Summary
Background
Children with dilated cardiomyopathy in advanced heart failure may spend a long time awaiting heart transplantation. Consequently, mechanical circulatory support is sometimes required as a bridge to transplantation. Levosimendan, a positive inotropic agent, has been reported to be safe and efficient for the treatment of paediatric heart failure.
Aims
To report our experience with levosimendan in children with decompensated dilated cardiomyopathy.
Methods
Paediatric patients with dilated cardiomyopathy on the transplant waiting list and with criteria for mechanical support were included in this single-centred retrospective study. Each patient received at least one 24-hour infusion of levosimendan before mechanical circulatory support was considered. Biological and echocardiographic data were analysed.
Results
Six patients were included over a 24-month period. The median age was 25.5 months (7.7–34.2 months); 82 infusions were performed. Median B-type natriuretic peptide concentration decreased significantly between days 0 and 2 (2443 ng/L [1458–3819 ng/L] vs 1358 ng/L [1025–2534 ng/L]; P = 0.003). While only a trend was noted in left ventricular ejection fraction improvement ( P = 0.054 by Simpson’s method and P = 0.068 by the Teicholz method), the subaortic velocity time integral rose significantly between days 0 and 8 (12.8 cm/s [10–14.5 cm/s] vs 15.3 cm/s [14.3–16.9 cm/s]; P = 0.041).
Conclusions
Levosimendan seems to improve haemodynamics in children with decompensated dilated cardiomyopathy; repeated infusions may delay the need for mechanical circulatory support while awaiting heart transplantation. This therapeutic agent should be systematically considered in this setting, in addition to conventional inotropic drugs.
Résumé
Contexte
Les enfants qui ont une cardiomyopathie dilatée en insuffisance cardiaque terminale et qui sont sur liste de transplantation cardiaque sont susceptibles d’attendre longtemps un greffon. Ainsi, le recours à une assistance mécanique circulatoire est parfois nécessaire lorsque l’état du patient ne lui permet plus d’attendre. Le levosimendan, inotrope positif, a précédemment été rapporté sûr et efficace pour le traitement de l’insuffisance cardiaque de l’enfant.
Objectifs
Rapporter notre expérience du levosimendan chez des enfants avec cardiomyopathie dilatée en insuffisance cardiaque terminale.
Méthodes
Ont été inclus, dans une étude rétrospective monocentrique, tous les enfants ayant une cardiomyopathie dilatée sur liste de transplantation cardiaque et avec des critères d’assistance circulatoire mécanique. Avant la mise sous assistance, chaque patient a au moins reçu une cure de levosimendan de 24 h. Les paramètres biologiques et échocardiographiques ont ensuite été analysés.
Résultats
Six patients ont été inclus sur une période de 24 mois. L’âge médian était de 25,5 mois (7,7–34,2). Quatre-vingt-deux infusions ont été réalisées au total. Le taux médian de BNP diminuait significativement entre j0 et j2 (2443 ng/L [1458–3819 ng/L] contre 1358 ng/L [1025–2534 ng/L] ; p = 0,003). Alors que seule une tendance à l’amélioration était notée pour la fraction d’éjection ventriculaire gauche ( p = 0,054 par la méthode de Simpson et p = 0,068 en Teicholz), l’ITV sous-aortique augmentait significativement entre j0 et j8 (12,8 cm/s [10–14,5 cm/s] contre 15,3 cm/s [14,3–16,9 cm/s] ; p = 0,041).
Conclusion
En considérant la possibilité de perfusions itératives, le levosimendan semble améliorer l’état hémodynamique de ces patients. Afin d’attendre au mieux un greffon cardiaque, le levosimendan devrait être systématiquement considéré dans cette indication et en association avec les traitements habituels.
Background
Dilated cardiomyopathy (DCM), with an annual incidence of 0.57 to 0.72 per 100,000 children, is the most common form of paediatric cardiomyopathy . Indeed, within the Pediatric Heart Transplant Study group, DCM accounts for 83% of all paediatric cardiomyopathy . This disease is caused by a variety of conditions: idiopathic, familial, neuromuscular disorders, post-myocarditis, chemotherapeutic drugs, metabolic disorders and ventricular non-compaction. Despite the use of conventional therapies, the prognosis for DCM has not changed appreciably in recent decades . DCM accounts for > 50% of indications for paediatric heart transplantation , which remains the gold standard therapy for end-stage heart failure. Because the wait for a transplant may be long, the use of mechanical circulatory support (MCS) is sometimes required as a bridge to transplantation, despite the use of conventional inotropic drugs.
Levosimendan, being a calcium sensitizer of cardiac troponin and an adenosine triphosphate-sensitive potassium agonist, improves myocardial contraction and allows relaxation of the vascular smooth muscle cells , which are responsible for coronary vasodilatation. Maximal haemodynamic effects of levosimendan have been shown to occur 1–3 days after starting the infusion and are sustained for at least a week. Although this positive inotropic agent has been widely investigated in adults , only a few studies have tested its use in children . Nevertheless, levosimendan has been shown to be safe and effective after paediatric cardiac surgery , especially in case of low cardiac output syndrome . These results have encouraged many European centres to use levosimendan routinely to prevent postoperative low cardiac output syndrome . In a population of children with DCM and chronic heart failure, the use of levosimendan was rarely reported , despite a shared perception of efficacy among physicians who tried it . Finally, one study has advocated rotative inotrope therapy, with levosimendan infusions, in children with decompensated heart failure .
Because of these promising results, levosimendan has been used frequently in our institution in the past few years. The aim of this study was to retrospectively evaluate the effects of levosimendan in children with DCM who were on the waiting list for heart transplantation.
Methods
Study design
This was a single-centred retrospective study. Over a period of 24 months (February 2010–January 2012), we enrolled all children with DCM in end-stage heart failure and listed for heart transplantation. Inclusion criteria were: patients aged < 18 years, in stage D according to the last paediatric classification of heart failure proposed by the International Society of Heart and Lung Transplantation , who were on the waiting list for heart transplantation, with, initially, indications for MCS, and who received at least one infusion of levosimendan before they had either a transplant or MCS. Indications for mechanical assistance–extracorporeal membrane oxygenation (ECMO) or any ventricular assist device (VAD)–were: left ventricular ejection fraction (LVEF) < 30% (by the Teicholz method and Simpson’s method); metabolic acidosis with a pH ≤ 7.30; and B-type natriuretic peptide (BNP) concentration > 500 ng/L, despite continuous conventional intravenous inotropic support (milrinone and epinephrine). Patients with DCM but without indications for MCS were excluded from the study. Biological and echocardiographic data were collected and analysed according to the levosimendan infusions. Continuation of conventional inotropic therapies was at the discretion of the physicians. All of our patients with DCM receive angiotensin-converting enzyme inhibitors, beta-blockers and diuretics.
Infusions of levosimendan
Because the use of levosimendan (Simdax ® ; Orion, Espoo, Finland) is limited to exceptional circumstances in France (a temporary certificate of use is delivered by the public health authorities), physicians had to obtain an informed consent form from the parents before the infusions. The patients received at least one continuous infusion of levosimendan at a dose of 0.2 μg/kg/min for 24 hours, without any loading dose. Use of further infusions was at the discretion of the physicians, on the basis of clinical, biological (BNP concentration) and echocardiographic arguments.
Serum analysis
Measurements of BNP concentration were requested by physicians according to their own practice. Depending on the size of the patient, venous samples were collected either in 1.3 mL K 3 EDTA microtubes (Sarstedt, Nümbrecht, Germany) or in 4 mL K 3 EDTA BD Vacutainer ® tubes (Beckton Dickonson, Franklin Lakes, NJ, USA). Blood samples were immediately transported to the laboratory after collection. BNP concentrations were measured in whole blood by a fluorescent immunoassay method (Biosite Diagnostic, San Diego, CA, USA) on a UniCel ® DxI 800 system (Beckman Coulter, Fullerton, CA, USA). Measurements were completed within 2 hours of sample collection.
Echocardiographic evaluation
Echocardiographic acquisitions were performed in the same manner three paediatric cardiologists experienced in echocardiography. Thus, for each patient, a single echocardiogram was acquired daily by the practitioner who was present in the unit. All images were acquired using a Vivid i ® system (GE Healthcare, Little Chalfont, UK). A 3S-RS or a 7S-RS transducer was used, depending of the age of the patient. LVEF was determined using two methods: the Teicholz method, using the M-mode in a parasternal long-axis view; and the Simpson’s method, in a two-dimensional apical four-chamber view. The subaortic velocity time integral was determined from an apical five-chamber view using the Doppler mode. Each echocardiographic acquisition was transferred and recorded on our institution’s network, and was later reviewed, using EchoPAC ® software (GE Healthcare, Little Chalfont, UK), by a fourth cardiologist who was blinded to the outcome of the patients. Because of the retrospective design of the study, no variability analysis (intra- or intervariability) was performed.
Statistical analysis
All the data, which were collected at the time of each infusion of levosimendan, were pooled to analyse the evolution of the different variables. All values are expressed as the median and first and third quartiles. We used a Mann-Whitney U test to compare values. The software package SPSS for Windows, version 17.0 (SPSS Inc., Chicago, IL, USA) was used for statistical calculations. P values < 0.05 were considered significant.
Ethics
The study was approved by our local ethics committee. A written consent form was not required, according to French law, because the studies were part of the regular management of the children. No examinations were performed only for the purpose of the study.
Results
During this period, of the 91 patients followed in our centre for paediatric DCM, only six were eligible for MCS and were included. Table 1 summarizes the characteristics of the study population. The median age at inclusion (i.e. at the time of the first infusion of levosimendan) was 25.5 months (7.7–34.2 months) and the median weight was 10.7 kg (5.5–13.5 kg). The sex ratio was 2:1 (four boys). At inclusion, all patients had a central venous line and inotropic support. Four patients had a skin-tunnelled central venous catheter (patients 1, 3, 5 and 6). None of the patients had respiratory support (invasive or non-invasive). The aetiology of DCM was idiopathic for four patients, immunological as a result of maternal systemic lupus for one patient and secondary to a myocarditis (Epstein-Barr virus) for the last patient. The immunological cardiomyopathy had been suspected since the foetal stage because of the detection of an atrioventricular block associated with ventricular dysfunction in the presence of lupic maternal antibodies. Autopsies of the explanted hearts confirmed the absence of myocarditis lesions in the three patients with idiopathic DCM and who could have been transplanted.
| Patient no. | Sex | Weight (kg) | Aetiology of DCM | Age at diagnosis | Age at inclusion (months) | Inotropic support | pH | BNP (ng/L) | Serum creatinine (μmol/L) | LVEF a (%) | Subaortic VTI (cm/s) | Normal subaortic VTI according to age (cm/s) b |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | 11.4 | Immunological (maternal lupus) | Prenatal | 37 | Milrinone | 7.28 | 6671 | 38 | 20 | 10.8 | 20.3–26.0 |
| 2 | M | 62 | Idiopathic | 15 years | 182 | Milrinone | 7.25 | 3421 | 85 | 15 | 12.8 | 23.3–29.7 |
| 3 | F | 4 | Idiopathic | 2 months | 2 | Milrinone | 7.30 | 4819 | 28 | 18 | 11.7 | 13.1–18.6 |
| 4 | M | 14.3 | Idiopathic | 2 years | 26 | Milrinone | 7.26 | 1415 | 38 | 24 | 12.5 | 20.1–25.6 |
| 5 | M | 3.3 | Idiopathic | 2 months | 2 | Milrinone | 7.30 | 11,878 | 44 | 22 | 13 | 13.1–18.6 |
| 6 | F | 10 | Post-myocarditis | 2 years | 25 | Dobutamine | 7.27 | 2243 | 23 | 21 | 11.5 | 20.1–25.6 |
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