Anaerobic Metabolism During Cardiopulmonary Bypass: Predictive Value of Carbon Dioxide Derived Parameters

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1 Anaerobic Metabolism During Cardiopulmonary Bypass: Predictive Value of Carbon Dioxide Derived Parameters Marco Ranucci, MD, Giuseppe Isgrò, MD, Federica Romitti, MD, Sara Mele, MD, Bonizella Biagioli, MD, PhD, and Pierpaolo Giomarelli, MD, PhD Department of Cardiothoracic Anesthesia, Policlinico San Donato, Milan, and the Thoracic and Cardiovascular Unit, Department of Surgery and Bioengineering, University of Siena, Siena, Italy Background. Hyperlactatemia during cardiopulmonary bypass (CPB) is a common event and is associated to a high morbidity and mortality after cardiac operations. The present study is aimed to identify the possible predictors of hyperlactatemia during CPB among a series of oxygen and carbon dioxide derived parameters measured during CPB. Methods. This is a prospective observational study on 54 patients undergoing cardiac surgery with CPB. Hyperlactatemia was defined as an arterial lactate concentration higher than 3 mmol/l. Serial blood lactate assays have been performed during CPB, and their association to a number of oxygen and carbon dioxide derived parameters was explored. Results. Arterial blood lactate concentration was positively correlated to the CPB duration, the carbon dioxide elimination, and the respiratory quotient, and negatively correlated to the presence of the aortic cross-clamping, the body surface area, the ratio between the oxygen delivery and the carbon dioxide production, and the arterial oxygen saturation. Predictors of hyperlactatemia during CPB are a carbon dioxide production higher than 60 ml min -1 m -2, a respiratory quotient higher than 0.9, and a ratio between oxygen delivery and carbon dioxide production lower than 5. Conclusions. Carbon dioxide derived parameters are representative of hyperlactatemia during CPB, as a result of the carbon dioxide produced under anaerobic conditions through the buffering of protons by the bicarbonate system. The carbon dioxide elimination rate measured at the exhaled site of the oxygenator may be used for an indirect assessment of the metabolic state of the patient. (Ann Thorac Surg 2006;81: ) 2006 by The Society of Thoracic Surgeons Accepted for publication Jan 3, Address correspondence to Dr Ranucci, Policlinico S. Donato, Via Morandi 30, San Donato Milan, Italy; cardioanestesia@virgilio.it. At the end of cardiac operations, the finding of elevated blood lactate levels is quite common [1 5]. This pattern is generally attributed to tissue hypoxia (type A hyperlactatemia) [1 5] but type B hyperlactatemia (in absence of tissue hypoxia) has been advocated in some cases [2]. The presence of hyperlactatemia at the intensive care unit (ICU) admission after cardiac operations is associated to a poor outcome [5]; however, the development of lactic acidosis may occur during the early phases of ICU recovery, or during cardiopulmonary bypass (CPB) [6]. Even in this last case, it is associated to an increased risk of morbidity and mortality [6]. Conventional monitoring with arterial and mixed venous blood gas analysis during CPB may help in detecting the adequacy of tissue perfusion, and the on-line measurement of mixed venous oxygen saturation (Svo 2 ) may offer additional information. However, blood lactate concentration monitoring seems more adequate for detecting the correct matching of oxygen supply and demand during CPB [7, 8]. The association of a low oxygen delivery during CPB with an increased postoperative morbidity and mortality has been recently hypothesized in various papers focused on excessive hemodilution during CPB [9, 10], and is demonstrated as an independent risk factor for acute renal failure after cardiac operations with CPB [11]. Blood lactate concentration is presently not available as on-line monitoring during CPB or in critically ill patients. For this reason, various possible predictors of critical hypoperfusion (defined as hyperlactatemia) have been tested in critically ill patients and good correlations have been found for carbon dioxide derived parameters alone [12] or in association with oxygen derived parameters [13, 14]. In spite of the evidence that hyperlactatemia during CPB is associated with a bad outcome [6] we have found no information about the association between these parameters and blood lactate levels during CPB. The primary endpoint of this study is exploring a number of oxygen and carbon dioxide derived parameters in order to detect their association with hyperlactatemia during CPB; the secondary endpoint is establishing an indirect on-line monitoring system for blood lactate formation during CPB by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 2190 RANUCCI ET AL Ann Thorac Surg HYPERLACTATEMIA DURING CPB 2006;81: Patients and Methods Study Design This is a prospective observational study conducted during one month of activity in the Cardiac Surgery Departments of the two participating institutions. All the patients gave a written consent to the scientific treatment of their data. The Local Ethical Committee waived the need for the approval. Patient Population Exclusion criteria were age less than 18 years and cardiac transplant operation. Fifty-four patients undergoing cardiac surgery with CPB were enrolled in the study; isolated coronary artery bypass graft operations were 29 (54%), isolated valve procedures were 7 (13%), and combined coronary artery valve or double-triple valve operations were 18 (33%). Three patients reached the operating theater under emergency conditions due to failed percutaneous coronary angioplasty or congestive heart failure, while the remaining 51 were elective patients. Thirty-three patients (61%) were male; the mean age was years and the CPB duration was minutes. Anesthesia, Surgery, and CPB Management The patients were treated with a totally intravenous anesthesia with remifentanil and midazolam plus cisatracurium for muscle relaxation, or with a combined intravenous-inhalatory anesthesia according to the anesthesiologist s preference. Cardiopulmonary bypass was established after a standard median sternotomy, aortic root cannulation, and single or double atrial cannulation for venous return. Lowest core body temperature during CPB varied from 27 C to 37 C as requested by the surgeon. Body temperature was measured at the nasopharingeal site and at the rectal site. This last temperature was considered for correcting the values of blood gas analyses. The perfusate temperature was measured at the oxygenator site and used for correcting the values of exhaled carbon dioxide. Antegrade intermittent cold crystalloid or cold blood cardioplegia was used according to the surgeon s preference. The circuit was primed with 700 ml of a gelatin solution (Eufusin; Bieffe Medical, Modena, Italy), and 200 ml of trihydroxymethylaminomethane solution. Roller (Stockert, Munich, Germany) or centrifugal pumps (Medtronic Bio-Medicus, Eden Prairie, MN) were used according to the availability; a biocompatible treatment (phosphorylcholine coating) and a closed circuit with separation of the blood suctions were used in 24% of the patients. The oxygenator was a hollow fiber D 905 Avant (Dideco, Mirandola, Italy). The pump flow was targeted between 2.0 and 2.4 L min m 2, and the target mean arterial pressure was settled at 60 mm Hg. The gas flow was initially settled at 50% oxygen to air ratio and a 1:2 flow ratio with the pump flow indexed, and subsequently arranged in order to maintain an arterial oxygen tension greater than 150 mm Hg and an arterial carbon dioxide tension between 33 and 38 mm Hg. Anticoagulation was established with an initial dose of 300 IU per kilogram of body weight of porcine intestinal heparin injected into a central venous line 10 minutes before the initiation of CPB, and a target activated clotting time of 480 seconds; patients receiving closed and biocompatible circuits received a reduced dose of heparin with a target activated clotting time settled at 300 seconds. At the end of CPB, heparin was reversed by protamine chloride at a 1:1 ratio of the loading dose, regardless of the total heparin dosage. Immediately after establishing CPB, and every 20 minutes, a standard arterial and mixed venous blood gas analysis was performed on the arterial and venous blood of the CPB circuit. Additional blood gas analyses were done according to the perfusionist s needs and in case of hyperlactatemia. Data Collection and Definitions The following demographic and operative variables were collected for each patient: age (years); gender; weight (kgs); body surface area (BSA, m 2 ); and CPB duration (minutes). At each sampling time, the following variables were recorded: pump flow indexed (L/min -1 /m -2 ); arterial oxygen tension (mm Hg); arterial oxygen saturation (%); arterial carbon dioxide tension (mm Hg); arterial hemoglobin (Hb) concentration (mg/dl); arterial lactate concentration (mmol/l); mixed venous oxygen tension (mm Hg); mixed venous oxygen saturation (SVo 2 ) (%); and mixed venous carbon dioxide tension (mm Hg). Blood gas analyses were performed using a blood gas analyzer Nova Stat Profile (Nova Biomedical, Waltham, MA). All blood gas data were corrected for temperature according to standard equations. Simultaneously, the carbon dioxide exhaled from the oxygenator (eco 2, mm Hg), and the gas flow into the oxygenator (Ve) were recorded. Exhaled carbon dioxide was measured with a mainstream capnograph Capnostat (Novametrix Medical Systems Inc, Wallingford, CT). Arterial and mixed venous oxygen content was calculated according to the following equation: oxygen content (ml) Hb (mg/dl) 1.34 Hb saturation (%) oxygen tension (mm Hg). Carbon dioxide production (Vco 2 ) was calculated according to the following equation [14]: VCO 2 indexed ml min -1 m -2 : eco 2 mm Hg Ve L/min 1, BSA m 2. (1) Gas volumes and flows are expressed in standard temperature 0 degrees, pressure 760 mm Hg, and dry (STPD). Since gas pressures are expressed in body temperature, ambient pressure, and saturated with water vapor (BTPS), and considering that the body temperature may change during CPB, the following relationship has been applied: Volume STPD Barometric pressure-h 2 O vapor pressure 273. (2) Body temperature

3 Ann Thorac Surg RANUCCI ET AL 2006;81: HYPERLACTATEMIA DURING CPB 2191 On the basis of the above data, the following oxygen and carbon dioxide derived variables have been calculated: (a) Arteriovenous oxygen content difference (ml); (b) Oxygen consumption indexed (Vo 2 i): (ml min -1 m -2 ): 10 pump flow indexed (L min -1 m -2 ) arteriovenous oxygen content difference (ml/100 ml); (c) Oxygen delivery indexed (Do 2 i): (ml min -1 m -2 ): 10 pump flow indexed (L min -1 m -2 ) arterial oxygen content (ml/100 ml); (d) Oxygen extraction ratio (O 2 ER):Vo 2 i/ Do 2 i; (e) Venoarterial carbon dioxide tension difference (mm Hg): mixed venous carbon dioxide tension arterial carbon dioxide tension; (f) Pco 2 /C (a-v) O 2 : venoarterial carbon dioxide tension difference (mm Hg)/arteriovenous oxygen content difference (ml/100 ml); (g) Do 2 i/ Vco 2 i; (h) Respiratory quotient (RQ): Vco 2 i/vo 2 i. Hyperlactatemia was defined as an arterial blood lactate level greater than 3 mmol/l [5]. Statistical Analysis Data are expressed as mean standard deviation (continuous variables), or as frequency and percentage (categoric variables). Operative and demographics variables, and oxygen-carbon dioxide derived variables during CPB have been tested for association with arterial blood lactate value, first using a bivariate linear regression analysis and subsequently testing different regression analyses (linear, quadratic, cubic, exponential, logarithmic, potential) for defining the best approximating equation. Factors being significantly associated to arterial blood lactate value were subsequently tested for association with hyperlactatemia, using an unpaired t test or a Pearson s 2 test when appropriate. The predictive value of the variables associated to hyperlactatemia was tested using receiver operating characteristics (ROC) curves. The area under the ROC curve was used to define the best predictive variables; adequate cutoff values have been searched based on the best coupling between sensitivity and specificity. For all the statistical tests, a p value less than 0.05 was considered significant. Results The various intraoperative factors considered in the study were tested for association with the arterial blood lactate concentration (Table 1). Seven factors were significantly associated to arterial blood lactate concentration: a positive correlation was found for Vco 2 i, Vco 2 /Vo 2 ratio, and CPB time; a negative correlation was found for Do 2 /Vco 2 ratio, arterial oxygen saturation, aortic crossclamping on, and BSA. A borderline (p 0.06) correlation was found for SVo 2 (negative) and O 2 ER (positive). The univariate relationship for Vco 2 i, Do 2 /Vco 2 ratio, and Vco 2 /Vo 2 ratio was explored with a best-fit equation Table 1. Correlation Between Oxygen-Carbon Dioxide Derived Parameters, Other Intraoperative Variables and Arterial Lactate Concentration Parameter Correlation Coefficient Arterial oxygen saturation (%) Mixed venous oxygen saturation (%) Arteriovenous oxygen content difference (ml) Oxygen consumption indexed (ml min 1 m 2 ) Oxygen delivery indexed (ml min 1 m 2 ) Oxygen extraction ratio Arterial CO 2 tension (mm Hg) Mixed venous CO 2 tension (mm Hg) Venoarterial CO 2 tension difference (mm Hg) Pco 2 /C (a-v) O Vco 2 indexed (ml min 1 m 2 ) Do 2 /Vco Respiratory quotient Pump flow indexed (L min m 2 ) Hemoglobin concentration (mg/dl) Aortic cross-clamping on Body surface area (m 2 ) CPB time (min) Temperature ( C) CPB cardiopulmonary bypass; Pco 2 /C (a-v) O 2 venoarterial carbon dioxide tension difference/arteriovenous oxygen content difference; Do 2 /Vco 2 oxygen delivery/carbon dioxide elimination; eco 2 exhaled carbon dioxide tension; Vco 2 carbon dioxide elimination. for each factor. The Vco 2 i relationship with arterial blood lactate concentration follows a cubic equation with a p value less than 0.001; the Do 2 /Vco 2 ratio relationship with arterial blood lactate concentration follows a cubic equation with a p value less than 0.001; and the Vco 2 /Vo 2 ratio relationship with arterial blood lactate concentration follows a quadratic equation with a p value less than (Fig 1). In all three cases, curvilinear equations demonstrated a higher correlation coefficient than simple linear relationships (r 2 values, respectively: 0.59 vs 0.52; 0.45 vs 0.29; 0.61 vs 0.54). In particular, the Vco 2 i and Do 2 /Vco 2 ratio relationships with arterial blood lactates tend to reach an asymptotic value for the higher levels of blood lactates, therefore reflecting the common clinical practice, where arterial blood lactates very rarely reach values higher than 18 to 20 mmol/l. According to previous published papers [5] and to the usually accepted higher value for normal arterial lactates concentration (2 mmol/l), hyperlactatemia was defined as an arterial blood lactate concentration greater than 3 mmol/l. According to this cutoff value, the abovementioned variables were tested with respect to the presence of hyperlactatemia (Table 2). Six factors were signifi- p

4 2192 RANUCCI ET AL Ann Thorac Surg HYPERLACTATEMIA DURING CPB 2006;81: Fig 1. Relationships between arterial blood lactate concentration and (A) carbon dioxide production (Vco 2 i), (B) oxygen delivery (Do 2 i) to carbon dioxide production (Vco 2 i) ratio, and (C) respiratory quotient (Vco 2 i/vo 2 i). cantly different in normal versus hyperlactatemia conditions: Vco 2 i, Do 2 i/vco 2 i,vco 2 i/vo 2 i, aortic cross-clamp on, BSA, and CPB time. A receiver operating characteristic (ROC) analysis was applied to each of the above variables (except the binary variable aortic cross-clamp on) in order to assess their predictive value for hyperlactatemia and the adequate best cutoff values according to sensitivity and specificity. An area under the curve (AUC) greater than 0.75 was considered acceptable for predictivity [15]; the BSA and CPB time failed to reach this value. The Do 2 i/vco 2 i ratio had an AUC of 0.852, the Vco 2 i had an AUC of 0.838, and the Vco 2 i/vo 2 i ratio had an AUC of (Fig 2). The complete analysis, with the best cutoff values identified for the three variables is reported in Table 3. The best predictive values for hyperlactatemia are a Do 2 i/vco 2 i Table 2. Univariate Analysis of Oxygen-Carbon Dioxide Derived Parameters and Other Intraoperative Variables at Arterial Lactate Determinations Below or Above the Threshold Value (3 mmol/l). Parameter Arterial Lactates 3 mmol/l (n 130) Arterial Lactates 3 mmol/l (n 37) p Pao 2 (mmhg) Svo VCO 2 i (ml min 1 m 2 ) DO 2 i/vco 2 i VCO 2 i/vo 2 i Aortic cross-clamp on 72% 46% BSA (m 2 ) CPB time (min) BSA body surface area; CPB cardiopulmonary bypass; Do 2 i/vco 2 i oxygen delivery indexed/carbon dioxide elimination indexed; Pao 2 arterial oxygen tension; Svo 2 mixed venous oxygen saturation; Vco 2 i carbon dioxide elimination indexed; Vco 2 i/vo 2 i respiratory quotient.

5 Ann Thorac Surg RANUCCI ET AL 2006;81: HYPERLACTATEMIA DURING CPB 2193 Fig 2. Receiver operating characteristic curves for carbon dioxide production (Vco 2 i), oxygen delivery to carbon dioxide production ratio (Do 2 i/vco 2 i), and respiratory quotient (Vco 2 i/vo 2 i), as predictors of hyperlactatemia. ( Vco 2 i;--- Vco 2 i/vo 2 i; Do 2 i/vco 2 i.) ratio lower than 5, a Vco 2 i higher than 60 ml minute -1 m -2,andaVco 2 i/vo 2 i ratio higher than 0.9. Comment Under normal resting conditions, the oxygen delivery matches the overall metabolic demands of the organs, the Vo 2 is about 25% of the Do 2, and energy is produced basically through the aerobic mechanism (oxidative phosphorylation). When the Do 2 starts decreasing (due to a decreased cardiac output, extreme hemodilution, or both), the Vo 2 is maintained until a critical level is reached [16 18]. Below this critical point the oxygen consumption starts decreasing, becoming dependent on the oxygen delivery, and the failing aerobic energy production is progressively replaced by anaerobic adenosine triphosphate production (pyruvate conversion to lactate). As a result, blood lactate concentration starts rising, and numerous studies have established the use of lactates as a marker of global tissue hypoxia in circulatory shock [19 21]. Under these circumstances, the anaerobic metabolism results in an excess of proton production and tissue acidosis; buffering of the protons by bicarbonate ions results, in turn, in an anaerobic carbon dioxide production [22]. Therefore, below the critical Do 2, there is a linear decrease of both Vo 2 and Vco 2, but due to the anaerobic CO 2 production, the RQ increases. When the critical Do 2 is reached due to a decrease in cardiac output (cardiogenic shock), the above relationship becomes more complex. Due to the reduced pulmonary flow and to ventilation-perfusion mismatch the ability of the lung to eliminate carbon dioxide is impaired, and carbon dioxide elimination and end-tidal carbon dioxide tension are decreased [12]. Consequently, carbon dioxide starts accumulating in the venous compartment, and venoarterial carbon dioxide gradient is increased. In other terms, the Vco 2 (intended as carbon dioxide production by the tissues) becomes progressively higher than carbon dioxide elimination. Under CPB conditions the above pattern changes again. The artificial lung is much more efficient than the natural lung in terms of carbon dioxide clearance, and is maintained even for a very low pump flow. Not by chance, under specific circumstances like deep hypothermia and according to the ph strategy, it is clinically needed to add carbon dioxide to the gas flow in order to avoid dramatic and dangerous patterns of hypocapnia. In this setting, the Vco 2 is strictly correlated to the carbon dioxide elimination. Therefore, while in a normal setting the venous carbon dioxide tension (Pvco 2 ) is inversely correlated to the carbon dioxide elimination [12], during CPB the two parameters are positively correlated, as we could check through a linear regression analysis in our patient population (Vco 2 i Pvco 2; r , p 0.005). On the basis of the above pathophysiological considerations, our results may be interpreted in the following ways. (1) At the lactate threshold of 3 mmol/l, there is an increase of Vco 2 i and RQ above their respective cutoff values of 60 ml -1 m 2 and 0.9. This behavior reflects the increased anaerobic carbon dioxide production with concomitant normal or slightly decreased Vo 2. (2) The best predictor of lactate threshold is the Do 2 i/ Vco 2 i ratio, with a cutoff value at 5. Actually, the normal Do 2 i/vco 2 i is 5, being the Do 2 about 1,000 ml/minute and the Vco 2 about 200 ml/minute. This ratio is maintained until the critical Do 2 is reached, because above this limit the Vo 2 does not change and the aerobic-derived Vco 2 is unchanged as well. Below the critical Do 2 the Vo 2 Table 3. Receiver Operating Characteristic Analysis and Relative Cutoff Values Factor AUC p Cutoff Value Sensitivity Specificity Do 2 i/vco 2 i % 74% Vco 2 i % 70.7% Vco 2 i/vo 2 i % 77.2% AUC area under the curve; Do 2 i/vco 2 i oxygen delivery indexed/ carbon dioxide elimination indexed; Vco 2 i carbon dioxide elimination indexed; Vco 2 i/vo 2 i respiratory quotient.

6 2194 RANUCCI ET AL Ann Thorac Surg HYPERLACTATEMIA DURING CPB 2006;81: decreases, the aerobic-derived Vco 2 decreases in a linear fashion with Vo 2, but the total Vco 2 decreases less than the Vo 2 due to the contribution of the anaerobic-derived Vco 2. Therefore, the Do 2 i/ Vco 2 i decreases below 5. (3) The venoarterial carbon dioxide tension gradient, and its ratio with the arteriovenous oxygen saturation, which in previous papers had a clear correlation with the arterial blood lactate concentration in patients not under CPB [12, 13], failed to demonstrate this association during CPB. Again, we must consider that the artificial lung is much more efficient than the natural lung in terms of carbon dioxide elimination; therefore, the effect of venous blood carbon dioxide accumulation in case of critical Do 2 is blunted by the artificial lung carbon dioxide removal, and the excess carbon dioxide anaerobically produced is found at the gas exhaled site of the oxygenator (eco 2 ) rather than in the venous compartment. (4) The value of oxygen derived parameters (namely, the SVo 2 ) is poor in terms of predictivity for the lactate threshold during CPB. Our data are in agreement with other observations [15], demonstrating that SVo 2 and other oxygen derived parameters are not predictive for hyperlactatemia. It has been demonstrated that during CPB systemic microvascular control may become disordered, inducing peripheral arteriovenous shunting that is associated to a rise in lactate levels despite an apparently adequate oxygen supply [6]. Moreover, selective splanchnic hypoperfusion has been considered responsible for the production of lactate during CPB [1, 8]. Even considering that under these circumstances the venous blood from the splanchnic district has probably a low oxygen content, the mixing of this blood with highly oxygen saturated blood from many other organs at metabolic rest during anesthesia may result in a normal oxygen content of the mixed venous blood. (5) Other determinants of lactate production, albeit nonpredictive factors for hyperlactatemia, are the CPB duration, a small BSA, and the release of the aortic cross-clamp. Cardiopulmonary bypass duration already has been mentioned as a determinant of lactate concentration [6]. A small BSA is often associated to a poor venous blood return to the heart-lung machine, with consequent reduced pump flow, and to a higher hemodilution. Both these factors may determine a reduced oxygen delivery during CPB. Finally, the release of the aortic cross-clamp admits to the systemic circulation the previously ischemic heart, with a release of lactates from the coronary circulation that has been already demonstrated in studies dealing with myocardial ischemia-reperfusion during cardiac operations [23]. Body temperature during CPB was not significantly correlated to arterial blood lactate values, but only demonstrated a trend (p 0.11). This apparently could be difficult to explain, as it is reasonable to hypothesize that with increasing metabolic needs the likelihood of having an inadequate oxygen supply may be higher. However, some of our patients developed an anaerobic status before the operation (emergency procedures) or during the operation, before going on CPB (due to overt or subtle low cardiac output), and therefore the relationship is probably biased by this condition. We are aware that interpretation of lactate measurement requires caution. The lactate concentration depends on a balance between production and clearance; while the first is very rapid, the second depends on metabolic elimination and requires a prolonged (hours) time in critical patients [24]. Therefore, the presence of an elevated lactate concentration in blood does not necessarily mean that the anaerobic metabolism is activated at that time, often being associated to lactate production which occurred maybe hours before. For this reason, in our series we have considered only the serial measurements until the highest lactate concentration was reached, not considering the relationship between oxygen and carbon dioxide derived parameters and lactate concentration when (and if) the lactate concentration started decreasing. This study is not intended to address the complex topic of the origin of hyperlactatemia during CPB, but to identify predictive parameters being clinically measurable in a continuous way. To this respect, we believe that the online monitoring of carbon dioxide derived parameters, together with the oxygen delivery, may be of considerable aid during CPB in order to optimize the pump flow, the arterial oxygen content, and therefore the oxygen delivery, to finally avoid the establishment of a critical hyperlactatemia that has a well-defined role in determining postoperative morbidity and mortality. References 1. Landow L. Splanchnic lactate production in cardiac surgery patients. Crit Care Med 1993;21(suppl):S84 S Raper RF, Cameron G, Walker D, Bowey CJ. Type B lactic acidosis following cardiopulmonary bypass. Crit Care Med 1997;25: Boldt J, Piper S, Murray P, Lehmann A. Severe lactic acidosis after cardiac surgery: sign of perfusion deficits. J Cardiothorac Vasc Anesth 1999;13: Totaro R, Raper RF. Epinephrine induced lactic acidosis following cardiopulmonary bypass. Crit Care Med 1997;25: Maillet J-M, Le Besnerais P, Cantoni M, et al. 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