Fulminant myocarditis

Article written and reviewed by Dr Luca Moretti

Fulminant myocarditis is a syndrome of rapidly progressive myocardial inflammation in which pump function becomes insufficient to maintain organ perfusion and requires inotropic, vasopressor or mechanical circulatory support. The definition is clinical and hemodynamic: a very low ejection fraction in a well-perfused patient is not sufficient by itself, whereas less conspicuous dysfunction with low cardiac output and arrhythmias may represent a fulminant form. In the ACC pathway, fulminant myocarditis falls within stage D because of hemodynamic instability; stage D is, however, broader and also includes forms with electrical instability requiring intervention.

Deterioration develops over hours or days, often after infectious or systemic prodromes, and combines dyspnea, pain, arrhythmias and signs of heart failure in varying proportions. Although diffuse edema and depressed contractility may be extraordinarily reversible, the useful window for preserving organs and sufficient myocardial mass is short. The therapeutic principle is therefore to support perfusion and oxygenation early, while biopsy and diagnostic testing proceed in parallel to identify an etiology capable of modifying immunotherapy, antimicrobial treatment and the probability of recovery.

The term fulminant does not identify a histologic subtype, because lymphocytic, giant-cell and necrotizing eosinophilic myocarditis, sarcoidosis, infectious forms and checkpoint inhibitor toxicity can all produce shock, while requiring different immunotherapies, antimicrobials and expectations of recovery. Endomyocardial biopsy is therefore part of urgent management and is not a test to be postponed until late failure to recover. Epidemiology remains uncertain because historical definitions selected different populations: the syndrome accounts for a minority of recognized acute myocarditis, but is overrepresented in shock and mechanical-support registries and has markedly higher rates of death or transplantation than nonfulminant acute forms with dysfunction. Among those who survive the critical phase, especially patients with lymphocytic patterns, recovery may nevertheless be rapid and far more complete than the initial severity would suggest.

The contrast between high early mortality and potential recovery requires avoiding both excessive delay before support, justified by the assumption that the disease may resolve spontaneously, and the opposite error of considering a severely depressed ventricle irreversible during the first few days. Decisions must integrate histologic subtype, hemodynamic trajectory, lactate, organ injury and early signs of recovery within a network linking the shock center, advanced heart-failure team, cardiac surgery, cardiovascular pathology and transplantation.

Etiology, Pathogenesis and Pathophysiology

Fulminant lymphocytic myocarditis may follow an infection or an immune activation in which no agent remains demonstrable. Cellular invasion, innate immunity and the T-cell response contribute to diffuse edema, cardiomyocyte injury and depressed contractility, but a substantial component of the latter results from cytokine-mediated inflammatory stunning and may therefore regress. Absence of viral genome in tissue modifies the assessment of immunosuppression, but does not by itself identify the mechanism or automatically demonstrate autoimmune pathogenesis.

Giant-cell myocarditis produces extensive necrosis with T lymphocytes, histiocytes and multinucleated giant cells, without the well-formed granulomas that characterize sarcoidosis. The process has a marked propensity for electrical involvement and often presents with ventricular tachycardia, block and shock; in the absence of combined immunosuppression, progression to death or transplantation may be rapidly destructive. A history of autoimmune disease increases suspicion when present, but in most cases there is no premonitory clinical marker, making biopsy decisive.

Necrotizing eosinophilic myocarditis combines diffuse infiltration, degranulation, necrosis and microthrombosis, but peripheral eosinophilia may be absent at presentation and, in the presence of shock, biopsy should not be delayed while waiting for it to appear; drugs, DRESS, EGPA, hypereosinophilic syndromes and parasitic infections are causes that must be investigated urgently. Checkpoint inhibitors, by removing PD-1/PD-L1- or CTLA-4-mediated inhibition, may instead release autoreactive T-cell clones and cause early myocarditis often associated with myositis, myasthenia and conduction disorders. In this phenotype troponin may be markedly elevated while ejection fraction is initially preserved and electrical instability precedes shock; combined checkpoint-inhibitor therapy carries a higher risk than monotherapy.

Regardless of subtype, loss of contractile force and compliance raises filling pressures; edema increases wall thickness without true hypertrophy, reduces distensibility and may limit stroke volume even in nondilated ventricles. The classic echocardiographic pattern of small cavities, thickened walls and severe dysfunction is suggestive but not universal. As cardiac output falls, activation of the sympathetic nervous system, renin-angiotensin system and vasopressin temporarily maintains pressure through vasoconstriction, at the cost of increased afterload and oxygen consumption, while tachycardia further reduces filling. Exogenous catecholamines may amplify arrhythmias and injury and should therefore be regarded as a short bridge, not the definitive response to progressive collapse.

Venous congestion and hypoperfusion reduce glomerular filtration, while hepatic congestion and low cardiac output cause cytolysis and coagulopathy and intestinal hypoperfusion impairs the barrier, amplifying inflammation. Lactic acidosis in turn reduces vascular responsiveness and contractility, closing a cycle of refractory shock that explains why prevention of multiorgan failure is the true rationale for early escalation. The right ventricle may fail because of direct involvement, hypoxia, positive-pressure ventilation or increased pulmonary vascular resistance, making a strategy that supports only the left ventricle inadequate; echocardiography and hemodynamics then help distinguish right-sided congestion, inadequate preload and increased afterload.

VA-ECMO returns flow to the aorta and supports oxygenation, but its retrograde component increases left ventricular afterload; if the ventricle cannot open the aortic valve, intracavitary pressure and stasis increase, promoting pulmonary edema and thrombosis. In these circumstances, decompression with an axial-flow pump, atrial septostomy or surgical venting may be necessary. The term ECMELLA describes the combination of ECMO and a microaxial pump, a flow-and-unloading strategy to be selected in experienced centers while accounting for the greater hemorrhagic, hemolytic and vascular risk.

Recovery requires resolution of edema, reduction of cytokine signaling, restoration of intracellular calcium handling and survival of sufficient myocyte mass. Absence of pulsatility during the first days does not prove irreversibility, which must be assessed through the trajectory of function, aortic valve opening, lactate and the amount of support required; conversely, extensive necrosis and aggressive histologic subtypes reduce the probability that the device can serve as a bridge to recovery.

Clinical Manifestations

The history should reconstruct above all the speed of deterioration, linking fever, respiratory or gastrointestinal symptoms, rash and arthralgia that appeared during the preceding days to subsequent dyspnea; a new drug or initiation of immunotherapy instead defines different etiologic windows. Chest pain may be present, but progressive fatigue and dyspnea often dominate, accompanied by extreme weakness, dizziness, confusion, somnolence, oliguria and abdominal pain as manifestations of low cardiac output. Dyspnea at rest, orthopnea and frothy cough indicate pulmonary edema, whereas nausea and anorexia may result from hepatic congestion or splanchnic ischemia; palpitations or syncope may precede cardiac arrest from ventricular tachycardia or fibrillation.

At triage, tachycardia, tachypnea, hypoxemia, cold or mottled skin and altered mental status must be interpreted together, remembering that hypotension may develop late in young people capable of intense vasoconstriction and that an apparently acceptable systolic pressure does not exclude shock if lactate rises and urine output collapses. Capillary refill time, peripheral temperature, pulse amplitude and pulse pressure provide immediate information on perfusion. Jugular venous distention, hepatomegaly and edema indicate right-sided congestion, whereas crackles and hypoxemia reflect increased pulmonary capillary pressure; a third heart sound and a new functional mitral murmur are common, whereas absence of a friction rub does not reduce suspicion of myocardial disease.

Bradycardia and atrioventricular dissociation indicate involvement of the conduction system, whereas progressive QRS widening may reflect diffuse edema and injury; in patients supported with VA-ECMO, complete block, VT/VF and a wide QRS have been associated with higher mortality. The ECG must therefore be read as a dynamic trajectory rather than a static classification. The hemodynamic phenotype may also be right-sided, left-sided or biventricular: right ventricular failure causes elevated jugular venous pressure, a tender liver and low output with relatively clear lungs, left ventricular failure causes pulmonary edema, and involvement of both combines the two physiologies, with immediate consequences for ventilation, fluid management and device selection.

In young children, irritability, poor feeding, tachypnea and pallor may be mistaken for sepsis, whereas hepatomegaly is often an early sign of heart failure; because infants have less reserve and require support more often, doses, cannulas and strategies must be managed by a dedicated pediatric team. Extracardiac findings can suggest the histologic subtype without replacing biopsy: rash and eosinophilia suggest hypersensitivity, asthma and neuropathy suggest EGPA, ptosis and weakness suggest a checkpoint-inhibitor overlap syndrome, and lymphadenopathy and pulmonary lesions suggest sarcoidosis. Their evaluation must proceed during stabilization and must not delay it.

The initial response to fluids may be misleading because a small bolus increases output when preload is inadequate, but repeated volumes in an edematous, stiff ventricle rapidly worsen congestion and edema. Every intervention must therefore be guided by ultrasound, venous pressure, perfusion signs and output dynamics. Rising lactate, increases in creatinine, transaminases, bilirubin and INR, or neurologic deterioration indicate progression toward multiorgan failure, and their trajectory determines urgency and prognosis more than ejection fraction alone; close serial reassessment identifies the point at which pharmacologic therapy is no longer sufficient.

Investigations and Diagnosis

Investigations must proceed simultaneously with resuscitation, using continuous ECG, blood gas analysis, lactate, troponin, natriuretic peptide, complete blood count with differential, electrolytes, renal and hepatic function, coagulation tests and CK to define injury, severity and possible overlap syndromes; when feasible without delaying therapy, blood cultures and microbiologic samples are obtained before antimicrobials. Bedside echocardiography is repeated to follow chamber size, wall thickness, ejection fraction, VTI, right ventricular function, regurgitation, effusion, aortic valve opening and stasis and, during VA-ECMO, to detect left ventricular distention and the need for unloading. Because function is strongly load-dependent, it should not be interpreted separately from device flow and vasoactive drugs.

Exclusion of acute coronary syndrome, pulmonary embolism, aortic dissection, tamponade, acute valvular regurgitation and sepsis is immediate, and coronary angiography may be performed in the same setting as biopsy when age, ECG or the clinical picture requires it; cardiac arrest with ST elevation should not be attributed to myocarditis before an occlusion has been excluded. An arterial catheter allows continuous blood-pressure measurement and central access permits drug administration and venous oxygen saturation measurement, whereas a pulmonary artery catheter may clarify output, filling pressures, vascular resistance and right ventricular involvement in complex cases. Invasive hemodynamics is useful only when the data change device selection or escalation and should not become a cause of delay in initiating support.

Endomyocardial biopsy is performed urgently and, when safe, before immunosuppression, assigning multiple specimens to histology, immunohistochemistry, microscopy and PCR and selecting the access route and sampling site according to experience and the distribution of involvement. Demonstration of giant cells, eosinophils, granulomas or a lymphocytic infiltrate changes treatment and prognosis. CMR retains major value but is deferred until transport, monitoring and device compatibility are safe, often after initial stabilization; edema and LGE define extent and alternative diagnoses, but a positive CMR does not replace etiologic biopsy in shock.

18F-FDG PET is not a first-line test in shock, but after stabilization it may support suspicion of sarcoidosis and identify safer extracardiac sites for biopsy; CT of the chest and abdomen instead evaluates for malignancy, lymphadenopathy, infection and complications, always adapting imaging to the clinical question and patient stability. No single diagnostic criterion justifies waiting for completion of all testing. According to the AHA, ESC and ACC, the fulminant syndrome combines suspicion of myocarditis with shock or instability requiring support, whereas confirmation of the histologic subtype depends on tissue: the working diagnosis and causal characterization must therefore advance in parallel.

Severity is followed through lactate, urine output, mental status, pH, venous oxygen saturation, cardiac output, vasoactive-drug doses and organ function; a generic shock score may facilitate communication but does not replace the phenotype or hourly evolution, and no isolated parameter should delay a multidisciplinary decision. During support, diagnosis extends to the complications that must be identified to keep the bridge safe, monitoring hemolysis, platelets, fibrinogen, anticoagulation, limb perfusion and neurologic status. Vascular ultrasound verifies cannulas and distal flow, whereas brain imaging is indicated in the presence of deficits or failure to awaken.

Treatment and Prognosis

The first objective is to maintain perfusion pressure and oxygenation, using norepinephrine for vasoplegia and hypotension and, when necessary, dobutamine or milrinone to increase cardiac output, at the lowest doses and for the shortest possible time. Progressive escalation of vasoactive drugs without improvement in lactate indicates the need to move to mechanical support. Noninvasive ventilation can reduce work of breathing and left ventricular afterload in selected patients, whereas severe edema, shock, arrhythmias or altered mental status require intubation; because induction can precipitate collapse by reducing preload and sympathetic tone, it must be planned with vasoactive drugs and a team ready for support, while also limiting pressures that would increase right ventricular afterload.

VA-ECMO is rapidly deployable, supports both ventricles and provides oxygenation, making it indicated in refractory shock, cardiac arrest or rapidly accelerating deterioration; however, it requires anticoagulation, vascular monitoring, distal perfusion of the cannulated limb and surveillance for left ventricular distention. A microaxial pump unloads the left ventricle and increases antegrade output, but does not provide oxygenation and may be inadequate in right ventricular failure; its combination with ECMO provides flow and unloading at the cost of greater hemorrhagic, hemolytic and vascular risk. Device, combination and timing must be selected on the basis of individual physiology, not the center's habitual preference.

Temporary pacing treats hemodynamically significant block, whereas VT and VF require defibrillation together with correction of hypoxia, acidosis and electrolyte abnormalities; amiodarone is frequently used and beta-blockers or other negatively inotropic drugs are avoided in shock. Recurrent arrhythmia may reflect inadequate support, ischemia or interaction with cannulas and its mechanism should be investigated. Immunosuppression depends on etiology: giant-cell myocarditis requires a corticosteroid combined with other immunosuppressive agents, often from the outset, whereas necrotizing eosinophilic and checkpoint inhibitor-associated myocarditis require early high-dose corticosteroids and targeted escalation if refractory. In lymphocytic myocarditis without a defined cause, evidence for empiric immunotherapy is much less certain and the value of biopsy becomes greatest.

Broad-spectrum antibiotics are justified when sepsis or bacterial infection cannot be excluded in shock and are subsequently de-escalated according to cultures and diagnosis; specific antimicrobials treat diphtheria, Lyme disease, rickettsial infections, fungal infections or parasitic infections in the appropriate settings, coordinating immunosuppression with infectious prophylaxis and surveillance. Renal and hepatic function must be supported while avoiding fluid overload, with ultrafiltration or renal replacement therapy to control volume, acidosis and electrolytes when necessary. Early enteral nutrition is preferable when intestinal perfusion is adequate, whereas glycemia, temperature, blood products and anticoagulation are managed by balancing metabolism, circuit thrombosis and bleeding.

Weaning is considered when pulsatility, aortic valve opening, VTI, biventricular function, lactate and organ function improve even at reduced flows; trials are conducted with echocardiography and a multidisciplinary team because early removal exposes the patient to relapse whereas excessive continuation increases complications. Failure to recover opens the pathway toward durable VAD support or transplantation. Prognosis depends on histologic subtype: lymphocytic forms that survive shock may recover remarkably, whereas giant-cell and necrotizing eosinophilic myocarditis carry a higher risk of death or transplantation; age, cardiac arrest, lactate, neurologic injury, multiorgan failure and duration of shock further worsen outcome. Support provides the greatest benefit when started before extracardiac injury becomes irreversible.

After hemodynamic recovery, heart-failure therapy, CMR, arrhythmia monitoring and rehabilitation continue, because normalization of ejection fraction does not exclude scar or recurrence and residual risk depends on the cause. Immunosuppression is titrated by integrating histology, imaging and biomarkers, while prolonged follow-up accompanies return to work and physical activity and evaluates the less visible consequences of intensive care.

Complications

Multiorgan failure is the main complication of prolonged shock because renal injury, hepatic cytolysis, coagulopathy, intestinal ischemia and encephalopathy progressively reduce both the probability of recovery and access to transplantation; early treatment of low cardiac output is therefore organ therapy as well as cardiac therapy. Cardiac arrest and arrhythmias may add hypoxic brain injury, making temperature control, multimodal neurologic prognostication and prevention of secondary hypoxia and hypotension essential. An assessment performed too early after sedatives or hypothermia risks overestimating neurologic irreversibility.

VA-ECMO may cause bleeding, hemolysis, thrombosis, infection, limb ischemia and Harlequin syndrome, while retrograde flow increases afterload and promotes left ventricular distention, pulmonary edema and intracardiac thrombi; timely monitoring and unloading can prevent some of these consequences. Microaxial pumps add risks of hemolysis, aortic regurgitation, valvular injury, migration and vascular complications, and incorrect positioning reduces flow while increasing trauma. Echocardiography and device signals guide correction, whereas combining multiple support devices makes anticoagulation management particularly complex.

Pacing and catheters increase the risk of perforation, tamponade, infection and thrombosis, while biopsy may cause effusion, arrhythmias or valvular injury; in experienced centers this risk remains acceptable relative to the therapeutic impact and can be further reduced by coordinating access and sampling. Immunosuppression instead exposes patients to opportunistic infections, reactivations, cytopenias, hyperglycemia and organ toxicity, making prophylaxis, screening and monitoring proportional to intensity and duration. Because distinguishing myocarditis from sepsis may remain difficult in shock, even appropriate immunologic therapy does not eliminate the need for microbiologic surveillance.

Failure to recover leads to durable support or transplantation, but active infection, malignancy, neurologic injury and multiorgan failure may limit both options; transplant evaluation should therefore begin early rather than after weeks of ineffective support. In giant-cell myocarditis the disease may recur in the graft and requires specific surveillance. Even after weaning, ventricular dysfunction, mitral regurgitation or right ventricular failure may persist, together with intensive care unit-acquired weakness, neuropathy and sarcopenia; rehabilitation must therefore be multidisciplinary, because hospital survival does not equal complete functional recovery.

Residual scar maintains the risk of ventricular tachycardia and sudden death, so monitoring, CMR, selective electrophysiologic study and the decision regarding a defibrillator are deferred long enough to observe recovery without leaving a high-risk patient unprotected; in appropriate cases, a wearable device can serve as a bridge. Recurrence of inflammation is possible especially in autoimmune causes, sarcoidosis, giant-cell myocarditis, checkpoint inhibitor-associated forms and genetic substrates. A new rise in troponin requires distinguishing recurrence, ischemia, rejection and device-related injury, whereas maintenance therapy must be defined by the cause and not by the severity of the index episode alone.

Death may result from refractory shock, arrhythmia, hemorrhage, thrombosis, infection or neurologic injury, often through the interaction of multiple mechanisms. An organized network reduces transfer delays, makes biopsy and support available and connects the patient promptly to the transplant program; in fulminant myocarditis, time and coordination therefore represent genuinely modifiable prognostic determinants.