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Magnesium Sulfate in Obstetrics: Indications and Complications

Magnesium Sulfate in Obstetrics: Indications and Complications. Siri L. Kjos , MD Department of OBGYN, Harbor UCLA . Magnesium Sulfate in Obstetrics Indications and Complications: Objectives. State mechanism of action on muscles and cells

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Magnesium Sulfate in Obstetrics: Indications and Complications

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  1. Magnesium Sulfate in Obstetrics: Indications and Complications Siri L. Kjos, MD Department of OBGYN, Harbor UCLA

  2. Magnesium Sulfate in ObstetricsIndications and Complications: Objectives • State mechanism of action on muscles and cells • State the serum levels associated with side effects and toxicity—know how to monitor for toxicity • State benefits and risks of use in preeclampsia and preterm labor

  3. Seizure Prophylaxis in Preeclampsia/Eclampsia

  4. Magnesium Sulfate and Effect on Musculature • Slows or blocks neuromuscular and cardiac conducting system transmission • Inhibit release of acetylcholine from presynaptic nerve terminal, • Depresses postjunctional membrane response and response of underlying myofibrils • Result: Muscle weakness and respiratory depression with overdose • Decreases smooth muscle contractility • Uterine smooth muscle: tocolytic • ↓myocardial contractility, respiration • Depress central nervous system irritability (anticonvulsant) • Little effect on Blood pressure in therapeutic ranges

  5. Magnesium Sulfate and Effect on Musculature • Dosage for seizure prophylaxis: 1 g/hr or 2 g/hr: • both doses safe with normal renal function • 1 g/hr appears equally effective (Magpie trial) without serious complications • Neonatal serum [Mg] ~ maternal serum [Mg] • AFI levels increase with prolonged infusion secondary to fetal renal excretion but fetal serum [Mg] do not increase • Average newborn serum [Mg] 3.7 mEq/dl • No correlation of NN [Mg] and APGAR • No evidence of cumulative effects on neonate from prolonged magnesium infusion Depression DTR’s [10 mEq/L] occur below levels of cardiac or respiratory depression • Use to monitor high levels but not to monitor therapeutic levels—brisk reflexes do occur with anticonvulsant doses [4-6 mEq/l]. Do not need to monitor levels for efficacy • Monitor DTR’s at least every 2 hours • Load: 4-6 g over 15-30 minutes → Continuous infusion 1-2 g/hr. • Impaired renal function: [Cr>1.0 mg/dl] • Rate 1.0 g/hr; Obtain [Magnesium] • Calcium Gluconate (10ml of 10% solution given IV over 3 minutes)

  6. Pharmacology of Magnesium Sulfate • Volume distribution: beyond extracellular fluid, enters bones and cells • Circulates largely unbound to protein • Exclusively excreted in the urine • Reabsorbed in the proximal tubule, limited by transport maximum (Tmax) • Excretion increases as filtered load increases above Tmax. • T ½ time for excretion: 4 H (normal renal function) • Excretion prolonged in women with↓GFR

  7. Preeclampsia / Eclampsia • In the US, the frequency of eclamptic seizures in preeclampsia is < 1%, with reported incidence in the Western world of 1/2,000- 1/3,000 deliveries 1 • Estimated < 1/200 for mild and 1/50 for severe disease 2 • Percentage of eclamptic fits that occur intrapartum: • - UK 18% 3; Tennessee 19% 4; Scandinavia 29% 5 • Incidence of intrapartum eclampsia: < 1/600 (0.17%) of cases of mild preeclampsia 1.Sibai BM. Magnesium sulfate is the ideal anticonvulsant in preeclampsia-eclampsia. Am J Obstet. Gynecol. 1990; 162:1141-45. 2.Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: Lessons learned from recent trials. Am J Obstet Gynecol. 2004. 190:1520-26. 3. Douglas KA, Redman CW. Eclampsia in the United Kingdom. BMJ. 1994; 309:1395-1400. 4. Mattar F, Sibai BM. Eclampsia. Risk factors for maternal morbidity. Am J Obstet Gynecol. 2000; 182:307-312. 5. .Andersgaard, AB, et al. Eclampsia in Scandinavia: incidence, substandard care, and potentially preventable cases. Acta Obstetricia et Gynecologica. 2006; 85:929-36.

  8. Frequency of symptoms preceding Eclampsia Sibai BM. Obstet Gynecol 57:199-202, 1981 In the US, prophylactic anticonvulsant therapy for all women meeting criteria for preeclampsia is recommended

  9. Intrapartum Management Eclampsia: 1:300-1,000 Seizures are usually self-limited (1-2 minutes) Prevent aspiration of gastric contents Diazepam or Ativan only if sustained Prolonged deceleration will recover after seizure If possible, allow time for full fetal recovery Cesarean only if vaginal birth not possible within a reasonable time frame

  10. Treatment of severe preeclampsia with Magnesium sulfate is supported by level I evidence, ACOG (level A) Seizure incidence Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998; 92:883-9.

  11. Treatment of eclampsia with Magnesium sulfate Supported by level I evidence, ACOG (level A) Recurrent seizures Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998; 92:883-9.

  12. Magnesium Sulfate: Do women with mild preeclampsia need prophylaxis? When does risk of Magnesium prophylaxis exceed seizure risk? Magpie Study1: Magnesium safe and effective even in developing countries Most had severe preeclampsia (75% needed anti-hypertensive Rx) When Magnesium limited to severe disease → ↓ 50% in seizures2 Difficult to select which women with preeclampsia will progress to eclampsia based on symptoms3 1. Altman D, Lancet 359:1877-90, 2002 2. Alexander JM. ObstetGynecol 108:826-32, 2006. 3. Sibai BM. ObstetGynecol 57:199-202, 1981

  13. Magnesium sulfate and Mild Preeclampsia“Magpie Trial” • Magpie Trial (n=10,141) 33 countries involved • Double-blind, placebo RCT • Criteria: SBP  140 or DBP  90 (x2), Proteinuria  1+ • Magnesium sulfate vs. Placebo • * All patients from US (43), and 248/251 patients from Cuba, had mild preeclampsia (severe cases not generally enrolled) The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:1877-90.

  14. The Magpie Trial Seizure incidence * Two or more of the following: hyperreflexia, frontal headache, blurred vision, epigastric tenderness (regardless of blood pressure and proteinuria) The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:1877-90.

  15. The Magpie Trial • Conclusions • Women with severe preeclampsia, imminent eclampsia, and those with preeclampsia in high PMR countries, appear to benefit the most. • No benefit of Magnesium sulfate in countries with low PMR • Magnesium sulfate is effective in reducing the risk of eclampsia in women with preeclampsia: * Perinatal mortality rate The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:1877-90

  16. Placebo-controlled trials of Magnesium Sulfate in mild preeclampsia* AGOG Bulletin #33 January 2002 “Although there is no unanimity of opinion regarding the prophylactic use of magnesium sulfate for the prevention of seizures in women with mild preeclampsia or gestational hypertension, a significant body of evidence attests to the efficacy of magnesium sulfate in women with severe preeclampsia or eclampsia.” *Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: lessons learned from recent trials. AM J Obstet Gynecol. 2004. 190: 1520-26. Wtilin AG. The efect of magnesium sulfate therapy on the duration of labor in women with mild preeclampsia at term: A randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 1997; 176:623-27. Livingston, JC. Magnesium sulfate in women with mild preeclampsia: a randomized control trial. Obstet Gynecol. 2003; 101:217-220.

  17. When should Magnesium Sulfate Therapy be initiated in preeclampsia? Timing of Initiation in clinical trials In clinical trials, in which the methods were clearly described, Magnesium sulfate was always initiated once the decision was made for delivery Regardless of mild or severe status, no investigator has described waiting until the active phase of labor to start Magnesium sulfate

  18. Magnesium Sulfate: Duration of prophylaxis • Conclusion • Magpie trial ’02 (N=10,141) limited Magnesium sulfate to 24hrs. • After 24hrs, if delivery had not occurred, the decision for continued treatment was physician-dependent • Concluded that exceeding 24hr limit has not been proven safe • Belfort ’03 (N=1650), also limited Magnesium sulfate to 24hrs, and protocol called for C/S unless delivery imminent

  19. Magpie Trial: Maternal Morbidity

  20. Magpie Trial: Perinatal morbidity • Conclusion • Magpie trial concluded that there was no difference in maternal or perinatal morbidity in patients receiving 24hrs Magnesium sulfate vs. placebo • There are no large clinical trials evaluating the effects of Magnesium sulfate >24 hrs in preeclampsia • Earlier observational studies had suggested risks of: • - postpartum hemorrhage • - pulmonary edema • - respiratory depression

  21. Are Magnesium levels beneficial, or can we rely on clinical symptoms to determine Magnesium Sulfate toxicity? Therapeutic dose • Zuspan initiated IV infusion : 4g load, and 1g/hr • Pritchard identified therapeutic range : • -serum magnesium 4.2-8.4 mEq/L • In study by Sibai, he found that with: • 4g load, 1g/hr: 1.7% (2/115 ) in therapeutic range • 4g load, 2g/hr: 5.1% (23/45 )in therapeutic range • 6g load, 2g/hr: 100% within therapeutic range Zuspan FP. Treatment of severe preeclampsia and eclampsia. Clin Obstet Gynecol. 1966;9:954-72. Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet 1955; 100: 131-140. Sibai BM. Magnesium sulfate is the ideal anticonvulsant in preeclampsia-eclampsia. Am J Obstet Gynecol. 1990; 162:1141-45.

  22. Magnesium Sulfate: How do we monitor for toxicity? • Most physicians rely on clinical signs/symptoms • In Magpie trial respiratory signs were more telling than tendon reflexes: • MagnesiumPlacebo • Reduced tendon reflexes 1.2% 1.2% • Respiratory depression 1.0%0.5% • Major differences were in minor symptoms: • -Flushing, N/V, muscle weakness The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002; 359:1877-90.

  23. Magnesium Sulfate How do we monitor for toxicity? • Many clinicians send level when concern for toxicity arises. However, levels >12 mEq/L are rare with proper infusion, and in the absence of renal disease. • Toxic levels: • N/V, flushing, weakness: 9-12 mEq/L • Loss of tendon reflexes: >12 mEq/L • Respiratory depression: >14 mEq/L • Paralysis, respiratory arrest: 15-17 mEq/L • Cardiac arrest: >25 mEq/L • When monitoring toxicity need to realize: • Magnesium is cleared by the kidneys in concentration-dependent manner • Usually, a higher Magnesium concentration leads to higher excretion from the body • However, patients with oliguria, elevated creatinine, and/or chronic renal disease (e.g. DM, CHTN) should be monitored very closely due to impaired excretion Lindow SW. Magnesium sulphate: a review of clinical pharmacology applied to obstetrics. British Journal of Obstetrics and Gynecology. 1998; vol.105:260-68.

  24. Magnesium SulfateHow long should we treat postpartum? • 12-24 hr regimen postpartum followed in most trials • 27-65% of eclamptic seizures occur post-partum, and 38-84% occur within 48hrs • However, studies on patients with eclampsia have concluded that postpartum eclampsia is usually self-limited and associated with decreased morbidity • This has triggered desire to decrease post-partum Magnesium sulfate Mattar F, Sibai BM. Eclampsia: Risk factors for maternal morbidity. Am J Obstet Gynecol. 2000; 182:307-312.

  25. Is postpartum magnesium sulfate necessary?Postpartum magnesium sulfate: using maternal clinical parameters to guide therapy • Study: (Isler, 2003) Prospective clinical trial (n=503) • Gave Magnesium sulfate 2g/hr postpartum until: • absence of persistent headache / visual changes • absence of epigastric pain • greater than 50% BP readings <150/100 • BP <160/110 preceding 2hrs • diuresis of >100ml/hr for >2hrs consecutive Isler CM, et al. Postpartum seizure prophylaxis: Using maternal clinical parameters to guide therapy. Obstet Gynecol. 2003; 101:66-69.

  26. Postpartum magnesium sulfate: using maternal clinical parameters to guide therapy Isler CM, et al. Postpartum seizure prophylaxis: Using maternal clinical parameters to guide therapy. Obstet Gynecol. 2003; 101:66-69.

  27. Postpartum magnesium sulfate: using maternal diuresis to guide therapy • Study: (Fontenot , 2005). RCT to assess the use of diuresis as a determinant of postpartum MgSO4 therapy in severe preeclampsia • Control group: MgSO4 2g/hr x 24 hrs • Study group: MgSO4 until urine output >100 ml/hr x 2hrs • Proposed that diuresis is indicative of diminishing vasospastic response Fontenot et al. A prospective randomized trial of magnesium sulfate in severe preeclampsia: Use of diuresis as a clinical parameter to determine the duration of postpartum therapy. Am J Obstet Gynecol. 2005. 192:1788-94.

  28. Postpartum magnesium sulfate: using maternal diuresis to guide therapy • Study: (Fontenot , 2005). RCT to assess the use of diuresis as a determinant of postpartum MgSO4 therapy in severe preeclampsia • Control group: MgSO4 2g/hr x 24 hrs • Study group: MgSO4 until urine output >100 ml/hr x 2hrs • Proposed that diuresis is indicative of diminishing vasospastic response Fontenot et al. A prospective randomized trial of magnesium sulfate in severe preeclampsia: Use of diuresis as a clinical parameter to determine the duration of postpartum therapy. Am J Obstet Gynecol. 2005. 192:1788-94.

  29. Postpartum magnesium sulfate: using maternal diuresis to guide therapy • Study was underpowered • (powered to find a 20% difference in re-initation of magnesium sulfate therapy) • Cost difference • Difference in cost per day in lower acuity nursing unit (postpartum unit) is: $764 • Duration of treatment 65% less in study group • Reduction in cost/patient: $495 • Total cost (n=98): $48,510 *underpowered, to find a 2-fold difference would require 33,000 patients ^Study powered to find 20% increased risk of re-initiation of MgSO4 therapy Fontenot et al. A prospective randomized trial of magnesium sulfate in severe preeclampsia: Use of diuresis as a clinical parameter to determine the duration of postpartum therapy. Am J Obstet Gynecol. 2005. 192:1788-94.

  30. Postpartum Magnesium Sulfate and Breastfeeding • Magnesium still elevated in colostrum x24hrs after infusion, but the level is considered safe in breastfeeding 1 • The decision to treat mild preeclampsia with magnesium sulfate, and the duration of post-partum treatment in severe preeclampsia can delay breastfeeding and infant bonding • It is well studied that delayed initiation of breastfeeding leads to lower rates of long-term success 2 1. Cruikshank DP, et al. Breast milk magnesium and calcium concentrations following magnesium sulphate treatment. Am J Obstet Gynecol. 1982; 143:685-88. 2.Yamauchi Y, Yamanouchi I. Breastfeeding frequency during the first 24 hours after birth in full-term neonates. Pediatrics. 1990;86:171-75.

  31. Summary: Magnesium sulfate use in preeclampsia/eclampsia • Magpie trial supports use of magnesium sulfate in mild preeclampsia for countries with medium-high PMR • RCT’s show no benefit of magnesium sulfate in mild preeclampsia in US and countries with low PMR • Magpie trial (N=10,141) concluded no difference in maternal / perinatal morbidity between magnesium sulfate and placebo (24hrs) • No clinical trial has been performed to evaluate the initiation of magnesium sulfate in active labor, or to evaluate its use >24hrs

  32. Magnesium Sulfate for Tocolysis

  33. Pharmocologic Therapy for Preterm Labor Contraindications toMagnesium Sulfate Intravenous administration Load:4-6 g; 1-4 g/H--titrate to response

  34. Complications from Tocolysis with Magnesium Sulfate • Toxicity • Inhibition of myometrial contractility (5-8 mg/dl) • Loss of deep tendon reflexes (9-13 mg/dl) • Respiratory depression (>13 mg/dl) • Pulmonary edema (similar to -adrenergics) •  Twins (volume expansion);  Anemia • Urinary output (renal excretion) • Tocolysis >24 hours ( colloid oncotic pressure) • Fluid overload (overhydration) • Careful attention to fluids decreases risk: • Corticosteroids do not affect risk

  35. Administration of Magnesium Sulfate as a tocolytic • Loading dose: 4-6 g in 10%-20% solution • Give over 30 minutes • 60 ml of 10% magnesium sulfate in D5NS • Maintenance dose 2 g/hr • 40g magnesium sulfate to 1 L D5NS @ 50 ml/hr • Increase dose by 1g/hr until <1 U.C. per Hour • Maximum: 4 g/hr • Total fluids 125 ml/hr

  36. Monitoring Tocolysis with Magnesium Sulfate Summary “Magnesium sulfate is a familiar agent but its tocolytic efficacy is poor. Maybe a useful choice if the diagnosis of preterm labor is early and uncertain and in patients in whom other agents are contraindicated (e.g. diabetes)” Creasy & Resnik’s Maternal-Fetal Medicine 6th Ed • Hourly monitoring of • Fluid status (>30 cc/hr); DTR’s • Vitals –respiratory rate • Magnesium levels may be obtained • If suspected toxicity or impaired renal status ([Cr]>0.9 mg/dl] • Reduce or stop infusion if respiration or urine output declines • Calcium gluconate readily available to reverse effects of Magnesium sulfate

  37. When to discontinue tocolysis with Magnesium Sulfate • When U.C.s decreased < 1 every 10-15 minutes or have ceased • Magnesium sulfate sometimes continued to arbitrary endpoint is reached (12 H after U.C.s stopped or until steroid course completed) • Not supported by data

  38. : Conclusion “Magnesium Sulfate is ineffective at delaying or preventing preterm birth and its use is associated with increased mortality for the infant.*” *one trial only, subsequent RCTs for neuroprotective have enrolled >30 times subjects without any increased evidence of neonatal mortality/morbidity Inconsistent evidence Magnesium Sulphate for Preventing PTB Cochrane Meta-analysis 2002 Evaluated 23 RCTs: 9 RCTs included: Rx vs Control Crowther CA, Hiller JE Doyle LW. Cochrane Collaboration 2002

  39. : A RCT (double-masked, placebo-controlled trial) of Magnesium Sulfate for Prevention of Cerebral Palsy Conclusion of RCT “Fetal exposure to Magnesium Sulfate before anticipated Early preterm deliver did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduce in survivors.” May be a role for prenatally administered magnesium sulfate as a neuroprotectant to infants born <32 weeks. Creasy & Resnik’s Maternal-Fetal Medicine 6th Ed Study: N= 2241, multi-center (20 sites), 22-31 weeks, 6 g load, 2 g/H Rouse DJ, et al. New Eng J Med 359:895-905

  40. Magnesium Sulfate and Anesthesia • General anesthesia • Neuromuscular blocking agents used to facilitate endotracheal intubation and relax abdominal musculature for cesarean delivery • Magnesium potentiates and prolongs the action of depolarizing agents (succinylcholine) and non-deplorizing agents (rocuronium, vecuronium, atracurium). • Need lower doses of these agents • Electronic monitoring of neuromuscular junction is helpful. • End of surgery need to evaluate sufficient muscle strength to sustain ventilation • Discontinue Magnesium during general anesthesia as drugs used during general anesthesia are anticonvulsants

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