title: 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: BACKGROUND
  Over 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
  We 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.
  
  
  CONCLUSIONS
  Given 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.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 August 2013).
authors.affiliation: Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam. phantuqui@gmail.com.|Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. phantuqui@gmail.com.
authors.forename: Phan Tu
authors.initials: PT
authors.lastname: Qui
authors.affiliation: Children's Hospital Number 1, 341 Sư Vạn Hạnh, District 10, Ho Chi Minh City, Vietnam. truonghuukhanh@gmail.com.
authors.forename: Truong Huu
authors.initials: TH
authors.lastname: Khanh
authors.affiliation: Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam. huynhtrieu82@gmail.com.
authors.forename: Huynh Trung
authors.initials: HT
authors.lastname: Trieu
authors.affiliation: Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam. chuotchui1007@yahoo.com.
authors.forename: Phạm Thanh
authors.initials: PT
authors.lastname: Giang
authors.affiliation: Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam. drngocbich@yahoo.com.vn.
authors.forename: Nguyen Ngọc
authors.initials: NN
authors.lastname: Bich
authors.affiliation: Children's Hospital Number 1, 341 Sư Vạn Hạnh, District 10, Ho Chi Minh City, Vietnam. thoalephan@gmail.com.
authors.forename: Le Phan Kim
authors.initials: le PK
authors.lastname: Thoa
authors.affiliation: Children's Hospital Number 1, 341 Sư Vạn Hạnh, District 10, Ho Chi Minh City, Vietnam. drnhanbvnhidong1@yahoo.com.vn.
authors.forename: Le Nguyen Thanh
authors.initials: le NT
authors.lastname: Nhan
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. saras.whitehorn@googlemail.com.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, OX1 2JD, UK. saras.whitehorn@googlemail.com.
authors.forename: Saraswathy
authors.initials: S
authors.lastname: Sabanathan
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. hrogier@gmail.com.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, OX1 2JD, UK. hrogier@gmail.com.
authors.forename: Rogier
authors.initials: R
authors.lastname: Van Doorn
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. toannd@oucru.org.
authors.forename: Nguyen Duc
authors.initials: ND
authors.lastname: Toan
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. lmerson@oucru.org.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, OX1 2JD, UK. lmerson@oucru.org.
authors.forename: Laura
authors.initials: L
authors.lastname: Merson
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. dungntp@oucru.org.
authors.forename: Nguyen Thi Phuong
authors.initials: NT
authors.lastname: Dung
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. lampk@oucru.org.
authors.forename: Lam Phung
authors.initials: LP
authors.lastname: Khanh
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. mwolbers@oucru.org.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, OX1 2JD, UK. mwolbers@oucru.org.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.affiliation: Children's Hospital Number 1, 341 Sư Vạn Hạnh, District 10, Ho Chi Minh City, Vietnam. drthanhhung@gmail.com.
authors.forename: Nguyen Thanh
authors.initials: NT
authors.lastname: Hung
authors.affiliation: Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam. chaunvv@oucru.org.
authors.forename: Nguyen Van Vinh
authors.initials: NV
authors.lastname: Chau
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam. bwills@oucru.org.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, OX1 2JD, UK. bwills@oucru.org.
authors.forename: Bridget
authors.initials: B
authors.lastname: Wills
mesh_terms: D001342:Autonomic Nervous System Diseases / Q000188:drug therapy*; D002985:Clinical Protocols; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D006232:Hand, Foot and Mouth Disease / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007258:Informed Consent; D007275:Injections, Intravenous; D008278:Magnesium Sulfate / Q000008:administration & dosage* / Q000009:adverse effects; D020105:Milrinone / Q000008:administration & dosage; D018401:Sample Size
chemical_list: D008278:Magnesium Sulfate; D020105:Milrinone