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

Phan Tu Qui, Truong Huu Khanh, Huynh Trung Trieu, Phạm Thanh Giang, Nguyen Ngọc Bich, Le Phan Kim Thoa, Le Nguyen Thanh Nhan, Saraswathy Sabanathan, Rogier Van Doorn, Nguyen Duc Toan, Laura Merson, Nguyen Thi Phuong Dung, Lam Phung Khanh, Marcel Wolbers, Nguyen Thanh Hung, Nguyen Van Vinh Chau, Bridget Wills, Phan Tu Qui, Truong Huu Khanh, Huynh Trung Trieu, Phạm Thanh Giang, Nguyen Ngọc Bich, Le Phan Kim Thoa, Le Nguyen Thanh Nhan, Saraswathy Sabanathan, Rogier Van Doorn, Nguyen Duc Toan, Laura Merson, Nguyen Thi Phuong Dung, Lam Phung Khanh, Marcel Wolbers, Nguyen Thanh Hung, Nguyen Van Vinh Chau, Bridget Wills

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).

Figures

Fig. 1
Fig. 1
Screening flow chart
Fig. 2
Fig. 2
Treatment flow chart

References

    1. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 2010;10:778–90. doi: 10.1016/S1473-3099(10)70194-8.
    1. Vietnam Ministry of Health: Health Statistics Yearbook 2011. Hanoi: Medical Publisher; 2012:175–76
    1. WHO. A Guide to Clinical Management and Public Health Response for Hand Foot Mouth Disease (HFMD) 2010.. Accessed 2 Dec 2011.
    1. Fu YCCC, Chiu YT, Hsu SL, Hwang B, Jan SL, Chen PY, et al. Cardiac complications of enterovirus rhombencephalitis. Arch Dis Child. 2004;89:368–73. doi: 10.1136/adc.2003.029645.
    1. Fu YC, Chi CS, Chiu YT, Hsu SL, Hwang B, Jan SL, Chen PY, Huang FL, Chang Y. Cardiac complications of enterovirus rhombencephalitis. Arch Dis Child. 2004;89(4):368–73. PubMed PMID: 15033850; PubMed Central PMCID: PMC1719879.
    1. Fu YC, Chi CS, Lin NN, Cheng CC, Jan SL, Hwang B, Hsu SL, Gong CL, Chen YT, Chiu YT. Comparison of heart failure in children with enterovirus 71 rhombencephalitis and cats with norepinephrine cardiotoxicity. Pediatr Cardiol. 2006;27(5):577-84. PubMed PMID: 16933070.
    1. Wang S-M, Lei H-Y, Yu C-K, Wang J-R, Su I-J, Liu C-C. Acute Chemokine Response in the Blood and Cerebrospinal Fluid of Children with Enterovirus 71–Associated Brainstem Encephalitis. J Infect Dis. 2008;198:1–5. doi: 10.1086/591462.
    1. Zubcevic J, Waki H, Raizada MK, Paton JFR. Autonomic-Immune-Vascular Interaction: An Emerging Concept for Neurogenic Hypertension. Hypertension. 2011;57:1026–33. doi: 10.1161/HYPERTENSIONAHA.111.169748.
    1. Wang SM, Lei HY, Huang MC, Wu JM, Chen CT, Wang JN, et al. Therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema. Pediatr Pulmonol. 2005;39:219–23. doi: 10.1002/ppul.20157.
    1. Chi CY, Khanh TH, le PK T, Tseng FC, Wang SM, Thinh le Q, et al. Milrinone Therapy for Enterovirus 71-Induced Pulmonary Edema and/or Neurogenic Shock in Children: A Randomized Controlled Trial. Crit Care Med. 2013;41:1–7. doi: 10.1097/CCM.0b013e31828a2a85.
    1. Vietnamese Ministry of Health: Guideline for HFMD Management. Hà Nộ i, 2012..Accessed 9 April 2012.
    1. . Milrinone injection - FDA prescribing information, side effects and uses. . Accessed 16 Feb 2016.
    1. Smith AH, Owen J, Borgman KY, Fish FA, Kannankeril PJ. Relation of milrinone after surgery for congenital heart disease to significant postoperative tachyarrhythmias. Am J Cardiol. 2011;108:1620–4. doi: 10.1016/j.amjcard.2011.07.023.
    1. Thwaites CL, Yen LM, Cordon SM, Thwaites GE, Loan HT, Thuy TT, et al. Effect of magnesium sulphate on urinary catecholamine excretion in severe tetanus. Anaesthesia. 2008;63:719–25. doi: 10.1111/j.1365-2044.2008.05476.x.
    1. Thwaites CL, Yen LM, Cordon SM, Binh NT, Nga NTN, White NJ, et al. Urinary catecholamine excretion in tetanus. Anaesthesia. 2006;61:355–9. doi: 10.1111/j.1365-2044.2006.04580.x.
    1. Thwaites CL, Yen LM, Loan HT, Thuy TT, Thwaites GE, Stepniewska K, Soni N, White NJ, Farrar JJ. Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial. Lancet. 2006;368(9545):1436-43. PubMed PMID: 17055945.
    1. James MF, Beer RE, Esser JD. Intravenous magnesium sulfate inhibits catecholamine release associated with tracheal intubation. Anesth Analg. 1989;68:772–6.
    1. Rowe BHBJ, Bourdon C, Bota G, Blitz S, Camargo CA. Magnesium sulfate for treating exacerbations of acute asthma in the emergency department (Review) The Cochrane Library. 2009;3:25.
    1. Tolsa JF, Cotting J, Sekarski N, Payot M, Micheli JL, Calame A. Magnesium sulphate as an alternative and safe treatment for severe persistent pulmonary hypertension of the newborn. Arch Dis Child. 1995;72:F184–7. doi: 10.1136/fn.72.3.F184.
    1. Jones NAJS. Management of life-threatening autonomic hyper-reflexia using magnesium sulphate in a patient with a high spinal cord injury in the intensive care unit. Br J Anaesth. 2002;88:434–8. doi: 10.1093/bja/88.3.434.
    1. Maehama TIH, Kanazawa K. Management of autonomic hyperreflexia with magnesium sulfate during labor in a woman with spinal cord injury. Am J Obstet Gynecol. 2000;183:492–3. doi: 10.1067/mob.2000.104230.
    1. Smyth RMSP, Armstrong N, Duley L. Magpie Trial in the UK: methods and additional data for women and children at 2 years following pregnancy complicated by pre-eclampsia. BMC Pregnancy Childbirth. 2009;9.
    1. Touyz RM. Role of magnesium in the pathogenesis of hypertension. Mol Asp Med. 2003;24:107–36. doi: 10.1016/S0098-2997(02)00094-8.
    1. Sugimoto J, Romani AM, Valentin-Torres AM, Luciano AA, Ramirez Kitchen CM, Funderburg N, et al. Magnesium Decreases Inflammatory Immunomodulatory Mechanism: A Novel Innate Cytokine Production. J Immunol. 2012;188:6338–46. doi: 10.4049/jimmunol.1101765.
    1. Muroi CBJ, Hugelshofer M, Seule M, Mishima K, Keller E. Magnesium and the inflammatory response: potential pathophysiological implications in the management of patients with aneurysmal subarachnoid hemorrhage? Magnes Res. 2012;25:64–71.
    1. Ho JJRG. Magnesium sulfate for persistent pulmonary hypertension of the newborn. The Cochrane Library. 2010; 3
    1. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. Pediatrics. 2004; 114:555.
    1. Flynn JT. Management of hypertensive emergencies and urgencies in children. . Accessed 16 Nov 2012.
    1. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE). version 4.03. 2010.. Accessed 17 Feb 2013.

Source: PubMed

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