Ann Thorac Surg 2000;69:1823-1826
© 2000 The Society of Thoracic Surgeons
Original articles: Cardiovascular
Milrinone for long-term pharmacologic support of the status 1 heart transplant candidates
Charles C. Canver, MDa,
Jyotirmay Chanda, MD, PhDa
a Division of Cardiothoracic Surgery, Albany Medical College, Albany, New York, USA
Address reprint requests to Dr Canver, Division of Cardiothoracic Surgery, Albany Medical College, 47 New Scotland Ave, Mail Code 55, Albany, NY 12208–3479
e-mail: canverc{at}mail.amc.edu
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Abstract
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Background. We determined the efficacy of long-term therapy with milrinone alone or in combination with inotropic agents in status 1 heart transplant candidates as a pharmacological support until heart transplantation.
Methods. Hemodynamic and biochemical variables were recorded in 29 status 1 men with symptoms of severe congestive heart failure, who received continuous intravenous milrinone alone (group 1, n = 21) or in combination with inotropic agents (group 2, n = 8) while awaiting heart transplantation.
Results. Symptomatic relief was noted in all patients of both groups without any preoperative deaths. One patient (4.8%) of group 1 died on the second day and 1 patient of group 2 died 16.4 months after transplantation. Although pulmonary capillary wedge pressure (group 1, p = 0.021; group 2, p = 0.0002), mean pulmonary artery pressure (group 1, p = 0.051; group 2, p = 0.004), and pulmonary vascular resistance (group 1, p = 0.0026; group 2, p = 0.056) were reduced by 1 hour after the onset of treatment and maintained unchanged until transplantation, the changes in mean pulmonary artery pressure in group 1 and pulmonary vascular resistance in group 2 were statistically insignificant except in the posttransplantation period.
Conclusions. Long-term therapy with milrinone in combination with inotropic agents is safe and effective when only milrinone infusion is inadequate for pharmacologic support in status 1 candidates.
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Introduction
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The clinical success of cardiac transplantation has resulted in a dramatic increase in the number of patients referred and subsequently listed for heart transplantation [1]. However the shortage of donor hearts has increased both the waiting time for transplantation and the number of patients who die while on the waiting list [2–4]. The current United Network for Organ Sharing (UNOS) heart allocation system presently grants no waiting list priority status benefit to candidates who receive intravenous inotropic therapy in the outpatient setting (UNOS status 2), whereas identical therapy given in an intensive care unit setting does convert the patient to priority status (UNOS status 1) [5]. When high-risk patients are selected for nonurgent transplant listing, the mortality rate remains high, even among those who survive the initial 6 months after listing [6]. The hospitalized candidates who receive priority for the limited donor hearts are largely these deteriorating patients with dependency on intravenous inotropic or mechanical circulatory support [7].
The phosphodiesterase III inhibitor milrinone can result in marked improvement in the performance of the failing heart without increasing myocardial oxygen consumption. This appears to result from reduction in left ventricular systolic wall stress due to peripheral arteriolar vasodilatation, which offsets the increase in myocardial oxygen consumption that would otherwise result from an enhanced inotropic state. In comparison, dobutamine, given at doses that achieve the same level of inotropic enhancement or improved left ventricular performance, produces less associated arteriolar vasodilatation and a significant (approximately 30%) increase in myocardial oxygen consumption. This difference between milrinone and dobutamine might be clinically important in patients with limited coronary flow reserve as a result of severe congestive heart failure [8–10]. High levels of endogenous plasma catecholamines in patients with severe congestive heart failure induce down-regulation of myocardial ß-adrenoreceptors and thus cause adrenoreceptor agonists, such as dobutamine, to be less effective in the treatment of these patients. Milrinone works independently of adrenoreceptor activity and plasma catecholamine levels, so this agent is likely to be more effective in the treatment of severe heart failure [11]. Milrinone has been administered successfully to control the acute exacerbation of heart failure [12–16]. In several studies milrinone has been used successfully as the sole pharmacologic support before cardiac transplantation [17–19]. In this study we used long-term intravenous milrinone infusion alone or in combination with inotropic agents in status 1 patients as the primary pharmacologic agent to support the failing heart until the time of cardiac transplantation.
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Patients and methods
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We retrospectively reviewed charts of 29 men, with a mean age of 52 ± 9.5 years (range, 32 to 67 years), who had orthotopic heart transplantation between October 1993 and October 1996. All these patients were admitted to the hospital with symptoms of severe congestive heart failure (New York Heart Association class III or IV) presenting as pulmonary hypertension associated with low cardiac output state and were classified as status 1 cardiac transplant candidates (Table 1). Each patient was given a loading dose of intravenous milrinone of 50 µg/kg for more than 10 minutes followed by continuous infusion of 0.375 to 0.75 µg · kg-1 · min-1 alone or in combination with dobutamine (3–10 µg · kg-1 · min-1) or dopamine (3–5 µg · kg-1 · min-1) until the time of heart transplantation. Heart rate, pulmonary capillary wedge pressure, mean pulmonary artery pressure, pulmonary vascular resistance, mean arterial pressure, cardiac index, platelet count, serum bilirubin, creatinine, and blood urea nitrogen were measured in each patient before and during treatment. Average status 1 waiting time was 39.6 ± 30.3 days (range, 3 to 160 days).
All data were collected retrospectively and are presented as mean ± standard deviation. Values were compared by means of repeated measures of analysis of variance complex compact variable techniques (StatView version 5.0.1, SAS Institute Inc, Cary, NC). Multiple comparisons were carried out with Fisher protected least significant difference test. A p value less than 0.05 was assumed as statistically significant.
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Results
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Objective improvement in symptoms and signs of congestive heart failure was noted in all patients after milrinone infusion. Eight of 29 patients (27.6%) required an additional inotropic agent (dopamine or dobutamine) after 60 minutes of intravenous milrinone therapy (group 2). The 21 patients treated with milrinone only comprised group 1. Reducing the rate of intravenous milrinone infusion effectively controlled wide-complex ventricular tachycardia, which occurred in 2 patients (9.5%) of group 1. There were no deaths related to long-term intravenous milrinone during the waiting period. One patient (4.8%) of group 1 died on the second day after transplantation and 1 patient of group 2 died in the late follow-up period (16.4 months postoperatively). There were no other deaths in either group in the late follow-up period (mean follow up: group 1, 12.7 ± 8.3 months, group 2, 21.6 ± 3.2 months). The hemodynamic and metabolic variables of groups 1 and 2 are summarized in Tables 2 and 3, respectively. An insignificant change in heart rate was noticed in both groups. The mean arterial pressure increased a trivial amount during the initial treatment period (group 1, +3.8%, p = 0.55; group 2, +3.4%, p = 0.47 from baseline) and practically maintained the baseline level until transplantation (+1.6% from base line, p = 0.74; group 2, +10% from base line, p = 0.058). In both groups there was substantial decrease in pulmonary capillary wedge pressure (group 1, -20.8% from baseline, p = 0.021; group 2, -39.3% from baseline, p = 0.0002), mean pulmonary artery pressure (group 1, -12.5% from baseline, p = 0.051; group 2, -31% from baseline, p = 0.004), and pulmonary vascular resistance (group 1, -37.5% from baseline, p = 0.0026; group 2, -40.3% from baseline, p = 0.056) after 1 hour. These values were maintained until transplantation, but the changes in mean pulmonary artery pressure in group 1 and pulmonary vascular resistance in group 2 were not statistically significant except in the posttransplantation period. The cardiac index improved in both groups; a significant increase in cardiac index was noticed after 1 week of treatment in group 2 and in the posttransplantation period in group 1. There was a significant reduction in platelet count in the posttransplantation period in both groups of patients. The changes in serum creatinine, bilirubin, and blood urea nitrogen were statistically insignificant in group 2, whereas serum creatinine and bilirubin were significantly higher in the posttransplantation period in group 1.
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Table 2. Effect of Long-Term Milrinone Infusion Only on Hemodynamic and Metabolic Variables in Group 1 Patients (n = 21)a
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Table 3. Effect of Long-Term Milrinone in Combination With Dobutamine or Dopamine Infusion on Hemodynamic and Metabolic Variables in Group 2 Patients (n = 8)a
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Comment
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Cardiac failure is treated with increasing success by the phosphodiesterase-III inhibitor, milrinone [12–16]. Whereas relatively pure positive inotropic substances, such as dopamine and dobutamine, are limited by development of tolerance and increased myocardial oxygen consumption, the efficacy of milrinone is maintained by avoiding catecholamine and ß-receptors. Milrinone has positive inotropic, positive lusitropic, and vasodilatory properties. Myocardial oxygen consumption remains unaltered, and milrinone acts selectively by inhibiting phosphodiesterase III, leading to increased cyclic adenosine monophosphate concentration in myocardial and smooth muscle cells [7–11]. However the pharmacokinetic profile of milrinone is not optimal for short-term critical care medicine. With a mean terminal elimination half-life of 1.5 to 2 hours [20], the time to peak pharmacodynamic effect of any dose is relatively delayed, as is the correction of any adverse effect on drug discontinuation, compared with dobutamine, dopamine, nitroprusside, or parenteral nitroglycerin. Bolus administration is required to attain a quicker hemodynamic response, but bolus injection is not a particularly convenient mode of delivering powerful cardiovascular support drugs in the critical care setting [9].
Although milrinone infusion for an average of 39.6 days was associated with substantial improvement of hemodynamic status in 21 (72.4%) of 29 patients, we found that addition of inotropic agents improved the hemodynamic status when milrinone infusion alone was inadequate in status 1 candidates awaiting heart transplantation. Substantial decrease in pulmonary capillary wedge pressure, mean pulmonary artery pressure, and pulmonary vascular resistance indicated the efficacy of the therapeutic strategy in both groups.
We support the strategy [19] of initially administering intravenous milrinone, with dobutamine added later as an adjunct when necessary, because it reduced the need for mechanical cardiac intervention compared with the strategy of initially administering dobutamine and adding milrinone later. The wide-complex ventricular tachycardia that occurred in 2 patients of group 1 was controlled effectively by reducing the rate of intravenous milrinone infusion. Careful observation and instantaneous dose reduction during the first hour of infusion might prevent the occurrence of milrinone-induced ventricular tachycardia.
The positive hemodynamic effects of milrinone, with little or no increase in oxygen consumption, are likely attributable to milrinone’s predominant mechanism of action in heart failure, namely, vasodilation, with positive inotropy contributing only modestly to its effect [9]. Nevertheless, 8 of our 29 patients did not respond adequately to milrinone administration alone. Patients with atrial fibrillation can have increased ventricular rates even at low doses of dobutamine [10–13, 16]. Despite two incidences of milrinone-induced ventricular tachycardia in our study, at doses short of provoking a positive chronotropic response, milrinone can be considered a safe cardiovascular support drug, especially when the risk of dysrhythmia exists. In our patients, who were given doses that evoked a similar improvement in ventricular systolic performance, stroke volume, and insignificant cardiac output, the predominant site of vasodilatory effect of milrinone whether systemic or pulmonary still remains elusive.
There was significant reduction in platelet count in the posttransplantation period in both groups of patients. Serum creatinine, blood urea nitrogen, and bilirubin levels were insignificantly changed in group 2 patients. However, it is difficult to explain why these values were significantly increased in group 1 patients in the posttransplantation period. Insignificant deviation of bilirubin level and other metabolic variables from baseline indicates that milrinone alone or in combination with dobutamine or dopamine infusion is safe when metabolic toxicity is a concern.
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Acknowledgments
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We appreciate the assistance of Diane E. May in the preparation of the manuscript.
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References
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Accepted for publication December 6, 1999.
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Abstract
Introduction
