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Milrinone Therapy for Enterovirus 71-Induced Pulmonary Edema and/or Neurogenic Shock in Children

A Randomized Controlled Trial*

Chi, Chia-Yu MD1,2; Khanh, Truong Huu MD3; Thoa, Le Phan Kim MD3; Tseng, Fan-Chen PhD1; Wang, Shih-Min MD, PhD4,5; Thinh, Le Quoc MD3; Lin, Chia-Chun MSc1; Wu, Han-Chieh MSc1; Wang, Jen-Ren PhD5,6; Hung, Nguyen Thanh MD, PhD3; Thuong, Tang Chi MD3; Chang, Chung-Ming PhD1; Su, Ih-Jen MD, PhD1; Liu, Ching-Chuan MD, MPH2,5

doi: 10.1097/CCM.0b013e31828a2a85
Pediatric Critical Care
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SDC

Objective: Enterovirus 71-induced brainstem encephalitis with pulmonary edema and/or neurogenic shock (stage 3B) is associated with rapid mortality in children. In a small pilot study, we found that milrinone reduced early mortality compared with historical controls. This prospective, randomized control trial was designed to provide more definitive evidence of the ability of milrinone to reduce the 1-week mortality of stage 3B enterovirus 71 infections.

Design: Prospective, unicenter, open-label, randomized, controlled study.

Setting: Inpatient ward of a large tertiary teaching hospital in Ho Chi Minh City, Vietnam.

Patients: Children (≤18 yr old) admitted with proven enterovirus 71-induced pulmonary edema and/or neurogenic shock.

Interventions: Patients were randomly assigned to receive intravenous milrinone (0.5 μg/kg/min) (n = 22) or conventional management (n = 19). Both groups received dopamine or dobutamine and intravenous immunoglobulin.

Measurements and Main Results: The primary endpoint was 1-week mortality. The secondary endpoints included length of ventilator dependence and hospital stay and adverse events. The median age was 2 years with a predominance of boys in both groups. The 1-week mortality was significantly lower, 18.2% (4/22) in the milrinone compared with 57.9% (11/19) in the conventional management group (relative risk = 0.314 [95% CI, 0.12–0.83], p = 0.01). The median duration of ventilator-free days was longer in the milrinone treatment group (p = 0.01). There was no apparent neurologic sequela in the survivors in either group, and no drug-related adverse events were documented.

Conclusions: Milrinone significantly reduced the 1-week mortality of enterovirus 71-induced pulmonary edema and/or neurogenic shock without adverse effects. Further studies are needed to determine whether milrinone might be useful to prevent progression of earlier stages of brainstem encephalitis.

1National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.

2Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.

3Children’s Hospital No. 1, Ho Chi Minh City, Vietnam.

4Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.

5Center of Infectious Diseases and Signaling Research, National Cheng Kung University, Tainan City, Taiwan.

6Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.

*See also p. 1821.

Clinical Trial Registration:http://www.controlled-trials.com/ISRCTN76926623/76926623. Unique identifier: ISRCTN76926623.

Drs. Chia-Yu Chi and Truong Huu Khanh contributed equally.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by the National Health Research Institutes (NHRI-CL-097-SP01).

The authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: liucc@mail.ncku.edu.tw

© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins