magnesium sulfate for cerebral palsy prevention
DESCRIPTION
Drs. Brocato and Goodwin.TRANSCRIPT
MAGNESIUM SULFATE FOR CEREBRAL PALSY PREVENTIONA. Goodwin-Samson, MD B. Brocato, DO
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Objectives
Define Cerebral Palsy Review hypoxia-ischemia injury at
neuronal level Discuss magnesium sulfate as a
potential neuroprotective agent Review the current literature of postnatal
magnesium sulfate (MgSO4) Review the current literature of
antenatal MgSO4
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Cerebral Palsy: History
1861 Dr. William John Little described a disorder that was crippling and made children’s muscle weak, stiff and prone to twitching. Little’s Disease Followed complicated delivery lack of O2 brain
damage
1897 Dr. Sigmund Freud disputed Dr. Little's claim disorder began before birth
Research by National Institute of Neurological Disorders and
Stroke (NINDS) in 1980’s No single etiology of CP
Cerebral Palsy
Definition: Global term for a group of disorder which effect movement and muscle coordination which is nonprogressive in nature.
Incidence: 2-3 children per 1,000 Increasing in the US increased survival of premature
infants
Etiology: Multifactorial Damage to a developing brain
Risk Factors: Preterm Birth Birth Asphyxia 6-20% Hypoxia Ischemic encephalopathy(HIE)
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Hypoxia-Ischemia Background Hypoxia-Ischemic encephalopathy: clinical
and lab evidence of acute or subacute brain injury secondary to asphyxia
Hypoxia-Ischemia Encephalopathy can result in CP
2 to 4/1000 full-term infants suffer asphyxia
Incidence of asphyxia leading to CP 0.2 to 0.4/1000 infants
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Ischemic Brain Injury (IBI) 6
Hypoxia-Ischemia at Neuronal Level
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Background: Sodium and Potassium Regulation
Presynaptic membrane Na+/K+ pump Maintains ion gradient across cell membrane Adenosine TriPhosphate (ATP) driven
↑↑Na+
↑↑K+
2K+
3Na+
3Na+
2K+
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2K+
K+
K+
Na+
3Na+
+++++++ ++
Na+
Background: Calcium Regulation
Ca2+ is 10,000X extracellular>> cytoplasm
ATP-driven pump
Voltage-gated ion channel
Ion-Exchangers
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Cellular Energy
ATP in manufactured in the mitochondria Na+/K+ pump
require ATP to continue to work
ATP in mitochondria requires O2
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Hypoxia: Cellular Level
Generate ATP Glycolysis
Glucose 2 ATP + Lactate
Regenerate ATP Phosphocreatine
(PCr) ADP ATP
Hypoxic Environment Phosphocreatine (PCr)/ATP vs. Time
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Hypoxia-Ischemia: Cellular Level
Net breakdown of glycolysis ADP, AMP, phosphate, lactate and acid
accumulation
↑ CO2 carbonic acid (H2CO3)
Within mins w/o 02 ↓↓ ATP Na+/K+ pump stops working depolarization K+ exits cell Na+ influx
Acidosis
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Depolarization of Presynaptic Neuron
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PostsynapticNeuron
Presynaptic Neuron
IBI: Cellular Level Voltage-Dependent Calcium Channels Glutamate receptors
N-Methyl-D-Aspartate (NMDA) AMPA
Glutamate receptors ↑↑ Ca 2+ entry into intracellular space
NMDA RECEPTOR
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Glutamate Recognition Site
Ca 2+
Biochemical Cascade: Increased Calcium
Excitotoxic Interference with
enzymatic reactions Phospholipase
Membrane phospholipid hydrolysis
Arachidonic acid cycle
Prostaglandin synthesis Gene expression Protein synthesis Production of free radical
Release of Cytochrome C
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Glutamate
In Neuron culture Glutamate toxic
Glutamate or glutamate agonist injected into regions of the brain neuronal injury = after hypoxia-ischemia
Deafferentation of glutaminergic excitatory input in hippocampus ↓ damage from hypoxia-ischemia
In Vitro In Vivo
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Potential Neuroprotective Strategies
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Magnesium
Intracellular cation, Mg ++ Essential for cellular functions
DNA transcription Hormone receptor binding, mitochondrial oxidative phosphorylation Gating calcium channels Transmembrane ion flux Adenylate cyclase regulation Muscle contraction Control of vasomotor tone Cardiac excitability Neuronal transmitter release
Block Voltage Dependent Ca2+ Channel NMDA receptor antagonist
Anticonvulsant
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Why Would Magnesium Sulfate Work??
Magnesium is a non-competitive antagonist of the glutamate NMDA receptor
↑ Extracellular magnesium block calcium influx into the cell block neuronal injury
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Post Magnesium: NDMA Receptor
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Ca2+
Animal Studies In Vitro
Neuron culture and hippocampal slices die in anoxic environment In presence of Mg 2+ death is prevented
Hamsters Mg2+ def ↑ susceptibility of hamster hearts to free radical
damage
Immature Rats ↓ Brain lesions after Magnesium sulfate
Piglets Does not protect against cerebral damage
Near-Term (Late Preterm?) Lamb No improvement neuro outcome after umbilical cord occlusion
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Postnatal Magnesium Sulfate ICHIBA et al. (2002). Randomized controlled
trial of magnesium sulfate infusion for severe birth asphyxia.
Randomized controlled trial 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
Magnesium Sulfate 250mg/kg q 24h X 3 days Conclusion:
Postnatal magnesium safe Improved short-term outcomes
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Postnatal Magnesium Sulfate• Ichiba H, et al (2006). Neurodevelopmental
outcome of infants with birth asphyxia treated with magnesium sulfate.
• 30 Term Newborns, nonrandomized• 250mg/kg of Magnesium Sulfate within 6 hours of
birth q 12hr x two additional doses• No sign adverse effects• Follow up at 18months of age
• 6 infants with cerebral palsy• 73% with nL development
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Postnatal Magnesium Sulfate Bhat MA, et al 2009 Magnesium Sulfate in Severe
Perinatal Asphyxia: A Randomized, Placebo-Controlled Trial
Randomized, Placebo-Controlled Trial Objective: To study whether postnatal magnesium sulfate
infusion could improve neurologic outcomes at discharge for term neonates with severe perinatal asphyxia.
Eligibility: ≥ 37 weeks < 6 hours of age Severe asphyxia
Moderate or severe HIE Treatment Group vs. Placebo
Magnesium sulfate 250mg/kg per dose q 24hrs Normal Saline same volume
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Postnatal Magnesium: Status at Discharge
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Postnatal Magnesium: Study Conclusion
Primary Outcome: neurologic outcomes at discharge Neuro exam CT scan EEG Oral feedings Seizures Composite good short term outcome
Study Conclusion: Postnatal magnesium sulfate treatment improves neurologic outcomes at discharge for term neonates with severe perinatal asphyxia.
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Conclusion
Magnesium has potential neuroprotective use in hypoxic-ischemic insults to the newborn brain.
Pros Cheap No equipment to buy Easy to administer
Literature: Studies results variable
Some reports promising Multicenter randomized placebo controlled trial
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Antepartum Magnesium Sulfate
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Antenatal MgSO4 - Opinions vary. . .
“MgSO4 for CP prevention: too good to be true? . . . helped me put the confusing data into context”. -Macones, MD
“. . .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
“. . . results suggest that antenatal magnesium sulfate could be used for the primary prevention of cerebral palsy in preterm infants. . .”-Conde-Agudelo, MD, Romero, MD
“. . .trials provide strong support for the utilization of MgSO4 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
Early Studies and Theories of Mechanism Early hypothesis was that intracranial hemorrhage lead to
CP
1980’s, studies showed decreased rates of IVH in VLBW infants born to women with preeclampsia.
Could this be explained by exposure to MgSO4?
Early 1990’s, it was shown that VLBW infants exposed to MgSO4 for tocolysis also had decreased rates of IVH.
1995 – Nelson and Grether found a lower rate of CP in VLBW infants exposed MgSO4
Review of recent studies
MagNET ACTOMgSO4
MAGPIE PREMAG BEAM Metaanalysis of these 5 studies
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MagNET
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)
• Objective: determine whether antenatal MgSO4 prevents adverse outcomes ( IVH/Periventricular leukomalacia/CP/Death)
• 149 women• Singleton or twin 24-34 weeks c PPROM or PTL• 2 protocols; one which examined use for CP
prevention, the other evaluated MgSO4 as a tocolytic• Prevention group - >4cm, received 4 gm load
MagNET - Outcomes
• In neuroprophylaxis arm – 37% (11/30) had an adverse event compared to 21% (6/29) of those that received placebo.
• When the 2 arms were combined, 32% of infants that received MgSO4 had an adverse event compared to 19% of the infants of mothers that received placebo.
• 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.
ACTOMgSO4
Crowther, et al 2003. Effect of Magnesium Sulfate Given for Neuroprotection Before Preterm Birth.• Objective: determine effectiveness of MgSO4
given for neuroprotection to women @ risk for preterm delivery before 30 wks
• RCT at 16 tertiary hospitals in Australia and New Zealand
• 1062 women, less than 30 wks gestation. Single/twin/triplet/quadruplet pregnancies
• Birth expected within 24 hours.• 4 gram load followed by 2 grams/hr.
ACTOMgSO4 - Inclusion criteria
ACTOMgSO4 - Outcomes
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.
There was a reduction in substantial gross motor dysfuction in the group treated with MgSO4
MAGPIE – Trial follow-Up Study
MAGPIE – Prospective RCT conducted at 175 hospitals in 33 countries. Originally included 8804 women with pre-eclampsia randomized to MgSO4 or placebo. Concluded that risk of seizure was 58% lower in pre-eclamptic women given MgSO4. • 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 MgSO4 safe?)
• 2895 of 4483 children assessed at 18 months of age for the primary outcome of death or neurosensory disability.
MAGPIE - Conclusion
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
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.
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PREMAG
Marret, et al 2008. Benefit of Magnesium Sulfate Given before Very Preterm Birth to Protect Infant Brain.• 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.
• Carried out in 18 French tertiary hospitals• Gestational age < 33 weeks whose birth was planned
or expected within 24 hours• Women received a single 4 gram infusion of MgSO4 or
placebo
PREMAG – Maternal Characteristics
• Preterm labor – 84%• PPROM – 53%• Chorioamnionitis – 9.5%• Antepartum hemorrhage – 19%• Other – 9.8%• Tocolysis – 67%• Antibiotics – 77%• Corticosteriods – 95%
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PREMAG - Outcomes
Primary outcomes were rates of severe white-matter injury (WMI) or total mortality before hospital discharge, and their combined outcome.
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
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BEAM
Rouse, et al 2008. A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy. (Beneficial Effects of Antenatal Magnesium Sulfate Trial)• Objective: Test the hypothesis that the
administration of MgSO4 to women at high risk for early preterm delivery would reduce the risk of cerebral palsy in their children.
• 20 participating centers across the US• 2241 women, singleton or twin gestations 24-31
wks.• 6 gram loading dose of MgSO4 followed by 2 g/hr
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BEAM
Primary outcomes measured:• Composite of stillbirth or infant death by 1
year or moderate to severe cerebral palsy at or beyond 2 years
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BEAM
The rate of the primary outcome was not significantly different in the MgSO4 group and the placebo group (11.3% and 11.7%, respectively )
Secondary analysis: When mortality and CP looked at separately, CP occurred significantly less frequently in the MgSO4 group than the placebo group (1.9% vs 3.5%, respectively )
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BEAM
Criticisms of the Study:• The composite outcomes are competing risk
for the outcome of interest: CP. Infants who die before their first birthday cannot be evaluated for CP.
• How many of those infants that died at their first birthday had CP?
• How many of the 99 infants who died in the MgSO4 group would have needed to survive and be diagnosed with CP for the results to no longer be statistically significant? = 2
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BEAM
Praise of the study: Although it is a small effect, it is statistically significant.• Number needed to treat (NNT) = overall 63• NNT in high-risk group (<28wks) = 29• Low risk (>28wks)= 265
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Metaanalysis
Constantine M 2009. Effects of Antenatal Exposure to Magnesium Sulfate on Neuroprotection and Mortality in Preterm Infants: A Meta-analysis.• Objective: To review the evidence of of fetal
neuroprotection by MgSO4 and specifically explore the findings at different gestational ages.
• Two thresholds for analysis• Less than 32-34 wks• Less than 30 weeks
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Table 1
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Metaanalysis
Primary outcome:• Composite of perinatal/infant death or CP
among survivors Secondary outcomes:
• Death • CP• moderate-severe CP• Combined death or moderate-severe CP
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Metaanalysis
Results:• In utero fetal exposure to magnesium sulfate
given to women at risk of preterm delivery significantly reduced the risk of cerebral palsy• NNT = 46 ( before 30 wks gestation )• NNT = 56 ( before 32-34 wks gestation )
• No increase in the risk of perinatal or infant death
• The benefit of using magnesium sulfate beyond 32-34 weeks for fetal neuroprotection is unproven.
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Metaanalysis
Strengths:• RCT’s specifically designed to study
neuroprotective effects of MgSO4
• Reassurance of safety of MgSO4
• Demonstrates beneficial effect of 32-34 wks, as well as less than 30 wks
Limitations:• MgSO4 regimen differed among trials• Dose received differed as well as timing• Differences in patient characteristics
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Conclusion
Drs Mercer and Merlino, Sept 2009 Green Journal Clinical Expert Series. Magnesium sulfate for Preterm Labor and Preterm Birth.
Recommendations/comments:• Four randomized trials have been
specifically designed to evaluate magnesium sulfate for neuroprotection
• each of these four neuroprotection trials failed to demonstrate significant improvements in the designated primary outcome
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Conclusion
• None found increased pediatric morbidities or mortality with magnesium sulfate treatment given for this indication
• Comparisons between the published trials are made difficult by differences in inclusion criteria, study interventions, and evaluated outcomes
• 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
• 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
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References
Vannucci, R. and Perlman JM. Interventions for Perinatal Hypoxic-Ishemic Encephalopathy. Pediatrics. 1997;100;1004-1114
Leone CR and Barbosa N. Magnesium and Perinatal Asphyxia. Neoreviews. 2007;8;e3387-3393.
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
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
Khashaba MT, Shouman BO, Shaltout AA, et al. Excitatory amino acids and magnesium sulfate in neonatal asphyxia. Brain Dev 2006;28:375-379
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
Nelson KB. The epidemiology of cerebral palsy in term infants. Ment Retard Dev Disabil Res Rev. 2002;8:146–150
Hankins GDV, Speer M. Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy. Obstet Gynecol. 2003;102:628–636
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33:696–705
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References
o Cahill A, Caughey A. Magnesium for neuroprophylaxis: fact or fiction? Am J Obstet Gynecol 2009;200:590-4
o 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.
o 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.
o 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.
o 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.
o Marret S, Marpeau L, Bénichou J. Benefit of magnesium sulfate given before very preterm birth to protect infant brain. Pediatrics 2008;121:225-6
o 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
o 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
o Mercer B, Merlino A. Magnesium Sulfate for Preterm Labor and Preterm Birth. Clinical Expert Series. Obstetrics & Gynecology. 2009;114:650-668
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