Elevated blood lactate levels associated with metabolic

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1 Outcome With High Blood Lactate Levels During Cardiopulmonary Bypass in Adult Cardiac Operation Philippe Demers, MD, Stéphane Elkouri, MD, Raymond Martineau, MD, André Couturier, MSc, and Raymond Cartier, MD Division of Cardiothoracic Surgery, Departments of Surgery, and Departments of Anesthesia and Biostatistics, Montreal Heart Institute, Montreal, Quebec, Canada Background. High blood lactate levels during cardiopulmonary bypass (CPB) are associated with tissue hypoperfusion and may contribute to postoperative complications or death. The objective of this study was to determine an association between blood lactate levels during CPB and perioperative morbidity and mortality. Methods. We reviewed 1,376 patients who underwent cardiac operation with CPB. Patients with abnormal preoperative blood lactate levels were excluded (n 101). Blood lactate concentration during CPB, clinical data, and perioperative events were recorded. Results. Peak blood lactate levels of 4.0 mmol/l or higher during CPB were present in 227 patients (18.0%). Postoperative mortality was higher in this group than in the patients who had peak blood lactate levels of less than 4.0 mmol/l during CPB (11.0% versus 1.4%; p < 0.001, relative risk [RR] 9.0). Postoperative hemodynamic instability occurred in 29.5% of patients with elevated levels of lactate during CPB compared with 10.9% of patients with lower lactate levels (p < 0.001, RR 3.4). Overall, major postoperative complications occurred in 43.2% and 21.8% of patients in each group, respectively (p < 0.001, RR 2.7). Logistic regression analysis revealed that peak blood lactate levels of 4.0 mmol/l or higher during CPB were strongly associated with postoperative mortality (p ) and morbidity (p 0.013). Conclusions. Blood lactate concentration of 4.0 mmol/l or higher during CPB identifies a subgroup of patients with increased risk of postoperative morbidity and mortality. (Ann Thorac Surg 2000;70:2082 6) 2000 by The Society of Thoracic Surgeons Accepted for publication May 15, Address reprint requests to Dr Cartier, Montreal Heart Institute 5000 Bélanger St E, Montreal, Qc, H1T 1C8, Canada; cartierr@icm. umontreal.ca. Elevated blood lactate levels associated with metabolic acidosis are common among critically ill patients with systemic hypoperfusion and tissue hypoxia [1]. This situation represents type A lactic acidosis, resulting from an imbalance between tissue oxygen supply and demand. Lactate production results from cellular metabolism of pyruvate into lactate under anaerobic condition. Therefore, blood lactate level in type A lactic acidosis is related to the total oxygen debt and the magnitude of tissue hypoperfusion [1 3]. Several studies have suggested that blood lactate concentration has prognostic value in patients with circulatory shock [2 4]. Identification of predictors of morbidity and mortality is an important issue for the optimal management of cardiac surgical patients. Stratification of risk in the cardiac surgical population involves mainly preoperative factors. However, intraoperative events related to surgical technique, myocardial protection, and cardiopulmonary bypass (CPB) may modify the postoperative course [5]. Intraoperative monitoring of these factors and early intervention might improve outcome. Cardiopulmonary bypass is used during cardiac operation to allow adequate systemic oxygenation and perfusion during the surgical procedure. Metabolic acidosis associated with elevated blood lactate levels during CPB in cardiac operation patients was first described in 1958 [6] and led to numerous studies on the adequacy of tissue perfusion during CPB [7 9]. Conventional monitoring with blood gases during CPB may detect inadequate tissue oxygenation. However, blood lactate concentration monitoring during CPB might be more sensitive to detecting an imbalance between oxygen supply and demand [10, 11]. Type A lactic acidosis during CPB appears to be multifactorial [6 8, 10 13]. However, the outcome associated with high blood lactate level is unknown. The hypothesis of this study was that patients with high blood lactate levels during CPB are at higher risk of postoperative complications as a result of intraoperative occult tissue hypoperfusion. The objective of this study was to evaluate the relationship between elevated blood lactate concentration during CPB and perioperative morbidity and mortality. Patients and Methods Patients From January 1 to December 31, 1995, 1,376 consecutive adult patients who underwent cardiac operations at the Montreal Heart Institute were studied retrospectively to collect pre- and intraoperative data, and perioperative 2000 by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (00)

2 Ann Thorac Surg DEMERS ET AL 2000;70: BLOOD LACTATE LEVELS DURING CPB 2083 mortality and morbidity. Patients with any of the following criteria were excluded [1]: intraoperative mortality (n 11) [2]; preoperative blood lactate level higher than 2.5 mmol/l (n 101); and [3] missing data (n 5). Cardiopulmonary Bypass All patients were treated with the same CPB technique. After systemic heparinization, the aorta and the vena cavas were cannulated and nonpulsatile CPB initiated using either a roller or a centrifugal pump. Disposable membrane oxygenators were used and the circuit was primed with 2Lofacrystalloid solution (Ringer s lactate: Na mmol/l; K 5 mmol/l; Ca 2 2 mmol/l; Cl 111 mmol/l; lactate 29 mmol/l). Systemic temperature was decreased to 32 C during perfusion. Flow rates were maintained at 2.2 L min 1 m 2 at 37 C and 2.0 L min 1 m 2 at 32 C to maintain a venous oxygen saturation at higher than 70%. Mean systemic arterial pressure was continuously monitored and maintained between 60 and 80 mm Hg. During perfusion, hemoglobin was maintained more than 60 g/l. Gas flow was adjusted to maintain ph and pco 2 in the normal range, according to the alpha stat ph management technique. Blood Lactate Concentration Arterial blood samples were drawn after the induction of anesthesia and at 20-minute intervals during CPB and stored immediately on ice to prevent lactate production by blood cells. Blood lactate concentration was measured on a Novastat profile 9 commercial analyzer (Boston, MA). For the purpose of the study, blood lactate levels during CPB with a pump-prime solution containing lactate, as in Ringer s lactate, were expected to be normally less than 4.0 mmol/l, according to previous studies [9, 14, 15]. Definition of Preoperative Data and Postoperative Events Hypertension and diabetes were diagnosed if the patient had a history of the condition. Congestive heart failure was defined as present or previously documented episode(s) of pulmonary congestion in a patient with left ventricular dysfunction. Arteriosclerosis was defined by the presence of carotid stenosis, previous cerebrovascular accident, intermittent claudication, or a previous peripheral vascular operation. Left ventricular function was evaluated by echocardiography. Emergency cases were those characterized by unstable hemodynamics, such as acute coronary occlusion following angioplasty or complications of acute myocardial infarction not controlled medically, necessitating emergent operation. Complex operation was defined as multivalvular, valvular with coronary artery bypass grafting, operation for ascending thoracic aorta, congenital lesions, or complications of acute myocardial infarction. Postoperative morbidity was defined as the presence of one or more of the following events during hospitalization for the operation: (1) myocardial infarction documented by new Q wave on the electrocardiogram or serum creatine kinase MB band concentration higher than 100 IU/L 24 to 48 hours after the operation; (2) low output syndrome: the use of vasoactive or inotropic drugs for 24 hours or more or the use of an intraaortic balloon pump or a ventricular assist device; (3) neurologic: a focal brain lesion confirmed by clinical findings or computed tomographic scan, or both, or diffuse postoperative encephalopathy, convulsions, or severely altered mental status; (4) pulmonary: mechanical ventilation for 48 hours or more, or acute respiratory failure necessitating reintubation; (5) digestive: peritonitis necessitating emergency laparotomy, upper or lower gastrointestinal bleeding, or hepatic dysfunction defined as alanine transaminase level higher than 100 U/L or total bilirubin level higher than 35 mol/l; (6) renal: absolute rise of more than 100 mmol/l of serum creatinine or institution of hemodialysis or hemofiltration, or both; or (7) infectious: culture-proven septicemia or pneumonia. Postoperative mortality was defined as death occurring during hospitalization for the operation. Statistical Analysis Data were analyzed by Student s t test for continuous variables and by the 2 test or Fisher s exact test for categorical variables. Factors considered for the multiple logistic regression included preoperative variables: age, gender, congestive heart failure, left ventricle ejection fraction less than 30%, hypertension, diabetes, arteriosclerosis, redo operation, complex operation, and emergency operation; also included were intraoperative variables: CPB time and peak blood lactate level of 4.0 mmol/l or higher during CPB. Factors identified as significant (p 0.05) by univariate analysis were included in the model. Analyses were performed with the NCSS 6.0 software (Kaysville, UT). Data are expressed as mean and standard deviation. Statistical significance was considered for a p value less than Results Study Population Patients in the study (n 1259) had a mean age of years. There were 901 men (71.6%) and 358 women (28.4%). Coronary artery bypass operation was performed in 79.2% of the study population and valvular operation in 16.9%. Among the patients included in the present study, 1,032 (82.0%) had blood lactate levels less than 4.0 mmol/l during the perfusion and 227 (18.0%) had a peak blood lactate level of 4.0 mmol/l or higher during CPB. Preoperative Characteristics Patients with a blood lactate level of 4.0 mmol/l or more were older and were more often women. The prevalence of congestive heart failure, left ventricular ejection fraction less than 30%, and arteriosclerosis was significantly higher in patients with lactate levels of 4.0 mmol/l or more. No differences were found according to the presence of hypertension or diabetes mellitus. Preoperative hemoglobin was lower in patients with lactate levels of 4.0 mmol/l or higher ( g/l) than in patients with lactate levels less than 4.0 mmol/l ( g/l).

3 2084 DEMERS ET AL Ann Thorac Surg BLOOD LACTATE LEVELS DURING CPB 2000;70: Table 1. Preoperative Characteristics of 1,259 Patients Undergoing Cardiac Operation According to Peak Blood Lactate Levels During Cardiopulmonary Bypass p Value Age (years) Sex Men 77.2% 45.8% Women 22.8% 54.2% CHF 22.8% 48.9% Hypertension 40.9% 45.4% 0.22 Atherosclerosis 17.4% 24.2% Diabetes 14.9% 17.7% 0.29 Preop hemoglobin (g/l) Redo 10.3% 27.3% Complex surgery 10.0% 30.4% Emergency 2.4% 4.4% 0.16 LVEF 30% 7.7% 12.7% CHF congestive heart failure; fraciton; Preop preoperative. LVEF left ventricular ejection Moreover, patients with lactate levels of 4.0 mmol/l or more during CPB were more likely to undergo reoperation or a complex operation (Table 1). Operative Data Patients with lactate levels of 4.0 mmol/l or higher had significantly longer CPB time ( versus minutes) and aortic cross-clamping time ( versus minutes). The correlation between CPB time and peak blood lactate level was weak but statistically significant (Pearson correlation coefficient r 0.29; p 0.001) (Fig 1). Also, the lowest hemoglobin value recorded during CPB tended to be lower in patients with lactate levels of 4.0 mmol/l or higher ( versus g/l) [Correlation between CPB time and peak blood lactate level (r 0.288; p 0.001] (Table 2). Postoperative Morbidity and Mortality The hospital mortality was significantly higher in group 2 than in group 1 (11.0% versus 1.4%, p 0.001; relative risk [RR] 9.0). Patients with higher blood lactate levels during CPB were also more likely to have myocardial infarction (17.2% versus 6.8%, RR 2.9) and postoperative complications previously defined as neurologic (9.3% versus 1.7%, RR 6.1), hemodynamic (29.5% versus 10.9%, RR 3.4), pulmonary (8.8% versus 3.6%, RR 2.6), digestive (7.5% versus 3.0%, RR 2.6), or renal (9.3% versus 3.5%, RR 2.8). There was also a trend toward more postoperative infectious complications in group 2 (7.1% versus 4.2%; p 0.06). Length of stay in the intensive care unit and in the hospital were both longer in the patients with higher blood lactate levels during CPB (Table 3). The correlation between peak blood lactate levels during CPB and the rate of postoperative morbidity and mortality shows a significant increase in mortality and in the occurrence of postoperative adverse events with increasing levels of lactate concentration (Fig 2; p for mortality, p for morbidity). The logistic regression analysis showed that the independent factors most strongly associated with postoperative morbidity were peak blood lactate concentration higher than 4.0 mmol/l during CPB ( , p 0.013), age ( , p 0.002), preoperative congestive heart failure ( , p 0.002), and reoperative operation ( , p ). The independent factors most strongly associated with postoperative mortality were peak blood lactate concentration during CPB higher than 4.0 mmol/l ( , p ), age ( , p 0.008), female gender ( , p 0.02), and preoperative congestive heart failure ( , p 0.003). Comment Outcome after cardiac operation is determined by preoperative characteristics of the patient in addition to intraoperative factors such as surgical technique, myocardial protection, and CPB. Several risk status models have been developed to predict outcome after cardiac operations but very few consider intraoperative events [5 16]. Such intraoperative factors may modify the postoperative course. Monitoring of such factors during the surgical procedure may lead to early therapeutic intervention that might improve outcome. Cardiopulmonary bypass is widely used to maintain Table 2. Operative Data of 1,259 Patients Undergoing Cardiac Operation According to Peak Blood Lactate Levels During Cardiopulmonary Bypass p Value Fig 1. Correlation between cardiopulmonary bypass (CPB) time and peak blood lactate level (R 0.288; p 0.001). CPB time (min) Ischemic time (min) Lowest hemoglobin (g/l) CPB cardiopulmonary bypass.

4 Ann Thorac Surg DEMERS ET AL 2000;70: BLOOD LACTATE LEVELS DURING CPB 2085 Table 3. Postoperative Mortality, Morbidity, and Hospital Length of Stay of 1,259 Patients Undergoing Cardiac Operation According to Peak Blood Lactate Levels During Cardiopulmonary Bypass p Value Death within 30 days 1.4% 11.0% Neurologic 1.7% 9.3% Myocardial infarction 6.8% 17.2% Hemodynamic 10.9% 29.5% Pulmonary 3.6% 8.8% Digestive 3.0% 7.5% Renal 3.5% 9.3% Infectious 4.2% 7.1% Length of stay (days) Intensive care unit Hospital systemic perfusion and oxygenation during coronary artery bypass grafting and open heart operations. Tissue hypoperfusion with lactic acidosis during CPB may occur despite normal blood gas concentrations [10]. Therefore, high blood lactate levels during CPB may be used as a marker of inadequate tissue oxygen delivery. The goal of this study was to evaluate the association between peak blood lactate level during CPB and postoperative morbidity and mortality in an adult cardiac surgical population. Under anaerobic condition, oxidative phosphorylation is not possible and ATP is produced from pyruvate metabolized into lactate. The normal lactate/pyruvate ratio ( 10:1) is thus modified under anaerobic conditions, being superior to 10:1. Anaerobic glycolysis results when there is an imbalance between systemic oxygen delivery and tissue oxygen consumption, producing a type A lactic acidosis. In this Fig 2. The positive correlation between peak blood lactate levels during cardiopulmonary bypass (CPB) and the rate of postoperative morbidity and mortality (p 0.001). situation, lactate is a sensible marker of the magnitude of anaerobic metabolism and tissue oxygen deficit [1]. Several studies have shown a strong positive correlation between blood lactate levels and the risk of morbidity and mortality in clinical situations such as circulatory shock, extracorporeal support, and in children after operation for complex congenital heart disease [1 4, 17, 18]. As early as 1964, Broder and Weil [2] documented that only 11% of patients with excess lactate concentration of more than 4.0 mmol/l survived circulatory shock. Later, these authors showed that as lactate levels increased from 2.0 to 8.0 mmol/l, the probability of survival from shock decreased from 90% to 10% [3]. These findings were confirmed more recently by other groups [1, 4]. Moreover, serial blood lactate determination has also been reported to be useful to assess response of patients in shock to therapy as a decrease in lactate concentrations exceeding 5% of the initial value was associated with reversibility of shock and survival [19]. In high-risk general surgical patients, a positive correlation between the estimated intraoperative oxygen deficit and postoperative lactate concentrations was observed [20]. It was concluded that lactate determination may be used to assess the degree of accumulated oxygen deficit and in titrating therapy to support postoperative physiologic compensation. Tissue perfusion and oxygenation during CPB is achieved by adjusting flow rate, temperature, gas flow, and hemoglobin to maintain oxygen delivery. Monitoring of the balance between oxygen supply and demand usually consists of serial arterial and venous blood gas determination. In 1958, Clowes and colleagues [6] reported the occurrence of metabolic acidosis with lactate accumulation during CPB in some patients. Early experimental evidence showed the critical role of high perfusion flow rate and hypothermia in preventing lactic acidosis during CPB [6, 8]. Several contributing factors have been linked to regional tissue hypoperfusion and lactic acidosis occurring in some patients during the course of CPB. Recently, splanchnic hypoperfusion during CPB, related to the production of endogenous vasoactive mediators and a decrease in arterial oxygen content during bypass, was proposed as an important event in the generation of lactate during CPB [11, 12]. Systemic microvascular control may become disordered in CPB resulting in peripheral arteriovenous shunting and a rise in lactate levels despite an apparently adequate oxygen supply. Extreme hemodilution, hypothermia, low-flow CPB, and excessive neurohormonal activation have also been linked to lactic acidosis during CPB [10]. An abrupt increase in lactate concentration may result at the institution of CPB when priming solutions containing lactate are used. Several studies comparing different priming solutions have shown, however, that blood lactate levels during bypass are lower than 4.0 mmol/l even when lactate is present in the priming fluid [9, 14, 15]. An impaired hepatic clearance of lactate during CPB, related to a hypothermia-induced defect in pyruvate metabolism, has also been suggested [12]. In the immediate postoperative period, a hypermetabolic response, characterized by an increased oxygen consumption and carbon dioxide production, has been shown to occur after CPB [21 23]. This response may be related to

5 2086 DEMERS ET AL Ann Thorac Surg BLOOD LACTATE LEVELS DURING CPB 2000;70: intraoperative oxygen deficit and may represent a high-risk period for decompensation. In the present study, patients undergoing cardiac operation with peak blood lactate concentrations of 4.0 mmol/l or higher during CPB were older, more likely to be female, and were at higher risk according to clinical history. They also had a lower left ventricular ejection fraction, lower preoperative and perioperative hemoglobin concentrations and were more likely to have reoperative or complex operation. There was a weak but significant correlation between CPB time and peak blood lactate level, suggesting that high blood lactate levels are more likely to occur with long CPB duration but are dependent of other preoperative and intraoperative factors. Postoperative mortality was significantly higher in patients with high blood lactate levels during CPB. Moreover, postoperative complications, including neurologic, hemodynamic, pulmonary, renal, and digestive complications and myocardial infarction, were significantly more frequent in these patients. This group of patients also needed greater and longer hospital care. Finally, a peak blood lactate level of 4.0 mmol/l or higher during CPB was identified as a strong independent predictor of mortality and morbidity by logistic regression analysis and suggests that occult tissue hypoperfusion occurred during CPB. However, further studies are needed to evaluate the association between blood lactate levels and occult oxygen deficit occurring during CPB. Identification of high blood lactate levels during CPB should prompt further evaluation of all potential factors that may modify oxygen delivery and consumption. A prospective study would help to determine the benefits of early intervention during the course of CPB to enhance systemic oxygen delivery by increasing hemoglobin concentration or pump flow rate. Several limitations are inherent to the present study. First, the study was retrospective and the population studied was heterogeneous, including all the patients undergoing cardiac operation with CPB during 1 year in our institution. The proposed threshold value for blood lactate levels differed from the value chosen by other authors for different clinical situations [3]. Also, isolated lactate values were recorded while the area under the curve of lactate concentrations per time unit might be a better indicator of metabolic disturbances provoked by CPB, as recently suggested [24]. However, isolated values are easier to obtain than the area under the curve and allow immediate intervention. In conclusion, our data suggest that a peak blood lactate level of 4.0 mmol/l or higher during CPB is associated with an increased risk of perioperative morbidity and mortality. Further studies are needed to determine if serial blood lactate level determination during CPB and interventions based on lactate values improve survival in cardiac surgical patients. References 1. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992;20: Broder G, Weil MH. Excess lactate: an index of reversibility of shock in human patients. Science 1964;143: Weil MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure. Circulation 1970;41: Bitek V, Cowley RA. Blood lactate in the prognosis of various forms of shock. Ann Surg 1971;173: Higgins TL, Estafanous FG, Loop FD, et al. ICU admission score for predicting morbidity, and mortality after coronary artery bypass grafting. 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