Extreme Hyperlactatemia After Heart Transplantation: One Center's Experience

Extreme Hyperlactatemia After Heart Transplantation: One Center’s Experience Y.C. Hsua, C.H. Hsua, G.S. Huanga, C.C. Lub, Z.F. Wua, Y.T. Tsaic, C.Y. Linc, Y.C. Linc,d, C.S. Tsaic, and T.C. Lina,* a Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; bDepartment of Anesthesiology, Taipei Veterans General Hospital, National Defense Medical Center, Taipei, Taiwan; cDivision of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; and dDepartment of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan

ABSTRACT Introduction. Hyperlactatemia may occur early after cardiac surgery and is correlated with prognosis. This study was conducted to analyze the perioperative variables and postoperative outcomes among heart transplant recipients with extremely high lactate levels (>15 mmol/L). Methods. The single-center medical records of heart transplantation from June 2006 to May 2013 were retrospectively reviewed for patient characteristics, perioperative hemodynamic variables, arterial blood gas analysis data, and postoperative mortality. Results. Among 58 consecutive heart transplant recipients, lactate levels over the detectable upper limit (>15 mmol/L) were identified in 12 patients after intensive care unit admission, with peak time at 1.9
2.0 (range 0e6.1) hours. The maximal preoperative lactate level was 3.1 mmol/L, and most (11/12) postoperative lactate levels returned to <4 mmol/L at 27.5
12.8 hours after surgery (range 15e58, median 24), displaying a trend toward delayed extubation time in 10 recipients (P < .01). Blood glucose levels elevated significantly from preoperative 148.9
45.2 to 375.7
96.9 mg/dL at peak lactate level (P < .01). Four patients died in the ICU (range 5e32 days), 4 died after discharge (range 5e57 months), with 6 in total surviving over 1 year. Conclusion. Extreme hyperlactatemia commonly occurred early after heart transplantation and mostly recovered within 30 hours; however, with delayed extubation time after operation.

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YPERLACTATEMIA and lactic acidosis are commonly encountered during and after cardiac surgery [1]. Low cardiac output and tissue hypoperfusion increase perioperative lactate production before and during hypothermic cardiopulmonary bypass. The lower flow rate is a risk factor for hyperlactatemia after pediatric open heart surgery [2]. Multivariate analysis has identified elevated lactate levels as an independent predictor for postoperative morbidity and mortality in adult [3e9] and pediatric [10] cardiac surgical patients. Heart transplantation has been one of the most effective therapies for end-stage heart diseases [11]. A robust donor heart is assumed to provide improved cardiac output and tissue perfusion, with consequently less lactate accumulation after transplantation. However, a previous analysis demonstrated 13 of 60 recipients developing moderate-to-severe

lactic acidosis (5.9e14.6 mmol/L) immediately after surgery [12]. In another study, lactate values 4 mmol/L on intensive care unit (ICU) admission occurred in 9 of 16 patients, with higher mortality rate and neurological complications, as compared with those <4 mmol/L [13]. In our clinical experience, some recipients experienced very high lactate levels (>15 mmol/L) by arterial blood gas analysis in the ICU. We therefore retrospectively reviewed our data to verify its incidence and analyze the

*Address correspondence to Tso-Chou Lin, MD, Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, No 325, Sec 2, ChengGong Road, Taipei City 114, Taiwan. E-mail: [email protected]

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0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.02.027

Transplantation Proceedings, 47, 1945e1948 (2015)

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Table 1. Patient Characteristics and Perioperative Variables Gender (N ¼ 12) Age, y Height, cm Weight, kg BMI, kg/m2 Ischemic cardiomyopathy, n Dilated cardiomyopathy, n Hypertension, n Diabetes mellitus, n Preoperative support, n IABP only IABP þ ECMO þ tracheal intubation Dobutamine Dopamine Epinephrine Preoperative ejection fraction, % Allograft cold ischemic time, min Aortic clamp time, min Cardiopulmonary bypass time, min General anesthesia duration, min Preoperative AST, U/L Preoperative ALT, U/L Preoperative creatinine, mg/dL Postoperative creatinine, mg/dL Preoperative glucose level, mg/dL Postoperative glucose level, mg/dl Glucose level at peak lactate level, mg/dL Postoperative cardiac index, L/min/m2

Male 11/female 1 52.1
11.2 167.8
8.3 76.5
22.5 27.0
7.3 7 5 4 7

19.5 144.9 137.8 173.3 532.8 37.8 29.7 1.5 1.7 148.9 249.7 375.7 2.6

3 2 3 2 1














4.2 72.3 50.9 35.4 82.9 25.6 17.6 0.6 0.5 45.2 53.6* 96.9* 0.8

Abbreviations: IABP, intra-aortic balloon pump; ECMO, extracorporeal membrane oxygenation; AST, aspartate aminotransferase; ALT, alanine aminotransferase. *P < .01, as compared with the preoperative glucose level.

perioperative variables and postoperative outcomes in these patients. METHODS After obtaining approval of our institutional review board, we retrospectively reviewed the medical records of 58 consecutive heart transplant recipients by the same surgeon (C.S. Tsai) between June 2006 and May 2013. All patients received general anesthesia with midazolam 5 mg, fentanyl 1.5e3 mg/kg, thiamylal 2e4 mg/kg or propofol 0.5e1.5 mg/ kg, and cisatracurium 0.1 mg/kg for induction, and isoflurane or sevoflurane for maintenance after tracheal intubation. A 3-lumen central venous catheter was placed through the left internal jugular vein and transesophageal echocardiography was used to monitor real-time cardiac performance throughout the whole procedure. Intravenous infusion of rabbit anti-thymocyte-globulin 1.2e2.5 mg/ kg was administered through the central venous catheter during the first 24 hours. Standard hypothermic cardiopulmonary bypass (Sarns 8000, Terumo, Ann Arbor, Mich., United States) with an extracorporeal membrane oxygenator (CapioxSX 18, Terumo) were carried out in sequence to maintain the body temperature at 26e30 C during surgery. The perfusionist adjusted isoflurane or sevoflurane concentration on the vaporizer to keep mean arterial blood pressure 50e80 mm Hg during implantation of the donor’s heart. Following standard rewarming and deairing, the pump was weaned with routine inotropic support, including dopamine 3e10 mg/kg/min for acceptable cardiac output and isopreterenol for

heart rate around 100e120 beats/min. Additional dobutamine, epinephrine, and norepinephrine infusion, as well as intra-aortic balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO) [14] were applied for hemodynamic or cardiopulmonary support. A pulmonary artery catheter was regularly inserted later through the left subclavian vein at the end of the operation for postoperative hemodynamic monitoring. All patients were transferred to the cardiovascular surgical ICU with endotracheal intubation after surgery. Arterial blood gas analysis was routinely examined perioperatively and immediately upon ICU admission by GEM Premier 3000 (Instrumentation Laboratory, Lexington, Mass., United States), including plasma lactate (detectable limit, 0.3e15 mmol/L) and glucose (detectable limit, 20e500 mg/dL) levels. Postoperative hemodynamic variables, inotropic doses, extubation time, length of stay in ICU, and postoperative mortality also were recorded. The patient demographic data and perioperative variables were presented as mean
SD. Determination of the relationship between extubation time and time to lactate levels returning to <4 mmol/L was performed using a linear regression analysis based on the least squares method. P value < .05 was considered statistically significant.

RESULTS

Among 58 consecutive heart transplant recipients, we identified 12 patients developing severe lactic acidosis (>15 mmol/ L) after surgery from June 2006 to August 2012 (Table 1). Before transplantation, 5 patients required IABP and 2 received combined ECMO and endotracheal intubation due to cardiopulmonary failure. Three patients needed preoperative inotropic support, including dobutamine (all 3 patients), dopamine (2 patients), and epinephrine (1 patient). The perioperative laboratory data, including plasma AST, ALT, and creatinine levels excluded acute hepatic or renal failure. The mean blood glucose level significantly elevated upon arriving at the ICU (249.7
53.6 mg/dL, P < .01), with peak lactate level at the time of (375.7
96.9 mg/dL, P < .01), as compared with the preoperative level (148.9
45.2 mg/dL). However, a similar trend of elevating blood glucose levels was observed among others beyond these 12 patients on arriving at the ICU (239.0
71.1 mg/dL, P < .01) and with peak lactate level at the time of (317.8
106.8 mg/dL, P < .01), as compared with the preoperative level (150.2
66.8 mg/dL). As shown in Table 2, the lactate levels over the detectable upper limit (>15 mmol/L) were immediately recognized in 4 patients upon arrival at the ICU. Preoperative and postbypass lactate levels were 1.7
0.7 (range 0.8e3.1) and 8.6
2.7 (range 3.5e13.4) mmol/L, and reached the peak level (>15 mmol/L) at 1.9
2.0 (range 0e6.1) hours postoperatively. Most (11/12) lactate levels returned to <4 mmol/L at 27.5
12.8 (range 15e58, median 24) hours after ICU admission, which were associated with delayed extubation time (P ¼ .0009), with mean 106.5
56.4 (range 10e168) hours. Meanwhile, the others beyond these 12 patients had a shorter extubation time as 65.2
49.6 hours (P < .05). In total, 4 patients died in the ICU (range 5e32 days), including 2 with postoperative heart failure and multiple organ failure, 1 with acute antibodymediated rejection and cardiogenic shock, and 1 with

EXTREME HYPERLACTATEMIA AFTER HEART TX

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Table 2. Clinical Outcomes of Heart Transplant Recipients With Postoperative Plasma Lactate Level >15 mmol/L No.

Lactate Before CPB

Lactate After CPB

Lactate Upon Arriving at the ICU

Time to Lactate >15 mmol/L, h

Time to Lactate <4 mmol/L, h

1 2 3 4 5 6 7 8 9 10 11 12 Mean SD

0.8 1.3 1.2 1.2 1.5 2.1 3.1 1.6 1.5 2.8 2.0 1.2 1.7 0.7

13.4 8.7 8.2 7.3 12.8 7.2 7.5 8.1 6.8 3.5 8.3 11.4 8.6 2.7

>15.0 >15.0 12.8 10.7 >15.0 11.3 12.2 11.1 13.2 >15.0 9.9 12.2 12.8 1.9

0 0 1.7 0.9 0 5.3 2.3 6.1 2.3 0 1.9 2.1 1.9 2.0

* 29 17 22 44 28 19 26 24 58 15 20 27.5 12.8

Time to Extubation, h

ICU Stay, d

Hospital Stay, d

Died After Operation

†

†

†

†

†

†

†

†

†

†

32 7 7 8 12 13 8 8 11.9 8.4

38 46 31 29 26 32 24 23 31.1 7.7

5 days‡ 9 days‡ 23 days§ 32 daysk 5 months 8 months 37 months 57 months

156 154 156 96 22 10 120 168 75 108 106.5 56.4

Survival Until May 2013

20 34 38 46

months months months months

Case 1 and 4, preoperative IABP and postoperative IABP þ ECMO; case 2 and 5, preoperative and postoperative IABP þ ECMO; case 9, preoperative and postoperative IABP. Abbreviations: CPB, cardiopulmonary bypass; IABP, intra-aortic balloon pump; ECMO, extracorporeal membrane oxygenation. *The lowest lactate level as 5.0 mmol/L until died. † Keeping endotracheal intubation or stay in intensive care unit (ICU) until died. Four patients died in the ICU: ‡heart failure and multiple organ failure; §acute antibody-mediated rejection and cardiogenic shock; knosocomial pneumonia with septic shock and multiple organ failure.

nosocomial pneumonia and septic shock (Table 2). Another 4 died after discharge (range 5e57 months), including 1 with refractory ventricular tachycardia and heart failure, 1 with hepatitis C viruserelated liver cirrhosis and hepatic failure, 1 with spontaneous intracranial hemorrhage, and 1 with septic shock and multiple organ failure. Among these 12 recipients, 6 in total survived over 1 year. DISCUSSION

We presented 12 from 58 heart transplant recipients developing extremely high lactate levels shortly after ICU admission, exceeding the detectable upper limit (>15 mmol/ L) of the arterial blood gas machine. Most lactate levels returned to <4 mmol/L within 30 hours after arriving at the ICU by routine inotropic support for acceptable hemodynamics, but with delayed extubation time in the ICU. Cardiopulmonary bypass (CPB) is an important contributor to lactate production even with maintenance of oxygenation and circulation [9]. Bypass-induced hypothermia, ischemiareperfusion injury, gut-derived endotoxemia, and splanchnic hypoperfusion [15] are all potential contributors to tissue hypoperfusion and metabolic derangement [16], such as stress hyperglycemia [17]. During CPB, perioperative lactate production increases in the myocardium, skeletal muscle, lungs, and in the splanchnic circulation [1]. Abraham et al [2] demonstrated that CPB flow rate is an independent risk factor for early postoperative hyperlactatemia, with an odds ratio of 7.67, as the flow rate was <100 mL/kg/min in pediatric cardiac surgery. Among our 12 heart transplant recipients, hyperlactatemia developed immediately after cessation of CPB (mean 8.9 mmol/L) and an extremely high level (>15 mmol/L) was identified shortly upon ICU admission (mean 1.9 hours), despite normal preoperative lactate levels

(maximal 3.1 mmol/L). In clinical practice, patients with acute exaggeration of congestive or valvular heart diseases commonly received diuretics to reduce fluid overloading. It would then contribute to the relative hypovolemia before anesthesia. If the comparable mean arterial blood pressure during CPB was achieved by inadequate anesthetic depth, sympathetic activation might result in vasoconstriction and ensuing generalized tissue hypoperfusion and lactate production. To keep the balance between mean arterial blood pressure, flow rate and anesthetic depth are essential during CPB, especially detecting an increasing lactate level before its cessation. An early increase of lactate level is suggestive of tissue ischemia and is associated with a prolonged ICU stay, a prolonged requirement for respiratory and cardiovascular support, and increased postoperative mortality [1]. Demers et al [9] demonstrated that 18% of patients developed blood lactate level 4.0 mmol/L during CPB, which have been identified for increased risk of postoperative morbidity and mortality. Maillet et al [8] reported that 20.6% patients had hyperlactatemia (>3 mmol/L) immediately on arrival of ICU, which could more accurately predict ICU mortality after cardiac surgery. Kogan et al [5] also found that maximal lactate threshold 4.4 mmol/L in the first 10 hours after cardiac surgery accurately predicts postoperative prolonged ventilation time, longer ICU stay, and increased mortality. In our patients, delayed extubation time was correlated with a prolonged duration of lactate level >4 mmol/L. Mohacsi et al [12] analyzed 13 of 60 consecutive heart transplant patients who developed moderate or severe lactic acidosis (5.9e14.6 mmol/L) after transplantation. Serum lactate levels increased immediately after surgery, with a peak at 6.3 hours, spontaneously returning to normal values within 24 hours. They also found a significant

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correlation between the maximal serum lactate level and the dosage of inotropic drugs administered during the reperfusion phase and continued for 12e24 hours postoperatively. It is reasonable for a patient with worse cardiac output to receive more inotropics to support tissue perfusion, and vice versa. On account of rapid recovery of lactate levels and acceptable postoperative creatinine level and cardiac index in most of our recipients, we thus initially excluded the possibility of renal or hepatic failure, or septic shock in the first postoperative day after ICU admission. However, 4 (33%) of 12 patients developed cardiogenic or septic shock with ensuing multiple organ failure and died in the ICU and in total 6 (50%) recipients died within 1 year. Both were higher than the average in-hospital mortality rate of 11.6% in Italy [11] and 1-year mortality rate of 20% in Taiwan [18] after heart transplantation. Two limitations should be stated. First, we did not have the preoperative data regarding pulmonary artery pressure, transpulmonary pressure gradient, or pulmonary vascular resistance of recipients, which might affect the outcome of transplantation, especially acute right ventricular failure. In our hospital, most heart transplant recipients regularly received a central venous, but not pulmonary artery catheterization after general anesthesia induction. A pulmonary artery catheter was inserted later at the end of the operation. Second, hyperlactatemia is generally defined as lactate level over 4 mmol/L in recent studies [3,5,6,13]. In addition, Mohasci et al [12] defined moderate or severe lactatic acidosis by lactate levels >5.0 mmol/L after heart transplantation. In this study, we arbitrarily described a very high lactate level >15 mmol/L as extreme hyperlactatemia because of undetectable actual lactate levels by the artery blood gas machine we used, but not a formal definition of lactate levels. If severe hyperlactatemia is defined by a lower lactate level, such as 10 or 12 mmol/L, more patients could be included to analyze the risk factors for developing hyperlactatemia or the prognostic effects after heart transplantation. In conclusion, approximately 1 in 5 heart transplant recipients developed extremely high lactate levels shortly after ICU admission among 58 patients in our hospital, exceeding the detectable upper limits (>15 mmol/L) of the arterial blood gas machine. Most lactate levels spontaneously returned to <4 mmol/L within 30 hours of arriving in the ICU, indicating improved tissue perfusion but with delayed extubation time after surgery. ACKNOWLEDGMENT Grant support from Tri-Service General Hospital (TSGH-C103184, TSGH-C96-15-S04, and TSGH-C97-8-S04).

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