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European Journal of Heart Failure 2002 4(2):175-179; doi:10.1016/S1388-9842(02)00007-7
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© 2002 European Society of Cardiology

Lactic acidosis following heart transplantation: a common phenomenon?

Paul Mohacsia,1,*, Giovanni Pedrazzinia,1, Hildegard Tannera, Hans-Ueli Tschanza, Roger Hullina and Thierry Carrelb

a Cardiology, Swiss Cardiovascular Center Bern University Hospital (Inselspital), CH-3010 Bern, Switzerland
b Cardiovascular Surgery, Swiss Cardiovascular Center Bern University Hospital, Bern, Switzerland

* Corresponding author. Tel.: +41-31-632-4464; fax: +41-31-632-4299. E-mail address: paul.mohacsi{at}insel.ch


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: Lactic acidosis (LAc) is a common form of metabolic acidosis early after heart transplantation (HTX). The mechanism remains unclear. This study analyzed 13 patients who developed severe LAc after HTX.

Methods: From a series of 60 consecutive heart transplant patients, we identified 13 patients with LAc in the first hours following HTX. Nine patients with normal or mildly elevated lactate levels (<5.0 mmol/l) were investigated as controls.

Results: Thirteen patients developed a moderate or severe LAc (up to 14.6 mmol/l) after HTX. Serum lactate levels increased immediately following surgery with a peak after 6.3±1.4 h, spontaneously returning to normal values within 24 h. In contrast to the control group, a significant correlation was found between the maximal serum lactate level and the maximal dosage of inotropic drugs (r=0.93, P<0.02), administered during the reperfusion phase and continued for 12–24 h postoperatively. No correlation was found between LAc and blood gas analysis during extracorporeal perfusion period.

Conclusion: LAc can occur after HTX and seems to be related to the inotropic support of the graft. In contrast to other forms, LAc after HTX has an excellent prognosis and resolves rapidly and spontaneously without treatment. The fact that inotropic support during and immediately after cardiac transplantation can enhance preexisting severe peripheral metabolic cellular dysfunction remains hypothetical.

Key Words: Cardiac transplantation • Lactic acidosis • Inotropic support

Received April 16, 2001; Revised August 1, 2001; Accepted October 23, 2001


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Lactic acidosis is one of the most common forms of metabolic acidosis. In a steady-state metabolic situation, the production and consumption of lactate are balanced since the liver and kidneys metabolize the lactate produced by the skin, the musculature and the erythrocytes. If oxygen delivery becomes insufficient to cover normal energy requirements, an upregulation of lactate, due to pyruvate overproduction which cannot follow the aerobic pathway, is observed. During exhaustive exercise the overproduction of lactate is physiological. On the other hand, severe clinical disorders (like sepsis, hypoxia, pulmonary disease, liver failure), drugs and a variety of toxins can cause lactic acidosis, which is associated with a poor prognosis, when left untreated.

Interestingly, lactic acidosis can be observed in the early postoperative period after HTX, although the etiology for this condition remains hypothetical. This type of lactate acidosis has, in contrast to other forms of metabolic acidosis, a favorable outcome, because it resolves spontaneously within hours following HTX. This paper deals with a retrospective analysis of pre-, intra- and postoperative details of 13 heart transplant recipients who developed moderate to severe lactic acidosis. Predictive factors for this clinical situation are analyzed.


   2. Patients and methods
Top
 Notes
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
In a series of 60 consecutive cardiac transplantations, we identified 13 patients (11 males; mean age 51.4 years) who developed moderate to severe lactic acidosis in the very early postoperative period. Eight patients suffered from end-stage ischemic heart disease, three from idiopathic dilatated cardiomyopathy, one patient presented with complex congenital heart disease and the last one had an unusual form of familial hypertrophic non-obstructive cardiomyopathy. Preoperative heart failure medication included diuretics in 12 patients, ACE-inhibitors in 11, beta-blockers in 8 and digoxin in three patients (Table 1).


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  		Table 1 Patients’ characteristics: cohort of 13 cases with high serum lactate levels

 
Two of these 13 patients had normal left-ventricular systolic function (one with familial hypertrophic cardiomyopathy and one with severe coronary artery disease not amenable to PTCA or surgery): heart transplantation was indicated because of severe diastolic dysfunction or intractable angina at rest. One patient received transplantation at the start of multiorgan failure; he suffered postoperatively from transient liver and renal failure but recovered well.

All allografts were examined by echocardiography (n=13) and cardiac catheterization (n=8) and were explanted in hemodynamically stable donors. During organ procurement, the donor hearts were arrested and preserved with 1000 ml of St. Thomas or Celsior® (Pasteur Mérieux, Paris, France) solution. Mean cold ischemic time of the allograft was 81±60 min. In the recipient, perioperative monitoring consisted of a central venous catheter, a peripheral arterial line, transcutaneous oxygen saturation and ECG registrations (II and V5).

Cardiopulmonary bypass was instituted after aortic and bicaval cannulation and conducted in mild hypothermia (32 °C), according to the alpha-state regime.

In three patients, arterial return was achieved through the external iliac artery to reduce the danger of right ventricular injury during sternum re-entry. Warm blood cardioplegia was instillated in the aortic root immediately before declamping the aorta. Mean extracorporeal circulation time was 89±47 min (Table 1).

All patients received some inotropic support, starting usually at the dosage that the organ donor received immediately prior to or during procurement. This included epinephrine (mean dosage 4±2.5 µg/kg per min) and/or dobutamine (5–10 µg/kg per min). Mean arterial pressure was targeted at 80 mmHg. Modest inotropic support was usually continued for up to 24 h in the majority of patients. Standard immunosuppression consisted of preoperative intravenous azathioprine (5 mg/kg) and 1 g of methylprednisolone intraoperatively before starting reperfusion. Oral cyclosporine (2–4 mg/kg daily) was started 12–36 h after HTX, prednisone was started with 0.8 mg/kg and azathioprine was continued postoperatively with a dosage of 1.0–1.5 mg/kg. Intravenous rabbit anti-thymocyte-globuline (ATG) (3–5 mg/kg per day) was administered during the first 5 days. In 12 patients, extubation was possible after a mean of 9 h, one patient with prolonged preoperative cardiogenic shock was intubated for 6 days.

Serum lactate was assessed in 8 of the 13 patients before surgery, during reperfusion and at 4, 8, 12 and 24 h after surgery. Arterial blood gas analysis (pH, bicarbonate, base excess, arterial oxygen saturation) as well as glucose and electrolyte determination were performed at the same time intervals. Lactate level was determined in the peripheral arterial and venous blood as well as in the right atrium; for this purpose, 5 ml of blood (EDTA) was centrifuged and frozen at –80 °C. Analysis was carried out using an electrolytic reaction (Radiometer Copenhagen ABL 625).

As a control group we investigated nine patients with normal or mildly elevated lactate levels (<5.0 mmol/l). Patients with borderline lactate levels were excluded.

The investigation conformed with the principles outlined in the Declaration of Helsinki.

2.1. Statistical analysis
Data are shown as mean±1 S.D. or as median and range values. Serial changes in blood chemistry and lactate levels were assessed using the Kruskal–Wallis one-way analysis of variance.

Determination of the relationship between lactate levels and pre- or postoperative inotropic support was performed using a linear regression analysis based on the least squares method. Statistical significance was considered when the P value was less than 0.05.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
3.1. Lactic acidosis and evolution over time
Twelve patients developed moderate to severe lactic acidosis (5.9 to 14.6 mmol/l, normal range: 0.63–2.44 mmol/l). One patient (Table 2, No. 4) who was investigated for lactic acidosis evolution over time had a slight elevation of the peak lactate level (2.6 mmol/l). Plasma lactate levels increased soon after transplantation, with a peak between 4–8 h (mean 6.3±1.4) following surgery (Table 2). All patients, even those with moderate lactate increase, demonstrated some degree of metabolic acidosis, which resolved spontaneously within 24 h.


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  		Table 2 Serum lactate levels, acidosis and time point of peak serum lactate levels after HTX

 
No patients received specific therapy to correct lactic acidosis but 8 out of 13 patients were hyperventilated. Surprisingly, these 13 patients all developed some degree of hypokalemia (3.2 to 4.1 mmol/l), which was corrected with potassium substitution. All patients had postoperative moderate to severe hyperglycemia (12.5 to 23.8 mmol/l) and all but one received insulin for a short period of time.

3.2. Relationship between lactic acidosis and perioperative factors
No relationship could be found between lactic acidosis and the length of extracorporeal circulation, the aortic cross-clamping time, the overall period of cold graft ischemia or the blood gas analysis immediately before transplantation.

3.3. Lactate levels and intra-/postoperative inotropic support
All patients received perioperative inotropic support, started during reperfusion and adjusted first to the dose with which the donor was treated immediately prior to or during organ procurement. At arrival in the intensive care unit, nine patients received epinephrine (mean dose 4±2.5 µg/kg per min) and four patients received dobutamine (mean dose 5–10 µg/kg per min). Six hours later, dobutamine had been added to the epinephrine support in four patients. Eight patients were treated with intravenous nitroglycerin and two patients received nitric oxide at a dosage of 20 and 40 ppm, respectively, because of elevated pulmonary pressure (>50 mmHg systolic pressure) or preoperatively elevated pulmonary vascular resistance (>450 dyn/s m–5).

A highly significant correlation was found between peak lactate levels and the maximal dosage of inotropic support (r=0.93, P<0.02). Reduction of inotropic support was associated with a decrease in serum lactate and a rapid resolution of lactic acidosis. During the observation period, all patients showed stable hemodynamics and no patient presented significant hypotension or signs of peripheral hypoperfusion.

3.4. Serial measurement
The difference between peripheral venous, peripheral arterial and central venous lactacte levels did not reach statistical significance (P>0.05) (data not shown).

3.5. Control group with normal or slightly elevated lactate levels
We studied nine cardiac transplanted patients with lactate levels of <5 mmol/l. Median lactate level was 3.1 mmol/l (range 0.6–4.2). In contrast to the patient group with moderate or severe elevated lactic acidosis (mean dose 4±2.5 µg/kg per min), this group received epinephrine in a mean dose of 1.6±1.3 µg/kg per min. We found no correlation between the maximal serum level of lactate and the maximal dosage of inotropic drugs (r=0.008, P>0.8).


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
Lactic acidosis is one manifestation of severe metabolic dysfunction; when it is related to low cardiac output [1], and it is associated with a poor prognosis. Increase in serum lactate has also been observed in patients undergoing coronary artery bypass grafting, especially in those with compromised left-ventricular function [2]. This is typically due to poor peripheral perfusion.

The present observation demonstrates that lactic acidosis can also be observed in the first few hours after transplantation. Although the exact pathophysiological mechanism of lactate acidosis is still hypothetical, we found a strong correlation between the severity of lactic acidosis and the maximal dosage of inotropic support in the perioperative period to wean the patient from extracorporeal circulation and to stabilize hemodynamics in the intensive care unit. This type of lactic acidosis surprisingly resolves rapidly without treatment. Previous reports have shown that catecholamine infusions can induce a slight increase in serum lactate with concomitant hypokalemia [3,4].

We could not confirm Robbins’ observation of a suggested relationship between lactic acidosis and the preoperative afterload reduction by ACE-inhibitors or other drugs administered preoperatively as treatment of heart failure [5]. We were not able to find any correlation between the serum lactate levels and the length of the operation nor the period of cold graft ischemia. In addition, in our study there was no relationship between post cardiac transplant peak lactate levels and the duration of heart failure (data not shown).

The serum lactate levels we found were surprisingly high. So far, we believe that the administration of catecholamines alone is not sufficient to explain this rapid increase in serum lactate and have to hypothesize that a metabolic predisposition at the cellular level was most probably co-responsible for the development of lactic acidosis. This can frequently occur in patients with end-stage heart failure and is not always clinically apparent [1].

Patients with end-stage heart disease have a pathological reduction in oxygen consumption (VO2 max), with a rapid switch to anaerobic metabolism [6]. In fact, heart failure patients, even those with preserved cardiac output (cardiac index >2 l min/m2), can have a severe reduction in peak oxygen consumption in preoperative spiroergometry. Metabolic acidosis can occur either during exercise or in the recovery period. In these patients, the capacity to perform exercise can be more limited through hypoperfusion of the skeletal muscles rather than because of primary poor ventricular performance. Several studies have shown a close relationship between early metabolic (lactate) acidosis and abnormal exercise capacity in patients with chronic heart failure. Exercise tolerance appears to be inversely related to the decrease in blood flow, and shows a strong correlation to the blood lactate level [7]. Poor exercise tolerance is explained by early anaerobic metabolism. When metabolic acidosis develops, glycolysis is increased but oxidative phosphorylation is decreased. Concentration of endogenous catecholamine is generally increased in these patients, and neurohumoral activation can accentuate the shift from aerobic to anaerobic metabolism through peripheral vasoconstriction.

The exogenous administration of catecholamines can promote lactic acidosis in patients undergoing cardiac transplantation. This phenomenon is accelerated by preexisting pathological cellular derangements. Spontaneous resolution of metabolic acidosis reflects the rapid adaptation to the favorable metabolic and hemodynamic conditions following the restoration of a normal cardiac output.


   Acknowledgements
 
The authors acknowledge Prof. Marianne Bachofen, MD, Institute of Anesthesiology for invaluable help. This work was supported by the K. Huber–Steiner Foundation.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
1 Paul Mohacsi and Giovanni Pedrazzini contributed in equal parts to this study. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

  1. Schaufelberger M., Eriksson B.O., Lonn L., et al. Skeletal muscle characteristics, muscle strength and thigh muscle area in patients before and after cardiac transplantation. Eur J Heart Fail (2001) 3:59–67.[Abstract/Free Full Text]
  2. Ariza M., Gothard J.W., MacNaughton P., et al. Blood lactate and mixed venous-arterial PCO2 gradient as indices of poor peripheral perfusion following cardiopulmonary bypass surgery. Intensive Care Med (1991) 17:320–324.[CrossRef][Web of Science][Medline]
  3. Daul A.E., Wenzel R.F., Schaiers R.F., et al. Catecholamine-induced hypokalaemia may be caused by intracellular lactic acidosis (EDTA-ERA Congress, abstract). Nephrol Dial Transplant (1995) 10:919.
  4. Daul A.E., Schaiers R.F., Wenzel R.F., Philipp T.H. Effective therapy of hyperkalaemia by the 2-adrenoreceptor-agonist terbutaline is associated with lactataemia (EDTA-ERA Congress Abstract). Nephrol Dial Transplant (1995) 10:993.
  5. Robbins R.C., Smith J.A., Rihakove G.H., et al. Low systemic resistance syndrome following heart transplantation. 14th Annual Meeting of the American Society of Transplant Physicians. Chicago: Abstract booklet (P-72) (1994) 1994:143.
  6. Myers J., Froehlicher V.F. Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Int Med (1991) 115:377–386.[Abstract/Free Full Text]
  7. Weber K.T., Janicki J.S. Lactate production during maximal and submaximal exercise in patients with severe left ventricular dysfunction. J Am Coll Cardiol (1985) 6:717–724.[Abstract]

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