12
Magnesium

Magnesium is an essential nutrient that serves as a cofactor for more than 300 enzymes involved in biological reactions important for cellular energy metabolism, protein synthesis, maintenance of cardiovascular health, regulation of blood glucose levels, and normal nervous system functioning. Approximately 50 percent of the magnesium in the body is found in bone, while the other 50 percent is found predominantly in soft tissue (Fleet and Cashman, 2001; Shils, 1999). Magnesium levels in the body are tightly regulated by absorption and excretion of the mineral. Increasing dietary magnesium intake leads to reductions in magnesium absorption and increases in urinary output. Conversely, reductions in magnesium intake are compensated by more efficient gastrointestinal absorption and renal reabsorption (Shils, 1999).

MAGNESIUM AND THE BRAIN

Magnesium, which is transported to the brain by an active mechanism, plays an important role in brain functioning. Under normal conditions, magnesium inhibits the actions of the excitatory neurotransmitter glutamate. More specifically, magnesium blocks the calcium channel of the N-methyl-D-aspartate (NMDA) glutamate receptor, and thereby regulates calcium entry into the postsynaptic neuron. Magnesium also relaxes vascular smooth muscle, resulting in vasodilation and increased cerebral blood flow.

Moreover, magnesium plays an important role in the homeostatic regulation of the pathways involved in the secondary phase of brain injury (Sen and Gulati, 2010). Following traumatic brain injury (TBI), reduction in magnesium levels in the brain is associated with an influx of glutamate and calcium into the postsynaptic neuron. The entry of these compounds into the brain is considered to be the predominant contributor to neuronal degeneration and cell death, secondary to the original insult (Bullock et al., 1998; Faden et al., 1989; Fleet and Cashman, 2001; McKee et al., 2005a; Sen and Gulati, 2010). Magnesium has also been linked to antidepressant effects in experimental studies because it affects the functioning of monoaminergic and serotonergic neurotransmitter systems, which are disrupted as part of the secondary injury cascade following TBI, and alters the activity of the hypothalamic-pituitary-adrenocortical system (Fromm et al., 2004).



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12 Magnesium Magnesium is an essential nutrient that serves as a cofactor for more than 300 enzymes involved in biological reactions important for cellular energy metabolism, protein synthe- sis, maintenance of cardiovascular health, regulation of blood glucose levels, and normal nervous system functioning. Approximately 50 percent of the magnesium in the body is found in bone, while the other 50 percent is found predominantly in soft tissue (Fleet and Cashman, 2001; Shils, 1999). Magnesium levels in the body are tightly regulated by ab- sorption and excretion of the mineral. Increasing dietary magnesium intake leads to reduc- tions in magnesium absorption and increases in urinary output. Conversely, reductions in magnesium intake are compensated by more efficient gastrointestinal absorption and renal reabsorption (Shils, 1999). MAGNESIUM AND THE BRAIN Magnesium, which is transported to the brain by an active mechanism, plays an impor- tant role in brain functioning. Under normal conditions, magnesium inhibits the actions of the excitatory neurotransmitter glutamate. More specifically, magnesium blocks the calcium channel of the N-methyl-D-aspartate (NMDA) glutamate receptor, and thereby regulates cal- cium entry into the postsynaptic neuron. Magnesium also relaxes vascular smooth muscle, resulting in vasodilation and increased cerebral blood flow. Moreover, magnesium plays an important role in the homeostatic regulation of the pathways involved in the secondary phase of brain injury (Sen and Gulati, 2010). Following traumatic brain injury (TBI), reduction in magnesium levels in the brain is associated with an influx of glutamate and calcium into the postsynaptic neuron. The entry of these compounds into the brain is considered to be the predominant contributor to neuronal degeneration and cell death, secondary to the original insult (Bullock et al., 1998; Faden et al., 1989; Fleet and Cashman, 2001; McKee et al., 2005a; Sen and Gulati, 2010). Magnesium has also been linked to antidepressant effects in experimental studies because it affects the functioning of monoaminergic and serotonergic neurotransmitter systems, which are disrupted as part of the secondary injury cascade following TBI, and alters the activity of the hypothalamic- pituitary-adrenocortical system (Fromm et al., 2004). 157

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158 NUTRITION AND TRAUMATIC BRAIN INJURY A relevant selection of human and animal studies (years 1990 and later) examining the effectiveness of magnesium intake in providing resilience or treating TBI in the acute phase of injury is presented in Table 12-1. This table elaborates on the treatment methodology and includes review articles on magnesium intake in humans for other central nervous system (CNS) injuries such as subarachnoid hemorrhage, stroke, and hypoxia in the case of human studies. The occurrence or absence of adverse effects in humans is included if reported by the authors. USES AND SAFETY The Recommended Dietary Allowance (RDA) for magnesium ranges from 80 mg/day in children between the ages of one and three, to 420 mg/day in males over the age of 30 and 320 mg/day in females over the age of 30. Recommendations for military personnel in garrison training are the same as those for adults over 30 years of age (IOM, 2006). Good dietary sources of magnesium include green leafy vegetables, beans, nuts, seeds, and unre- fined whole grains. According to 2005–2006 data from the National Health and Nutrition Examination Survey (NHANES), just more than half (56 percent) of all individuals aged one year and older had inadequate intakes of magnesium.1 The percentage below the Estimated Average Requirement (EAR) was greatest among 14- to 18-year-olds and adults aged 71 years and over. Two small research studies assessing dietary intake of Army Rangers and Special Forces soldiers in garrison found that approximately 40 percent of these individuals were not meet- ing the EAR for magnesium, and about 60 percent were not meeting the RDA (IOM, 2006). Although a 2006 analysis found that First Strike Rations and Meals, Ready-to-Eat (MREs) contained sufficient magnesium (IOM, 2006), the Institute of Medicine Committee on Min- eral Requirements for Cognitive and Physical Performance of Military Personnel concluded that the information on magnesium status of military personnel in various types of training was too limited to provide evidence of magnesium sufficiency (IOM, 2006). Magnesium toxicity is not a problem in the context of normal dietary intake. However, intake of magnesium supplements can lead to decreased blood pressure, abdominal cramp- ing, and nausea. These adverse effects have been observed primarily with pharmacologi- cal uses of magnesium, rather than intake from food and water. Derived from studies on excessive intake from nonfood sources, the Tolerable Upper Intake Level (UL) of 350 mg/ day for individuals nine years of age and over is based on diarrhea as the critical endpoint (IOM, 1997). The risk of magnesium-induced diarrhea mediates against the use of high- dose magnesium supplements. Symptoms of magnesium toxicity are more likely to occur in individuals suffering from renal failure, when the kidney loses its ability to remove excess magnesium (Fleet and Cashman, 2001; IOM, 1997).2 EVIDENCE INDICATING EFFECT ON RESILIENCE Human Studies The committee’s review of the literature found no clinical trials investigating the effects of magnesium on resilience for TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, or epilepsy). An 1 Available online at http://www.cdc.gov/nchs/nhanes.htm (accessed December 22, 2010). 2 Available online at http://ods.od.nih.gov/factsheets/magnesium/ (accessed December 22, 2010).

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159 MAGNESIUM TABLE 12-1 Relevant Data Identified for Magnesium Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Tier 1: Clinical trials Kidwell Acute ischemic Multicenter, Magnesium For all patients, baseline lesion volume measured by DWI (rb=0.654, p < 0.001) et al., 2009 stroke randomized, sulfate (MgSO4) double-blind, solution (bolus and perfusion-weighted imaging (r=0.805, p < 0.001) correlated with final infarct placebo- dose of 16 mmol controlled infused over 15 size. clinical trial minutes, then At day 90, there was no significant (substudy of 65 mmol/day) difference between the MgSO4 group and IMAGES trial) or matching placebo group in lesion growth, clinical amount of na=104 outcome, or mortality rate. However, saline) patients with patients with poor clinical outcome tended diffusion- to have greater percentage infarct growth weighted (p=0.015) and absolute infarct growth imaging (p=0.004). (DWI) lesion Although baseline serum glucose level volume of ≥ correlated with infarct growth (p ≤ 0.028) 3 mL in the MgSO4 group, higher glucose level was not detected in patients with growth of > 0% compared to those with growth of ≤ 0%. Serum glucose level was not significantly correlated with infarct growth in placebo patients. No adverse effects were mentioned. Wong et al., Aneurysmal Multi-center, MgSO4 infusion Throughout the study, the treatment group 2009 subarachnoid randomized, (80mmol/day) had a higher plasma magnesium level than the control group (p < 0.001). The average hemorrhage placebo- or normal saline (SAH) controlled trial for 10–14 days plasma magnesium level in the treatment group was between 1.59–1.84 mmol/L, n=22 patients while the average in the control group who were ranged from 0.85–1.02 mmol/L. simultaneously participating Although the treatment group had higher in an levels of cerebrospinal fluid magnesium intravenous overall, the difference was significant only on day 2 and days 5–8 (p ≤ 0.035). MgSO4 after aneurysmal The average levels of cerebrospinal fluid SAH trial magnesium ranged from 1.22–1.278 mmol/L in the treatment group, and from 1.09–1.10 mmol/L in the control group; the increase ranged from 10.5–21.3%. The treatment group also had significantly higher 24-hour urine levels of magnesium (p ≤ 0.005); the group’s average ranged from 47.9–77.3 mmol, while the control group’s average ranged from 2.7–3.5 mmol. No adverse effects were mentioned. continued

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160 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Dhandapani Closed TBI Randomized Postinjury, At 3 months, 73.3% of the patients on et al., 2008 trial standard care or MgSO4 supplementation had good to supplementation moderate outcome compared to just 40% n=60 of the standard care group (ORc=4.13, with MgSO4 95% CId: 1.39–12.27, p=0.009). (initiation of 4 g intravenously Specifically, 46.7% of patients in MgSO4 [i.v.] and 5 g group had good recovery compared to intramuscularly 20% of the patients in standard care [i.m.], then group (OR=3.5, 95% CI: 1.11–11.02, continuation p=0.028). of 5 g every 4 Significantly greater number of patients hours for 24 in the control group (73.3%) experienced hours) intra-operative brain swelling during surgical decompression than patients in the MgSO4 group (29.4%, OR=0.15, 95% CI: 0.03–0.71, p=0.01). At 1 month, mortality rate was higher in control group (43.3%) than MgSO4 group (13.3%, OR=0.2, 95% CI: 0.06–0.72, p=0.01). Logistic regression analysis showed that favorable outcome was associated with patients’ early entry into trial (< 8 hours, OR=8.2, p=0.008), CT finding of uneffaced cisterns (OR=4.67, p=0.04), and assignment to MgSO4 treatment (OR=0.038). No significant adverse effects were observed.

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161 MAGNESIUM TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results van den SAH Randomized, I.v. MgSO4 (64 Regression analysis showed that serum Bergh et al., placebo- mmol/day) vs. magnesium level is inversely associated 2008 controlled trial placebo (saline) with ionized serum calcium level (Be=–0.09; 95% CI: –0.12 to –0.06). for up to 20 n=167 days This relationship remained the same even after adjusting for parathyroid hormone (PTH) and calcitriol levels (B=–0.11; 95% CI: –0.12 to 0.06). Further, the analysis showed no relationship between serum magnesium and PTH (B=–0.37; 95% CI: –3.44 to 2.70) or calcitriol (B=50.4; 95% CI: –11.7 to 112.4). Increased level of serum PTH heightened the risk of poor outcome, defined by having a modified Rankin Scale score of 4 or worse (OR=5.4; 95% CI: 1.6–8.9), but not the risk of developing delayed cerebral ischemia. PTH’s effect on risk of poor outcome increased after adjusting for age and gender (OR=16.3; 95% CI: 2.2–119.2). No other adverse effects were mentioned. continued

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162 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Dorhout SAH Randomized, MgSO4 therapy Over the course of the study, 17% of Mees et al., placebo- (64 mmol/day) the patients developed delayed cerebral 2007 controlled trial vs. placebo for ischemia (DCI) (median day of onset up to 20 days was day 8), and 26% had poor outcome, n=155 defined by modified Rankin score of ≥ 4. During treatment, the average serum magnesium level of patients with poor outcome was 0.22 mmol/L higher than patients with no poor outcome (95% CI: 0.09–0.36 mmol/L). The serum magnesium level measured at day 8 (the median day of onset of DCI) was 0.42 mmol/L higher in patients with poor outcome than in those with no poor outcome (95% CI: 0.14–0.69 mmol/L). Patient with serum magnesium levels of > 1.28 mmol/L at day 8 (categorized as quartiles 2nd–4th) had lower risk (adjusted OR=0.2; 95% CI: lower limit 0.0–0.1, upper limit 0.8–0.9) of developing DCI than patients whose serum magnesium was between 1.10–1.28 mmol/L at day 8 (1st quartile). Compared to the 1st quartile, patients in 2nd (1.28–1.40 mmol/L) and 4th (> 1.62 mmol/L) quartiles tended to have higher risk developing poor outcome (adjusted OR=1.8, 95% CI: 0.5–7.0; adjusted OR=4.9, 95% CI: 1.2–19.7, respectively). The risk was not higher for patients in the 3rd quartile (1.40–1.62 mmol/L). No other adverse effects were mentioned. Natale et al., Severe TBI Randomized, Postinjury, saline Mean arterial pressure, at 14–24 hour 2007 double-blind, vs. MgSO4 (50 period of the infusion, showed significant placebo- mg/kg bolus change from baseline with an 11 mmHg controlled, followed by increase. multi-center 8.3 mg/kg/hr The other 4 variables used to determine trial infusion for 24 hemodynamic effects of MgSO4— hours) n=6 pediatric heart rate, corrected quartile interval, (3 months intracranial pressure, and cerebral to 18 yrs) perfusion pressure—showed no significant patients with changes during the administration of severe TBI MgSO4 bolus or 24-hour infusion when compared to baseline. MgSO4 had no adverse effect on cerebral blood flow velocity, and no other adverse effects were mentioned.

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163 MAGNESIUM TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Temkin Moderate and Single center, Postinjury, i.v. MgSO4 treatment at the higher target level et al., 2007 severe TBI randomized, MgSO4 (low had no effect on the composite outcome double-blind, target group: measure (variables include survival, parallel group loading dose seizure occurrence, and neurobehavioral trial of 0.30 mmol/ functioning). But, at the lower target level, kg over 15 patients treated with MgSO4 had worse n=499 patients minutes within 8 outcomes than those treated with placebo with moderate hours of injury, (p=0.007). or severe TBI, followed by with Glasgow Analysis of the characteristics of patients a continuous Coma Score in the low target group showed that infusion of (GCS) MgSO4 was associated with worse 0.05 mmol/ outcomes if patients were ≤ 40 years between 3–12 kg/hour; high old (p=0.02), male (p=0.007), an ethnic target group: minority (p=0.01), had severe injury loading dose of (p=0.001), had no emergent intracranial 0.425 mmol/kg, surgery (p=0.02), and/or began their followed by an loading dose > 4 hours from injury infusion of 0.10 (p=0.03). mmol/kg/hour for 5 days) or Analysis of individual outcomes showed placebo that mortality rate was higher with MgSO4 treatment than with placebo (p=0.05) at the high target level and functional status at 6 months was worse with MgSO4 than placebo at the low target group (p=0.05). No other adverse effects were mentioned. Van de SAH Randomized, Postinjury, i.v. There was an inverse relationship between Water et al., placebo- magnesium serum magnesium and serum calcium (B=–0.27; 95% CI: –0.33 to 0.20; p < 2007 controlled trial (64 mmol/day; 0.001). Patients with low calcium levels (< n=70) or normal n=137 saline (50 mL/ 2.0 mmol/L) were more likely to develop day; n=67) delayed cerebral ischemia than patients with normal calcium level (HRf=2.1; 95% CI: 1.0–4.3). Hypocalcaemic patients also had significantly higher risk of poor outcome after 3 months (OR=2.9; 95% CI: 1.4– 6.4); however the risk was not significantly higher when multivariable analysis was used to adjust for age, World Federation of Neurological Surgeons (WFNS) score, and ventricular blood (OR=1.9; 95% CI: 0.8–4.7). No other adverse effects were mentioned. continued

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164 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Arango and Acute TBI Meta- Magnesium vs. Analysis of mortality showed that Bainbridge, analysis of 3 no magnesium magnesium treatment increased mortality (RRg=1.48, 95% CI: 1.00–2.19, overall 2006 randomized or placebo effect: zh=1.96, p=0.05). However, there controlled trials was evidence of heterogeneity among the studies. Analysis of functional outcome showed that magnesium had no significant effect on Glasgow Outcome Scale (GOS) at 6 months. There was also evidence of heterogeneity. No differences in medical complications were observed. Schmid- Aneurysmal Pilot study, I.v. MgSO4 Although there was no significant Elsaesser SAH randomized (loading 10 mg/ difference of mean maximum neuronal et al., 2006 trial kg followed markers level between MgSO4 and by continuous nimodipine groups, there was a significant n=104 infusion of 30 difference when comparing patients with mg/kg daily) or different severity of neurological outcome. nimodipine (48 Patients with worse neurological outcome mg/day) (WFNS grades 4–5) in both MgSO4 and nimodipine groups had significantly higher levels of S-100 in serum (p < 0.05). Patients with WFNS grades 4–5 in MgSO4 group also had a higher level of S-100 in cerebrospinal fluid, as well as higher levels of neuron-specific enolase in both serum and cerebrospinal fluid (p < 0.05). There was no significant difference in blood flow velocity and incidence of vasospasm between MgSO4 and nimodipine groups. Among patients who experienced vasospasm, incidence of cerebral infarction was approximately equal regardless of treatment. There was no difference in outcomes after 1 year between the two treatment groups; 55% of patients in each group had GOS scores of 4–5. No adverse effects were mentioned.

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165 MAGNESIUM TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Gorelick Acute ischemic Multicenter, MgSO4 solution At day 90, magnesium had no effect on and Ruland, stroke randomized, (bolus dose death or disability (common OR=0.95, 2004; placebo- of 16 mmol 95% CI: 0.80–1.12; p=0.53). The controlled, infused over 15 magnesium group was not significantly IMAGES double-blind minutes, then different from the placebo group in Study trial 65 mmol/day) terms of risk of death (OR=1.22, 95% Investigators, or matching CI: 0.98–1.53; p=0.073); when time to 2004 n=2,386 amount of saline death was examined with Kaplan-Meier stroke patients analysis, HR for death was 1.18 (95% CI: ≥ 18 years old 0.97–1.42; p=0.098). The length of time between injury and treatment and the type of stroke (ischemic vs. intracerebral hemorrhage) had no effect on outcome. However, patients without cortical ischemic stroke had significantly fewer poor outcomes if treated with magnesium (OR=0.75, 95% CI: 0.58–0.97; p=0.026); analysis showed a significant interaction between magnesium treatment and the group of patients with non-cortical syndromes (p=0.011). Post hoc analysis showed that there were also fewer poor outcomes in magnesium- treated patients with lacunar syndromes (OR=0.70, 95% CI: 0.53–0.92) and with mean arterial pressure > 108.3 mmHg (OR=0.78, 95% CI: 0.61–0.99); there was significant interaction with both sub- groups of patients (p=0.0046, p=0.019, respectively). Compared to placebo group, blood pressure was lower in magnesium group (p ≤ 0.0001) up to 24 hours after starting treatment, but it was not different at 48 hours. Heart rate of magnesium-treated patients was lower after 12 hours of treatment, but not at other times. No other adverse effects were mentioned. continued

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166 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Saver et al., Acute stroke Non- A loading dose The average time between paramedics’ 2004 randomized, of 2.5 g MgSO4 arrival on scene and initiation of treatment open-label, during transport was significantly shorter in FAST-MAG phase II to hospital, patients (26 minutes, 95% CI: 21.8–30.2; feasibility trial then another range 15–61) than in control patients (139 1.5 g MgSO4 minutes, 95% CI: 111–167; range 66–300; n=20, aged p < 0.0001). Duration of transport to in the ER, was 44–92 followed by hospital was not significantly different maintenance between the two groups. infusion of Paramedics completed Paramedic Global 16 g/day Impression Change Form and rated the MgSO4. Time condition of 4 patients as improved, 15 as to treatment of unchanged, and 1 as worsened. At day 90, study subjects 60% of patients had a modified Rankin was compared score of ≤ 2, and 40% had ≤ 1. to control group, which No significant adverse events were consisted associated with treatment. of patients participating in other neuroprotective trials at UCLA Chia et al., Aneurismal Non- Nimodipine (20 No adverse event was associated with μg/kg/hr) alone 2002 SAH randomized, magnesium treatment. 70% of patients pilot study vs. nimodipine treated with nimodipine alone developed supplemented by cerebral vasospasm compared to 15% of n=23 magnesium-supplemented patients (p < 1.0–1.5 mmol/L/ hr of MgSO4 0.008).

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167 MAGNESIUM TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Lampl et al., Acute stroke Randomized, Magnesium (i.v. Compared to patients treated with 2001 placebo- loading dose placebo, those treated with magnesium controlled, of 4 g over 15 had significantly higher Orgogozo double-blind minutes and score beginning on day 3 (p=0.0173) trial a continuous that continued into day 30 (p=0.0002). infusion of 35 g/ Magnesium-treated patients also had n=44 day for 5 days) higher Matthew score beginning on day or placebo 8 (p=0.044) that continued into day 30 (p=0.0087). Although both groups of patients recovered in the first month (p for time < 0.001), as demonstrated by improvement in Orgogozo score, magnesium-treated patients recovered at a faster rate than placebo-treated patients (p=0.007). However, magnesium had no significant effect on recovery as measured by Matthew score, Rankin disability score, and Barthel Index. The magnesium group also had greater percentage of patients with improvement of > 20 points on the Orgogozo scale (p=0.0003) and the Matthew scale (p=0.003). No adverse effects were mentioned. Tier 2: Observational studies Serum Mg2+ levels of both groups of Bayir et al., Acute ischemic Case-control 2009 or hemorrhagic study, n=60 stroke patients were not significantly stroke (n=20 healthy different from controls. No significant controls, relationship was observed between serum Mg2+ level and either GCS or cerebral n=20 ischemic spinal fluid (CSF) Mg2+ level. However, stroke mean CSF Mg2+ levels were significantly patients, n=20 hemorrhagic lower in ischemic stroke patients (0.6±0.4) stroke when compared to controls (0.9±0.1) and patients); hemorrhagic stroke patients (0.8±0.2; stroke patients p=0.006). arrived at ER There was a correlation between CSF within 3 hours Mg2+ level and GCS for ischemic stroke of symptom patients (r=55; p=0.031), with CSF onset) Mg2+ level decreasing as GCS decreased. Ischemic patients with GCS ≤ 8 had the lowest CSF Mg2+ level compared to all other cases and was significantly lower than controls (p < 0.05). Ischemic stroke patients who died 7 days after stroke onset had significantly lower Mg2+ levels than controls (p=0.002), while the CSF Mg2+ level of hemorrhagic stroke patients was not significantly different from controls. continued

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177 MAGNESIUM TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Ionized, free Mg2+ level in serum in Bareyre TBI, LFPI Male Sprague- Postinjury, et al., 1999 Dawley rats MgCl2 (125 injured rats treated with saline was μmol) or saline decreased compared to uninjured controls (p < 0.01) and was lower than injured rats administered 1 hour after injury treated with MgCl2 throughout the 24- hour period (p < 0.05). Mean total Mg2+ level was unchanged in all saline-treated rats. It was increased in injured rats treated with MgCl2 at 2 hours (p < 0.001), but it returned to normal level after 24 hours. At days 14 and 15, learning deficit was smaller in uninjured rats than injured rats (p < 0.001) and was not affected by MgCl2 treatment. MgCl2 treatment did not affect neurologic motor function in injured rats in the first 48 hours after injury, but it improved motor function after 1 week (p < 0.01) and 2 weeks (p < 0.001). Ionized, free Mg2+ level at 24 hours was correlated with neurologic motor function at week 1 (r=0.51, p < 0.05) and week 2 (r=0.81, p < 0.001). Heath and Closed head Male, Postinjury, TBI led to significant reduction in Rotarod scores in untreated rats (p < Vink, 1999a model of Sprague- i.m. MgSO4 diffused axonal Dawley rats (bolus of 750 0.001), but MgSO4 30 minutes after μmol/kg 30 injury injury significantly improved the scores (p < 0.01). Rats treated at 8, 12, and 24 minutes, 8 hours, 12 hours, hours postinjury also had significantly improved scores (p < 0.05) compared to or 24 hours after injury, saline-treated rats, but the rate of their or initial dose improvement was slower than rats treated at 30 minutes at 30 minutes. postinjury, then For up to 2 days after injury, blood additional doses free-Mg2+ level was significantly every 12 hours lower in untreated rats (p < 0.05), but after injury) or administration of MgSO4 at 30 minutes no treatment after injury increased and sustained blood free-Mg2+ to above preinjury level for up to 12 hours. Although rats that had repeated injection of MgSO4 at 12-hour intervals for 1 week after injury had better neurological motor performance than untreated rats, their performance was not significantly different from rats treated with a single bolus of MgSO4. continued

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178 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Heath and Severe, diffuse Male, Postinjury, Compared to untreated, injured controls, Vink, 1999b closed TBI Sprague- i.v. or i.m. bolus performance on Rotarod test was better in Dawley rats of MgSO4 or rats treated with i.m. MgSO4 at 250– 1,000 μmol/kg, i.v. MgSO4 at 250–500 MgCl2 (both at μmol/kg, i.m. MgCl2 at 750 μmol/kg, and doses of 100, i.v. MgCl2 at 100–250 μmol/kg (p < 0.05 250, 500, 750, 1,000, or 1,250 for all). μmol/kg) 30 Metabolic outcome was analyzed minutes after using phosphorus magnetic resonance injury spectroscopy with i.m. MgSO4 at 750 μmol/kg. Injury did not change the brain intracellular pH level or ATP concentration. Free magnesium in both control and treated rats declined significantly (p < 0.01) from preinjury level; however, the MgSO4 group experienced an increase that was significantly higher than controls (p < 0.05) but not significantly different from preinjury level. Brain bioenergetic status declined after injury in both control and MgSO4 groups (p < 0.05). Bioenergetic status of rats with MgSO4 treatment was increased to preinjury level and was higher than controls (p < 0.05). Rotarod scores were highly correlated with free magnesium concentration (r=0.92, p < 0.001) and bioenergetic status (r=0.94, p < 0.001).

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179 MAGNESIUM TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Hoane et al., TBI, electrolytic Male Wistar Preinjury In both the vibrissae-forelimb placing 1998 lesion model of rats, 11–12 daily test and forelimb-forelimb placing test, cortical injury weeks old intraperitoneal rats treated for 5 or 2 days showed injections of significantly less impairment for up to n=24 3 weeks after surgery (p < 0.0001 for MgCl2 (1 mmol/ vibrissae-forelimb placing and p < 0.02 for kg) or saline (1 mL/kg) starting forelimb-forelimb placing) compared to at 5 or 2 days saline-treated rats, but the difference was before injury; minimized after 3 weeks, showing that the last injection at number of days after injury has significant 24 hours before effect on impairment reduction (on both tests: p < 0.0001 for effect of number of injury days). Analysis of recovery rate showed that rats treated for 5 or 2 days recovered significantly faster than saline-treated rats (treatment/days interactions for vibrissae-forelimb test: p < 0.0001; for forelimb-forelimb: p < 0.009). In vibrissae- forelimb test, both 5-day and 2-day group recovered significantly faster than saline group (p < 0.0001 for both groups). But in forelimb-forelimb test, only 2-day group recovered faster than saline group (p < 0.0004). In both tests, difference in recovery rate of 5-day and 2-day groups was not significantly different. In the foot-fault test, 5-day and 2-day rats made fewer mistakes than saline-treated rats (p < 0.0002), but that difference disappeared after 7 days, suggesting that number of days has an effect on test performance test (p < 0.0001). MgCl2- treated rats also recovered faster than saline-treated rats (p < 0.0002 for both 2-day and 5-day vs. saline comparisons). There was a difference in recovery rate between 5-day group and 2-day group (p < .005). Comparison of striatal atrophy between 5-day group and saline group showed that saline group had significantly greater reduction in ipsilateral striatum volume (p < 0.05), with 20% reduction in saline rats and almost no reduction in 5-day treated rats. continued

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180 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 12-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Feldman TBI, Male, Postinjury, At both 18 and 48 hours after injury, et al., 1996 closed head Sprague- MgSO4 (600 injured rats treated with MgSO4 had injury Dawley rats mg/kg 1 hour significantly improved neurological severity score than untreated rats (p < 0.05 after injury) or no treatment for both times). TBI led to brain edema in injured rats compared to sham-injured rats (p < 0.05). Rats treated for 48 hours had reduced edema compared to untreated rats (p < 0.05). However 18 hours of MgSO4 treatment had no effect on edema size. Brain Mg2+ level in rats treated with MgSO4 for 48 hours was significantly higher when compared to sham-injured, untreated rats (p < 0.01), but not when compared to injured, untreated rats. Serum osmolality was not significantly different from baseline after MgSO4 treatment. a n: sample size. b r: correlation coefficient. c OR: odds ratio. d CI: confidence interval. e B: regression coefficient. f HR: hazard ratio. g RR: relative risk. h z: z-score. observational study by Larsson and colleagues (2008) examined the relationship between di- etary magnesium intake and the risk of stroke among the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of more than 26,000 male Finnish smokers. The subjects were 50 to 69 years of age and free from stroke at baseline. After adjusting for age and cardiovascular risk factor, magnesium intake was significantly inversely associated with risk of cerebral infarction, but not intracerebral or subarachnoid hemorrhage. This association was found to be strongest in men younger than 60 years of age. A similar inverse association was observed in the Health Professionals Follow-up Study of more than 43,000 U.S. men. Specifically, magnesium intake was significantly inversely associated with risk of total stroke, most strongly among hypertensive subjects (Ascherio et al., 1998). Other cohort studies did not find a significant association between magnesium intake and risk of stroke (Iso et al., 1999; Song et al., 2005).

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181 MAGNESIUM Animal Studies The majority of recent animal studies of magnesium therapy for TBI have investigated its effectiveness as a treatment for physiological events that occur during the secondary injury process. However, early animal head-injury models involving magnesium examined its prophylactic use to determine whether an intervention before injury would improve neurological outcome and decrease mortality by attenuating the postinjury decline of intra- cellular magnesium concentration (McIntosh et al., 1988; Vink and McIntosh, 1990; Vink et al., 1988). The prevention of such postinjury decline of intracellular magnesium levels was associated with enhanced neurological recovery following intravenous magnesium sulfate administration 15 minutes before fluid percussion brain injury (McIntosh et al., 1988). Rats receiving prophylactic administration of magnesium chloride prior to electrolytic lesions of the somatic sensorimotor cortex also had more improved sensorimotor recovery than control rats (Hoane et al., 1998). Enomoto and colleagues reported in 2005 that intrave- nous administration of magnesium 5 to 20 minutes before the induction of traumatic brain damage by a lateral fluid percussion brain injury model prevented injury-induced neuronal loss in the hippocampus, as well as injury-induced impairments in working and reference memory on the Morris water maze, a test of spatial memory. Experimental studies have also examined the effect of preinjury magnesium deficiency on postinjury outcomes. When compared to controls fed a normal diet, rats fed a magnesium- deficient diet for two weeks prior to lateral fluid percussion brain injury responded with significantly greater neurological impairment that persisted for four weeks postinjury, as well as increased mortality (McIntosh et al., 1988). EVIDENCE INDICATING EFFECT ON TREATMENT Human Studies Based on studies demonstrating negative correlations between serum magnesium levels and the severity of neurological deficits following brain trauma as well as the neuroprotec- tive effects of magnesium observed in experimental animals, a number of clinical studies have assessed the contribution of magnesium to recovery following stroke. Overall, the results of these studies indicate that intravenous administration of magnesium sulfate raises cerebrospinal fluid and brain extracellular levels of magnesium. Magnesium administration also appears to be well tolerated, with few side effects reported (Dorhout Mees et al., 2007; McKee et al., 2005a; Meloni et al., 2006). The results of studies examining the neuroprotective effects of magnesium have been mixed. On the positive side, Dhandapani and colleagues (2008) reported that patients given parenteral magnesium sulfate within 12 hours after closed head injury displayed less brain swelling and lower mortality than patients not given magnesium. Further evidence of ben- eficial effects of magnesium comes from work demonstrating that patients given magnesium sulfate within the first 24 hours after a stroke displayed more functional independence one month after the stroke than patients given a placebo (Lampl et al., 2001). Patients given magnesium within 4 days of suffering a subarachnoid hemorrhage, and then for the subse- quent 20 days, also reportedly had less risk of delayed cerebral ischemia than patients given a placebo. However, the authors did note that a high concentration of serum magnesium could have a negative effect on clinical outcome (Dorhout Mees et al., 2007). Although the results of some clinical studies indicate a neuroprotective role for mag- nesium, results of other studies have been less positive (Kidwell et al., 2009; McKee et al.,

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182 NUTRITION AND TRAUMATIC BRAIN INJURY 2005a; Stippler et al., 2007; Temkin et al., 2007). In a double-blind trial, Temkin and col- leagues (2007) evaluated the effects of intravenous administration of two doses of magne- sium sulfate or placebo given within eight hours of traumatic brain injury and continuing for five days in 499 patients. Magnesium had no significant positive effects on survival, seizure occurrence, or neurobehavioral functioning. Similarly, the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial failed to demonstrate a survival benefit in more than 2,500 pa- tients with acute ischemic stroke who received either magnesium sulfate or placebo within 12 hours of stroke onset (IMAGES Study Investigators, 2004). Moreover, in a subsequent report of a substudy within the IMAGES trial using magnetic resonance imaging, there were no differences in infarct growth observed between patients who had received magnesium and those who had not (Kidwell et al., 2009). In an analysis of three randomized control trials, a Cochrane review concluded that magnesium therapy in patients with acute brain injury is not currently supported by the evidence (Arango and Mejia-Mantilla, 2006). Animal Studies More than 20 years ago, Vink and colleagues (Heath and Vink, 1998; Vink et al., 1988) reported that TBI in laboratory rodents was associated with a decline in intracellular free magnesium and further noted that the greater the reduction in magnesium, the more severe the trauma-induced neurological deficits. In subsequent work, these investigators demon- strated that magnesium deficiency exacerbated the physiological and behavioral outcomes of traumatic brain injury, while pretreatment with magnesium improved them (McIntosh et al., 1988, 1989). More specifically, they found that rats receiving a magnesium-deficient diet for 14 days before a fluid percussion injury displayed more profound neurological impairments and higher mortality rates than rats fed a standard laboratory diet. In comparison, rats given intravenous infusions of magnesium sulfate 15 minutes before injury demonstrated improved cellular bioenergetics and neurological functioning relative to rats fed the standard diet (McIntosh et al., 1988). Since 1990, a variety of animal models of TBI that included fluid percussion injury, impact-acceleration injury, cortical contusion injury, and focal and global cerebral ischemia has repeatedly documented that treatment with magnesium shortly after the induction of injury is effective in limiting the detrimental neural and behavioral consequences of brain trauma (for reviews see: Hoane, 2007; Meloni et al., 2006; Sen and Gulati, 2010). Admin- istration of magnesium prevents the postinjury decline in free magnesium, reduces cortical and hippocampal cell loss, ameliorates cortical alterations in microtubule-associated protein, and enhances cellular bioenergetic status (Enomoto et al., 2005; Heath and Vink, 1999b; Saatman et al., 2001; Turner et al., 2004). Treatment with magnesium can also attenuate the development of brain edema (Feldman et al., 1996), avert apoptotic changes in neurons (Park and Hyun, 2004), and diminish defects in the blood-brain barrier that result from TBI (Esen et al., 2003). Magnesium also can improve the behavioral consequences of TBI. Heath and Vink (1999a) reported that the administration of magnesium salts after severe TBI resulted not only in dose-related increases in brain intracellular free magnesium, but also led to improve - ments in motor behavior. Similarly, Hoane et al. (2003) found that magnesium chloride therapy facilitated reduction of sensorimotor deficits in a dose-dependent manner following bilateral damage to the anterior medial cortex. The effects of magnesium on recovery are not limited to the transient phase of secondary injury, but rather have long-term functional significance. Research has demonstrated that posttraumatic administration of magnesium sulfate diminishes spatial and motor deficits

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183 MAGNESIUM and attenuates anxiety in rats for up to four weeks after the induction of severe diffuse TBI (Vink et al., 2003). Further evidence of the potential long-term effects of magnesium comes from Browne and colleagues, who reported that magnesium given 15 minutes after fluid percussion injury significantly reduced tissue loss in the hippocampus when measured eight months after the induction of brain damage. However, although magnesium did reduce tissue loss, there were no differences observed in cognitive behavior between treated and untreated animals (Browne et al., 2004). Most studies examining the therapeutic effects of magnesium following TBI in experi- mental animals have concentrated on recovery of sensory functions, motor functions, or both. Studies conducted since 2000, however, also indicate that magnesium therapy can improve deficits in cognitive function that result from TBI (Enomoto et al., 2005; Hoane, 2007; Hoane et al., 2003). As mentioned in the earlier section on resilience, a significant reduction in ipsilateral hippocampal cell loss was seen when magnesium therapy was admin - istered prior to fluid percussion brain injury; accordingly, the magnesium therapy prevented injury-induced cognitive dysfunction in the Morris water maze (Enomoto et al., 2005). Hoane (2007) similarly reported that rats given magnesium chloride shortly after brain injury displayed fewer deficits in both reference and working memory on the Morris water maze than controls not given magnesium. It should be noted, however, that magnesium did not improve all aspects of cognitive behavior. In fact, daily administration of a high dose of magnesium produced amnesia and impairments in the acquisition of reference memory task on the Morris water maze. These findings indicate that the type of task used must be considered when evaluating the effects of magnesium on recovery of function following TBI. TBI can affect brain regions and neurotransmitter systems involved in the modulation of mood, making depression and anxiety common occurrences in brain-damaged individu- als (Bombardier et al., 2010; Jorge and Starkstein, 2005). It has been hypothesized that magnesium could be useful in alleviating mood disturbances related to TBI. In support of this hypothesis, rats given magnesium sulfate 30 minutes after impact-acceleration injury displayed less anxiety in an open field test 1 and 6 weeks after injury than brain-damaged animals not given magnesium (Fromm et al., 2004). Taken together, the results of the previous animal studies strongly suggest that magne- sium plays a role in the pathophysiological processes following TBI, and that magnesium therapy may be useful in recovery of both neural functioning and behavior. It is important to note, however, that not all studies have confirmed the neuroprotective effects of magne- sium (Hoane, 2007; Hoane and Barth, 2002; Meloni et al., 2006); in reviewing studies that investigated the neuroprotective effects of magnesium in animals that had experienced global or focal cerebral ischemia, Meloni et al. (2006) reported that approximately 40 percent of the studies failed to find any positive effect for magnesium. These conflicting findings are important, because they suggest that the types of brain damage; the dose, route, and timing of magnesium administration; the species and strain of animal; and temperature can influ- ence the neuroprotective effects of magnesium (see below). One obvious factor that could contribute to the discrepancies in the results of studies assessing the neuroprotective effects of magnesium is the dosage used. With few exceptions (Heath and Vink, 1999b; Hoane et al., 2003), researchers have not examined dose-related responses to magnesium. Across studies, doses of magnesium have ranged from 80 mg/kg to more than 2,000 mg/kg, and in some studies animals were given only one dose of mag- nesium, while in others they were given multiple doses (Meloni et al., 2006). Unfortunately, there are no consistent relationships evident between dosage and the neuroprotective effects of magnesium. Results of a number of studies suggest that the timing of administration is another

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184 NUTRITION AND TRAUMATIC BRAIN INJURY important factor in determining whether magnesium can provide neuroprotective effects. Most studies demonstrating such an effect had administered magnesium either immediately before or very shortly (15 to 30 minutes) after the induction of brain injury. It is therefore likely that magnesium levels in the brain were elevated at the time of the injury or shortly thereafter (Meloni et al., 2006). When administration of magnesium was delayed for sev- eral hours, neuroprotective effects have been less consistent. For example, although motor behavior improved in response to magnesium treatment provided up to 24 hours after brain damage, earlier treatments provided the most significant benefit (Heath and Vink, 1999a; Hoane and Barth, 2002). Cell death following brain injury was likewise reduced when mag- nesium was given 15 minutes after injury, but not when it was given either 8 or 24 hours after injury (Hoane and Barth, 2002). The extent of the damage following TBI may also moderate the neuroprotective effects of magnesium. Following impact-acceleration injury, magnesium treatment improved brain magnesium levels and motor behavior in rats that did not develop subdural hematomas. However, no such improvement was observed in rats that did develop subdural hematomas (Heath and Vink, 2001). It has been hypothesized that magnesium’s neuroprotective effects following the induc- tion of cerebral ischemia are only observed when combined with post-ischemia hypothermia (Campbell et al., 2008; Meloni et al., 2006, 2009; Zhu et al., 2004). Most studies have not considered body temperature following the induction of brain damage. In studies that have monitored body temperature, however, magnesium treatment reduced the death of hippocampal neurons in rats that were mildly hypothermic in the immediate hours after the induction of brain damage, but did not reduce neuronal death in animals that were normo- thermic (Campbell et al., 2008; Meloni et al., 2006). CONCLUSIONS AND RECOMMENDATIONS A number of variables including dose and duration of treatment could modify the neuro- protective effects of magnesium. Findings from both human and animal studies indicate that the most critical issue yet to be addressed is the window of opportunity for magnesium use in the treatment of TBI. Animal studies suggest that the therapeutic window within which neuroprotective effects of magnesium are observed is very brief. As described in preceding paragraphs, most animal studies demonstrating a beneficial effect of magnesium have admin- istered the mineral within 60 minutes following brain damage, which may not be practical or feasible in an uncontrolled environment, such as in combat operations. Results of studies employing longer time intervals between injury and magnesium administration have not been as positive. With respect to clinical trials, results from a small number of patients in the IMAGES trial indicated a beneficial effect of magnesium when it was given within three hours of injury.3 To further evaluate the importance of rapid treatment with magnesium, the Field Administration of Stroke Therapy—Magnesium (FAST-MAG) phase III clinical trial (Saver et al., 2004) is comparing the effects of magnesium given intravenously by paramedics within 1 to 2 hours of symptom onset on scales of global handicap, neurological deficits, quality of life, and mortality, to placebo three months following injury.4 Results of this study have yet to be published. Results of studies employing experimental animals have shown that magnesium can protect against a number of the secondary consequences of traumatic brain injury. Clini- 3 Available online at http://www.fastmag.info/sci_bkg.htm (accessed December 22, 2010). 4 Available online at http://www.fastmag.info/sci_bkg.htm (accessed December 22, 2010).

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185 MAGNESIUM cal studies have had more mixed results, however, with several large trials (e.g., IMAGES) failing to observe a beneficial effect of the mineral on recovery from stroke; indeed, a Co- chrane review concluded that the evidence does not currently support magnesium therapy in patients with acute brain injury. No large clinical studies have assessed the neuroprotective effects of magnesium on other types of brain injury, including TBI. At present, there is no clear evidence that magnesium would be useful in the treatment of TBI occurring in military personnel. However, it is recommended that the results of the FAST-MAG trial be monitored to determine if administration of magnesium within a two- hour window after brain damage can alleviate some of the detrimental consequences of TBI. REFERENCES Arango, M. F., and D. Bainbridge. 2006. Magnesium for acute traumatic brain injury. Cochrane Database of Systematic Reviews (4):CD005400. Ascherio, A., E. B. Rimm, M. A. Hernan, E. L. Giovannucci, I. Kawachi, M. J. Stampfer, and W. C. Willett. 1998. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among us men. Circulation 98(12):1198–1204. Bareyre, F. M., K. E. Saatman, M. A. Helfaer, G. Sinson, J. D. Weisser, A. L. Brown, and T. K. McIntosh. 1999. Alterations in ionized and total blood magnesium after experimental traumatic brain injury: Relationship to neurobehavioral outcome and neuroprotective efficacy of magnesium chloride. Journal of Neurochemistry 73(1):271–280. Bayir, A., A. Ak, H. Kara, and T. K. Sahin. 2009. Serum and cerebrospinal fluid magnesium levels, Glasgow Coma Scores, and in-hospital mortality in patients with acute stroke. Biological Trace Element Research 130(1):7–12. Begum, R., A. Begum, R. Johanson, M. N. Ali, and S. Akhter. 2001. A low dose (“Dhaka”) magnesium sulphate regime for eclampsia. Acta Obstetricia et Gynecologica Scandinavica 80(11):998–1002. Bombardier, C. H., J. R. Fann, N. R. Temkin, P. C. Esselman, J. Barber, and S. S. Dikmen. 2010. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. Journal of the American Medical Association 303(19):1938–1945. Browne, K. D., M. J. Leoni, A. Iwata, X. H. Chen, and D. H. Smith. 2004. Acute treatment with MgSO4 at- tenuates long-term hippocampal tissue loss after brain trauma in the rat. Journal of Neuroscience Research 77(6):878–883. Bullock, R., A. Zauner, J. J. Woodward, J. Myseros, S. C. Choi, J. D. Ward, A. Marmarou, and H. F. Young. 1998. Factors affecting excitatory amino acid release following severe human head injury. Journal of Neurosurgery 89(4):507–518. Campbell, K., B. P. Meloni, H. D. Zhu, and N. W. Knuckey. 2008. Magnesium treatment and spontaneous mild hypothermia after transient focal cerebral ischemia in the rat. Brain Research Bulletin 77(5):320–322. Chia, R. Y., R. S. Hughes, and M. K. Morgan. 2002. Magnesium: A useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. Journal of Clinical Neuroscience 9(3):279–281. Dhandapani, S. S., A. Gupta, S. Vivekanandhan, B. S. Sharma, and A. K. Mahapatra. 2008. Randomized con- trolled trial of magnesium sulphate in severe closed traumatic brain injury. Indian Journal of Neurotrauma 5(1):27–33. Dorhout Mees, S. M., W. M. van den Bergh, A. Algra, and G. J. E. Rinkel. 2007. Achieved serum magnesium concentrations and occurrence of delayed cerebral ischaemia and poor outcome in aneurysmal subarachnoid haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 78(7):729–731. Enomoto, T., T. Osugi, H. Satoh, T. K. McIntosh, and T. Nabeshima. 2005. Pre-injury magnesium treatment pre- vents traumatic brain injury-induced hippocampal ERK activation, neuronal loss, and cognitive dysfunction in the radial-arm maze test. Journal of Neurotrauma 22(7):783–792. Esen, F., T. Erdem, D. Aktan, R. Kalayci, N. Cakar, M. Kaya, and L. Telci. 2003. Effects of magnesium adminis- tration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats. Journal of Neurosurgical Anesthesiology 15(2):119–125. Faden, A. I., P. Demediuk, S. S. Panter, and R. Vink. 1989. The role of excitatory amino acids and NMDA recep- tors in traumatic brain injury. Science 244(4906):798–800. Feldman, Z., B. Gurevitch, A. A. Artru, A. Oppenheim, E. Shohami, E. Reichenthal, and Y. Shapira. 1996. Effect of magnesium given 1 hour after head trauma on brain edema and neurological outcome. Journal of Neuro- surgery 85(1):131–137.

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