Experimental validation of approaches to pancuronium bromide use for correction of myasthenic syndrome in anticholinesterase poisoning

Introduction. The problem of intermediate syndrome following anticholinesterase poisoning remains poorly studied. This syndrome is clinically manifested as a myasthenic condition developing after the cholinergic crisis, affecting the muscles of the face, neck, proximal limbs, and respiratory muscles. The current literature describes limited attempts to use non-depolarizing muscle relaxants for the prevention and treatment of this condition. However, given the diversity of mechanisms underlying toxic myasthenia in anticholinesterase poisoning and the low safety profile of non-depolarizing muscle relaxants, research into the effective and toxic doses of these drugs is highly relevant for establishing the principles of their use in correcting neuromuscular transmission disorders.

Objective. To experimentally evaluate the efficacy of pancuronium bromide, a non-depolarizing muscle relaxant, in correcting neuromuscular transmission impairments in cases of anticholinesterase poisoning.

Materials and methods. Experimental, two-stage studies were conducted using male outbred white rats weighing 220–250 g (n = 78). Initially, pancuronium bromide was administered subcutaneously to intact animals to determine effective doses. The severity and duration of the muscle relaxant effect were assessed using clinical and functional tests (hanging on a horizontal bar, assessment of movement impairments according to the De Bleecker scale), and electromyography (single and rhythmic stimulation at 30 Hz). Subsequently, therapeutic doses of the drug were determined in a rat model of fenthion poisoning (12 h after its single subcutaneous administration at an LD₅₀ dose of 479.4 mg/kg) based on data from the aforementioned methods and evaluation of changes in animal mortality rates. Statistical analysis of the results was performed using non-parametric statistical methods in the Prism GraphPad 9.0 software environment.

Results. Based on the assessment of neurological status and electromyography results, the median effective dose (ED₅₀) of pancuronium upon subcutaneous administration in intact rats was found to be 238.0 [95% CI: 219.8; 257.7] μg/kg. In contrast, against the background of severe fenthion poisoning, its therapeutic dose was statistically significantly lower (p < 0.05, Student’s t-test), amounting to 90.1 [95% CI: 77.3; 105.1] μg/kg. Similar trends were observed for the median lethal doses (LD₅₀) of pancuronium bromide: 321.1 [95% CI: 305.8; 337.1] μg/kg and 152.3 [130.6; 177.6] μg/kg, respectively. Administration of pancuronium at the median therapeutic dose reduced the severity of the myasthenic syndrome induced by fenthion poisoning, manifesting as restored muscle strength and normalized electrophysiological characteristics of neuromuscular transmission.

Conclusions. The experiment demonstrated that pancuronium bromide can be used to correct neuromuscular transmission disorders underlying the intermediate syndrome emerging as a result of anticholinesterase poisoning. The effective dose for this correction is 90.1 μg/kg, which is 2.6-fold lower than the effective dose for healthy animals (238.0 μg/kg). The main electrophysiological criteria for the regression of the neuromuscular block should include a reduction in the number of repeated M-responses and the restoration of the decrement-increment pattern of the M-response series, which persist for 1 h after pancuronium bromide administration.

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