Fulminant Myocarditis

Fulminant myocarditis is acute myocarditis with severe haemodynamic compromise: cardiogenic shock, refractory ventricular arrhythmia or heart block, usually appearing within days to 2 weeks of a viral prodrome and needing vasoactive drugs or mechanical support. The ventricle is often non-dilated with thickened walls from oedema.

Causes are viral (parvovirus B19, enteroviruses, adenovirus, human herpesvirus 6, influenza, SARS-CoV-2, HIV), and also giant cell myocarditis, eosinophilic myocarditis, immune checkpoint inhibitor myocarditis, systemic autoimmune disease and sarcoidosis, drug hypersensitivity, diphtheria, Chagas disease and rheumatic carditis.

Survivors of the acute phase often recover well, with long term transplant free survival higher than in non-fulminant disease, but in hospital mortality is about 20 to 40% and is lower when mechanical support is used early.

Severity grades (descriptive, not a validated score):

• Grade 1: haemodynamically stable with troponin rise, impaired ventricular function, or arrhythmia
• Grade 2: shock that responds to low dose vasoactive drugs
• Grade 3: refractory shock, recurrent ventricular arrhythmia, or multi-organ failure needing mechanical circulatory support
• Grade 4: cardiac arrest

Pathophysiology. Direct viral injury and a cytokine mediated immune response cause myocardial oedema, necrosis and stunning, with loss of contractility and arrhythmia. The injury is often reversible, so support to recovery is the goal.

• Prodrome of fever, myalgia, upper respiratory or gastrointestinal illness in the preceding 1 to 3 weeks, then rapid onset of dyspnoea, chest pain, palpitations, syncope or shock.
• Cool peripheries, tachycardia, hypotension, oliguria, third heart sound, pulmonary oedema, and raised venous pressure.
• ECG: ST elevation or depression, T wave inversion, low voltage, wide QRS, atrioventricular block, ventricular tachycardia or fibrillation.
• Rash, eosinophilia or drug exposure suggest eosinophilic or hypersensitivity disease. Ptosis or weakness suggests checkpoint inhibitor disease or myasthenia.

Red flags.

• Hypotension, lactate over 2 mmol/L, or oliguria
• Ventricular tachycardia, fibrillation or high grade atrioventricular block
• Ejection fraction under 30%, or right ventricular failure
• QRS over 120 ms or rising troponin
• Rash with eosinophilia, or immune checkpoint inhibitor exposure
• Persistent shock despite moderate dose vasoactive drugs

• Immediate. 12-lead ECG and continuous monitoring, high sensitivity troponin, natriuretic peptide, CRP, lactate, blood gas, creatinine, liver enzymes, full blood count with eosinophils, blood cultures, respiratory virus panel including SARS-CoV-2 and influenza, HIV and hepatitis testing.
• Echocardiography. Ejection fraction, wall thickness, regional pattern, right ventricle, effusion, valve function and thrombus.
• Coronary assessment. Angiography or CT coronary angiography to exclude acute coronary syndrome in adults with risk factors or ST elevation.
• Endomyocardial biopsy. Indicated in unexplained fulminant presentation, to exclude giant cell, eosinophilic and checkpoint inhibitor myocarditis, which change treatment. Complication rate is low in experienced hands (perforation about 0.1 to 0.5%). Cardiac MRI when stable enough, showing oedema and late gadolinium enhancement.
• Later workup: autoimmune screen, thyroid function, tuberculosis and Chagas serology in endemic regions.

Differential diagnosis.

• Acute myocardial infarction and spontaneous coronary artery dissection
• Takotsubo syndrome
• Septic and toxic cardiomyopathy
• Pulmonary embolism and tamponade
• Acute valvular catastrophe and aortic dissection
• Peripartum cardiomyopathy
• Thyrotoxic crisis and phaeochromocytoma crisis
• Decompensated dilated cardiomyopathy
• Giant cell and eosinophilic myocarditis
• Checkpoint inhibitor myocarditis
• Diphtheritic and Lyme carditis

Minutes 0 to 30: stabilise.

• Move to a cardiac intensive care unit in a centre with mechanical circulatory support. Apply defibrillator pads. Oxygen to a saturation of 94 to 98%, non-invasive ventilation for hypoxaemia, and intubation with vasopressors ready, because induction can precipitate arrest.
• Noradrenaline 0.05 microgram/kg/min intravenously, titrated to a mean pressure of 65 mm Hg, usual maximum 0.5 microgram/kg/min. Dobutamine 2.5 to 5 microgram/kg/min, maximum 20 microgram/kg/min, for low output, or milrinone 0.25 to 0.75 microgram/kg/min without a loading dose (reduce in renal impairment), with blood pressure and rhythm monitoring. Use the lowest effective doses, because catecholamines worsen myocardial injury and arrhythmia.
• Diuretics for pulmonary oedema only if blood pressure allows. Avoid beta blockers, negative inotropes and non-steroidal anti-inflammatory drugs in the acute phase.
• Defibrillate ventricular tachycardia or fibrillation. Amiodarone 150 mg intravenously over 10 minutes, repeated for recurrence, then 1 mg/min for 6 hours, then 0.5 mg/min for 18 hours, maximum 2.2 g in 24 hours. Contraindicated in severe sinus node disease and high grade atrioventricular block without pacing. Temporary pacing for high grade block.

Hours 1 to 6: escalate.

• Early mechanical circulatory support when shock persists on moderate vasoactive doses, lactate is rising, arrhythmia is refractory, or end organ function is falling: venoarterial extracorporeal membrane oxygenation, with percutaneous left ventricular unloading or a left ventricular assist device when the left ventricle distends. Early use before multi-organ failure improves survival to about 60 to 70%. On extracorporeal support or a percutaneous pump, give unfractionated heparin with the target set by the unit's circuit policy, and a lower anti-Xa target with bleeding.
• Cause directed therapy once samples are taken:
  • Methylprednisolone 500 to 1,000 mg intravenously once daily for 3 days in unexplained fulminant myocarditis while biopsy and viral studies are pending, and for giant cell, eosinophilic, sarcoid, autoimmune and checkpoint inhibitor disease. Evidence for steroids in lymphocytic viral myocarditis is limited. Follow with prednisolone 1 mg/kg orally once daily and tailor to the biopsy result.
  • Influenza: oseltamivir 75 mg orally twice daily for 5 days (30 mg twice daily at creatinine clearance 31 to 60 mL/min; 30 mg once daily at 11 to 30 mL/min).
  • Intravenous immunoglobulin 2 g/kg in total, given over 2 to 5 days, in some centres (evidence is limited). Contraindicated in IgA deficiency with anti-IgA antibodies. Risk of thrombosis, haemolysis and volume overload; slow the infusion and check creatinine in renal impairment.
  • Immunosuppression for giant cell or eosinophilic disease with methylprednisolone 500 to 1,000 mg intravenously once daily for 3 days, then prednisolone 1 mg/kg orally once daily, and ciclosporin 2 mg/kg orally twice daily (trough 150 to 250 ng/mL) for giant cell disease.

Hours 6 to 72 and beyond: recover and decide.

• Avoid permanent device implantation early, because arrhythmia and block often resolve within days to weeks. Use a wearable defibrillator or temporary pacing, and implant a pacemaker or defibrillator only after persistent block or arrhythmia beyond about 2 weeks, or when the cause is giant cell myocarditis or sarcoidosis.
• Wean support when ejection fraction recovers (usually in 1 to 2 weeks). When no recovery occurs in 2 to 4 weeks, assess for a durable ventricular assist device or transplantation.
• Heart failure therapy when stable and off inotropes: sacubitril/valsartan 24/26 mg orally twice daily, bisoprolol 1.25 mg orally once daily, spironolactone 12.5 mg orally once daily and dapagliflozin 10 mg orally once daily, titrated slowly with potassium and creatinine checks 1 to 2 weeks after each change.
• Exercise is stopped for 3 to 6 months and restarted only after normal ventricular function, biomarkers and ambulatory ECG, with cardiac MRI to assess scar.

Special groups. Pregnancy: delivery and mechanical support are decided with obstetric and cardiac teams, and steroids are used when indicated. Children: intravenous immunoglobulin 2 g/kg and milrinone are used, with weight based dosing under paediatric cardiology supervision.

Monitoring. Continuous ECG, arterial pressure, lactate, urine output, troponin and natriuretic peptide in intensive care. Daily echocardiography on support. Step down after at least 48 hours off vasoactive drugs and support, with no ventricular arrhythmia, and follow up with echocardiography at 1, 3 and 6 months, cardiac MRI at 3 to 6 months, and ambulatory ECG at 3 and 12 months.

Referral and escalation. Immediate transfer to a centre with extracorporeal support and transplantation. Notify the transplant team early for refractory cases.