PROGRESSIVE MAGNESIUM, DEFICIENCY INCREASES MORTALITY FROM ENDOTOXIN CHALLENGE - PROTECTIVE EFFECTS OF ACUTE MAGNESIUM REPLACEMENT THERAPY

Objectives: To study the effects of endotoxin on magnesium homeostasis ; to determine if progressive magnesium deficiency alters outcome from endotoxin challenge; and to evaluate the efficacy of magnesium therap y in reducing endotoxin-induced mortality. Design: Prospective, placeb o-controlled, randomized, multiexperiment studies. Setting: Research l aboratory of a university hospital. Subjects: Male Sprague Dawley rats (n = 299). Interventions: Experiment 1 was designed to test if endoto xin alters magnesium homeostasis. Circulating total and ionized magnes ium (estimated by ultrafilterable values) concentrations were determin ed in blood samples collected from animals after the randomized admini stration of placebo or 0.3, 3.0, or 30 mg/kg of endotoxin. A baseline blood sample was collected and then a second blood sample was obtained at 5, 15, 30, 60, 120, or 180 mins after endotoxin or placebo adminis tration. In experiment 2, animals were randomized to receive magnesium -sufficient diets or magnesium-deficient diets for 6 wks. After 6 wks, the effects of the randomized administration of 3.0 mg/kg endotoxin o r placebo were evaluated on mortality and analyte values (pH and blood gases, sodium, potassium, chloride, glucose, ionized calcium, hematoc rit, total and ultrafilterable magnesium concentrations) in the three study groups (magnesium-sufficient, 3-wk magnesium-deficient, or 6-wk magnesium-deficient). In experiment 3, magnesium-deficient animals mer e randomized to receive 50 mmol/kg magnesium chloride or placebo, befo re or after the administration of 3.0 mg/kg of endotoxin. Baseline and 24-hr analyte determinations were performed and outcome was analyzed. Measurements and Main Results: Experiment 1: Significant increases (p < .05) in circulating total magnesium concentrations were found in an imals that received 30 mg/kg of endotoxin, at 120 mins (0.79 +/- 0.10 vs. 0.60 +/- 0.05 mmol/L), and 180 mins (0.74 +/- 0.01 vs. 0.56 +/- 0. 04 mmol/L) compared with baseline values. Similarly, significant incre ases (p < .05) in ionized magnesium concentrations were observed 120 a nd 180 mins after 3.0 and 30 mg/kg of endotoxin compared with baseline values. Experiment 2: Magnesium deficiency was strongly (p < .02) ass ociated with increased mortality from endotoxin challenge. Endotoxin a dministration (3.0 mg/ kg) was lethal in 10 (43%) of 23 magnesium-suff icient animals, 15 (65%) of 23 3-wk magnesium-deficient animals, and 2 0 (83%) of 24 6-wk magnesium-deficient animals. Experiment 3: In magne sium-deficient animals, rats treated with magnesium replacement therap y had significantly increased survival from endotoxin administration ( 15 [52%] of 29 vs. five [17%] of 29, p < .01) compared with placebo-tr eated animals. Conclusions: a) Endotoxin challenge causes significant increases in circulating total and ionized magnesium concentrations. b ) Progressive magnesium deficiency is strongly associated with increas ed lethality, and magnesium replacement therapy provides significant p rotection from endotoxin challenge. c) These experimental results supp ort the concept that cellular injury is probably associated with incre ases in circulating magnesium concentrations. Furthermore, these exper imental findings suggest that magnesium deficiency predisposes to wors e outcome from endotoxin challenge, and that replacement therapy in th e setting of magnesium deficiency may be warranted, especially in crit ically ill subjects.