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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel 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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel 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 unrefined 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 meeting 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 Mineral 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 cramping, and nausea. These adverse effects have been observed primarily with pharmacological 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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel TABLE 12-1 Relevant Data Identified for Magnesium Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Tier 1: Clinical trials Kidwell et al., 2009 Acute ischemic stroke Multicenter, randomized, double-blind, placebo-controlled clinical trial (substudy of IMAGES trial) Magnesium sulfate (MgSO4) solution (bolus dose of 16 mmol infused over 15 minutes, then 65 mmol/day) or matching amount of saline) For all patients, baseline lesion volume measured by DWI (rb=0.654, p < 0.001) and perfusion-weighted imaging (r=0.805, p < 0.001) correlated with final infarct size. At day 90, there was no significant difference between the MgSO4 group and placebo group in lesion growth, clinical outcome, or mortality rate. However, patients with poor clinical outcome tended to have greater percentage infarct growth (p=0.015) and absolute infarct growth (p=0.004). na=104 patients with diffusion-weighted imaging (DWI) lesion volume of ≥ 3 mL Although baseline serum glucose level correlated with infarct growth (p ≤ 0.028) 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., 2009 Aneurysmal subarachnoid hemorrhage (SAH) Multi-center, randomized, placebo-controlled trial MgSO4 infusion (80mmol/day) or normal saline for 10–14 days Throughout the study, the treatment group had a higher plasma magnesium level than the control group (p < 0.001). The average plasma magnesium level in the treatment group was between 1.59–1.84 mmol/L, while the average in the control group ranged from 0.85–1.02 mmol/L. n=22 patients who were simultaneously participating in an intravenous MgSO4 after aneurysmal SAH trial Although the treatment group had higher levels of cerebrospinal fluid magnesium overall, the difference was significant only on day 2 and days 5–8 (p ≤ 0.035). The average levels of cerebrospinal fluid 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.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Dhandapani et al., 2008 Closed TBI Randomized trial Postinjury, standard care or supplementation with MgSO4 (initiation of 4 g intravenously [i.v.] and 5 g intramuscularly [i.m.], then continuation of 5 g every 4 hours for 24 hours) At 3 months, 73.3% of the patients on MgSO4 supplementation had good to moderate outcome compared to just 40% of the standard care group (ORc=4.13, 95% CId: 1.39–12.27, p=0.009). Specifically, 46.7% of patients in MgSO4 group had good recovery compared to 20% of the patients in standard care group (OR=3.5, 95% CI: 1.11–11.02, p=0.028). n=60 Significantly greater number of patients in the control group (73.3%) experienced 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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results van den Bergh et al., 2008 SAH Randomized, placebo-controlled trial I.v. MgSO4 (64 mmol/day) vs. placebo (saline) for up to 20 days Regression analysis showed that serum magnesium level is inversely associated with ionized serum calcium level (Be=–0.09; 95% CI: –0.12 to –0.06). 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). n=167 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.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Dorhout Mees et al., 2007 SAH Randomized, placebo-controlled trial MgSO4 therapy (64 mmol/day) vs. placebo for up to 20 days Over the course of the study, 17% of the patients developed delayed cerebral ischemia (DCI) (median day of onset was day 8), and 26% had poor outcome, defined by modified Rankin score of ≥ 4. n=155 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., 2007 Severe TBI Randomized, double-blind, placebo-controlled, multi-center trial Postinjury, saline vs. MgSO4 (50 mg/kg bolus followed by 8.3 mg/kg/hr infusion for 24 hours) Mean arterial pressure, at 14–24 hour period of the infusion, showed significant change from baseline with an 11 mmHg increase. The other 4 variables used to determine hemodynamic effects of MgSO4—heart rate, corrected quartile interval, intracranial pressure, and cerebral perfusion pressure—showed no significant changes during the administration of MgSO4 bolus or 24-hour infusion when compared to baseline. n=6 pediatric (3 months to 18 yrs) patients with severe TBI MgSO4 had no adverse effect on cerebral blood flow velocity, and no other adverse effects were mentioned.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Temkin et al., 2007 Moderate and severe TBI Single center, randomized, double-blind, parallel group trial Postinjury, i.v. MgSO4 (low target group: loading dose of 0.30 mmol/kg over 15 minutes within 8 hours of injury, followed by a continuous infusion of 0.05 mmol/kg/hour; high target group: loading dose of 0.425 mmol/kg, followed by an infusion of 0.10 mmol/kg/hour for 5 days) or placebo MgSO4 treatment at the higher target level had no effect on the composite outcome measure (variables include survival, seizure occurrence, and neurobehavioral functioning). But, at the lower target level, patients treated with MgSO4 had worse outcomes than those treated with placebo (p=0.007). n=499 patients with moderate or severe TBI, with Glasgow Coma Score (GCS) between 3–12 Analysis of the characteristics of patients in the low target group showed that MgSO4 was associated with worse outcomes if patients were ≤ 40 years old (p=0.02), male (p=0.007), an ethnic minority (p=0.01), had severe injury (p=0.001), had no emergent intracranial surgery (p=0.02), and/or began their loading dose > 4 hours from injury (p=0.03). Analysis of individual outcomes showed 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 Water et al., 2007 SAH Randomized, placebo-controlled trial Postinjury, i.v. magnesium (64 mmol/day; n=70) or normal saline (50 mL/day; n=67) There was an inverse relationship between serum magnesium and serum calcium (B=−0.27; 95% CI: −0.33 to 0.20; p < 0.001). Patients with low calcium levels (< 2.0 mmol/L) were more likely to develop delayed cerebral ischemia than patients with normal calcium level (HRf=2.1; 95% CI: 1.0–4.3). n=137 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.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Arango and Bainbridge, 2006 Acute TBI Meta-analysis of 3 randomized controlled trials Magnesium vs. no magnesium or placebo Analysis of mortality showed that magnesium treatment increased mortality (RRg=1.48, 95% CI: 1.00–2.19, overall effect: zh=1.96, p=0.05). However, there 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-Elsaesser et al., 2006 Aneurysmal SAH Pilot study, randomized trial I.v. MgSO4 (loading 10 mg/kg followed by continuous infusion of 30 mg/kg daily) or nimodipine (48 mg/day) Although there was no significant difference of mean maximum neuronal markers level between MgSO4 and nimodipine groups, there was a significant difference when comparing patients with different severity of neurological outcome. n=104 Patients with worse neurological outcome (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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Gorelick and Ruland, 2004; Acute ischemic stroke Multicenter, randomized, placebo-controlled, double-blind trial MgSO4 solution (bolus dose of 16 mmol infused over 15 minutes, then 65 mmol/day) or matching amount of saline At day 90, magnesium had no effect on death or disability (common OR=0.95, 95% CI: 0.80–1.12; p=0.53). The magnesium group was not significantly different from the placebo group in terms of risk of death (OR=1.22, 95% CI: 0.98–1.53; p=0.073); when time to death was examined with Kaplan-Meier analysis, HR for death was 1.18 (95% CI: 0.97–1.42; p=0.098). IMAGES Study Investigators, 2004 n=2,386 stroke patients ≥ 18 years old 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 subgroups 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.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Saver et al., 2004 Acute stroke Non-randomized, open-label, phase II feasibility trial A loading dose of 2.5 g MgSO4 during transport to hospital, then another 1.5 g MgSO4 in the ER, was followed by maintenance infusion of 16 g/day MgSO4. Time to treatment of study subjects was compared to control group, which consisted of patients participating in other neuroprotective trials at UCLA The average time between paramedics’ arrival on scene and initiation of treatment was significantly shorter in FAST-MAG patients (26 minutes, 95% CI: 21.8–30.2; range 15–61) than in control patients (139 minutes, 95% CI: 111–167; range 66–300; p < 0.0001). Duration of transport to hospital was not significantly different between the two groups. n=20, aged 44–92 Paramedics completed Paramedic Global Impression Change Form and rated the condition of 4 patients as improved, 15 as unchanged, and 1 as worsened. At day 90, 60% of patients had a modified Rankin score of ≤ 2, and 40% had ≤ 1. No significant adverse events were associated with treatment. Chia et al., 2002 Aneurismal SAH Non-randomized, pilot study Nimodipine (20 μg/kg/hr) alone vs. nimodipine supplemented by 1.0–1.5 mmol/L/hr of MgSO4 No adverse event was associated with magnesium treatment. 70% of patients treated with nimodipine alone developed cerebral vasospasm compared to 15% of magnesium-supplemented patients (p < 0.008). n=23
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Lampl et al., 2001 Acute stroke Randomized, placebo-controlled, double-blind trial Magnesium (i.v. loading dose of 4 g over 15 minutes and a continuous infusion of 35 g/day for 5 days) or placebo Compared to patients treated with placebo, those treated with magnesium had significantly higher Orgogozo score beginning on day 3 (p=0.0173) that continued into day 30 (p=0.0002). Magnesium-treated patients also had higher Matthew score beginning on day 8 (p=0.044) that continued into day 30 (p=0.0087). n=44 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 Bayir et al., 2009 Acute ischemic or hemorrhagic stroke Case-control study, n=60 (n=20 healthy controls, n=20 ischemic stroke patients, n=20 hemorrhagic stroke patients); stroke patients arrived at ER within 3 hours of symptom onset) Serum Mg2+ levels of both groups of stroke patients were not significantly different from controls. No significant relationship was observed between serum Mg2+ level and either GCS or cerebral spinal fluid (CSF) Mg2+ level. However, mean CSF Mg2+ levels were significantly lower in ischemic stroke patients (0.6±0.4) when compared to controls (0.9±0.1) and hemorrhagic stroke patients (0.8±0.2; p=0.006). There was a correlation between CSF Mg2+ level and GCS for ischemic stroke patients (r=55; p=0.031), with CSF 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.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Bareyre et al., 1999 TBI, LFPI Male Sprague-Dawley rats Postinjury, MgCl2 (125 μmol) or saline administered 1 hour after injury Ionized, free Mg2+ level in serum in injured rats treated with saline was decreased compared to uninjured controls (p < 0.01) and was lower than injured rats 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 Vink, 1999a Closed head model of diffused axonal injury Male, Sprague-Dawley rats Postinjury, i.m. MgSO4 (bolus of 750 μmol/kg 30 minutes, 8 hours, 12 hours, or 24 hours after injury, or initial dose at 30 minutes postinjury, then additional doses every 12 hours after injury) or no treatment TBI led to significant reduction in Rotarod scores in untreated rats (p < 0.001), but MgSO4 30 minutes after injury significantly improved the scores (p < 0.01). Rats treated at 8, 12, and 24 hours postinjury also had significantly improved scores (p < 0.05) compared to saline-treated rats, but the rate of their improvement was slower than rats treated at 30 minutes. For up to 2 days after injury, blood free-Mg2+ level was significantly lower in untreated rats (p < 0.05), but administration of MgSO4 at 30 minutes 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.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Heath and Vink, 1999b Severe, diffuse closed TBI Male, Sprague-Dawley rats Postinjury, i.v. or i.m. bolus of MgSO4 or MgCl2 (both at doses of 100, 250, 500, 750, 1,000, or 1,250 μmol/kg) 30 minutes after injury Compared to untreated, injured controls, performance on Rotarod test was better in rats treated with i.m. MgSO4 at 250–1,000 μmol/kg, i.v. MgSO4 at 250–500 μmol/kg, i.m. MgCl2 at 750 μmol/kg, and i.v. MgCl2 at 100–250 μmol/kg (p < 0.05 for all). Metabolic outcome was analyzed using phosphorus magnetic resonance 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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Hoane et al., 1998 TBI, electrolytic lesion model of cortical injury Male Wistar rats, 11–12 weeks old Preinjury daily intraperitoneal injections of MgCl2 (1 mmol/kg) or saline (1 mL/kg) starting at 5 or 2 days before injury; last injection at 24 hours before injury In both the vibrissae-forelimb placing test and forelimb-forelimb placing test, rats treated for 5 or 2 days showed significantly less impairment for up to 3 weeks after surgery (p < 0.0001 for vibrissae-forelimb placing and p < 0.02 for forelimb-forelimb placing) compared to saline-treated rats, but the difference was minimized after 3 weeks, showing that the number of days after injury has significant effect on impairment reduction (on both tests: p < 0.0001 for effect of number of days). n=24 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.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Feldman et al., 1996 TBI, closed head injury Male, Sprague-Dawley rats Postinjury, MgSO4 (600 mg/kg 1 hour after injury) or no treatment At both 18 and 48 hours after injury, injured rats treated with MgSO4 had significantly improved neurological severity score than untreated rats (p < 0.05 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 dietary 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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel 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 intracellular 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 intravenous 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 neuroprotective 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 beneficial 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 subsequent 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 magnesium, results of other studies have been less positive (Kidwell et al., 2009; McKee et al.,
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel 2005a; Stippler et al., 2007; Temkin et al., 2007). In a double-blind trial, Temkin and colleagues (2007) evaluated the effects of intravenous administration of two doses of magnesium 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 patients 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 demonstrated 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). Administration 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 improvements 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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel 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 experimental 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 administered 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 individuals (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 magnesium 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 magnesium (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 influence 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 magnesium, 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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel 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 several 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 magnesium 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 induction 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 normothermic (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 administered 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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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel 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 Cochrane 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 attenuates 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 controlled 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 prevents 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 administration 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 receptors 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 Neurosurgery 85(1):131–137.
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