INSULIN-TREATMENT OF CORTICOSTEROID-ASSOCIATED HYPERGLYCEMIA AND ITS EFFECT ON OUTCOME AFTER FOREBRAIN ISCHEMIA IN RATS

Background Recent studies have reported that dexamethasone worsens neu ronal injury after brain ischemia. This effect is assumed to be second ary to drug-induced hyperglycemia. The current study used a rat model to test the hypotheses that insulin treatment of dexamethasone-induced hyperglycemia would result in a postischemic neurologic outcome that is: (1) better than that of hyperglycemic, dexamethasone-treated subje cts; and (2) better than, of equal to, that of saline-treated control subjects. Methods: Twenty-four halothane-anesthetized (1.0% inspired) rats were randomly assigned to one of three treatment groups (N = 8 in each group): (1) normoglycemic, placebo-treated rats (group P) receiv ed an intravenous saline infusion; (2) hyperglycemic, dexamethasone-tr eated rats (group D) received 2 mg/kg. intraperitoneal dexamethasone a t 2 days, 1 day, and 3 h before ischemia plus an intravenous saline in fusion: and (3) normoglycemic, dexamethasone- and insulin-treated rats (group DI) received the same treatment as group D, plus an intravenou s insulin infusion shortly before ischemia. Blood gases and acid-base status were maintained within normal physiologic ranges. Pericranial a nd rectal temperatures were maintained at normothermia. Forebrain isch emia of 10 min duration was produced using an established model. Neuro logic function was assessed by a blinded observer at 24 and 48 h posti schemia. Brain histopathology was assessed at the time of ischemia-rel ated death or after the examination at 48 h. All 24 rats were included in the analysis of neurologic function; however, only 21 rats that su rvived for greater than or equal to 24 h postischemia were included in the histologic analysis. Results: Rats were web matched for systemic physiologic variables, with the exception of glucose concentrations. P lasma glucose concentration immediately before ischemia was as follows : group P = 129 +/- 8 mg/dl (mean +/- SD), group D = 344 +/- 29 mg/dl, and group DI = 123 +/- 17 mg/dl. At 48 h postischemia, groups P and D I were minimally Injured and had similar functional scores. In contras t, all group D rats died of cerebral ischemia, Histologic injury was s ignificantly worse in group D than in either group P or DI, but did no t differ significantly between groups P and DI. When all groups were c ombined, there was a significant correlation between neurologic functi on and total histopathology score ranks. Conclusions in the current st udy, dexamethasone administration before brain ischemia resulted in a worsening of postichemic outcome that was related to drug-induced hype rglycemia. Restoration of normoglycemia, using insulin, resulted in a functional outcome similar to that in group P, and an attenuation of d examethasone-associated histologic injury.