reaching stable hypothermia (27° to 30°C) (average esophageal temperature 28° ± 1.2°C); and (3) rewarming: about 10 minutes before the expected aortic unclamping time (average esophageal temperature 34° ± 1.7°C).
Blood was collected from the arterial and venous ports of the oxygenator in heparinized syringes. Before collecting the blood from the venous port, the perfusionist artificially created some degree of turbulence by partially clamping the venous line of the CPB circuit to obtain a completely mixed venous blood. The syringes were immediately put on ice, and the samples were subsequently analyzed, as stated before, at 37°C for blood gases, pH, bicarbonates, base excess, hematocrit, hemoglobin concentration, and oxygen saturation.
Arterial and venous oxygen content (CaO2 and CvO2), DO2, whole body VO2 and oxygen extraction (ExO2) were calculated at each experimental time by means of standard formulas:
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In addition, a total of 38 variables were recorded and collected at each experimental time, as reported in the Appendix. Finally, the shift of the metabolic rate per 10°C change in temperature (Q10) was calculated for the intervals cooling–hypothermia and hypothermia–rewarming in each patient as previously described [10].
Statistical analysis
Continuous variables are reported as mean ± 1 standard deviation (median in brackets), categorical as percentage. A commercial statistical package (SPSS for Windows version 6.0, SPSS Inc, Chicago, IL) was used for data analysis.
The relation between VO2, DO2, and hemodynamic variables were explored by graphic display of the VO2/DO2 and VO2/hemodynamic variables scatterplots, and by linear regression analysis and the computation of the Pearson correlation coefficient (r) of the rough data and of their transformations (square, square root, reciprocal, natural logarithm), to stabilize variances and achieve better residual distribution. The following models have been tested: (1) the observations separated according to three experimental times (cooling, hypothermia, rewarming); (2) the observations based on DO2crit corrected for the temperature of each determination (DO2crit is the theoretical delivery level where VO2 begins to decrease with further reductions of DO2) and on the three experimental times simultaneously. For the computation of the DO2crit, the theoretical delivery level of each observation was derived from a previous experience of Shibutani and colleagues [11], which showed that at a mean temperature of 35.5°C, VO2 begins to decrease for values of DO2 less than 330 mL · min-1 · m-2, or 8.2 mL · min-1 · kg-1. Therefore, using a previously described formula [10]: 
, where R = metabolic rate at the temperature T [°C] and T = esophageal temperature and using the computation of the value of Q10 (2.5), which could be obtained from our data, all the observations could be categorized into the categories DO2 > DO2crit or DO2 < DO2crit [10].
A p value less than 0.05 has been considered statistically significant.
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Results |
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Oxygen delivery and oxygen consumption
There was a significant direct linear relation between DO2 and VO2 for all three experimental times (cooling: r = 0.37, p < 0.001; hypothermia: r = 0.26, p = 0.009; rewarming: r = 0.41, p < 0.001; Fig 1); a plateau in the DO2/VO2 relation was not detectable at any experimental time. The same result was found from the analysis of the observations of the three experimental times by DO2crit, and no diphasic relation could be demonstrated also in these cases (Table 8).
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Comment |
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In ventilated individuals, this relation is diphasic, and VO2 begins to decrease concurrently with DO2 only when a critical threshold of delivery is reached and anaerobic metabolism ensues [11, 12]. In some patients, this relation can shift to a linear relation in conditions such as shock, adult respiratory distress syndrome, or endotoxemia. This condition, called pathologic oxygen supply dependency, was explained by a diminished ability of the tissues to extract oxygen, an increased tissue oxygen demand, or both [12–14].
Much less information exists about the behavior of the DO2/VO2 relation during clinical CPB; moreover, the literature evidences on the relations between VO2 and hemodynamic variables during a clinical perfusion are also relatively few, conflicting, and mostly address the modifications of VO2 concurrent with variations in pump flow rate.
Concerning pump flow rate, the University of Alabama at Birmingham group [5] showed that by varying the flow rates from 0.25 to 2 L · min-1 · m-2 at an average temperature of 20°C (a deep hypothermic condition that is relatively unusual in clinical practice), there was an hyperbolic relation between these two variables, and the VO2 began to decrease concurrently with the perfusion flow at flow rates of 1.2 L · min-1 · m-2.
Similar results were found by Alston and colleagues [7] at moderate hypothermic conditions (28°C), when a reduction of pump flow from 2 to 1.5 L · min-1 · m-2 reduced VO2 without any modification in the oxygen extraction levels. In this case a redistribution of blood flow through the microvascular beds was hypothesized. On the other hand, other experiments performed with moderate hypothermia did not show any reduction in VO2 concurrent with the reduction in flow rates, attributable only to an increase in oxygen extraction rates [2, 6].
Concerning whole body VO2, arterial pressure, and vascular resistances, Osipov and associates [9] evaluated the relation between the perfusion pressure and VO2 documenting a inverse linear relation.
The clinical design of our study carries some limitations. It was designed to be a merely speculative study of a clinical event (CPB), with no intentional variation of the clinical variables of the perfusion; therefore, only a relatively narrow range of flows and deliveries, as currently used in clinical practice, could be studied. Moreover, the determination of the value of DO2crit and its correction for the temperature of each determination must have been an artifact, even if based on previous studies by Shibutani [11] and Dantzker [12] and their colleagues, which showed that, at a mean temperature of 35.5°C, the critical DO2 level was 330 mL O2 · min-1 · m-2, or 8.2 mL · min-1 · kg-1, a value confirmed also in animal studies [15]. Furthermore, it was based on the evaluation of the Q10 value, which could be derived from the mean of the Q10 value for each patient of this study during the periods of cooling–hypothermia and hypothermia–rewarming, which was 2.5, consistent with previous findings in the literature [1, 3, 4, 8].
Although artificial, these results let us differentiate two groups of observations (DO2 > DO2crit and DO2 < DO2crit) substantially different in mixed venous oxygen tension (52 ± 9 mm Hg versus 42 ± 7 mm Hg; p < 0.001), mixed venous oxygen saturation (85% ± 6% versus 76% ± 8%; p < 0.001), and oxygen extraction rate (19% ± 5% versus 28% ± 6%; p < 0.001). In addition, this value of oxygen extraction with a delivery level less than DO2crit approaches the critical value of oxygen extraction (0.30 to 0.33) previously described in humans under anesthesia [11, 12].
Another point of concern might be that the eventual observed relation between the explored variables, and especially between DO2, pump flow rate, and whole body VO2, which could be ascribed partially to a mathematical artifact, because one of the variables, the pump flow rate, was present in the formulas for the computation of both DO2 and VO2. Previous studies were able to demonstrate that the linear relations eventually found in these cases are real, and not only attributable to mathematical coupling [16].
About the DO2/VO2 relation, at the studied conditions a diphasic relation was not demonstrated in any patient, neither was a plateau level. Either when all the observations were divided on the basis of the experimental times, or when they were considered by experimental time and critical delivery level, there was a statistically significant linear relation between these two variables. Moreover, in all linear regression analyses the regression lines showed similar slopes and intercepts (data not shown). Finally, also from the graphic display and from the simple visual analysis of all data sets it was not possible to perceive a plateau level in any patient.
To explain the behavior of VO2 during clinical CPB a two-step model can be hypothesized: (1) when the delivery decreases there is a progressive increase in the oxygen extraction up to a value of about 30%, which seems to be the critical level of oxygen extraction in the studied conditions. When this critical threshold of extraction is reached, there is a concurrent reduction in VO2 entirely dependent to the delivery level; therefore, there is a redistribution of blood flow and some microvascular beds become either inevitably underperfused or not perfused at all [7]. (2) For delivery levels above the critical threshold, there is a progressive increase of VO2 concurrent with the increase of delivery, remaining constantly lower than the extraction rate. Neither a plateau level can be reached, nor a hyperbolic relation can be detected. Those findings imply also a recruitment of new capillary beds that can accept the increase of delivery and use the supplementary oxygen delivered. In this case too, the vascular system, together with the capillary bed, is the only factor to which the regulation of this phenomenon can be ascribed.
Therefore, during clinical CPB the behavior of whole body VO2 with respect to DO2 seems to be relatively far away from the response previously described in humans under anesthesia as "diphasic" and to be similar to some pathophysiologic conditions of the body such as supply-dependency models [11–14].
To add strength to this hypothesis it has to be stressed that, at the studied conditions, a relative impairment of the capability to extract more oxygen from the blood, which is a frequent finding in the supply-dependency models [12], cannot be completely excluded. In fact, even if the higher extraction levels (28% to 35%) reached in this study are concordant, as stated before, with previous studies done on humans under general anesthesia (30% to 33%) [11, 12], the extraction rates reached in this study did not reach previously described levels of animal studies during CPB (extraction rates between 50% and 80%) [17, 18], previous experiences done in humans during deeply hypothermic perfusion (extraction levels up to 50%) [5] or measurements done in the early postoperative course after cardiac operation [19], where oxygen extraction could reach levels up to 50%.
The increase in oxygen metabolism, which is detectable concurrently with progressive increases of DO2, together with the reduced capability to extract oxygen from blood, conditions used in our protocol, led us to hypothesize a chronic underperfusion of the body capillary beds that might ensue with the current perfusion protocols, which might not allow complete tissue perfusion. That hypothesis might explain previous findings showing that in the early hours after CPB, there is an hypermetabolic body response probably attributable to inadequate tissue oxygenation during CPB [19, 20].
In contrast to the relation between VO2 and DO2, the analysis of the relation with hemodynamic variables showed a marked heterogeneity at the 3 time points. Concerning perfusion, there was an increasing influence of the hemodynamics on the behavior of the oxygen metabolism. During cooling, VO2, and therefore, the metabolic status of the body tissues, seems to be unrelated to the hemodynamic status of the patients. At hypothermia only arterial resistances significantly affect it and there is a trend toward a direct linear relation with pump flows, whereas during rewarming the perfusion hemodynamics strongly influence VO2.
We cannot formulate any certain explanation about the progressive effect of hemodynamic variables on the metabolic status during CPB. The hypothesis that could be drawn, although no data from our study are available to substantiate it, is that the production and the release of some humoral factor (inflammatory? hormones? cathecolamines? prostanoids?) during CPB might affect and modify the relation between hemodynamics and VO2, by influencing in different ways the vascular reactivity of the vascular and microvascular beds, whose functional heterogeneity was previously described [21, 22], as well as the release and production of many substances during CPB [23, 24]. In addition, a direct role of the microcirculation with blood flow redistribution through capillary beds with different vascular resistances, possibly attributable to a different degree of metabolic activity and oxygen demand could not be excluded as a factor influencing the behavior of oxygen metabolism during CPB, especially in the late phases [7, 9]. Moreover, the increase of VO2, concurrent with the rewarming phase, might increase the response of the capillary beds even to relatively minor hemodynamic changes.
Another point of interest is that the relations between VO2 and CPB hemodynamics found at the different times of our study protocol were substantially the same both at DO2 levels lower and higher than the theoretical critical delivery level. Even if the two groups of observations (more or less than the theoretical delivery level, DO2crit) were substantially different in terms of mixed venous oxygen tension, mixed venous oxygen saturation, and oxygen extraction rate, there were no substantial change in the behavior of the relation between oxygen metabolism and hemodynamic variables. That evidence may suggest that these relations are independent to DO2, and supports the hypothesis that VO2 during clinical CPB is a multifactorial event.
In conclusion, the constantly linear relation between DO2 and VO2 suggests that during CPB higher delivery levels may perfuse and recruit more vascular beds and, whenever possible, higher deliveries are recommended to avoid underperfusion of the body tissues. The hemodynamic variables affect VO2 in different ways, depending on the phases of CPB. Their influence is maximal during rewarming and minimal during the cooling period. This implies that lower peripheral arterial resistances, together with higher perfusion flow rates and lower arterial pressures, are desirable conditions to achieve an optimal whole body oxygen metabolism, when the patients are in hypothermic conditions, but especially when they are rewarmed and then weaned from cardiopulmonary bypass.
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Acknowledgments |
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Appendix |
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References |
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