Abstract and Introduction

Abstract

Objective: To describe our preliminary experience with Levosimendan, a new calcium-sensitizing agent in critically unwell infants and children with severe heart failure.
Design: Retrospective cohort analysis.
Setting: Pediatric intensive care unit.
Patients: Fifteen children aged 7 days to 18 yrs (median age 38 months) with severe myocardial dysfunction secondary to end-stage heart failure, or acute heart failure, who were inotrope-dependent (requiring at least one catecholamine).
Interventions: A single dose (bolus and intravenous infusion over 24-48 hrs) of Levosimendan was given under continuous hemodynamic monitoring in our intensive care unit. Eleven children received a single dose, three children received two doses, and one child received four doses. Echocardiographic assessments of ventricular function were made before and 3-5 days after Levosimendan infusion.
Measurements and Main Results: Heart rate, systolic pressure, diastolic pressure, mean blood pressure, and central venous pressure were unchanged during and after Levosimendan. Levosimendan allowed for discontinuation of catecholamines in ten patients and a dose reduction in three. The dose of dobutamine was reduced from 6.4 μg/kg/min pre-Levosimendan to 1.8 μg/kg/min on day 5 (p < .01). Ejection fraction for the group as a whole improved from 29.8% to 40.5% (p = .015); this did not increase significantly in patients with end-stage heart failure but increased by 63% in the children with acute heart failure.
Conclusions: Levosimendan can be safely administered to infants and children with severe heart failure. Levosimendan allowed for substantial reduction in catecholamine infusions in children with end-stage or acute heart failure and also produced an objective improvement in myocardial performance in children with acute heart failure.

Introduction

Decompensated heart failure can affect infants and children with primary myocardial disease secondary to myocarditis or idiopathic dilated cardiomyopathy, after systemic sepsis, and, perhaps most commonly, after surgery for congenital heart disease. The intensive care management of severe cardiac failure in children is aimed at improving myocardial performance and modifying loading conditions, using pharmacologic agents and nonpharmacologic therapies including ventilation. Catecholamines are often useful in the short term but may have unwanted chronotropic effects and can increase myocardial oxygen consumption. Tachyphylaxis, desensitization of β-adrenergic pathways in patients with chronic heart failure, and concomitant use of β-blockers may further limit the efficacy of catecholamines in those patients who are in greatest need of effective inotropic therapy ^[1]. Thus, agents with alternative modes of action may be particularly appealing for these children.

Levosimendan (Levo) is a calcium-sensitizer that exerts inotropic actions by binding to cardiac troponin C and increasing the sensitivity of the contractile apparatus to calcium ^[2]. Levo also produces coronary and peripheral vasodilation by opening the mitochondrial adenosine triphosphate-dependent potassium channels of vascular smooth muscle ^[3]. In the recent LIDO study, Levo improved hemodynamic performance and survival, compared with dobutamine, in adults with severe heart failure ^[4]. We have recently demonstrated improved systolic and diastolic myocardial performance and afterload conditions with Levo in an infant model of cardiopulmonary bypass ^[5], but little is known about the usefulness of Levo in the pediatric clinical setting. In this article, we describe our preliminary experience with Levo in 15 consecutive critically ill infants and children with severe heart failure in our intensive care unit (ICU).

Materials and Methods

This was a retrospective review of patients' notes and ICU charts, which was registered as an audit with our Institutional Review Board. Fifteen children, median age 38 months (range 7 days to 18 yrs), with severe heart failure and ventricular dysfunction received 22 courses of intravenous Levosimendan (Simdax, Abbott, Australasia) between December 2003 and May 2005. Levo was obtained on a named-patient basis, and parental consent was given each time it was administered. All patients were in the ICU at The Royal Children's Hospital and already receiving intravenous catecholamines that could not be weaned. All children were on intravenous or oral vasodilators, and three were on an oral β-blocker. Children with a recent need for cardioversion or defibrillation, those with a history of sustained ventricular arrhythmias, or those who were receiving milrinone were deemed unsuitable for Levo. All children had invasive monitoring of arterial blood pressure, and ten had monitoring of central venous pressure. Echocardiograms were performed in all patients before and 3-5 days after commencing Levo. . Seven children had longstanding end-stage heart failure (ESHF), and the remaining eight children had acute heart failure-four after recent cardiac surgery or transcatheter intervention for congenital heart disease, one after cardiac transplantation, one following acute viral myocarditis, and one following septic myocardial dysfunction and multiple system failure after chemotherapy for relapsed leukemia. Three children received Levo during weaning from extracorporeal life support.

All patients received Levo as a loading dose (6-12 μg/kg over 10 mins) followed by a continuous infusion (0.1 μg/kg/min for 24 hrs in 13 children and 0.05 μg/kg/min for 48 hrs in two children). Inotrope doses and echocardiographic measurements of contractility were compared before and after Levo for the group as a whole. Further comparisons were made between patients with ESHF and those with acute heart failure.

Statistics

Data are expressed as mean (confidence intervals); comparisons were made using Student's t-test or one-way analysis of variance with Tukey's correction for multiple comparisons.

Results

One child (patient 15) developed a single episode of ventricular tachycardia that required cardioversion during Levo infusion. Following this, he remained stable. Administration of Levo was not associated with any other adverse hemodynamic effects. Heart rate, systolic and diastolic blood pressures, and central venous pressure did not change with Levo . The mean arterial lactate concentrations tended to decrease over the first 48 hrs, although this was not statistically significant (p = .068). We do not routinely measure cardiac output or left atrial pressure in the majority of our patients, and so further supportive hemodynamic data are not available in this group.

Catecholamine Infusions

All children were receiving dobutamine before commencing Levo.  The mean dose of dobutamine was 6.4 (1.2) μg/kg/min before Levo, 3.6 (2.1) μg/kg/min on completion of the infusion, and 1.8 (1.3) μg/kg/min at 5 days. Thus, Levo allowed for a significant reduction in intravenous catecholamines over the 5-day period (p < .001).

Ventricular Function

Serial ejection fractions were measured in 11 children (Fig. 1). Baseline ejection fractions for children with ESHF were lower than for children with acute heart failure-26.0% (4.1%) vs. 34.4% (6.2%) (p = .01). Ejection fractions for the group as a whole increased from 29.8% (4.1%) at baseline to 40.5% (11.4%) after Levo (p = .015). The ejection fraction was unchanged in the ESHF patients but increased for those with acute heart failure (34.4 ± 2.2 to 56.2 ± 4.6%, p = .002).

Outcome

Eleven children were discharged from ICU after the primary admission (during which Levo was given), of whom seven are still alive. Two of the children with ESHF have been transplanted. Patient 7 died of an intracerebral bleed, related to anticoagulation for a venous thrombosis. Patient 13, with relapsed leukemia, was readmitted to ICU 11 days after receiving Levo, with extensive necrotizing fasciitis that proved rapidly fatal. Patient 11 died 10 days after receiving Levo, after suffering a cardiac arrest during anesthesia for a central venous line insertion.

Four children died during the primary ICU admission, of whom two died within 1 wk of receiving Levo. They were both given the drug as rescue therapy during weaning from extracorporeal life support: after a Ross operation (patient 2) and after transplantation (patient 3). The other two died relatively late after receiving Levo. One small infant (patient 14) with a metabolic cardiomyopathy died of end-stage heart failure; the fourth died of necrotizing enterocolitis.

Discussion

Our preliminary experience with Levo in critically ill children with heart failure shows promise. Levo appeared to be safe and efficacious in this small sample, undoubtedly supporting the need for a multiple-center trial to determine its safety profile and clinical application in pediatric patients. In Australia, Levo is currently only available under the Special Access Scheme of the Therapeutic Goods Administration in Australia, as rescue hemodynamic therapy on a named-patient basis.

In the absence of detailed invasive hemodynamic end points, our primary, clinically useful, objective was to offer a period of alternative inotropic therapy in children with severe heart failure who had been receiving prolonged infusions of catecholamines that could not be weaned. Our secondary objective was to explore any additional, more objective evidence of measurable improvement in terms of myocardial function.

Levo allowed for the weaning and, in the majority, complete cessation of catecholamine infusions. Patients with ESHF are the subgroup who would be most likely to require prolonged inotropic support. Encouragingly, Levo allowed us to discontinue dobutamine in all but one of the patients with ESHF. In those with acute heart failure, Levo clearly improved myocardial contractility, as evidenced by an increase in ventricular ejection fraction. In patients with longstanding myocardial dysfunction, however, we did not find a measurable improvement in contractility in the time frame reported.

The pharmacokinetics of Levo underpin the prolonged hemodynamic effects that result from a single-dose infusion regime. Although the plasma concentration of Levo decreases rapidly, its active metabolites continue to accumulate in the plasma for >48 hrs ^[6], and these have an elimination half-life of 75-78 hrs ^[7]. Several of our patients received multiple doses of Levo, at intervals of 1 ≥wk. Levo is an appealing alternative, or intermittent adjunct, to dobutamine therapy in children with chronic heart failure, especially those awaiting transplantation and those making slow progress after cardiac surgery. Through its non-β-adrenergic actions, Levo allows for interruption of catecholamine infusions, which may mitigate the tolerance or tachyphylaxis associated with these drugs, an approach that has been reported in adult patients ^[8]. Finally, its inotropic properties may be particularly desirable in children who are receiving β-blockers, for whom catecholamines may provide only limited benefit.

One child developed an arrhythmia that required cardioversion. A previous 24-hr electrocardiogram had demonstrated isolated premature ventricular beats, but the patient had never had documented sustained arrhythmias. His suitability for Levo was therefore in accordance with those used for the LIDO study in adults ^[4], and recent studies have suggested that Levo does not increase the risk of arrhythmias ^[9]. Levo was otherwise well-tolerated in our patients.

The current experience with Levo in infants and children with acute heart failure is limited to case reports ^[10]. Although we were limited to its use late into their illnesses, we were encouraged that Levo allowed weaning of catecholamines in our patients and resulted in objective improvement in myocardial performance. Clearly, formal studies will be necessary to delineate the role of Levo as treatment for, or prophylaxis of, a low cardiac output in children.

Our study has a number of limitations. First, this is a retrospective review, with a heterogeneous selection of patients. However, our data provide the ideal substrate to support formal, prospective studies of Levo in two of our most important patient groups. Second, again because of the nature of the review, supportive hemodynamic data are limited. In particular, echocardiographic assessment of diastolic myocardial performance (transmitral flow, or tissue Doppler) and measurement of cardiac output would be particularly useful. These issues could be addressed in a prospective pediatric study. Finally, the degree of sickness of most of our patients (all but three were ventilated during Levo) precludes us from giving further information regarding comparing functional status before and after Levo.

Conclusion

Levo was found to be a safe and useful drug when given to the sickest children with heart failure. Its longer duration of action enabled substantial reductions in the doses of other inotropes, and its administration was associated with measurable improvement in myocardial function in children with acute heart failure. The role of Levo in the management of acute and end-stage cardiac failure in children warrants formal, prospective evaluation.