Combined neuro protective effect of magnesium sulphate and therapeutic hypothermia versus therapeutic hypothermia alone in management of term and near term infants with hypoxic ischaemic encephalopathy : An open labelled randomized controlled study Dr Sainik Dutta Co-author : Dr Geeta Gathwala, Dr Poonam Dalal
Introduction Birth asphyxia is one of the leading causes of perinatal death and a recognized cause of neuromotor disability The overall incidence of perinatal asphyxia accounts for 1.0-1.5% of all term live births whereas In developing countries like India, this percentage may reach up to a 5% %. "National Neonatal Perinatal database”, which gathers perinatal data from 18 centres states that out of 1800 neonatal deaths, 517 (28.7%) were due to perinatal asphyxia studies showed a higher case fatality rate ( 9 to 35% ) for those with severe birth asphyxia and one-third of the survivors of birth asphyxia are left with some kind of neuro-developmental abnormalities, ranging from seizure disorders to intellectual delay and cerebral palsy
Birth asphyxia manifests neuronal injury by different mechanism Interrupting Na-K ATPase pump and thus accumulating sodium ions within 1. the neurons which causes causes influx of water causing cell swelling and lysis By both caspase dependent and independent apoptosis 2. Releasing excess amount of glutamate which in turn causes calcium influx by 3. activating NMDA receptor gated channels and augmenting cell lysis Mild hypothermia attenuates blood‐brain barrier damage, release of excitatory neurotransmitters is reduced, free radical production is lessened, and IL‐10 (an anti‐inflammatory cytokine) is increased blocking NMDA channels, magnesium prevent calcium influx and subsequently minimize brain injury
Rationale of present study Therapeutic Hypothermia is now standard of care for term infants with Hypoxic Ischaemic Encephalopathy and neuroprotective role of magnesium sulphate is already well established Moreover, the drug is is inexpensive, easily available and can be safely administered Although in isolation, both therapeutic hypothermia and magnesium sulphate infusion have been considered as neuroprotective agents in asphyxia, it is still undetermined whether a combination of these two measures would improve the neonatal outcome Hence, the present study was designed to evaluate the combined neuroprotective effect of magnesium sulphate plus therapeutic hypothermia in comparison to therapeutic hypothermia alone
Aim and objectives To evaluate the efficacy of magnesium sulphate plus therapeutic hypothermia on combined outcome of mortality or abnormal neurological outcome among asphyxiated term and near term neonates when compared to therapeutic hypothermia alone Objectives 1. To evaluate the efficacy of magnesium sulphate combined with therapeutic hypothermia on neurological outcome at 1 month of corrected age as determined by Hammer Smith method among asphyxiated term and near term neonates when compared to therapeutic hypothermia alone 2. To determine the safety of magnesium sulphate combined with therapeutic hypothermia when compared to therapeutic hypothermia alone on term and near term neonates with birth asphyxia 3. To evaluate the effect of magnesium sulphate combined with therapeutic hypothermia on radiological evidence of neuronal injury at 1 month of age when compared to therapeutic hypothermia alone
Inclusion criteria A) Essential criterias : (all three criterias should be met) 1. Infants of ≥ 36 weeks of gestational period. 2. Admitted to NICU within 6 hrs of birth. 3. Birth weight ≥2000gm. B) Evidence of birth asphyxia (any one of the following should be met) 1. Apgar score <5 at 5 minutes after birth due to birth asphyxia/perinatal depression. 2. Continued need for resuscitation, including endotracheal or mask ventilation at 5 minutes after birth. 3. Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord/arterial capillary pH <7.00) 4. Base deficit (>16 m.mol/l) in umbilical cord or any blood sample taken within 60 minutes of birth
C) Evidence of encephalopathy (any one of the following should be met) 1. Clinical seizures. 2. Evidence of moderate to severe encephalopathy, consisting of altered state of consciousness including lethargy, stupor or coma and at least one of the following; a. Hypotonia b. Abnormal reflexes including occulomotor or pupillary reflexes c. Absent or weak suck
Exclusion criteria Babies with gross congenital malformation Treatment of mother with magnesium sulphate for pregnancy induced hypertension Babies with little chance to survive. (Apgar score less than 1 at 10 minutes) Infants received after 6 hrs of birth
Methods Study setting Neonatal Services, Dept of Paediatrics, Pt B.D. Sharma Post Graduate Institute of Medical Science, Rohtak, Haryana. Study period One year Study design : An open labelled randomized controlled study. Ethical Consideration Patient information sheet in Hindi/English was given to parents/caregivers. A written consent was obtained from the parents of all enrolled neonates. Ethical clearance was obtained from Institutional Ethics Committee Statistical analysis All data was entered in MS excel and analyzed using SPSS 21.0 version, Outcome variable was compared between intervention and control group using Fisher exact test. A P value <0.05 was considered significant
Intervention Infants enrolled in control group received TH at 33.5 degree C followed by 1. gradual rewarming for 12 hours Infants enrolled in study group received magnesium sulphate @250mg/kg ( 2. three doses spaced 24 h ours apart with the first dose given within 6 hours of life ) in addition to TH All the babies were monitored for vital parameters as well as investigations as 3. per institution protocol All infants were examined neurologically ( Hammer smith ) at the time of 4. discharge MRI were done of the surviving infants at one month of age 5.
Primary outcome: Combined outcome of mortality or abnormal neurological examination at time of discharge Secondary outcome: Abnormal MRI finding at 1 month of age and abnormal neurological examination at one month of age
88 newborns were screened, 26 met inclusion criteria 17 babies were allotted 9 babies were allotted to to control group, TH study group, TH had to was abandoned in 6 of abandoned in 3 of them them 4 patients expired 7 patients were examined 6 patients were neurologically at time of examined at time of discharge discharge 1 patient 2 patients was lost to were lost to f/u f/u 5 infants were 5 infants were assessed at 1 month assessed at 1 of age for month of age for secondary outcome secondary outcome
Results : Primary outcome Study group Control group Count 0 4 Mortality ( percentage ) ( 0.0% ) ( 36.4% ) P value 0.23 Count 2 3 Abnormal ( percentage ) ( 33.3% ) ( 42.9% ) neurological finding P value 1.0 at discharge Count 2 7 Combined outcome ( Percentage ) ( 18.8% ) ( 63.63% ) P value 0.23
Secondary outcomes Study Control P value group group counts 0.42 Abnormal 1 3 percentage ( 16.6% ) ( 42.9% ) neurological findings Counts Abnormal MRI 4 5 0.93 Percentage ( 66.6% ) ( 71.4% ) findings
Conclusions Although the results doesn’t show any significant statistical outcome as the sample size was small, percentage wise the present study clearly documented better combined outcome of mortality & abnormal neurological outcome& better survival chances in asphyxiated neonates who received both therapeutic hypothermia & magnesium sulphate compared to those who received therapeutic hypothermia alone at the time of discharge Further studies with a larger sample size is needed to establish superiority of therapeutic hypothermia plus magnesium sulphate as neuroprotective strategy in asphyxiated newborns
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