Burned patients have an aberrant response to neuromuscular (NM) blocking drugs. They develop hyperkalemia and cardiac arrest with the administration of depolarizing relaxant, succinylcholine (SCh), while recent studies indicate that they have a three-to-five fold increase in the dose and plasma concentration requirement for non-depolarizing muscle relaxants such as d-tubocurarine (dTC). Such hyposensitivity to the effects of an NM relaxant has not been observed in any other pathological state. The etiology of the altered response is unknown. We believe that altered pharmacokinetics and/or physicochemical changes such as an increase in acetycholine receptors (AChR) or depressed function of acaetycholinesterase enzyme (AChE) at the NM junction cause the altered response to NM blockers. In this proposal, we have both a clinical and a scientific objective. The clinical aim is to characterize the pharmacokinetic and pharmacodynamic response of burned patients to non-depolarizing NM blocking drugs presently in clinical use. The scientific aim is to study the etiology of the altered response in both humans and in guinea pigs. In the burned patients and in guinea pigs by correlating AChE activity to pharmacodynamics (dose, recovery time, etc.) we will test the hypothesis that depressed AChE activity due to inanition or circulating toxins results in decreased breakdown and increased levels of acetycholine (ACh) at the NM junction and causes the altered pharmacodynamics. To confirm the above hypothesis, in the nonburned guinea pigs we will attempt to simulate these altered responses to NM blockers by chronic pharmacologic inhibition of AChE with neostigmine. In the guinea pig burn model, using 125I Alpha-bungarotoxin, a specific binder to muscle AChR, we will test the other hypothesis that the altered NM responses are due to burn induced formation of new AChR outside the NM junction (extra-junctional receptors). By repeated injections of Beta-receptor agonist isoproterenol to nonburned guinea pigs and observing changes in AChR number, we will verify that the changes at the NM junction following burns are brought about by the continuous sympathetic overactivity of burn trauma. The clinical studies will result in improved and effective use of the NM relaxants in burned patients. Study of the etiology of the response will characterize some of the physico-chemical changes at the NM junction and may provide some insight into the etiology of peripheral neuropathies and muscular complications accompanying severe burn injury. Thus, in the long term, this study may provide a rational basis pharmacologic manipulation to prevent these complications.
