Therapeutic efficacy of milrinone in the management of enterovirus 71‐induced pulmonary edema

Abstract

Hand, foot, and mouth disease and herpangina are the major clinical manifestations of enterovirus 71 (EV71) infections. Brain-stem encephalitis and pulmonary edema are severe complications that can lead to death. This study was designed to evaluate the potential therapeutic effect of milrinone, a phosphodiesterase (PDE) inhibitor, in the treatment of patients with EV71-induced pulmonary edema. We conducted a historically controlled trial of 24 children with severe EV71-induced pulmonary edema from April 1998-June 2003 in southern Taiwan. Patients were divided into groups treated before and after the introduction of milrinone therapy. Etiological diagnosis was established by viral cultures and confirmed by specific immunofluorescence and neutralization tests. All 24 patients were below 5 years of age. The mortality was lower in the milrinone-treated vs. nontreated group (36.4% vs. 92.3%, P=0.005). Sympathetic tachycardia was decreased in patients treated with milrinone compared to controls (144 +/- 17/min vs. 206 +/- 26/min, P=0.004). A marked decrease in IL-13 (77 +/- 9 pg/ml vs. 162 +/- 88 pg/ml, P=0.001) was observed in milrinone-treated patients compared to controls. There was a significant reduction in white blood cell (10,838 +/- 4,537/mm3 vs. 19,475 +/- 7,798/mm3, P=0.009) and platelet (257 +/- 45 x 10(3)/mm3 vs. 400 +/- 87 x 10(3)/mm3, P=0.001) counts in milrinone-treated patients compared to controls. These results were associated with improvement in sympathetic regulation and decrease in IL-13 production. Milrinone therapy may provide a useful therapeutic approach for this highly lethal disorder.

Clinical Features and Management Outcomes of Severe Hand, Foot and Mouth Disease

“…In a smaller proportion of patients (32, 21.8%), amrinone, a cyclic nucleotide phosphodiesterase inhibitor, was used in the treatment of congestive heart failure. Although the effect of amrinone in treating heart failure following HFMD has not been prospectively studied, a retrospective analysis of a similar drug, milrinone, showed that in children with EV71-induced pulmonary edema milrinone treatment was associated with a reduced tachycardia and lower mortality [18]. …”

Acute Chemokine Response in the Blood and Cerebrospinal Fluid of Children with Enterovirus 71–Associated Brainstem Encephalitis

“…Overproduction of specific inflammatory cytokines, interleukin (IL)-10, IL-13, and interferon (IFN)-␥ is strongly associated with PE [8]. Administration of milrinone, a phosphodiesterase inhibitor, and intravenous immunoglobulin has been shown to decrease sympathetic overactivity, decrease inflammation, and improve survival in patients with EV71-associated PE [10,11]. Controlled clinical trials are needed to confirm this observation.…”

Enteroviral encephalitis in children: clinical features, pathophysiology, and treatment advances

“…Peripheral white cell and platelet counts and plasma IL-13 concentrations were also lower, which might indicate an immunomodulatory effect of the drug. 53,54 Use of large volumes for management of shock with EV 71 outbreaks in Asia, frequently precipitated PE. After it became clear that impaired cardiac function is an important contributor to shock, clinicians were more judicious in their use of intravenous fluids and used inotrope support.…”