Magnesium Sulfate Neuroprotection For the Prevention of Cerebral Palsy APRIL 2011
Biologic Plausibility MgSO4 Neuroprotection <ul><li>MgSO4 may exert a vasodilator effect in the fetal cerebral vessels mitigating hypoxia and/or ischemia induced brain damage. </li></ul><ul><li>MgSO4 exerts an anti-inflammatory effect resulting in decreased production of pro-inflammatory cytokines and free radicals which ultimately decreases cerebral cell death secondary to inflammation. </li></ul><ul><li>MgSO4 down regulates NMDA receptors for the neurotransmitter glutamate thereby decreasing Calcium entry into the cell and modulating a protective mitigation of excitatory action potential propagation. </li></ul>
ACOG COMMITTEE OPINION 455 MARCH 2010 <ul><li>Available evidence suggests that magnesium sulfate given before early preterm birth reduces the risk of cerebral palsy in surviving infants. </li></ul><ul><li>Physicians electing to use magnesium sulfate for fetal neuroprotection should develop specific guidelines regarding inclusion criteria, treatment regimens, and monitoring in accordance with one of the larger trials. </li></ul>
Referenced by ACOG opinion 455 3 Largest Neuroprotection Trials n = 4,184 <ul><li>N Engl J Med 2008;359:895 (BEAM TRIAL) ( < 34 weeks 6g/2g /12-24hrs) The rate of moderate to severe cerebral palsy was significantly lower in the magnesium group (1.9 versus 3.5 percent; RR 0.55; 95% CI 0.32-0.95) RCT N= 2,241 </li></ul><ul><li>JAMA 2003;290:2669 (ACTOMgSO4) ( < 30 weeks 4g/1g /24hrs) When gross motor function was considered the magnesium group had significantly lower rates of substantial gross motor dysfunction (3.4 vs 6.6 %) and the combined outcome of death or substantial gross motor dysfunction (17.0 vs 22.7 %). RCT N=1,255 </li></ul><ul><li>BJOG 2007;114:310 (PREMAG) ( < 33 weeks 4g load only) Exposure to magnesium sulfate was protective against "severe motor dysfunction or death" (OR 0.62, 95% CI 0.41-0.93) N= 688 </li></ul><ul><li>Gynecol Obstet Fertil 2008;36:278 Effect of magnesium sulphate on mortality and neurologic morbidity of the very-preterm newborn (of less than 33 weeks) with two-year neurological outcome: results of the prospective PREMAG trial. </li></ul>
Meta Analysis Conclusions <ul><li>Cochrane 2009 The neuroprotective role for antenatal magnesium sulphate therapy given to women at risk of preterm birth for the preterm fetus is now established. The number of women ( < 34 weeks ) needed to be treated to benefit one baby by avoiding cerebral palsy is 63 (95% confidence interval 43 to 155) n = 6,145 </li></ul><ul><li>Obstet Gynecol 2009;114:354 (NICHD) Fetal exposure to magnesium sulfate in women at risk of preterm delivery significantly reduces the risk of cerebral palsy without increasing the risk of death. n = 5,235 </li></ul><ul><li>AJOG 2009; 200:595 In conclusion, magnesium sulfate administered to women at risk of delivery before 34 weeks of gestation reduces the risk of cerebral palsy. n = 5,357 </li></ul><ul><li>Obstet Gynecol 2009;113:1327 Antenatal magnesium sulfate therapy given to women at risk of preterm birth is neuroprotective against motor disorders in childhood for the preterm fetus. n=4,446 </li></ul>
NNT Prevention Ratios <ul><li>(Cochrane) The number of women that would need to be treated to prevent one child from developing cerebral palsy less than 34 weeks was 63 </li></ul><ul><li>(NICHD) The number of women that would need to be treated to prevent one child from developing cerebral palsy in the 32-34 wk group was 56 </li></ul><ul><li>(NICHD) The number of women that would need to be treated to prevent one child from developing cerebral palsy in the less than 30 week group was 46 </li></ul><ul><li>(AJOG 2009;200:610) The number of women that would need to be treated to prevent one child from developing cerebral palsy in the less than 28 week group estimated to be 29 </li></ul><ul><li>Additional outcomes reviewed included: </li></ul><ul><li>In utero magnesium exposure did not significantly reduce the risk of -blindness </li></ul><ul><li>- deafness </li></ul><ul><li>- developmental delay </li></ul><ul><li>No significant adverse Neonatal effects such as increased risk of Apgar score less than seven at five minutes, intraventricular hemorrhage, periventricular leukomalacia, neonatal seizures, or need for ongoing respiratory support </li></ul>
DATA SUMMARY Arch Pediatr. 2011 Mar;18(3):324-30. <ul><li>It was shown in the Cochrane database and in 3 meta-analyses of 5 randomized trials: (Magpie (PIH), MagNet (Tocolysis/Neuroprotect), ActoMgSO [neuroprotection], PreMag [neuroprotection], and Beam [neuroprotection]) that prenatal magnesium sulfate given to mothers at risk of pre-term birth does not increase pediatric mortality and decreases the risk of cerebral palsy. </li></ul><ul><li>Magnesium Sulfate exerts significant neuroprotective effects on the occurrence of cerebral palsy at 2 years of age (relative risk, 0.69; 95% CI, 0.54-0.87) </li></ul><ul><li>Magnesium Sulfate decreased the risk of pediatric mortality and cerebral palsy (relative risk: 0.85; 95% confidence interval: 0.74-0.98). </li></ul><ul><li>The number needed to treat (NTT) to prevent 1 case of cerebral palsy was 63 (95% CI, 39-172) and the NTT for an extra survivor free of cerebral palsy in the neuroprotection subgroup was 42 (95% CI, 22-357), justifying that magnesium sulfate should be justifying that magnesium sulfate should be discussed as a stand-alone treatment </li></ul>
Riverside Neuroprotection MODIFIED BEAM TRIAL PROTCOL <ul><li>Neuroprotection protocol INITIATED for IMMINENT delivery FROM 23 0/7 – 33 6/7 weeks with @ least 2 hours Magnesium infusion prior to delivery for benefit. Exclude patients anticipated to deliver in < 2 hours or CI to MgSO4 ( eg. myasthenia gravis or severe sirs/sepsis ) </li></ul><ul><li>Delivery is considered imminent if clinically anticipated within ~ 12-24 hours. </li></ul><ul><li>1) Regular contractions ASSOCIATED with advanced cervical dilation ( 3-4 cm) with either preterm rupture of membranes OR intact membranes. </li></ul><ul><li>2) OR clinical suspicion for imminent delivery with isolated premature preterm rupture of membranes. </li></ul><ul><li>3) OR clinical suspicion of imminent delivery with antenatal bleeding </li></ul><ul><li>4) OR before an indicated preterm delivery </li></ul>
Riverside Neuroprotection Modification of the BEAM trial <ul><li>Neuroprotection PROTOCOL : 6 gram MgSo4 LOAD followed by 2 grams / hour for 12-24 hours until delivery. Discontinue MgS04 2g/hr maintenance if delivery is not anticipated to be imminent after the initial 12 hrs. </li></ul><ul><li>HOWEVER ; If after the initial 12 hours delivery is still anticipated within the subsequent 24 hours ( ie within 36 hours from protocol enrollment ) continue with 2 g / hr maintenance until delivery or 24 hours elapsed. Discontinue if delivery not imminent. </li></ul><ul><li>If MgSo4 2g/ hr maintenance has been previously discontinued WHEN subsequently delivery again appears imminent ( ie onset of labor OR delivery indicated ) </li></ul><ul><li>1) If more than 6 hours has elapsed since discontinuation of 2 g / hour MgSo4 maintenance ; RELOAD with MgSO4 6 grams and continue with MgSo4 2 grams / hour until delivery or 12 hours elapsed. </li></ul><ul><li>2) If 6 hours has not elapsed since discontinuation of previous 2 g / hr maintenance , Reload not recommended; only Re-Initiate 2 grams/ hour maintenance dosage and continue until delivery or 12 hours elapsed. </li></ul>
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