Magnesium Sulfate for Cerebral Palsy Prevention


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Drs. Brocato and Goodwin.

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  • Initial after a asphyxial event there is an increase of systemic BP and a redistribution of cardiac output so that the brain recieves an increased proportion of the cardiac output. After sustained insult both this CBF autoregulation and BP starts to fail. The end results is a decrease in the blood flow to the brain and resulting ischemic brain injury. Brain hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow (CBF), or both are the primary physiological processes that lead to hypoxic-ischemic encephalopathy. The initial compensatory adjustment to an asphyxial event is an increase in the CBF due to hypoxia and hypercapnia. This is accompanied by a redistribution of cardiac output such that the brain receives an increased proportion of the cardiac output. A borderline increase in the systemic blood pressure (BP) further enhances the compensatory response. The BP increase is due to increased release of epinephrine; these are classic early cardiovascular compensatory responses to asphyxia.  In the fetus and newborn suffering from acute asphyxia, after the early compensatory adjustments fail, the CBF can become pressure-passive, at which time brain perfusion is depends on systemic BP. As BP falls, CBF falls below critical levels, and the brain suffers from diminished blood supply and a lack of sufficient oxygen to meet its needs. This leads to intracellular energy failure.
  • Most of the metabolic energy of neurons is expended on maintaining ion gradient across the cell membrane. The sodium potassium pump pumps out 3 sodium ions for each 2 potassium ions. This keep extracellular K+ low and extracellular sodium high. The unequal pumping of Na (3) and K (2) results in a more positive charge on the outside as compared to the inside making the neuron polarized. This pump is driven by energy stored in Adenosine triphosphate molecules (or ATP) >
  • Another ATP-driven pump helps keep extracellular calcium ion 10,000X more concentrated than within the cytoplasm. Other pump such voltage gated and ion exchanges also regulate ion concentrations
  • ATP molecule are made in the mitochondria. Once the ATP is used for energy a phosphate is removed and results in adenosine diphosphate or ADP and hydrogen ion (acid) Generally making ATP requires O2
  • . But in the absence of O2 some energy can be generated outside the mitochondria by glycolyis. (on anareobic) In glycolysis a glucose molecule produces 2 ATP and lactate. Once the is a lack of blood flow to the brain ATP can be regenerated from ADP by phosphate for phosphocreatine (pCr) Glycolysis uses glucose to produce 2 ATP and lactate With the breakdown of ATP from it produces adenoside diphophate (ADP)and hydrogen ion (acid)
  • Net breakdwon of glycolis Within two mins of ischemia extracellular pH can drop about 7.3 to 6.7 A reduction of ATP synethesis caused by hypoxia disrupts ionic equilirbirum across the membrane (or deplorization). K quickly exits the cell, while There is also rapid influx of sodium, chloride and water resulting in cell swelling and lysis.
  • Deplorizing of the presynaptic membranes results in release of the neurotransmitter glutamate. Glutamte is one of the most important excitatory neurotransmitters in the brain. The postsynaptic membrane have many glutamate receptors notably N-Methyl-D-Aspartate NMDA and AMPA receptors.
  • Loss of membrane potentional or depolarization leads to the opening of voltage gated calcium channels. In addition NMDA stimulated calcium channel results in an increase in cytosolic calcium NMDA is particulary adept at allowing large amounts of calcium ion to enter the cells. This is particularly important in the fetal brain because of the larger proportion of NMDA receptors in the neurons than in the adult brain. It is important to note that these NMDA dependent reaction are delayed and may occur 24 hours after the insult.
  • High levels of Ca iis excitotxicic which initiate brain ischemia. The excessive increase in intracellular calcium interferes with many enzymatic reactions. Activation of Phospholiipase which leads to membrand phospholipid hydrolysis with the subquent disruption of cellular and organelle membranes. Alterations of the arachidonic acid cycle which effects prostaglandin syntehesis, gene expression, protein synthesis and increases free radical activate proteolytic ezyme (a=calpains  breack down cell protein esp thosy in cytoskeleton of neuron. ) Cytochrome C initiator of apoptosis It is believed that the influx of calcium through the NMDA stimulated calcium concentration is a delayed mechanism that can occur 24 hours after initial insult
  • Several lines of research in experimental animals have implicated a role for the excitatory amino acid glutamate in the production of hypoxia ischemic brain damage in the immature brain. These studies provide evidence that excessive glutamate leads to morphologic alterations characteristic of ischemic neuronal necrosis. Given the premise that excessive stimulation of neurons by glutamate promotes cellular death and antagonist to the nmda receptor should be neuroprotective
  • Several molecules have been suggested as candidate scavengers and protectors fr clinical use in fetal and neonatal brain hypoxia/perfusion failure
  • Magnesium is essential for a number of cellular function including
  • Distributions of perinatal factors, neonatal baseline characteristics and severity of hyoxic-ischemic encephalopathy were similar in treated and control groups. No significant differences were observed in duration of clinical seizures, or need for assisted ventilation. Survival with normal results of cranial computed tomography, electroencephalography and establishment of oral feeding by 14 days of age, was significantly more frequent in the treated group than in the control group (12/17 vs 5/16, P = 0.04). No significant differences in blood pressure, heart rate or respiratory rate were observed between groups.
  • Magnesium Sulfate for Cerebral Palsy Prevention

    2. 2. Objectives <ul><li>Define Cerebral Palsy </li></ul><ul><li>Review hypoxia-ischemia injury at neuronal level </li></ul><ul><li>Discuss magnesium sulfate as a potential neuroprotective agent </li></ul><ul><li>Review the current literature of postnatal magnesium sulfate (MgSO 4 ) </li></ul><ul><li>Review the current literature of antenatal MgSO 4 </li></ul>
    3. 3. Cerebral Palsy: History <ul><li>1861 Dr. William John Little described a disorder that was crippling and made children’s muscle weak, stiff and prone to twitching. </li></ul><ul><ul><li>Little’s Disease </li></ul></ul><ul><ul><li>Followed complicated delivery  lack of O 2  brain damage </li></ul></ul><ul><li>1897 Dr. Sigmund Freud disputed Dr. Little's claim  disorder began before birth </li></ul><ul><li>Research by National Institute of Neurological Disorders and Stroke (NINDS) in 1980’s  No single etiology of CP </li></ul>
    4. 4. Cerebral Palsy <ul><li>Definition: Global term for a group of disorder which effect movement and muscle coordination which is nonprogressive in nature. </li></ul><ul><li>Incidence: 2-3 children per 1,000 </li></ul><ul><ul><li>Increasing in the US  increased survival of premature infants </li></ul></ul><ul><li>Etiology: Multifactorial </li></ul><ul><ul><li>Damage to a developing brain </li></ul></ul><ul><li>Risk Factors: </li></ul><ul><ul><li>Preterm Birth </li></ul></ul><ul><ul><li>Birth Asphyxia 6-20% </li></ul></ul><ul><ul><li>Hypoxia Ischemic encephalopathy(HIE) </li></ul></ul>
    5. 5. Hypoxia-Ischemia Background <ul><li>Hypoxia-Ischemic encephalopathy: clinical and lab evidence of acute or subacute brain injury secondary to asphyxia </li></ul><ul><li>Hypoxia-Ischemia Encephalopathy can result in CP </li></ul><ul><li>2 to 4/1000 full-term infants suffer asphyxia </li></ul><ul><li>Incidence of asphyxia leading to CP 0.2 to 0.4/1000 infants </li></ul>
    6. 6. Ischemic Brain Injury (IBI)
    7. 7. Hypoxia-Ischemia at Neuronal Level
    8. 8. Background: Sodium and Potassium Regulation <ul><li>Presynaptic membrane Na + /K + pump </li></ul><ul><ul><li>Maintains ion gradient across cell membrane </li></ul></ul><ul><ul><li>Adenosine TriPhosphate (ATP) driven </li></ul></ul>↑↑ Na + ↑↑ K + 2K + 3Na + 3Na + 2K + 2K + K + K + Na + 3Na + +++++ ++ ++ Na +
    9. 9. Background: Calcium Regulation <ul><li>Ca 2+ is 10,000X extracellular>> cytoplasm </li></ul><ul><ul><li>ATP-driven pump </li></ul></ul><ul><ul><li>Voltage-gated ion channel </li></ul></ul><ul><ul><li>Ion-Exchangers </li></ul></ul>
    10. 10. Cellular Energy <ul><ul><li>ATP in manufactured in the mitochondria </li></ul></ul><ul><ul><ul><li>Na + /K + pump require ATP to continue to work </li></ul></ul></ul><ul><ul><li>ATP in mitochondria requires O 2 </li></ul></ul>
    11. 11. Hypoxia: Cellular Level <ul><li>Generate ATP </li></ul><ul><ul><li>Glycolysis </li></ul></ul><ul><ul><ul><li>Glucose  2 ATP + Lactate </li></ul></ul></ul><ul><li>Regenerate ATP </li></ul><ul><ul><li>Phosphocreatine (PCr) </li></ul></ul><ul><ul><ul><li>ADP  ATP </li></ul></ul></ul><ul><li>Hypoxic Environment </li></ul><ul><li>Phosphocreatine (PCr)/ATP vs. Time </li></ul>
    12. 12. Hypoxia-Ischemia: Cellular Level <ul><li>Net breakdown of glycolysis </li></ul><ul><ul><li>ADP, AMP, phosphate, lactate and acid accumulation </li></ul></ul><ul><li>↑ CO 2  carbonic acid (H 2 CO 3 ) </li></ul><ul><li>Within mins w/o 0 2  ↓↓ ATP  Na+/K+ pump stops working  depolarization </li></ul><ul><ul><li>K + exits cell </li></ul></ul><ul><ul><li>Na + influx </li></ul></ul>Acidosis
    13. 13. Depolarization of Presynaptic Neuron Postsynaptic Neuron Presynaptic Neuron
    14. 14. IBI: Cellular Level <ul><li>Voltage-Dependent Calcium Channels </li></ul><ul><li>Glutamate receptors </li></ul><ul><ul><li>N-Methyl-D-Aspartate (NMDA) </li></ul></ul><ul><ul><li>AMPA </li></ul></ul><ul><li>Glutamate receptors  ↑↑ Ca 2+ entry into intracellular space </li></ul>NMDA RECEPTOR Glutamate Recognition Site Ca 2+
    15. 15. Biochemical Cascade: Increased Calcium <ul><li>Excitotoxic </li></ul><ul><li>Interference with enzymatic reactions </li></ul><ul><ul><li>Phospholipase </li></ul></ul><ul><ul><ul><li>Membrane phospholipid hydrolysis </li></ul></ul></ul><ul><ul><li>Arachidonic acid cycle </li></ul></ul><ul><ul><ul><ul><li>Prostaglandin synthesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Gene expression </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Protein synthesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Production of free radical </li></ul></ul></ul></ul><ul><ul><li>Release of Cytochrome C </li></ul></ul>
    16. 16. Glutamate <ul><ul><li>In Neuron culture  Glutamate toxic </li></ul></ul><ul><ul><li>Glutamate or glutamate agonist injected into regions of the brain  neuronal injury = after hypoxia-ischemia </li></ul></ul><ul><ul><li>Deafferentation of glutaminergic excitatory input in hippocampus ↓ damage from hypoxia-ischemia </li></ul></ul><ul><li>In Vitro </li></ul><ul><li>In Vivo </li></ul>
    17. 17. Potential Neuroprotective Strategies
    18. 18. Magnesium <ul><li>Intracellular cation, Mg ++ </li></ul><ul><li>Essential for cellular functions </li></ul><ul><ul><li>DNA transcription </li></ul></ul><ul><ul><li>Hormone receptor binding, mitochondrial oxidative phosphorylation </li></ul></ul><ul><ul><li>Gating calcium channels </li></ul></ul><ul><ul><li>Transmembrane ion flux </li></ul></ul><ul><ul><li>Adenylate cyclase regulation </li></ul></ul><ul><ul><li>Muscle contraction </li></ul></ul><ul><ul><li>Control of vasomotor tone </li></ul></ul><ul><ul><li>Cardiac excitability </li></ul></ul><ul><ul><li>Neuronal transmitter release </li></ul></ul><ul><li>Block Voltage Dependent Ca 2+ Channel </li></ul><ul><li>NMDA receptor antagonist </li></ul><ul><li>Anticonvulsant </li></ul>
    19. 19. Why Would Magnesium Sulfate Work?? <ul><li>Magnesium is a non-competitive antagonist of the glutamate NMDA receptor </li></ul><ul><li>↑ Extracellular magnesium  block calcium influx into the cell  block neuronal injury </li></ul>
    20. 20. Post Magnesium: NDMA Receptor Ca 2+
    21. 21. Animal Studies <ul><li>In Vitro </li></ul><ul><ul><ul><li>Neuron culture and hippocampal slices die in anoxic environment </li></ul></ul></ul><ul><ul><ul><li>In presence of Mg 2+ death is prevented </li></ul></ul></ul><ul><li>Hamsters </li></ul><ul><ul><li>Mg2+ def ↑ susceptibility of hamster hearts to free radical damage </li></ul></ul><ul><li>Immature Rats </li></ul><ul><ul><li>↓ Brain lesions after Magnesium sulfate </li></ul></ul><ul><li>Piglets </li></ul><ul><ul><li>Does not protect against cerebral damage </li></ul></ul><ul><li>Near-Term (Late Preterm?) Lamb </li></ul><ul><ul><li>No improvement neuro outcome after umbilical cord occlusion </li></ul></ul>
    22. 22. Postnatal Magnesium Sulfate <ul><li>ICHIBA et al. (2002). Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia . </li></ul><ul><li>Randomized controlled trial </li></ul><ul><li>Objective: To determine whether postnatal MgSO4 infusion (250 mg/kg per day) for 3 days is both safe and able to improve outcome in infants with severe birth asphyxia </li></ul><ul><li>Magnesium Sulfate 250mg/kg q 24h X 3 days </li></ul><ul><li>Conclusion: </li></ul><ul><ul><li>Postnatal magnesium safe </li></ul></ul><ul><ul><li>Improved short-term outcomes </li></ul></ul>
    23. 23. Postnatal Magnesium Sulfate <ul><li>Ichiba H, et al (2006). Neurodevelopmental outcome of infants with birth asphyxia treated with magnesium sulfate. </li></ul><ul><li>30 Term Newborns, nonrandomized </li></ul><ul><li>250mg/kg of Magnesium Sulfate within 6 hours of birth q 12hr x two additional doses </li></ul><ul><li>No sign adverse effects </li></ul><ul><li>Follow up at 18months of age </li></ul><ul><ul><li>6 infants with cerebral palsy </li></ul></ul><ul><ul><li>73% with nL development </li></ul></ul>
    24. 24. Postnatal Magnesium Sulfate <ul><li>Bhat MA, et al 2009 Magnesium Sulfate in Severe Perinatal Asphyxia: A Randomized, Placebo-Controlled Trial </li></ul><ul><li>Randomized, Placebo-Controlled Trial </li></ul><ul><li>Objective: To study whether postnatal magnesium sulfate infusion could improve neurologic outcomes at discharge for term neonates with severe perinatal asphyxia. </li></ul><ul><li>Eligibility: </li></ul><ul><ul><li>≥ 37 weeks </li></ul></ul><ul><ul><li>< 6 hours of age </li></ul></ul><ul><ul><li>Severe asphyxia </li></ul></ul><ul><li>Moderate or severe HIE </li></ul><ul><li>Treatment Group vs. Placebo </li></ul><ul><ul><li>Magnesium sulfate 250mg/kg per dose q 24hrs </li></ul></ul><ul><ul><li>Normal Saline same volume </li></ul></ul>
    25. 25. Postnatal Magnesium: Status at Discharge
    26. 26. Postnatal Magnesium: Study Conclusion <ul><ul><li>Primary Outcome: neurologic outcomes at discharge </li></ul></ul><ul><ul><ul><li>Neuro exam </li></ul></ul></ul><ul><ul><ul><li>CT scan </li></ul></ul></ul><ul><ul><ul><li>EEG </li></ul></ul></ul><ul><ul><ul><li>Oral feedings </li></ul></ul></ul><ul><ul><ul><li>Seizures </li></ul></ul></ul><ul><ul><ul><li>Composite good short term outcome </li></ul></ul></ul><ul><ul><li>Study Conclusion: Postnatal magnesium sulfate treatment improves neurologic outcomes at discharge for term neonates with severe perinatal asphyxia. </li></ul></ul>
    27. 27. Conclusion <ul><li>Magnesium has potential neuroprotective use in hypoxic-ischemic insults to the newborn brain. </li></ul><ul><li>Pros </li></ul><ul><ul><li>Cheap </li></ul></ul><ul><ul><li>No equipment to buy </li></ul></ul><ul><ul><li>Easy to administer </li></ul></ul><ul><li>Literature: </li></ul><ul><ul><li>Studies results variable </li></ul></ul><ul><ul><ul><li>Some reports promising </li></ul></ul></ul><ul><ul><li>Multicenter randomized placebo controlled trial </li></ul></ul>
    28. 28. Antepartum Magnesium Sulfate
    29. 29. Antenatal MgSO 4 - Opinions vary. . . <ul><li>“ MgSO 4 for CP prevention: too good to be true? . . . helped me put the confusing data into context”. -Macones, MD </li></ul><ul><li>“ . . .the answer to the question of whether evidence-based medicine supports the use of magnesium for neuroprophylaxis in preterm infants remains unclear.” – Cahill, MD , Caughey, MD </li></ul><ul><li>“ . . . results suggest that antenatal magnesium sulfate could be used for the primary prevention of cerebral palsy in preterm infants. . .” </li></ul><ul><li>-Conde-Agudelo, MD, Romero, MD </li></ul><ul><li>“ . . .trials provide strong support for the utilization of MgSO 4 to lower the risk of cerebral palsy among survivors of early preterm birth. . . Has the potential to prevent 1000 cases of handicapping cerebral palsy annually.” – Rouse, MD </li></ul>
    30. 30. Early Studies and Theories of Mechanism <ul><li>Early hypothesis was that intracranial hemorrhage lead to CP </li></ul><ul><li>1980’s, studies showed decreased rates of IVH in VLBW infants born to women with preeclampsia. </li></ul><ul><li>Could this be explained by exposure to MgSO4? </li></ul><ul><li>Early 1990’s, it was shown that VLBW infants exposed to MgSO4 for tocolysis also had decreased rates of IVH. </li></ul><ul><li>1995 – Nelson and Grether found a lower rate of CP in VLBW infants exposed MgSO4 </li></ul>
    31. 31. Review of recent studies <ul><li>MagNET </li></ul><ul><li>ACTOMgSO 4 </li></ul><ul><li>MAGPIE </li></ul><ul><li>PREMAG </li></ul><ul><li>BEAM </li></ul><ul><li>Metaanalysis of these 5 studies </li></ul>
    32. 32. MagNET <ul><li>Mittendorf, et al 2002. Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants.( Magnesium and Neurologic Endpoints Trial) </li></ul><ul><ul><ul><li>Objective: determine whether antenatal MgSO 4 prevents adverse outcomes ( IVH/Periventricular leukomalacia/CP/Death) </li></ul></ul></ul><ul><ul><li>149 women </li></ul></ul><ul><ul><li>Singleton or twin 24-34 weeks c PPROM or PTL </li></ul></ul><ul><ul><li>2 protocols; one which examined use for CP prevention, the other evaluated MgSO 4 as a tocolytic </li></ul></ul><ul><ul><li>Prevention group - >4cm, received 4 gm load </li></ul></ul>
    33. 33. MagNET - Outcomes <ul><li>In neuroprophylaxis arm – 37% (11/30) had an adverse event compared to 21% (6/29) of those that received placebo. </li></ul><ul><li>When the 2 arms were combined, 32% of infants that received MgSO 4 had an adverse event compared to 19% of the infants of mothers that received placebo. </li></ul><ul><li>The findings were not statistically significant (p=.07) yet raised concern that MgSO4 might be harmful to neonates. There appeared to be a dose response relationship between magnesium sulfate and adverse outcomes. </li></ul>
    34. 34. ACTOMgSO4 <ul><li>Crowther, et al 2003. Effect of Magnesium Sulfate Given for Neuroprotection Before Preterm Birth. </li></ul><ul><ul><li>Objective: determine effectiveness of MgSO 4 given for neuroprotection to women @ risk for preterm delivery before 30 wks </li></ul></ul><ul><ul><li>RCT at 16 tertiary hospitals in Australia and New Zealand </li></ul></ul><ul><ul><li>1062 women, less than 30 wks gestation. Single/twin/triplet/quadruplet pregnancies </li></ul></ul><ul><ul><li>Birth expected within 24 hours. </li></ul></ul><ul><ul><li>4 gram load followed by 2 grams/hr. </li></ul></ul>
    35. 35. ACTOMgSO4 - Inclusion criteria
    36. 36. ACTOMgSO4 - Outcomes <ul><li>The primary outcomes of total pediatric mortality, cerebral palsy in survivors, and combined death or cerebral palsy were all lower in the magnesium sulfate group, but no differences were statistically significant. </li></ul><ul><li>There was a reduction in substantial gross motor dysfuction in the group treated with MgSO 4 </li></ul>
    37. 37. MAGPIE – Trial follow-Up Study <ul><li>MAGPIE – Prospective RCT conducted at 175 hospitals in 33 countries. Originally included 8804 women with pre-eclampsia randomized to MgSO 4 or placebo. Concluded that risk of seizure was 58% lower in pre-eclamptic women given MgSO 4 . </li></ul><ul><ul><li>Objective of the follow-Up study – assess long-term effects of in utero exposure to magnesium sulfate for children whose mothers had pre-eclampsia. (Is MgSO 4 safe?) </li></ul></ul><ul><ul><li>2895 of 4483 children assessed at 18 months of age for the primary outcome of death or neurosensory disability. </li></ul></ul>
    38. 38. MAGPIE - Conclusion <ul><li>Original study – Magnesium sulfate for women with pre-eclampsia more than halves the risk of eclampsia and probably reduces the risk of maternal death before discharge from the hospital </li></ul><ul><li>No substantive harmful effects were apparent in the short term, for either mother or baby. Exposure to magnesium sulfate while in utero was not associated with a clear difference in the risk of death or disability for children at 18 months. </li></ul>
    39. 39. PREMAG <ul><li>Marret, et al 2008. Benefit of Magnesium Sulfate Given before Very Preterm Birth to Protect Infant Brain. </li></ul><ul><ul><li>Objective: To evaluate whether magnesium sulfate given to women at risk of very-preterm birth would be neuroprotective in preterm newborns and would prevent neonatal mortality and severe white-matter injury. </li></ul></ul><ul><ul><li>Carried out in 18 French tertiary hospitals </li></ul></ul><ul><ul><li>Gestational age < 33 weeks whose birth was planned or expected within 24 hours </li></ul></ul><ul><ul><li>Women received a single 4 gram infusion of MgSO 4 or placebo </li></ul></ul>
    40. 40. PREMAG – Maternal Characteristics <ul><li>Preterm labor – 84% </li></ul><ul><li>PPROM – 53% </li></ul><ul><li>Chorioamnionitis – 9.5% </li></ul><ul><li>Antepartum hemorrhage – 19% </li></ul><ul><li>Other – 9.8% </li></ul><ul><li>Tocolysis – 67% </li></ul><ul><li>Antibiotics – 77% </li></ul><ul><li>Corticosteriods – 95% </li></ul>
    41. 41. PREMAG - Outcomes <ul><li>Primary outcomes were rates of severe white-matter injury (WMI) or total mortality before hospital discharge, and their combined outcome. </li></ul><ul><li>The rates of total mortality before hospital discharge, severe WMI, and the combination of severe WMI and/or death were all lower for the MgSO4 group, but no differences were statistically significant </li></ul>
    42. 42. BEAM <ul><li>Rouse, et al 2008. A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy. (Beneficial Effects of Antenatal Magnesium Sulfate Trial) </li></ul><ul><ul><li>Objective: Test the hypothesis that the administration of MgSO 4 to women at high risk for early preterm delivery would reduce the risk of cerebral palsy in their children. </li></ul></ul><ul><ul><li>20 participating centers across the US </li></ul></ul><ul><ul><li>2241 women, singleton or twin gestations 24-31 wks. </li></ul></ul><ul><ul><li>6 gram loading dose of MgSO 4 followed by 2 g/hr </li></ul></ul>
    43. 43.
    44. 44. BEAM <ul><li>Primary outcomes measured: </li></ul><ul><ul><li>Composite of stillbirth or infant death by 1 year or moderate to severe cerebral palsy at or beyond 2 years </li></ul></ul>
    45. 45. BEAM <ul><li>The rate of the primary outcome was not significantly different in the MgSO 4 group and the placebo group (11.3% and 11.7%, respectively ) </li></ul><ul><li>Secondary analysis: When mortality and CP looked at separately, CP occurred significantly less frequently in the MgSO 4 group than the placebo group (1.9% vs 3.5%, respectively ) </li></ul>
    46. 46. BEAM <ul><li>Criticisms of the Study: </li></ul><ul><ul><li>The composite outcomes are competing risk for the outcome of interest: CP. Infants who die before their first birthday cannot be evaluated for CP. </li></ul></ul><ul><ul><li>How many of those infants that died at their first birthday had CP? </li></ul></ul><ul><ul><li>How many of the 99 infants who died in the MgSO 4 group would have needed to survive and be diagnosed with CP for the results to no longer be statistically significant? = 2 </li></ul></ul>
    47. 47. BEAM <ul><li>Praise of the study: Although it is a small effect, it is statistically significant. </li></ul><ul><ul><li>Number needed to treat (NNT) = overall 63 </li></ul></ul><ul><ul><li>NNT in high-risk group (<28wks) = 29 </li></ul></ul><ul><ul><li>Low risk (>28wks)= 265 </li></ul></ul>
    48. 48. Metaanalysis <ul><li>Constantine M 2009. Effects of Antenatal Exposure to Magnesium Sulfate on Neuroprotection and Mortality in Preterm Infants: A Meta-analysis. </li></ul><ul><ul><li>Objective: To review the evidence of of fetal neuroprotection by MgSO 4 and specifically explore the findings at different gestational ages . </li></ul></ul><ul><ul><li>Two thresholds for analysis </li></ul></ul><ul><ul><ul><li>Less than 32-34 wks </li></ul></ul></ul><ul><ul><ul><li>Less than 30 weeks </li></ul></ul></ul>
    49. 49. Table 1 1
    50. 50. Metaanalysis <ul><li>Primary outcome: </li></ul><ul><ul><li>Composite of perinatal/infant death or CP among survivors </li></ul></ul><ul><li>Secondary outcomes: </li></ul><ul><ul><li>Death </li></ul></ul><ul><ul><li>CP </li></ul></ul><ul><ul><li>moderate-severe CP </li></ul></ul><ul><ul><li>Combined death or moderate-severe CP </li></ul></ul>
    51. 51.
    52. 52. Metaanalysis <ul><li>Results: </li></ul><ul><li>In utero fetal exposure to magnesium sulfate given to women at risk of preterm delivery significantly reduced the risk of cerebral palsy </li></ul><ul><ul><li>NNT = 46 ( before 30 wks gestation ) </li></ul></ul><ul><ul><li>NNT = 56 ( before 32-34 wks gestation ) </li></ul></ul><ul><li>No increase in the risk of perinatal or infant death </li></ul><ul><li>The benefit of using magnesium sulfate beyond 32-34 weeks for fetal neuroprotection is unproven. </li></ul>
    53. 53. Metaanalysis <ul><li>Strengths: </li></ul><ul><ul><li>RCT’s specifically designed to study neuroprotective effects of MgSO 4 </li></ul></ul><ul><ul><li>Reassurance of safety of MgSO 4 </li></ul></ul><ul><ul><li>Demonstrates beneficial effect of 32-34 wks, as well as less than 30 wks </li></ul></ul><ul><li>Limitations: </li></ul><ul><ul><li>MgSO 4 regimen differed among trials </li></ul></ul><ul><ul><li>Dose received differed as well as timing </li></ul></ul><ul><ul><li>Differences in patient characteristics </li></ul></ul>
    54. 54. Conclusion <ul><li>Drs Mercer and Merlino, Sept 2009 Green Journal Clinical Expert Series. Magnesium sulfate for Preterm Labor and Preterm Birth. </li></ul><ul><li>Recommendations/comments: </li></ul><ul><ul><li>Four randomized trials have been specifically designed to evaluate magnesium sulfate for neuroprotection </li></ul></ul><ul><ul><li>each of these four neuroprotection trials failed to demonstrate significant improvements in the designated primary outcome </li></ul></ul>
    55. 55. Conclusion <ul><li>None found increased pediatric morbidities or mortality with magnesium sulfate treatment given for this indication </li></ul><ul><li>Comparisons between the published trials are made difficult by differences in inclusion criteria, study interventions, and evaluated outcomes </li></ul><ul><li>Although a 2009 meta-analysis was supportive of magnesium sulfate for neuroprotection before preterm birth, the optimal treatment indication(s), gestational age range, and therapeutic regimen remain to be determined </li></ul><ul><li>Because the potential benefits of antenatal magnesium sulfate were identified only in secondary analyses from the recent major prospective trials, caution is warranted in incorporating such treatment into clinical practice </li></ul>
    56. 56. References <ul><li>Vannucci, R. and Perlman JM. Interventions for Perinatal Hypoxic-Ishemic Encephalopathy. Pediatrics . 1997;100;1004-1114 </li></ul><ul><li>Leone CR and Barbosa N. Magnesium and Perinatal Asphyxia. Neoreviews. 2007;8;e3387-3393. </li></ul><ul><li>Icchiba H, Yokoi T, Tamai H, Ueda T, Kim TJ. Neurodevelopmental outcome of infants with birth asphyxia treated with magnesium sulfate. Pediar Int. 2006; 48:70-75 </li></ul><ul><li>Ichiba H, Tamai H, Negishi H, et al. Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia. Pediatr Int. 2002;44 (5):505 –509 </li></ul><ul><li>Khashaba MT, Shouman BO, Shaltout AA, et al. Excitatory amino acids and magnesium sulfate in neonatal asphyxia. Brain Dev 2006;28:375-379 </li></ul><ul><li>Mushtaq AB, Bashir Ahmad C. et al, Magnesium Sulfate in Severe Perinatal Asphyxia: A Randomized, Placebo-Controlled Trial. Pediatrics. Vol. 123 No. 5 May 2009, pp. e764-e769 </li></ul><ul><li>Nelson KB. The epidemiology of cerebral palsy in term infants. Ment Retard Dev Disabil Res Rev. 2002;8:146–150 </li></ul><ul><li>Hankins GDV, Speer M. Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy. Obstet Gynecol. 2003;102:628–636 </li></ul><ul><li>Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33:696–705 </li></ul>
    57. 57. References <ul><li>Cahill A, Caughey A. Magnesium for neuroprophylaxis: fact or fiction? Am J Obstet Gynecol 2009;200:590-4 </li></ul><ul><li>Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG, Besinger RE, et al. Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. Am J Obstet Gynecol 2002;186:1111-8. </li></ul><ul><li>Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:2669-76. </li></ul><ul><li>Magpie Trial Follow-Up Study Collaborative Group. The Magpie Trial: a randomised trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for children at 18 months. BJOG 2007;114:289-99. </li></ul><ul><li>  Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Lévêque Hellot MF, et al. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomised controlled PREMAG trial. BJOG 2007;114:310-8. </li></ul><ul><li>Marret S, Marpeau L, Bénichou J. Benefit of magnesium sulfate given before very preterm birth to protect infant brain. Pediatrics 2008;121:225-6 </li></ul><ul><li>Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895-905 </li></ul><ul><li>Constantine M, Weiner J. Effects of Antenatal Exposure to Magnesium Sulfate on Neuroprotection and Mortality in Preterm Infants, A Meta-analysis. Obstetrics and Gynecology 2009;114:354-64 </li></ul><ul><li>Mercer B, Merlino A. Magnesium Sulfate for Preterm Labor and Preterm Birth. Clinical Expert Series. Obstetrics & Gynecology. 2009;114:650-668 </li></ul>