Cyanide and Methemoglobinemia

1. Cyanide and Methemoglobinemia Presented by: Dr. Aric Storck Preceptor: Dr. Ingrid Vicas Core Rounds February 20, 2003

2. Cyanide

3. Cyanide • Anion (CN-) • solid and gaseous forms • Important component of many industrial reactions • mining - recover silver and gold from ores • photographic - recovery of silver • plastic manufacturing • Naturally occurs in many plant products • Tobacco, apricot pits

4. Cyanide pollution • 1997 - 4,513,410 cyanide released by top 100 polluters in USA • Bhopal, 1984 • worst industrial poisoning in history • 25,000 kg methyl isocyanate and combustion products released into atmosphere • 1,800 - 5,000 deaths • 200,000 injuries

5. Man carries his wife past the Union Carbide factory in Bhopal, India. Fumes from the factory killed her the previous day Source: Greenpeace

6. Skulls from victims of the Union Carbide disaster in the Hamidia Hospital in Bhopal, India. Source: Greenpeace

7. Cyanide … a potential disaster • 500,000 hazardous materials shipments / day in the USA • Average 12,115 hazardous material accidents per year (1990-1996) • Large potential for significant industrial accident involving cyanide

8. Cyanide and terrorism • 1984 - 7 Chicago area residents killed after ingesting cyanide-laced Tylenol • Cyanide gas precursors (cyanide salt + acid) found in Tokyo subway bathrooms following sarin gas attacks • Cyanide believed to be involved in World Trade Center bombing (incinerated in attack)

9. Cyanide and Fires • Cyanide is a combustion product of • plastic • rugs • silks • furniture • construction materials

10. Cyanide and Fires • Significant correlation between CO levels and CN- levels in fire victims • estimated 35% of fire victims have toxic levels of cyanide Source: Sauer S, Keim M. Hydroxocobalamin: Improved public health readiness for cyanide disasters. Ann Emerg Med. June 2001; 37:635-641.

11. Cyanide - Pathophysiology • CN- has high affinity for metals • Complexes with metallic cations at catalytic sites of several enzymes • Binds ferric (3+) iron of mitochondrial cytochrome oxidase (cytochrome a-a3) • cytochrome a-a3 – mediates transfer of electrons to molecular oxygen (final step in oxidative phosphorylation)

12. Oxidative Phosphorylation Source: Ford’s Clinical Toxicology

13. Blockade of oxidative phosphorylation • Tissue anoxia • Anaerobic metabolism • Lactic acidosis

14. Cyanide - Pathophysiology • Other metabolic effects • Less relevant (...because you die of anoxia first) • Interferes with lipid metabolism • Interferes with glycogen metabolism

15. Cyanide - Poisoning • Rapid absorption • Respiratory tract • Mucous membranes • Slow absorption • Skin • GI tract

16. Cyanide Poisoning - Inhalation • Hydrogen cyanide • Combustion of nitrogen containing polymers (vinyl, polyurethane, silk) • Immediate onset of symptoms • 50 ppm • Symptoms after several hours • Anxiety, SOB, palpitations, headache • 100 ppm • Death after 30 minutes • 270 ppm • Immediate coma, asystole, death

17. Cyanide – Ingested Salts • Symptoms within minutes • Caustic – oral burns • Smell of bitter almonds • 50 mg – has been reported to cause death • LD50 – 140-250 mg (untreated adult)

18. Ingestion – Cyanide producing compounds • Compounds require metabolic activation to produce cyanide • Organic nitriles • Cyanogenic glycosides • eg: amygdalin – found in bitter almonds, apricot pits • Hydrolyzed to CN in small bowel • Not toxic if taken intravenously • Acetonitrile (solvent in artificial nail remover) • Oxidized by hepatic enzymes • Delayed onset of symptoms (up to 24 hours)

19. Cyanide - Dermal Exposure • LD50 = 100 mg/kg

20. Cyanide & Nitroprusside • Deterioration in aqueous solutions releases cyanide • Hydroxycobalamin and thiosulfate co-infusions used in critical care settings

21. Chronic Cyanide Poisoning • Clinical relevance controversial • Cassava – contains linamarin (cyanogenic) • Common food in many countries • Some evidence that B12 deficiency, goiter, demyelinating diseases may be related

22. Cyanide - Detoxification • Naturally occurs in small quantities • tobacco • cassava • Small amounts routinely cleared from body

23. Cyanide - Detoxification • Cyanide + thiosulfate = thiocyanate • Enzymatically • Rhodanase • Beta-mercaptopyruvate-cyanide sulfur transferase • Nonenzymatically • Sulfane-albumin complex combines with cyanide

24. Cyanide - Elimination • Thiocyanate • Relatively non-toxic • Renal elimination (half life 2.5 days)

25. Cyanide – Clinical Presentation • Physiologic manifestations of hypoxia • Metabolic acidosis • Bradycardia • Dyspnea • CNS disturbances • Normal pulse oximetry

26. Cyanide – Clinical Presentation • CNS • Headaches • Drowsiness • Dizziness • Seizures • Coma

27. Cyanide – Clinical Presentation • Pulmonary • Dyspnea • Tachypnea • Apnea

28. Cyanide Poisoning - DDX • Ingestion with altered LOC and acidosis • sodium azide • salicylates • iron • Beta-adrenergic antagonists • cocaine • isoniazid • toxic alcohols

29. Cyanide Poisoning - DDX • Inhalational Exposures • hydrogen sulfide • carbon monoxide • simple asphyxiants

30. Cyanide – Clinical Presentation • Cardiovascular Effects • Hypertension • Tachycardia • Hypotension • Bradycardia • Asystole • Cardiac collapse

31. Laboratory Investigation • Electrolytes • Elevated anion gap (lactic acidosis) • ABG • Metabolic acidosis (lactic acidosis) • Normal PO2 • SaO2 • Normal

32. Laboratory Investigation • AVO2 • Decreased (decreased tissue oxygen utilization) • Cyanide levels • Not rapid enough for clinical utility • Serum cyanide level • Toxic = >0.5mg/L • Fatal = >3.0 mg/L • Erythrocyte cyanide level • Normal = <1.9 uM/L (50ug/L) • Fatal = > 40 uM/L (1mg/L)

33. Laboratory Investigation • Serum lactate – elevated • ECG • Sinus bradycardia • Sinus tachycardia

34. Cyanide Poisoning - Sequellae • Directly related to severity of exposure and delay in treatment • long term sequellae are those of hypoxia • cerebral hypoxia / encephalopathy (common)

35. Cyanide - Treatment • Monitors • IV access • Administer 100% O2 • Gastric lavage • Indicated in very recent ingestion • Activated charcoal (1g/kg)

36. Cyanide Antidote Kit Manufacturer: Taylor Pharmaceuticals Cost: $317 USD

37. Cyanide Antidote Kit • Contents • Amyl nitrite 0.3 ml x 12 • Inhaled while IV access established • Not necessary if immediate IV access • Can be given in pre-hospital setting • Sodium nitrite 300mg/10cc x 2 • Sodium thiosulfate 12.5g/50cc x2 • syringes, needles, tourniquet, stomach tube, instructions

38. Cyanide Antidote Kit • Instructions • Crush and inhale one ampoule (0.3ml) of amyl nitrite q15-30 seconds until iv access achieved • Rapid infusion sodium nitrite 300mg • Infuse sodium thiosulfate 12.5g over 10 minutes • Repeat sodium nitrite and thiosulfate infusion at half dose prn x 1 • Caution • Sodium nitrite infusion limited by hypotension

39. Cyanide Antidote Kit - Mechanism • Nitrites • Therapeutic induction of methemoglobinemia NO2 + Hb = MHb • Methemoglobin binds strongly to CN- and removes it from tissues CN- + MHB = cyanomethemoglobin • cyanomethemoglobin relatively non-toxic

40. Sodium Thiosulfate • donates sulfur molecule to rhodanese (enzyme which catalyzes formation of thiocyanate) Na2S2O3 + HCN + O = HSCN • Synergistic effect • Oxygen • Synergy of 100% O2 with nitrites/thiosulfate

41. CAK - Children • 0.33 mL/kg of 3% NaNO2 • Adjust dose if anemic • Hb 70 – 0.19mL/kg • Hb 100 – 0.27mL/kg • Hb 120 – 0.33mL/kg • Hb 140 – 0.39mL/kg • 1.65 mL/kg of 25% Na2S2O3

42. Cyanide Antidote Kit • Effectiveness • able to detoxify 20 lethal ingested doses in dogs • effective even after respiratory arrest as long as no cardiac arrest • Complications • Hypotension • Related to vasodilatory effects of nitrites • Methemoglobinemia • Death reported in asymptomatic cyanide poisonings (NB: only use CAK if symptomatic poisoning)

43. Cyanide Antidote Kit • Limitations • MHb production prevents its use in unconfirmed cases • not practical for smoke inhalation victims (bad idea to induce MHb when already high level of carboxyhemoglobin) • many hospitals poorly supplied • 81% of Tennessee hospitals unable to treat two 70 kg patients

44. Cyanide – other antidotes • Hyperbaric Oxygen • No therapeutic effect • Useful if concomitant CO inhalation • Dicobalt edetate • Widely used in UK • Effective antidote with significant toxicity (esp. when cyanide not present)

45. DMAP (4-dimethylaminophenol) • Produces very rapid methemoglobinemia • Used widely in Germany • No more effective than sodium nitrite • Less hypotension than sodium nitrite • Linked with renal failure in animal models

46. Hydroxycobalamin (vitamin B12a) • Widely used in France • Very effective and non-toxic • precursor of B12 (cyanocobalamin) • ideal choice for vegan victims of cyanide poisoning • Recognized by FDA for cyanide poisoning • Used in ICU settings to mitigate nitroprusside toxicity

47. Reduces cyanide to cyanocobalamin B12a + CN- = B12 • 5g B12a will treat patients with up to 40 umol/L • Low concentrations available in US mean very large quantities required

48. Hydroxycobalamin (vitamin B12a) • When combined with sodium thiosulfate end product is thiocyanate Na2S2O3 + B12 = HSCN + B12a • Recycling of hydroxycobalamin • Renally cleared • Synergistic effect of thiosulfate and B12a

49. Hydroxycobalamin (vitamin B12a) • Advantages vs CAK • less toxic • does not produce MHb (thus appropriate for smoke inhalation victims) • may be administered out of hospital • cheaper

50. Hydroxycobalamin (vitamin B12a) • Available in Europe as Cyanokit • 2.5 and 5.0 g doses • very concentrated (5g/100 ml) • in USA hydroxycobalamin available in 1mg/mL (5L infusion required for 5g dose) • No pharmaceutical company willing to sponsor FDA approval and development in North America