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Mechanisms of respiratory failure produced by neostigmine and diisopropyl fluorophosphate
N W Fleming1, T R Henderson, K L Dretchen
1Department of Anesthesia, Georgetown University School of Medicine, Washington, DC 20007.
Abstract:
Acetylcholinesterase inhibitors produce diverse physiologic effects, but lethal exposure consistently produces respiratory failure due to neuromuscular paralysis or depression of respiratory control centers in the medulla. Simultaneous measurement of gastrocnemius muscle contraction and efferent phrenic nerve activity was used to determine the primary cause of respiratory failure produced by neostigmine and diisopropyl fluorophosphate (DFP) in anesthetized cats. Both neostigmine and DFP abolished phrenic nerve activity prior to producing neuromuscular blockade. Furthermore, neostigmine did not alter brain acetylcholinesterase activity and pretreatment with either atropine methylbromide or atropine increased the dose of neostigmine required to abolish phrenic nerve activity. In contrast, DFP abolished brain cholinesterase activity and only atropine inhibited its respiratory effects. Despite the loss of efferent phrenic nerve activity, there is no evidence of a direct effect of neostigmine on respiratory control centers. Neostigmine may instead alter afferent inputs which modulate respiration to produce a reflex respiratory failure.
Insights
Lethal exposure to acetylcholinesterase inhibitors causes respiratory failure. In cats, both neostigmine and diisopropyl fluorophosphate (DFP) suppressed phrenic nerve activity before causing neuromuscular blockade, indicating a central respiratory control issue.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Acetylcholinesterase inhibitors (AChEIs) are widely used but can cause severe toxicity.
- Lethal AChEI exposure leads to respiratory failure, primarily attributed to neuromuscular paralysis or medullary respiratory center depression.
Purpose of the Study:
- To elucidate the primary mechanism of respiratory failure induced by neostigmine and diisopropyl fluorophosphate (DFP) in anesthetized cats.
- To differentiate between central and peripheral effects on respiration.
Main Methods:
- Simultaneous measurement of gastrocnemius muscle contraction and efferent phrenic nerve activity.
- Administration of neostigmine and DFP to anesthetized cats.
- Assessment of brain acetylcholinesterase activity and effects of atropine pretreatment.
Main Results:
- Both neostigmine and DFP abolished phrenic nerve activity before inducing neuromuscular blockade.
- Neostigmine did not affect brain acetylcholinesterase activity; atropine increased the dose required to abolish phrenic nerve activity.
- DFP inhibited brain cholinesterase activity, and atropine mitigated its respiratory effects.
- No direct effect of neostigmine on respiratory control centers was observed, suggesting reflex respiratory failure.
Conclusions:
- Respiratory failure from neostigmine and DFP in cats is primarily due to the abolition of phrenic nerve activity, indicative of central respiratory depression.
- Neostigmine may induce respiratory failure via altered afferent inputs modulating respiration, rather than direct action on respiratory centers.
- DFP's effects are consistent with widespread cholinesterase inhibition, while neostigmine's mechanism appears more nuanced, potentially involving reflex pathways.