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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