Victims of thermal injury undergo profound physiologic changes; e.g. increases in basal metabolic rate, cardiac output and glomerular filtration rate. Physiologic responses to thermal injury result in altered requirements for many different types of drugs. One system amenable to study of mechanisms of altered response is the nicotinic acetylcholine receptor of the neuromuscular junction. Burned patients develop resistance to non-depolarizing muscle relaxants (NDMR) such as d- tubocurarine. We have demonstrated that resistance to atracurium (a new short-acting NDMR) develops after 7 days post injury, peaks at 30-50 days, decreases by 90 days, and is proportional to the size of burn. Preliminary work has established that rats with a 30% total body surface area thermal injury show a similar time course of resistance to atracurium as that observed with patients. This proposal is designed to investigate the mechanism of altered response to one specific category of drug - specifically - the resistance to the action of NDMR. We hypothesize that a substance produced in burned tissue is released into the circulation and triggers events which result in the development at the neuromuscular junction of resistance to NDMR. This substance may cause this alteration by several mechanisms. 1) Acetylcholine receptors (AChR) are increased in number or affinity for ACh at neuromuscular junction (NMJ). Conversely AChR may have decreased affinity for antagonist i.e. NDMR. 2) AChR may be increased at extrajunctional sites on skeletal muscle thus binding NDMR and decreasing amount available for binding at the NMJ. 3) Acetylcholinesterase activity at the NMJ is decreased allowing ACh to be increased relative to its competitive antagonist NDMR. 4) Voltage sensitive Na+ channels are increased in skeletal muscle allowing muscle depolarization to result at lower AChR occupancy. 5) Pharmacokinetics are altered in burned patients allowing less drug to reach the NMJ. Mechanisms 1-4 will be investigated utilizing a rat model of thermal injury which bears close resemblance to the resistance to NDMR seen in burned humans. Pharmacokinetic studies will be carried out in burned patients during the course of anesthesia for excision of burn wound. We also plan to establish whether the initiating factor for the alterations come from burned skin tissue and whether it circulates in plasma in two series of experiments in which 1) burn wound is excised at various times after burn injury and 2) exchange blood transfusion with normal rat blood will take place early in the burn injury. Resistance to NDMR will be examined at approximately 30-40 days post burn. In elucidating these mechanisms of resistance to NDMR at the neuromuscular junction, we hope to gain some insight into metabolic adaptations and responses to trauma.
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| Marathe, P H; Dwersteg, J F; Pavlin, E G et al. (1989) Effect of thermal injury on the pharmacokinetics and pharmacodynamics of atracurium in humans. Anesthesiology 70:752-5 |
| Marathe, P H; Haschke, R H; Slattery, J T et al. (1989) Acetylcholine receptor density and acetylcholinesterase activity in skeletal muscle of rats following thermal injury. Anesthesiology 70:654-9 |
