Dose Optimization of Intravenous Magnesium Sulfate After Acute Stroke

Abstract

Background and Purpose-Parenterally administered MgSO 4 is neuroprotective in standard animal models of focal cerebral ischemia and in many other paradigms of brain injury. Previous small clinical trials in stroke patients have explored the safety and tolerability of different infusion regimens. This study was undertaken to optimize the regimen for a multicenter trial. Methods-Within 24 hours of the onset of clinically diagnosed stroke, patients were randomized to receive placebo or one of three intravenous MgSO 4 infusions: a loading infusion of 8, 12, or 16 mmol, followed by 65 mmol over 24 hours. Cardiovascular parameters, serum magnesium concentrations, and blood glucose concentrations were determined. Outcome at 30 and 90 days was recorded. Results-Twenty-five patients were recruited and treated at a mean time of 20 hours after stroke. No tolerability problems were identified. No effects of magnesium on heart rate, blood pressure, or blood glucose were evident. Serum magnesium concentrations rose to target levels most rapidly in the highest loading infusion group and were maintained in all groups for at least 24 hours. Conclusions-MgSO 4 infusions that rapidly elevate the serum magnesium concentration to potentially therapeutic levels are well tolerated and have no major hemodynamic effects in patients with acute stroke. The 16-mmol loading infusion achieved target serum concentrations most rapidly and has been chosen for further trials. (Stroke. 1998;29:918-923.)

Preclinical Drug Evaluation for Combination Therapy in Acute Stroke Using Systematic Review, Meta-Analysis, and Subsequent Experimental Testing

“…= 4.8%, 95% CI = À0.6% to 18.2%, N = 5) than for sulphate salt (M = 30.7%, s.e. = 2.6%, 95% CI = À25.7% to 35.7%, N = 5), consistent with the hypothesis that magnesium chloride may give rise to hyperglycaemia (Muir and Lees, 1998).…”

Clinical trials for cytoprotection in stroke

“…33,34 Administration of MgSO4 as loading dose followed by a 24-h continuous infusion has been studied in over 3,000 stroke patients within 48 h with no significant adverse events. The majority of these studies have not revealed significant hypotension or hyperglycemia that were experienced in some preclinical evaluations of MgCl.…”

“…A dose optimization study identified a dose (16 mmol bolus, 24-h continuous infusion of 65 mmol) capable of achieving the minimum neuroprotective serum levels in all patients while producing no adverse events. 34 A systematic review of four phase 2 clinical trials disclosed an insignificant, 8% absolute reduction in the combined endpoint of death or functional dependence. 30 One of the largest impediments to translating experimental efficacy to a clinical reality is the delayed administration of potentially cytoprotective therapies.…”

Magnesium in the Central Nervous System

“…Among these, 6 were randomized and 2 uncontrolled. All showed good safety with each randomized controlled trial (RCT) showing favourable effects on clinical outcome point estimates (Wester et al, 1984;Muir and Lees, 1995;Muir and Lees, 1998;Galeas et al, 1998;Bradford et al, 1998;Lampl et al, 2001;Saver et al, 2002;Muir et al, 2004). A meta--analysis of the four phase 2 RCTs with combinable data (total of 162 patients) found a favourable clinical outcome trend, with late disability or death seen in 44.3% of magnesium sulphate patients compared with 52.7% of placebo patients (OR 0.67,95% CI,) .…”

“…A meta--analysis of the four phase 2 RCTs with combinable data (total of 162 patients) found a favourable clinical outcome trend, with late disability or death seen in 44.3% of magnesium sulphate patients compared with 52.7% of placebo patients (OR 0.67,95% CI,) . The pilot trial that optimized a dose regimen for subsequent phase 3, pivotal trials was the dose ranging study reported by Muir and Lees (1998). They sought a regimen that efficiently and safely achieved a doubling of the serum magnesium concentration.…”