Whole body oxygen consumption (VO 2 ) is universally

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1 Cardiopulmonary Bypass and Oxygen Consumption: Oxygen Delivery and Hemodynamics Alessandro Parolari, MD, PhD, Francesco Alamanni, MD, Tiziano Gherli, MD, Antonella Bertera, CCP, Luca Dainese, MD, Cristina Costa, CCP, Mara Schena, CCP, Erminio Sisillo, MD, Rita Spirito, MD, Massimo Porqueddu, MD, Paolo Rona, MD, and Paolo Biglioli, MD Department of Cardiac Surgery, University of Milan, Centro Cardiologico, Fondazione I Monzino IRCCS, Milan, Italy Background. This study was undertaken to investigate the relations between whole body oxygen consumption (VO 2 ), oxygen delivery (DO 2 ), and hemodynamic variables during cardiopulmonary bypass. Methods. One hundred one patients were studied during cooling, hypothermia, and rewarming. Oxygen consumption, DO 2, hemodynamics, and DO 2crit were measured at these times. Results. There was a direct linear relation between DO 2 and VO 2 during all three times. No relation between VO 2 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 Whole body oxygen consumption (VO 2 ) is universally considered as a measure of the metabolic activity of the body [1], and an indicator of tissue perfusion adequacy during cardiopulmonary bypass (CPB) [2]. There is little agreement in the literature about the main determinants of VO 2 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 VO 2 and oxygen delivery (DO 2 ) [2, 4 8], and between VO 2 and hemodynamic variables during clinical CPB [5, 7, 9]. The present study was designed to study the relations between VO 2, DO 2, 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. Material and Methods Patients From January to February 1996, 101 consecutive patients undergoing elective cardiac procedures using CPB were Accepted for publication Nov 12, 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; corallo@imiucca.csi.unimi.it. 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 DO 2crit. Conclusions. During cardiopulmonary bypass there is a direct linear relation between DO 2 and VO 2 ; 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 VO 2. (Ann Thorac Surg 1999;67:1320 7) 1999 by The Society of Thoracic Surgeons studied, after informed consent, at our hospital. The clinical features of the study population are as follows: 73 men (72.3%) and 28 women (27.7%); years (median, 64 years); body surface area, m 2 (median, 1.8 m 2 ); coronary artery bypass grafting, 56 of 101 patients (55.4%); valve (single or double) procedures, 32 of 101 patients (31.7%); other procedures, 13 of median (12.9%); and CPB time, minutes (median, 73 minutes). All patients have been managed by the same surgical and anesthesiology team. 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 he by The Society of Thoracic Surgeons /99/$20.00 Published by Elsevier Science Inc PII S (99)

2 Ann Thorac Surg PAROLARI ET AL 1999;67: OXYGEN CONSUMPTION DURING CPB 1321 Table 1. Hemodynamic Parameters CPB flow (L min 1 m 2 ) (2.2) (1.9) a (2.3) b Mean arterial pressure (mm Hg) (67) (80) a (80) b Peripheral arterial vascular resistances (dynes sec/cm 5 ) 1, (1,292) 1, (1,816) a 1, (1,564) b,c a p 0.05 cooling versus hypothermia. b p 0.05 cooling versus rewarming. c p 0.05 hypothermia versus rewarming. matocrit 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 C); (2) hypothermia: at least 10 minutes after reaching stable hypothermia (27 to 30 C) (average esophageal temperature C); and (3) rewarming: about 10 minutes before the expected aortic unclamping time (average esophageal temperature 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 (CaO 2 and CvO 2 ), DO 2, whole body VO 2 and oxygen extraction (ExO 2 ) were calculated at each experimental time by means of standard formulas: CaO 2 SaO 2 Hb PaO 2 CvO 2 SvO 2 Hb PvO 2 DO 2 Qp 10 CaO 2 VO 2 ml min 1 m 2 Qp 10 CaO 2 CvO 2 ExO 2 VO 2 /DO 2 100, where SaO 2 arterial blood oxygen saturation (%); PaO 2 arterial blood oxygen partial pressure (mm Hg); SvO 2 venous blood oxygen saturation (%); PvO 2 venous blood oxygen partial pressure (mm Hg); Hb blood hemoglobin concentration (mg/dl); and Qp CPB flow (L min 1 m 2 ). 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 (Q 10 ) 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 Table 2. Temperatures Esophageal temperature ( C) (30.9) (27.8) a (34) b,c Rectal temperature ( C) (33) (30.2) a (32.1) b,c Arterial blood temperature ( C) (27) (27.5) a (35.8) b,c Venous blood temperature ( C) (28.8) (28) a (34.1) b,c Arteriovenous blood differential temperature ( C) ( 1.85) (.2) a (1.6) b,c a p 0.05 cooling versus hypothermia. b p 0.05 cooling versus rewarming. c p 0.05 hypothermia versus rewarming.

3 1322 PAROLARI ET AL Ann Thorac Surg OXYGEN CONSUMPTION DURING CPB 1999;67: Table 3. O 2 and Hemoglobin Air administered (L/min) (2.5) (2.5) (2.2) FiO 2 (%) (70) (65) a (75) b,c Blood (7.5) (8.5) a (8.6) b hemoglobin (g/100 ml) Blood hematocrit (23) (25) a (26) b (%) a p 0.05 cooling versus hypothermia. b p 0.05 cooling versus rewarming. c p 0.05 hypothermia versus rewarming. version 6.0, SPSS Inc, Chicago, IL) was used for data analysis. The relation between VO 2, DO 2, and hemodynamic variables were explored by graphic display of the VO 2 / DO 2 and VO 2 /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 DO 2crit corrected for the temperature of each determination (DO 2crit is the theoretical delivery level where VO 2 begins to decrease with further reductions of DO 2 ) and on the three experimental times simultaneously. For the computation of the DO 2crit, 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, VO 2 begins to decrease for values of DO 2 less than 330 ml min 1 m 2, or 8.2 ml min 1 kg 1. Therefore, using a previously described formula [10]: d log R/dT log Q 10 /10, where R metabolic rate at the temperature T [ C] and T esophageal temperature and using the computation of the value of Q 10 (2.5), which could be obtained from our data, all the observations Table 5. Plasma Electrolytes Plasma sodium (130) (132) a (132) b (meq/l) Plasma potassium (meq/l) (4.3) (4.1) (4.7) b,c a p 0.05 cooling versus hypothermia. b p 0.05 cooling versus rewarming. c p 0.05 hypothermia versus rewarming. could be categorized into the categories or [10]. A p value less than 0.05 has been considered statistically significant. Results Clinical Variables The analysis of the clinical variables collected at the three different time points is reported in Tables 1 through 7. Q 10 The evaluation of the change of the metabolic rate per 10 change in temperature, calculated for the intervals cooling hypothermia and hypothermia rewarming in each patient, showed no significant differences between the Q 10 of the cooling hypothermia versus hypothermia rewarming period ( versus , p not significant). Oxygen Delivery and Oxygen Consumption There was a significant direct linear relation between DO 2 and VO 2 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 DO 2 /VO 2 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 DO 2crit, and no diphasic relation could be demonstrated also in these cases (Table 8). Table 4. Hemogasanalitic Parameters Arterial blood ph (7.44) (7.42) a (7.42) Arterial blood po 2 (mm Hg) (421) (363) a (321) b,c Arterial blood pco 2 (mm Hg) (35.8) (36.2) (33.8) b,c Arterial blood bicarbonates (meq/l) (24.7) (23.9) a (22.6) b,c Arterial blood base excess (meq/l) (1.4) (0.5) a ( 0.7) b,c Arterial blood oxygen saturation (%) (98.3) (98.2) (98.2) Venous blood ph (7.40) (7.38) a (7.38) b Venous blood po 2 (mm Hg) (51) (51) (42) b,c Venous blood pco 2 (mm Hg) (40.5) (41.1) (38.8) b,c Venous blood bicarbonates (meq/l) (25.5) (24.9) a (23.7) b,c Venous blood bicarbonate excess (meq/l) (1.5) (0.4) a ( 0.5) b,c Venous blood oxygen saturation (%) (87.4) (84) (76.8) b,c a p 0.05 cooling versus hypothermia. b p 0.05 cooling versus rewarming. c p 0.05 hypothermia versus rewarming.

4 Ann Thorac Surg PAROLARI ET AL 1999;67: OXYGEN CONSUMPTION DURING CPB 1323 Table 6. Drugs (Administration of the Following Drugs Within 10 Minutes Before the Determination or Oxygen Consumption, or #, Continuous Administration of the Drug) p Fentanil 42/101 (41.6%) 58/101 (57.4%) 81/101 (80.2%) Sodium thiopental 5/101 (5.0%) 18/101 (17.8%) 16/101 (15.8%) Diazepam 12/101 (11.9%) 23/101 (22.8%) 53/101 (52.5%) Pancuronium bromide 27/101 (26.7%) 11/101 (10.9%) 58/101 (57.4%) Sodium nitroprusside# 1/101 (1.0%) 6/101 (5.9%) 9/101 (8.9%) Nitroglicerin# 1/101 (1.0%) 1/101 (1.0%) 5/101 (5.0%) Poligelatine 8/101 (7.9%) 15/101 (14.9%) 43/101 (43.0%) Sodium bicarbonate 0/101 2/101 (2.0%) 10/101 (9.9%) Cardioplegia 11/101 (10.9%) 71/101 (70.3%) 81/101 (80.2%) Hemodynamic Variables and Oxygen Consumption MEAN ARTERIAL PRESSURE. There was no linear relation between VO 2 and arterial pressure during cooling or when stable hypothermia was attained; but there was an inverse linear relation between these two variables during the rewarming phase (r 0.38, p 0.001; Fig 2). The analysis of the observations divided on DO 2crit corrected for the temperature of each determination did not show any linear association between these two variables for the times cooling and hypothermia, both for the determination done at delivery levels more than DO 2crit and at delivery levels less than DO 2crit ; during the rewarming phase there was an inverse linear relation between VO 2 and arterial pressure both for and for DO 2 DO 2crit (Table 9). PERIPHERAL ARTERIAL RESISTANCE. No linear relation was found during cooling, whereas a significant inverse relation could be detected both at stable hypothermia (r 0.30, p 0.002) and during rewarming (r 0.45, p 0.001; Fig 3). In addition, a significant inverse linear association could be shown during rewarming at both delivery levels; at hypothermia, there was a statistically significant inverse relation for delivery levels more than DO 2crit, whereas a marginally significant inverse relation was detected for delivery levels lower than DO 2crit. Finally, during the cooling phase there was no significant relation in both cases (Table 10). PUMP FLOW RATE. There was a direct linear association between VO 2 and pump flow only during the rewarming phase (r 0.33; p 0.001). No relation could be detected during cooling; at stable hypothermia there was a trend toward a statistically significant direct linear association (r 0.18, p 0.071; Fig 4). The analysis of the observations by DO 2crit revealed a linear association between these two variables during rewarming and hypothermia at both delivery levels, whereas during the cooling phase there was no significant relation in both cases (Table 11). Comment The precise relation between DO 2, hemodynamic variables, and whole body VO 2 during clinical CPB still needs to be defined in detail. In ventilated individuals, this relation is diphasic, and VO 2 begins to decrease concurrently with DO 2 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 DO 2 /VO 2 relation during clinical CPB; moreover, the literature evidences on the relations between VO 2 and hemodynamic variables during a clinical perfusion are also relatively few, conflicting, and mostly address the modifications of VO 2 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 VO 2 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] Table 7. Oxygen Consumption, Delivery, Extraction Oxygen delivery (ml min 1 m 2 ) (249) (233) a (282) b,c Oxygen extraction (%) (20.7) (19) a (26.9) b,c Oxygen consumption (ml min 1 m 2 ) (52) (44) a (73) b,c a p 0.05 cooling versus hypothermia. b p 0.05 cooling versus rewarming. c p 0.05 hypothermia versus rewarming.

5 1324 PAROLARI ET AL Ann Thorac Surg OXYGEN CONSUMPTION DURING CPB 1999;67: Fig 1. Linear regression analysis between oxygen consumption (VO 2 ) and oxygen delivery (DO 2 ) by the three experimental times. Predicted regression lines are plotted with their 70% prediction intervals. at moderate hypothermic conditions (28 C), when a reduction of pump flow from 2 to 1.5 L min 1 m 2 reduced VO 2 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 VO 2 concurrent with the reduction in flow rates, attributable only to an increase in oxygen extraction rates [2, 6]. Concerning whole body VO 2, arterial pressure, and vascular resistances, Osipov and associates [9] evaluated the relation between the perfusion pressure and VO 2 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 DO 2crit 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 Table 8. Linear Regression Analysis Between VO 2 and DO 2 (by DO 2crit and by Experimental Times) Fig 2. Linear regression analysis between oxygen consumption (VO 2 ) and mean arterial pressure by the three experimental times. Predicted regression lines are plotted with their 70% prediction intervals. critical DO 2 level was 330 ml O 2 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 Q 10 value, which could be derived from the mean of the Q 10 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 ( and DO 2 DO 2crit ) substantially different in mixed venous oxygen tension (52 9 mm Hg versus 42 7mmHg;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 DO 2crit 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 DO 2, pump flow rate, and whole body VO 2, which could be ascribed partially to a mathematical artifact, because one of the variables, the pump Table 9. Linear Regression Analysis Between VO 2 and Mean Arterial Pressure (by DO 2crit and by Experimental Times) Measurement n r p n r p Measurement n r p n r p Cooling Hypothermia Rewarming Cooling Hypothermia Rewarming

6 Ann Thorac Surg PAROLARI ET AL 1999;67: OXYGEN CONSUMPTION DURING CPB 1325 Fig 3. Linear regression analysis between oxygen consumption (VO 2 ) and peripheral arterial resistances by the three experimental times. Predicted regression lines are plotted with their 70% prediction intervals. flow rate, was present in the formulas for the computation of both DO 2 and VO 2. 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 DO 2 /VO 2 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 VO 2 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 VO 2 entirely dependent to the delivery level; therefore, there Table 10. Linear Regression Analysis Between VO 2 and Peripheral Arterial Resistances (by DO 2crit and by Experimental Times) Fig 4. Linear regression analysis between oxygen consumption (VO 2 ) and pump flow rate by the three experimental times. Predicted regression lines are plotted with their 70% prediction intervals. 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 VO 2 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 VO 2 with respect to DO 2 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 supplydependency 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 Table 11. Linear Regression Analysis Between VO 2 and Pump Flow Rate (by DO 2crit and by Experimental Times) Measurement n r p n r p Measurement n r p n r p Cooling Hypothermia Rewarming Cooling Hypothermia Rewarming

7 1326 PAROLARI ET AL Ann Thorac Surg OXYGEN CONSUMPTION DURING CPB 1999;67: 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 DO 2, 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 VO 2 and DO 2, 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, VO 2, 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 VO 2. 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 VO 2,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 VO 2, 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 VO 2 and CPB hemodynamics found at the different times of our study protocol were substantially the same both at DO 2 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, DO 2crit ) 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 DO 2, and supports the hypothesis that VO 2 during clinical CPB is a multifactorial event. In conclusion, the constantly linear relation between DO 2 and VO 2 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 VO 2 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. We thank Eugene H. Blackstone, MD, Cleveland Clinic Foundation, Cleveland, OH, for his invaluable help and constructive criticism to this study. We are also grateful to the anonymous reviewers of The Annals for their comments and suggestions. References 1. Kirklin JW, Barratt-Boyes BG. Hypothermia, circulatory arrest, and cardiopulmonary bypass. In: Kirklin JW, Barratt- Boyes BG, eds. Cardiac surgery, 2nd ed. New York: Churchill Livingstone, 1993: Hickey RF, Hoar PF. Whole body oxygen consumption during low-flow hypothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86: Shapiro H, Stoner EK. Body temperature and oxygen uptake in man. Ann Phys Med 1966;8: Harris EA, Seelye ER, Squire AW. Oxygen consumption during cardiopulmonary bypass with moderate hypothermia in man. Brit J Anaesth 1971;43: Fox LS, Blackstone EH, Kirklin JW, Stewart RW, Samuelson PN. Relationship of whole body oxygen consumption to perfusion flow rate during hypothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1982;83: Baraka A. The effect of perfusion flow on oxidative metabolism during cardiopulmonary bypass. Anesth Analg 1993;76: Alston RP, Singh M, McLaren AD. Systemic oxygen uptake during hypothermic cardiopulmonary bypass. Effect of flow rate, flow character, and arterial ph. J Thorac Cardiovasc Surg 1989;98: Lazenby WD, Ko W, Zelano JA, et al. Effect of temperature and flow rate on regional blood flow and metabolism during cardiopulmonary bypass. Ann Thorac Surg 1992;53: Osipov VP, Khodas MJ, Dementjeva II, Pjatnitskaja GK. Arterial pressure: its role in perfusion and as a criterion of extracorporeal circulation adequacy. Artif Organs 1982;6: Willford DC, Hill EP, Moores WY. Theoretical analysis of oxygen transport during hypothermia. J Clin Monit 1986;2:

8 Ann Thorac Surg PAROLARI ET AL 1999;67: OXYGEN CONSUMPTION DURING CPB Shibutani K, Komatsu T, Kubal K, Sanchala V, Kumar V, Bizzarri D. Critical level of oxygen delivery in anesthetized man. Crit Care Med 1983;11: Dantzker DR, Foresman, B, Gutierrez G. Oxygen supply and utilization relationships. A reevaluation. Am Rev Respir Dis 1991;143: Schlichtig R, Pinsky MR. Defining the hypoxic threshold. Crit Care Med 1991;19: Edwards JD. Practical application of oxygen transport principles. Crit Care Med 1990;18:S Cilley RE, Polley TZ Jr, Zwischenberger JB, Toomasian JM, Bartlett RH. Independent measurement of oxygen consumption and oxygen delivery. J Surg Res 1989;47: Stratton HH, Feustel PJ, Newell JC. Regression of calculated variables in the presence of shared measurement error. J Appl Physiol 1987;62: Cain SM. Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia. J Appl Physiol 1977;42: Gutierrez G, Warley AR, Dantzker DR. Oxygen delivery and utilization in hypothermic dogs. J Appl Physiol 1986;60: Routsi C, Vincent JL, Bakker J, et al. Relation between oxygen consumption and oxygen delivery in patients after cardiac surgery. Anesth Analg 1993;77: Chiara O, Giomarelli PP, Biagoli B, Rosi R, Gattinoni L. Hypermetabolic response after hypothermic cardiopulmonary bypass. Crit Care Med 1987;15: Wojita J, Hoover RL, Daniel TO. Vascular origin determines plasminogen activator expression in human endothelial cells. J Biol Chem 1989;264: Belloni P, Nicolson GL. Different expression of cell surface glycoproteins on various organ-derived microvascular endothelia and endothelial cell cultures. J Cell Physiol 1988;136: Parolari A, Alamanni F, Antona C, et al. Chirurgia cardiaca, bypass cardiopolmonare e risposta infiammatoria dell organismo. Parte I: Alterazioni a carico dei processi emostatici e del complemento. G Ital Cardiol 1996; 26: Parolari A, Alamanni F, Antona C, et al. Chirurgia cardiaca, bypass cardiopolmonare e risposta infiammatoria dell organismo. Parte II: Alterazioni dei leucociti, dei derivati dell acido arachidonico e degli ormoni. G Ital Cardiol 1996; 26: Appendix. Variables Collected at Each Experimental Time Hemodynamic variables CPB flow (L min 1 m 2 ) Mean arterial pressure (mm Hg) Peripheral arterial vascular resistances (dynes sec/ cm 5 ) Temperatures Esophageal temperature ( C) Rectal temperature ( C) Arterial blood temperature ( C) Venous blood temperature ( C) Arteriovenous blood differential temperature ( C) Oxygen and hemoglobin Liters of air administered per minute (L/min) Fractional concentration of oxygen (%) Blood hemoglobin (g/100 ml) Blood hematocrit (%) Blood gas analysis variables parameters Arterial blood ph Arterial oxygen tension (mm Hg) Arterial carbon dioxide tension (mm Hg) Arterial blood bicarbonates (meq/l) Arterial blood base excess (meq/l) Arterial blood oxygen saturation(%) Venous blood ph Venous blood oxygen partial pressure (mm Hg) Venous blood carbon dioxide partial pressure (mm Hg) Venous blood bicarbonates (meq/l) Venous blood bicarbonate excess (meq/l) Venous blood oxygen saturation (%) Plasma electrolytes Plasma sodium (meq/l) Plasma potassium (meq/l) Drugs (administration of the following drugs within 10 minutes before the determination or oxygen consumption, or #, means continuous administration of the drug) Fentanil (yes/no) Sodium thiopental (yes/no) Diazepam (yes/no) Pancuronium bromide (yes/no) Sodium nitroprusside # (yes/no) Nitroglicerin # (yes/no) Poligelatine (yes/no) Sodium bicarbonate (yes/no) Cardioplegia (yes/no) Oxygen delivery and extraction Oxygen delivery (ml min 1 m 2 ) Oxygen extraction (%) Oxygen consumption (ml min 1 m 2 )