Acute myocarditis is an uncommon condition in paediatric patients with an estimated incidence between 0.12% and 12%. These numbers increase at both ends of this age group, infancy, and adolescence, Reference Wu1–Reference Roeleveld and Mendonca3 and it may be underestimated due to the wide spectrum of clinical presentation. In fact, symptoms may vary from mild fever/fatigue to rapid cardiovascular collapse. Current evaluation of patients with suspected myocarditis includes electrocardiography, echocardiography, and cardiac MRI; however, the definitive diagnosis of acute myocarditis requires a histological analysis by endomyocardial biopsy.
At the worst end of the clinical spectrum, patients can rapidly develop severe heart failure refractory to maximal medical therapies. In these scenarios, the implant of mechanical circulatory devices like veno-arterial extra-corporeal membrane oxygenation is the best life-saving option after standard resuscitation manoeuvres have failed. This device restores normal perfusion while allowing organ function recovery and can be used as a bridge-to-recovery, bridge-to-bridge, or bridge-to-transplantation. Few studies have analysed the results of veno-arterial extra-corporeal membrane oxygenation in these patients, reporting a survival rate between 53.8% and 83.3%; Reference Wu1,Reference Rajagopal2 however, no previous paper described the clinical course of these young patients during a long-term follow-up.
Our aim is to investigate the patients’ in-hospital outcomes as well as their long-term results.
Methods
This is a single-centre retrospective study. The inclusion criteria were patient aged 0–18 years, definitive histological diagnosis of acute myocarditis through endomyocardial biopsy, and veno-arterial extra-corporeal membrane oxygenation implant due to refractory cardiogenic shock. All clinical and biochemical data were reviewed (echocardiographic data, arterial blood gas analysis, biochemical markers including Pro-B-type Natriuretic-Peptide, C-reactive protein, and creatine kinase). Follow-up data were gathered from outpatient clinical check and regional health database; data were complete and up to date in all cases.
Case series
Overall, 12 acute myocarditis paediatric patients (female 50%) with a median age of 9.69 years (IQR 0–18) received veno-arterial extra-corporeal membrane oxygenation support at our centre from January 2008 to December 2023. The median weight was 44 kg (IQR 4–89). Eleven patients (91.6%) were diagnosed with post-viral myocarditis, while in 1 (8.3%), the histological analysis showed giant cell myocarditis. In all patients, biopsy was performed within 48 hours from veno-arterial extra-corporeal membrane oxygenation implant.
Five patients (41.6%) had abnormal electrocardiographic findings: 4 patients (33.3%) had ST-elevation and 1 (8.3%) complete atrio-ventricular block; 6 patients (50%) showed elevated serum troponin T levels.
All patients on echocardiographic assessment presented an ejection fraction lower than 20%, moderate-to-severe mitral regurgitation, and moderate-to-severe right ventricle dysfunction, and 6 of them (50%) showed pericardial effusion.
All patients developed acute refractory cardiogenic shock, and 6 (50%) required cardiopulmonary resuscitation and 3 (25%) intra-aortic balloon pump insertion before veno-arterial extra-corporeal membrane oxygenation support.
Implant procedures were performed under general anaesthesia, and patients were supported by maximal inotropic infusion and mechanical ventilation for less than 24 hours prior to the initiation of the mechanical circulatory devices support.
All patients were treated by conventional heparin-based anticoagulation before implant. Anticoagulation monitoring during veno-arterial extra-corporeal membrane oxygenation support was obtained using the activated clotting time and the activated partial thromboplastin time, with target values > 180 s and > 55 s, respectively.
Seven patients (58.3%) received central veno-arterial extra-corporeal membrane oxygenation support between the right atrium and the ascending aorta, and 5 patients (41.6%) received peripheral cannulation, consisting in a femo-femoral access in 4 cases (33.3%) and carotid artery-femoral vein cannulation in 1 (8.3%). In 3 patients (25%), a left-heart vent was placed in the right superior pulmonary vein, and in 1 patient (8.3%), an Impella pump was implanted. We provided distal limb perfusion for patients with femoral artery cannulation. The median intraoperative time was 95 minutes (IQR 55–180).
Post-operatively, 6 patients (50%) developed acute kidney injury as 4 (33.3%) of them received hemofiltration. We registered 4 (33.3%) liver failures, 3 (25%) respiratory failures (1 pulmonary oedema and 2 prolonged intubation), 3 patients (25%) presented neurological events (1 subarachnoid haemorrhage and 2 ischaemic stroke), 3 patients (25%) underwent mediastinal re-exploration due to severe bleeding, and 2 patients (16.6%) developed major infections. We did not experience any device malfunction or clotting issues; however, due to failure to maintain adequate pump flow, 2 patients (16.6%) required change from peripheral cannulation sites (carotid artery/femoral artery) to central cannulation.
The median length of veno-arterial extra-corporeal membrane oxygenation support was 10 days (IQR 1–18), and the median ICU and hospital stays were 10 days (IQR 1–22) and 23 days (IQR 1–45), respectively. One patient (8.3%) received a left ventricular assist device 20 days after veno-arterial extra-corporeal membrane oxygenation support, and 1 patient (8.3%) underwent heart transplantation after 35 hours of veno-arterial extra-corporeal membrane oxygenation support. In-hospital mortality was 33.3% (4 patients): 3 patients died due to multi-organ failure and 1 because of brain death occurred 48 hours after implantation. At discharge, survivors showed good bi-ventricular function, normal lung capacity, and no chronic kidney disease. The median follow-up was 85 months (IQR 41.5–101.5). All patients were alive, in NYHA class I, and neither complications (cardiovascular, respiratory, renal, infective, or neurological) were observed during clinical examinations nor reported on the regional database.
All patients underwent echocardiography, and 4 of them (50%) underwent also an MRI. On echocardiography, the median left ventricular ejection fraction was 60% (IQR 55–70), left ventricle dimensions were normal in 7 patients (87.5%), while a mild dilatation was found in 1 (12.5%). Four patients (50%) presented a trivial mitral regurgitation.
Two patients (20%) were free from medical therapies, 4 patients (50%) were treated by beta-blockers, and diuretics and immunosuppressors were used in 2 and 3 patients, respectively.
Discussions
Acute myocarditis is an inflammatory disease characterised by a diffuse lymphocytic, eosinophilic, or giant-cells inflammatory infiltrate resulting in myocardial tissue degeneration or necrosis.
In the most severe circumstances, the only way to prevent imminent death is to support the patient’s circulation by inserting a veno-arterial extra-corporeal membrane oxygenation. This mechanical circulatory device is increasingly being used in the paediatric population, but its use for neonatal myocarditis is infrequent and still carries a high risk of complications and death. Reference Wu1–Reference Roeleveld and Mendonca3
In a study by Jung et al., Reference Jung4 among 17 patients with myocarditis, 13 were treated by extra-corporeal life support, 4 patients underwent veno-arterial extra-corporeal membrane oxygenation implantation within 24 hours after admission, and 3 of those died.
In another study by Lee et al. Reference Lee5 that reviewed data from patients diagnosed with acute fulminant myocarditis, it was observed that 75% of patients who did not survive veno-arterial extra-corporeal membrane oxygenation had support initiated more than 24 hours after admission, showing that an early mechanical circulatory device assistance results in better outcomes.
Our experience matches the results of these studies where veno-arterial extra-corporeal membrane oxygenation support was started within 24 hours after hospitalisation, suggesting that an early diagnosis and a prompt device implant are associated to a better prognosis.
It is important to underline that in this specific population, the diagnosis can be extremely difficult. Patients could initially be admitted to low-volumes hospital, where specific diagnostic tools and dedicated paediatric medical staff (i.e. MRI, congenital cardiologists, etc.) might not be always available. Furthermore, even stable patients can suddenly develop hemodynamic collapse in a few hours. Two of our patients (6 and 6.6 years of age) were initially admitted to a peripheral hospital, and after 6–12 hours since admission, their conditions started to deteriorate. In the first case, our veno-arterial extra-corporeal membrane oxygenation team rescued the patient at the peripheral centre implanting the device and accomplishing a safe transfer. Due to the development of an irreversible multi-organ failure, the child died after 48 hours of circulatory support. The second patient had multiple cardiac arrests during ambulance transport and was supported under cardiac resuscitation.
In our experience, the other two causalities happened in newborns: 71 and 11 days of life, respectively. At a very young age, as previously described, Reference Roeleveld and Mendonca3 it might be difficult to establish a correct diagnosis, hence, the institution of an appropriate treatment.
Truby et al. say that patients with severe left ventricular dysfunction under peripheral veno-arterial extra-corporeal membrane oxygenation support are at risk of left ventricular distension, intra-cardiac thrombosis, and pulmonary oedema. Therefore, left ventricular decompression is required: an intra-aortic balloon pump or Impella could be feasible depending on patient size, while in infants, direct left-heart venting may be the only possible solution.
Kotani et al. Reference Kotani7 used left atrial decompression in 12.9% (23/178) of their patients to improve left ventricular function and prevent pulmonary oedema; in our experience, left ventricular decompression by intra-aortic balloon pump, left-heart vent, or Impella was obtained in 58.3% of the overall cases.
Pulsatile mechanical circulatory device systems in paediatrics are being used more frequently to support children with myocarditis, and an improvement in outcomes for children with acute viral myocarditis has been documented in multiple single-center reports. Hetzer and colleagues Reference Hetzer8 demonstrated a significant increase, from 35% to 68%, in the use of ventricular assist devices in patients discharged from the hospital or bridged-to-transplant in two time frames, from 1990 to 1998 and from 1998 to 2004. In our group of patients, veno-arterial extra-corporeal membrane oxygenation support was a bridge-to-left ventricular assist device or transplantation in 16.6% of cases.
Compared to previous reports that evaluated mainly the in-hospital course, after veno-arterial extra-corporeal membrane oxygenation assistance in myocarditis patients, we focused also on the long-term results.
At a median follow-up of 85 months (IQR 41.5–101.5), we recorded no late deaths or episodes of hospital re-admission due to acute myocarditis-related complications (infections, heart failure, neurological events, liver or kidney dysfunction). The only patient who underwent heart transplantation did not have any complications and is on regular cardiology follow-up.
This important information confirms that, despite the need for veno-arterial extra-corporeal membrane oxygenation support, paediatric patients discharged following this disease continue normal growth, and the event does not impact their survival.
There are a few limitations in this work. First, it is a single-centre retrospective study involving a small number of cases, not sufficient to perform any statistical analysis. Second, we did not present data regarding inotropic supports or immunoglobulin therapies. Finally, the overall number of acute myocarditis admitted to our centre in the frame of time of this study is unknown.
Conclusion
In paediatric patients with refractory cardiogenic shock due to acute myocarditis, the prompt implant of veno-arterial extra-corporeal membrane oxygenation support improved the clinical conditions with a survival rate of 66.6%. In case of cardiac arrest at implant or very young age (newborn), mortality was increased.
During a long-term follow-up in discharged patients, no complication or death was observed, and a normal growth continued.
Acknowledgements
None.
Financial support
None.
Competing interests
None.
Ethical standard
The study was approved by the Institutional Review Board no. 654-17112020. Written informed consent was waived by the ethics commission of the designated hospital, in accordance with governmental regulations on observational retrospective studies.
