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Judicious use of magnesium sulfate for eclampsia
- Give magnesium sulfate at the time of diagnosis to all preeclamptic patients who are to be delivered.
- Administration of magnesium sulfate for new-onset hypertension and preeclampsia remote from term is controversial.
- Even with therapeutic serum concentrations of magnesium, convulsions are possible.
- Magnesium sulfate should be administered for 24 hours after delivery or after the last postpartum seizure.
- Safe administration requires vigilant monitoring of reflexes, respiratory status, and urine output.
Last year’s headline-grabbing Magpie Trial1 confirmed a previous, smaller randomized study2 as well as a number of small controlled trials3 indicating that magnesium sulfate is better than placebo1,2 for seizure prophylaxis. Other large, randomized trials have demonstrated the drug’s superiority to nimodipine4 and phenytoin5 in preventing convulsions and to diazepam and phenytoin6 as therapy for eclampsia (TABLE 1).
As a result, magnesium sulfate remains a reliable tool for preventing eclampsia.3 Because clinical symptoms and signs are notoriously unreliable in predicting which gravidas will develop seizures, it is reasonable to administer magnesium at the time of diagnosis to all preeclamptic patients who are to be delivered.
This article reviews the practical implications of recent findings on prophylactic and therapeutic use, patient selection and risk assessment, and administration and monitoring protocols.
TABLE 1
Incidence of seizures according to therapy
| PROPHYLAXIS | ||||
| STUDY | THERAPY GROUPS | SEIZURES (%) | PREECLAMPSIA DEFINED AS … | STUDY CHARACTERISTICS |
| Magpie Trial1 | Magnesium | 0.8 | BP 140/90 mm Hg, proteinuria, nulliparity | n = 10,110, P.0001> |
| Placebo | 1.9 | |||
| Coetzee et al2 | Magnesium | 0.3 | Presence of 2 or more of the following: diastolic BP 110 mm Hg, proteinuria, prodromal symptoms | n = 699, P.003> |
| Placebo | 3.2 | |||
| Belfort et al4 | Magnesium | 0.8 | BP 140/90 mm Hg and proteinuria with 1 or more of the following: headache, clonus, visual disturbances, epigastric/right upper quadrant pain, oliguria, pulmonary edema, elevated liver enzymes, elevated creatinine, hemolysis, thrombocytopenia, intrauterine growth retardation, oligohydramnios | n = 1,650, P.01 |
| Nimodipine | 2.6 | |||
| Lucas et al5 | Magnesium | 0 | BP 140/90 mm Hg | n = 2,138, P.004> |
| Phenytoin | 0.9 | |||
| TREATMENT | ||||
| STUDY | THERAPY | RECURRENT SEIZURES (%) | STUDY CHARACTERISTICS | |
| Eclampsia Trial Collaborative Group6 | Magnesium | 13.2 | n = 905, P.0005> | |
| Diazepam | 27.9 | |||
| Eclampsia Trial Collaborative Group6 | Magnesium | 5.7 | n = 775, P.0005> | |
| Phenytoin | 17.1 | |||
| BP = blood pressure | ||||
Magnesium increases vasodilatation
The prophylactic and therapeutic benefits of magnesium likely derive from its ability to counteract vasospasm; the mechanism by which magnesium protects against seizures has not been established.
Transcranial Doppler ultrasound studies indicate that magnesium increases cerebral blood flow in preeclamptic7 and eclamptic women.8 Magnesium-induced vasodilatation involves a number of factors,9 such as blockade of calcium entry into vascular smooth muscle, antagonism of intracellular calcium activity, and release of nitric oxide10 and prostacyclin.11
In addition, magnesium inhibits platelet aggregation and protects endothelial cells from injury by free radicals. This action, along with stabilization of vascular tone, can potentially reduce the risk of cerebral thrombosis.9,12 The anticonvulsant effects of magnesium in clinically relevant doses do not involve depression of the neuromuscular junction.13
Magnesium also can directly affect the central nervous system by antagonizing N-methyl-D-aspartate receptor activation, which inhibits calcium influx and subsequent neuronal injury.9 This mechanism of action requires that plasma magnesium pass freely into the interstitial fluid of the brain. (Magnesium has already been shown to readily enter the cerebrospinal fluid after intravascular injection.14) The extent to which blockade of N-methyl-D-aspartate receptors contributes to magnesium prophylaxis and therapy remains to be established.
Women with preeclampsia or eclampsia often have electroencephalogram abnormalities that typically involve diffuse slowing (delta waves). These nonspecific electroencephalogram changes develop independently of arterial pressure and are not suppressed by intravenous (IV) magnesium.15,16
Eclamptic women have undergone renal decapsulation, spinal fluid drainage, implantation of the ureters into the colon, mastectomy, and oophorectomy. Each of these treatments was once considered rational based on hypotheses about the cause of eclampsia.
Although descriptions of convulsions in pregnancy date to antiquity, it was not until the 18th century that eclampsia was distinguished from tonic-clonic seizures in the nonpregnant state.
Eventually eclampsia was thought to be one of the pregnancy toxemias caused by a circulating toxin that acted on “nerve centers.”1 Thus, in the 1920s, a popular treatment for eclampsia involved eliminative measures, such as stomach lavage and high colonic flushings, as well as phlebotomy. Later, sedation with morphine sulfate and chloral hydrate without bleeding, popularized by Stroganoff in the 1930s, became prominent.2,3
Magnesium enters the picture. In 1924, an intern at Los Angeles General Hospital suggested using intravenous magnesium sulfate to treat eclamptic seizures, knowing that it controlled tetanic convulsions and had mild sedative effects. As a result, intravenous magnesium sulfate was added to the elimination protocol for eclampsia. In the initial trial, which included 17 eclamptic women, all seizures were controlled by magnesium, and maternal mortality was only 6%, compared with the historical average of 30%.4
By the 1960s, magnesium therapy combined with antihypertensive medication and delivery had been adopted in the United States as frontline therapy for eclamptic seizures—an approach that reduced maternal mortality to 5% or less.5-8 The associated perinatal mortality, which was due largely to abruptio placentae, prematurity, and complications of fetal growth restriction, also was substantially reduced—from 30% to about 10%.5-8
Criticism of this therapy has centered on 2 perceptions of the pharmacology of magnesium: It acted only at the neuromuscular junction, and it did not penetrate the blood-brain barrier.9,10 These effects seemed less than optimal when compared to those of newly developed antiepileptic medications, which had well-described mechanisms of action involving rapid transfer from blood to brain and stabilization of neuronal membranes.
Newer findings. In the 1990s, however, small controlled studies suggested that magnesium is surprisingly effective in preventing seizures in both preeclampsia and eclampsia.11 Recurrent seizures occurred in 9% of eclamptic women who received magnesium, which was about 40% less than in those given the anticonvulsants diazepam or phenytoin. In patients with severe preeclampsia, magnesium prophylaxis reduced the risk of seizures to 0.9% from 2.8% in women who received antihypertensive agents but no anticonvulsants. Large randomized trials confirmed these findings.12-16
REFERENCES
1. Loudan I. Some historical aspects of toxaemia of pregnancy. A review. Br J Gynecol. 1991;98:853-858.
2. Lawson J. Complications of eclampsia: Abruptio placentae, cardiac failure, renal failure, hyperpyrexia, uncontrollable fits, prolonged coma. Clinics Obstet Gynaecol. 1982;9:711-721.
3. O’Dowd MJ, Philipp EE. The History of Obstetrics and Gynecology. New York: Parthenon; 1994:23.
4. Lazard EM. A preliminary report on the intravenous use of magnesium sulphate in puerperal eclampsia. Am J Obstet Gynecol. 1925;9:178-188.
5. Zuspan FP, Ward MC. Improved fetal salvage in eclampsia. Obstet Gynecol. 1965;26:893-897.
6. Pritchard JA, Stone SR. Clinical and laboratory observations on eclampsia. Am J Obstet Gynecol. 1967;99:754-762.
7. Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: Evaluation of 245 cases. Am J Obstet Gynecol. 1984;148:951-960.
8. Sibai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol. 1990;63:1049-1055.
9. Kaplan PW, Lesser RP, Fisher RS, Repke JT, Hanley DF. No, magnesium sulfate should not be used in treating eclamptic seizures. Arch Neurol. 1988;45:1361-1364.
10. Donaldson JO. The case against magnesium sulfate for eclamptic convulsions. Int J Obstet Anesth. 1992;1:159-166.
11. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998;92:883-889.
12. Coetzee EJ, Dommisse J, Anthony J. A randomized controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe preeclampsia. Br J Obstet Gynecol. 1998;105:300-303.
13. 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;359:1877-1890.
14. Belfort MA, Anthony J, Saade GR, Allen JC. for the Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.
15. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333:201-205.
16. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463.
Incidence
- The maternal death rate for eclampsia varies geographically, according to the quality of the area’s health-care system. In developed countries, the rate ranges from 1.8% to 7.2%, while in countries with less available medical care, it can exceed 25%.1-3
- Although the maternal mortality rate for preeclampsia is lower (approximately 0.34% in the United States) than for eclampsia, preeclampsia still accounts for more than half of the maternal deaths linked to pregnancy “toxemia.”3,4
- Eclampsia-associated perinatal mortality remains high—about 10%—even in developed countries.
Risk of eclampsia
- Eclampsia usually involves reversible cerebral edema and endangers the mother principally through seizure-related aspiration (2%) or underlying disturbances such as acute renal failure (5%), pulmonary edema (4%), cardiorespiratory arrest (3%), and abruptio placentae.5,6
- Eclamptic seizures also carry the risk of permanent brain injury or death when they are associated with hemorrhagic or ischemic stroke or with tentorial herniation.
- Recurrent seizures—in which prolonged activation of N-methyl-D-aspartate receptors can produce toxic brain levels of calcium—also may lead to permanent injury and death.
- About 7% of eclamptic women develop significant neurologic sequelae, including aphasia, psychosis, cortical blindness, weakness, coma, or cerebrovascular accident.7
- More than half of eclamptic women who die within 48 hours after the onset of convulsions have cerebral petechiae, hemorrhage, or ischemic softening (nonhemorrhagic) of the brain,8 which may result from thrombosis of cerebral vessels9 or other complications of cerebral vasospasm.8,10
- Necrosis of the walls and endothelium of precapillary arterioles also can occur.
- Cerebral edema in gross specimens has not been a consistent finding at autopsy.8,11 Although this seems to run counter to expectations, a detailed microscopic analysis of the brain would be necessary to identify focal edema affecting a small brain sector.
REFERENCES
1. Douglas KA, Redman CWG. Eclampsia in the United Kingdom. BMJ. 1994;309:1395-1400.
2. Majoko F, Mujaji C. Maternal outcome in eclampsia at Harare Maternity Hospital. Cent Afr J Med. 2001;47:123-128.
3. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97:533-538.
4. 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;359:1877-1890.
5. Lawson J. Complications of eclampsia: Abruptio placentae, cardiac failure, renal failure, hyperpyrexia, uncontrollable fits, prolonged coma. Clinics Obstet Gynaecol. 1982;9:711-721.
6. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333
7. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333.
8. Sheehan JL, Lynch JB. Pathology of Toxaemia of Pregnancy. London: Churchill Livingston; 1973;524-582.
9. McKay DG. Clinical significance of the pathology of toxemia of pregnancy. Circulation. 1964;30(suppl 2):66-75.
10. Will AD, Lewis KL, Hinshaw DB, Jr, et al. Cerebral vasoconstriction in toxemia. Neurology. 1987;37:1555-1557.
11. Hibbard LT. Maternal mortality due to acute toxemia. Obstet Gynecol. 1973;42:263-270.
Give magnesium to all preeclamptic patients to be delivered
Clinical symptoms and signs are unreliable predictors of which pregnant women will develop seizures. For example, eclampsia can occur in gravidas without hypertension or proteinuria. When these conditions are present, the risk of eclampsia is not proportional to their severity.1,17-20 Thus, given the relative safety of magnesium therapy with appropriate monitoring, a reasonable approach is to initiate therapy at the time of diagnosis in all preeclamptic patients who are to be delivered.
If all clinicians followed this management approach, about 5% of gravidas would receive therapy to prevent a rare but potentially injurious event, although for most (more than 97%) the treatment would be unnecessary.
Pregnancy-induced hypertension. The administration of magnesium sulfate to women with new-onset hypertension (arterial blood pressure of 140/90 mm Hg or more) without proteinuria is controversial. Some physicians do not give magnesium to these patients because the risk of eclampsia is lower than in those with preeclampsia (as characterized by hypertension and proteinuria).
About 25% of women with pregnancy-induced hypertension will develop preeclampsia, but those who will go on to develop proteinuria or seizures cannot be identified prospectively. For this reason, other physicians favor prophylactic magnesium for this group.5 They point out that, once a seizure has occurred, recurrence may be more difficult to prevent. We do not routinely administer magnesium to women with pregnancy-induced hypertension unless they have or develop prodromal symptoms (e.g., headache, epigastric pain), high arterial pressures (more than 160/105 mm Hg), proteinuria, or hemolysis, elevated liver enzymes, and low platelets syndrome.
Clinical symptoms and signs are unreliable predictors of which pregnant women will develop seizures.
Mild preeclampsia. Similar arguments also have been given for and against magnesium prophylaxis in women with mild preeclampsia. In the Magpie trial, magnesium sulfate administration was associated with a reduction in the incidence of eclampsia of approximately 56% (placebo: 1.6%; magnesium: 0.7%) in 7,468 gravidas who did not have severe preeclampsia by the definition used in the study. In light of this evidence, we have maintained our practice of giving magnesium to those with mild preeclampsia.
Preeclampsia remote from term. The role of magnesium in the management of patients with preeclampsia remote from term (less than 34 weeks of gestation), when continuation of the pregnancy can provide fetal benefit, also is unclear. We administer magnesium sulfate for the first 24 to 48 hours of hospitalization in patients with severe preeclampsia.
The multiple mechanisms by which magnesium counters preeclampsia-induced vasoconstriction have the potential to improve blood flow in the pulmonary, renal, hepatic, gastrointestinal, and placental circulations, as well as the central nervous system, thus delaying the need for delivery. Whether prolonged infusion of magnesium can be an effective component of therapy to delay delivery and improve fetal outcome remains to be determined.
Abruptio placentae. Magnesium also may reduce the risk of abruptio placentae,1 although 1 small study did not find IV magnesium infusion beneficial in this setting.20
Over the normal range of arterial pressure, cerebral blood flow and capillary hydrostatic pressures remain relatively constant thanks to accompanying adjustments in cerebral vascular resistance. But when arterial pressures are high, elevations in vascular resistance may not completely compensate for them. Thus, capillary blood flow and hydrostatic pressure are increased, disrupting endothelial tight junctions and promoting leakage of small ions and water into the brain parenchyma. The result is cerebral edema and convulsions.
Yet an increase in arterial pressure cannot be the sole mechanism at work, since eclampsia can occur in apparently normotensive patients. Nor is the risk of seizures in preeclamptic women directly proportional to the rise in arterial pressure. Cerebral vasogenic edema may also result from disruptions in cerebral vascular resistance and/or from increased capillary permeability due to endothelial dysfunction or injury, which are unrelated to changes in arterial pressure.1,2 Cytotoxic edema as a result of vasoconstriction or infarction3,4 is another possible mechanism, as are disturbances in brain metabolism.
Imaging studies. Until recently, imaging studies were unable to distinguish between vasogenic and cytotoxic edema; both present as hypodensities on computed tomography and magnetic resonance imaging.5-7 But diffusion-weighted imaging techniques demonstrate that focal vasogenic edema, which disappears with resolution of clinical symptoms, is more consistently observed in eclamptic women.8,9 Petechial brain hemorrhages also have been detected in patients with eclampsia or severe preeclampsia.10
REFERENCES
1. Bhatia RK, Bottoms SF, Saleh AA, Norman GS, Mammen EF, Sokol RJ. Mechanisms for reduced colloid osmotic pressure in preeclampsia. Am J Obstet Gynecol. 1987;157:106.-
2. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: An endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200-1204.
3. Sheehan JL, Lynch JB. Pathology of Toxaemia of Pregnancy. London: Churchill Livingston; 1973;524:582.-
4. McKay DG. Clinical significance of the pathology of toxemia of pregnancy. Circulation. 1964;30(suppl 2):66-75.
5. Milliez J, Dohoun A, Boudraa M. Computed tomography of the brain in eclampsia. Obstet Gynecol. 1990;75:975-980.
6. Dahmus MA, Barton JR, Sibai BM. Cerebral imaging in eclampsia: magnetic resonance imaging versus computed tomography. Am J Obstet Gynecol. 1992;167:935-941.
7. Cunningham FG, Twickler D. Cerebral edema complicating eclampsia. Am J Obstet Gynecol. 2000;182:94-100.
8. Kanki T, Tsukimori K, Mihara F, Nakano H. Diffusion-weighted images and vasogenic edema in eclampsia. Obstet Gynecol. 1999;93:821-823.
9. Friese S, Fetter M, Küker W. Extensive brainstem edema in eclampsia: Diffusion weighted MRI may indicate a favourable prognosis. J Neurol. 2000;247:465-466.
10. Drislane FW, Wang A-M. Multifocal cerebral hemorrhage in eclampsia and severe pre-eclampsia. J Neurol. 1997;244:194-198.
Administration
Protocols based on observational data. Therapeutic magnesium concentrations in maternal plasma have been deduced from empiric studies.21 In a protocol for eclampsia, both IV and intramuscular (IM) administration of magnesium sulfate were associated with initial maternal plasma magnesium levels of 7 to 9 mEq/L, with subsequent stabilization at 4 to 7 mEq/L. For patients with preeclampsia, IM administration of magnesium resulted in concentrations of 3.5 to 6 mEq/L. Because these protocols were generally effective, 4 to 7 mEq/L has been used as a therapeutic range, though no formal dose-response testing has been performed.
The lower limit of target plasma magnesium concentrations is about twice the mean physiologic concentration (approximately 1.7 mEq/L).
Optimum IV infusion rate. Continuous IV infusion of magnesium sulfate—rather than IM injection—is now the norm in most US hospitals.22 However, the infusion rate of 1 g/h, which is generally effective for prophylaxis and treatment of seizures,22 often fails to meet target maternal serum magnesium concentrations.19 Thus, an infusion rate of 2 g/h is recommended (TABLE 2).
We generally start with a loading dose of 4 to 6 g over 10 to 15 minutes in women with normal renal function, using the hydrated form of the drug. In patients with oliguria, we give a loading dose of 4 g over 15 minutes, followed by a maintenance infusion of 1 g/h. Even at the higher infusion rate (2 g/h), plasma levels are usually in the lower therapeutic range.19
IM injection remains an option. Intravenous infusion of magnesium sulfate may not always be practical—for example, when infusion pumps or close patient supervision are unavailable, or when a patient is transported to another facility. Intramuscular injections can be used in these situations.
We give an initial dose of 5 g (10 mL as a 50% solution) of magnesium sulfate with 1 mL of 2% xylocaine deep in the upper outer quadrant of each buttock (10 g total magnesium sulfate). The magnesium solution is injected in several different sites as the needle (3 inches long, 20 gauge) is advanced in muscle. Each injection should be preceded by aspiration to ensure that the needle tip is not in a blood vessel. Massaging the buttock after the injection will help disperse the magnesium in the tissue. Five grams of magnesium sulfate (10 mL as a 50% solution with 1 mL of 2% xylocaine) is subsequently administered as a single intramuscular injection every 4 hours to maintain circulating magnesium levels, provided there is no evidence of magnesium toxicity. Patients with severe preeclampsia, prodromal symptoms of eclampsia, or eclampsia should be given 4 g of magnesium sulfate intravenously (20 mL as a 20% solution) over 5 minutes to more rapidly establish therapeutic magnesium levels immediately prior to the initial intramuscular injection of 10 g of magnesium sulfate.
Convulsions may occur even at therapeutic levels. Even with therapeutic serum magnesium concentrations, seizures are possible.18,23 Recurrent convulsions in patients already receiving magnesium should be treated with an additional 2 g IV magnesium sulfate administered over 5 minutes. Another 2-g dose (4 g total) can be given, but the patient must be carefully watched for signs of respiratory depression. If magnesium fails to control the seizures, additional measures are needed, such as IV anticonvulsants or muscular paralysis in conjunction with intubation and mechanical ventilation.24
Continue administration postpartum. Magnesium sulfate generally is administered for 24 hours after delivery or after the last postpartum seizure, although optimal length of treatment is not firmly established. The clinical state of the patient may be a useful index for individualizing duration of magnesium infusion,25,26 but the risks and benefits of this approach have not been examined in a large patient population.
Know the contraindications. Contraindications to magnesium therapy include myasthenia gravis and myocardial ischemia/failure. Magnesium, which is excreted almost exclusively by the kidneys, should be administered with extreme caution to patients in renal failure (because of the risk of cardiorespiratory depression) and with care to those receiving other calcium-channel antagonists, such as nifedipine (though the incidence of significant maternal hypotension under these circumstances is low).13
The effects of magnesium toxicity can be rapidly reversed with 1 g intravenous calcium chloride or calcium gluconate.
Magnesium can interact with other cardiovascular drugs to elicit arrhythmias or reduce myocardial contractility, and can potentiate the action of muscle relaxants and anesthetics. Thus, use the drug cautiously under these conditions.
TABLE 2
Magnesium sulfate administration*
| INTRAVENOUS INFUSION | |
| Normal renal function | |
| Loading dose: | 4-6 g over 10-15 min |
| Maintenance infusion: | 2 g/h |
| Oliguria† | |
| Loading dose: | 4 g over 15 min |
| Maintenance infusion: | 1 g/h |
| INTRAMUSCULAR INJECTION | |
| Loading dose: | 5 g in each buttock (10 g total) |
| Maintenance injection: | 5 g in 1 buttock (5 g total) every 4 h |
| *All dosages refer to the hydrated form (MgSO 4 7H 2 O) | |
| †Must continuously monitor pulse oximetry and measure magnesium levels 2 hours after starting the infusion. Calcium chloride or calcium gluconate and emergency intubation should be immediately available, and fluids should be restricted provided renal failure is not due to hypovolemia. | |
Risks of magnesium
At therapeutic concentrations of magnesium, about one quarter of pregnant women experience nausea, emesis, flushing, or weakness.1 Magnesium therapy also can be associated with lethargy, blurred vision, and urinary retention.24 Toxic effects, which vary in a dose-dependent manner (TABLE 3), include loss of reflexes, respiratory depression, cardiac arrhythmias, and cardiac arrest.14
Theoretical concerns include prolonged labor or increased blood loss at delivery, but these have not posed a significant problem in actual practice.1,27
Magnesium-induced neonatal depression, as evidenced by hypotonia and low Apgar scores, also may occur, but have not been observed in all studies.28,29 Obviously, pediatricians should attend these deliveries in case such complications are encountered.
TABLE 3
Maternal serum magnesium concentrations associated with toxicity
| MMOL/L | MEQ/L | MG/DL | |
|---|---|---|---|
| Loss of patellar reflexes | 3.5–5 | 7–10 | 8.5–12 |
| Respiratory depression | 5–6.5 | 10–13 | 12–16 |
| Altered cardiac conduction | >7.5 | >15 | >18 |
| Cardiac arrest | >12.5 | >25 | >30 |
| Source: Lu and Nightingale14 | |||
Preventing magnesium toxicity
Closely monitor the patient. Safe administration requires vigilant monitoring of reflexes, respiratory status, and urine output. Prior to initiating therapy, document deep tendon reflexes, respirations of 16 or more per minute, and urinary excretion exceeding 25 mL/h.14 During magnesium infusion, regularly assess respiratory rate, patellar reflexes, and urine output (TABLE 4).
Serum magnesium levels can guide therapy in patients with signs of toxicity, renal insufficiency, or recurrent seizures, but offer no advantage over close clinical scrutiny in typical patients. Steady-state plasma magnesium levels are about the same in the fetus as in the mother to whom magnesium is administered.21 High fetal levels can impair fetal breathing movements, which could lower biophysical profile scores in the absence of significant fetal hypoxia.
- Pulmonary function. Onset of a dry cough should raise suspicion of incipient pulmonary edema. Pulmonary auscultation detects rales that can accompany disease- or therapy-related pulmonary edema. Pulse oximetry, which provides continuous arterial oxygen saturation levels, can be very helpful in alerting the health-care team to both magnesium-induced respiratory depression and significant limitations in pulmonary gas exchange that accompany pulmonary edema.
- Urine output. In the presence of oliguria (less than 100 mL in 4 hours), the rate of magnesium administration should be reduced by 50%.
Also give IV calcium chloride or calcium gluconate for respiratory depression or other signs of cardiorespiratory toxicity. Immediate intubation with assisted ventilation is necessary in cases of cardiorespiratory failure. Fortunately, this phenomenon occurs very rarely with proper patient selection and rigorous surveillance.
TABLE 4
Monitoring guidelines for patients receiving magnesium
| FUNCTION | WHEN TO MONITOR | SUSPECT MAGNESIUM TOXICITY AND COMPLICATIONS WHEN… |
|---|---|---|
| Patellar reflexes | Every 1–4 h* | Reflexes are absent |
| Respiratory rate | Every 1–4 h* | Rate is |
| Pulmonary auscultation | Every 12 h or with development of respiratory symptoms or signs | Rales are present |
| Pulse oximetry | Every 1–4 h* | |
| Urine output | Every 1–4 h* | |
| Serum magnesium levels | In presence of oliguria, persistent seizures, or signs of toxicity | >8 mEq/L |
| *Depending on clinical state | ||
1. 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;359:1877-1890.
2. Coetzee EJ, Dommisse J, Anthony J. A randomized controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia. Br J Obstet Gynecol. 1998;105:300-303.
3. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998;92:883-889.
4. Belfort MA, Anthony J, Saade GR, Allen JC. for the Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.
5. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333:201-205.
6. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463
7. Belfort M, Moise KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: A randomized, placebo-controlled study. Am J Obstet Gynecol. 1992;167:661-666.
8. Naidu S, Payne AJ, Moodley J, Hoffmann M, Gouws E. Randomized study assessing the effect of phenytoin and magnesium sulphate on maternal cerebral circulation in eclampsia using transcranial Doppler ultrasound. Br J Obstet Gynaecol. 1996;103:111-116.
9. Fawcett WJ, Haxby EJ, Male DA. Magnesium: Physiology and pharmacology. Br J Anaesthesia. 1999;83:302-320.
10. Yang Z-W, Gebrewold A, Nowakowski M, Altura BT, Altura BM. Mg2+ -induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO. Am J Physiol. 2000;R628-R639.
11. Sipes SL, Weiner CP, Gellhaus TM, Goodspeed JD. Effects of magnesium sulfate infusion upon plasma prostaglandins in preeclampsia and preterm labor. Hypertens Pregnancy. 1994;13:293-302.
12. Richards A, Graham D, Bullock R. Clinicopathological study of neurological complications due to hypertensive disorders of pregnancy. J. Neurol Neurosurg Psych. 1988;51:416-421.
13. Pritchard JA. The use of magnesium sulfate in preeclampsia-eclampsia. J Reprod Med. 1979;23:107-114.
14. Lu JF, Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia. Clin Pharmacokinet. 2000;38:305-314.
15. Sibai BM, Spinnato JA, Watson DL, Lewis JA, Anderson GD. Effect of magnesium sulfate on electroencephalographic findings in preeclampsia-eclampsia. Obstet Gynecol. 1984;64:261-266.
16. Sibai BM, Spinnato JA, Watson DL, Lewis JA, Anderson GD. Eclampsia. IV. Neurological findings and future outcome. Am J Obstet Gynecol. 1985;152:184-192.
17. Douglas KA, Redman CWG. Eclampsia in the United Kingdom. BMJ. 1994;309:1395-1400.
18. Sibai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol. 1990;163:1049-1055.
19. Sibai BM, Lipshitz J, Anderson GD, Dilts PV. Reassessment of intravenous MgSO4 therapy in preeclampsia-eclampsia. Obstet Gynecol. 1981;57:199.-
20. Katz VL, Farmer R, Kuller JA. Preeclampsia into eclampsia: Toward a new paradigm. Am J Obstet Gynecol. 2000;182:1389-1396.
21. Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet. 1955;100:131-140.
22. Zuspan FP. Problems encountered in the treatment of pregnancy-induced hypertension. A point of view. Am J Obstet Gynecol. 1978;131:591-597.
23. Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: Evaluation of 245 cases. Am J Obstet Gynecol. 1984;148:951-960.
24. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333.
25. Ascarelli MH, Johnson V, May WL, Martin RW, Martin JN. Individually determined postpartum magnesium sulfate therapy with clinical parameters to safely and cost-effectively shorten treatment for pre-eclampsia. Am J Obstet Gynecol. 1998;179:952-956.
26. Isler CM, Barrilleaux PS, Rinehart BK, Magann EF, Martin JN, Jr. Postpartum seizure prophylaxis: Using maternal clinical parameters to guide therapy. Obstet Gynecol. 2003;101:66-69.
27. Atkinson MW, Guinn D, Owen J, Hauth JC. Does magnesium sulfate affect the length of labor induction in women with pregnancy-associated hypertension? Am J Obstet Gynecol. 1995;173:1219-1222.
28. Witlin AG, Friedman SA, Sibai BM. The effect 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;177:623-627.
29. Riaz M, Porat R, Brodsky NL, Hurt J. The effects of maternal magnesium sulfate treatment on newborns: A prospective controlled study. Perinatology. 1998;18:449-454.
- Give magnesium sulfate at the time of diagnosis to all preeclamptic patients who are to be delivered.
- Administration of magnesium sulfate for new-onset hypertension and preeclampsia remote from term is controversial.
- Even with therapeutic serum concentrations of magnesium, convulsions are possible.
- Magnesium sulfate should be administered for 24 hours after delivery or after the last postpartum seizure.
- Safe administration requires vigilant monitoring of reflexes, respiratory status, and urine output.
Last year’s headline-grabbing Magpie Trial1 confirmed a previous, smaller randomized study2 as well as a number of small controlled trials3 indicating that magnesium sulfate is better than placebo1,2 for seizure prophylaxis. Other large, randomized trials have demonstrated the drug’s superiority to nimodipine4 and phenytoin5 in preventing convulsions and to diazepam and phenytoin6 as therapy for eclampsia (TABLE 1).
As a result, magnesium sulfate remains a reliable tool for preventing eclampsia.3 Because clinical symptoms and signs are notoriously unreliable in predicting which gravidas will develop seizures, it is reasonable to administer magnesium at the time of diagnosis to all preeclamptic patients who are to be delivered.
This article reviews the practical implications of recent findings on prophylactic and therapeutic use, patient selection and risk assessment, and administration and monitoring protocols.
TABLE 1
Incidence of seizures according to therapy
| PROPHYLAXIS | ||||
| STUDY | THERAPY GROUPS | SEIZURES (%) | PREECLAMPSIA DEFINED AS … | STUDY CHARACTERISTICS |
| Magpie Trial1 | Magnesium | 0.8 | BP 140/90 mm Hg, proteinuria, nulliparity | n = 10,110, P.0001> |
| Placebo | 1.9 | |||
| Coetzee et al2 | Magnesium | 0.3 | Presence of 2 or more of the following: diastolic BP 110 mm Hg, proteinuria, prodromal symptoms | n = 699, P.003> |
| Placebo | 3.2 | |||
| Belfort et al4 | Magnesium | 0.8 | BP 140/90 mm Hg and proteinuria with 1 or more of the following: headache, clonus, visual disturbances, epigastric/right upper quadrant pain, oliguria, pulmonary edema, elevated liver enzymes, elevated creatinine, hemolysis, thrombocytopenia, intrauterine growth retardation, oligohydramnios | n = 1,650, P.01 |
| Nimodipine | 2.6 | |||
| Lucas et al5 | Magnesium | 0 | BP 140/90 mm Hg | n = 2,138, P.004> |
| Phenytoin | 0.9 | |||
| TREATMENT | ||||
| STUDY | THERAPY | RECURRENT SEIZURES (%) | STUDY CHARACTERISTICS | |
| Eclampsia Trial Collaborative Group6 | Magnesium | 13.2 | n = 905, P.0005> | |
| Diazepam | 27.9 | |||
| Eclampsia Trial Collaborative Group6 | Magnesium | 5.7 | n = 775, P.0005> | |
| Phenytoin | 17.1 | |||
| BP = blood pressure | ||||
Magnesium increases vasodilatation
The prophylactic and therapeutic benefits of magnesium likely derive from its ability to counteract vasospasm; the mechanism by which magnesium protects against seizures has not been established.
Transcranial Doppler ultrasound studies indicate that magnesium increases cerebral blood flow in preeclamptic7 and eclamptic women.8 Magnesium-induced vasodilatation involves a number of factors,9 such as blockade of calcium entry into vascular smooth muscle, antagonism of intracellular calcium activity, and release of nitric oxide10 and prostacyclin.11
In addition, magnesium inhibits platelet aggregation and protects endothelial cells from injury by free radicals. This action, along with stabilization of vascular tone, can potentially reduce the risk of cerebral thrombosis.9,12 The anticonvulsant effects of magnesium in clinically relevant doses do not involve depression of the neuromuscular junction.13
Magnesium also can directly affect the central nervous system by antagonizing N-methyl-D-aspartate receptor activation, which inhibits calcium influx and subsequent neuronal injury.9 This mechanism of action requires that plasma magnesium pass freely into the interstitial fluid of the brain. (Magnesium has already been shown to readily enter the cerebrospinal fluid after intravascular injection.14) The extent to which blockade of N-methyl-D-aspartate receptors contributes to magnesium prophylaxis and therapy remains to be established.
Women with preeclampsia or eclampsia often have electroencephalogram abnormalities that typically involve diffuse slowing (delta waves). These nonspecific electroencephalogram changes develop independently of arterial pressure and are not suppressed by intravenous (IV) magnesium.15,16
Eclamptic women have undergone renal decapsulation, spinal fluid drainage, implantation of the ureters into the colon, mastectomy, and oophorectomy. Each of these treatments was once considered rational based on hypotheses about the cause of eclampsia.
Although descriptions of convulsions in pregnancy date to antiquity, it was not until the 18th century that eclampsia was distinguished from tonic-clonic seizures in the nonpregnant state.
Eventually eclampsia was thought to be one of the pregnancy toxemias caused by a circulating toxin that acted on “nerve centers.”1 Thus, in the 1920s, a popular treatment for eclampsia involved eliminative measures, such as stomach lavage and high colonic flushings, as well as phlebotomy. Later, sedation with morphine sulfate and chloral hydrate without bleeding, popularized by Stroganoff in the 1930s, became prominent.2,3
Magnesium enters the picture. In 1924, an intern at Los Angeles General Hospital suggested using intravenous magnesium sulfate to treat eclamptic seizures, knowing that it controlled tetanic convulsions and had mild sedative effects. As a result, intravenous magnesium sulfate was added to the elimination protocol for eclampsia. In the initial trial, which included 17 eclamptic women, all seizures were controlled by magnesium, and maternal mortality was only 6%, compared with the historical average of 30%.4
By the 1960s, magnesium therapy combined with antihypertensive medication and delivery had been adopted in the United States as frontline therapy for eclamptic seizures—an approach that reduced maternal mortality to 5% or less.5-8 The associated perinatal mortality, which was due largely to abruptio placentae, prematurity, and complications of fetal growth restriction, also was substantially reduced—from 30% to about 10%.5-8
Criticism of this therapy has centered on 2 perceptions of the pharmacology of magnesium: It acted only at the neuromuscular junction, and it did not penetrate the blood-brain barrier.9,10 These effects seemed less than optimal when compared to those of newly developed antiepileptic medications, which had well-described mechanisms of action involving rapid transfer from blood to brain and stabilization of neuronal membranes.
Newer findings. In the 1990s, however, small controlled studies suggested that magnesium is surprisingly effective in preventing seizures in both preeclampsia and eclampsia.11 Recurrent seizures occurred in 9% of eclamptic women who received magnesium, which was about 40% less than in those given the anticonvulsants diazepam or phenytoin. In patients with severe preeclampsia, magnesium prophylaxis reduced the risk of seizures to 0.9% from 2.8% in women who received antihypertensive agents but no anticonvulsants. Large randomized trials confirmed these findings.12-16
REFERENCES
1. Loudan I. Some historical aspects of toxaemia of pregnancy. A review. Br J Gynecol. 1991;98:853-858.
2. Lawson J. Complications of eclampsia: Abruptio placentae, cardiac failure, renal failure, hyperpyrexia, uncontrollable fits, prolonged coma. Clinics Obstet Gynaecol. 1982;9:711-721.
3. O’Dowd MJ, Philipp EE. The History of Obstetrics and Gynecology. New York: Parthenon; 1994:23.
4. Lazard EM. A preliminary report on the intravenous use of magnesium sulphate in puerperal eclampsia. Am J Obstet Gynecol. 1925;9:178-188.
5. Zuspan FP, Ward MC. Improved fetal salvage in eclampsia. Obstet Gynecol. 1965;26:893-897.
6. Pritchard JA, Stone SR. Clinical and laboratory observations on eclampsia. Am J Obstet Gynecol. 1967;99:754-762.
7. Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: Evaluation of 245 cases. Am J Obstet Gynecol. 1984;148:951-960.
8. Sibai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol. 1990;63:1049-1055.
9. Kaplan PW, Lesser RP, Fisher RS, Repke JT, Hanley DF. No, magnesium sulfate should not be used in treating eclamptic seizures. Arch Neurol. 1988;45:1361-1364.
10. Donaldson JO. The case against magnesium sulfate for eclamptic convulsions. Int J Obstet Anesth. 1992;1:159-166.
11. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998;92:883-889.
12. Coetzee EJ, Dommisse J, Anthony J. A randomized controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe preeclampsia. Br J Obstet Gynecol. 1998;105:300-303.
13. 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;359:1877-1890.
14. Belfort MA, Anthony J, Saade GR, Allen JC. for the Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.
15. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333:201-205.
16. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463.
Incidence
- The maternal death rate for eclampsia varies geographically, according to the quality of the area’s health-care system. In developed countries, the rate ranges from 1.8% to 7.2%, while in countries with less available medical care, it can exceed 25%.1-3
- Although the maternal mortality rate for preeclampsia is lower (approximately 0.34% in the United States) than for eclampsia, preeclampsia still accounts for more than half of the maternal deaths linked to pregnancy “toxemia.”3,4
- Eclampsia-associated perinatal mortality remains high—about 10%—even in developed countries.
Risk of eclampsia
- Eclampsia usually involves reversible cerebral edema and endangers the mother principally through seizure-related aspiration (2%) or underlying disturbances such as acute renal failure (5%), pulmonary edema (4%), cardiorespiratory arrest (3%), and abruptio placentae.5,6
- Eclamptic seizures also carry the risk of permanent brain injury or death when they are associated with hemorrhagic or ischemic stroke or with tentorial herniation.
- Recurrent seizures—in which prolonged activation of N-methyl-D-aspartate receptors can produce toxic brain levels of calcium—also may lead to permanent injury and death.
- About 7% of eclamptic women develop significant neurologic sequelae, including aphasia, psychosis, cortical blindness, weakness, coma, or cerebrovascular accident.7
- More than half of eclamptic women who die within 48 hours after the onset of convulsions have cerebral petechiae, hemorrhage, or ischemic softening (nonhemorrhagic) of the brain,8 which may result from thrombosis of cerebral vessels9 or other complications of cerebral vasospasm.8,10
- Necrosis of the walls and endothelium of precapillary arterioles also can occur.
- Cerebral edema in gross specimens has not been a consistent finding at autopsy.8,11 Although this seems to run counter to expectations, a detailed microscopic analysis of the brain would be necessary to identify focal edema affecting a small brain sector.
REFERENCES
1. Douglas KA, Redman CWG. Eclampsia in the United Kingdom. BMJ. 1994;309:1395-1400.
2. Majoko F, Mujaji C. Maternal outcome in eclampsia at Harare Maternity Hospital. Cent Afr J Med. 2001;47:123-128.
3. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97:533-538.
4. 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;359:1877-1890.
5. Lawson J. Complications of eclampsia: Abruptio placentae, cardiac failure, renal failure, hyperpyrexia, uncontrollable fits, prolonged coma. Clinics Obstet Gynaecol. 1982;9:711-721.
6. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333
7. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333.
8. Sheehan JL, Lynch JB. Pathology of Toxaemia of Pregnancy. London: Churchill Livingston; 1973;524-582.
9. McKay DG. Clinical significance of the pathology of toxemia of pregnancy. Circulation. 1964;30(suppl 2):66-75.
10. Will AD, Lewis KL, Hinshaw DB, Jr, et al. Cerebral vasoconstriction in toxemia. Neurology. 1987;37:1555-1557.
11. Hibbard LT. Maternal mortality due to acute toxemia. Obstet Gynecol. 1973;42:263-270.
Give magnesium to all preeclamptic patients to be delivered
Clinical symptoms and signs are unreliable predictors of which pregnant women will develop seizures. For example, eclampsia can occur in gravidas without hypertension or proteinuria. When these conditions are present, the risk of eclampsia is not proportional to their severity.1,17-20 Thus, given the relative safety of magnesium therapy with appropriate monitoring, a reasonable approach is to initiate therapy at the time of diagnosis in all preeclamptic patients who are to be delivered.
If all clinicians followed this management approach, about 5% of gravidas would receive therapy to prevent a rare but potentially injurious event, although for most (more than 97%) the treatment would be unnecessary.
Pregnancy-induced hypertension. The administration of magnesium sulfate to women with new-onset hypertension (arterial blood pressure of 140/90 mm Hg or more) without proteinuria is controversial. Some physicians do not give magnesium to these patients because the risk of eclampsia is lower than in those with preeclampsia (as characterized by hypertension and proteinuria).
About 25% of women with pregnancy-induced hypertension will develop preeclampsia, but those who will go on to develop proteinuria or seizures cannot be identified prospectively. For this reason, other physicians favor prophylactic magnesium for this group.5 They point out that, once a seizure has occurred, recurrence may be more difficult to prevent. We do not routinely administer magnesium to women with pregnancy-induced hypertension unless they have or develop prodromal symptoms (e.g., headache, epigastric pain), high arterial pressures (more than 160/105 mm Hg), proteinuria, or hemolysis, elevated liver enzymes, and low platelets syndrome.
Clinical symptoms and signs are unreliable predictors of which pregnant women will develop seizures.
Mild preeclampsia. Similar arguments also have been given for and against magnesium prophylaxis in women with mild preeclampsia. In the Magpie trial, magnesium sulfate administration was associated with a reduction in the incidence of eclampsia of approximately 56% (placebo: 1.6%; magnesium: 0.7%) in 7,468 gravidas who did not have severe preeclampsia by the definition used in the study. In light of this evidence, we have maintained our practice of giving magnesium to those with mild preeclampsia.
Preeclampsia remote from term. The role of magnesium in the management of patients with preeclampsia remote from term (less than 34 weeks of gestation), when continuation of the pregnancy can provide fetal benefit, also is unclear. We administer magnesium sulfate for the first 24 to 48 hours of hospitalization in patients with severe preeclampsia.
The multiple mechanisms by which magnesium counters preeclampsia-induced vasoconstriction have the potential to improve blood flow in the pulmonary, renal, hepatic, gastrointestinal, and placental circulations, as well as the central nervous system, thus delaying the need for delivery. Whether prolonged infusion of magnesium can be an effective component of therapy to delay delivery and improve fetal outcome remains to be determined.
Abruptio placentae. Magnesium also may reduce the risk of abruptio placentae,1 although 1 small study did not find IV magnesium infusion beneficial in this setting.20
Over the normal range of arterial pressure, cerebral blood flow and capillary hydrostatic pressures remain relatively constant thanks to accompanying adjustments in cerebral vascular resistance. But when arterial pressures are high, elevations in vascular resistance may not completely compensate for them. Thus, capillary blood flow and hydrostatic pressure are increased, disrupting endothelial tight junctions and promoting leakage of small ions and water into the brain parenchyma. The result is cerebral edema and convulsions.
Yet an increase in arterial pressure cannot be the sole mechanism at work, since eclampsia can occur in apparently normotensive patients. Nor is the risk of seizures in preeclamptic women directly proportional to the rise in arterial pressure. Cerebral vasogenic edema may also result from disruptions in cerebral vascular resistance and/or from increased capillary permeability due to endothelial dysfunction or injury, which are unrelated to changes in arterial pressure.1,2 Cytotoxic edema as a result of vasoconstriction or infarction3,4 is another possible mechanism, as are disturbances in brain metabolism.
Imaging studies. Until recently, imaging studies were unable to distinguish between vasogenic and cytotoxic edema; both present as hypodensities on computed tomography and magnetic resonance imaging.5-7 But diffusion-weighted imaging techniques demonstrate that focal vasogenic edema, which disappears with resolution of clinical symptoms, is more consistently observed in eclamptic women.8,9 Petechial brain hemorrhages also have been detected in patients with eclampsia or severe preeclampsia.10
REFERENCES
1. Bhatia RK, Bottoms SF, Saleh AA, Norman GS, Mammen EF, Sokol RJ. Mechanisms for reduced colloid osmotic pressure in preeclampsia. Am J Obstet Gynecol. 1987;157:106.-
2. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: An endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200-1204.
3. Sheehan JL, Lynch JB. Pathology of Toxaemia of Pregnancy. London: Churchill Livingston; 1973;524:582.-
4. McKay DG. Clinical significance of the pathology of toxemia of pregnancy. Circulation. 1964;30(suppl 2):66-75.
5. Milliez J, Dohoun A, Boudraa M. Computed tomography of the brain in eclampsia. Obstet Gynecol. 1990;75:975-980.
6. Dahmus MA, Barton JR, Sibai BM. Cerebral imaging in eclampsia: magnetic resonance imaging versus computed tomography. Am J Obstet Gynecol. 1992;167:935-941.
7. Cunningham FG, Twickler D. Cerebral edema complicating eclampsia. Am J Obstet Gynecol. 2000;182:94-100.
8. Kanki T, Tsukimori K, Mihara F, Nakano H. Diffusion-weighted images and vasogenic edema in eclampsia. Obstet Gynecol. 1999;93:821-823.
9. Friese S, Fetter M, Küker W. Extensive brainstem edema in eclampsia: Diffusion weighted MRI may indicate a favourable prognosis. J Neurol. 2000;247:465-466.
10. Drislane FW, Wang A-M. Multifocal cerebral hemorrhage in eclampsia and severe pre-eclampsia. J Neurol. 1997;244:194-198.
Administration
Protocols based on observational data. Therapeutic magnesium concentrations in maternal plasma have been deduced from empiric studies.21 In a protocol for eclampsia, both IV and intramuscular (IM) administration of magnesium sulfate were associated with initial maternal plasma magnesium levels of 7 to 9 mEq/L, with subsequent stabilization at 4 to 7 mEq/L. For patients with preeclampsia, IM administration of magnesium resulted in concentrations of 3.5 to 6 mEq/L. Because these protocols were generally effective, 4 to 7 mEq/L has been used as a therapeutic range, though no formal dose-response testing has been performed.
The lower limit of target plasma magnesium concentrations is about twice the mean physiologic concentration (approximately 1.7 mEq/L).
Optimum IV infusion rate. Continuous IV infusion of magnesium sulfate—rather than IM injection—is now the norm in most US hospitals.22 However, the infusion rate of 1 g/h, which is generally effective for prophylaxis and treatment of seizures,22 often fails to meet target maternal serum magnesium concentrations.19 Thus, an infusion rate of 2 g/h is recommended (TABLE 2).
We generally start with a loading dose of 4 to 6 g over 10 to 15 minutes in women with normal renal function, using the hydrated form of the drug. In patients with oliguria, we give a loading dose of 4 g over 15 minutes, followed by a maintenance infusion of 1 g/h. Even at the higher infusion rate (2 g/h), plasma levels are usually in the lower therapeutic range.19
IM injection remains an option. Intravenous infusion of magnesium sulfate may not always be practical—for example, when infusion pumps or close patient supervision are unavailable, or when a patient is transported to another facility. Intramuscular injections can be used in these situations.
We give an initial dose of 5 g (10 mL as a 50% solution) of magnesium sulfate with 1 mL of 2% xylocaine deep in the upper outer quadrant of each buttock (10 g total magnesium sulfate). The magnesium solution is injected in several different sites as the needle (3 inches long, 20 gauge) is advanced in muscle. Each injection should be preceded by aspiration to ensure that the needle tip is not in a blood vessel. Massaging the buttock after the injection will help disperse the magnesium in the tissue. Five grams of magnesium sulfate (10 mL as a 50% solution with 1 mL of 2% xylocaine) is subsequently administered as a single intramuscular injection every 4 hours to maintain circulating magnesium levels, provided there is no evidence of magnesium toxicity. Patients with severe preeclampsia, prodromal symptoms of eclampsia, or eclampsia should be given 4 g of magnesium sulfate intravenously (20 mL as a 20% solution) over 5 minutes to more rapidly establish therapeutic magnesium levels immediately prior to the initial intramuscular injection of 10 g of magnesium sulfate.
Convulsions may occur even at therapeutic levels. Even with therapeutic serum magnesium concentrations, seizures are possible.18,23 Recurrent convulsions in patients already receiving magnesium should be treated with an additional 2 g IV magnesium sulfate administered over 5 minutes. Another 2-g dose (4 g total) can be given, but the patient must be carefully watched for signs of respiratory depression. If magnesium fails to control the seizures, additional measures are needed, such as IV anticonvulsants or muscular paralysis in conjunction with intubation and mechanical ventilation.24
Continue administration postpartum. Magnesium sulfate generally is administered for 24 hours after delivery or after the last postpartum seizure, although optimal length of treatment is not firmly established. The clinical state of the patient may be a useful index for individualizing duration of magnesium infusion,25,26 but the risks and benefits of this approach have not been examined in a large patient population.
Know the contraindications. Contraindications to magnesium therapy include myasthenia gravis and myocardial ischemia/failure. Magnesium, which is excreted almost exclusively by the kidneys, should be administered with extreme caution to patients in renal failure (because of the risk of cardiorespiratory depression) and with care to those receiving other calcium-channel antagonists, such as nifedipine (though the incidence of significant maternal hypotension under these circumstances is low).13
The effects of magnesium toxicity can be rapidly reversed with 1 g intravenous calcium chloride or calcium gluconate.
Magnesium can interact with other cardiovascular drugs to elicit arrhythmias or reduce myocardial contractility, and can potentiate the action of muscle relaxants and anesthetics. Thus, use the drug cautiously under these conditions.
TABLE 2
Magnesium sulfate administration*
| INTRAVENOUS INFUSION | |
| Normal renal function | |
| Loading dose: | 4-6 g over 10-15 min |
| Maintenance infusion: | 2 g/h |
| Oliguria† | |
| Loading dose: | 4 g over 15 min |
| Maintenance infusion: | 1 g/h |
| INTRAMUSCULAR INJECTION | |
| Loading dose: | 5 g in each buttock (10 g total) |
| Maintenance injection: | 5 g in 1 buttock (5 g total) every 4 h |
| *All dosages refer to the hydrated form (MgSO 4 7H 2 O) | |
| †Must continuously monitor pulse oximetry and measure magnesium levels 2 hours after starting the infusion. Calcium chloride or calcium gluconate and emergency intubation should be immediately available, and fluids should be restricted provided renal failure is not due to hypovolemia. | |
Risks of magnesium
At therapeutic concentrations of magnesium, about one quarter of pregnant women experience nausea, emesis, flushing, or weakness.1 Magnesium therapy also can be associated with lethargy, blurred vision, and urinary retention.24 Toxic effects, which vary in a dose-dependent manner (TABLE 3), include loss of reflexes, respiratory depression, cardiac arrhythmias, and cardiac arrest.14
Theoretical concerns include prolonged labor or increased blood loss at delivery, but these have not posed a significant problem in actual practice.1,27
Magnesium-induced neonatal depression, as evidenced by hypotonia and low Apgar scores, also may occur, but have not been observed in all studies.28,29 Obviously, pediatricians should attend these deliveries in case such complications are encountered.
TABLE 3
Maternal serum magnesium concentrations associated with toxicity
| MMOL/L | MEQ/L | MG/DL | |
|---|---|---|---|
| Loss of patellar reflexes | 3.5–5 | 7–10 | 8.5–12 |
| Respiratory depression | 5–6.5 | 10–13 | 12–16 |
| Altered cardiac conduction | >7.5 | >15 | >18 |
| Cardiac arrest | >12.5 | >25 | >30 |
| Source: Lu and Nightingale14 | |||
Preventing magnesium toxicity
Closely monitor the patient. Safe administration requires vigilant monitoring of reflexes, respiratory status, and urine output. Prior to initiating therapy, document deep tendon reflexes, respirations of 16 or more per minute, and urinary excretion exceeding 25 mL/h.14 During magnesium infusion, regularly assess respiratory rate, patellar reflexes, and urine output (TABLE 4).
Serum magnesium levels can guide therapy in patients with signs of toxicity, renal insufficiency, or recurrent seizures, but offer no advantage over close clinical scrutiny in typical patients. Steady-state plasma magnesium levels are about the same in the fetus as in the mother to whom magnesium is administered.21 High fetal levels can impair fetal breathing movements, which could lower biophysical profile scores in the absence of significant fetal hypoxia.
- Pulmonary function. Onset of a dry cough should raise suspicion of incipient pulmonary edema. Pulmonary auscultation detects rales that can accompany disease- or therapy-related pulmonary edema. Pulse oximetry, which provides continuous arterial oxygen saturation levels, can be very helpful in alerting the health-care team to both magnesium-induced respiratory depression and significant limitations in pulmonary gas exchange that accompany pulmonary edema.
- Urine output. In the presence of oliguria (less than 100 mL in 4 hours), the rate of magnesium administration should be reduced by 50%.
Also give IV calcium chloride or calcium gluconate for respiratory depression or other signs of cardiorespiratory toxicity. Immediate intubation with assisted ventilation is necessary in cases of cardiorespiratory failure. Fortunately, this phenomenon occurs very rarely with proper patient selection and rigorous surveillance.
TABLE 4
Monitoring guidelines for patients receiving magnesium
| FUNCTION | WHEN TO MONITOR | SUSPECT MAGNESIUM TOXICITY AND COMPLICATIONS WHEN… |
|---|---|---|
| Patellar reflexes | Every 1–4 h* | Reflexes are absent |
| Respiratory rate | Every 1–4 h* | Rate is |
| Pulmonary auscultation | Every 12 h or with development of respiratory symptoms or signs | Rales are present |
| Pulse oximetry | Every 1–4 h* | |
| Urine output | Every 1–4 h* | |
| Serum magnesium levels | In presence of oliguria, persistent seizures, or signs of toxicity | >8 mEq/L |
| *Depending on clinical state | ||
- Give magnesium sulfate at the time of diagnosis to all preeclamptic patients who are to be delivered.
- Administration of magnesium sulfate for new-onset hypertension and preeclampsia remote from term is controversial.
- Even with therapeutic serum concentrations of magnesium, convulsions are possible.
- Magnesium sulfate should be administered for 24 hours after delivery or after the last postpartum seizure.
- Safe administration requires vigilant monitoring of reflexes, respiratory status, and urine output.
Last year’s headline-grabbing Magpie Trial1 confirmed a previous, smaller randomized study2 as well as a number of small controlled trials3 indicating that magnesium sulfate is better than placebo1,2 for seizure prophylaxis. Other large, randomized trials have demonstrated the drug’s superiority to nimodipine4 and phenytoin5 in preventing convulsions and to diazepam and phenytoin6 as therapy for eclampsia (TABLE 1).
As a result, magnesium sulfate remains a reliable tool for preventing eclampsia.3 Because clinical symptoms and signs are notoriously unreliable in predicting which gravidas will develop seizures, it is reasonable to administer magnesium at the time of diagnosis to all preeclamptic patients who are to be delivered.
This article reviews the practical implications of recent findings on prophylactic and therapeutic use, patient selection and risk assessment, and administration and monitoring protocols.
TABLE 1
Incidence of seizures according to therapy
| PROPHYLAXIS | ||||
| STUDY | THERAPY GROUPS | SEIZURES (%) | PREECLAMPSIA DEFINED AS … | STUDY CHARACTERISTICS |
| Magpie Trial1 | Magnesium | 0.8 | BP 140/90 mm Hg, proteinuria, nulliparity | n = 10,110, P.0001> |
| Placebo | 1.9 | |||
| Coetzee et al2 | Magnesium | 0.3 | Presence of 2 or more of the following: diastolic BP 110 mm Hg, proteinuria, prodromal symptoms | n = 699, P.003> |
| Placebo | 3.2 | |||
| Belfort et al4 | Magnesium | 0.8 | BP 140/90 mm Hg and proteinuria with 1 or more of the following: headache, clonus, visual disturbances, epigastric/right upper quadrant pain, oliguria, pulmonary edema, elevated liver enzymes, elevated creatinine, hemolysis, thrombocytopenia, intrauterine growth retardation, oligohydramnios | n = 1,650, P.01 |
| Nimodipine | 2.6 | |||
| Lucas et al5 | Magnesium | 0 | BP 140/90 mm Hg | n = 2,138, P.004> |
| Phenytoin | 0.9 | |||
| TREATMENT | ||||
| STUDY | THERAPY | RECURRENT SEIZURES (%) | STUDY CHARACTERISTICS | |
| Eclampsia Trial Collaborative Group6 | Magnesium | 13.2 | n = 905, P.0005> | |
| Diazepam | 27.9 | |||
| Eclampsia Trial Collaborative Group6 | Magnesium | 5.7 | n = 775, P.0005> | |
| Phenytoin | 17.1 | |||
| BP = blood pressure | ||||
Magnesium increases vasodilatation
The prophylactic and therapeutic benefits of magnesium likely derive from its ability to counteract vasospasm; the mechanism by which magnesium protects against seizures has not been established.
Transcranial Doppler ultrasound studies indicate that magnesium increases cerebral blood flow in preeclamptic7 and eclamptic women.8 Magnesium-induced vasodilatation involves a number of factors,9 such as blockade of calcium entry into vascular smooth muscle, antagonism of intracellular calcium activity, and release of nitric oxide10 and prostacyclin.11
In addition, magnesium inhibits platelet aggregation and protects endothelial cells from injury by free radicals. This action, along with stabilization of vascular tone, can potentially reduce the risk of cerebral thrombosis.9,12 The anticonvulsant effects of magnesium in clinically relevant doses do not involve depression of the neuromuscular junction.13
Magnesium also can directly affect the central nervous system by antagonizing N-methyl-D-aspartate receptor activation, which inhibits calcium influx and subsequent neuronal injury.9 This mechanism of action requires that plasma magnesium pass freely into the interstitial fluid of the brain. (Magnesium has already been shown to readily enter the cerebrospinal fluid after intravascular injection.14) The extent to which blockade of N-methyl-D-aspartate receptors contributes to magnesium prophylaxis and therapy remains to be established.
Women with preeclampsia or eclampsia often have electroencephalogram abnormalities that typically involve diffuse slowing (delta waves). These nonspecific electroencephalogram changes develop independently of arterial pressure and are not suppressed by intravenous (IV) magnesium.15,16
Eclamptic women have undergone renal decapsulation, spinal fluid drainage, implantation of the ureters into the colon, mastectomy, and oophorectomy. Each of these treatments was once considered rational based on hypotheses about the cause of eclampsia.
Although descriptions of convulsions in pregnancy date to antiquity, it was not until the 18th century that eclampsia was distinguished from tonic-clonic seizures in the nonpregnant state.
Eventually eclampsia was thought to be one of the pregnancy toxemias caused by a circulating toxin that acted on “nerve centers.”1 Thus, in the 1920s, a popular treatment for eclampsia involved eliminative measures, such as stomach lavage and high colonic flushings, as well as phlebotomy. Later, sedation with morphine sulfate and chloral hydrate without bleeding, popularized by Stroganoff in the 1930s, became prominent.2,3
Magnesium enters the picture. In 1924, an intern at Los Angeles General Hospital suggested using intravenous magnesium sulfate to treat eclamptic seizures, knowing that it controlled tetanic convulsions and had mild sedative effects. As a result, intravenous magnesium sulfate was added to the elimination protocol for eclampsia. In the initial trial, which included 17 eclamptic women, all seizures were controlled by magnesium, and maternal mortality was only 6%, compared with the historical average of 30%.4
By the 1960s, magnesium therapy combined with antihypertensive medication and delivery had been adopted in the United States as frontline therapy for eclamptic seizures—an approach that reduced maternal mortality to 5% or less.5-8 The associated perinatal mortality, which was due largely to abruptio placentae, prematurity, and complications of fetal growth restriction, also was substantially reduced—from 30% to about 10%.5-8
Criticism of this therapy has centered on 2 perceptions of the pharmacology of magnesium: It acted only at the neuromuscular junction, and it did not penetrate the blood-brain barrier.9,10 These effects seemed less than optimal when compared to those of newly developed antiepileptic medications, which had well-described mechanisms of action involving rapid transfer from blood to brain and stabilization of neuronal membranes.
Newer findings. In the 1990s, however, small controlled studies suggested that magnesium is surprisingly effective in preventing seizures in both preeclampsia and eclampsia.11 Recurrent seizures occurred in 9% of eclamptic women who received magnesium, which was about 40% less than in those given the anticonvulsants diazepam or phenytoin. In patients with severe preeclampsia, magnesium prophylaxis reduced the risk of seizures to 0.9% from 2.8% in women who received antihypertensive agents but no anticonvulsants. Large randomized trials confirmed these findings.12-16
REFERENCES
1. Loudan I. Some historical aspects of toxaemia of pregnancy. A review. Br J Gynecol. 1991;98:853-858.
2. Lawson J. Complications of eclampsia: Abruptio placentae, cardiac failure, renal failure, hyperpyrexia, uncontrollable fits, prolonged coma. Clinics Obstet Gynaecol. 1982;9:711-721.
3. O’Dowd MJ, Philipp EE. The History of Obstetrics and Gynecology. New York: Parthenon; 1994:23.
4. Lazard EM. A preliminary report on the intravenous use of magnesium sulphate in puerperal eclampsia. Am J Obstet Gynecol. 1925;9:178-188.
5. Zuspan FP, Ward MC. Improved fetal salvage in eclampsia. Obstet Gynecol. 1965;26:893-897.
6. Pritchard JA, Stone SR. Clinical and laboratory observations on eclampsia. Am J Obstet Gynecol. 1967;99:754-762.
7. Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: Evaluation of 245 cases. Am J Obstet Gynecol. 1984;148:951-960.
8. Sibai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol. 1990;63:1049-1055.
9. Kaplan PW, Lesser RP, Fisher RS, Repke JT, Hanley DF. No, magnesium sulfate should not be used in treating eclamptic seizures. Arch Neurol. 1988;45:1361-1364.
10. Donaldson JO. The case against magnesium sulfate for eclamptic convulsions. Int J Obstet Anesth. 1992;1:159-166.
11. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998;92:883-889.
12. Coetzee EJ, Dommisse J, Anthony J. A randomized controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe preeclampsia. Br J Obstet Gynecol. 1998;105:300-303.
13. 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;359:1877-1890.
14. Belfort MA, Anthony J, Saade GR, Allen JC. for the Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.
15. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333:201-205.
16. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463.
Incidence
- The maternal death rate for eclampsia varies geographically, according to the quality of the area’s health-care system. In developed countries, the rate ranges from 1.8% to 7.2%, while in countries with less available medical care, it can exceed 25%.1-3
- Although the maternal mortality rate for preeclampsia is lower (approximately 0.34% in the United States) than for eclampsia, preeclampsia still accounts for more than half of the maternal deaths linked to pregnancy “toxemia.”3,4
- Eclampsia-associated perinatal mortality remains high—about 10%—even in developed countries.
Risk of eclampsia
- Eclampsia usually involves reversible cerebral edema and endangers the mother principally through seizure-related aspiration (2%) or underlying disturbances such as acute renal failure (5%), pulmonary edema (4%), cardiorespiratory arrest (3%), and abruptio placentae.5,6
- Eclamptic seizures also carry the risk of permanent brain injury or death when they are associated with hemorrhagic or ischemic stroke or with tentorial herniation.
- Recurrent seizures—in which prolonged activation of N-methyl-D-aspartate receptors can produce toxic brain levels of calcium—also may lead to permanent injury and death.
- About 7% of eclamptic women develop significant neurologic sequelae, including aphasia, psychosis, cortical blindness, weakness, coma, or cerebrovascular accident.7
- More than half of eclamptic women who die within 48 hours after the onset of convulsions have cerebral petechiae, hemorrhage, or ischemic softening (nonhemorrhagic) of the brain,8 which may result from thrombosis of cerebral vessels9 or other complications of cerebral vasospasm.8,10
- Necrosis of the walls and endothelium of precapillary arterioles also can occur.
- Cerebral edema in gross specimens has not been a consistent finding at autopsy.8,11 Although this seems to run counter to expectations, a detailed microscopic analysis of the brain would be necessary to identify focal edema affecting a small brain sector.
REFERENCES
1. Douglas KA, Redman CWG. Eclampsia in the United Kingdom. BMJ. 1994;309:1395-1400.
2. Majoko F, Mujaji C. Maternal outcome in eclampsia at Harare Maternity Hospital. Cent Afr J Med. 2001;47:123-128.
3. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97:533-538.
4. 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;359:1877-1890.
5. Lawson J. Complications of eclampsia: Abruptio placentae, cardiac failure, renal failure, hyperpyrexia, uncontrollable fits, prolonged coma. Clinics Obstet Gynaecol. 1982;9:711-721.
6. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333
7. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333.
8. Sheehan JL, Lynch JB. Pathology of Toxaemia of Pregnancy. London: Churchill Livingston; 1973;524-582.
9. McKay DG. Clinical significance of the pathology of toxemia of pregnancy. Circulation. 1964;30(suppl 2):66-75.
10. Will AD, Lewis KL, Hinshaw DB, Jr, et al. Cerebral vasoconstriction in toxemia. Neurology. 1987;37:1555-1557.
11. Hibbard LT. Maternal mortality due to acute toxemia. Obstet Gynecol. 1973;42:263-270.
Give magnesium to all preeclamptic patients to be delivered
Clinical symptoms and signs are unreliable predictors of which pregnant women will develop seizures. For example, eclampsia can occur in gravidas without hypertension or proteinuria. When these conditions are present, the risk of eclampsia is not proportional to their severity.1,17-20 Thus, given the relative safety of magnesium therapy with appropriate monitoring, a reasonable approach is to initiate therapy at the time of diagnosis in all preeclamptic patients who are to be delivered.
If all clinicians followed this management approach, about 5% of gravidas would receive therapy to prevent a rare but potentially injurious event, although for most (more than 97%) the treatment would be unnecessary.
Pregnancy-induced hypertension. The administration of magnesium sulfate to women with new-onset hypertension (arterial blood pressure of 140/90 mm Hg or more) without proteinuria is controversial. Some physicians do not give magnesium to these patients because the risk of eclampsia is lower than in those with preeclampsia (as characterized by hypertension and proteinuria).
About 25% of women with pregnancy-induced hypertension will develop preeclampsia, but those who will go on to develop proteinuria or seizures cannot be identified prospectively. For this reason, other physicians favor prophylactic magnesium for this group.5 They point out that, once a seizure has occurred, recurrence may be more difficult to prevent. We do not routinely administer magnesium to women with pregnancy-induced hypertension unless they have or develop prodromal symptoms (e.g., headache, epigastric pain), high arterial pressures (more than 160/105 mm Hg), proteinuria, or hemolysis, elevated liver enzymes, and low platelets syndrome.
Clinical symptoms and signs are unreliable predictors of which pregnant women will develop seizures.
Mild preeclampsia. Similar arguments also have been given for and against magnesium prophylaxis in women with mild preeclampsia. In the Magpie trial, magnesium sulfate administration was associated with a reduction in the incidence of eclampsia of approximately 56% (placebo: 1.6%; magnesium: 0.7%) in 7,468 gravidas who did not have severe preeclampsia by the definition used in the study. In light of this evidence, we have maintained our practice of giving magnesium to those with mild preeclampsia.
Preeclampsia remote from term. The role of magnesium in the management of patients with preeclampsia remote from term (less than 34 weeks of gestation), when continuation of the pregnancy can provide fetal benefit, also is unclear. We administer magnesium sulfate for the first 24 to 48 hours of hospitalization in patients with severe preeclampsia.
The multiple mechanisms by which magnesium counters preeclampsia-induced vasoconstriction have the potential to improve blood flow in the pulmonary, renal, hepatic, gastrointestinal, and placental circulations, as well as the central nervous system, thus delaying the need for delivery. Whether prolonged infusion of magnesium can be an effective component of therapy to delay delivery and improve fetal outcome remains to be determined.
Abruptio placentae. Magnesium also may reduce the risk of abruptio placentae,1 although 1 small study did not find IV magnesium infusion beneficial in this setting.20
Over the normal range of arterial pressure, cerebral blood flow and capillary hydrostatic pressures remain relatively constant thanks to accompanying adjustments in cerebral vascular resistance. But when arterial pressures are high, elevations in vascular resistance may not completely compensate for them. Thus, capillary blood flow and hydrostatic pressure are increased, disrupting endothelial tight junctions and promoting leakage of small ions and water into the brain parenchyma. The result is cerebral edema and convulsions.
Yet an increase in arterial pressure cannot be the sole mechanism at work, since eclampsia can occur in apparently normotensive patients. Nor is the risk of seizures in preeclamptic women directly proportional to the rise in arterial pressure. Cerebral vasogenic edema may also result from disruptions in cerebral vascular resistance and/or from increased capillary permeability due to endothelial dysfunction or injury, which are unrelated to changes in arterial pressure.1,2 Cytotoxic edema as a result of vasoconstriction or infarction3,4 is another possible mechanism, as are disturbances in brain metabolism.
Imaging studies. Until recently, imaging studies were unable to distinguish between vasogenic and cytotoxic edema; both present as hypodensities on computed tomography and magnetic resonance imaging.5-7 But diffusion-weighted imaging techniques demonstrate that focal vasogenic edema, which disappears with resolution of clinical symptoms, is more consistently observed in eclamptic women.8,9 Petechial brain hemorrhages also have been detected in patients with eclampsia or severe preeclampsia.10
REFERENCES
1. Bhatia RK, Bottoms SF, Saleh AA, Norman GS, Mammen EF, Sokol RJ. Mechanisms for reduced colloid osmotic pressure in preeclampsia. Am J Obstet Gynecol. 1987;157:106.-
2. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: An endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200-1204.
3. Sheehan JL, Lynch JB. Pathology of Toxaemia of Pregnancy. London: Churchill Livingston; 1973;524:582.-
4. McKay DG. Clinical significance of the pathology of toxemia of pregnancy. Circulation. 1964;30(suppl 2):66-75.
5. Milliez J, Dohoun A, Boudraa M. Computed tomography of the brain in eclampsia. Obstet Gynecol. 1990;75:975-980.
6. Dahmus MA, Barton JR, Sibai BM. Cerebral imaging in eclampsia: magnetic resonance imaging versus computed tomography. Am J Obstet Gynecol. 1992;167:935-941.
7. Cunningham FG, Twickler D. Cerebral edema complicating eclampsia. Am J Obstet Gynecol. 2000;182:94-100.
8. Kanki T, Tsukimori K, Mihara F, Nakano H. Diffusion-weighted images and vasogenic edema in eclampsia. Obstet Gynecol. 1999;93:821-823.
9. Friese S, Fetter M, Küker W. Extensive brainstem edema in eclampsia: Diffusion weighted MRI may indicate a favourable prognosis. J Neurol. 2000;247:465-466.
10. Drislane FW, Wang A-M. Multifocal cerebral hemorrhage in eclampsia and severe pre-eclampsia. J Neurol. 1997;244:194-198.
Administration
Protocols based on observational data. Therapeutic magnesium concentrations in maternal plasma have been deduced from empiric studies.21 In a protocol for eclampsia, both IV and intramuscular (IM) administration of magnesium sulfate were associated with initial maternal plasma magnesium levels of 7 to 9 mEq/L, with subsequent stabilization at 4 to 7 mEq/L. For patients with preeclampsia, IM administration of magnesium resulted in concentrations of 3.5 to 6 mEq/L. Because these protocols were generally effective, 4 to 7 mEq/L has been used as a therapeutic range, though no formal dose-response testing has been performed.
The lower limit of target plasma magnesium concentrations is about twice the mean physiologic concentration (approximately 1.7 mEq/L).
Optimum IV infusion rate. Continuous IV infusion of magnesium sulfate—rather than IM injection—is now the norm in most US hospitals.22 However, the infusion rate of 1 g/h, which is generally effective for prophylaxis and treatment of seizures,22 often fails to meet target maternal serum magnesium concentrations.19 Thus, an infusion rate of 2 g/h is recommended (TABLE 2).
We generally start with a loading dose of 4 to 6 g over 10 to 15 minutes in women with normal renal function, using the hydrated form of the drug. In patients with oliguria, we give a loading dose of 4 g over 15 minutes, followed by a maintenance infusion of 1 g/h. Even at the higher infusion rate (2 g/h), plasma levels are usually in the lower therapeutic range.19
IM injection remains an option. Intravenous infusion of magnesium sulfate may not always be practical—for example, when infusion pumps or close patient supervision are unavailable, or when a patient is transported to another facility. Intramuscular injections can be used in these situations.
We give an initial dose of 5 g (10 mL as a 50% solution) of magnesium sulfate with 1 mL of 2% xylocaine deep in the upper outer quadrant of each buttock (10 g total magnesium sulfate). The magnesium solution is injected in several different sites as the needle (3 inches long, 20 gauge) is advanced in muscle. Each injection should be preceded by aspiration to ensure that the needle tip is not in a blood vessel. Massaging the buttock after the injection will help disperse the magnesium in the tissue. Five grams of magnesium sulfate (10 mL as a 50% solution with 1 mL of 2% xylocaine) is subsequently administered as a single intramuscular injection every 4 hours to maintain circulating magnesium levels, provided there is no evidence of magnesium toxicity. Patients with severe preeclampsia, prodromal symptoms of eclampsia, or eclampsia should be given 4 g of magnesium sulfate intravenously (20 mL as a 20% solution) over 5 minutes to more rapidly establish therapeutic magnesium levels immediately prior to the initial intramuscular injection of 10 g of magnesium sulfate.
Convulsions may occur even at therapeutic levels. Even with therapeutic serum magnesium concentrations, seizures are possible.18,23 Recurrent convulsions in patients already receiving magnesium should be treated with an additional 2 g IV magnesium sulfate administered over 5 minutes. Another 2-g dose (4 g total) can be given, but the patient must be carefully watched for signs of respiratory depression. If magnesium fails to control the seizures, additional measures are needed, such as IV anticonvulsants or muscular paralysis in conjunction with intubation and mechanical ventilation.24
Continue administration postpartum. Magnesium sulfate generally is administered for 24 hours after delivery or after the last postpartum seizure, although optimal length of treatment is not firmly established. The clinical state of the patient may be a useful index for individualizing duration of magnesium infusion,25,26 but the risks and benefits of this approach have not been examined in a large patient population.
Know the contraindications. Contraindications to magnesium therapy include myasthenia gravis and myocardial ischemia/failure. Magnesium, which is excreted almost exclusively by the kidneys, should be administered with extreme caution to patients in renal failure (because of the risk of cardiorespiratory depression) and with care to those receiving other calcium-channel antagonists, such as nifedipine (though the incidence of significant maternal hypotension under these circumstances is low).13
The effects of magnesium toxicity can be rapidly reversed with 1 g intravenous calcium chloride or calcium gluconate.
Magnesium can interact with other cardiovascular drugs to elicit arrhythmias or reduce myocardial contractility, and can potentiate the action of muscle relaxants and anesthetics. Thus, use the drug cautiously under these conditions.
TABLE 2
Magnesium sulfate administration*
| INTRAVENOUS INFUSION | |
| Normal renal function | |
| Loading dose: | 4-6 g over 10-15 min |
| Maintenance infusion: | 2 g/h |
| Oliguria† | |
| Loading dose: | 4 g over 15 min |
| Maintenance infusion: | 1 g/h |
| INTRAMUSCULAR INJECTION | |
| Loading dose: | 5 g in each buttock (10 g total) |
| Maintenance injection: | 5 g in 1 buttock (5 g total) every 4 h |
| *All dosages refer to the hydrated form (MgSO 4 7H 2 O) | |
| †Must continuously monitor pulse oximetry and measure magnesium levels 2 hours after starting the infusion. Calcium chloride or calcium gluconate and emergency intubation should be immediately available, and fluids should be restricted provided renal failure is not due to hypovolemia. | |
Risks of magnesium
At therapeutic concentrations of magnesium, about one quarter of pregnant women experience nausea, emesis, flushing, or weakness.1 Magnesium therapy also can be associated with lethargy, blurred vision, and urinary retention.24 Toxic effects, which vary in a dose-dependent manner (TABLE 3), include loss of reflexes, respiratory depression, cardiac arrhythmias, and cardiac arrest.14
Theoretical concerns include prolonged labor or increased blood loss at delivery, but these have not posed a significant problem in actual practice.1,27
Magnesium-induced neonatal depression, as evidenced by hypotonia and low Apgar scores, also may occur, but have not been observed in all studies.28,29 Obviously, pediatricians should attend these deliveries in case such complications are encountered.
TABLE 3
Maternal serum magnesium concentrations associated with toxicity
| MMOL/L | MEQ/L | MG/DL | |
|---|---|---|---|
| Loss of patellar reflexes | 3.5–5 | 7–10 | 8.5–12 |
| Respiratory depression | 5–6.5 | 10–13 | 12–16 |
| Altered cardiac conduction | >7.5 | >15 | >18 |
| Cardiac arrest | >12.5 | >25 | >30 |
| Source: Lu and Nightingale14 | |||
Preventing magnesium toxicity
Closely monitor the patient. Safe administration requires vigilant monitoring of reflexes, respiratory status, and urine output. Prior to initiating therapy, document deep tendon reflexes, respirations of 16 or more per minute, and urinary excretion exceeding 25 mL/h.14 During magnesium infusion, regularly assess respiratory rate, patellar reflexes, and urine output (TABLE 4).
Serum magnesium levels can guide therapy in patients with signs of toxicity, renal insufficiency, or recurrent seizures, but offer no advantage over close clinical scrutiny in typical patients. Steady-state plasma magnesium levels are about the same in the fetus as in the mother to whom magnesium is administered.21 High fetal levels can impair fetal breathing movements, which could lower biophysical profile scores in the absence of significant fetal hypoxia.
- Pulmonary function. Onset of a dry cough should raise suspicion of incipient pulmonary edema. Pulmonary auscultation detects rales that can accompany disease- or therapy-related pulmonary edema. Pulse oximetry, which provides continuous arterial oxygen saturation levels, can be very helpful in alerting the health-care team to both magnesium-induced respiratory depression and significant limitations in pulmonary gas exchange that accompany pulmonary edema.
- Urine output. In the presence of oliguria (less than 100 mL in 4 hours), the rate of magnesium administration should be reduced by 50%.
Also give IV calcium chloride or calcium gluconate for respiratory depression or other signs of cardiorespiratory toxicity. Immediate intubation with assisted ventilation is necessary in cases of cardiorespiratory failure. Fortunately, this phenomenon occurs very rarely with proper patient selection and rigorous surveillance.
TABLE 4
Monitoring guidelines for patients receiving magnesium
| FUNCTION | WHEN TO MONITOR | SUSPECT MAGNESIUM TOXICITY AND COMPLICATIONS WHEN… |
|---|---|---|
| Patellar reflexes | Every 1–4 h* | Reflexes are absent |
| Respiratory rate | Every 1–4 h* | Rate is |
| Pulmonary auscultation | Every 12 h or with development of respiratory symptoms or signs | Rales are present |
| Pulse oximetry | Every 1–4 h* | |
| Urine output | Every 1–4 h* | |
| Serum magnesium levels | In presence of oliguria, persistent seizures, or signs of toxicity | >8 mEq/L |
| *Depending on clinical state | ||
1. 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;359:1877-1890.
2. Coetzee EJ, Dommisse J, Anthony J. A randomized controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia. Br J Obstet Gynecol. 1998;105:300-303.
3. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998;92:883-889.
4. Belfort MA, Anthony J, Saade GR, Allen JC. for the Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.
5. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333:201-205.
6. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463
7. Belfort M, Moise KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: A randomized, placebo-controlled study. Am J Obstet Gynecol. 1992;167:661-666.
8. Naidu S, Payne AJ, Moodley J, Hoffmann M, Gouws E. Randomized study assessing the effect of phenytoin and magnesium sulphate on maternal cerebral circulation in eclampsia using transcranial Doppler ultrasound. Br J Obstet Gynaecol. 1996;103:111-116.
9. Fawcett WJ, Haxby EJ, Male DA. Magnesium: Physiology and pharmacology. Br J Anaesthesia. 1999;83:302-320.
10. Yang Z-W, Gebrewold A, Nowakowski M, Altura BT, Altura BM. Mg2+ -induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO. Am J Physiol. 2000;R628-R639.
11. Sipes SL, Weiner CP, Gellhaus TM, Goodspeed JD. Effects of magnesium sulfate infusion upon plasma prostaglandins in preeclampsia and preterm labor. Hypertens Pregnancy. 1994;13:293-302.
12. Richards A, Graham D, Bullock R. Clinicopathological study of neurological complications due to hypertensive disorders of pregnancy. J. Neurol Neurosurg Psych. 1988;51:416-421.
13. Pritchard JA. The use of magnesium sulfate in preeclampsia-eclampsia. J Reprod Med. 1979;23:107-114.
14. Lu JF, Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia. Clin Pharmacokinet. 2000;38:305-314.
15. Sibai BM, Spinnato JA, Watson DL, Lewis JA, Anderson GD. Effect of magnesium sulfate on electroencephalographic findings in preeclampsia-eclampsia. Obstet Gynecol. 1984;64:261-266.
16. Sibai BM, Spinnato JA, Watson DL, Lewis JA, Anderson GD. Eclampsia. IV. Neurological findings and future outcome. Am J Obstet Gynecol. 1985;152:184-192.
17. Douglas KA, Redman CWG. Eclampsia in the United Kingdom. BMJ. 1994;309:1395-1400.
18. Sibai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol. 1990;163:1049-1055.
19. Sibai BM, Lipshitz J, Anderson GD, Dilts PV. Reassessment of intravenous MgSO4 therapy in preeclampsia-eclampsia. Obstet Gynecol. 1981;57:199.-
20. Katz VL, Farmer R, Kuller JA. Preeclampsia into eclampsia: Toward a new paradigm. Am J Obstet Gynecol. 2000;182:1389-1396.
21. Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet. 1955;100:131-140.
22. Zuspan FP. Problems encountered in the treatment of pregnancy-induced hypertension. A point of view. Am J Obstet Gynecol. 1978;131:591-597.
23. Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: Evaluation of 245 cases. Am J Obstet Gynecol. 1984;148:951-960.
24. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333.
25. Ascarelli MH, Johnson V, May WL, Martin RW, Martin JN. Individually determined postpartum magnesium sulfate therapy with clinical parameters to safely and cost-effectively shorten treatment for pre-eclampsia. Am J Obstet Gynecol. 1998;179:952-956.
26. Isler CM, Barrilleaux PS, Rinehart BK, Magann EF, Martin JN, Jr. Postpartum seizure prophylaxis: Using maternal clinical parameters to guide therapy. Obstet Gynecol. 2003;101:66-69.
27. Atkinson MW, Guinn D, Owen J, Hauth JC. Does magnesium sulfate affect the length of labor induction in women with pregnancy-associated hypertension? Am J Obstet Gynecol. 1995;173:1219-1222.
28. Witlin AG, Friedman SA, Sibai BM. The effect 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;177:623-627.
29. Riaz M, Porat R, Brodsky NL, Hurt J. The effects of maternal magnesium sulfate treatment on newborns: A prospective controlled study. Perinatology. 1998;18:449-454.
1. 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;359:1877-1890.
2. Coetzee EJ, Dommisse J, Anthony J. A randomized controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia. Br J Obstet Gynecol. 1998;105:300-303.
3. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998;92:883-889.
4. Belfort MA, Anthony J, Saade GR, Allen JC. for the Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.
5. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333:201-205.
6. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463
7. Belfort M, Moise KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: A randomized, placebo-controlled study. Am J Obstet Gynecol. 1992;167:661-666.
8. Naidu S, Payne AJ, Moodley J, Hoffmann M, Gouws E. Randomized study assessing the effect of phenytoin and magnesium sulphate on maternal cerebral circulation in eclampsia using transcranial Doppler ultrasound. Br J Obstet Gynaecol. 1996;103:111-116.
9. Fawcett WJ, Haxby EJ, Male DA. Magnesium: Physiology and pharmacology. Br J Anaesthesia. 1999;83:302-320.
10. Yang Z-W, Gebrewold A, Nowakowski M, Altura BT, Altura BM. Mg2+ -induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO. Am J Physiol. 2000;R628-R639.
11. Sipes SL, Weiner CP, Gellhaus TM, Goodspeed JD. Effects of magnesium sulfate infusion upon plasma prostaglandins in preeclampsia and preterm labor. Hypertens Pregnancy. 1994;13:293-302.
12. Richards A, Graham D, Bullock R. Clinicopathological study of neurological complications due to hypertensive disorders of pregnancy. J. Neurol Neurosurg Psych. 1988;51:416-421.
13. Pritchard JA. The use of magnesium sulfate in preeclampsia-eclampsia. J Reprod Med. 1979;23:107-114.
14. Lu JF, Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia. Clin Pharmacokinet. 2000;38:305-314.
15. Sibai BM, Spinnato JA, Watson DL, Lewis JA, Anderson GD. Effect of magnesium sulfate on electroencephalographic findings in preeclampsia-eclampsia. Obstet Gynecol. 1984;64:261-266.
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