A Randomized, Placebo-controlled, Double-blind Trial of Intravenous Magnesium Sulfate for the Management of Severe Hand, Foot and Mouth Disease With Autonomic Nervous System Dysregulation in Vietnamese Children.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 2
- 主要终点
- Number of patients who experience at least one of the clinical events listed below (composite endpoint)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Months 至 15 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 6 months to 15 years
- •Clinical suspicion of HFMD requiring PICU/HDU admission
- •Considered severe enough to warrant invasive blood pressure monitoring by PICU/HDU staff
- •Development of hypertension defined as follows:
- •For children aged 1 year and over, at least 3 consecutive systolic blood pressure recordings above the 95th centile for age, gender and length (USA guidelines for defining Stage 1 hypertension in children, (Appendix 2)) measured invasively over a period of 20 minutes provided the child is not distressed or crying [30, 31].
- •For children aged 6 months to 1 year, systolic BP > 100 mm Hg measured invasively on at least 3 occasions over a period for 20 minutes provided the child is not distressed or crying
- •Plus one or more of the following criteria:
- •Tachypnoea for age
- •Irregular or labored breathing, but with SpO2 above 92% in air and normal ABG (pH, pCO2, pO2, HCO3 all within the normal range for the local laboratory)
- •Resting heart rate > 150 bpm
- •Mottled skin
- •Profuse sweating
- •Refractory fever
- •Hyperglycemia
- •Informed consent
排除标准
- •Past history of hypertension, chronic renal, cardiac or pulmonary disease, or any neurological disorder
- •Hypertensive emergency
- •Already commenced milrinone or any other inotropic agents
- •Respiratory distress with SpO2<92% in air or PaCO2>45 mm Hg
- •AV block or any arrhythmia
- •Acute renal failure
研究组 & 干预措施
Sterile water
Sterile water will be packaged identically to the active comparator.
Each patient randomized to the placebo arm of the trial will receive a loading dose of 0.5ml/kg intravenous over 20 minutes , followed by a maintenance dose of 0.3 ml/kg/hr to 0.5 ml/kg/hr randomly adjusted by an independent doctor to mimic adjustments made in the active comparator arm for 72 hrs.
干预措施: Sterile water (Drug)
Magnesium sulphate
Each patient randomized to the treatment arm of the trial will receive a loading dose of 50mg/kg intravenous over 20 minutes (0.5ml/kg), followed by a maintenance dose of 30-50 mg/kg/hr (0.3 ml/kg/hr to 0.5 ml/kg/hr) for 72 hrs.
The maintenance dose will be determined by increasing the loading infusion dose 0.1 ml/kg/hr (10mg/kg/hr) every 15 minutes to a maximum dose of 0.5 ml/kg/hr (50 mg/kg/hr), with the following caveats:
- If the systolic BP decreases to < 90th percentile for age, gender and length the dose will be reduced by 1 stage every 15 mins
- If the systolic BP increases to the levels detailed in the study protocol for treatment failure, action will be taken as indicated
- If the systolic BP decrease rapidly more than 25% over 15 minutes
- If the plasma Mg level > 2.5 mmol/l or < 1.8 mmol/l a 25% increase or decrease in the infusion rate will be implemented as appropriate.
干预措施: Magnesium Sulphate (Drug)
结局指标
主要结局
Number of patients who experience at least one of the clinical events listed below (composite endpoint)
时间窗: 72 hours after start of study drug infusion
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
次要结局
- Presence of neurological sequelae at discharge in survivors(At hospital discharge - expected average discharge day 5)
- Blood pressure criteria necessitating addition of milrinone following Vietnam Ministry of Health guidelines for the treatment of hand, foot and mouth disease(72 hours after start of study drug infusion)
- Need for mechanical ventilation(72 hours after start of study drug infusion)
- Requirement for inotropic agents (eg dobutamine)(During hospital admission - expected average length of admission 5 days)
- Number of adverse events and serious adverse events(During hospital admission - expected average length of admission 5 days)
- Death(72 hours after start of study drug infusion)
- Development of shock(72 hours after start of study drug infusion)
- Duration of hospitalization(At hospital discharge - expected average discharge day 5)
- Neurodevelopmental status(6 months)