Magnesium Sulphate for Severe Hand, Foot and Mouth Disease in Vietnam
Condition: Hand, Foot and Mouth Disease
MeSH terms: Foot-and-Mouth Disease; Hand, Foot and Mouth Disease; Mouth Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      Hand foot and mouth disease (HFMD) is a common infectious disease caused by a number of
      different viruses - a small proportion of children infected with a particular type of
      enterovirus (EV71) develop neurological and systemic complications that may prove fatal. Very
      large epidemics of EV71 related HFMD have occurred across Asia in recent years; in 2011, in
      excess of 100,000 Vietnamese children were diagnosed with HFMD and 164 died.

      In children with severe HFMD the particular part of the brain that regulates the heart, blood
      circulation, and breathing responses can be affected. Management of this complication is very
      difficult and we currently use an expensive drug (milrinone) that is hard to obtain and has
      significant side effects, without having good evidence that it is effective.

      Magnesium sulphate (Mg) is a cheap, readily available drug that has been used in other
      diseases with similar complications, and we have preliminary data from a small case series
      that suggests it might be a good treatment for HFMD patients with signs indicating this type
      of brain involvement.

      We think that early intervention with Mg, when signs of brain involvement are still
      relatively mild, will control this problem better than waiting until it is well established
      and giving milrinone as at present, and this in turn may prevent progression to severe
      disease. The aims of the project are to evaluate the effects of Mg on hypertension, signs of
      brain dysfunction, outcome (death or neurological sequelae), changes in a variety of blood
      and urine components, and measures of cardiovascular function, in severe HFMD.

      The study design is a randomized double-blind placebo-controlled clinical trial. Children on
      the pediatric intensive care unit with a clinical diagnosis of hand, foot and mouth disease
      will be eligible for enrolment if the blood pressure exceeds the internationally recognized
      threshold for Stage 1 hypertension, they exhibit at least one other sign of brain stem
      dysfunction, and there is written informed consent by a parent or guardian.

      According to the randomization, patients will receive an initial loading dose followed by a
      maintenance infusion, of either Mg or identical placebo for 72 hours; all staff involved in
      patient care will remain unaware of the treatment allocation, but staff from another
      department will monitor Mg blood levels to ensure safety and adequate dosing. A total of 190
      patients (95 in each arm) will be recruited.
    

Detailed description: 
      Background:

      Hand foot and mouth disease (HFMD) is a common infectious disease caused by a variety of
      enteroviruses. A small proportion of those infected with enterovirus 71 (EV71) develop
      neurological and systemic complications that may prove fatal. Over the past 15 years EV71
      related HFMD has caused increasing epidemics of HFMD across Asia; in 2011, in excess of
      100,000 Vietnamese children were diagnosed clinically with HFMD and 164 died. The
      neurological problem of most concern is brainstem encephalitis, causing autonomic nervous
      system (ANS) dysregulation that may progress rapidly to cardiopulmonary failure. Management
      of ANS dysregulation is difficult even in sophisticated western intensive care units. The
      phosphodiesterase-3 inhibitor, Milrinone, was reported to control hypertension and support
      myocardial function in a small informal study of severe HFMD compared to historical controls,
      but in practice treatment remains largely empirical. ANS dysregulation also occurs in severe
      tetanus and there is a body of evidence indicating that intravenous magnesium sulphate (Mg)
      is effective in controlling tetanus-associated cardiovascular instability. Mg is also used
      widely for eclampsia, severe asthma and pulmonary hypertension, and there are reports of
      rapid control of life-threatening autonomic hyperreflexia in patients with spinal lesions.
      Formal safety data in children are limited, but adverse effects appear to be infrequent. In a
      series of 24 severe EV71 confirmed HFMD cases managed recently at the Hospital for Tropical
      Diseases, Ho Chi Minh City, Mg was added when hypertension remained poorly controlled despite
      high-dose Milrinone. In all cases the blood pressure (BP) reduced within 30-60 minutes and
      remained stable subsequently on a continuous Mg infusion for 48-72 hours.

      Hypothesis and Aims:

      We hypothesize that early intervention with Mg, when ANS dysregulation first becomes
      apparent, will control cardiovascular instability and prevent progression to severe disease.
      The main aims are as follows:-

        -  To evaluate the effects of Mg on hypertension and ANS dysregulation in severe HFMD

        -  To evaluate the effects of Mg on outcome (death or neurological sequelae) in severe HFMD

        -  To evaluate changes in plasma/urine catecholamine levels, cardiac output and systemic
           vascular resistance (SRV) in severe HFMD, and to assess the impact of Mg on these
           parameters.

      Study Design:

      We plan a randomized double blind trial comparing intravenous Mg with placebo in children
      admitted to the pediatric intensive care unit with clinical HFMD, ANS dysregulation, and
      Stage 1 hypertension. Patients will be eligible for enrolment if the arterial blood pressure
      exceeds the 95th centile for age, gender and length/height for at least 30 minutes while the
      child is not distressed, they exhibit at least one other criterion for ANS dysregulation, and
      a parent/guardian gives written informed consent. Specific renal and cardio-respiratory
      exclusion criteria will apply.

      A loading dose of 50mg/kg of either Mg or identical placebo will be given over 20 minutes
      followed by a maintenance infusion for 72 hours according to response, aiming for Mg levels
      2-3 times normal in the treatment arm. All staff involved in clinical care will be blind to
      the treatment allocation, and Mg levels will be monitored and adjusted by independent doctors
      from another clinical facility.

      The primary endpoint will be a composite endpoint of disease progression defined as
      occurrence of any of the following within 72 hours: specific blood pressure criteria
      necessitating addition of milrinone, need for ventilation, development of shock, or death.
      Secondary endpoints will include presence of neurological sequelae at discharge in survivors,
      and various measures of cardiac output and systemic vascular resistance, catecholamine and
      cytokine levels.

      Based on 1:1 randomization, an anticipated relative reduction of the risk of progression of
      50% (from 50% in the control arm to 25% in Mg recipients, information from our case series
      plus indirect evidence from studies on severe tetanus), 90% power and a two-sided 5%
      significance level, 85 patients per treatment group are required. To allow for some
      violations of our assumptions and losses to follow-up, we plan to recruit 190 patients (95
      patients per treatment arm) into the study.

      Potential Impact:

      Given the very large numbers of HFMD cases being seen in hospitals in Asia currently, if Mg
      is shown to be effective in controlling ANS dysregulation and preventing severe HFMD
      complications this would be of major importance for paediatric care throughout the Asian
      region. Mg is cheap, readily available and safe whereas milrinone is expensive, has a
      significant side effect profile and is often not available outside major centres.
    

Intervention name(s): Magnesium Sulphate; Sterile water
Intervention type(s): Drug; Drug
Intervention description(s): MgSO4 IV infusion; H2O IV infusion
Other intervention name(s): magnesi sulfat krabi 15%
Intervention MeSH terms: Magnesium Sulfate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hand, foot and mouth disease; Autonomic nervous system dysregulation; Magnesium sulphate