Hypothermia Enhanced by Magnesium Sulphate

Overview

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

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.