Magnesium sulfate treatment for the prevention of eclampsia: A brief review

Abstract

Background and Purpose:

Magnesium sulfate is used extensively for prevention of eclamptic seizures. Empirical and clinical evidence supports the effectiveness of magnesium sulfate; however, questions remain as to its safety and mechanism. This review summarizes current evidence supporting the possible mechanisms of action and several controversies for magnesium sulfate treatment.

Summary of Review:

Several mechanisms are presented, including the effects of magnesium sulfate on peripheral and cerebral vasodilation, blood-brain barrier protection, and as an anticonvulsant.

Conclusions:

Though the specific mechanisms of action remain unclear, the effect of magnesium sulfate in the prevention of eclampsia is likely multi-factorial. Magnesium sulfate may act as a vasodilator, with actions in the peripheral vasculature or the cerebrovasculature, to decrease peripheral vascular resistance and/or relieve vasoconstriction. Additionally, magnesium sulfate may also protect the blood-brain barrier and limit cerebral edema formation, or it may act through a central anticonvulsant action.

Introduction

Magnesium sulfate (MgSO₄) has been used throughout the 20^th century for prevention of eclamptic seizures^{1, 2} and continues to be used extensively^3-5. Empirical evidence supports the effectiveness of MgSO₄ in preventing and treating eclamptic seizures^{1, 6-8}, in addition to recent controlled clinical trials^{5, 9, 10}. For eclamptic seizure prophylaxis in preeclamptic women, MgSO₄ is superior to phenytoin^{11, 12}, nimodipine¹³, diazepam¹⁴, and placebo⁹. In the multinational Collaborative Eclampsia Trial, MgSO₄ reduced the risk of recurrent seizures in eclamptic women by 52% when compared to diazepam and by 67% when compared to phenytoin¹⁵. The publication of these clinical trials significantly increased the use of magnesium sulfate versus other anticonvulsants in the United Kingdom and Ireland where the reported use in preeclampsia increased from 2% to 40%¹⁶. In addition, 60% of providers surveyed indicated they would use magnesium as an anticonvulsant for eclampsia in 1998, up from only 2% of eclamptic women who received magnesium sulfate in 1992^{16, 17}.

Although the effectiveness of MgSO₄ in treating and preventing eclampsia has been established, questions still exist as to its safety. There are concerns regarding the possibility of hypermagnesemia toxicity in eclampsia treatment. Normal serum concentrations of Mg⁺² are 1.5-2.5 mEq/L (1.8-3.0 mg/dL), with one-third to one-half bound to plasma proteins^{18, 19}. Total magnesium serum concentrations advocated for the treatment of eclamptic convulsions are 3.5-7 mEq/L (4.2-8.4 mg/dL)^{2, 20, 21}, which can be obtained by administering it intramuscularly (6 g loading dose followed by 2 g/h), intravenously (2-4 g dose up to 1 g/min) or a combination of both^{6, 18, 22}. Areflexia, particularly loss of the patellar deep tendon reflex, has been observed at 8-10 mEq/L, and respiratory paralysis seen at >13 mEq/L^{6, 18, 22}. Progressively higher serum magnesium levels can ultimately lead to cardiac arrest^{18, 22, 23}. Some suggest that using standard infusion protocols may not lead to therapeutic serum magnesium levels in all patients, with 36.2% of patients found to have total serum magnesium lower than 4 mEq/L at 30 minutes after treatment initiation in one study²⁴, though no eclamptic seizures were reported during MgSO₄ treatment. In addition, there are reports that in some patients eclamptic seizures do not cease even with elevated levels of MgSO₄^{6, 7, 25}, suggesting that MgSO₄ is not effective in treating all cases of eclampsia.

As technologic advances allow for ionized magnesium to be more readily measured, questions have arisen as to whether it is more appropriate to monitor total serum magnesium or the ionized, physiologically active, form. Studies have shown little correlation between total and ionized magnesium levels, either at baseline prior to treatment or during MgSO₄ treatment for preeclampsia^{19, 24}. In preeclamptic patients treated with a loading dose of 4 g intravenously followed by 2 g per hour infusion, it was found that both total and ionized Mg⁺² concentrations increased quickly after infusion, but steady-state concentrations for total magnesium were 4.84 ± 0.24 mg/dL, whereas for ionized magnesium it was 2.04 ± 0.14 mg/dL¹⁹. Similar results have been found by other groups using the same infusion protocol²⁴. Interestingly, as MgSO₄ infusion caused significant increases in ionized Mg⁺² levels, serum ionized calcium (Ca⁺²) concentrations were unchanged²⁶, suggesting that the effect of MgSO₄ is not exerted through modulations of ionized calcium levels.

Though the use of MgSO₄ is wide-spread and effective, its mechanism of action remains unclear. Several possible mechanisms of action have been proposed, including acting as a vasodilator, with actions either peripherally or in the cerebral circulation to relieve vasoconstriction, protecting the blood-brain barrier (BBB) to decrease cerebral edema formation, and acting as a central anticonvulsant. Each of these possible mechanisms of action are discussed below.

Magnesium-induced Vasodilation

Magnesium is a unique calcium antagonist as it can act on most types of calcium channels in vascular smooth muscle²⁷ and as such would be expected to decrease intracellular calcium. One major effect of decreased intracellular calcium would be inactivation of calmodulin-dependent myosin light chain kinase activity and decreased contraction²⁷, causing arterial relaxation that may subsequently lower peripheral and cerebral vascular resistance, relieve vasospasm, and decrease arterial blood pressure. The vasodilatory effect of MgSO₄ has been investigated in a wide variety of vessels. For example, both in vivo and in vitro animal studies have shown that it is a vasodilator of large conduit arteries such as the aorta^{28, 29}, as well as smaller resistance vessels including mesenteric^{27, 30-32}, skeletal muscle²⁷, uterine³³, and cerebral arteries^{27, 30, 34}. However, the importance of magnesium-induced vasodilation in the treatment and prevention of eclampsia is not completely understood.

The theory of cerebrovascular vasospasm as the etiology of eclampsia seemed to be reinforced by transcranial Doppler (TCD) studies which suggested that MgSO₄ treatment caused dilation in the cerebral circulation^35-37 as well as in animal studies that used large cerebral arteries³⁴. However, a vasodilator such as MgSO₄ would seem to be a paradoxical treatment choice for eclamptic encephalopathy. Eclampsia is thought to be a form of posterior reversible encephalopathy syndrome (PRES) and similar to hypertensive encephalopathy, in which acute elevations in blood pressure cause forced dilatation of the myogenic vasoconstriction of cerebral arteries and arterioles, increased BBB permeability and edema formation^38-40. Studies from our lab have shown that MgSO₄ causes concentration-dependent vasodilatation in both cerebral and mesenteric resistance arteries; however, mesenteric arteries were significantly more sensitive to MgSO₄, particularly during pregnancy³⁰. The finding of a modest vasodilatory effect in the cerebral circulation are consistent with other findings that MgSO₄ treatment caused no significant change in cerebral blood flow (CBF), large cerebral artery diameter, or mean middle cerebral artery velocity as determined by magnetic resonance imaging (MRI)⁴¹ and TCD^{42, 43}. Together, these results suggest that the effects of MgSO₄ as an eclamptic seizure prophylaxis may be more closely related to an effect on peripheral vascular resistance and lowering of systemic blood pressure than to a direct effect on CBF (Table 1 and Figure 1).

Table 1.

Vascular Effects of Magnesium Sulfate.

Cellular Target	Mode of Action	Possible Mechanism(s)
Smooth Muscle Uterine +++ Mesenteric +++ Aorta +++ Cerebral +	Relaxation ↓ Vasodilation ↓ Decreased Vascular Resistance	Calcium Antagonism Decreased Voltage-operated Calcium Channel (VOCC) Activity Decreased [Ca+2]i Release From Sarcoplasmic Reticulum
Endothelium	Decreased Platelet Aggregation	Increased Prostaglandin I2 (PGI2)
	Vasodilation	Increased Nitric Oxide (NO, Gestation Dependent)

Figure 1. Vascular Effects of Magnesium Sulfate.

Magnesium is a potent vasodilator of uterine and mesenteric arteries, and aorta, but has minimal effect on cerebral arteries. In vascular smooth muscle, magnesium competes with calcium for binding sites, in this case for voltage-operated calcium channels (VOCC). Decreased calcium channel activity lowers intracellular calcium, causing relaxation and vasodilation. In endothelium, magnesium has been shown to increase production of prostaglandin I₂ (through unknown mechanisms), which in turn decreases platelet aggregation. Magnesium also increases NO production causing vasodilation.

Reports of the effects of MgSO₄ treatment on arterial blood pressure have been mixed. Hypotensive effects have been noted in various studies particularly with bolus injections^{2, 36, 44}, though the duration of decreased blood pressure was varied. In pregnant rats treated with the nitric oxide synthase inhibitor L-NAME to induce hypertension, combination treatment with MgSO₄ resulted in significantly lower blood pressures at term and better neonatal outcomes versus animals treated with L-NAME alone⁴⁵. However, it has been cautioned that MgSO₄ should not be considered primarily an anti-hypertensive agent, as there are other drugs better suited for that purpose in eclampsia, including hydralazine, labetalol, and nifedipine ^{20, 22}.

Several reports have suggested that gestation may influence vascular reactivity to MgSO₄ and that sensitivity varies with vascular bed^{28-30, 33}. Human uterine arteries from pregnant patients are three-fold more reactive to MgSO₄ than uterine arteries from non-pregnant patients³³. In aorta from pregnant and non-pregnant rats, both increased and decreased sensitivity to MgSO₄-induced vasodilation have been shown based on the preconstriction agent used for in vitro studies. These studies also suggest that pregnancy may differentially affect receptor versus voltage-operated calcium channels in aortic smooth muscle²⁸. In another study of rat aortic rings, the effect of MgSO₄ was dependent on gestation and nitric oxide production such that vasodilation was less at term than during late pregnancy²⁹. Our studies found that while mesenteric resistance arteries showed no change in sensitivity with gestation, posterior cerebral resistance arteries from late-pregnant and postpartum animals were significantly less sensitive to MgSO₄-induced vasodilation versus those from nonpregnant animals³⁰. This may be due to gestation-induced changes in the cerebral endothelial vaodilatory mechanisms that have been demonstrated during pregnancy and the postpartum state⁴⁶.

MgSO₄ may have other effects within the vasculature that could also explain its effectiveness in eclampsia (included in Figure 1). Magnesium may act by stimulating production of prostacyclin by endothelial cells causing vasodilation⁴⁷, or by inhibiting platelet aggregation^{47, 48}. In patients with pregnancy-induced hypertension, MgSO₄ treatment significantly decreased circulating levels of angiotensin-converting enzyme⁴⁹. These actions may attenuate the endothelial dysfunction associated with (pre)eclampsia^50-52.

Effects on the Blood-brain Barrier and Cerebral Edema Formation

The cerebral endothelium that forms the BBB has unique features compared to the peripheral endothelium including a lack of capillary fenestrations⁵³, a low basal rate of pinocytosis^{54, 55}, and the presence of high electrical resistance tight junctions between adjacent endothelial cells^{54, 56}. Disruption of the BBB can result in vasogenic edema formation, an important component in the clinical picture of eclampsia^{57, 58}. Decreased BBB permeability with MgSO₄ treatment has been reported in a variety of animal models of BBB disruption including traumatic brain injury⁵⁹, septic encephalopathy⁶⁰, hypoglycemia⁶¹, and mannitol injection⁶². We recently reported MgSO₄ treatment decreased BBB permeability in response to acute hypertension in late-pregnant rats⁶³. In addition, several studies have shown that MgSO₄ decreases cerebral edema formation after brain injury^{59, 62, 64-67}. Together, these studies importantly suggest that one mechanism by which MgSO₄ is effective in eclampsia treatment may be through protection of the BBB and decreased cerebral edema formation.

Several mechanisms of action have been proposed to explain the neuroprotective effects of MgSO₄ (Table 2 and Figure 2). Magnesium is a calcium antagonist that acts both intracellularly and extracellularly⁶⁸, and may act directly on cerebral endothelial cells. It is possible that by acting as a calcium antagonist at the level of the endothelial cell actin cytoskeleton, MgSO₄ opposes paracellular movement of solutes through the tight junctions (Figure 2). This hypothesis is supported by several studies which demonstrated that inhibition of myosin light chain (MLC) phosphorylation decreases agonist-induced permeability by inhibiting actin stress fiber contraction^69-71. Alternatively, pinocytosis is induced by acute hypertension and may contribute to increased BBB permeability during elevated intravascular pressure.⁷² MgSO₄ treatment may therefore decrease pinocytosis caused by acute hypertension and restrict the movement of water and solutes into the brain by transcellular transport, thereby limiting edema formation and improving clinical outcomes in eclampsia.

Table 2.

Effect of Magnesium Sulfate on Cerebral Edema and the Blood-brain Barrier.

Cellular Target	Mode of Action	Possible Mechanism
Cerebral Endothelium	Decreased Blood-brain Barrier (BBB) disruption ↓ Limited Cerebral Edema Formation Via Paracellular Transport	Calcium Antagonism ↓ Decreased Cell Contraction ↓ Decreased Tight Junction Permeability
	Limited Transcellular Transport	Decreased Pinocytosis
Astrocyte	Limited Cerebral Edema	Decreased Aquaporin 4 (AQP4) Expression

Figure 2. Effect of Magnesium Sulfate on Cerebral Edema and the Blood-brain Barrier.

The calcium antagonistic effects of magnesium can also affect the cerebral endothelium that forms the blood-brain barrier. Decreased cell calcium inhibits endothelial contraction and opening of tight junctions that are linked to the actin cytoskeleton. Decreased tight junction permeability limits paracellular transport of vascular contents, ions and proteins, which can promote vasogenic edema and seizures. It is also possible that magnesium sulfate diminishes transcellular transport by limiting pinocytosis that is known to occur rapidly during acute hypertension. Magnesium may also downregulate aquaporin 4 (AQP4), a water channel protein localized to astrocytic endfeet, and possibly cerebral endothelium, that is associated with cerebral edema formation (through unknown mechanisms).

Anticonvulsant Activity

Although widely used, there is controversy regarding the use of MgSO₄ treatment for neurological conditions, such as eclamptic seizures. Concerns have been raised that MgSO₄ treatment may mask the outward signs of convulsions through its action at the neuromuscular junction without treating the cause of the seizure in the central nervous system^{18, 73}. Dose-related depression of neuromuscular transmission has been shown in preeclamptic women receiving traditional MgSO₄ therapy⁷⁴. Studies have also shown that there is little to no change in electroencephalograms obtained during MgSO₄ treatment, and minimal signs of central nervous system depression in both normal⁷⁵ and eclamptic patients²⁵, and in animals⁷⁶. However, clinical trials have demonstrated the efficacy of MgSO₄ in the treatment and prevention of eclamptic seizures versus more traditional anticonvulsant drugs, including phenytoin and diazepam ^{12, 14, 15}.

The possible anticonvulsant activity of magnesium may be related to its role as an N-methyl-d-aspartate (NMDA) receptor antagonist^77-79, shown in Table 3 and Figure 3. Seizures are thought to be mediated at least in part by stimulation of glutamate receptors, such as the NMDA receptor^{79, 80}. In rats, systemic magnesium treatment results in a resistance to both electrically stimulated⁸¹ and NMDA-induced hippocampal seizures⁸². In addition, systemic treatment with MgSO₄ causes a significant reduction in the NMDA receptor binding capacity in the brain⁷⁸. Animal studies have also shown that MgSO₄ reduces epileptic seizure activity⁸³, though these findings have been challenged due to inadequate controls⁷⁶.

Table 3.

Anticonvulsant Activity of Magnesium Sulfate.

Cellular Target	Mode of Action	Possible Mechanism
Neurons	Increased Seizure Threshold	N-Methyl-d-Aspartate (NMDA) Receptor Antagonism ↓ Decreased Effect of Glutamate, Limiting Massive Neuronal Depolarization

Figure 3. Anticonvulsant Activity of Magnesium Sulfate.

Seizures consist of an excessive release of excitotoxic neurotransmitters including glutamate. Excessive glutamate can activate the N-methyl-d-aspartate (NMDA) receptor, leading to massive depolarization of neuronal networks and bursts of action potentials. Magnesium may act to increase the seizure threshold by inhibiting NMDA receptors, thereby limiting the effect of glutamate.

Magnesium ions must cross the BBB in order to elicit a central anticonvulsant effect. It has been demonstrated in animals that MgSO₄ can cross the intact BBB and enter the central nervous system in correlation with the level of serum hypermagnesemia⁸¹. Interestingly, seizure activity increases the movement of magnesium into the brain⁸¹. Human studies have also shown small but significant increases in cerebrospinal fluid concentrations of MgSO₄ after systemic administration^{2, 84}. Conversely, other work has suggested that the BBB prevents changes in brain and cerebrospinal fluid magnesium concentrations⁸⁵. However, this same group later suggested that even a small amount of magnesium in the central nervous system may suppress cortical neuronal activity⁸⁶. The possibility remains that acute hypertension that leads to convulsions and BBB disruption may permit MgSO₄ to enter the brain parenchyma and act as an anticonvulsant during eclampsia.

Future Directions

A better understanding of the mechanisms of action of MgSO₄ could allow for more directed use in the treatment of eclampsia and other brain injury disorders. An interesting area for future studies is the relationship between MgSO₄ and cerebral edema formation, as it has been proposed that MgSO₄ may limit cerebral edema formation through an effect on aquaporin (AQP) expression. Aquaporin-4 (AQP4) is a water channel protein that has been localized to astrocytic endfeet^{87, 88} and has also been reported to have a perivascular domain⁸⁹. Cerebral edema in response to brain injury is associated with an upregulation of AQP4 in the brain^{90, 91}, and it has been suggested that MgSO₄ treatment attenuates cerebral edema formation via downregulation of AQP4 expression in astrocytes⁶⁵, though the mechanism of action has not been delineated. This idea is particularly interesting with respect to eclampsia as cerebral AQP4 expression is significantly increased during pregnancy⁹².

One of the difficulties in studying preeclampsia and eclampsia is the lack of appropriate animal models, particularly as (pre)eclampsia is a disease specific to bipedal species⁹³. In our lab, we have used a rat model of hypertensive encephalopathy during pregnancy to study the neurologic outcomes of eclampsia, specifically how acute elevations in blood pressure lead to forced dilatation of myogenic vasoconstriction, causing increased blood-brain barrier permeability and subsequent edema formation^{63, 94}. Other animal models of preeclampsia and eclampsia exist, including reduced uterine placental perfusion (RUPP), Dahl Salt-Sensitive rats, nitric oxide synthase inhibition, and exogenous soluble fms-like tyrosine receptor kinase-1 (sFlt-1). These models focus on different aspects of the disease including the impact of placental perfusion, preexisting hypertension, and the significance of endothelial dysfunction, oxidative stress and circulating anti-angiogenic factors. The pros and cons of the different models have been reviewed elsewhere^{93, 95}, all of which provide opportunities to further study the specific actions of MgSO₄ for seizure prophylaxis.

Conclusion

MgSO₄ has been shown to be an effective treatment option for the prevention of eclampsia. Its mechanism of action is likely multi-factorial, encompassing both vascular and neurological mechanisms. Being a calcium antagonist, its effect on vascular smooth muscle to promote relaxation and vasodilation may have a role in lowering total peripheral vascular resistance. In addition, MgSO₄ may have an effect on the cerebral endothelium to limit vasogenic edema by decreasing stress fiber contraction and paracellular permeability via calcium-dependent second messenger systems such as MLC kinase. Lastly, MgSO₄ may also act centrally to inhibit NMDA receptors, providing anticonvulsant activity by increasing the seizure threshold. A more complete understanding of the effects of MgSO₄ will likely promote safer and more effective treatments of eclampsia.