A Multicenter Randomized Controlled Trial of Therapeutic Hypothermia Plus Magnesium Sulphate (MgSO4) Versus Therapeutic Hypothermia Plus Placebo in the Management of Term and Near Term Babies With Hypoxic Ischemic Encephalopathy
Trial Snapshot
- Phase
- Phase 3
- Sponsor
- Enrollment
- 300
- Locations
- 7
- Primary Endpoint
- Combined outcome of Mortality and Severe Neurodevelopmental Disability
Study Overview
Brief Summary
The purpose of this study is to assess whether the addition of a drug such as Magnesium sulphate while providing therapeutic hypothermia (or cooling) to babies who are asphyxiated at birth provides additional benefit to the babies' survival and outcome compared to cooling alone.
Detailed Description
Perinatal Asphyxia continues to be a major cause of neonatal mortality and morbidity even in the most technologically advanced and prosperous countries of the world. The incidence remains unchanged; 1-2% of live births in developed world countries and much higher in developing world countries. Perinatal Asphyxia is a multisystem disorder. Neonatal brain is the most important organ affected by Asphyxic insult because the resulting neuronal damage is permanent. Hypoxic Ischemic Encephalopathy (HIE), the pathognomonic clinical syndrome of asphyxic neuronal insult, occurs in 50-60% of babies with Perinatal Asphyxia. Moderate and severe HIE causes significant neonatal mortality and morbidity. Among patients with moderate HIE, 10-20% die and 30-40% develop neurological deficit, whereas 50% of patients with severe HIE die and almost all survivors develop neurological deficits. Hence the toll on the society continues to be very high in spite of dramatic improvements in neonatal intact survival, particularly in developed world countries.
Until recent years, the management of HIE was limited to supportive intensive care only because there was no specific treatment available to rescue neurons during HIE. However, over the last decade, therapeutic Hypothermia, has emerged as a promising new therapy in reducing neonatal mortality and morbidity due to HIE. This is due to improved understanding of the physiology of neuronal damage during asphyxia insult. Hypoxic Ischemic Encephalopathy (HIE) is a dynamic process which evolves over a period of seventy two hours starting from the time of insult. Two distinct episodes of neuronal damage occur during this time:
- The immediate (primary) hypoxic insult followed by a
- latent period of recovery which lasts for almost six hours.
This is followed by a much longer and profound period of secondary neuronal damage due to the release of chemical mediators. Therapeutic modalities which can potentially reduce the release of these chemical mediators will provide neuronal rescue. Moderate controlled hypothermia (33.5-34.5 0C) offered during the first 72 hours after the asphyxic insult is one such therapeutic modality which has been the subject of animal studies as well as extensive multicenter trails in human infants over the last two decades.
The studies on animal models have not only confirmed the safety of moderate therapeutic hypothermia; they have also shown a dramatic neuronal rescue in experimental HIE model of lambs subjected to prolonged therapeutic hypothermia immediately after birth. This was followed by pilot RCT's in human infants; the outcomes of which were very encouraging. However a universal change of practice requires large well designed multicenter trails and Meta analyses.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- — to 6 Hours (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •The babies will be assessed sequentially by criteria A, B and C listed below:
- •A. Evidence of Perinatal Asphyxia at birth: Infants ≥35 completed weeks gestation admitted to the NICU with at least one of the following:
- •Apgar score of <5 at 10 minutes after birth
- •Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth
- •Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord arterial or venous pH <7.00 or otherwise arterial or capillary pH <7.00)
- •Base Deficit (-16 mmol/L or more) in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth
- •Infants that meet criteria A will be assessed for whether they meet the neurological abnormality entry criteria (B) by trained personnel:
- •B. Clinical Evidence of Moderate to severe encephalopathy, consisting of altered state of consciousness (lethargy, stupor or coma) AND at least one of the following:
- •abnormal reflexes including oculomotor or pupillary abnormalities
- •absent or weak suck
- •clinical seizures
- •Infants who meet criteria A & B will be assessed by aEEG only in units where facility for Cerebral Function Monitoring (CFM) is available.
- •C. (Optional) At least 30 minutes duration of amplitude integrated EEG recording that shows abnormal background aEEG activity or seizures. There must be one of the following:
- •normal background with some seizure activity
- •continuous seizure activity
- •moderately abnormal activity: Only Lower border below 5 mV. upper border remains above 10mV
- •Severely Abnormal activity (suppressed activity): Both Lower border below 5 mV and upper border below 10mV
Exclusion Criteria
- •Infants expected to be > 6 hours of age at the time of randomization.Every effort will be made to ensure entry to the study before 3 hours of age.
- •Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation, or congenital abnormalities suggestive of chromosomal anomaly or other syndromes that includes brain dysgenesis.
Arms & Interventions
Hypothermia + Magnesium Sulphate
Intervention: Magnesium Sulphate (Drug)
Hypothermia+ Placebo
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Combined outcome of Mortality and Severe Neurodevelopmental Disability
Time Frame: 18 - 24 months of age
Severe Neurodevelopmental Disability will be assessed at discharge from hospital and at 18-24 months of age to assess developmental delay and cerebral palsy using the Bayley Scale of Infant Development II.
Secondary Outcomes
- Persistent Hypotension(Duration of hypothermia therapy( ie during the first 96 hours))
- Prolonged Blood Coagulation time(Duration of hypothermia therapy ( ie during the first 96 hours))
- Culture Proven sepsis(Duration of hospital stay, an expected average of up to 4 weeks)
- Necrotizing enterocolitis(Duration of hospital stay, an expected average of up to 4 weeks)
- Pulmonary Hemorrhage(Duration of hospital stay, an expected average of up to 4 weeks)
- Intracranial Hemorrhage(Duration of hospital stay, an expected average of up to 4 weeks)
- Pulmonary Hypertension(Duration of Hypothermia therapy (ie during the first 96 hours))
- Thrombocytopenia(Duration of hypothermia therapy (ie during the first 96 hours))
- Abnormal liver funcion tests (elevated liver enzymes)(Duration of hospital stay, an expected average of up to 4 weeks)
- Pulmonary air leak syndrome(Duration of hospital stay, an expected average of up to 4 weeks)
- Prolonged vs shortened hospital stay(First day of NICU admission till the day of discharge, an expected average of up to 4 weeks)
- Bayley Psychomotor Development Score less than 70(18-24 months of age)
- Sensorineural hearing loss equal to, or more than, 40 dB(18-24 months of age)
- Cardiac Arrhythmias(Duration of hypothermia therapy (ie during the first 96 hours))
- Major venous thrombosis(Duration of hospital stay, an expected average of up to 4 weeks)
- Neurodevelopment score(On the day of discharge from hospital, an expected average of 4 weeks after admission)
- Renal Failure(Duration of hospital stay, an expected average of up to 4 weeks)
- Pneumonia(Duration of hospital stay, an expected average of up to 4 weeks)
- Abnormal aEEG(Before randomization and during hypothermia therapy (0 hours till 96 hours))
- Presence of multiple handicaps(18-24 months of age)
- Epilepsy(18-24 months of age)
- Microcephaly(18-24 months of age)
- Result of EEG or MRI(within the first 14 days of life)
Investigators
Sajjad Rahman
Senior Consultant Perinatal Medicine
Hamad Medical Corporation