EM@3AM: Cyanide Toxicity

Author: Rachel Bridwell, MD (@rebridwell, EM Chief Resident Physician, SAUSHEC / San Antonio, TX); Amber Cibrario, DO (@amcibrario, EM Staff Attending Physician, San Antonio, TX) // Reviewed by: Brit Long, MD (@long_brit, EM Attending Physician, San Antonio, TX) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Welcome to EM@3AM, an emDOCs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.


A 13-year-old male is brought in by EMS for altered mental status after being found in a house fire. The fire department found burned couches in the house with melted plastic covering. The patient has been mildly responsive en route with noisy breathing. His vital signs include BP 78/40, HR 155, T 99.9 Oral, RR 40, SpO2 92% on 15L NRB. He is somnolent but withdraws to pain. He has soot in his nares with carbonaceous sputum, and auscultation reveals rhonchorous and wheezing breath sounds bilaterally. Point of care VBG demonstrates a lactate of 16.

What’s the next step in your evaluation and treatment?


Answer: Cyanide Toxicity1-21

 

Epidemiology:

  • Most common sources of cyanide1
    • CN salts
      • NaCN– gold mining
      • KCN—Jewelry cleaner/buffer
    • HCN
      • Nylon, plastic, and fumigant manufacturing
    • Acetonitrile
      • Rubber, pesticide, battery manufacturing
    • Nitroprusside
    • Fruit pits or improperly prepared cassava—cyanogenic glycosides
    • Agroterrorism
  • Of these etiologies, structural fire exposure is most common
    • 35% of fire victims will present with CN toxicity2
  • Based on national poison control reports, approximately 250 cases of chemical CN toxicity are reported annually, with 5 fatalities in 20073
  • Historical: used as a component of Zyklon B by Nazis in extermination camps and was the lethal ingredient in koolaid mix at Jonestown in Guyana Esequiba
    • This mass suicide in Jim Jones’ Peoples Temple is the etymology of the phrase “Don’t drink the koolaid”

 

Mechanism of Action:

  • Inhibition of Cyotchrome oxidase a3 of complex IV by binding to iron in the complex—hard stop ATP production and entirely anaerobic metabolism despite available oxygen1

 

Clinical Presentation:

  • Early—Oral mucosal membrane irritation if ingested -> sympathetic activation causing anxiety, tachycardia, tachypnea, hypertension, headache, confusion, dyspnea, hypotension and bradycardia4
  • Late—Neuro symptoms to include decreased level of consciousness, seizures, trismus, opisthotonos, pulmonary edema, and cardiac arrest5
  • Chronic—(long term exposures with sub-lethal concentrations) nonspecific symptoms of headaches, weakness, pruritic rash, chest and abdominal pain6
  • Bitter almond smell is classically associated with cyanide gaseous odor, though sensitivity of 18% in men and 4% in women7

 

Evaluation:

  • ABCs
    • In setting of a house fire, assess for imminent airway, breathing, circulatory, or trauma
    • Profound hypotension
  • Early oxygen administration—100%
    • Addresses potential concomitant CO toxicity
    • Hypothesized mechanism is cyanide’s redistribution from intravascular compartment to intracellular8
    • Oxygen enhanced effects of sodium nitrite and sodium thiosulfate9
  • Perform a complete physical examination.
    • Cardiovascular: tachycardia, dysrhythmia
    • Pulm: rales from pulmonary edema
    • Neuro: seizures, decreased LOC, coma
    • Integumentary: cherry red skin (very late and not often present), cyanosis
  • Laboratory evaluation:
    • CBC, BMP, VBG with lactate, liver function
      • Anion gap metabolic acidosis (AGMA)
      • Severely elevated lactate
        • >8mmol/L 94% sensitive for cyanide toxicity10
      • ASA, salicylates in setting of coingestion and AGMA
      • Cyanide level is usually a send out and should not delay treatment
      • ECG to assess for dysrhythmia
    • Imaging: As dictated by history and exam

 

Treatment:

  • Antidote options:
    • Amyl nitrate+sodium thiosulfate+sodium nitrite (Cyanide Antidote Kit)
      • Amyl nitrite—crush pearls and place near nares with inhalation for every 30-60 seconds for 30-60 seconds over 5 minutes.
        • Generates unpredictable levels of methemoglobinemia11
      • Sodium thiosulfate—50 mL (12.5 g) IV over 10-30 minutes (1-1.65 mL/kg for pediatrics)12
        • Thiosulfate binds cyanomethemoglobin to create thiocyanate via rhodanese which is excreted renally11
        • Slower onset of action with poor mitochondrial penetration and short half life12
        • Adverse effects: methemoglobinemia, hypotension11,12
      • Sodium nitrite—10 mL (300 mg) (0.2 mL/kg or 6 mg/kg for pediatrics) over 2-4 minutes13
        • Induces methemoglobinemia due to cyanide’s stronger affinity for ferric iron over cytochrome oxidase1
        • Adverse effects: potent vasodilation due to nitric oxide11
      • Goal to create methemoglobinemia
        • Sick patients do not need an additional hemoglobinopathy
      • Sodium thiosulfate alone IM works well in porcine model14
    • Hydroxocobalamin (Cyanokit)
      • 5g IV over 15 min (70 mg/kg for pediatrics with max of 5g)15
      • Generally preferred antidote since FDA approval with faster onset, better tolerated side effects16,17
      • Cyanide has a higher affinity for Cobalt than cytochrome oxidase a3, forms Vitamin B12—renal excretion16
      • Hypertension from nitric oxide scavenging may help hypotension from cyanide toxicity5
      • Can be used in conjunction with sodium thiosulfate or sodium nitrite
      • Adverse reactions: rare anaphylactoid reaction, draw labs prior since colorimetric changes may alter lab results for up to 28 days and hemodialysis, acute renal injury15,18,19

  • Selecting an antidote
    • IV hydroxocobalamin had a faster return to baseline MAP in porcine models vs sodium nitrite and sodium thiosulfate20
    • IV hydroxocobalamin + sodium thiosulfate didn’t improve mortality over hydroxocobalamin alone21
    • Sodium thiosulfate alone did not reverse hemodynamics secondary to cyanide and was uniformly fatal21
    • Check out this excellent post for more information: http://www.emdocs.net/toxcard-cyanide-toxicity-and-treatment/

 

Disposition:

  • Consult medical toxicologist and local poison control center
  • Check co-oximetry
  • ICU admission for serious signs and symptoms of methanol ingestion
  • Burn ICU if concomitant burn

 

Pearls:

  • In the setting of a house fire, lactate above 8mmol/L should trigger consideration of CN toxicity
  • Anticipate seizures and cardiovascular collapse in cyanide toxicity
  • Ifn using sodium thiosulfate+sodium nitrite, anticipate hypotension and intentional hemoglobinopathy
  • Acquire baseline labs before administering hydroxocobalamin as it distorts colorimetry, affecting labs and hemodialysis

A 45-year-old man presents to the emergency department after being rescued from a house fire. The patient is unresponsive on arrival and intubated for airway protection. Vital signs are remarkable for oxygen saturation of 87%, HR 55, RR 38, and BP 85/55. On physical examination the patient has partial and full thickness burns noted on 30% of his body that spare the patient’s mouth and face. No soot or singed nostril hairs noted on examination. Initial lab work is remarkable for Na 138 mEq/L, K 4.5 mEq/L, Cl 98 mEq/L, HCO3 15 mEq/L, and lactate 12 mmol/L. What is the most likely cause of his acidosis?

A) Carbon monoxide poisoning

B) Cyanide toxicity

C) Inhalation injury

D) Methemoglobinemia

 

 

 

Answer: B

Cyanide is a metabolic toxin that causes uncoupling of the electron transport chain and, as a result, anaerobic metabolism occurs. This results in the clinical features seen on presentation as well as a severe metabolic acidosis and lactic acidosis. Exposure to cyanide most commonly occurs as a result of fires that involve plastics, wools, and synthetic materials. Cyanide can also be associated with vermicidals, chemical laboratories, precious metals, and prunus seeds. Initially the cardiovascular and nervous systems are affected. A lactic acidosis subsequently develops, causing perceived dyspnea and ultimately coma, cardiovascular collapse, and death. Clinical features at presentation are usually unexplained confusion, tachypnea, hypotension, and a bradycardia with an unexplainable lactic acidosis. Serum cyanide levels are not readily available, therefore, cyanide toxicity needs to be diagnosed clinically as delays in treatment can result in significant comorbidities and death. The patient’s ABCs require attention and supportive measures which include securing the patient’s airway as needed and giving intravenous fluids and vasopressors if indicated. However, the treatment of cyanide toxicity relies on administering an antidote. Historically cyanide toxicity has been treated with sodium nitrite and sodium thiosulfate. This induces a methemoglobinemia which removes cyanide from cytochrome and increases cyanide’s metabolism to a less toxic metabolite. The new treatment involves administering hydroxocobalamin intravenously and can be repeated every 15 minutes as clinically indicated. There may be additional benefit if given with sodium thiosulfate but these must be run through separate IV lines.

Carbon monoxide poisoning (A) is formed due to incomplete combustion of carbonaceous fuels. It is a colorless, odorless, non-irritating gas that has a higher affinity for hemoglobin than oxygen. Due to this property it displaces oxygen from hemoglobin resulting in tissue hypoxia and neurological damage. Patients presenting with neurological complaints, even a mild headache, with a history of gas heat or smoke inhalation should raise suspicion of carbon monoxide exposure. Clinical features are highly variable and are caused by the hypoxic effects on the neurologic and cardiovascular systems. Some clinical features include headache, visual disturbances, confusion, altered mental status, syncope, ataxia, ECG changes, chest pain, seizure, dyspnea, focal neurological findings, or vomiting. Patients may have the classic “cherry-colored lips” and will have a normal oxygen saturation measured by pulse oximetry. Treatment for carbon monoxide poisoning is focused on supplemental oxygen. Patients should be placed on high-concentration supplemental oxygen via nonrebreather or other face mask device with reservoir. Hyperbaric oxygen therapies are indicated if carboxyhemoglobin levels are greater than 25% in all patients: coma, syncope, those with neurologic symptoms, or hemodynamic compromise. All patients presenting from a house fire should raise a suspicion for an inhalation injury (C) and a thorough examination should evaluate for this as airway compromise can occur quickly even when patients present appearing well and in no respiratory distress. Clinical features for inhalation injury include posterior pharynx edema or erythema, uvula edema or erythema, singed nostril hairs, soot in the posterior pharynx, hoarse or raspy voice, or wheezing on exam. Unless a patient has a concomitant inhalation injury, patients with cyanide toxicity should not demonstrate the physical exam findings noted above. Establishing a definitive airway is critical in the treatment of inhalation injuries. Patients with methemoglobinemia (D) will typically present to the ED with complaints of cyanosis. Children are most commonly affected, especially less than 4 months of age, as they lack a key enzyme that is required for conversion of methemoglobinemia. Three of the most common presenting scenarios are a child with an acute febrile illness (especially with diarrhea and dehydration), exposure to benzocaine (commonly in teething gels), and exposure to nitrate in water from agricultural runoff. Clinical features occur in proportion to declining oxygen delivery. Headache, nausea, and fatigue occur at levels around 20%–30%. Dyspnea, angina, and dysrhythmias can occur, especially in patients with coronary artery disease. Loss of consciousness and metabolic acidosis can occur at levels around 50%, and levels above 70% can be lethal. Regardless of the methemoglobin level, lactic acidosis is rare and should prompt consideration of other diagnoses. Treatment initially is with close monitoring and supplemental oxygen. Classically, patients supplemented with oxygen will continue to have oxygen saturations in the upper 80s but their pO2 measured on blood gases will be significantly elevated. This is in contrast to cyanide toxicity where supplemental oxygen will improve oxygen saturation but the patient’s presentation will remain dire. Methemoglobinemia of greater than 25% and those with symptoms require methylene blue for treatment.

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Further Reading:

Further FOAMed:

  1. http://www.emdocs.net/toxcard-cyanide-toxicity-and-treatment/
  2. https://coreem.net/tag/cyanide/
  3. https://foamcast.org/tag/cyanide-toxicity/
  4. http://emcrit.org/podcasts/cardiac-arrest-after-smoke-inhalation/

 

References:

  1. Holstege CP, Kirk MA. Cyanide and Hydrogen Sulfide. In: Goldfrank’s Toxicologic Emergencies. 11th ed. New York: McGraw Hill; 2019. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210264536. Accessed June 29, 2020.
  2. Hamad E, Babu K, Bebarta VS. Case Files of the University of Massachusetts Toxicology Fellowship: Does This Smoke Inhalation Victim Require Treatment with Cyanide Antidote? J Med Toxicol. 2016;12(2):192-198. doi:10.1007/s13181-016-0533-0
  3. Giebułtowicz J, Rużycka M, Wroczyński P, Purser DA, Stec AA. Analysis of fire deaths in Poland and influence of smoke toxicity. Forensic Sci Int. 2017;277:77-87. doi:10.1016/j.forsciint.2017.05.018
  4. DesLauriers CA, Burda AM, Wahl M. Hydroxocobalamin as a cyanide antidote. Am J Ther. 2006;13(2):161-165. doi:10.1097/01.mjt.0000174349.89671.8c
  5. Reade MC, Davies SR, Morley PT, Dennett J, Jacobs IC. Review article: Management of cyanide poisoning. Emerg Med Australas. 2012;24(3):225-238. doi:10.1111/j.1742-6723.2012.01538.x
  6. SANDBERG CG. A Case of Chronic Poisoning with Potassium Cyanide? Acta Med Scand. 1967;181(2):233-236. doi:10.1111/j.0954-6820.1967.tb07252.x
  7. Kirk RL, Stenhouse NS. Ability to smell solutions of potassium cyanide. Nature. 1953;171(4355):698-699. doi:10.1038/171698b0
  8. Lawson-Smith P, Jansen EC, Hilsted L, Johnsen AH, Hyldegaard O. Effect of Acute and Delayed Hyperbaric Oxygen Therapy on Cyanide Whole Blood Levels During Acute Cyanide Intoxication – PubMed. Undersea Hyperb Med. 2011;38(1):17-26. https://pubmed.ncbi.nlm.nih.gov/21384760/. Accessed June 29, 2020.
  9. Way JL, End E, Sheehy MH, et al. Effect of oxygen on cyanide intoxication IV. Hyperbaric oxygen. Toxicol Appl Pharmacol. 1972;22(3):415-421. doi:10.1016/0041-008X(72)90247-5
  10. Baud FJ, Borron SW, Mégarbane B, et al. Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning. Crit Care Med. 2002;30(9):2044-2050. doi:10.1097/00003246-200209000-00015
  11. Marrs TC. Antidotal Treatment of Acute Cyanide Poisoning. Advers Drug React Acute Poisoning Rev. 1988;7(4):179-206. https://pubmed.ncbi.nlm.nih.gov/3071112/. Accessed June 29, 2020.
  12. FDA, CDER. Sodium Thiosulfate. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203923s000lbl.pdf. Published 2012. Accessed June 29, 2020.
  13. FDA, CDER. Sodium Nitrite. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203922s000lbl.pdf. Published 2012. Accessed June 29, 2020.
  14. Bebarta VS, Brittain M, Chan A, et al. Sodium Nitrite and Sodium Thiosulfate Are Effective Against Acute Cyanide Poisoning When Administered by Intramuscular Injection. Ann Emerg Med. 2017;69(6):718-725.e4. doi:10.1016/j.annemergmed.2016.09.034
  15. FDA. CYANOKIT® (Hydroxocobalamin for Injection) for Intravenous Infusion.
  16. Anseeuw K, Delvau N, Burillo-Putze G, et al. Antidotes for cyanide poisoning. Eur J Emerg Med. 2013;20(1):66-67. doi:10.1097/MEJ.0b013e32835a6d31
  17. Meilier A, Heller C. Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments With Two Outcomes Following One Exposure Event – PubMed. Case Rep Med. October 2015. https://pubmed.ncbi.nlm.nih.gov/26543483/. Accessed June 29, 2020.
  18. Lim K, Heher E, Steele D, et al. Hemodialysis Failure Secondary to Hydroxocobalamin Exposure. Baylor Univ Med Cent Proc. 2017;30(2):167-168. doi:10.1080/08998280.2017.11929569
  19. Dépret F, Hoffmann C, Daoud L, et al. Association between hydroxocobalamin administration and acute kidney injury after smoke inhalation: A multicenter retrospective study. Crit Care. 2019;23(1):421. doi:10.1186/s13054-019-2706-0
  20. Bebarta VS, Tanen DA, Lairet J, Dixon PS, Valtier S, Bush A. Hydroxocobalamin and Sodium Thiosulfate Versus Sodium Nitrite and Sodium Thiosulfate in the Treatment of Acute Cyanide Toxicity in a Swine (Sus scrofa) Model. Ann Emerg Med. 2010;55(4):345-351. doi:10.1016/j.annemergmed.2009.09.020
  21. Bebarta VS, Pitotti RL, Dixon P, Lairet JR, Bush A, Tanen DA. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2012;59(6):532-539. doi:10.1016/j.annemergmed.2012.01.022

 

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