title: Reversal of succinylcholine induced apnea with an organophosphate scavenging recombinant butyrylcholinesterase.
abstract: BACKGROUND
  Concerns about the safety of paralytics such as succinylcholine to facilitate endotracheal intubation limit their use in prehospital and emergency department settings. The ability to rapidly reverse paralysis and restore respiratory drive would increase the safety margin of an agent, thus permitting the pursuit of alternative intubation strategies. In particular, patients who carry genetic or acquired deficiency of butyrylcholinesterase, the serum enzyme responsible for succinylcholine hydrolysis, are susceptible to succinylcholine-induced apnea, which manifests as paralysis, lasting hours beyond the normally brief half-life of succinylcholine. We hypothesized that intravenous administration of plant-derived recombinant BChE, which also prevents mortality in nerve agent poisoning, would rapidly reverse the effects of succinylcholine.
  
  
  METHODS
  Recombinant butyrylcholinesterase was produced in transgenic plants and purified. Further analysis involved murine and guinea pig models of succinylcholine toxicity. Animals were treated with lethal and sublethal doses of succinylcholine followed by administration of butyrylcholinesterase or vehicle. In both animal models vital signs and overall survival at specified intervals post succinylcholine administration were assessed.
  
  
  RESULTS
  Purified plant-derived recombinant human butyrylcholinesterase can hydrolyze succinylcholine in vitro. Challenge of mice with an LD100 of succinylcholine followed by BChE administration resulted in complete prevention of respiratory inhibition and concomitant mortality. Furthermore, experiments in symptomatic guinea pigs demonstrated extremely rapid succinylcholine detoxification with complete amelioration of symptoms and no apparent complications.
  
  
  CONCLUSIONS
  Recombinant plant-derived butyrylcholinesterase was capable of counteracting and reversing apnea in two complementary models of lethal succinylcholine toxicity, completely preventing mortality. This study of a protein antidote validates the feasibility of protection and treatment of overdose from succinylcholine as well as other biologically active butyrylcholinesterase substrates.
authors.affiliation: School of Life Sciences and The Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Geyer
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Larrimore
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Kilbourne
authors.forename: Latha
authors.initials: L
authors.lastname: Kannan
authors.forename: Tsafrir S
authors.initials: TS
authors.lastname: Mor
mesh_terms: D000818:Animals; D001049:Apnea / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D002091:Butyrylcholinesterase / Q000008:administration & dosage*; D002384:Catalysis; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D011994:Recombinant Proteins / Q000008:administration & dosage*; D013379:Substrate Specificity; D013390:Succinylcholine / Q000009:adverse effects* / Q000378:metabolism / Q000633:toxicity
chemical_list: D011994:Recombinant Proteins; D002091:Butyrylcholinesterase; D013390:Succinylcholine
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