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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.

Qui PT, Khanh TH, Trieu HT, Giang PT, Bich NN, Thoa le PK, Nhan le NT, Sabanathan S, Van Doorn R, Toan ND, Merson L, Dung NT, Khanh LP, Wolbers M, Hung NT, Chau NV, Wills B - Trials (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam. phantuqui@gmail.com.

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/design: 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.

Discussion: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 August 2013).

No MeSH data available.


Related in: MedlinePlus

Treatment flow chart
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Fig2: Treatment flow chart

Mentions: MgSO4 15 % solution and placebo (sterile water) are available in 10 ml visually matched ampoules supplied by Fresenius Kabi. Study drug packages are prepared centrally by the un-blinded Clinical Trials Pharmacist and distributed to the sites as required. Drugs are stored in accordance with the manufacturers’ recommendations in a secure area. All movements of study medication are recorded. Both individual subject and overall drug accountability records are kept up to date. Prior to administration each vial is diluted with 5 ml 0.9 % saline solution by trained study nurses, to give a volume of 15 ml and provide a 10 % MgSO4 solution for the magnesium intervention arm.


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.

Qui PT, Khanh TH, Trieu HT, Giang PT, Bich NN, Thoa le PK, Nhan le NT, Sabanathan S, Van Doorn R, Toan ND, Merson L, Dung NT, Khanh LP, Wolbers M, Hung NT, Chau NV, Wills B - Trials (2016)

Treatment flow chart
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4759733&req=5

Fig2: Treatment flow chart
Mentions: MgSO4 15 % solution and placebo (sterile water) are available in 10 ml visually matched ampoules supplied by Fresenius Kabi. Study drug packages are prepared centrally by the un-blinded Clinical Trials Pharmacist and distributed to the sites as required. Drugs are stored in accordance with the manufacturers’ recommendations in a secure area. All movements of study medication are recorded. Both individual subject and overall drug accountability records are kept up to date. Prior to administration each vial is diluted with 5 ml 0.9 % saline solution by trained study nurses, to give a volume of 15 ml and provide a 10 % MgSO4 solution for the magnesium intervention arm.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam. phantuqui@gmail.com.

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/design: 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.

Discussion: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 August 2013).

No MeSH data available.


Related in: MedlinePlus