Pediatric Cardiac Intensive Care Society 2014 Consensus Statement

Pharmacotherapies in Cardiac Critical Care Immune Therapy

Rakesh K. Singh, MD, MS; Timothy Humlicek, PharmD; Aamir Jeewa, MD3; Keith Fester, PharmD, BCPS

Disclosures

Pediatr Crit Care Med. 2016;17(S1):S69-S76. 

In This Article

Myocarditis

Introduction

Myocarditis is an inflammatory condition of the myocardium with resultant myocardial damage in the form of necrosis and/or degeneration that leads to myocardial dysfunction.[1–3] The true prevalence of myocarditis is difficult to estimate as the current diagnostic testing lacks a high degree of sensitivity or specificity for establishing the diagnosis in suspected cases. Current data report myocarditis prevalence of 1 per 100,000 children.[4] The most common etiology for myocarditis is virally mediated. Most common causes of viral myocarditis include enteroviruses (coxsackie B), adenovirus, parvovirus, Epstein-Barr virus, cytomegalovirus, and human herpesvirus-6.[1,5] Less commonly seen are episodes of myocarditis that are caused by bacterial infections, autoimmune disorders, or drug reactions.[6] The clinical presentation can be varied with asymptomatic cases to those with florid heart failure symptoms, which include abdominal pain, respiratory distress, tachypnea, tachycardia, hepatosplenomegaly, exertional fatigue, arrhythmias, and even sudden death.[5,7] Diagnostic testing includes electrocardiogram with a wide of variety of conduction abnormalities ranging from sinus tachycardia to ventricular tachycardia to complete heart block.[7,8] Cardiac biomarkers have provided some utility in the determining myocarditis versus dilated cardiomyopathy. Echocardiography can help grade the level of ventricular dysfunction and rule out other etiologies such as anomalous left coronary artery from the pulmonary artery and dilated cardiomyopathy.[9] Endomyocardial biopsy has been perceived as the gold standard for making the diagnosis of myocarditis; however, it is a procedure infrequently done in children due to its invasive nature.[2,5] The role of cardiac MRI has increased recently as there are changes seen with the increase in myocardial edema that is reflected by late gadolinium enhancement.[1] However, in cases that are too unstable to perform either endomyocardial biopsy or MRI requiring general anesthesia, the diagnosis is made on clinical findings alone.

Immunomodulatory Treatments

Corticosteroids. As with many immunomodulatory treatments for myocarditis, there is an overall lack of large randomized controlled trials (RCT) evaluating the efficacies of each therapy. Intuitively, corticosteroids would seem to have an overall benefit as they are often used for their anti-inflammatory effects. However, a Cochrane Database review of corticosteroid use in eight RCTs, which included both pediatric and adult studies (n = 719), found no difference in mortality in the corticosteroid groups and the control groups. However, the corticosteroid group did have a higher left ventricular ejection fraction (LVEF) and a decrease in cardiac biomarker (creatinine kinase-MB) although overall these studies were determined to be of low quality and of small sample size.[10] Challenges occur in determining the effect of corticosteroids alone as they are often used in combination with other immunosuppressive agents.[11,12]

Corticosteroids decrease inflammation by suppression of migration of neutrophils and reversal of increased capillary permeability. In addition, they suppress the immune system by reducing activity and volume of the lymphatic system.

The usual dose of corticosteroids for myocarditis is 0.5–2 mg/kg/d divided 1–4 times/d. The European Society of Cardiology Trial on the efficacy of immusouprrsive therapy in patients with virtu-negative inflammatory cardiomyopathy trial used 1 mg/kg/d for 4 weeks and then reduced to 0.33 mg/kg/d over the next 5 months in combination with azathioprine.[13] Parrillo et al[14] used 60 mg/d for 3 months and another used 50 mg/d for the first 2 weeks and followed by a 10-mg/wk taper until discontinued. Overall, an approximate 1 mg/kg/d would be similar to the prior adult studies that used corticosteroids alone. Common side effects of corticosteroids at these dosages are hypertension, adrenal insufficiency, diabetes, fluid retention, peptic ulcers, muscle weakness, and psychic derangements.

IV Immunoglobulin. The use of IV immunoglobulin (IVIG) is highly controversial in the treatment of pediatric myocarditis. To date, there is no pediatric RCT for its use and much of the evidence is based on retrospective analysis. The International Myositis Assessment and Clinical Study was an RCT in which 62 adults with biopsy and clinical evidence of myocarditis were studied upon receiving IVIG. This study showed no difference in mortality or LVEF between the IVIG group and the control group.[15] Drucker et al[16] conducted a multicenter retrospective review of pediatric myocarditis cases and found no survival benefit in 21 children treated with IVIG when compared with 25 in the control group. This study did show an overall decreased LV end-diastolic dimension in the IVIG group. Prasad and Chaudhary[17] studied 28 pediatric patients in whom 12 received IVIG when compared with 16 controls and again showed no difference in mortality (two deaths in the IVIG group and seven in the control group). However, there was significant improvement in LVEF, end-diastolic dimension, and heart block/arrhythmia. In addition, Klugman et al[18] reviewed the Pediatric Health Information System database with regards to the diagnosis of myocarditis and the IVIG use between 2006 and 2011. Over this 5-year span, 216 cases were identified and there was no difference in survival as well between groups. However, data from registries such as Pediatric Health Information System are highly dependent on accurate documentation, and that the endpoint occurred during the same admission. A Cochrane database review of the IVIG use in pediatric and adult myocarditis could only review the previously mentioned IMAC study as it was the only study to meet criteria for inclusion, highlighting the paucity of data available to make an accurate assessment of the role of IVIG in myocarditis.[19]

IVIG suppresses the immune response. In addition, IVIG may replace antibodies, enhance viral clearance, neutralize pathogens, and enhance clearance of inflammatory cytokines that contribute to myocyte destruction. The usual dose of IVIG for myocarditis is 2 g/kg/dose once. Common side effects of IVIG at this dosage are headache, fatigue, rash, pruritis, nausea, diarrhea, vomiting, fever, arthralgias, and hypersensitivity reactions (including anaphylaxis).

Cyclosporine/Azathioprine. There is a significant challenge in determining the effects of immunosuppression agents as often a combination approach is used as discussed above. The Myocarditis Treatment Trial studied the role of immunosuppression in adults with myocarditis and found no benefit among patients treated with azathioprine and prednisone, cyclosporine and prednisone, and conventional therapy.[11] The TIMIC study was an RCT in 85 adults with virus-negative myocarditis, which studied the role of prednisone and azathioprine for 6 months when compared with a placebo group. This study noted significant improvement in LVEF and a decrease in LV dimensions when compared with the placebo group.13 However, no such pediatric data exist to date.

Cyclosporine inhibits interleukin (IL)-2 production, and azathioprine is a purine synthesis inhibitor. The mechanism of action and side effect profiles is detailed in the transplant medication section. No myocarditis-specific dosing exists for either cyclosporine or azathioprine. In TIMIC, a 2-mg/kg/d dose of azathioprine was used for 6 months.

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