Cyanide: Underappreciated risks, novel diagnostic approaches, therapeutic alternatives

1. Stephen W. Borron, MD, MS South Texas Poison Center University of Texas Health Science Center at San Antonio San Antonio, Texas, USA Cyanide: Underappreciated risks, novel diagnostic approaches, therapeutic alternatives

2. Cyanide continues to be considered a rare poisoning, in spite of growing evidence to the contrary This talk will review some underappreciated sources of cyanide poisoning, ways of detecting cyanide, and provide an update on antidotal therapy through a review of recent literature Background

3. Cyanide in Terrorism

4. Terrorism involving cyanide is a significant risk • Availability • 1.84 billion of HCN produced worldwide each year • Incidents of concern: • 2002: Ten tons of NaCN stolen in Mexico. Only 1/5 recovered • 2002: Joseph Konopka (“Dr. Chaos”) indicted for possession of chemical weapons including KCN and NaCN in Chicago • 2004: South Korea reports that North Korea had imported 175 tons of NaCN in 2003 Keim, 2005 Keim 2006 Prehosp Disast Med 21(2):s56-s60

5. 2003: In May 2003 a cyanide bomb was found in the possession of white supremacists in Texas 2003: Two letters reportedly containing CN were sent to a New Zealand newspaper 2003: An Algerian terrorist was arrested in London with cyanide and “recipes” for creating chemical weapons 2006: Another arrest in London for “cyanide-laced bomb” 2007: A methamphetamine drug lab bust revealed the presence of a cyanide bomb in California Other recent incidents

6. CYANIDE IN SMOKE

7. The potential for cyanide poisoning from smoke inhalation was identified by Wetherell in 1966 Smoke inhalation continues to be referred to as “carbon monoxide poisoning” even in respected, peer-reviewed literature This misnomer results in ignorance of the risk of cyanide and perhaps under-treatment Cyanide in Smoke

8. Review of coroner’s reports in 178 fire deaths • 146 died at scene, 32 in hospital • Bloods obtained at autopsy and from stored hospital samples • No detail provided regarding sampling delays • Whole blood CN measured in 137/178 cases • COHb obtained in 154/178 cases Yeoh, 2004 Yeoh 2004 Clin Toxicol 42;855-863

9. YEOH, 2004 • All mortal fire victims included • No requirement for closed space fire • 32 deaths (18%) from self-immolation • Authors speculate differences from Baud 1991 on basis of different building materials Yeoh 2004 Clin Toxicol 42;855-863

10. Study by F.J. Baud in Paris with Paris Fire Brigade • 69 victims of smoke inhalation with: • Confined space fire • Soot in the mouth or nose • Altered mental status (LOC, confusion, slowness of ideation) • Blood samples drawn on scene for cyanide and carbon monoxide Borron, 2007

11. Borron, 2007 Borron 2007 Ann Emerg Med 49:794-801

12. Brown, 2007 Brown 2007 J Burn Care Res 28;533-536

13. 76 y/o female found under a bed in a fire Unresponsive, GCS=3, irregular ECG rhythm pH 7.11, pCO2 39, pO2 491, AG 19, Glu 145 COHb 35%  8% after HBO, but still GCS=7 Persistent fluctuation of SBP from 230s to 80s EEG showed status epilepticus w/o motor sz Is this CO poisoning? Brown, 2007 Brown 2007 J Burn Care Res 28;533-536

14. Chou, 2000 Comparison of variables in 150 children with CO poisoning alone versus CO with smoke inhalation Chou 2000 Pediatr Emerg Care 16;151-155

15. Smoke vs. CO: Arterial Blood gases • Myers, 1989 • 114 cases of CO ± smoke inhalation • COHb • 1.3 to 62% Acidotic • 1.9 to 56% Alkalotic • 1 to 58% Normal pH • pH range • 6.8 to 7.9 • Lebby, 1989 • 46 cases of pure CO poisoning • COHb • 10-63.9% • (mean 21.8 ± 10.2%) • pH range • 7.37 to 7.54 • Mean 7.43 ± 0.04 Myers 1989 Crit Care Med 17;139-142 Lebby 1989 Vet Human Toxicol 31;138-140

16. Baud, unpublished review of 142 cases of pure CN poisoning: 26% had seizures Benaissa, published review of 146 cases of pure CO poisoning: 0% had seizures Choi, published review of 188 cases of pure* CO poisoning: 2.1% had seizures CN vs. CO: Seizures * Source of CO not stated, but not from structure fires Baud, 2007 Manuscript in Preparation Benaissa, 2003 Intensive Care Med 29:1372–1375 Choi 1998 J Korean Neurol Assoc 16;500-505

17. An unrecognized source of cyanide? • Baum et al tested vehicles for HCN production for environmental impact • Reports that older vehicles produced HCN orders of magnitude above current • “Severe residential garage” scenario poses potential toxicity risk at today’s emissions levels • Warm vehicles emitted up to 60 mcg/min of HCN Baum 2007 Environ Sci Technol 41;857-862

18. diagnostic methods

19. Non-invasive optical spectroscopy • Rabbits given intravenous NaCN, total dose of 6 mg • Broadband diffuse optical spectroscopy (DOS) used to non-invasively monitor physiological changes • Oxygen saturation ↑ 10%, Oxidized cytox ↓ Lee 2007 Physiol Meas 28;1057-1066

20. Diagnostic imaging • Cyanide tends to cause symmetrical lesions in the globi palladi and putamina. The hippocampal gyri are usually spared. • Lesions in the substantia nigra, subthalamic nucleus and cerebellum are also reported • Associated extrapyramidal signs are common • Hemorrhagic lesions are common (generally more common than in CO poisoning) • MRI is generally superior to CT • Lesions may be reversible Hantson 2006 Toxicol Rev 25;87-98

21. Therapeutic options

22. So Easy, Even a kid Can do it • KCN ordered on the internet, given to a ‘friend’ vying for a girl’s affection • Patient apneic, GCS=3, hypotensive, zero A-V 02 sat difference, lactate 20 mmol/l • Received antidote at 4h • Total 1.8 g sodium nitrite • 75g sodium thiosulfate • Continuous infusions of both • Iatrogenic methemoglobinia 35% • Death: organs donated Peddy 2006 Pediatr Crit Care Med

23. Dimethylaminophenol • 39 y/o male with dyspnea, drowsiness, upper respiratory irritation after transporting barrels of MIC • Desaturated to 67% in ED requiring intubation • Report from scene that CN released as well • Given 450 mg DMAP, bicarbonate and sodium thiosulfate for metabolic acidosis with lactate of 1.8 mmol/l • Iatrogenic methemoglobin 86.7% requiring toluidine • Hypotension, hemolysis, MOF ensued, Survived! Kerger 2005 Resuscitation 66;231-235

24. Hydroxocobalamin or thiosulfate? • Hydroxocobalamin • Enters the CNS • Rapidly, irreversibly binds cyanide • Efficacy demonstrated in GLP animal study • Safety demonstrated in clinical trials and healthy volunteer study • Sodium thiosulfate • Limited entry into CNS, mitochondria • Enzyme-dependent for function • No clinical trials • Efficacy in humans based on case reports and mixed animal reviews Uhl 2006 Clin Toxicol 44;17-28 Hall 2007 Ann Emerg Med 49;806-813 Borron 2006 Clin Toxicol 44;1-11

25. Survey of hospitals in British Columbia following recommendations to hospitals in 2003 re: stocking 70-90% of hospitals had “adequate stocking” of cyanide antidotes Adequate stocking for the cyanide antidote kit was 1 kit Primary barrier to obtain antidotes: cost of $10,000 to obtain the minimum list Adequate Antidote stocking? Wiens 2006 Can J Emerg Med 8;409-416

26. Cyanide poisoning continues to be under-recognized, particularly in the setting of smoke inhalation It likewise poses a risk as an agent of suicide, homicide, or terror Diagnosis is often difficult and therapy can be dangerous Stocking of antidotes is insufficient to deal with multiple casualties Summary