Annals of Cardiac Anaesthesia 2005; 8: Shinde et al. Blood Lactate Levels during CPB 39

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1 Annals of Cardiac Anaesthesia 2005; 8: Shinde et al. Blood Lactate Levels during CPB 39 Blood Lactate Levels During Cardiopulmonary Bypass for Valvular Heart Surgery ORIGINAL ARTICLES Santosh B Shinde, Kumud K Golam, Pawan Kumar, Neela D Patil Departments of Biochemistry, Anaesthesiology, and Cardiovascular and Thoracic Surgery, Lokmanya Tilak Municipal Medical College and Hospital, Sion, Mumbai Cardiopulmonary bypass (CPB) is widely used to maintain systemic perfusion and oxygenation during open-heart surgery. Tissue hypoperfusion with resultant lactic acidosis during CPB, may occur during hypothermia, extreme haemodilution, low flow CPB, and excessive neurohormonal activation. There has been no documentation of the correlation between blood lactate level elevations in the perioperative period, and its relation to preoperative New York Heart Association (NYHA) classification and the use of ionotropic support during weaning from CPB, duration of postoperative ventilatory support and perioperative mortality. We studied the perioperative blood lactate levels in 82 patients undergoing valvular heart surgery. Arterial blood samples were collected at different stages of CPB. The observed mean baseline lactate levels were 1.9±0.8 mmol/l (normal range of 0.9 to 1.7 mmol/l). The mean circulating lactate levels at 15 min and 45 min after institution of CPB increased to 7.01±2.6 mmol/l and 9.92±3.5 mmol/l. A progressive decline in the mean lactate level, was seen during rewarming (at 35 C), immediately off-bypass, 24 hours and 48 hours postoperatively with mean lactate levels being 7.01±3.2 mmol/l, 4.75±1.01 mmol/l, 3.06±1.1 mmol/l, and 2.10±1.05 mmol/l respectively. Comparison of mean lactate levels in NYHA class I, II, III, and IV patients showed that in the intraoperative period and immediately after CPB, the elevation in lactate levels were statistically significant (p< 0.001) in patients in NYHA Class IV. However the values, in all classes, were similar at 24 and 48 hours after CPB. Also, patients with lactate levels >4 mmol/ L required prolonged inotropic and ventilatory support. (Annals of Cardiac Anaesthesia 2005; 8: 39 44) Key words:- Lactic acidosis, CPB, Hyperlactataemia, NYHA classification Cardiopulmonary bypass (CPB) is instituted, during various cardiac operations, to allow adequate systemic perfusion. Presently there are no definitive biochemical markers of prognostic value in patients undergoing valvular heart surgery under CPB. Tissue perfusion is at risk during CPB and in the immediate postoperative period. 1 The duration of CPB, degree of hypothermia, duration of cooling and rewarming, ph management strategy and the haematocrit value are all potential factors that may contribute to tissue hypoperfusion during CPB. 1 In addition, factors like impaired venous drainage or Address for Correspondence: Dr. K. K. Golam, D2/10 KINARA, 358, Municipal Tenements, A.G. Road, Worli Seaface, Mumbai drkumudgolam@yahoo.com anatomic lesions characterised by reduced splanchnic flow or excessive systemic runoff may limit perfusion. Finally the systemic inflammatory response to CPB may also impair tissue oxygenation and perhaps more specifically, tissue oxygen extraction. 1 Improvements in CPB and overall haemodynamic management have reduced the incidence of severe perioperative tissue hypoperfusion. 2 It is an established fact that tissue hypoperfusion is associated with lactic acidosis secondary to anaerobic metabolism. Measurement of blood lactate levels can, hence be used as a marker to assess the adequacy of tissue perfusion. 2 Glycolysis is the first step of glucose metabolism and occurs in the cytoplasm of virtually all cells. 39

2 40 Shinde et al. Blood Lactate Levels during CPB Annals of Cardiac Anaesthesia 2005; 8: The end product of this pathway is pyruvate, which can then diffuse into mitochondria and get metabolised to carbon dioxide by the Kreb s cycle. 3 Increased blood lactate may occur with or without concomitant metabolic acidosis. Such hyperlactataemia is usually seen in subclinical tissue hypoperfusion, secondary to elevated blood catecholamine levels. This is either stress induced, due to administration of catecholamine or due to alkalosis where buffering systems are able to mitigate any fall in the ph. 4 This study was conducted to establish blood lactate level, as a prognostic tool, in patients undergoing valvular heart surgery under CPB. The following were evaluated: - Lactate levels and its correlation with preoperative clinical condition (as per New York Heart Association). - The intra and postoperative outcomes, following CPB for valvular heart surgery. Methods Eighty two consecutive patients undergoing valvular heart surgery under CPB were included in this study. On the basis of history, the patients were allocated to their respective class as per the NYHA functional classification 5 (Table 1). The departmental review board of Lokamanya Tilak Municipal Medical College and General Hospital approved the study. Diabetic patients on treatment with phenformin were excluded from the study. The reason being that in this group there is increased peripheral extrasplanchnic glucose utilisation by a shift from oxidative to anaerobic metabolism. As such they have been associated with development of lactic acidosis. Anaesthesia Technique On the day of surgery, the patient was premedicated with morphine (0.2 mg/kg) and promethazine (0.5 mg/kg) intramuscularly about minutes prior to induction of anaesthesia. Anaesthesia was induced with thiopentone (5 mg/ kg) and vecuronium was used to accomplish endotracheal intubation with appropriate sized tube, (generally 9.0 mm for males and 7.5 mm for females). Anaesthesia was maintained with 50% oxygen (O 2 ), 50% nitrous oxide (N 2 O) along with halothane 0.5% to 1%. Morphine (0.05 mg/kg) was given before incision and 0.15 mg/kg was added to the pump prime. Additional morphine (0.1 mg/kg) and vecuronium (0.1 mg/kg) were administered during rewarming. Post-CPB anaesthesia was maintained with 50% O 2, 50% N 2 O, halothane 0.5 to 1%, and vecuronium (1/4 th of induction dose). The bypass circuit was primed with a mixture of Ringer s lactate and gelofusine to make the priming volume 1500 ml. Standard bypass techniques with systemic hypothermia of 28-32ºC were employed. Mean arterial pressure was continuously monitored and maintained between 50 and 60 mm Hg. The haemoglobin was maintained between 6 and 8 gm%. Urine output was monitored throughout the procedure. Blood sugar was monitored using a glucometer intraoperatively and the sugar levels were maintained between 180 and 240 mg%. After surgery was completed, CPB was discontinued and heparin was neutralised with protamine. Patients received ionotropic support in the form of dopamine (5-10 µg/kg/min) and adrenaline ( µg/kg/min) was added if required to attain the desired haemodynamic stability. Before shifting the patient to cardiac intensive care unit, morphine 0.1 mg/kg was given intravenously. In the intensive care unit the patient was electively ventilated with continuous monitoring of haemodynamic parameters and arterial blood gas analysis. Blood lactate level measurement: For measuring lactate levels, arterial blood was collected through the intra-arterial catheter (inserted for blood pressure monitoring) immediately after induction of anaesthesia. This was termed as the baseline sample. Subsequent samples were collected at the following intervals minutes after institution of CPB - 45 minutes after institution of CPB (if any) - Rewarming (at 35 C) 40

3 Annals of Cardiac Anaesthesia 2005; 8: Shinde et al. Blood Lactate Levels during CPB 41 - Immediately after terminating the CPB - 24 hours post-surgery, and - 48 hours post-surgery. The blood samples were collected in a sample tube containing 3 ml of 5% metaphosphoric acid. Samples were stored in ice carriers and transferred to the laboratory where they were immediately centrifuged. The protein free filtrate was then collected in another tube for the estimation of lactate (using the spectrophotometer method at 340 nm). 6 The endpoint of the study was predetermined with the last sample being collected at 48 hours after termination of CPB. The one-way ANOVA was used for statistical analysis. Results Demographic data showed average age of 35±10.2 years with weight of 50±12.4 kg. There were 43 males and 39 females. Table 1 shows distribution of patients according to their NYHA class. Maximum patients (34) belonged to NYHA class II. Table 2 shows the distribution of various surgical procedures. Most patients (37) underwent mitral valve replacement. Table 3 shows mean lactate levels during the perioperative period. Table 4 shows the mean lactate levels in different NYHA class patients. No statistically significant changes were seen in NYHA class I, II and III. However, NYHA class IV patients showed significant (p<0.001) elevation in the mean lactate levels, as compared to NYHA class I, II and III, throughout the study period. Two patients in NYHA class IV demonstrated abnormally high lactate levels and were excluded. Table 5 shows the changes in perioperative lactate levels in relation to duration of CPB. Levels were significantly higher (p<0.05) during rewarming at 35 C and off-bypass in patients requiring CPB for more than one hour as compared to those with less than 1 hour. Lactate levels returned to normal levels in 24 and 48 hours Table 1. Distribution of patients according to the New York Heart Association (NYHA) Classification NYHA class No. of patients I 15 II 34 III 20 IV 11 Table 2. Types of surgeries performed Type of surgery No. of patients MVR 37 AVR 20 DVR 13 MVR+TVR 2 R. MVR 5 R. AVR 1 R. DVR 2 MVR: mitral valve replacement, AVR: aortic valve replacement, DVR: double valve replacement, TVR: tricuspid valve replacement, R: redo. Table 3. Mean lactate levels (mmol/l) during the perioperative period N=80 Pre-op 15 min 45 min Rewarming Off- 24 Hour 48 Hour CPB CPB 35 0 C Bypass Postop Postop Mean levels of Lactate 1.90± ±2.69* 9.92±3.58* 7.01±3.20* 4.75±1.01* 3.06± ±1.05 The results are given as Mean±SD. * P<0.001 Values as compared to Pre-op CPB: cardiopulmonary Bypass, Pre-op: preoperative, Postop: postoperative Table 4. Comparison of NYHA class and their mean lactate levels (mmol/l) during preoperative period N=80 Pre-op 15 min 45 min Rewarming Off- 24 Hour 48 Hour 35 0 C Bypass NYHA I (n=15) 1.66± ± ± ± ± ± ±0.84 NYHA II (n=34) 1.92± ± ± ± ± ± ±1.17 NYHA III (n=20) 1.93± ± ± ± ± ± ±1.16 NYHA IV (n=11) 2.22± ±2.22* 9.10±1.61* 7.05±2.53* 6.25±2.39* 5.00±1.74* 4.47±2.12* The results are given as Mean±SD. * P<0.001 Values as compared to NYHA Class I, II, III 41

4 42 Shinde et al. Blood Lactate Levels during CPB Annals of Cardiac Anaesthesia 2005; 8: Table 5. Comparison of duration of CPB and changes in perioperative Lactate levels Duration Base line 15 minutes 45 minutes Rewarming Off-Bypass 24 hrs. 48 hrs. of CPB 35 0 C <1 hrs. (n=40) 1.25± ± ± ± ± ± ± hrs. (n=40) 2.20± ±3.35 NS 7.59±2.95 NS 8.35±4.75* 5.85±3.90* 4.68± ±1.75 The results are given as Mean±SD. * P<0.05 Values as compared to less than 1 hrs. duration of CPB. after surgery. Table 6 shows the comparison of changes in lactate levels with mean duration of ionotropic and ventilator support. The average duration of mechanical ventilation and duration of inotropic support was significantly more in the group which demonstrated a change in lactate level of more than 4 mmol/l (for baseline to off-bypass) (p<0.05). Table 7 shows the relation of NYHA class to lactate level variations. The patients were designated to three groups. Group I Patients having a change in lactate level of < 2 mmol/l Group II Patients having a change in lactate level of 2-4 mmol/l Group III Patients having a change in lactate level of >4 mmol/l It reveals that 66.6% of NYHA Class I patients showed a change in lactate levels of <2 mmol/l during CPB. Fifty percent NYHA class II and 55% NYHA class III patient showed increase in lactate levels of 2-4 mmol/l during CPB, and 63.6% of Table 6. Changes in lactate levels during CPB (off-bypassbase line lactate) and duration of postoperative ionotropic support and mechanical ventilation Change in Lactate Mean duration Mean duration of mmol/ L) of inotropic mechanical Support (hours) ventilation (hours) <2 (n = 25) 13.12± ± (n = 33) 15.92± ±6.01 >4 (n = 22) 17.20±5.55* 15.82±5.25 * The results are given as Mean±SD. * P<0.05 Values as compared to Less than 2 mmol/l and 2-4 mmol/l lactate. Table 7. Comparison of NYHA class to lactate level variation NYHA Changes in lactate levels during CPB Class <2 2-4 >4 (n = 27) (n = 31) (n = 22) I 10 (66.6%) 3 (20%) 2 (13.33%) II 11 (32.35%) 17 (50%) 6 (17.64%) III 2 (10 %) 11 (55%) 7 (35%) IV 4 (36.36%) - 7 (63.63%) NYHA IV patients showed an increase of >4 mmol/l during CPB. Due to small number of patients in the subgroups a statistical analysis could not be performed. Discussion CPB is used to maintain systemic perfusion and oxygenation during open-heart operations. This is achieved by adjusting flow rate, temperature, gas flow and haemoglobin to maintain oxygen delivery. Tissue hypoperfusion may occur due to low flow CPB, hypothermia, extreme haemodilution and excessive neurohormonal activation. This leads to an anaerobic condition in which oxidative phosphorylation is not possible and adenosine triphosphate (ATP) is produced from pyruvate, the latter being metabolised into lactate. 7 An increase in lactate concentration may be the result of diminished tissue perfusion and oxygen delivery, decreased oxygen extraction and decreased hepatic lactate clearance. 1 Plasma lactate concentrations reflect a balance between lactate production by regional tissue beds and the ability of the liver (and to a lesser extent, the heart and renal cortex) to metabolise lactate via the Cori Cycle, gluconeogenesis, and the Krebs cycle. Systemic lactic acidosis has often been attributed to the overproduction of lactic acid by hypoxic tissues. 7 The organs most likely to produce lactate, in response to hypoperfusion or decreased oxygen extraction, include the brain, gut, liver, kidneys and skeletal muscles. 8 Hyperlactataemia is classified as mild (lactate level 2 mmol/l), moderate (lactate level 5 mmol/l, with persistent increase in blood lactate concentration without metabolic acidosis) and severe (characterised by persistently increased 42

5 Annals of Cardiac Anaesthesia 2005; 8: Shinde et al. Blood Lactate Levels during CPB 43 blood lactate levels, usually >5 mmol/l, in association with metabolic acidosis). The distinction between the types of lactic acidosis is based on the presence or absence of clinical evidence of tissue hypoperfusion. 4 Cohen & Woods have classified lactic acidosis into two categories: Type A (lactic acidosis in association with clinical evidence of poor tissue perfusion) and Type B (lactic acidosis with no evidence of poor tissue perfusion). 9 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, septic shock, hypovolaemic shock, severe hypoxaemia, liver failure, diabetes mellitus, and following exercises. 4 Studies on blood lactate levels in children undergoing cardiac surgery for congenital heart diseases have also shown similar results. 1 However, literature on adult patients undergoing valvular heart surgery under CPB is limited. Literature also fails to explain the relation of elevations in serum lactate levels during or after CPB, to definite postoperative mortality and morbidity. Furthermore, none of the studies have compared the preoperative clinical condition as per the NYHA classification to the changes in lactate levels during CPB. Studies performed in patients with shock and also other critically ill patients have demonstrated that a circulating blood lactate level of 4 mmol/l or more predisposes to a striking increase in morbidity and mortality rate. 4 Demers et al 7 showed that blood lactate concentration of 4 mmol/l or higher during CPB identifies a subgroup of patients with increased risk of postoperative morbidity and mortality. In our study, the baseline mean lactate level was 1.89±0.94 mmol/l which is similar to that shown by Himpe. 11,12 In our study, the mean lactate levels at 15 and 45 minutes on CPB increased to 7.01 mmol/l and 9.92 mmol/l respectively. The reasons for this increase have been enlisted earlier. We also observed a progressive decline in mean lactate levels during rewarming (at 35 C), off bypass, 24 hours and 48 hours postoperatively with mean lactate levels being 7.01 mmol/l, 4.75 mmol/l, 3.06 mmol/l and 2.10 mmol/l respectively. The elevations in mean lactate levels were significant (p< 0.001) in patients in NYHA class IV at 15 minutes and 45 minutes on CPB, during rewarming and 24 and 48 hours post-cpb. Comparison of mean lactate levels with relation to duration of CPB revealed higher levels in those who had CPB lasting more than 1 hour (p< 0.05). However, the levels returned to normal 48 hours after surgery in both the groups. An increase in the levels of circulating catecholamines has been reported to cause moderate hyperlactataemia, usually attributed to the metabolic effects of catecholamine on glycolysis and gluconeogenesis. 4 Furthermore, an increase in circulating catecholamines is responsible for splanchnic vasoconstriction thereby reducing perfusion to the gastrointestinal tract during and after surgery. 4 However, studies done by Shoemaker and Tuchschmidt 13 have reported that inotropic agents and vasodilators, used to achieve specific optimised oxygen transport goal, reduce the incidence of postoperative hyperlactataemia. 4 In our study the inotropes used were dopamine and adrenaline. Dopamine was used in doses less than 10 µg/kg/min and hence the possibility of dopamine-induced vasoconstriction is unlikely. The patients with elevations in lactate levels of more than 4 mmol/l had the longest duration of mechanical ventilation and inotropic support while those with lactate levels < 2 mmol/l had least duration of postoperative mechanical ventilation and inotropic requirement. There was no mortality. This is in contrast to the study by Munoz et al 1 who have shown a high mortality in patients with serum lactate levels of >4 mmol/l. Correlation between mean lactate levels and NYHA class shows that as the NYHA class of a patient increases from I to IV, the extent of elevation in lactate levels during CPB also increases. However due to limited number of patients in each subgroup a statistical analysis could not be performed. 43

6 44 Shinde et al. Blood Lactate Levels during CPB Annals of Cardiac Anaesthesia 2005; 8: With regards to mortality and morbidity, there was no mortality, with morbidity occurring in 2 patients. Both these patients had elevated lactate levels starting from baseline till 48 hours postoperative. We conclude that a high NYHA class and longer duration of CPB is associated with a significant increase in lactate levels during perioperative period and that increased lactate levels are directly proportional to the duration of mechanical ventilation and inotropic support. References 1. Munoz R, Laussen PC, Palacio G. Changes in whole blood lactate levels during CPB for surgery for congenital cardiac disease: an early indicator of morbidity and mortality. J Thorac Cardiovasc Surg 2000; 119: Hue L, Rider MH. Role of fructose 2,6-biphosphate in the control of glycolysis in mammalian tissues. Biochem J 1987; 245: Boyer PD. Lipid Enzymology. In: Denmis EA, The Enzymes, Academic press, Inc., San Diego, CA, 1984; pp Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med, 1992; 20: Mangano DT. Preoperative assessment of cardiac risk. In: Kaplan JA, Cardiac Anesthesia. Philadelphia; W B Saunders, 1999; pp 9 6. Edward P, Marbach. Rapid enzymatic measurement of blood lactate and pyruvate; Clinical chemistry 1967; 13: Demers P, Elkouri S, Martineau R. Outcome with high blood lactate levels during cardiopulmonary bypass in adult cardiac operation. Ann Thorac Surg 2000; 70: Vitek V, Cowley RA. Blood lactate in prognosis of various forms of shock. Ann Surgery 1971; 173: Kruse JA, Carlson RW. Lactate metabolism. Crit Care Med 1987; 5: Raper RF, Bowey CJ. Type B lactic acidosis following cardiopulmonary bypass. Crit Care Med 1997; 25: Himpe D. Anion gap, lactate and acid-base status after cardiac surgery. Crit Care Med 1993; 21: Himpe D, Neel H, Vancauwelaert P. Priming solutions for cardiopulmonary bypass: comparison of three colloids. J Cardiothorac Anesth 1991; 5: Shoemaker WC. Tuchschmidt C. Sequential perioperative lactate determination. Crit Care Med 1982; 10: