Ischemic brain damage, with profound neurologic deficits, are the major sequelae of successful cardiopulmonary resuscitation (CPR). We will determine the extent to which metabolic factors alter these sequelae. Dextrose used in i.v. fluids was found to be extremely detrimental to the neurologic outcome of resuscitated dogs. Dextrose-free fluids produce a significantly more favorable outcome. Our general working hypothesis is: Metabolic substrate (i.e. glucose and ketones) availability and utilization alters tissue reaction to ischemia. Corollaries are: Hyperglycemia, prior to or following cardiac arrest, is detrimental to brain electrical, behavioral and biochemical recovery. The exacerbated brain damage in the presence of hyperglycemia is mediated through glycolytic metabolism. Inhibition of glycolytic metabolism by 2- deoxyglucose will protect from CPR-induced hyperglycemic- ischemic damage. Increasing the availability of ketones, as an alternate metabolic substrate, by infusion of lipid emulsions or 1, 3-butanediol, will reduce ischemic brain damage. Controlled cardiac arrest and resuscitation will model global cerebral ischemia and test this hypothesis by evaluating neurologic performance, biochemical indices of tissue damage, EEG, cerebrospinal fluid pressure, and histologic integrity in response to four specific conditions: (1) when mild hyperglycemia (300-350 mg/dL) is induced, (2) when hyperglycemia is induced in the presence of 2-deoxyglucose, (3) when ketosis is induced by lipid emulsions or (4) by 1, 3-butanediol. Deoxyglucose blocks glycolysis while maintaining the hyperglycemia and should inhibit excess brain lactate build up, reduce tissue enzyme loss, protect tissue from damage, and help separate possible osmotic from metabolic mechanisms of damage. Lipid emulsions and ketosis provide alternate metabolic substrates and should likewise minimize lactate build up and protect. Pre-arrest (prophylactic therapy) and postarrest (CPR) testing is planned. Arterial blood pressure, and arterial pO2, pCO2, pH, hematocrit, glucose, osmolarity, lactate, 1, 3-butanediol, and ketones will be measured at to define physiological status. We have consistent outcomes with better than 95% resuscitation rate and are thus confident that controlled CPR in the dog is a useful and clinically relevant model. The project addresses the specific metabolic needs of the ischemic brain that have not been previously evaluated. The long- term objective is to improve patients' neurologic outcome following cerebral ischemic insults.
| Natale, J E; Stante, S M; D'Alecy, L G (1990) Elevated brain lactate accumulation and increased neurologic deficit are associated with modest hyperglycemia in global brain ischemia. Resuscitation 19:271-89 |
| Natale, J A; D'Alecy, L G (1989) Protection from cerebral ischemia by brain cooling without reduced lactate accumulation in dogs. Stroke 20:770-7 |
