Smoke inhalation from closed-space fires remains a major cause of preventable death in the United States. A combination of smoke inhalation and burns (49 percent), and smoke inhalation alone (35 percent), are the leading causes of U.S. fire-related civilian fatalities.¹  /Although  carbon monoxide (CO) poisoning is widely recognized for its role in fire-related fatalities, hydrogen cyanide (HCN) exposure is an underappreciated and potentially lethal contributor to morbidity and mortality.

HCN generation from dominating synthetic material household items including mattresses, upholstered furniture, and insulation foam can exceed lethal concentrations within minutes of ignition.^2,3

In enclosed fires, victims are often exposed to both CO and cyanide. The result is a dangerous combination: impaired oxygen delivery from CO and impaired oxygen utilization from cyanide.

For emergency physicians, rapid recognition and early empiric treatment may be lifesaving.

Why Cyanide Is Different

Cyanide exerts toxicity at the cellular level by binding cytochrome oxidase in mitochondria, halting oxidative phosphorylation. Oxygen may be present in the bloodstream, but cells cannot use it. The result is rapid anaerobic metabolism, severe lactic acidosis, cardiovascular collapse, and potentially death within minutes.

Unlike CO poisoning, which reduces oxygen-carrying capacity, cyanide blocks oxygen utilization. When both are present, as commonly occurs in closed-space fires, the physiologic insult is profound.

The management of cyanide exposure presents several challenges. Currently, there is no rapid or reliable method to diagnose cyanide poisoning in these patients during initial care.  Additionally, after absorption, cyanide quickly clears from the bloodstream, with a half-life ranging from one to three hours, and a terminal elimination time of approximately 44 hours. This rapid clearance complicates efforts to accurately determine peak cyanide levels.⁴

When to Suspect Cyanide Toxicity

Consider cyanide poisoning in patients with:

• History from pre-hospital personnel of the victim’s environment (Closed-space smoke exposure);
• Altered mental status or coma;
• Soot around the oral and nasal pharynx, confirmed in the oropharynx;
• Hypotension or cardiovascular collapse;
• Cardiac or respiratory arrest at the scene of a fire;
• Severe metabolic acidosis; or
• Markedly elevated lactate (often >8–10 mmol/L).

An elevated lactate in the appropriate fire setting is a particularly important clue. Analytical findings have revealed information around the diagnostic use of lactic acid blood testing as a confirmatory and severity value in cyanide intoxication population.⁵ Cyanide is a strong decoupler of oxidative phosphorylation, interrupting adenosine triphosphate (ATP) synthesis by blocking cytochrome oxidase a₃. Subsequently, aerobic respiration ceases and anaerobic respiration develops leading to excessive lactate formation.⁶ Exposure to CO also produces tissue hypoxia, interfering with oxidative phosphorylation resulting in carboxyhemoglobin (COHb) producing lactic acidosis.^6,7 While nonspecific, severe lactic acidosis after smoke exposure should raise concern for cyanide toxicity. A normal COhb level does not exclude cyanide exposure, although  CO and cyanide are commonly co-occurring.

First Priorities: ABCs and Oxygen

Initial management mirrors other critical inhalation injuries:

1. Remove from the source
2. Secure the airway early if needed
3. Provide 100 percent oxygen
4. Stabilize circulation

High-flow oxygen treats concurrent CO poisoning and optimizes oxygen delivery. However, oxygen alone does not reverse cyanide’s mitochondrial blockade.

Hydroxocobalamin is recommended in the American Heart Association national resuscitation guidelines for suspected cyanide poisoning in cases of life-threatening toxicity. If cyanide poisoning is suspected, do not wait for confirmatory testing. Treat immediately with hydroxocobalamin (preferred). Because hydroxocobalamin neither causes hypotension nor worsens concerns about reduced oxygen-carrying capacity, it is the primary recommended treatment for patients with suspected cyanide poisoning.⁸ When suspicion is high, antidotal therapy should not be delayed.

Hydroxocobalamin: Practical Emergency Department Use

Hydroxocobalamin, known by its brand nameCyanokit, is a vitamin B12 precursor that binds cyanide to form nontoxic cyanocobalamin, which is renally excreted. Unlike older cyanide antidotes, it does not induce methemoglobinemia—an important advantage in patients who may also have CO poisoning.

Adult Dosing

• 5 g IV over 15 minutes
• A second 5 g dose may be given based on clinical severity and response

Most reported patients receive 5–10 g total.

Does Timing Matter?

Nearly half of reported cases involve prehospital administration. Overall survival across published series is approximately two-thirds of treated patients. While observational data cannot establish causation, earlier treatment has been associated with improved survival in some cohorts.

Patients who receive antidote in the field are often more critically ill, which complicates outcome comparisons. Nevertheless, cyanide acts quickly, and its short half-life supports the biological rationale for early administration.

Emergency physicians should ask:

• Does our EMS system carry hydroxocobalamin?
• How quickly can we administer it upon emergency department (ED) arrival?
• Do we have a clear protocol?
• Is care coordinated with a regional burn center?

What Adverse Effects Should You Expect?

Although hydroxocobalamin is generally well-tolerated, common and expected side effects include:

• Transient bright red skin discoloration
• Transient dark red urine (chromaturia), and
• Mild transient hypertension. These effects are self-limited.

Acute Kidney Injury

Acute kidney injury (AKI) has been reported in a minority of patients. However, a recent (2024) study aimed at determining whether hydroxocobalamin use in inhalation injury (IHI) patients is associated with a difference in nephrotoxicity incidence did not demonstrate a difference in the incidence of AKI in patients with IHI who did or did not receive hydroxocobalamin.⁹ In most cases, renal dysfunction resolves prior to discharge and is likely multifactorial in critically ill burn patients. Rare cases of oxalate nephropathy have been described.

Monitor renal function and ensure appropriate fluid resuscitation.

Laboratory Interference

Hydroxocobalamin’s deep red color can interfere with certain laboratory assays and may trigger false blood-leak alarms on dialysis machines. Notify the laboratory when the antidote has been administered.

When Should You Treat?

Strong consideration for empiric hydroxocobalamin is appropriate when Closed-space smoke exposure is confirmed, The patient has severe altered mental status, shock, or cardiac/respiratory arrest, and Severe metabolic acidosis or markedly elevated lactate is present. In fire-related cardiac arrest, early antidote therapy is reasonable.

Observation and further workup are appropriate in mild smoke exposure with normal mentation and minimal metabolic abnormalities.

System-Level Barriers

Despite long-standing approval and guideline endorsement, hydroxocobalamin use remains inconsistent. Barriers include its cost,(approximately $1000 per 5 g vial),  Limited shelf life, Lack of EMS protocols, and Variable clinician familiarity.Fewer than one in five EMS agencies report having formal cyanide treatment protocols.

Emergency physicians can lead system improvements by Advocating for stocking in high-risk regions, Developing clear ED and EMS algorithms, Educating staff about appropriate indications and side effects, and Partnering with burn centers and trauma systems.

Closed-space fire victims represent a small but high-risk population.

Bottom Line

Cyanide toxicity from smoke inhalation is uncommon but catastrophic. It frequently coexists with CO exposure and should be suspected in any closed-space fire victim with altered mental status or severe lactic acidosis.

Hydroxocobalamin is mechanistically sound, generally safe, and recommended for suspected life-threatening cyanide poisoning. Treatment decisions must be clinical and should not await confirmatory testing.

Early recognition, early oxygenation, and early antidote administration—supported by clear system protocols—offer the best opportunity to improve outcomes in these critically ill patients.¹⁰

Dr. Dunne is a professor at Wayne State University School of Medicine in Detroit and EMS medical director for the Detroit East Medical Control Authority and the City of Detroit Fire Department. He is subspecialty board-certified in EMS by the American Board of Medical Specialties and is director of the Wayne State University EMS fellowship. He also has served as a tactical medical physician for the Detroit Metropolitan Airport Special Response Team, Michigan FBI SWAT team and the Wayne County Sheriff.  He has been a DMAT medical officer since 1998 and is the chief medical consultant for the City of Detroit.

References

1. S. Fire Administration. Civilian fire fatalities in residential buildings, 2017–2019. Topical Fire Research Series. 2021; 21(3). U.S. Fire Administration. https://www.usfa.fema.gov/downloads/pdf/statistics/v21i3.pdf
2. Purser DA. Toxicity assessment of combustion products. In: DiNenno PJ, ed. SFPE handbook of fire protection engineering. 3rd ed. Quincy, MA: National Fire Protection Association; 2002:2-83–2-171.
3. Kerber S. Analysis of changing residential fire dynamics and its implications on firefighter operational timeframes. Fire Technol. 2012;48(4):865-891. doi:10.1007/s10694-011-0249-2
4. O’Brien DJ, Walsh DW, Terriff CM, Hall AH. Empiric management of cyanide toxicity associated with smoke inhalation. Prehosp Disaster Med. 2011;26(5):374-382. doi:10.1017/S1049023X11006625
5. Baud FJ, Borron SW, Mégarbane B, Trout H, Lapostolle F, Vicaut E, 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. Parker-Cote JL, Rizer J, Vakkalanka JP, Rege SV, Holstege CP. Challenges in the diagnosis of acute cyanide poisoning. Clin Toxicol (Phila). 2018;56(7):609-617. doi:10.1080/15563650.2018.1435886
7. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309-2319. doi:10.1056/NEJMra1309483
8. Lavonas EJ, Akpunonu PD, Arens AM, et al. 2023 American Heart Association focused update on the management of patients with cardiac arrest or life-threatening toxicity due to poisoning: an update to the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. 2023;148(16):eXXX–eXXX. doi:10.1161/CIR.0000000000001161
9. Mann EM, Boyd AN, Walroth TA, et al. 511: Hydroxocobalamin not the clear culprit of nephrotoxicity after cyanide poisoning. J Burn Care Res. 2024;45(suppl 1):119. doi:10.1093/jbcr/irae036.146
10. Dunne R, Goodloe JM, Augustine JJ, Begres T, Crowe RP, Carney E. Intravenous hydroxocobalamin for cyanide poisoning from smoke inhalation: a comprehensive scoping review. J Am Coll Emerg Physicians Open. 2026;7(2):100340. doi:10.1016/j.acepjo.2026.100340.