So Long, Cyanide

Cyanokit, Hydroxocobalamin packaged for US in cyanide toxicity.
Hydroxocobalamin packaged for us in cyanide toxicity / Photo Credit: Doc James / CC BY-SA 4.0

Take Home points

  • Cyanide inhibits oxidative phosphorylation, leading to widespread organ dysfunction.
  • Hydroxocobalamin is the preferred FDA-approved antidote for cyanide toxicity.
  • Hydroxocobalamin may interfere with standard laboratory tests and some hemodialysis machines due to its strong red color.
  • Call the Utah Poison Control Center if you suspect a patient has cyanide toxicity at 1-800-222-1222, 24/7.

Cyanide  

The first thing that often comes to mind about cyanide is a tiny capsule that a character in a James Bond film may bite down on to die by suicide and escape being captured by “007” himself. In reality, this thought is not too far from the truth. Cyanide is a substance that has historically been used in warfare as a lethal poison; used in World War I and II, the Iran-Iraq War, as well as a lethal adulteration of Tylenol bottles in the 1980s, cyanide certainly has made itself known as a deadly weapon.1,2,3 
 

However, cyanide is not always used with lethal intent; in fact, many natural substances like almonds and lima beans actually release cyanide. Cyanide can also be found in many pesticides and solutions, as well as products for manufacturing like rubber and plastic.3 Because cyanide is commonly found in rubber and plastic products, when these items burn, they can release the gas formulation of cyanide, resulting in toxic exposure.1,2,3 Structural fires are the most common cause of cyanide toxicity, as cyanide gas is released when products containing cyanide burn.4  

Toxicity

Cyanide exists in inorganic (salts, gases) and organic (nitriles) forms. Cyanide inhibits oxidative phosphorylation through its ability to bind to the enzyme cytochrome oxidase in the electron transport chain.4 When oxidative phosphorylation is inhibited, ATP production halts, and the body shifts from aerobic to anaerobic metabolism.3  

Cyanide toxicity occurs rapidly due to its quick absorption via the respiratory tract, stomach, and skin. Depending on the route of exposure, patients can develop symptoms within seconds to minutes of cyanide exposure. Due to its mechanism of toxicity, early symptoms are typically similar to hypoxia and may include headache, dizziness, and an altered mental status. Patients may also present with tachycardia and tachypnea. Later symptoms may consist of anion gap metabolic acidosis, elevated lactate concentration, hypotension, bradycardia, apnea, seizures, or cardiovascular collapse.3 When evaluating for cyanide toxicity, a lactate above 8-10 mmol/L is typically considered significant and indicative of toxic cyanide concentrations.5 Blood cyanide concentrations are not readily available and are unlikely to guide acute management. 

Hydroxocobalamin

The FDA approved hydroxocobalamin, as the brand product CYANOKIT®, in 2006 for the treatment of known or suspected cyanide poisoning.6  

Other approved uses of hydroxocobalamin include treating vitamin B12 deficiency secondary to conditions like macrocytic anemia, malabsorption, infection, or cancer.7 Off-label uses of hydroxocobalamin include treating hydrogen sulfide poisoning and vasoplegic syndrome.8    

Hydroxocobalamin Pharmacology

Hydroxocobalamin contains a cobalt ion at its center that binds to cyanide in a 1:1 molar relationship to form cyanocobalamin, a form of vitamin B12. This prevents cyanide from binding to cytochrome oxidase, and ATP production remains uninterrupted.6,9

Notably, hydroxocobalamin can also bind to nitric oxide, contributing to vasoconstriction. In cases where cyanide toxicity is present, and a patient may be hypotensive, this aspect of hydroxocobalamin may help improve hemodynamics for the patient.6 This effect is also utilized when using hydroxocobalamin for vasoplegic shock.

Efficacy of Hydroxocobalamin

The efficacy of hydroxocobalamin was primarily established in fire victims. One prospective study evaluated 69 victims of smoke inhalation empirically treated with hydroxocobalamin 5g IV and admitted to an intensive care unit. Of the total number of patients enrolled, 72% survived.  In patients with confirmed cyanide toxicity (n=42), there was a 67% survival rate after treatment with hydroxocobalamin. 10  In a retrospective study from the Paris Fire Brigade, 101 smoke inhalation victims were treated with hydroxocobalamin (CYANOKIT®) IV in a prehospital setting. In patients with a known outcome, the survival rate was 41.7% after the administration of hydroxocobalamin. Of the patients who did not survive (n=42), seventeen died on scene, and the leading cause of death was cardiac arrest.11

Indications, Dosing & Administration

Administer hydroxocobalamin without delay if clinical suspicion of cyanide toxicity is high. Reasonable criteria for an empiric diagnosis of cyanide toxicity include closed space fire victims with 1) altered mental status, 2) soot in mouth/nares (evidence of smoke inhalation), and 3) hypotension in the absence of significant trauma or burns. In the emergency department, a lactate > 8-10 mmol/L provides further evidence of cyanide toxicity in the appropriate setting.

Hydroxocobalamin (CYANOKIT®) is administered via intravenous infusion and is available as a 250mL glass vial with 5g hydroxocobalamin powder for injection.12 Reconstitute with 200mL of normal saline, lactated ringers, or D5W. The diluent is not included in the kit.

Dosing:

     Adult initial dose: 5g IV over 15 minutes 
          Repeat dose: 5g IV over 15 minutes to 2 hours, if necessary 
     Pediatric Dose: 70mg/kg up to 5g IV

Adverse Effects  

Hydroxocobalamin has a wide therapeutic index and is typically well-tolerated.  A unique side effect of hydroxocobalamin is red discoloration of the mucous membranes, serum, and urine, lasting hours to days.6 This can interfere with standard serum and urine laboratory tests by causing artificial increases in parameters like serum creatinine, bilirubin, glucose, liver function tests, hemoglobin, urine pH, urine glucose, urine erythrocytes, and leukocytes; artificial decreases in carboxyhemoglobin percentages; and varying effects on activated partial thromboplastin time (aPTT) and INR values.12 The red discoloration in the serum can also cause a “false blood leak” alarm in specific hemodialysis machines, prohibiting the initiation of hemodialysis.13  

Other side effects associated with hydroxocobalamin include hypertension, headache, rash, and injection site reactions. There are also reports of acute tubular necrosis causing acute renal failure and the presence of urine calcium crystals following the use of hydroxocobalamin. It has no absolute contraindications other than hypersensitivity to any ingredients in the medication.12  

Hydroxocobalamin Shortage

As of November 1, 2024, hydroxocobalamin (CYANOKIT®) is on the American Society of Health-System Pharmacists (ASHP) Drug Shortage List with no anticipated resolution date from the manufacturer.14

Other treatment options for cyanide toxicity include the combination of historical cyanide antidotes, sodium nitrite and sodium thiosulfate. Sodium nitrite oxidizes the iron in hemoglobin to form methemoglobin, which cyanide preferentially binds to over cytochrome oxidase to create cyanomethemoglobin. Sodium thiosulfate acts as a sulfur donor in a reaction that converts cyanide into thiocyanate, a less toxic compound excreted by the kidneys.15,16 Although both are effective for cyanide toxicity, sodium thiosulfate is slower than hydroxocobalamin, and sodium nitrite creates another potentially life-threatening medical condition.

Call the Utah Poison Control Center if you suspect a patient has cyanide toxicity at 1-800-222-1222, 24/7.

References  

  1. The Chicago Tylenol Murders. Chicago History Museum. September 28, 2022. Accessed January 29, 2025. https://www.chicagohistory.org/tylenol-murders/
  2. Quality NRC (US) S on G for MFDW. Guidelines for Cyanide. In: Guidelines for Chemical Warfare Agents in Military Field Drinking Water. National Academies Press (US); 1995. Accessed January 29, 2025. https://www.ncbi.nlm.nih.gov/books/NBK224200/
  3. Graham J, Poole ND, Traylor J. Cyanide Toxicity. In: StatPearls. StatPearls Publishing; 2025. Accessed January 29, 2025. http://www.ncbi.nlm.nih.gov/books/NBK507796/
  4. Cyanide. John Hopkins Center for Health Security. November 2, 2022. Accessed January 29, 2025. https://centerforhealthsecurity.org/sites/default/files/2023-02/cyanide.pdf  
  5. 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
  6. Howland M. Hydroxocobalamin. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw-Hill Education; 2019.  https://accessemergencymedicine.mhmedical.com/content.aspx?bookid=2569&sectionid=210264007  
  7. PubChem. Hydroxocobalamin. Accessed January 29, 2025. https://pubchem.ncbi.nlm.nih.gov/compound/44475014
  8. Up To Date Lexi-Drug. Cyanokit. Accessed January 29, 2025. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7055?cesid=7lTqb08svJ5&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dcyankit%26t%3Dname%26acs%3Dfalse%26acq%3Dcyankit#off-label
  9. Ramezanpour Ahangar E, Annamaraju P. Hydroxocobalamin. In: StatPearls. StatPearls Publishing; 2025. Accessed January 29, 2025. http://www.ncbi.nlm.nih.gov/books/NBK557632/
  10. Borron SW, Baud FJ, Barriot P, Imbert M, Bismuth C. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med. 2007;49(6):794-801, 801.e1-2. doi:10.1016/j.annemergmed.2007.01.026
  11. Fortin JL, Giocanti JP, Ruttimann M, Kowalski JJ. Prehospital Administration of Hydroxocobalamin for Smoke Inhalation-Associated Cyanide Poisoning: 8 Years of Experience in the Paris Fire Brigade. Clinical Toxicology. 2006;44(sup1):37-44. doi:10.1080/15563650600811870
  12. DailyMed - CYANOKIT- hydroxocobalamin injection, powder, lyophilized, for solution. Accessed January 29, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d56fcc8d-bd64-46ab-b0c0-2124bd745a6b
  13. Sutter M, Tereshchenko N, Rafii R, Daubert GP. Hemodialysis complications of hydroxocobalamin: a case report. J Med Toxicol. 2010;6(2):165-167. doi:10.1007/s13181-010-0067-9
  14. Drug Shortage Detail: Hydroxocobalamin Injection. Accessed January 29, 2025. https://www.ashp.org/Drug-Shortages/Current-Shortages/Drug-Shortage-Detail.aspx?id=1112
  15. 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
  16. DailyMed - NITHIODOTE- sodium nitrite and sodium thiosulfate kit. Accessed January 29, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ff4941b3-9901-4aab-adcf-c5327bede34e 

Alexis Marsden, PharmD, PGY2 Emergency Medicine, University of Utah Health & Amberly R. Johnson, PharmD, DABAT, Utah Poison Control Center

Poison Control