Milrinone Therapy for Enterovirus 71-Induced Pulmonary Edema and/or Neurogenic Shock in Children: A Randomized Controlled Trial* Chia-Yu Chi, MD'-^; Truong Huu Khanh, MD'; Le Phan Kim Thoa, MD^; Fan-Chen Tseng, PhD'; Shih-Min Wang, MD, PhD*^; Le Quoc Thinh, MD-^ Chia-Chun Lin, MSc'; Han-Chieh Wu, MSc'; Jen-Ren Wang, PhD'-^^; Nguyen Thanh Hung, MD, PhD^; Tang Chi Thuong, Chung-Ming Chang, PhD'; Ih-Jen Su, MD, PhD'; Ching-Chuan Liu, MD, Objective: Enterovirus 71-induced brainstem encephalitis pulmonary edema and/or neurogenic shock (stage 3B) is associ- ated 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-weekmortality of stage 3B enterovirus 71 infections. Design: Prospective, unicenter, open-label, randomized, con- trolled study. 'See also p. 1821. ^National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan. ^Department of Pediatrics, National Cheng Kung University Hospital, Col- lege of Medicine, National Cheng Kung University, Tainan City, Taiwan. ^Children's Hospital No. 1, Ho Chi Minh City, Vietnam. •"Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan. ^Center of Infectious Diseases and Signaling Research, National Cheng Kung University, Tainan City, Taiwan. ^Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan. Clinical Trial Registration: http://www.controlled-trials.com/ISRCTN 76926623/76926623. Unique identifier: ISRCTN76926623. Drs. Chia-Yu Chi and Truong Huu Khanh contributed equally. Supplemental digital content is available for this article. Direct URL cita- tions 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 Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.ObOI 3e31828a2a85 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 intra- venous milrinone (0.5 |ig/kg/min) {n = 22) or conventional man- agement (n = 19). Both groups received dopamine or dobutamine and intravenous Immunoglobulin. Measurements and Main Resuits: 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 con- ventional 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 progres- sion of earlier stages of brainstem encephalitis. {Crit Care Med 2013; 4111754-1760) Key Words: brainstem encephalitis; enterovirus 71; milrinone; neurogenic shock; pulmonary edema E nterovirus 71 (EV71) is an important cause of wide- spread epidemics of hand, foot, and mouth (HFM) disease in children (1-3). EV71 can cause aseptic meningitis, a poliomyelitis-like syndrome, encephalitis, and meningoencephalitis (Appendix). The most severe form (3B) is brainstem encephahtis with acute pulmonary edema (PE) (2,4-8). This stage is associated with a high early mortality of 1754 viAAAAi.ccmjournal.org July 2013 • Volume 41 • Number 7