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Abstract: Introduction: Extracellular histones have been determined as significant mediators of sepsis, which can induce endothelial cell injury and promote coagulation activation, and ultimately contribute to multiorgan failure. Evidence suggests that magnesium sulfate (MgSO 4 ) exerts a potential coagulation-modulating activity; however, whether MgSO 4 ameliorates histone-induced coagulation dysfunction and organ damage remains unclear. Methods: To measure circulating histone levels, blood specimens were collected from septic patients and mice, and the relationship between circulating histone levels, coagulation parameters, and Mg 2+ levels in sepsis was investigated. Furthermore, to explore the possible protective effects of MgSO 4 , we established a histone-induced coagulation model in mice by intravenous histone injection. The survival rate of mice was assessed, and the histopathological damage of the lungs (including endothelial cell injury and coagulation status) was evaluated using various methods, including hematoxylin and eosin staining, immunohistochemistry, immunofluorescence, electron microscopy, and quantitative polymerase chain reaction. Results: The circulating histone levels in septic patients and mice were significantly associated with several coagulation parameters. In septic patients, histone levels correlated negatively with platelet counts and positively with prothrombin time and D-dimer levels. Similarly, in cecal ligation and puncture mice, histones correlated negatively with platelet counts and positively with D-dimer levels. Interestingly, we also observed a positive link between histones and Mg 2+ levels, suggesting that Mg 2+ with anticoagulant activity is involved in histone-mediated coagulation alterations in sepsis. Further animal experiments confirmed that MgSO 4 administration significantly improved survival and attenuated histone-mediated endothelial cell injury, coagulation dysfunction, and lung damage in mice. Conclusion: These results suggest that therapeutic targeting of histone-mediated endothelial cell injury, coagulation dysfunction, and lung damage, for example, with MgSO 4 , may be protective in septic individuals with elevated circulating histone levels., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Background: Magnesium sulfate (MgSO4) is widely used in analgesia for different conditions. Recent randomized controlled trials (RCTs) have evaluated the effects of MgSO4 on renal colic; however, this new evidence has not been synthesized. Thus, we conducted a systematic review and meta-analysis to assess the efficacy and safety of MgSO4 in comparison with control for renal colic., Methods: PubMed, EMBASE, and Scopus databases were searched from inception to February 2020. We included RCTs that evaluated MgSO4 vs control for patients with renal colic. Data were independently extracted by 2 reviewers and synthesized using a random-effects model., Results: Four studies with a total of 373 patients were analyzed. Intravenous MgSO4 15 to 50 mg/kg did not significantly reduce renal colic pain severity at 15 minutes (mean difference [MD] = 0.35, 95% confidence interval [CI] -0.51 to 1.21; 2 RCTs), 30 minutes (MD = 0.19, 95% CI -0.74 to 1.13; 4 RCTs), and 60 minutes (MD = -0.28, 95% CI -0.72 to 0.16; 3 RCTs) in comparison with controls. In patients who failed to respond to initial analgesics, intravenous MgSO4 15 mg/kg or 2 ml of 50% solution provided similar pain relief to ketorolac or morphine at 30 minutes (P = .90) and 60 minutes (P = .57). No significant hemodynamic changes were observed with short-term use of MgSO4 in these studies., Conclusion: MgSO4 provides no superior therapeutic benefits in comparison with control treatments. MgSO4 may be used as a rescue medication in patients not responding to initial analgesics. The short-term use of MgSO4 did not affect hemodynamic values.

Background: Diaphragm dysfunction could be induced by sepsis with subsequent ventilatory pump failure that is associated with local infiltration of inflammatory factors in the diaphragm. It has been shown that the administration of anticonvulsant agent, magnesium sulfate (MgSO4) could decrease systematic inflammatory response. We recently reported that MgSO4 could inhibit macrophages high mobility group box 1 (HMGB1) secretion that confirms its anti-inflammatory properties. Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signal pathway appears to be involved in the pathology of septic experimental animal's inflammatory response and involve in the pathogenic mechanisms of sepsis-induced diaphragm dysfunction. Thus, in this study, we are aiming to explore whether MgSO4 could ameliorate sepsis-induced diaphragm dysfunction via TLR4/NF-κB pathway in a rodent model with controlled mechanical ventilation (CMV) and subsequent septic challenge., Methods: Rats were randomly assigned into (1) control group: having an identical laparotomy but without ligation or puncture in the cecum; (2) CLP group: cecal ligation and puncture (CLP) with continuous saline infusion; (3) CLP + MgSO4 group: CLP with continuous MgSO4 administration; and (4) MgSO4 group: a sham surgery with MgSO4 administration. After surgery, all rats were submitted to CMV for 18 h. After completion of the study protocol, blood inflammatory cytokine/chemokine was detected by ELISA, as well as diaphragm contractility, TLR4, NF-κB (p65), phospho-NF-κB (p65) and HMGB1 protein expression., Results: The level of inflammatory cytokine/chemokine includes interleukin-6, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and HMGB1 in blood were significantly increased at 18-h post-CLP compared with the control group. We found that rats in the CLP group had substantial diaphragm dysfunction with a distinct downshift of the force-frequency curve. Furthermore, expression of HMGB1, TLR4, NF-κB (p65) and phospho-NF-κB (p65) in diaphragm were significantly increased in the CLP group. In contrast, MgSO4 attenuated the septic inflammation reaction in diaphragm and serum and preserved diaphragm function., Conclusion: MgSO4 protects against sepsis-induced diaphragm dysfunction. This may be associated with its anti-inflammatory effect on HMGB1/TLR4/NF-κB signal pathway.

Purpose of Review: The aim of this review is to describe the proposed mechanisms of action of magnesium sulfate for fetal neuroprotection, different dosing regimens of the drug that have shown benefit, and to review recent pharmacokinetic studies of the drug to better inform clinicians regarding expected benefits and remaining research questions., Recent Findings: Retrospective secondary analysis of the beneficial effects of antenatal magnesium sulfate trial database and prospective pharmacokinetic/pharmacodynamic modeling indicate magnesium sulfate administration for duration longer than 18 h, given within 12 h of delivery, and maintaining a maternal serum level of 4.1 mg/dl may maximize the neuroprotective benefits of the drug., Summary: Magnesium sulfate in some dosage given before very preterm pregnancy delivery is beneficial for fetal neuroprotection. The exact dose, duration, and timing of administration to maximize this benefit may be more precisely studied using pharmacokinetic/pharmacodynamic modeling techniques before conducting larger randomized trials.

Background: The impact of magnesium sulfate on hemodynamic responses during laparoscopic cholecystectomy remains controversial. We conduct a systematic review and meta-analysis to explore the influence of magnesium sulfate on hemodynamic responses for laparoscopic cholecystectomy., Methods: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through June 2018 for randomized controlled trials (RCTs) assessing the effect of magnesium sulfate on hemodynamic responses for laparoscopic cholecystectomy. Meta-analysis is performed using the random-effect model., Results: Four RCTs involving 208 patients are included in the meta-analysis. Overall, compared with control group in laparoscopic cholecystectomy, intravenous magnesium sulfate is associated with systolic blood pressure at 30 minutes [Std. MD = -1.34; 95% confidence interval (95% CI) = -1.86 to -0.82; P < .00001], diastolic blood pressure at 30 minutes (Std. MD = -1.40; 95% CI = -1.86 to -0.94; P < .00001), mean arterial pressure at 30 minutes (Std. MD = -1.19; 95% CI = -1.91 to -0.46; P = .001), systolic blood pressure at 10 minutes (Std. MD = -1.61; 95% CI = -2.08 to -1.13; P < .00001), diastolic blood pressure at 10 minutes (Std. MD = -1.54; 95% CI = -2.68 to -0.40; P = .008), heart rate at 30 minutes (Std. MD = -2.09; 95% CI = -2.87 to -1.32; P < .00001), but results in prolonged extubation time (Std. MD = 0.96; 95% CI = 0.18-1.74; P = .02)., Conclusion: Magnesium sulfate can reduce blood pressure, but with the increase in extubation time for laparoscopic cholecystectomy.

Posterior reversible encephalopathy syndrome (PRES) is a potentially reversible failure of cerebral autoregulation managed by correction of hypertension or underlying medical condition. Nonresponding cases progress to irreversible brain damage. There is some evidence of association of hypomagnesemia with PRES. We describe a case of nonresolving PRES where use of magnesium sulfate led to improvement in neurological function and eventual recovery. Our case highlights the need for a randomized controlled trial to test the efficacy of magnesium in PRES.

Background and Purpose: Paramedic use of fixed-size lumen, gravity-controlled tubing to initiate intravenous infusions in the field may allow rapid start of neuroprotective therapy for acute stroke. In a large, multicenter trial, we evaluated its efficacy in attaining target serum levels of candidate neuroprotective agent magnesium sulfate and the relation of achieved magnesium levels to outcome., Methods: The FAST-MAG phase 3 trial (Field Administration of Stroke Therapy - Magnesium) randomized 1700 patients within 2 hours of onset to paramedic-initiated, a 15-minute loading intravenous infusion of magnesium or placebo followed by a 24-hour maintenance dose. The drug delivery strategy included fixed-size lumen, gravity-controlled tubing for field drug administration, and a shrink-wrapped ambulance kit containing both the randomized field loading and hospital maintenance doses for seamless continuation., Results: Among patient randomized to active treatment, magnesium levels in the first 72 hours were assessed 987 times in 572 patients. Mean patient age was 70 years (SD±14 years), and 45% were women. During the 24-hour period of active infusion, mean achieved serum level was 3.91 (±0.8), consistent with trial target. Mg levels were increased by older age, female sex, lower weight, height, body mass index, and estimated glomerular filtration rate, and higher blood urea nitrogen, hemoglobin, and higher hematocrit. Adjusted odds for clinical outcomes did not differ by achieved Mg level, including disability at 90 days, symptomatic hemorrhage, or death., Conclusions: Paramedic infusion initiation using gravity-controlled tubing permits rapid achievement of target serum levels of potential neuroprotective agents. The absence of association of clinical outcomes with achieved magnesium levels provides further evidence that magnesium is not biologically neuroprotective in acute stroke., (© 2017 American Heart Association, Inc.)

Background: Magnesium enhances the effect of rocuronium. Sugammadex reverses rocuronium-induced neuromuscular block. The authors investigated whether magnesium decreased the efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular block., Methods: Thirty-two male patients were randomized in a double-blinded manner to receive magnesium sulfate (MgSO4) 60 mg/kg or placebo intravenously before induction of anesthesia with propofol, sufentanil, and rocuronium 0.6 mg/kg. Neuromuscular transmission was monitored using TOF-Watch SX acceleromyography (Organon Ltd., Dublin, Ireland). In 16 patients, sugammadex 2 mg/kg was administered intravenously at reappearance of the second twitch of the train-of-four (moderate block). In 16 further patients, sugammadex 4 mg/kg was administered intravenously at posttetanic count 1 to 2 (deep block). Primary endpoint was recovery time from injection of sugammadex to normalized train-of-four ratio 0.9. Secondary endpoint was recovery time to final T1., Results: Average time for reversal of moderate block was 1.69 min (SD, 0.81) in patients pretreated with MgSO4 and 1.76 min (1.13) in those pretreated with placebo (P = 0.897). Average time for reversal of deep block was 1.77 min (0.83) in patients pretreated with MgSO4 and 1.98 min (0.58) in those pretreated with placebo (P = 0.572). Times to final T1 were longer compared with times to normalized train-of-four ratio 0.9, without any difference between patients pretreated with MgSO4 or placebo., Conclusion: Pretreatment with a single intravenous dose of MgSO4 60 mg/kg does not decrease the efficacy of recommended doses of sugammadex for the reversal of a moderate and deep neuromuscular block induced by an intubation dose of rocuronium.

Oxidized low-density lipoprotein (oxLDL) is elevated during several neurologic conditions that involve cerebral edema formation, including severe preeclampsia and eclampsia; however, our understanding of its effect on the cerebral vasculature is limited. We hypothesized that oxLDL induced blood-brain barrier (BBB) disruption and changes in cerebrovascular reactivity occur through NADPH oxidase-derived superoxide. We also investigated the effect of MgSO₄ on oxLDL-induced changes in the cerebral vasculature as this is commonly used in preventing cerebral edema formation. Posterior cerebral arteries from female rats were perfused with 5 µg/mL oxLDL in rat serum with or without 50 µM apocynin or 16 mM MgSO₄ and BBB permeability and vascular reactivity were compared. oxLDL increased BBB permeability and decreased myogenic tone that were prevented by apocynin. oxLDL increased constriction to the nitric oxide synthase inhibitor nitro-L-arginine that was unaffected by apocynin. oxLDL enhanced dilation to the NO donor sodium nitroprusside that was prevented by apocynin. MgSO₄ prevented oxLDL-induced BBB permeability without affecting oxLDL-induced changes in myogenic tone. Thus, oxLDL seems to cause BBB disruption and vascular tone dysregulation through NADPH oxidase-derived superoxide. These results highlight oxLDL and NADPH oxidase as potentially important therapeutic targets in neurologic conditions that involve elevated oxLDL.

Purpose of Review: Cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage remains a considerable challenge in neurocritical care medicine. This review aims to cover the recent novel aspects and results in CVS treatment., Recent Findings: On the basis of the recent literature, treatment focusing on CVS alone is outdated. A considerable amount of evidence suggests CVS not to be the sole cause of delayed cerebral ischemia (DCI) and poor outcome. Early brain injury, cortical spreading depolarization, inflammation and microthrombosis have recently been discussed as additional factors. The results of a well designed phase III trial, using an endothelin-1 antagonist, indicated a decrease in the occurrence of CVS but did not change the clinical outcome significantly. Induced hypertension is currently recommended for treating suspected DCI, whereas hemodilution and hypervolemia are not. Endovascular intervention is only recommended in case of refractory symptomatic CVS. A couple of newer treatment strategies are under evaluation. Phase III trials are underway for magnesium sulfate and statins. Clinical trials aiming specifically at recently discussed factors other than CVS have not been reported., Summary: Reviewing the recent literature, there have been some updates on recommendations and newer treatment modalities are under evaluation. However, a novel treatment with convincing evidence has not been reported so far.

Background: Magnesium sulfate (MgSO4) possesses potent anti-inflammation capacity. We sought to elucidate the effects of MgSO4 on mitigating acute lung injury induced by endotoxemia. MgSO4 is an antagonist of the L-type calcium channels and the N-methyl-D-aspartate (NMDA) receptor. The roles of the L-type calcium channels and NMDA receptor in this regard were also elucidated., Methods: Ninety-six adult male rats were randomized to receive normal saline, MgSO4 (100 mg/kg), lipopolysaccharide (LPS), LPS plus MgSO4 (10, 50, or 100 mg/kg), LPS plus MgSO4 (100 mg/kg) plus the L-type calcium channel activator BAY-K8644, or LPS plus MgSO4 (100 mg/kg) plus exogenous NMDA (n=12 in each group). Between-group differences in lung injury were evaluated., Results: Histologic findings, in concert with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that LPS induced acute lung injury. LPS also caused significant inflammatory response (increases in chemokine, cytokine, and prostaglandin E2 concentrations) and imposed significant oxidative stress (increases in nitric oxide and malondialdehyde concentrations) in rat lungs. MgSO4 at the dosages of 50 mg/kg and 100 mg/kg, but not at 10 mg/kg, significantly mitigated the acute lung injury, lung inflammatory response, and oxidative stress caused by endotoxemia. Moreover, the protective effects of MgSO4 were counteracted by BAY-K8644 and exogenous NMDA., Conclusions: MgSO4 mitigates lung inflammatory response, oxidative stress, and acute lung injury in endotoxemia rats in a dose-dependent manner. The mechanisms may involve antagonizing the L-type calcium channels and the NMDA receptor.

Objective: To estimate the effects of maternal administration of magnesium sulfate on the fetal middle cerebral artery using Doppler., Methods: This is a single-center ancillary study done in conjunction with a randomized, double-masked, placebo- controlled trial in 20 centers. Women at imminent risk of preterm delivery (n=2,241) were allocated randomly to receive magnesium sulfate or placebo. Doppler measurements of the fetal middle cerebral artery were obtained before blinded study-drug administration and subsequently at 1-, 2-, 3-, and 4-hour intervals. Parameters studied included time-average velocity, peak systolic velocity, vessel diameter, heart rate, and calculated blood volume flow. A random-effects model with repeated-measures design was used for analysis., Results: A total of 38 fetuses were studied: 18 received magnesium sulfate and 20 received placebo. Peak systolic velocity was significantly related to gestational age (P<.001). There were no differences between the study groups for middle cerebral artery peak systolic velocity, average velocity, vessel diameter, or calculated volume flow. However, fetal heart rate significantly decreased after treatment with magnesium sulfate., Conclusion: Magnesium sulfate had no significant effects on fetal cerebral blood flow analyzed using Doppler. The only parameter in the fetal cerebral circulation significantly modified by magnesium sulfate was the heart rate. The significance of this heart-rate change, vis-à-vis the neuroprotective effects of magnesium sulfate, is unknown., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00014989., Level of Evidence: I.

Objective: To review the evidence regarding neuroprotective effects of antenatal exposure to magnesium sulfate., Data Sources: We conducted database searches of MEDLINE, the Cochrane Library and Controlled Trials Register, as well as the ClinicalTrials.gov and International Clinical Trials Register websites. Bibliographies of all relevant articles were reviewed., Methods of Study Selection: Randomized controlled trials comparing magnesium sulfate with placebo/other treatment in patients at risk of preterm delivery were evaluated for inclusion and methodological quality. The primary outcome was death or cerebral palsy by 18-24 months corrected age. Secondary outcomes were death, cerebral palsy, moderate-severe cerebral palsy, and death or moderate-severe cerebral palsy. Separate analyses were performed according to the gestational age (GA) at randomization (less than 32 to 34 weeks and less than 30 weeks) and for studies in which magnesium sulfate was used exclusively for fetal neuroprotection., Tabulation, Integration, and Results: Five randomized controlled trials were included (5,235 fetuses/infants). When analyzed by GA at randomization, in utero exposure to magnesium sulfate at less than 32-34 weeks did not reduce the rate of death or cerebral palsy (relative risk [RR] 0.92, 95% confidence interval [CI] 0.83-1.03). However, cerebral palsy (RR 0.70, 95% CI 0.55-0.89), moderate-severe cerebral palsy (RR 0.60, 95% CI 0.43-0.84), and death or moderate-severe cerebral palsy were significantly reduced, without an evident increase in the risk of death (RR 1.01, 95% CI 0.89-1.14). Similar results were obtained when the GA at randomization was less than 30 weeks. When only neuroprotection trials (four trials, 4,324 fetuses/infants) are analyzed, in utero exposure to magnesium sulfate additionally reduced the primary outcome of death or cerebral palsy. The number needed to treat to prevent one case of cerebral palsy among those who survive until age 18-24 months is 46 (95% CI 26-187) in infants exposed to magnesium sulfate in utero before 30 weeks, and 56 (95% CI 34-164) in infants exposed to magnesium sulfate in utero before 32 to 34 weeks., Conclusion: Fetal exposure to magnesium sulfate in women at risk of preterm delivery significantly reduces the risk of cerebral palsy without increasing the risk of death.

Background and Purpose: The study aim was to assess the effects of magnesium sulfate (MgSO(4)) administration on white matter damage in vivo in spontaneously hypertensive rats., Methods: The left internal capsule was lesioned by a local injection of endothelin-1 (ET-1; 200 pmol) in adult spontaneously hypertensive rats. MgSO(4) was administered (300 mg/kg SC) 30 minutes before injection of ET-1, plus 200 mg/kg every hour thereafter for 4 hours. Infarct size was measured by T2-weighted magnetic resonance imaging (day 2) and histology (day 11), and functional recovery was assessed on days 3 and 10 by the cylinder and walking-ladder tests., Results: ET-1 application induced a small, localized lesion within the internal capsule. Despite reducing blood pressure, MgSO(4) did not significantly influence infarct volume (by magnetic resonance imaging: median, 2.1 mm(3); interquartile range, 1.3 to 3.8, vs 1.6 mm(3) and 1.2 to 2.1, for the vehicle-treated group; by histology: 0.3 mm(3) and 0.2 to 0.9 vs 0.3 mm(3) and 0.2 to 0.5, respectively). Significant forelimb and hindlimb motor deficits were evident in the vehicle-treated group as late as day 10. These impairments were significantly ameliorated by MgSO(4) in both cylinder (left forelimb use, P<0.01 and both-forelimb use, P<0.03 vs vehicle) and walking-ladder (right hindlimb score, P<0.02 vs vehicle) tests., Conclusions: ET-1-induced internal capsule ischemia in spontaneously hypertensive rats represents a good model of lacunar infarct with small lesion size, minimal adverse effects, and a measurable motor deficit. Despite inducing mild hypotension, MgSO(4) did not significantly influence infarct size but reduced motor deficits, supporting its potential utility for the treatment of lacunar infarct.

Objective: Magnesium sulfate is neuroprotective in preclinical models, but there are limited safety data regarding its clinical use for pediatric traumatic brain injury. We conducted a pilot study in children with severe traumatic brain injury to a) examine if magnesium sulfate decreases mean arterial pressure, decreases cerebral perfusion pressure, increases intracranial pressure, or adversely effects cardiac conduction; and b) determine the feasibility of a multiple-center trial of magnesium sulfate., Design: Double-blinded, placebo-controlled, randomized pilot trial with repeated measurement of hemodynamic variables., Setting: Two pediatric trauma centers., Patients: Six children (3 months to 18 yrs) with severe traumatic brain injury., Interventions: : Magnesium sulfate (50 mg/kg) bolus followed by (8.3 mg/kg/hr) infusion for 24 hr vs. equivolume placebo., Measurements and Main Results: We screened 96 patients with severe traumatic brain injury during 24 months; 20 were eligible for enrollment, six provided informed consent, four received magnesium sulfate, and two received placebo. Before and after study drug infusion, we repeatedly measured blood ionized magnesium concentration, mean arterial pressure, cerebral perfusion pressure, intracranial pressure, heart rate, and corrected QT interval. Mean age (7.9 yrs), mean highest Glasgow Coma Scale score (6), gender (33% boys), inflicted injury rate (17%), and case mortality rate (17%) did not differ between those enrolled and those not enrolled. Compared with baseline, magnesium sulfate did not change cerebral perfusion pressure, intracranial pressure, heart rate, or corrected QT interval. Mean arterial pressure was unchanged until the late phase of magnesium sulfate infusion, when mean arterial pressure rose (82 +/- 5 vs. 93 +/- 6 mm Hg, p < .05). Sixty-four percent of corrected QT interval determinations obtained in the first 6 days after injury exceeded 440 msecs; 12% were >600 msecs., Conclusions: In children with severe traumatic brain injury, magnesium sulfate administration did not decrease mean arterial pressure or cerebral perfusion pressure or adversely effect cardiac conduction. Our data suggest that enrollment of brain-injured children in a therapeutic trial remains challenging. These results provide information important for clinical trials of magnesium sulfate in children with severe traumatic brain injury.

In this prospective, randomized, double-blind, placebo-controlled, crossover study we compared the effects of remifentanil or magnesium sulfate (MgSO4) versus placebo in attenuating the sympathetic response to electroconvulsive therapy. Twenty adults underwent a total of 115 anesthetics for therapeutic electroconvulsive therapy. Patients were randomly allocated twice into each of the three test groups: placebo control, MgSO4 30 mg/kg, or remifentanil 1.0 microg/kg. Systolic and diastolic arterial blood pressures, heart rate, and oxygen saturations were recorded before IV access was established. Anesthesia was induced with thiopental 4 mg/kg. The trial drug was then administered and neuromuscular blockade was followed with succinylcholine 0.5 mg/kg before electroconvulsive therapy was performed. All measurements were repeated at 0, 1, 3 and 10 min after the seizure ended. Remifentanil and MgSO4 produced a statistically significant attenuation of the increase in systolic arterial blood pressure at 0, 1, and 3 min (P < 0.05). Remifentanil, but not MgSO4 or placebo, attenuated the increase in heart rate at 1 and 3 min but not the peak rate. Remifentanil increased the duration of apnea (mean 90 s), with no other adverse respiratory effects. Mean seizure duration time was 33 (+/- 14) s, with no difference among the groups. In conclusion, remifentanil 1.0 microg/kg and MgSO4 30 mg/kg attenuated the systolic arterial blood pressure response to electroconvulsive therapy without reducing the duration of seizure activity. Because MgSO4 has less effect on HR, it might offer advantages over remifentanil in patients at risk for post-electroconvulsive therapy bradycardia.

We previously demonstrated that glucose and glutamine, solutes metabolized by the gut, replenish ATP and enhance gut function compared with alanine, a solute not metabolized by the gut, following mesenteric ischemia/reperfusion (I/R). The purpose of the present study was to determine if the nonmetabolizable solute alanine differentially modulates cytoskeletal organization and paracellular small intestinal permeability compared with the metabolizable solutes glucose and glutamine following mesenteric I/R. At laparotomy, rats had jejunal sacs filled with 10 mM glucose, glutamine, alanine, or magnesium sulfate (5 mm, osmotic control) followed by superior mesenteric artery clamping for 60 min and 30 min of reperfusion or sham laparotomy. Jejunum was harvested for evaluation by deconvolution microscopy, fluorescent measurement of F:G actin ratio, or mounted in an Ussing chamber for determination of intestinal permeability. Deconvolution microscopy revealed that the actin cytoskeleton was preserved by enteral glutamine, comparable to shams, but disrupted by enteral alanine. Glucose and controls resulted in comparable disruption, which was less than that with alanine. The F:G actin ratio was highest for glutamine and lowest for alanine; glucose was comparable to controls. Intestinal permeability was highest for alanine and lowest for glutamine, which was comparable to shams. Permeability following glucose and controls was higher than that following glutamine but lower than that following alanine. The nonmetabolizable solute alanine resulted in disruption of the actin cytoskeleton and enhanced intestinal permeability under conditions of mesenteric I/R. The metabolizable solute glutamine was protective under these conditions, whereas glucose exerted minimal effect on the integrity of the cytoskeleton and intestinal permeability. The individual components of enteral diets may differentially modulate intestinal barrier function, which could have important implications when administered to critically injured patients.

Objectives: To investigate fetal heart rate accelerations, fetal breathing movements, and fetal electrocortical activities during administration of magnesium sulfate to fetal goats., Methods: The fetal heart rate accelerations, fetal breathing movements, and fetal electrocortical activities during 6 hours of continuous magnesium sulfate infusion into the fetal jugular vein were examined in 8 chronically instrumented fetal goats at 124-131 days of gestation. Fetal breathing movements were defined as repetitive negative fluctuations of the fetal tracheal pressure. Fetal electrocortical activities were assessed by visual analysis of periods of high-voltage and low-voltage electrocortical activities., Results: Continuous infusion of magnesium sulfate for 6 hours significantly increased the fetal plasma magnesium concentration from 2.8 +/- 1.2 to 8.3 +/- 2.6 mg/dL without significant changes in fetal arterial blood gases. The incidence of fetal heart rate accelerations during magnesium infusion was significantly decreased from that found during the control periods. After 2 hours of infusion, the incidence of fetal breathing movements significantly decreased from 33.9% +/- 20.5% to 1.2% +/- 1.4% and remained at this level during the remaining 4 hours of magnesium infusion. The percentage of time that the fetuses were found to have low-voltage electrocortical activities decreased from 51.6% +/- 9.0% to 40.4% +/- 8.2% after 2 hours of infusion but recovered to 49.9% +/- 12.0% by 6 hours of magnesium infusion., Conclusion: We concluded that fetal magnesium sulfate administration affected fetal heart rate accelerations and fetal breathing movements continuously but electrocortical activities only temporarily during 6 hours of observations.

Background: The authors investigated whether an intravenous administration of magnesium sulfate reduces propofol infusion requirements during maintenance of propofol-N2O anesthesia., Methods: Part I study: 54 patients undergoing total abdominal hysterectomy were randomly divided into two groups (n = 27 per group). The patients in the control group received 0.9% sodium chloride solution, whereas the patients in the magnesium group received magnesium (50 mg/kg as a bolus, then 8 mg x kg(-1) x h(-1)). To maintain mean arterial blood pressure (MAP) and heart rate (HR) at baseline value, the propofol infusion rate was changed when the MAP or the HR changed. The amount of propofol infused excluding the bolus dosage was divided by patient's body weight and total infusion time. Part II study: Another 20 patients were randomly divided into two groups (n = 10 per group). When the MAP and HR had been maintained at baseline value and the propofol infusion rate had been maintained at 80 microg x kg(-1) x min(-1) (magnesium group) and 160 microg x kg(-1) x min(-1) (control group), bispectral index (BIS) values were measured., Results: Part I: The mean propofol infusion rate in the magnesium group (81.81 +/- 13.09 microg x kg(-1) x min(-1)) was significantly less than in the control group (167.57 +/- 47.27). Part II: BIS values in the control group (40.70 +/- 3.89) were significantly less than those in the magnesium group (57.80 +/- 7.32)., Conclusion: Intravenous administration of magnesium sulfate reduces propofol infusion requirements. These results suggest that magnesium administration may have an effect on anesthesia or analgesia and may be a useful adjunct to propofol anesthesia.

Magnesium sulfate has attracted interest as a potential neuroprotectant but passage of magnesium ion into the central nervous system has not been well documented. For this study, we quantified plasma and cerebrospinal fluid (CSF) ionized magnesium concentration after systemic magnesium sulfate infusion in patients with intracranial hypertension. Patients ( N = 9) received an intravenous infusion of 5 g/20 mmol magnesium sulfate (125 mL of a 4% wt/vol solution) over 30 minutes. Before and after dosing, CSF (from an indwelling ventricular catheter) and blood samples were collected at hourly intervals. Ionized magnesium concentration in all samples was determined using an electrolyte analyzer. Baseline plasma and CSF ionized magnesium concentrations were 0.58 +/- 0.05 and 0.82 +/- 0.06 mmol/L, respectively. Intravenous magnesium sulfate infusion significantly increased plasma ionized magnesium concentration (peak, 0.89 +/- 0.11 mmol/L), but CSF magnesium levels did not change during the 4-hour study. Systemic administration of magnesium sulfate failed to increase CSF ionized magnesium concentration in patients with intracranial hypertension despite increasing plasma magnesium levels by >50%.

Objective: To identify the role of physiologic magnesium concentrations on the induction of placental apoptosis in vitro and test the anti-apoptotic action of antioxidants., Methods: Placental tissue was obtained from normal pregnancies after cesarean delivery. Placental explants were incubated with increasing concentrations of extracellular magnesium (range 0-2.0 mM). Placental apoptosis was evaluated by tissue morphology, DNA fragmentation, cytokeratin-18 neoepitope formation, and cleavage of plasminogen activator inhibitor type 2., Results: Physiologic concentrations of extracellular magnesium stimulated placental apoptosis. Magnesium stimulated apoptosis within the physiologic range (0.8-1.2 mM) (n = 6, P <.001) and was associated with cleavage of plasminogen activator inhibitor type 2 and cytokeratin-18 neoepitope formation. These data implicate caspase activation in the transduction of the magnesium-induced apoptotic signal. Therapeutic concentrations of vitamin C, vitamin E, and acetylcysteine (all at 25 microg/mL) inhibited DNA fragmentation and attenuated cleavage of plasminogen activator inhibitor type 2 and cytokeratin-18 neoepitope formation., Conclusion: Magnesium-induced placental apoptosis is a potent mechanism of placental degeneration in vitro and may represent an important regulator of placental tissue dynamics in vivo. The ability of antioxidants to prevent magnesium-induced placental apoptosis implicates oxidation-reduction-dependent signaling events in this process. Furthermore, these findings provide a basis for further studies of antioxidants in mitigating the adverse effects of preeclampsia.

To examine the effects of calcium antagonists nimodipine and magnesium sulfate (MgSO4) on tissue endogenous antioxidant levels, the authors studied superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels in rabbit brain 1 hour after experimental head trauma. Forty New Zealand rabbits were anesthetized and randomly divided into four groups. Group 1 (n = 10) was the sham operated group. Group 2 (n = 10), the control group, received head trauma and no treatment. Group 3 (n = 10) received head trauma and intravenous (IV) 2 microgr/kg nimodipine. Group 4 (n = 10) received head trauma and IV 100 mg/kg MgSO4. Head trauma was delivered by performing a craniectomy over the right hemisphere and dropping a weight of 20 g from a height of 40 cm. In the right (traumatized) hemisphere, SOD and GPx decreased by 57.60% +/- 9.60% and 72.93% +/- 5.51% respectively from sham values. Magnesium sulfate, but not nimodipine, reduced the magnitude of decrease of SOD and GPx to 19.43% +/- 7.15% and 39.01% +/- 7.92% respectively from sham values. In the left (nontraumatized) hemisphere, MgSO4 increased SOD to 42.43% +/- 24.76% above sham values. The authors conclude that MgSO4 treatment inhibited the decrease in SOD and GPx levels in experimental brain injury.

Objective: To examine the influence of antenatally administered magnesium sulfate (MgSO4) and ritodrine on cerebral blood flow and systemic hemodynamics in preterm infants., Design: Prospective, observational study., Setting: Neonatal intensive care unit of a university central hospital., Patients: Fifty-five preterm infants age <33 wks of gestation., Interventions: Serial Doppler examinations of the brain circulation, heart rate, systemic blood pressure, and echocardiographic assessment of ductus arteriosus shunting were performed during the first week of life in infants exposed antenatally to maternal MgSO4 (n = 19) or ritodrine treatment (n = 17), and in 19 nonexposed preterm controls., Measurements and Main Results: Cerebral blood flow velocity measurements were obtained from the anterior cerebral artery and internal carotid artery. Perfusion pressure and indices of resistance and blood flow in both vessels were subsequently derived. Maternal MgSO4 had no effect on neonatal cerebral blood flow velocity or resistance, but was associated with decreased (p <.05) perfusion pressure and blood flow in the anterior cerebral artery and internal carotid artery during the first day of life. Systolic blood pressure and pulse pressure were also lower (p <.05) during the whole study period in the MgSO4-exposed infants when compared with the controls. Maternal ritodrine treatment, on the other hand, had no consistent effects on either neonatal cerebral or systemic hemodynamics., Conclusions: Our data indicate that maternal MgSO4 treatment, in contrast to antenatal ritodrine, is associated with lowered cerebral perfusion in preterm infants on the first day of life.

Unlabelled: Intrathecal magnesium sulfate coinfusion with morphine increases antinociception in normal rats; however, because magnesium also delays the onset of tolerance, it is not clear whether this additional antinociception is a result of potentiated analgesia or tolerance abatement. We examined the antinociceptive interaction of intrathecal (IT) bolus magnesium sulfate and morphine in morphine naive rats and those with mechanical allodynia after a surgical incision. After intrathecal catheter implantation, rats were given preinjections of magnesium or saline, followed by injections of morphine or saline. In morphine naïve rats, IT bolus magnesium sulfate 281 and 375 microg followed by IT morphine 0.25 or 0.5 nmol enhanced peak antinociception and area under the response versus time curve two-to-three-fold in the tail-flick test as compared with morphine alone. Likewise, in rats with incisional pain, IT bolus magnesium sulfate 188 and 375 microg followed by morphine 0.5 nmol reduced mechanical allodynia, whereas morphine 0.5 nmol alone did not. This study suggests that IT magnesium sulfate potentiates morphine at a spinal site of action., Implications: Magnesium sulfate potentiates morphine analgesia when coadministered intrathecally in normal rats, and in an animal model of mechanical allodynia after a surgical incision. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.

Intrathecal administration of MgSO(4) is reported to cause paralysis. However, the characteristic sensory disturbances have not been thoroughly investigated. We examined the effect of intrathecally administered MgSO(4) on the nociceptive threshold, using three different nociceptive measures, formalin test, hot plate test and paw pressure test in rats. The dose of MgSO(4) was 30, 100 or 300 microg. In acute nociceptive tests, intrathecal MgSO(4) did not cause any significant changes in the pain threshold. However, phase 2 of the formalin test was suppressed dose-dependently. It is known that spinal NMDA receptors are involved in the changes seen during the second (tonic) phase of the formalin test and in vitro studies showed that Mg(2+) can cause voltage-dependent blockade of NMDA receptor channel in the neurons of spinal dorsal horn. Thus, the suppressive effect of intrathecally administered MgSO(4) on the tonic inflammation-evoked behavior is mediated by the spinal NMDA receptors. Our results suggest that intrathecal administration of MgSO(4) may be therapeutically beneficial for patients with tonic pain involving the spinal NMDA receptors.

Objective: Magnesium sulfate (MgSO4) has been reported to produce bronchodilation in asthmatic patients. In vitro studies have suggested that divalent cations inhibit L-type voltage-sensitive calcium ion (Ca2+) channels in cardiac and smooth muscles. In this study, we evaluated the in vitro and in vivo effects of magnesium ion (Mg2+) and zinc ion (Zn2+) on the airway contracted by histamine., Setting: A university research laboratory., In Vitro: Tracheal smooth muscle from guinea pigs., In Vivo: Mongrel dogs., In Vitro Study: The tension of isolated guinea pig tracheal strips was measured isometrically with a force displacement transducer. The specimen was contracted with histamine (10 microM). Then, MgSO4 (n = 6), zinc sulfate (ZnSO4, n = 6), or sodium sulfate (Na2SO4, n = 6) was cumulatively added to the organ bath., In Vivo Study: The bronchial cross-sectional area of mongrel dogs was measured by a direct visualization method demonstrated previously. The dogs were randomly assigned to three groups: group Mg (n = 7), group Zn (n = 7), and group Na (n = 7). Bronchoconstriction was elicited with histamine (10 microg/kg plus 500 microg/kg/hr iv). Thirty minutes after the start of histamine infusion, 0 (saline), 1, 10, and 100 micromol/kg ZnSO4 or 1, 10, 100, and 1000 micromol/kg MgSO4 or Na2SO4 were administered intravenously in group Zn, Mg, or Na, respectively. The bronchial cross-sectional area was assessed before (basal) and 30 mins after the start of histamine infusion and 5 mins after each dose of ZnSO4, MgSO4, or Na2SO4. Arterial blood was also obtained to measure plasma levels of epinephrine and norepinephrine by gas chromatography-mass spectrometry. All data are expressed as mean +/- SEM. The doses of the divalent cations that reversed histamine-induced contraction by 50% were calculated by GraphPad Prism. MgSO4 and ZnSO4 (9.38+/-0.28 and 1.84+/-0.30 mM, respectively) relaxed histamine-contracted tracheal strip in a concentration-dependent manner, whereas Na2SO4 did not. Similarly, the in vivo study showed that MgSO4 and ZnSO4 dose-dependently reversed histamine-induced bronchoconstriction (potency, ZnSO4 > MgSO4), whereas Na2SO4 did not. In groups Mg and Zn, the plasma catecholamine levels also dose-dependently increased except when 1000 micromol/kg MgSO4 was administered., Conclusion: Because the divalent cations tested produced a spasmolytic effect on the contracted airway, infusion of divalent cations might be effective against asthmatic attack. However, high concentrations of these cations produce significant toxicity, so dosage will be an important concern in development of these agents.

Although there are data demonstrating reversal of cerebral vasospasm with magnesium sulfate, there is little information on the effects of magnesium on the normal intact cerebral vasculature. This study investigated the actions of magnesium on cerebral blood flow (CBF) velocity, cardiovascular variables, and arterial gas tensions. Magnesium sulfate was infused into awake, adult sheep at rates of 3 and 6 mmol/min to a total of 15 and 30 mmol, respectively. Direct arterial pressure, cardiac output, and CBF velocity were measured using chronically implanted catheters and a sagittal sinus Doppler flow probe. Arterial blood was sampled for magnesium concentrations and blood gas analysis. Infusion of both 15 and 30 mmol of magnesium increased CBF velocity by 14% (P = .056) and 24% (P = .023), respectively. These increases were accompanied by increases in arterial carbon dioxide tension (PaCO2) of 12% (P = .033) and 17% (P = .048). Multiple linear regression analysis revealed that both PaCO2 (P = .00037) and magnesium (P = .0012) were important predictors of CBF velocity.

Objective: Neonatal periventricular leucomalacia and intraventricular hemorrhage are strong correlates of cerebral palsy. Our objective was to evaluate the effect of maternal magnesium sulfate exposure on the incidence and severity of periventricular leucomalacia and intraventricular hemorrhage in preterm neonates., Methods: Nine hundred eighteen consecutive inborn neonates with birth weights from 500 to 1750 g were divided primarily into two groups on the basis of maternal exposure to magnesium sulfate. The groups were divided secondarily into two clinical groups, a physician-initiated group, which consisted of neonates delivered for maternal or fetal indications, and a preterm delivery group, which included neonates delivered as a result of preterm labor or preterm premature rupture of membranes. These clinical groups were stratified further into magnesium sulfate-exposed and -unexposed subgroups. Neonatal neurosonograms were performed on days 3 and 7 of life and described as normal or abnormal. Abnormal sonograms included any periventricular leucomalacia or intraventricular hemorrhage. Severe lesions included periventricular leucomalacia, periventricular leucomalacia with intraventricular hemorrhage, or grades 3 or 4 intraventricular hemorrhage. The magnesium sulfate groups and the clinical groups with their magnesium sulfate strata were compared for the incidence and severity of abnormal sonograms. They also were compared for maternal and neonatal characteristics., Results: Maternal magnesium sulfate exposure was not associated with reduction in the incidence of abnormal sonograms when compared with the unexposed group (27% compared with 33%, P = .06). However, fewer severe lesions were observed in the exposed group (14% compared with 21%, P = .004). When clinical groups were examined, magnesium sulfate was not associated with a decrease in abnormal sonograms (adjusted odds ratio [OR] 1.09, 95% confidence interval [CI] 0.78, 1.52, P = .40) or severe lesions (adjusted OR 1.11, 95% CI 0.73, 1.68, P = .42). Logistic regression analyses of magnesium sulfate exposure within clinical groups controlling for the confounding effects of maternal and neonatal characteristics revealed no protective effect of magnesium sulfate exposure on the incidence of abnormal sonograms (adjusted OR 1.01, 95% CI 0.70, 1.44, P = .97) or severe lesions (adjusted OR 1.01, 95% CI 0.70, 1.74, P = .69). Within clinical groups, the preterm delivery group exhibited an increased risk for abnormal sonograms (adjusted OR 1.63, 95% CI 1.01, 2.67, P = .05) and severe lesions (adjusted OR 9.79, 95% CI 3.27, 29.29, P = .001) when compared with the physician-initiated delivery group, independent of maternal magnesium sulfate exposure., Conclusion: Maternal magnesium sulfate exposure had no protective effect on the incidence or severity of periventricular leucomalacia and intraventricular hemorrhage in preterm neonates. The prevalence of these lesions was correlated better with the clinical group of origin and indication for its use.

Unlabelled: Ketamine and magnesium (Mg2+), well known bronchodilators, have been used to treat patients with status asthmaticus. Both can block the N-methyl-D-aspartic acid (NMDA) receptor. NMDA receptors exist in the airway, and their activation seems to be linked to the release actions of sensory neuropeptides resulting in increased airway tone. We sought to determine whether ketamine relaxes the guinea pig trachea contracted by histamine by blocking the NMDA receptor. Female guinea pigs (250-400 g) were killed with an overdose of pentobarbital. The trachea was removed and cut spirally into strips 3 mm wide and 15 mm long. The strips were mounted in a 10-mL organ bath filled with Tyrode's solution bubbled through with 95% O2/5% CO2 at 37 degrees C. Strip contractions were measured isometrically with a force displacement transducer. We then studied the effect of NMDA receptor antagonists on histamine-induced tracheal contraction. In this protocol, we examined the effect of ketamine, Mg2+, zinc (Zn2+), or MK-801 (a noncompetitive NMDA receptor blocker) on strips contracted by 10(-5) M histamine. After full contraction was attained, ketamine (0.5-1.5 mM), MgSO4 (2-8 mM), ZnCl2(0.2-0.8 mM), or MK-801 (1.5-6 x 10(-5) M) was added, and the strip tension was measured again. We also studied the effect of NMDA on the relaxation by ketamine. After full contraction by 10(-5) M histamine, 0.5-1.5 mM KET was added alone or in combination with 0.1 mM NMDA, and the strip tension was measured again. Finally, we measured the effect of MK-801 on the relaxant effect of ketamine. After full contraction by 10(-5) M histamine, 0.5-2 mM ketamine was added alone or in combination with 0.75 or 1.5 x 10(-5) M MK-801, and the strip tension was measured again. All NMDA receptor antagonists tested reversed the tracheal contraction induced by histamine in a dose-dependent manner. However, neither the agonist NMDA nor the noncompetitive receptor blocker MK-801 affected tracheal relaxation induced by ketamine. We conclude that ketamine relaxes the tracheal smooth muscle contracted by histamine through a mechanism independent of NMDA receptors. The decreased bronchomotor tone induced by ketamine is probably due to interference with a Ca2+-requiring step necessary to maintain the contraction caused by histamine., Implications: Stimulation of the N-methyl-D-aspartic acid (NMDA) receptor in the airway results in airway constriction. The bronchodilator ketamine blocks the NMDA receptor. However, ketamine relaxes the guinea pig trachea contracted by histamine through a mechanism independent of the NMDA receptor.

Objective: To review the available evidence regarding efficacy, benefits, and risks of magnesium sulfate seizure prophylaxis in women with preeclampsia or eclampsia., Data Sources: The English-language literature in MEDLINE was searched from 1966 through February 1998 using the terms "magnesium sulfate," "seizure," "preeclampsia," "eclampsia," and "hypertension in pregnancy." Reviews of bibliographies of retrieved articles and consultation with experts in the field provided additional references., Methods of Study Selection: All relevant English-language clinical research articles retrieved were reviewed. Randomized controlled trials, retrospective reviews, and observational studies specifically addressing efficacy, benefits, or side effects of magnesium sulfate therapy in preeclampsia or eclampsia were chosen., Tabulation, Integration, and Results: Nineteen randomized controlled trials, five retrospective studies, and eight observational reports were reviewed. The criteria used for inclusion were as follows: randomized controlled trials evaluating use of magnesium sulfate in eclampsia, preeclampsia, and hypertensive disorders of pregnancy; nonrandomized studies of historical interest; "classic" observational studies; and recent retrospective studies evaluating efficacy of magnesium sulfate therapy, using relative risk and 95% confidence intervals where applicable. Magnesium sulfate therapy has been associated with increased length of labor, increased cesarean delivery rate, increased postpartum bleeding, increased respiratory depression, decreased neuromuscular transmission, and maternal death from overdose. A summary of randomized, controlled trials in women with eclampsia reveals recurrent seizures in 216 (23.1%) of 935 women treated with phenytoin or diazepam, compared with recurrent seizures in only 88 (9.4%) of 932 magnesium-treated women. Randomized controlled trials in women with severe preeclampsia collectively revealed seizures in 22 (2.8%) of 793 women treated with antihypertensive agents, compared with seizures in only seven of 815 (0.9%) magnesium-treated women., Conclusion: The evidence to date confirms the efficacy of magnesium sulfate therapy for women with eclampsia and severe preeclampsia. However, there is a need for a randomized controlled trial to determine efficacy of magnesium sulfate therapy for women with mild preeclampsia and gestational hypertension.

Unlabelled: Laryngoscopy and endotracheal intubation may produce adverse hemodynamic effects. Magnesium has direct vasodilating properties on coronary arteries and inhibits catecholamine release, thus attenuating the hemodynamic effects during endotracheal intubation. We studied 36 patients with coronary artery disease (CAD) scheduled for elective coronary artery bypass grafting to evaluate the hemodynamic effects of magnesium and its efficacy in attenuating the response to endotracheal intubation. Patients received either 0.1 mL/kg (50%) magnesium sulfate (50 mg/kg) (Group A, n = 19) or isotonic sodium chloride solution (Group B, n = 17) before the induction of anesthesia and 0.05 mL/kg of isotonic sodium chloride solution (Group A) or lidocaine 2% (1 mg/kg) (Group B) before intubation. The hemodynamic variables were recorded before induction, after the trial drug, after induction, and after endotracheal intubation. Automatic ST segment analysis was performed throughout the study period. Magnesium sulfate administration was associated with increased cardiac index (P < 0.01), a minimal increase in heart rate, and a significant decrease in mean arterial pressure (MAP) and systemic vascular resistance (SVR) (P < 0.001). None of the patients in the magnesium group had significant ST depression compared with three patients in the control group. The magnesium group patients had a significantly lesser increase in MAP (P < 0.05) and SVR (P < 0.01) compared with the control group patients who received lidocaine before endotracheal intubation. Thus, magnesium is an useful adjuvant to attenuate endotracheal intubation response in patients with CAD., Implications: Endotracheal intubation produces adverse hemodynamic effects, which may be more detrimental in patients with coronary artery disease than in healthy patients. The present study shows that magnesium administered before endotracheal intubation can attenuate this response better than lidocaine.

The aim of this study was to investigate whether the neuroprotective properties of magnesium in cerebral ischaemia involve suppression of repetitive tissue depolarizations. Cortical spreading depressions (CSDs), evoked by cortical KCl application, and cardiac arrest-induced anoxic depolarization (AD) were measured by extracellular DC recording on intact rat brain. At 90 min after onset of CSDs saline, MK-801 (3 mg/kg) or MgSO4 (90 mg/kg) was given i.v. Latency time to AD was measured after 4 h. The frequency of CSDs was significantly reduced in animals treated with MgSO4 or MK-801. AD was significantly delayed by MgSO4 but not by MK-801. Our results suggest that suppression of depolarization by magnesium may play a role in its neuroprotective properties in cerebral ischaemia.

Unlabelled: N-methyl-D-aspartate (NMDA) antagonists, such as MK801, delay the development of morphine tolerance. Magnesium, a noncompetitive NMDA antagonist, reduces postoperative morphine requirements. The present study was designed to evaluate the effects of intrathecal co-administration of magnesium sulfate with morphine on antinociceptive potentiation, tolerance, and naloxone-induced withdrawal signs. Magnesium sulfate (40-60 microg/h) co-administration for 7 days, similar to MK801 (10 nmol/h), prevented the decline in antinociceptive response compared with morphine (20 nmol/h). Magnesium sulfate (60 microg/h) produced no antinociception, but co-infused with morphine (1 nmol/h), it resulted in potentiated antinociception compared with morphine throughout the 7-day period. Probe morphine doses after 7-day infusions demonstrated a significantly greater 50% effective dose value for morphine 1 nmol/h (109.7 nmol) compared with saline (10.9 nmol), magnesium sulfate 60 microg/h (10.9 nmol), and magnesium sulfate 60 microg/h plus morphine 1 nmol/h (11.2 nmol), which indicates that magnesium had delayed morphine tolerance. Morphine withdrawal signs after naloxone administration were not altered by the co-infusion of magnesium sulfate. Cerebrospinal fluid magnesium levels after intrathecal magnesium sulfate (60 microg/h) for 2 days increased from 17.0 +/- 1.0 microg/mL to 41.4 +/- 23.6 microg/mL, although serum levels were unchanged. This study demonstrates antinociceptive potentiation and delay in the development of morphine tolerance by the intrathecal coinfusion of magnesium sulfate and morphine in the rat., Implications: The addition of magnesium sulfate, an N-methyl-D-aspartate antagonist, to morphine in an intrathecal infusion provided better analgesia than morphine alone in normal rats. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.

Objective: To describe the occurrence, treatment, and outcome of maternal oxygen desaturation during magnesium sulfate therapy., Methods: A post hoc analysis of a randomized double-blind trial, designed to determine if mothers at risk for premature delivery treated with phenobarbital and vitamin K had less frequent intracranial hemorrhage in their newborns, was done. A subset of these patients at imminent risk for delivery received both intravenous magnesium sulfate and intravenous study drug (phenobarbital or placebo) and was monitored with maternal oxygen saturation monitoring., Results: One hundred one women (29%) in the trial had pulse oximetry; 47 were assigned to placebo and 54 to the treatment group. The placebo and treatment groups had the following similarities: mean lowest oxygen saturation by pulse oximeter (93.4% +/- 3.0 compared with 93.1% +/- 3.3). mean highest magnesium levels (6.3 mEq/L +/- 1.5 compared with 6.2 mEq/L +/- 0.9), frequencies of desaturation events defined as oxygen saturation below 90% (11% compared with 11%), gestational age at delivery, birth weight, Apgar scores, and cord arterial pH. Using regression analysis, multiple gestation was the only one of 14 independent variables associated with low maternal oxygen saturation. Preeclampsia was not associated with a greater risk of desaturation. The statistical power of this study is limited by its small sample sizes., Conclusion: Maternal oxygen desaturation occurs commonly with intravenous magnesium therapy, does not occur more frequently with simultaneous administration of intravenous phenobarbital, and does not cause decompensation in maternal or fetal status. Multiple gestation may be associated with lower maternal oxygen saturation.

Polymorphic ventricular arrhythmias induced by astemizole overdose have been reported to be successfully managed with intravenous magnesium sulfate. This study was designed to assess the effects of magnesium sulfate on the cardiovascular system, complicating astemizole overdose, the better to understand the therapeutic utility and undesirable effects of magnesium sulfate. Beagle dogs were anesthetized with halothane inhalation (n = 6). Monophasic action potential of the right ventricle, electrocardiogram, and systemic and left ventricular pressure were continuously monitored. Cardiac output was measured by a thermodilution method. Effective refractory period of the right ventricle was assessed by programmed electrical stimulation. An intentionally high dose of astemizole (3 mg/kg, i.v.) prolonged the repolarization and refractory period, while it decreased the sinus automaticity, ventricular contraction, and conduction. A canine antiarrhythmic dose of magnesium sulfate (100 mg/kg, i.v.) was additionally injected 1 h after i.v. astemizole. Magnesium sulfate increased the atrioventricular conduction time, electrical vulnerability, and preload of the left ventricle, while it decreased the blood pressure and cardiac output, besides the effects similar to those observed after i.v. astemizole. The plasma concentration of astemizole was at least 10 times higher than its therapeutic concentration during the experimental period. Magnesium sulfate could be expected to act as a calcium channel blocker during astemizole overdose; however, it may not antagonize the proarrhythmic effects of astemizole.

Lidocaine and MgSO4 are often coadministered to patients with pregnancy-induced hypertension. This study examined whether MgSO4 alters the lidocaine-seizure threshold in the rat and, if so, whether systemic MgSO4 administration is as effective as intracerebroventricular MgSO4 infusion. In Experiment 1, rats were administered 50% MgSO4 or 0.9% NaCl intravenously (IV) (20 microL/h) for 5 days. In Experiment 2, rats were administered 0.9% NaCl, 0.8% MgSO4, or 2.0% MgSO4 (10 microL/h) via intracerebroventricular infusion for 24 h. All rats then underwent continuous IV lidocaine infusion until onset of electroencephalographic seizures. In Experiment 1, plasma [Mg2+] was greater in the MgSO4 group (5.1 +/- 1.5 mg/dL vs 1.8 +/- 0.3 mg/dL) but neither the dose of lidocaine required to induce seizures (MgSO4 = 19 +/- 2 mg/kg; saline = 23 +/- 5 mg/kg) nor brain [Mg2+] (MgSO4 = 794 +/- 17 micrograms/g; saline = 788 +/- 33 micrograms/g) were changed. In Experiment 2, intracerebroventricular MgSO4 increased both brain [Mg2+] (2% MgSO4 = 923 +/- 79 micrograms/g; saline = 788 +/- 35 micrograms/g) and the lidocaine seizure dose (2% MgSO4 = 39 +/- 7 mg/kg; saline = 26 +/- 3 mg/kg). Although intracerebroventricular administration of MgSO4 produces an anticonvulsant effect, chronic hypermagnesemia does not alter whole brain [Mg2+] and therefore offers no protection from lidocaine-induced seizures in this model.

Since the first American report on the use of magnesium sulfate tocolysis in 1977, its popularity as a tocolytic agent has increased progressively. Primarily because of its safety and familiarity, magnesium has become the primary tocolytic agent in the majority of U.S. centers. The exact mechanism of action is unknown, and long-term effects on neonates have not been studied. Although randomized studies show similar success compared to other tocolytic agents, no placebo-controlled study has shown neonatal improvement with magnesium sulfate tocolysis. This is similar to the studies of beta-sympathomimetic tocolytics and has led some authors (e.g., Higby) to suggest that safe dosages of magnesium sulfate are ineffective in preventing preterm birth and should not be used as a tocolytic agent. Although magnesium sulfate, like other tocolytics, has not fulfilled the initial promise of preventing preterm birth, it does appear if used correctly in a well identified population of patients to at least transiently inhibit preterm labor as well as other tocolytic agents with fewer side effects and fewer contraindications.

Background: Magnesium therapy has been shown to improve survival and decrease the incidence of left ventricular failure when given to patients shortly after a myocardial infarction, but the mechanisms are unknown. We tested the hypothesis that the benefits of magnesium therapy are due to a favorable effect on early left ventricular remodeling, particularly on infarct shape changes., Methods: Rats were infarcted and randomly allocated to two groups: group 1 (n = 8) received intravenous magnesium sulfate (200 mumol/kg) over 10 min started 30 min after coronary ligation, then an intraperitoneal dose (800 mumol/kg), which was repeated 6 h later. Group 2 (n = 10) served as a control group, and received normal saline. Using this regimen, the trough level of ionized magnesium 12 h after the intravenous dose was 33% above the control level. Three weeks after infarction, the hearts of the rats were arrested with saturated potassium chloride and fixed in formalin at 7.5 mmHg. The hearts were cut transversely into four slices. Photographs of both sides of each slice were taken and projected for morphometric analysis., Results: Infarct size was similar in the magnesium and control groups (35 +/- 4 versus 30 +/- 2%). Infarct thickness, expansion index, and cavity area were also similar in both groups., Conclusions: Magnesium has no effect on early left ventricular remodeling or infarct expansion. The mechanism of its clinical benefits remains unexplained.

It has been well established that antiarrhythmic drugs can also have proarrhythmic effects such as torsade de pointes (TdP) arrhythmias. It was the purpose of this study to create an animal model with a high incidence of reproducible TdP that occurs under clinically relevant circumstances. Experiments were performed in anesthetized dogs that had been in chronic atrioventricular block for 9 +/- 6 weeks. TdP inducibility was attempted using different pacing modes before and after the administration of 2 mg/kg d-sotalol. In some experiments, endocardial monophasic action potentials were recorded. d-Sotalol increased the cycle length of the idioventricular rhythm (1475 +/- 460 to 1730 +/- 570 ms, P < .01) and the QT time (390 +/- 65 to 480 +/- 85 ms, P < .01). In 10% of the experiments, spontaneous TdP occurred after d-sotalol. The incidence of pacing-dependent TdP was 52% (P < .01). In the inducible group, the cycle length of idioventricular rhythm and QT time were significantly longer despite equal percentage increases in these parameters after d-sotalol in both groups. The pacing modes consisting of more than one frequency change had a higher TdP induction rate (P < .05). Reproducibility of TdP induction (three times or more using the same pacing train) remained present for approximately 60 minutes after d-sotalol and was greater than 90% within the same animal over weeks. TdP induction was related to the presence of early afterdepolarizations on the monophasic action potential recordings: five of six in the inducible group versus two of six in the nonresponders. Inducibility could be further increased to 89% when a second bolus of d-sotalol was administered to noninducible dogs. On the other hand, decreasing QT time by faster basic pacing or administration of isoproterenol, or MgSO4 prevented TdP induction. This effect of MgSO4 coincided with the disappearance of early afterdepolarizations. Our animal model shows a high incidence of reproducible acquired TdP arrhythmias, allowing study of the mechanism and treatment of TdP. TdP induction was related to the combination of a slow ventricular rate, the prolongation of QT time, a sudden induced rate change that often required two or more cycle length changes, and the presence of early afterdepolarizations.

Objective: To compare the tocolytic effects of magnesium sulfate, ritodrine, terbutaline, and nifedipine on human myometrial strips., Methods: Myometrial strips were suspended in organ chambers for isotonic measurements and contracted with KCI. STrips from nonpregnant patients were used to obtain concentration-response curves. Myometrial strips from pregnant uteri were then exposed to the molar concentrations causing 50% relaxation in the nonpregnant tissues., Results: In strips from nonpregnant patients, nifedipine was found to be the most potent tocolytic. Using strips from nonlaboring patients, nifedipine caused relaxation similar to ritodrine, and both were more effective than magnesium sulfate or terbutaline. Combinations were more effective than single agents. These agents were found to be equally less effective in myometrial strips from laboring patients., Conclusions: Nifedipine, alone or in combination, relaxes myometrial strips more effectively than the other agents studied. Myometrial strips from laboring patients are more resistant to inhibition, with none of the agents being superior.

We performed a comparative study to determine whether acute administration of MgSO4, moricizine, and verapamil to conscious dogs with normal plasma magnesium levels (0.75 +/- 0.06 mM) terminates ouabain-induced ventricular tachycardia (VT). This arrhythmia is dependent on triggered activity (TA) resulting from delayed afterdepolarizations (DADs). In animals with surgically induced complete atrioventricular (AV) block, monomorphic VT was induced by programmed ventricular stimulation during continuous intravenous (i.v.) infusion of ouabain. At the moment of drug administration, VT persisted for at least 20 min, while the rate was stable for at least 5 min. A single dose of MgSO4 (100 mg/kg i.v.) abolished only VTs with cycle lengths > or = 320 ms (335 +/- 10 ms); VTs with faster cycle lengths (300 +/- 20 ms) were merely slowed, although the increase in plasma magnesium levels was considerable and comparable in both groups (3.9 +/- 1.6 and 4.8 +/- 1.9 mM). In contrast, moricizine (2 mg/kg i.v.) and verapamil (0.5-1.0 mg/kg i.v.) terminated both fast and slow VTs. The cycle length of VT ranged from 280 to 320 ms (mean 300 +/- 15 ms) for moricizine and 260-330 ms (mean 300 +/- 25 ms) for verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

This column reviews the results of second Leicester Intravenous Magnesium Sulphate Intervention Trial (LIMIT-2), a clinical study investigating the effects of intravenous magnesium sulphate on 28-day mortality and morbidity in suspected AMI patients. Many LIMIT-2 subjects also received thrombolytic and anti-platelet therapy, differentiating findings of this study from earlier results. Implications for practice, education, and future research are discussed.

Objective: To compare the effects of maternally administered phenytoin and magnesium sulfate on the fetal heart rate (FHR) using computer analysis., Methods: Thirty-six nonlaboring preeclamptic women between 27-41 weeks' gestation were treated with either phenytoin or magnesium sulfate in a nonrandomized fashion. All fetuses were deemed to be well by traditional electronic-biophysical criteria. One-hour FHR recordings were analyzed by computer analysis before treatment. No other medications were administered. Tracings recorded 1 hour after drug administration were analyzed. Therapeutic serum levels were achieved in both groups before FHR tracings were reevaluated. Statistical analysis used paired Student t test, with significance set at P < or = .05., Results: There were no differences in birth weight, gestational age, Apgar scores, or computer-analyzed FHR characteristics between the groups before treatment. Magnesium sulfate reduced significantly the frequency of accelerations of ten and 15 beats per minute; caused a 62% reduction in reactivity, defined as accelerations of 15 beats per minute in 20 minutes of FHR tracing (but no change in reactivity with accelerations of ten beats per minute); and reduced short- and long-term variability. Phenytoin reduced short-term variability only., Conclusion: Phenytoin does not confound the computer analysis of FHR tracings and may offer some advantage over magnesium sulfate when used for prophylaxis against eclampsia.

In rats, recent evidence suggests that injury discharge caused by peripheral nerve section releases excitatory amino acids into the spinal cord which in turn influences decisively the development of autotomy, a self-mutilation behaviour directed towards the denervated areas. Autotomy has been proposed as a behavioural correlate of the neuropathic pain which occurs in humans after complete nerve lesions. Mg2+ ions have been shown to offer protection from neurological and degenerative disorders in which excitatory amino acids are putatively involved. To ascertain the preventive value of Mg2+ administration on autotomy, male rats underwent unilateral ligation and transection of the sciatic and saphenous nerves 30 min after being injected subcutaneously (s.c.) with 300 or 600 mg/kg MgSO4 or saline. Thereafter, autotomy was monitored for 8 weeks. Serum, lumbosacral (L1-S1) and brain magnesium levels were analyzed 0, 30, 60, 120, 180, 240, 360 min and 24 h after the s.c. injection of 600 mg/kg MgSO4. Serum magnesium levels increased quickly from 1.02 mM (0 time) to 4.52 mM (at 60 min) and dropped afterwards to reach physiological levels at 6 h. Peak increments in L1-S1 and brain Mg2+ levels were smaller (32% and 30%, respectively) although maintained for at least 6 h. Magnesium pretreatment in a significant and dose-dependent manner (1) largely suppressed autotomy, (2) decreased final autotomy scores, (3) delayed autotomy onset, and (4) decreased the percentage of animals engaged in high autotomy behaviors. The data support a role for excitatory amino acids in determining susceptibility to autotomy and suggest a hopeful way to prevent neuropathic pain in humans after peripheral deafferentation.

Background and Methods: Rats rapidly develop respiratory distress when exposed to 100% oxygen and die within a few days. Autopsy of the lung shows severe histologic damage characteristic of the adult respiratory distress syndrome. The purpose of this study was to evaluate the effects of magnesium sulfate loading in a rat model of acute oxygen toxicity. Thirty-four rats were divided into three groups. Group 1 (n = 18) served as a control (no magnesium therapy), while group 2 (n = 8) and group 3 (n = 8) received varying amounts of magnesium sulfate. All animals were exposed to 100% oxygen for 96 hrs or until death. Lung damage was quantitated by measuring the lung injury score on histologic examination., Results: Administering magnesium sulfate in moderate doses at infrequent intervals to rats (group 2) resulted in less severe oxygen-induced lung damage than that which occurred in rats not receiving magnesium (control group). However, the difference was not statistically significant. Rats (group 3) given doses of magnesium sulfate in amount and frequency adequate to maintain a serum magnesium concentration recognized as therapeutic in eclampsia significantly reduced oxygen-induced lung damage., Conclusion: High-dose magnesium sulfate therapy can reduce lung injury caused by acute oxygen toxicity in rats.

Magnesium sulfate (MgSO4) attenuates the maternal compensatory response to hemorrhage in gravid ewes, perhaps by decreasing the response to endogenous vasopressors. The purpose of this study was to determine whether MgSO4 alters the cardiovascular response of gravid ewes to vasopressor agents. Sixteen gravid ewes underwent a series of experiments consisting of administration of two exogenous and two endogenous vasopressors, each with and without a concurrent MgSO4 infusion. Dose-response curves were constructed for phenylephrine (an alpha 1-adrenergic agonist), ST-91 (an alpha 2-adrenergic agonist), angiotensin II, and arginine vasopressin (AVP). MgSO4 significantly attenuated the increase in maternal mean arterial pressure and systemic vascular resistance and the decrease in cardiac output during ST-91 infusion but not during phenylephrine, angiotensin II, or AVP infusions. MgSO4 significantly attenuated the increase in uterine vascular resistance during phenylephrine, ST-91, and angiotensin II infusions and the decrease in uterine blood flow during phenylephrine and angiotensin II infusions. MgSO4 also appeared to attenuate the decrease in uterine blood flow during ST-91 infusion (P = 0.067). The present study suggests that MgSO4 antagonizes the effects of alpha 1-adrenergic agonists, alpha 2-adrenergic agonists, and angiotensin II on the uterine vasculature, thus providing a level of protection for the fetus in situations of maternal stress.

We induced experimental delayed cerebral vasospasm by the intracisternal injection of greater than 0.5 ml blood in 30 rats. Seventy-two hours later the basilar artery was exposed via the transclival approach and photographed at high-power magnification through an operating microscope. We then evaluated the effect of topical (n = 30) and intravenous (n = 20) magnesium sulfate on the spastic artery by computerized image analysis. A greater than 50% reduction in baseline diameter of the basilar artery was observed in the rats subjected to subarachnoid hemorrhage compared with the 10 controls (p less than 0.0001). Intravenous magnesium sulfate dilated the spastic artery to approximately 75% of the baseline diameter in control rats (p less than 0.0001). Topical magnesium sulfate caused dramatic dilation of the basilar artery in both the control and the subarachnoid hemorrhage groups to near 150% of the baseline diameter in the controls (p less than 0.001). All rats receiving intravenous magnesium sulfate reached therapeutic plasma levels of the ion. Hemodynamic effects were mild and immediately reversible upon cessation of magnesium sulfate administration. We suggest that magnesium has a role in the treatment of subarachnoid hemorrhage-induced vasospasm in humans.

Forty term pregnant women with singleton breech gestations admitted for external cephalic version underwent biophysical profile testing before any fluid infusion or medication. After magnesium sulfate had been infused for contraction prophylaxis, the maternal serum magnesium level was measured and a second biophysical profile was performed. The mean (+/- SD) serum magnesium was 5.1 +/- 1.0 mg/dL. The biophysical profile score decreased significantly, reflecting a decrease in fetal breathing activity. In patients with therapeutic maternal serum magnesium levels, loss of any component of the biophysical profile other than respiration cannot be attributed to the elevation in magnesium concentration.