Levosimendan for Postoperative Ventricular Dysfunction Following Heart Transplantation

INTRODUCTION

Ventricular dysfunction and its most severe manifestation, postoperative primary graft failure following cardiac transplantation in adult patients, is a serious complication that can lead to low-output syndrome, hypoperfusion, multiorgan dysfunction, and even the death of the patient. The Registry of the International Society for Heart and Lung Transplantation states that primary graft failure is the cause of up to 40% of mortality in the first 30 days postransplantation.¹ Similar figures (43%) are reported by the Spanish Registry.²

The hemodynamic management of these patients is complex, and the therapeutic options are restricted to pharmacological and mechanical circulatory support. Catecholamines are used and are very effective for most patients. However, they sometimes have adverse effects and on occasions are insufficient to maintain satisfactory hemodynamic status. In the most severe cases, mechanical support can be established with intraaortic balloon counterpulsation and, on rare occasions, with ventricular assist devices.^3,4 On very few occasions, and in especially selected patients, retransplantation may be an option.

Levosimendan is an inotropic vasodilator belonging to the calcium sensitizer group and has been recently introduced into clinical practice. It has proven useful in various acute cardiac failure situations, including perioperative cardiac surgery⁵ and right ventricular dysfunction, by decreasing systolic pulmonary arterial pressure.⁶ We present our clinical experience and outcomes in the management of 6 patients with ventricular dysfunction following heart transplantation who were treated with levosimendan after standard management.

METHODS

The study was conducted between January 2006 and April 2007 in our center, a tertiary hospital with a multidisciplinary program for cardiac transplantation and access to ventricular assist devices.

This was a descriptive prospective observational study, which analyzed levosimendan in 6 adult heart transplantation patients who developed early moderate-severe postoperative ventricular dysfunction.

All patients presented end-stage chronic heart failure with severe ventricular dysfunction and were in NYHA functional class III-IV at the time of cardiac transplantation. During the postoperative period, they developed low cardiac output syndrome compatible with early ventricular dysfunction. Hemodynamic therapy was conducted with amine administration which is the standard protocol in our unit. Levosimendan was administered when the patient presented inotropic dependency for more than 72 h, to aid in amine withdrawal or to supplement them if satisfactory hemodynamic status was not achieved (ie, cardiac indexes >2.5 L/min/m² and mixed venous oxygen saturation >65%). Levosimendan was not administered to patients with arterial hypotension (systolic blood pressure £100 mm Hg) at the time of initiating drug administration.

Previous pulmonary hypertension and ischemia times were analyzed as possible preoperative and intraoperative factors that might have an effect on the development of ventricular dysfunction in the transplanted heart. Hemodynamic response to levosimendan and the overall postoperative evolution of the patients were also studied, as well as clinical tolerance to uncover potential adverse effects attributable to the drug.

RESULTS

A total of 6 patients were studied (3 men and 3 women). Table 1 shows the baseline clinical characteristics of the patients.

All patients were in NYHA functional class III-IV prior to surgery. One patient underwent emergency transplantation due to hemodynamic deterioration that required mechanical ventilation and mechanical circulatory support with intraaortic balloon counterpulsation and pharmacological intervention with amines. Prior to transplantation, all patients presented pulmonary hypertension which was moderate-severe in 5 out of the 6 patients, with a transpulmonary gradient (TPG) ranging from 9 mm Hg to 21 mm Hg. The 2 patients with TPG >15 mm Hg responded positively to a reversibility test with sildenafil, that is, there was a significant decrease in pulmonary pressures and TPG after administering the vasodilator (Table 1).

Immediately after transplantation, all patients presented low cardiac output syndrome due to postoperative ventricular dysfunction, with cardiac indexes measured via a lung artery catheter. All patients underwent echocardiography that ruled out pericardial effusion with hemodynamic deterioration in cardiac cavities and showed predominant right ventricular dysfunction (Table 2). Pulmonary hypertension and prolonged ischemia time (248 min) may have influenced the development of right ventricular dysfunction in the only patient with mild hypertension.

All patients were treated according to our standard immunosuppression protocol, which included basiliximab (2 doses, one 4-6 h after ICU admission and a second on the fourth day posttransplantation), steroids (3 doses of 125 mg methylprednisolone, followed by prednisone at 0.5 mg/kg/12 h), mycophenolate mofetil (1-1.5 g/12 h) and cyclosporin (1-4 mg/kg/24 h). In the last patient, cyclosporin was postponed due to kidney failure immediately after transplantation.

Multiple parameters were monitored and hemodynamic management performed in all patients according to standard practice. Thus, all patients received fluids to achieve satisfactory blood volume status (until normal preload ranges were achieved), atrial epicardial pacing was performed and inotropic support provided with sympathomimetic amines. Table 3 shows the evolution of hemodynamic parameters in the 6 patients treated with levosimendan. Catecholamine administration was initiated after 72 h in 3 patients, after 96 h in 2, and 6 days after transplantation in 1 female patient.

Levosimendan was used as single inotropic agent after 72 h of dobutamine administration in patient 4 because of the need to maintain inotropic treatment due a marked decrease in cardiac output after withdrawal. The hemodynamic status improved after levosimendan infusion and the patient was discharged 24 h later. Levosimendan was administered to the remaining patients together with other inotropic drugs to optimize their hemodynamic status and to enable the withdrawal of catecholamine inotropic agents. All these patients received intravenous dobutamine infusions; 1 patient also received dopamine and 2 also received adrenaline. Similarly, to diminish post-load, pulmonary arterial vasodilators in the form of inhaled nitric oxide, epoprostenol, and sildenafil were also administered to 2 patients with pulmonary hypertension and marked predominant right ventricular dysfunction. In addition, 2 patients needed temporary mechanical support with intraaortic balloon counterpulsation (patients 3 and 6). The possibility of retransplantation was also assessed, but we finally decided against this in the light of our previous experience in similar situations, the scarce bibliographical support, and the possibility of achieving satisfactory medical management.

Levosimendan contributed to hemodynamic optimization in nearly all the patients and probably enabled them to be weaned from the other vasoactive drugs and facilitated their discharge from the unit. However, 1 patient presented torpid clinical evolution, developing multiorgan dysfunction syndrome requiring a long ICU stay and finally died. However, given the complexity of these patients, it is understood that disease progress depends on multiple factors.

An initial bolus of levosimendan (12 µg/kg) was administered to the first 4 patients, whereas the other 2 patients did not receive a loading dose. After the initial bolus, continuous intravenous perfusion was started at 0.1 µg/kg/min, and was increased up to 0.15 µg/kg/min in 3 patients. It is worth highlighting that levosimendan was well tolerated by all patients. The only adverse effect observed was a slight reduction in blood pressure in 2 patients at the beginning of treatment, which did not require the dose to be adjusted.

Table 2 shows the overall postoperative evolution of patients during their ICU stay. Attention should be drawn to the clinical improvement obtained with the hemodynamic support provided, which enabled the withdrawal of inotropic agents and all the patients to be discharged from the ICU after 4-6 days except for the patient who suffered multiorgan dysfunction syndrome and died.

DISCUSSION

Orthotopic cardiac transplantation is an effective treatment in selected patients with terminal heart failure.⁷ Despite the advances in patient management before, during and after heart transplantation, postoperative ventricular dysfunction and its main manifestation, primary graft failure, continues to be a potentially severe complication following this intervention, associated with worse prognosis and early mortality in a high percentage of patients.^1,2

Factors contributing to the development of acute cardiac allograft rejection include inadequate preservation of the organ, prolonged ischemia time, myocardial stunning secondary to ischemia-reperfusion, cellular or humoral rejection, donor-dependent factors (such as female sex, weight mismatch between the donor and recipient, reduced contractility associated with brain death, or myocardial contusion) and some recipient-dependent factors, mainly preexisting pulmonary hypertension and baseline ischemic or valvular etiology.^8-11

The management of patients with ventricular dysfunction normally involves pharmacological intervention for circulatory support (catecholamines and phosphodiesterase inhibitors) and, on some occasions, mechanical support with intraaortic balloon counterpulsation or ventricular assist devices.

In recent years, levosimendan, an inotropic vasodilator, has been included in the pharmacological arsenal. This drug increases the sensitivity of contractile proteins in myofilaments to calcium via its direct action on troponin C. This increases myocardial contractility without increasing the amount of intracellular calcium and, as a result, without increasing myocardial oxygen consumption (unlike catecholamines). In addition, levosimendan stimulates the adenosine triphosphate-dependent potassium channels, which leads to arterial and venous vasodilatation and decreases afterload.^12,13 Other effects attributed to this drug include phosphodiesterase III inhibition at high doses, antistunning effects in post-ischemic myocardium,^14,15 and myocyte apoptosis inhibition.¹⁶

Numerous clinical trials with high numbers of patients have been conducted with levosimendan. These studies confirm the efficacy and safety of levosimendan in the context of acute heart failure of multiple origin.^17-20 The characteristics of this drug and the clinical results obtained from these studies have led the European Society of Cardiology to consider levosimendan as a therapeutic option in patients with heart failure with symptomatic low output secondary to systolic heart failure without severe arterial hypotension. This is a class IIa recommendation with a level of evidence B.²¹ The search for potential uses of levosimendan in different clinical situations involving ventricular dysfunction or low cardiac output has led to numerous studies being conducted in the context of acute decompensation episodes in chronic heart failure and in acute heart failure of different etiology, such as postoperative heart surgery, cardiogenic shock, and even ventricular dysfunction in septic shock.^22-26

Given that levosimendan combines pulmonary vasodilating properties and inotropic action, it has also been used in patients with right ventricular dysfunction,⁵ in the diagnosis of a potential reversible component in increased pulmonary vascular resistance, to predict post-transplantation cardiac performance²⁷ and even in isolated cases of graft failure after heart transplantation.^28,29

This article analyzes our clinical experience in the use of levosimendan in a series of patients with ventricular dysfunction in the immediate period after cardiac transplantation. Although our study deals with a small number of patients, it is the largest series published. It should be noted that levosimendan is well-tolerated, without serious adverse effects, and contributed to hemodynamic improvement in both the one patient who received it as the only inotropic administered (after stopping dobutamine) and in the remaining patients, except in the one who presented multiorgan failure. Similarly, it is very likely that it enabled amine withdrawal, but understood as a contributing factor in a complex situation where multiple factors play a role.

Therefore, we conclude that this new inotropic vasodilator, a calcium sensitizer, has a good safety profile and improves hemodynamic status in this subgroup of patients who are characterized by low cardiac output with predominant right ventricular dysfunction and relatively high pulmonary hypertension.

Nevertheless, this study is quite small and cannot provide solid recommendations; rather, it should be viewed as a seed to encourage setting up a multicenter study with a large number of patients capable of establishing suitable indications and guidelines for the use of levosimendan, as well as the profile of patients who would benefit most from its use.

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Correspondence:
Dr. J.L. Pérez Vela.
Atardecer, 3. 28223 Pozuelo de Alarcón. Madrid. España.
E-mail: [e-mail]

Received June 19, 2007.
Accepted for publication October 24, 2007.