Clinical Trial: Magnesium Sulphate for Severe Hand, Foot and Mouth Disease in Vietnam

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Randomized, Placebo-controlled, Double-blind Trial of Intravenous Magnesium Sulfate for the Management of Severe Hand, Foot and Mouth Disease With Autonomic Nervous Syst

Brief 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 clinica

Detailed Summary:

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:

Number of patients who meet one or more of the following criteria:

  1. Blood pressure criteria necessitating addition of milrinone following Vietnam Ministry of Health guidelines for the treatment of hand, foot and mouth disease
  2. Need for mechanical ventilation
  3. Development of shock
  4. Death


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Death [ Time Frame: 72 hours after start of study drug infusion ]
  • Blood pressure criteria necessitating addition of milrinone following Vietnam Ministry of Health guidelines for the treatment of hand, foot and mouth disease [ Time Frame: 72 hours after start of study drug infusion ]
  • Need for mechanical ventilation [ Time Frame: 72 hours after start of study drug infusion ]

    According to Viet Nam Ministry of Health guidelines: Ventilation Criteria:

    If a patient continues to display any of the following criteria despite oxygenation via nasal cannula and cardiac support with inotropic drugs for more than 60 minutes.

    • Labored breathing
    • Tachypnea with resting respiratory rate > 70 / minute without fever
    • Hypoxemia and/or fluctuating SpO2
    • Poor tissue perfusion and persistent resting heart rate > 180 beats/minute without fever

    Or

    • Decorticate or decerebrate rigidity
    • Coma (Glasgow Coma Scale < 10 )
  • Development of shock [ Time Frame: 72 hours after start of study drug infusion ]
  • Requirement for inotropic agents (eg dobutamine) [ Time Frame: During hospital admission - expected average length of admission 5 days ]
    If heart rate> 170 beats/minute
  • Presence of neurological sequelae at discharge in survivors [ Time Frame: At hospital discharge - expected average discharge day 5 ]
    Number of surviving patients who have neurological sequelae at hospital discharge
  • Neurodevelopmental status [ Time Frame: 6 months ]
    Measured by . Children 36 months and under at enrollment will use the Bayley infant scales of development III. Children 48 months and above at enrollment will use the Movement ABC-2 tool for their assessments. The children aged between 37 and 47 months at enrolment will have both assessments done at both visits.
  • Duration of hospitalization [ Time Frame: At hospital discharge - expected average discharge day 5 ]
    Number of days from study enrollment to discharge
  • Number of adverse events and serious adverse events [ Time Frame: During hospital admission - expected average length of admission 5 days ]
    Number of adverse events and severe adverse events that occur in the two treatment arms during hospitalization.


Original Secondary Outcome: Same as current

Information By: Oxford University Clinical Research Unit, Vietnam

Dates:
Date Received: August 22, 2013
Date Started: April 21, 2014
Date Completion:
Last Updated: March 6, 2017
Last Verified: November 2014