Intravenous magnesium sulfate for the management of severe hand, foot, and mouth disease with autonomic nervous system dysregulation in Vietnamese children: study protocol for a randomized controlled trial

Abstract

BackgroundOver the last 15 years, hand, foot, and mouth disease (HFMD) has emerged as a major public health burden across the Asia-Pacific region. A small proportion of HFMD patients, typically those infected with enterovirus 71 (EV71), develop brainstem encephalitis with autonomic nervous system (ANS) dysregulation and may progress rapidly to cardiopulmonary failure and death. Although milrinone has been reported to control hypertension and support myocardial function in two small studies, in practice, a number of children still deteriorate despite this treatment. Magnesium sulfate (MgSO4) is a cheap, safe, and readily available medication that is effective in managing tetanus-associated ANS dysregulation and has shown promise when used empirically in EV71-confirmed severe HFMD cases.Methods/DesignWe describe the protocol for a randomized, placebo-controlled, double-blind trial of intravenous MgSO4 in Vietnamese children diagnosed clinically with HFMD plus ANS dysregulation with systemic hypertension. A loading dose of MgSO4 or identical placebo is given over 20 min followed by a maintenance infusion for 72 h according to response, aiming for Mg levels two to three times the normal level in the treatment arm. The primary endpoint is a composite of disease progression within 72 h defined as follows: development of pre-specified blood pressure criteria necessitating the addition of milrinone, the need for ventilation, shock, or death. Secondary endpoints comprise these parameters singly, plus other clinical endpoints including the following: requirement for other inotropic agents; duration of hospitalization; presence of neurological sequelae at discharge in survivors; and neurodevelopmental status assessed 6 months after discharge. The number and severity of adverse events observed in the two treatment arms will also be compared. Based on preliminary data from a case series, and allowing for some losses, 190 patients (95 in each arm) will allow detection of a 50 % reduction in disease progression with 90 % power at a two-sided 5 % significance level.DiscussionGiven the large numbers of HFMD cases currently being seen in hospitals in Asia, if MgSO4 is shown to be effective in controlling ANS dysregulation and preventing severe HFMD complications, this finding would be important to pediatric care throughout the region.Trial registrationClinicalTrials.gov Identifier: NCT01940250 (Registered 22 August 2013).Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1215-6) contains supplementary material, which is available to authorized users.

Outbreak of brainstem encephalitis associated with enterovirus-A71 in Catalonia, Spain (2016): a clinical observational study in a children's reference centre in Catalonia

“…The Vietnamese Ministry of Health HFMD Classification and Management Guidelines were used to stratify the severity of patients with brainstem encephalitis or encephalomyelitis [22]. Ataxia was considered a Grade 2b Group 2 criterion [16] (see Table S1, supporting information).…”

“…Outcomes according to the WHO clinical classification[21] and the Vietnamese HFMD classification[22] HFMD, hand-foot-mouth disease; IVIG, intravenous immunoglobulin; NRL, neurologic; mRS, modified Rankin Scale; WHO, World Health Organization. Differences were considered significant at p <0.05, and these values are listed in bold type.…”

Assessing the efficacy and safety of magnesium sulfate for management of autonomic nervous system dysregulation in Vietnamese children with severe hand foot and mouth disease

“…The study was approved by the ethics committees of HTD and the Vietnamese MoH, as well as the Oxford University Tropical Research Ethics Committee, and was carried out in strict compliance with all ICH-GCP guidelines and recommendations. The trial was registered with ClinicalTrials.gov (NCT01940250), and the full protocol has been published [23].…”

Continuous hemodiafiltration as a rescue therapy for patients with cardiopulmonary failure caused by enterovirus-71: a retrospective observational study in a PICU

“…Inappropriate fluid resuscitation and acute kidney injury (AKI) may lead to FO in cases of severe HFMD. Limited studies have observed that hemofiltration is be an efficient rescue treatment in children with severe HFMD [9–11]. CRRT has been empirically used in patients with severe EV-A71-HFMD with cardiopulmonary failure since 2012 in our PICU.…”