eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Myocarditis, Viral

Edwin Rodriguez-Cruz, MD, Assistant Professor, Department of Pediatrics, San Juan Bautista Medical School and Medical Center; Consulting Interventional/Clinical Pediatric Cardiologist, Department of Pediatrics, Hospital El Maestro and San Juan Bautista Medical Center; Consulting Interventional/Clinical Pediatric Cardiologist, Department of Cardiology, Cardiovascular Center of Puerto Rico and the Caribbean and Veterans Affairs Hospital and Medical Center of Puerto Rico
Robert D Ross, MD, Co-Director of Pediatric Cardiology Fellowship Program, Department of Pediatrics, Division of Pediatric Cardiology, Professor, Children's Hospital of Michigan and Wayne State University

Updated: Nov 17, 2009

Introduction

Background

Myocarditis is an inflammatory disorder of the myocardium with necrosis of the myocytes and associated inflammatory infiltrate.¹ It is usually caused by a viral infection, particularly adenovirus and enterovirus infections (eg, coxsackievirus), although many infectious organisms commonly seen in infants and children have been implicated. Occasionally, myocarditis may be a manifestation of drug hypersensitivity or toxicity.

Hypersensitivity myocarditis. High magnification of myocardium with perivascular infiltrates rich in eosinophils. This patient had a clinical history compatible with drug-induced hypersensitivity myocarditis.

• Active myocarditis - Characterized by abundant inflammatory cells and myocardial necrosis
• Borderline myocarditis - Characterized by an inflammatory response that is too sparse for this type to be labeled as active myocarditis; degeneration of myocytes not demonstrated with light microscopy
• Nonmyocarditis

If an active or borderline inflammatory process is found, follow-up biopsy findings can be subclassified into ongoing, resolving, or resolved myocarditis.

Pathophysiology

Myocarditis generally results in a decrease in myocardial function, with concomitant enlargement of the heart and an increase in the end-diastolic volume caused by increased preload. Normally, the heart compensates for dilation with an increase in contractility (Starling law), but because of inflammation and muscle damage, a heart affected with myocarditis is unable to respond to the increase in volume.

In addition, inflammatory mediators, such as cytokines and adhesion molecules, as well as apoptotic mechanisms are activated. The progressive increase in left ventricular end-diastolic volume increases left atrial, pulmonary venous, and arterial pressures, resulting in increasing hydrostatic forces. These increased forces lead to both pulmonary edema and congestive heart failure. Without treatment, this process may progress to end-stage cardiac failure and death.

Frequency

International

Myocarditis is a rare disease. The World Health Organization reports that incidence of cardiovascular involvement after enteroviral infection is 1-4%, depending on the causative organism. Incidence widely varies among countries and is related to hygiene and socioeconomic conditions. Availability of medical services and immunizations also affect incidence. Occasional epidemics of viral infections have been reported with an associated higher incidence of myocarditis. Enteroviruses (eg, coxsackievirus, echovirus) and adenoviruses, particularly types 2 and 5, are the most commonly involved organisms.

Mortality/Morbidity

Studies give a wide spectrum of mortality and morbidity statistics. With suspected coxsackievirus B, the mortality rate is higher in newborns (75%) than in older infants and children (10-25%). Complete recovery of ventricular function has been reported in as many as 50% of patients. Some patients develop chronic myocarditis (ongoing or resolving), dilated cardiomyopathy, or both and may eventually require cardiac transplantation.

Race

No racial predilection is observed.

Sex

No sex predilection is observed in humans, but some research in laboratory animals suggests that the disease may be more aggressive in males than in females. Certain strains of female mice had a reduced inflammatory process when treated with estradiol. In other studies, testosterone appeared to increase cytolytic activity of T lymphocytes in male mice.

Age

No age predilection is noted. Younger patients, especially newborns and infants, and immunocompromised patients may have increased susceptibility to myocarditis.

Clinical

History

• Clinical presentation of viral myocarditis widely varies. In mild forms, few or no symptoms are noted. In severe cases, patients may present with acute cardiac decompensation and progress to death.
  • Heart failure: This is the most common presenting picture in all ages. The condition of patients who present with heart failure may rapidly deteriorate even with supportive care. Neonates and young children have higher mortality rates than older patients. Rapid supportive care with blood pressure support, afterload reduction, and control of arrhythmia may prevent early death.
  • Chest pain: Although rare in young children, this may be the initial presentation for older children, adolescents, and adults. Chest pain may be due to myocardial ischemia or concurrent pericarditis.
  • Arrhythmia: Patients can present with any type of dysrhythmia, including atrioventricular conduction disturbances. Sinus tachycardia is typical and the rate is faster than expected for the degree of fever present, which is typically low-grade. Junctional tachycardia is also seen and can be difficult to control medically.
  • Dilated cardiomyopathy: The debate continues over whether myocarditis progresses to dilated cardiomyopathy. Many investigators believe that dilated cardiomyopathy is a direct result of a previously burned-out myocarditis episode.
• Initial symptoms in infants include the following:
  • Irritability
  • Lethargy
  • Periodic episodes of pallor
  • Fever
  • Hypothermia
  • Tachypnea
  • Anorexia
  • Failure to thrive
• Older children present with similar symptoms and may experience lack of energy and general malaise.
• Parents may refer to a recent, nonspecific, flulike illness, GI symptoms, poor feeding, or rapid breathing.

Physical

Signs of diminished cardiac output, such as tachycardia, weak pulse, cool extremities, decreased capillary refill, and pale or mottled skin may be present. Heart sounds may be muffled, especially in the presence of pericarditis. An S₃ may be present, and a heart murmur caused by atrioventricular valve regurgitation may be heard. Hepatomegaly may be present in younger children. Rales may be heard in older children. Jugular venous distention and edema of the lower extremities may be present.

• Neonates
  • Neonates may seem irritable, be in respiratory distress, and exhibit signs of sepsis.
  • Somnolence, hypotonia, and seizures can be associated if the CNS is involved.
  • Hypothermia or hyperthermia, oliguria, elevated liver enzymes and elevated BUN and creatinine levels caused by direct viral damage, low cardiac output, or both may be present.
• Infants
  • Signs include failure to thrive, anorexia, tachypnea, tachycardia, wheezing, and diaphoresis with feeding.
  • In severe cases, low cardiac output may progress to acidosis and death.
  • End-organ damage may develop because of direct viral infestation or because of low cardiac output.
  • CNS involvement may also develop.
• Adolescents
  • Presentation may be similar to that of younger children but with a more prominent decrease in exercise tolerance, lack of energy, malaise, chest pain, low-grade fever, arrhythmia, and cough.
  • End-organ damage and low cardiac output may be present.

Causes

• Infecting organisms
  • Adenovirus and Ebstein-Barr virus have been considered the most common viruses that cause myocarditis. However, studies have found that, using polymerase chain reaction (PCR) for the diagnosis, parvovirus B19 and human herpesvirus-6 are the most frequent pathogens in patients with acute myocarditis.³
  • Infecting organisms include the following:
    • Coxsackievirus types A and B (especially type B)
    • Adenovirus (most commonly types 2 and 5)
    • Cytomegalovirus
    • Echovirus
    • Epstein-Barr virus
    • Hepatitis C virus
    • Herpes virus
    • Human immunodeficiency virus
    • Influenza and parainfluenza
    • Measles
    • Mumps, associated with endocardial fibroelastosis (EFE)
    • Parvovirus B19
    • Poliomyelitis virus
    • Rubella
    • Varicella
• Murine model
  • The coxsackievirus and adenovirus receptor acts as the receptor for the 4 most common viruses that cause human myocarditis: type C (type 2 and type 5) adenovirus and coxsackievirus B3 and B4.
  • Coxsackievirus B serotypes 1-6 have been associated with human myocarditis, but the most serious cases have been attributed to types 3 and 4.
  • In 1973, Lerner and Wilson developed an animal model of myocarditis using mice inoculated with coxsackievirus B3.⁴ This model was characterized by an early and a late phase. Following inoculation of the mice with the virus, initial replication of the virus occurred, with maximum replication within 3-5 days. By day 5, focal myocyte necrosis was evident. On day 7, most mice showed no further inflammation, and no organisms could be recovered; however, some mice showed ongoing worsening inflammation similar to that seen in humans.
  • The primary response to the early phase of viral infection is the release of natural killer (NK) cells, which lyse infected myocytes. This helps clear the virus from the system.
  • NK cells also induce expression of major histocompatibility complex antigens on myocytes by releasing cytokines, which prepare the NK cells to interact with T lymphocytes. Animal models depleted of NK cells develop a more severe form of myocarditis.
  • The late phase or second wave of T lymphocytes (CD4, CD8) begins approximately 1 week after the mouse has been inoculated with the virus. T lymphocytes can injure cells in the following 3 ways:
    • Stimulation of cytotoxic T cells
    • Production of antibody and antibody-dependent myotoxicity
    • Direct antibody and complement formation
  • These ongoing processes are considered genetically mediated autoimmune processes. Two different strains of cytolytic T cells have been recognized; one strain attacks virus-infected myocytes and the other strain attacks uninfected cells.
  • Enzymatic cleavage by viral proteins of cytoskeletal proteins appears to play a role in development of dilated cardiomyopathy.
  • Apoptosis appears to play a role in the development of dilated cardiomyopathy.
  • Various kinds of autoantibodies have been found in as many as 60% of patients with myocarditis. These include complement-fixing antimyolemmal antibodies, complement-fixing antisarcolemmal antibodies, antimyosin heavy chain antibodies, and anti–alpha myosin antibodies. Although their role in the disease is not completely understood, their presence may serve as a marker for diagnosing myocarditis in the future.

Differential Diagnoses

Other Problems to Be Considered

Medial necrosis of the coronary arteries
Shock

Workup

Laboratory Studies

The following studies are indicated for viral myocarditis:

• CBC count with differential
  • Acute anemia of any origin may cause heart failure, and chronic anemia exacerbates heart failure; both respond to blood transfusion.
  • The presence of lymphocytosis or neutropenia supports diagnosis of a viral infection.
• Blood cultures: Ruling out any bacterial infection is important.
• Sedimentation rate and C-reactive protein: These nonspecific markers of inflammation are usually elevated. However, a normal value does not rule out myocarditis, particularly in the presence of congestive heart failure, which may lower the sedimentation rate.
• Viral cultures: Nasopharyngeal and rectal swabs may help identify etiology.
• Viral titers: A 4-fold increase in a specific titer from the acute to convalescent phase is strong evidence of infection.
• In situ hybridization
  • This process identifies viral RNA in myocardial tissue of patients believed to have myocarditis.
  • The incidence of false-negative results is high.
• Polymerase chain reaction (PCR)⁵
  • PCR is used to find the viral genome in myocardial cells.
  • It is rapid, sensitive, and may become the test of choice for the diagnosis of viral myocarditis.
• Creatinine kinase–MB isoenzyme (CK-MB): These markers of myocardial damage are elevated most commonly when associated elevation of the ST segment on the ECG is present.
• Lactate dehydrogenase isoenzyme 1: This may be elevated in idiopathic myocarditis.
• Troponin I
  • This is another indicator of myocardial damage.
  • It is usually elevated up to a month after infection but is not specific for this disease.⁶

Imaging Studies

• Echocardiography
  • This is the most cost-effective test used for evaluation of myocardial function.
  • It is sensitive but not specific.
  • Findings include the following:
    • Global hypokinesis (the most common finding)
    • Increased left ventricular end diastolic and systolic dimensions
    • Left ventricular dysfunction, primarily systolic with decreased ejection fraction and shortening fraction
    • Segmental wall motion abnormalities
    • Pericardial effusion
• Chest radiography
  • Cardiomegaly and pulmonary edema may be depicted.
  • Incidentally noted cardiomegaly on chest radiography may be the initial presentation.
• Radionuclide imaging
  • This may be helpful as a screening tool.
  • Gallium citrate Ga 67 myocardial scintigraphy is useful to reveal chronic inflammatory processes. It is a sensitive test but is limited by its low specificity and predictive value.
  • Indium In 111 antimyosin antibody imaging is highly sensitive for myocardial necrosis, but has a high incidence of false-positive results. However, absence of antimyosin uptake is highly predictive of negative biopsy findings (92-98%).
  • Myocardial perfusion imaging with technetium Tc 99m–labeled labeled methoxyisobutyl isonitrile single-photon emission computed tomography (99mTc-MIBI SPECT) is usually a tool used to evaluate the severity of myocardial ischemia.⁷ Because the uptake and clearance of 99mTc-MIBI is affected by cell viability and membrane integrity, clinicians have recently used it as a marker for the severity of myocardial necrosis and inflammation in patients with myocarditis, with results comparable to those obtained with enzymatic cell damage markers.
• MRI: MRI with gadolinium is a newer technology to evaluate the cardiac muscle inflammation via a special protocol for myopericarditis.

Other Tests

• Electrocardiography (ECG)
  • In some patients with mild cardiac involvement, ECG changes may be the only abnormal findings suggestive of myocarditis.
  • Low-voltage QRS (<5 mm throughout the limb leads) is the classic pattern. Pseudoinfarction patterns with pathologic Q waves and poor progression of R waves in the precordial leads may also be present.
  • T-wave flattening or inversion is a common finding associated with small or absent Q waves in V₅ and V₆.
  • Left ventricular hypertrophy with strain may be present.
  • Other nonspecific findings include prolonged PR segment and prolonged QT interval.
  • Sinus tachycardia is the most common finding. Premature ventricular contractions and atrial tachycardias have been reported. Junctional tachycardia is common and may worsen congestive heart failure. Occasional second-degree and third-degree atrioventricular block may be present, requiring temporary pacing.
  • Ventricular tachycardia is commonly associated and may be the initial presentation.
• Other techniques: Other techniques are under investigation to determine a specific viral etiology of myocarditis, such as immunohistochemical stains, inflammatory mediators, and autoantibody measurements.

Procedures

• Biopsy is the criterion standard for the diagnosis of myocarditis.⁸ Myocardial biopsy findings establish diagnosis and classify disease stage.
• Biopsy is a relatively safe and effective way to sample heart muscle in older children; however, a risk of perforation in sick or younger infants is observed.
• The use of endomyocardial biopsy is controversial because of the possibility of a high false-negative result rate and because no proven therapy is available, even when a positive biopsy finding is obtained.
• Some advocate using radionuclide imaging techniques as screening tools before considering endomyocardial biopsy.
• Biopsy specimens may be useful for PCR diagnosis of viral etiology.

Histologic Findings

• Gross evaluation of the heart reveals flabby and pale muscle with petechiae. Ventricular muscle is usually thin and may be hypertrophied. Heart valves and the endocardium are not usually involved, but in cases of chronic myocarditis, they might appear as they appear in endocardial fibroelastosis. Some experts believe that endocardial fibroelastosis is a result of viral myocarditis.
• The microscopic hallmark of acute myocarditis is focal or diffuse interstitial infiltrate of mononuclear cells, lymphocytes, plasma cells, and eosinophils. Viral particles are rarely seen unless searched with special techniques (ie, PCR). Necrosis and disarrangement of the myocytes are typical and often are seen with coxsackievirus infection. In the chronic and healing stages, myocytes are replaced by fibroblasts (scar tissue).
• In adenoviral myocarditis, less severe infiltrate can be seen histologically than is seen in cases of enteroviral infection.

Treatment

Medical Care

In the acute phase of viral myocarditis, the patient should be admitted to the hospital, even if only mild signs of respiratory distress or congestive heart failure are present. Rapid progression to overt heart failure, hemodynamic collapse, or both may occur.

Medical care is aimed at minimizing hemodynamic demands of the body. No specific proven therapy is available to prevent the myocardial damage, but maintenance of tissue perfusion is the goal to avoid further complications. Normal arterial blood oxygen levels should be maintained with supplemental oxygen as needed.

Surgical Care

Extracorporeal membrane oxygenation (ECMO) has been used as an interim treatment to provide rest to the heart and as a bridge for transplant in selected patients with good results.

Consultations

Consultation with a cardiologist is indicated.

Diet

A low-salt diet is recommended for patients with congestive heart failure.

Activity

Bed rest is necessary during the acute phase of the illness and may slow the intramyocardial replication of the virus. Activity is permitted as partial or complete recovery is achieved.

Medication

If congestive heart failure is present in a patient with viral myocarditis, digitalis may be useful in maintaining adequate function. Diuretics can be given concomitantly to remove excess extracellular fluid and to decrease preload. Caution should be exercised because removal of fluid may cause low cardiac output and shock. A higher venous-filling pressure may be necessary to maintain an adequate cardiac output. Intracardiac pressure monitoring can facilitate maintenance of adequate filling pressures.

Inotropic agents are used when cardiac output cannot be maintained by less invasive measures. Dopamine, dobutamine, inamrinone (formerly amrinone), and milrinone are the most commonly used vasopressors.

Afterload reduction is most important in treating acute myocarditis and is used when hypotension is not present. This decreases the workload for the compromised myocardium and can allow patients to recover from the acute phase of illness. Agents that reduce afterload improve cardiac output by decreasing systemic arterial resistance. Intravenous medications such as nitroprusside, inamrinone, and milrinone can be replaced with oral ACE inhibitors when the patient stabilizes.

The use of immunosuppressive agents for the treatment of viral myocarditis is still controversial. Some animal studies revealed an exacerbation of viral cytotoxicity when treated with immunosuppressive agents. Other small series in humans have shown that the conditions of patients improve when the patients are treated with these agents. The Multicenter Myocarditis Treatment Trial aimed to establish differences in outcome among 3 treatment modalities.⁹ A total of 111 patients were randomized into one of the 3 following groups:

• Prednisone/azathioprine
• Prednisone/cyclosporine
• Conventional therapy without immunosuppression

Findings revealed left ventricular function and survival were not significantly different among the 3 groups.

Intravenous gamma globulin may be important in the treatment of acute myocarditis.^10,11 It has been associated with improved left ventricular function and improved survival.

New therapeutic agents are being studied as candidates for the treatment of myocarditis. These include agents that inhibit the virus entrance to the cells; antiviral agents that inhibit translation, transcription, or both; and interferon, among others. However, these strategies are still in early stages and, although they have promising results, some time may go by before they are widely accepted. Pleconaril, an investigational agent that inhibits viral attachment to host cell receptors, has a broad antienteroviral activity and, in clinical trials, has demonstrated benefit in children with enteroviral meningitis. This medicine is being tested in children with myocarditis. Pleconaril is currently an investigational drug from Schering-Plough Corporation.

Conventional management includes digoxin, diuretics, and afterload reduction. Severe cases with hemodynamic compromise may require intravenous inotropic agents, afterload reduction, vasodilators, and anticoagulation.

Cardiac glycosides

These agents may improve left ventricular function by increasing myocardial contraction by inhibiting the sodium/potassium adenosine triphosphatase (ATPase) pump. This leads to sodium accumulation within the myocyte, which stimulates the sodium-calcium exchange. The increased intracellular calcium increases the force of contraction.

Digoxin (Lanoxin)

Cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. Acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Dosing

Adult

Total digitalizing dose (TDD): 0.75-1.5 mg PO; 0.5-1 mg IV/IM
Divide TDD: Initially give 50% of TDD, and then give the remaining two 25% portions at 6- to 12-h intervals (1/2, 1/4, 1/4)
Maintenance dose: 0.125-0.5 mg PO; 0.1-0.4 mg IV/IM
Individualize dose based on levels

Pediatric

TDD PO:
Preterm infant: 20-30 mcg/kg
Term infant: 25-35 mcg/kg
1 month to 2 years: 35-60 mcg/kg
2-5 years: 30-40 mcg/kg
5-10 years: 20-35 mcg/kg
>10 years: 10-15 mcg/kg
TDD IV/IM:
Preterm infant: 15-25 mcg/kg
Term infant: 20-30 mcg/kg
1 month to 2 years: 30-50 mcg/kg
2-5 years: 25-35 mcg/kg
5-10 years: 15-30 mcg/kg
>10 years: 8-12 mcg/kg
Divide TDD: Initially give 50% of TDD, and then give the remaining two 25% portions at 6- to 12-h intervals (1/2, 1/4, 1/4)
Maintenance dose PO:
Preterm infant: 5-7.5 mcg/kg divided bid
Term infant: 6-10 mcg/kg divided bid
1 month to 2 years: 10-15 mcg/kg divided bid
2-5 years: 7.5-10 mcg/kg divided bid
5-10 years: 5-10 mcg/kg divided bid
>10 years: 2.5-5 mcg/kg qd
Maintenance dose IV/IM:
Preterm infant: 4-6 mcg/kg divided bid
Term infant: 5-8 mcg/kg divided bid
1 month to 2 years: 7.5-12 mcg/kg divided bid
2-5 years: 6-9 mcg/kg divided bid
5-10 years: 4-8 mcg/kg divided bid
>10 years: 2-3 mcg/kg qd

Interactions

Neomycin and phenytoin decrease the effects/levels of digoxin; drugs that increase the effects/toxicity/levels of digoxin include amphotericin B, erythromycin, cyclosporin, verapamil, calcium preparations, and itraconazole

Contraindications

Documented hypersensitivity; constrictive pericarditis; outflow tract obstruction; idiopathic hypertrophic subaortic stenosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

During periods of inflammation, myocardium may be sensitive to digitalis; TDD may need to be lowered based on drug concentrations obtained; adjust dose for patients with decreased renal function; dosing must be individualized and titrated; serum levels should be followed; this drug is arrhythmogenic and interacts with several drugs used commonly to treat arrhythmias; patients with hypokalemia, hypomagnesemia, hypercalcemia, and hypermagnesemia are predisposed to digoxin toxicity; CNS effects, such as drowsiness, and GI effects, such as nausea and vomiting, are some of the more common adverse drug reactions

Diuretics

Hypoperfusion of the kidneys causes retention of sodium and water, which produces peripheral and pulmonary edema. Diuretics decrease the intravascular volume overload.

Furosemide (Lasix)

This loop diuretic is the diuretic of choice in pediatric patients. Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.

Dosing

Adult

20-80 mg/d PO/IV/IM divided q6-12h

Pediatric

0.5-2 mg/kg/dose PO/IV/IM up to tid

Interactions

Pay special attention if given with aminoglycosides, cephalosporins, lithium, salicylates, ethacrynic acid, or indomethacin as concomitant administration with these medications may produce or worsen renal insufficiency; ototoxicity may be increased with concomitant administration of aminoglycosides

Contraindications

Documented hypersensitivity; hypokalemia; renal failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Potent diuretic that may cause profound diuresis and electrolyte loss; metabolic alkalosis is a common complication; should not be given in the same intravenous line with inamrinone since it may cause precipitation of the compounds; may cause renal stones, especially in premature newborns; concomitant administration of chlorothiazide may decrease the hypercalciuria; administer PO dose with food or milk to decrease stomach upset

Chlorothiazide (Diuril)

This is a thiazide diuretic. If given with furosemide, it may decrease hypercalciuria. Inhibits sodium reabsorption at the distal tubule in the kidney.

Dosing

Adult

500 mg to 2 g/d PO qd or divided bid
100-500 mg/d IV qd or divided bid

Pediatric

<6 months: 20-40 mg/kg/d PO divided bid; 2-8 mg/kg/d IV divided bid
>6 months: 20 mg/kg/d PO divided bid; 4 mg/kg/d IV divided bid

Interactions

Thiazide diuretics may decrease the effectiveness of anticoagulants, antigout agents, and sulfonylureas; effectiveness may be decreased by bile acid sequestrants, methenamine, and NSAIDs; thiazide diuretics may increase the toxicity of allopurinol, anesthetics, antineoplastics, calcium salts, diazoxide, digitalis, lithium, loop diuretics, methyldopa, muscle relaxants, and vitamin D; amphotericin B and anticholinergics may increase the toxicity of thiazide diuretics.

Contraindications

Documented hypersensitivity; anuria

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Safety of IV use in children has not been established; this drug can produce electrolyte imbalance; not to be given SC or IM

Spironolactone (Aldactone)

Potassium-sparing diuretic. Acts on the distal convoluted tubule of the kidney as an aldosterone antagonist.

Dosing

Adult

100-200 mg/d PO qd or divided bid

Pediatric

2-3 mg/kg/d PO divided bid/tid

Interactions

ACE inhibitors, cyclosporine, or potassium supplements increase risk of hyperkalemia; may increase the risk of digoxin toxicity; avoid salt substitutes or natural licorice

Contraindications

Documented hypersensitivity; hyperkalemia; hyponatremia; severe renal impairment; Addison disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause electrolyte imbalance, especially hyperkalemia; concomitant use with indomethacin or ACE inhibitors may cause hyperkalemia; main adverse effects are GI upset, hyponatremia, hyperkalemia, hepatotoxicity, lethargy, confusion, impotence and gynecomastia; spironolactone is carcinogenic in rodents

Angiotensin-converting enzyme (ACE) inhibitors

Cardiac output and systemic resistance determine blood pressure. When systemic resistance is decreased with afterload reduction, myocardial shortening and stroke volume improve. Therefore, cardiac output can be maintained at a lower heart rate with lower myocardial oxygen demand. ACE inhibitors decrease production of angiotensin II, a potent vasoconstrictor. High levels of angiotensin II have also been associated with cellular damage in patients with myocarditis.

Captopril (Capoten)

Reduces afterload and myocyte necrosis. Beneficial in all stages of chronic heart failure. Pharmacologic effects result in a decrease in systemic vascular resistance, reducing blood pressure, preload, and afterload. Dyspnea and exercise tolerance are improved.

Dosing

Adult

12.5-25 mg PO q8-12h; increase dose by 25 mg prn; not to exceed 450 mg/d divided tid

Pediatric

<6 months: 0.05-0.5 mg/kg/dose PO up to tid
>6 months: 0.5-2 mg/kg/dose PO up to tid
Test dose: 0.1 mg/kg/dose

Interactions

NSAIDs may reduce hypotensive effects of captopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases captopril levels; probenecid may increase captopril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity; pregnancy; unilateral renal artery stenosis is a relative contraindication

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Titrate to patient's tolerance and to effectiveness; decrease dose in renally impaired or volume depleted patients; may cause idiosyncratic hypotension after the first dose in children; test dose should be given and blood pressure monitored frequently after administration

Adrenergic agonist agents (inotropic agents)

Dopamine is a precursor to epinephrine, thus augmenting endogenous release of catecholamines. It also stimulates specific dopamine receptors. Dobutamine does not promote release of endogenous epinephrine. Dobutamine predominantly augments myocardial contractility via beta1 stimulation.

Dopamine (Intropin)

At lower doses, this drug stimulates beta1-adrenergic and dopaminergic receptors (renal vasodilation, positive inotropism); at higher doses, it stimulates alpha-adrenergic receptors (renal vasoconstriction).

Dosing

Adult

2-20 mcg/kg/min continuous IV infusion

Pediatric

Administer as in adults

Interactions

Effects are prolonged and intensified by MAOIs, alpha-blockers and beta-blockers, general anesthetics, and phenytoin

Contraindications

Documented hypersensitivity; outflow tract obstructions, such as subaortic stenosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypovolemia should be treated before infusion of this drug; extravasation should be treated promptly with SC administration of phentolamine (Regitine); administration through a central vein is recommended; do not use umbilical artery for infusion; if dosages >20 mcg/kg/min are required, a different agent should be considered (eg, epinephrine, dobutamine)

Dobutamine (Dobutrex)

Stimulates beta1-adrenergic receptors. It has less alpha1 stimulation than dopamine; therefore, it produces less increase in systemic vascular resistance.

Dosing

Adult

2-15 mcg/kg/min continuous IV infusion

Pediatric

Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects of dobutamine; general anesthetics may increase toxicity

Contraindications

Documented hypersensitivity; subaortic stenosis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Treat hypovolemia before infusion; treat extravasation promptly with SC administration of phentolamine (Regitine); administration through a central vein is recommended; do not use umbilical artery for infusion; may decrease central venous pressure (CVP) and wedge pressure

Cyclic adenosine monophosphate (c-AMP) phosphodiesterase inhibitors

Inotropic effects occur by inhibiting c-AMP phosphodiesterase, which increases the cellular levels of c-AMP. The sodium-potassium pump is not affected, as with digitalis. Vasodilatory activity is related to the direct relaxation effect on vascular smooth muscle.

Inamrinone - formerly amrinone (Inocor)

Produces vasodilation and increases inotropic state. More likely to cause tachycardia than dobutamine; may exacerbate myocardial ischemia.

Dosing

Adult

Loading dose: 0.75 mg/kg (undiluted) IV over 2-3 min
Maintenance dose: 5-10 mcg/kg/min IV; titrate to effect

Pediatric

Administer as in adults

Interactions

Furosemide should not be given in the same IV line as inamrinone because it may cause precipitation of the compounds; do not dilute in solutions containing glucose
Coadministration with diuretics, may result in hypovolemia and decrease in filling pressure; cardiac glycosides have additive effects on amrinone

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Like other inotropic agents, this drug may aggravate outflow tract obstructions; inamrinone should be monitored for hypotension, thrombocytopenia, and hepatotoxicity; GI symptoms, including nausea, vomiting, abdominal pain, and anorexia, are some of the more common adverse drug reactions

Milrinone (Primacor)

Bipyridine positive inotropic effect and vasodilator with little chronotropic activity. Different in mode of action from both digitalis glycosides and catecholamines.

Dosing

Adult

Loading dose: 50 mcg/kg (undiluted) IV over 10-15 min
Maintenance dose: 0.375-0.75 mcg/kg/min IV; titrate to effect

Pediatric

Administer as in adults

Interactions

Milrinone precipitates in presence of furosemide

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Like any other inotropic agent, this drug may aggravate outflow tract obstructions; use with caution in patients with a history of ventricular arrhythmias, atrial flutter, or atrial fibrillation; ventricular arrhythmias, supraventricular arrhythmias, hypotension, and headaches are some of the more common adverse drug reactions

Immunomodulatory agents

Immune globulin is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is comprised of 4 subclasses of antibodies, approximating the distribution of human serum.

Immune globulin (Carimune, Gammagard SD, Gammar-P, Gamunex, Polygam S/D)

Use of these agents in myocarditis is not widely accepted. Clinical studies have shown IVIG may improve left ventricular function and survival in children.

Dosing

Adult

2 g/kg IV as a single dose

Pediatric

Administer as in adults

Interactions

May interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

These agents may cause anaphylactic reactions, especially in IgA-deficient patients (procure low IgA product); flushing of the face, chills, nausea, dyspnea, and tachycardia, are the most common adverse effects seen with IVIG administration; other less common adverse effects include chest tightness, dizziness, fever, headache, and diaphoresis; initial infusion rate, maximum infusion rate, maximum concentration, and contraindications are based on the specific IVIG product; consult package insert

Follow-up

Further Inpatient Care

• Discharge patients with viral myocarditis when stable on oral medications.

Further Outpatient Care

• Monitor medication doses and adverse effects.
• Serial echocardiography is useful in monitoring ventricular function.

Inpatient & Outpatient Medications

• Medications include the following, when indicated:
  • Digitalis
  • Afterload reduction agents
  • Diuretics
  • Antiarrhythmics
  • Anticoagulants

Transfer

• Transfer to a facility with intensive and cardiology care may be required.

Deterrence/Prevention

• Limit patient activity until recovered.
• Avoid negative inotropes.
• Be aware of the possibility of further decrease in ventricular function.

Complications

• Arrhythmia
• Congestive heart failure
• Thromboembolism
• Further decrease in ventricular function
• Dilated cardiomyopathy

Prognosis

• Studies give a wide spectrum of mortality and morbidity statistics.
• With suspected coxsackievirus B, mortality rate is higher in newborns (75%) than in older infants and children (10-25%).
• Complete recovery of ventricular function has been reported in as many as 50% of patients.
• Some patients develop chronic myocarditis (ongoing or resolving), dilated cardiomyopathy, or both. Those who develop dilated cardiomyopathy may require a heart transplant.

Patient Education

• Restrict activity based on performance after the acute phase.

Miscellaneous

Medicolegal Pitfalls

• Failure to make a diagnosis

Special Concerns

• Viral myocarditis may be a fatal disease during pregnancy; however, pregnant women are not at a higher risk of developing viral myocarditis compared with the general population.

Multimedia

Media file 1: Hypersensitivity myocarditis. High magnification of myocardium with perivascular infiltrates rich in eosinophils. This patient had a clinical history compatible with drug-induced hypersensitivity myocarditis.

References

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Keywords

viral myocarditis, myocardium, adenovirus, enterovirus, coxsackievirus, active myocarditis, borderline myocarditis, drug hypersensitivity, Starling law, congestive heart failure, cardiac failure, chronic myocarditis, dilated cardiomyopathy, treatment, diagnosis

Contributor Information and Disclosures

Author

Edwin Rodriguez-Cruz, MD, Assistant Professor, Department of Pediatrics, San Juan Bautista Medical School and Medical Center; Consulting Interventional/Clinical Pediatric Cardiologist, Department of Pediatrics, Hospital El Maestro and San Juan Bautista Medical Center; Consulting Interventional/Clinical Pediatric Cardiologist, Department of Cardiology, Cardiovascular Center of Puerto Rico and the Caribbean and Veterans Affairs Hospital and Medical Center of Puerto Rico
Edwin Rodriguez-Cruz, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians-American Society of Internal Medicine, American Heart Association, American Medical Association, American Society of Echocardiography, Puerto Rico Medical Association, Society of Cardiac Angiography and Interventions, and Society of Pediatric Echocardiography
Disclosure: Nothing to disclose.

Coauthor(s)

Robert D Ross, MD, Co-Director of Pediatric Cardiology Fellowship Program, Department of Pediatrics, Division of Pediatric Cardiology, Professor, Children's Hospital of Michigan and Wayne State University
Robert D Ross, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Heart Association, and Society of Pediatric Echocardiography
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey Allen Towbin, MD, MSc, FAAP, FACC, FAHA, Professor, Departments of Pediatrics (Cardiology), Cardiovascular Sciences, and Molecular and Human Genetics, Baylor College of Medicine; Chief of Pediatric Cardiology, Foundation Chair in Pediatric Cardiac Research, Texas Children's Hospital
Jeffrey Allen Towbin, MD, MSc, FAAP, FACC, FAHA is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Cardiology, American College of Sports Medicine, American Heart Association, American Medical Association, American Society of Human Genetics, Cardiac Electrophysiology Society, New York Academy of Sciences, Society for Pediatric Research, Texas Medical Association, and Texas Pediatric Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Ameeta Martin, MD, Clinical Associate Professor, Department of Pediatric Cardiology, University of Nebraska College of Medicine
Ameeta Martin, MD is a member of the following medical societies: American College of Cardiology
Disclosure: Nothing to disclose.

CME Editor

Gilbert Z Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; Consulting Staff, Department of Pediatrics, Sound Shore Medical Center
Gilbert Z Herzberg, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Chief Editor

Stuart Berger, MD, Professor of Pediatrics, Division of Cardiology, Medical College of Wisconsin; Chief of Pediatric Cardiology, Medical Director of Pediatric Heart Transplant Program, Medical Director of The Heart Center, Children's Hospital of Wisconsin
Stuart Berger, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American College of Chest Physicians, American Heart Association, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

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