Hypothermia Enhanced by Magnesium Sulphate
Condition: Perinatal Anoxic-ischemic Brain Injury
MeSH terms: Brain Injuries; Hypothermia
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      New 2010 neonatal resuscitation guidelines state that offering therapeutic hypothermia (TH)
      should be a standard of care in managing neonates with perinatal hypoxic - ischemic insult
      and present with signs of moderate and/or severe hypoxic - ischemic encephalopathy (HIE) .
      Despite the evidence from several randomized control trial (RCT) proving its effectiveness,
      its effect is perceived insufficient or only modest. Thus today's research efforts are
      directed toward finding the new possibilities of enhancing the effects of hypothermia. List
      of agents with potential neuroprotective properties includes: erythropoetin, melatonin,
      topiramate, morphine, xenon, MgSO4. Given investigators previous experiences with preterm
      neonates exposed to MgSO4 prenatally or administered this drug after birth because of
      perinatal asphyxia, the investigators designed the trial which would evaluate the possibility
      of increasing the TH effect by combining this method with MgSO4. Until now there are several
      published studies evaluating the effectiveness of MgSO4 in the group of asphyxiated neonates,
      including one RCT. However, all of these studies were conducted before the era of TH
      Furthermore, irrespective of the potential benefits, safety of using MgSO4 during TH in the
      group of term neonates was not studied. It is particularly important in the light of the
      results presented by Mittendorf et.al. They studied the effects of prenatal aggressive
      treatment with MgSO4 on the outcome of preterm neonates showed that patients exposed to high
      doses of MgSO4 were at higher risk of severe intracranial bleeding. Other side effects of
      high serum magnesium levels are: vasodilatation, hypotension, cardiac arrhythmias,
      coagulopathy, and gastrointestinal disturbances. MgSO4 is a very attractive neuroprotective
      option,also because of its easy availability. Drug can be administered in the birth hospital
      while neonate is being prepared for the transport to TH center. Timing of the intervention is
      very important for neonates suffering from perinatal asphyxia. Both TH and administration of
      potentially neuroprotective drug should be started during "therapeutic window". It is the
      initial potentially reversible phase of hypoxic insult lasting about 6 hours. If the
      long-term follow up shows that MgSO4 has an additive neuroprotective effect and no
      significant side effects in the group of asphyxiated neonates treated with TH this relatively
      simple and not expensive intervention may be introduced into clinical practice
    

Detailed description: 
      First decade of the twenty first century is an era when the therapeutic hypothermia became a
      widely used procedure in managing neonates with hypoxic - ischemic encephalopathy. New 2010
      neonatal resuscitation guidelines state that offering therapeutic hypothermia should be a
      standard of care in managing neonates who sustained perinatal hypoxic - ischemic insult and
      present with signs of moderate and/or severe hypoxic - ischemic encephalopathy. Despite the
      evidence coming from several randomized controlled trials proving its effectiveness, in
      certain situations its effect is perceived insufficient or only modest at best. For this
      reason today's research efforts are directed toward finding the new possibilities of
      enhancing the effects of hypothermia. Some these new modalities are: modification of the
      hypothermia protocol, hypothermia combined with drugs which have a potential to be
      neuro-protective, and finally stem cell therapy. List of medications/substances with
      potential neuro - protective properties includes: erythropoetin, melatonin, topiramate,
      morphine, xenon, magnesium sulfate. Given investigators previous experiences with group of
      preterm neonates who were either exposed to magnesium sulfate prenatally or administered this
      drug after birth because of perinatal asphyxia, it was only natural to design the trial which
      would evaluate the possibility of increasing the effect of therapeutic hypothermia by
      combining this modality with administration of magnesium sulfate. Before the era of inhaled
      NO magnesium sulfate was widely used in the management of neonates with persistent pulmonary
      hypertension of neonates (PPHN), but then the level in the serum was kept in the high range
      (3,5 - 5,5 mmol/L). Until now there are several published studies evaluating the
      effectiveness of magnesium sulfate in the group of asphyxiated neonates, including one
      randomized controlled trial. Results are promising. However, all of these studies were
      conducted before the era of therapeutic hypothermia. Furthermore, irrespective of the
      potential benefits, safety of using magnesium sulfate during therapeutic hypothermia in the
      group of term and late preterm neonates was not studied. It is particularly important in the
      light of the results presented by Mittendorf et.al. They studied the effects of prenatal
      aggressive treatment with magnesium sulfate on the outcome of the neonates born with very low
      birth weight and showed that patients exposed to high doses of magnesium were at higher risk
      for developing severe intracranial bleeding. Other known side effects of high serum magnesium
      levels are: vasodilatation, hypotension, cardiac arrhythmias, coagulopathy, and
      gastrointestinal disturbances. Magnesium sulfate is a very attractive option as a
      neuroprotective drug also because of its easy availability. Drug can be administered to the
      patient in the birth hospital while neonate is being prepared for the transport to the center
      with therapeutic hypothermia. Timing of the intervention is very important in the management
      of the neonates suffering from perinatal asphyxia. Both, therapeutic hypothermia, as well as
      administration of potentially neuroprotective drug should be started during so called
      "therapeutic window". It is the initial potentially reversible phase of hypoxic insult
      lasting about 6 hours followed by the irreversible phase of apoptosis and destruction of
      neurons. If the long terms follow up shows that magnesium sulfate has an additive
      neuroprotective effect and no significant side effects in the group of asphyxiated neonates
      treated with therapeutic hypothermia this relatively simple and not expensive intervention
      may be introduced into clinical practice.
    

Intervention name(s): Magnesium Sulfate
Intervention type(s): Drug
Intervention description(s): intravenous infusion of magnesium sulphate
Other intervention name(s): Magnesii Sulfurici 20% Polpharma
Intervention MeSH terms: Magnesium Sulfate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: newborn; therapeutic hypothermia; magnesium sulphate