Neuromuscular Weakness and Paralysis Produced by Snakebite Envenoming: Mechanisms and Proposed Standards for Clinical Assessment

Abstract

Respiratory and airway-protective muscle weakness caused by the blockade of neuromuscular transmission is a major cause of early mortality from snakebite envenoming (SBE). Once weakness is manifest, antivenom appears to be of limited effectiveness in improving neuromuscular function. Herein, we review the topic of venom-induced neuromuscular blockade and consider the utility of adopting clinical management methods originally developed for the safe use of neuromuscular blocking agents by anesthesiologists in operating rooms and critical care units. Failure to quantify neuromuscular weakness in SBE is predicted to cause the same significant morbidity that is associated with failure to do so in the context of using a clinical neuromuscular block in surgery and critical care. The quantitative monitoring of a neuromuscular block, and an understanding of its neurophysiological characteristics, enables an objective measurement of weakness that may otherwise be overlooked by traditional clinical examination at the bedside. This is important for the initial assessment and the monitoring of recovery from neurotoxic envenoming. Adopting these methods will also be critical to the conduct of future clinical trials of toxin-inhibiting drugs and antivenoms being tested for the reversal of venom-induced neuromuscular block.

Keywords: ToF; anesthesia; neuromuscular junction; neurotoxin; paralysis; postsynaptic; presynaptic; snakebite; train-of-four; weakness.

Figure 1

Similarities and differences in mechanisms and effects of depolarizing neuromuscular block produced by (A) β-neurotoxins and (B) Succinylcholine. β-toxins and succinylcholine share the postsynaptic effects of depolarization and flaccid paralysis but diverge in that succinylcholine acts exclusively on the postsynapse while snake venom sPLA2 (svPLA2) classified as β-neurotoxins toxins produce effects directly on both the presynapse with postsynaptic sequelae resulting in paralysis and muscle membrane damage oftentimes from non-enzymatic svPLA2s. Postsynaptically, both classes of agents cause hyperactivation of nicotinic receptors (nAChRs), via uncontrolled acetylcholine (Ach) release, indirectly in the case of (A) β-neurotoxins because of uncontrolled release of Ach and directly in the case of (B) succinylcholine by persistent opening of the nAChR. Because activated nAChRs rapidly desensitize, profound but brief paralysis occurs with rapidly metabolized succinylcholine and prolonged weakness with sPLA2 toxins that also damage presynapse membranes. * Very rarely, succinylcholine can case Phase II block related to disease or repeated administration. Disruption of the presynaptic membrane and other inflammatory events may result in arachidonic acid-induced reductions in synaptic vesical regeneration with consequences for repopulation and further reduction in strength of synaptic transmission.

Figure 2

Neuromuscular responses to nerve stimulation with non-depolarizing and depolarizing blocker administration and recovery. Responses to “train-of-four” nerve stimulation are shown as vertical lines. (A) Pattern of evoked muscle responses to twitch stimulation after administration of a non-depolarizing neuromuscular blocking drug (NDNMB), followed by antagonism with neostigmine(▼), hastens the rate of recovery, if the twitch has already started to increase. (B) Pattern of evoked muscle responses to twitch stimulation after administration of succinylcholine. (C) ToF monitoring of onset and recovery from neuromuscular block produced by a NDNMB. Neostigmine can be utilized for reversal of NDNMBs such as naturally occurring curare or synthetics such as pancuronium, vecuronium or rocuronium.