title: Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium.
abstract: BACKGROUND
  Cyanide (CN) toxicity is a serious clinical problem and can occur with sodium nitroprusside (SNP) administration, accidental smoke inhalation, industrial mishaps, and bio-terrorism. In this study, we induced severe CN toxicity independently with SNP or sodium cyanide (NaCN) in a juvenile pig model to demonstrate reversal of severe CN toxicity with a new antidote, sulfanegen sodium, a prodrug of 3-mercaptopyruvate.
  
  
  METHODS
  SNP study: A pilot study in 11 anesthetized, mechanically ventilated juvenile pigs allowed us to determine the dose of SNP to induce CN toxicity. Blood CN, serum lactates, and blood gases were monitored. CN toxicity was defined as the occurrence of severe lactic acidosis accompanied by significant elevation in blood CN levels. Based on this pilot study, 8 anesthetized pigs received a high-dose i.v. infusion of SNP (100 mg/h) for 2 hours to induce CN toxicity. They were then randomized to receive either sulfanegen sodium or placebo. Four pigs received 3 doses of sulfanegen sodium (2.5 g i.v.) every hour after induction of severe CN toxicity, and 4 pigs received placebo. NaCN study: A pilot study was conducted in 4 spontaneously ventilating pigs sedated with propofol plus ketamine to demonstrate hemodynamic and metabolic stability for several hours. After this, 6 pigs were similarly sedated and given NaCN in bolus aliquots to produce CN toxicity ultimately resulting in death. Hemodynamics and metabolic variables were followed to define peak CN toxicity. In another group of 6 pigs, severe CN toxicity was induced by this method, and at peak toxicity, the animals were given sulfanegen sodium (2.5 g i.v.) followed by a repeat dose 60 minutes later in surviving animals.
  
  
  RESULTS
  SNP study: The pilot study demonstrated the occurrence of a significant increase in blood CN levels (P < 0.05) accompanied by severe lactic acidemia (P < 0.05) in all pigs receiving a high dose of SNP. Administration of the sulfanegen antidote resulted in progressive significant reduction in blood lactate and CN levels with 100% survival (P < 0.05), whereas the placebo-treated pigs deteriorated and did not survive (P < 0.05). NaCN study: NaCN injection resulted in CN toxicity accompanied by severe lactic acidosis and mortality in all the pigs. Sulfanegen sodium reversed this toxicity and prevented mortality in all the pigs treated with this antidote.
  
  
  CONCLUSIONS
  CN toxicity can be successfully induced in a juvenile pig model with SNP or NaCN. The prodrug, sulfanegen sodium, is effective in reversing CN toxicity induced by SNP or NaCN.
authors.affiliation: Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota 55455, USA. belan001@umn.edu
authors.forename: Kumar G
authors.initials: KG
authors.lastname: Belani
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh
authors.forename: David S
authors.initials: DS
authors.lastname: Beebe
authors.forename: Preeta
authors.initials: P
authors.lastname: George
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Herbert T
authors.initials: HT
authors.lastname: Nagasawa
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002496:Central Venous Pressure / Q000187:drug effects; D003486:Cyanides / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000097:blood; D009599:Nitroprusside / Q000009:adverse effects; D010865:Pilot Projects; D011355:Prodrugs / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects; D013552:Swine; D014665:Vasodilator Agents / Q000009:adverse effects
chemical_list: C572639:2,5-dihydroxy-1,4-dithiane-2,5-dicarboxylic acid; D003486:Cyanides; D006573:Heterocyclic Compounds, 1-Ring; D011355:Prodrugs; D014665:Vasodilator Agents; D009599:Nitroprusside; D019344:Lactic Acid; C008366:3-mercaptopyruvic acid; D003545:Cysteine