There are approximately 1.4 million fires each year in the United States. In 2016, 81% of civilian fire-related deaths occurred in residences/homes (Table 1). The National Fire Incident Reporting System (NFIRS) found that smoke inhalation was a factor in 85% of all residential fire fatalities between 2013 and 2015.
Thus, personal injury cases that stem from residential or occupational fires must take into consideration the science behind smoke inhalation. The following article is an overview of the toxic gas produced when combustible materials ignite, how to treat it, and how Emergency Physicians can err in their evaluation and treatment of smoke inhalation victims.
Toxic gas can be produced from the combustion of synthetic materials, including plastic, vinyl, acrylic, neoprene, rubber, and insulation. Reduced levels of oxygen in an enclosed-space fire leads to “incomplete combustion.” This “smoldering” fire rapidly produce vast amounts of smoke and gases, including hydrogen cyanide. Therefore, a feature of typical domestic fires is the risk of hydrogen cyanide, in addition to carbon monoxide (CO) exposure.
CYANIDE EXPOSURE IN ENCLOSED-SPACE FIRES
Cyanide is rapidly absorbed and acts as a cellular asphyxiant due to its high affinity for cytochrome C oxidase. This stops oxidative phosphorylation and, thus, the production of adenosine triphosphate, essentially shutting down aerobic respiration. Anaerobic metabolism creates lactic acid and leads to metabolic acidosis. Animal data also indicate that cyanide also causes pulmonary and coronary vasoconstriction (by stimulating the release of biogenic amines), which results in pulmonary edema and heart failure. First responders should also be aware of potential neurotoxic manifestations of hydrogen cyanide toxicity, including hypotension, apnea, dizziness, and confusion. Ultimately, hydrogen cyanide inhalation can rapidly lead to loss of consciousness and seizures and, if exposure is sufficient, death (Table 2).
Table 2. Cyanide Concentrations in the Air and Associated Effects.
Hydrogen Cyanide Concentration
in the Air
Max workspace concentration for
8-hour work day (in Europe)
Slight symptoms after several hours
Immediate and subsequent damage within 1 hour
Deadly after 30–60 minutes
ppm = parts per million.
There are numerous air-testing apparatuses readily available for assaying air composition during or after an enclosed-space fire. These can determine levels of CO and hydrogen cyanide and may aid in decision making regarding the administration of a cyanide antidote.
Cyanide concentrations in air can reach a lethal level (250-300 ppm) in an enclosed 18 x 12 ft room within 8 minutes of a fire igniting. The National Institute for Occupational Safety and Health short-term exposure limit for hydrogen cyanide is 4.7 ppm; the Occupational Safety and Health Administration permissible exposure limit is 10 ppm (time-weighted average).
Hydrogen cyanide is detectable in the blood of nearly 60% of enclosed-space fire fatalities. Similarly, cyanide blood concentrations were found to be toxic in 47% of cases from enclosed-space fires in Germany, and were at “lethal levels” in 13% of cases.
Any patient who presents from an enclosed-space fire should be assessed for cyanide toxicity. There is no quick test (such devices are in development); however, some clinical symptoms and signs can allow an assumption of possible cyanide exposure (Figure 2). In addition to lethargy, weakness, and drowsiness, hydrogen cyanide exposure can lead to bizarre or irrational behavior in hydrogen cyanide inhalation victims, hampering their ability to perform tasks or to self-rescue.
Hand-held hydrogen cyanide (and CO) detectors are readily available for monitoring ambient air at fire scenes. Such devices may aid fire fighters/first-responders in determining potential hydrogen cyanide exposure, which can support decision making.
Treating cyanide exposure following smoke Exposure.
Treating smoke inhalation in a pre-hospital setting is often limited to supportive care (administering of fluids and oxygen and performing manual respirations). However, frequently this may not be sufficient for moderately to severely ill patients and a cyanide antidote may be required.
FDA-approved antidotes for cyanide poisoning are sodium thiosulfate (administered on its own or with sodium nitrite) and hydroxocobalamin. Sodium thiosulfate is available individually or as part of a 2-component kit with sodium nitrite. The discontinued Cyanide Antidote Kit (CAK) also included amyl nitrite.
A. Sodium Nitrite/Sodium Thiosulfate:
Sodium nitrite oxidizes iron in hemoglobin, converting it to methemoglobin. Methemoglobin competes with cytochrome oxidase for cyanide, forming cyanomethemoglobin. This process restores the ability of the cell to maintain aerobic metabolism. Sodium thiosulfate reacts with cyanomethemoglobin to form thiocyanate, which is renally excreted, releasing hemoglobin.
Administration of nitrites (especially amyl nitrite) causes methemoglobinemia, impairing the ability of red blood cells to carry oxygen. As patients suffering from smoke inhalation will likely be exposed to CO, they will also be at risk of compromised oxygenation due to carboxyhemoglobinemia. Production of methemoglobin may further reduce the oxygen carrying capacity in the blood. Consequently, amyl nitrite is no longer recommended for treating cyanide toxicity and is no longer part of the kit.
Pulse oximetry measurements are often falsely high in patients presenting with high-level methemoglobinemia, and as such, the pulse oximeter is an unreliable tool in patients treated with sodium nitrite.
Both sodium nitrite and sodium thiosulfate are given intravenously; amyl nitrite as part of the CAK kit was inhaled. Case reports and case series assessing the clinical efficacy of sodium nitrite/sodium thiosulfate (with or without amyl nitrite) for cyanide exposure indicate efficacy (Table 3). However, potential adverse effects include vasodilation associated with syncope, nausea, vomiting and dizziness. (Administration may worsen hypotension commonly experienced by patients with smoke inhalation, and, as a result, it is generally accepted that sodium nitrite/sodium thiosulfate should not be used as a prophylaxis.
Hydroxocobalamin acts by binding cyanide to form cyanocobalamin, or synthetic vitamin B, which is then excreted in the urine (which will then likely be colored dark red). The standard dose of hydroxocobalamin is 5 g given intravenously over 15 minutes.
Studies demonstrate that the survival rate after hydroxocobalamin administration is over 70%.
In 2013, The European Center for Ecotoxicology and Toxicology of Chemicals designated hydroxocobalamin as the antidote of choice for severe cyanide toxicity from smoke inhalation.
A US retrospective study of burn patients from enclosed-space fires who were administered hydroxocobalamin as part of an institutional protocol, reported a 50% reduction in the incidence of pneumonia (which developed after patients were transferred to an intensive care unit), compared to a historical control group.
Hydroxocobalamin is well tolerated at the doses required for antidotal efficacy. However, isolated allergic reactions (eg, anaphylaxis, chest tightness, edema, urticaria, pruritus, dyspnea, and rash) and a temporary increase in blood pressure have been reported. Other transient adverse effects include red coloration of the skin, the infused vein, and the urine. (Urine color tends to return to normal after approximately 7 days. In the post-approval setting, serious adverse events, potentially associated with hydroxocobalamin use include a report of 2 cases of acute renal failure due to acute tubular necrosis due to oxalate nephropathy. In light of these concerns, it is recommended that renal function (including blood urea nitrogen and serum creatinine level) should be monitored for 7 days following hydroxocobalamin therapy.
PRE-HOSPITAL USE OF CYANIDE ANTIDOTES
Cyanide will likely be at toxic to lethal levels in the blood of many individuals exposed to smoke in enclosed-space fires shortly after smoke exposure. Cyanide disappears rapidly from the blood, and there is currently no device available for rapid analysis of blood from smoke inhalation victims. Therefore, treatment decisions must therefore be based on clinical history and symptoms.
However, prior to administrating a cyanide antidote, supportive care should be provided to (suspected) smoke inhalation patients with use of antidotes for suspected cyanide poisoning.
Lactic acidosis is a key feature of cyanide toxicity and correlates with the severity of intoxication. This is generally not applicable to determine cyanide toxicity in the pre-hospital setting, but for patients from enclosed-space fires arriving at a hospital with an altered level of consciousness, a plasma lactate level greater than or equal to 10 mmol/L has been shown to be a sensitive and specific marker of cyanide poisoning.
Medical Management Guidelines for Hydrogen Cyanide (updated in 2014) are available from the Agency for Toxic Substances and Disease Registry, but these do not include a protocol for managing suspected hydrogen cyanide toxicity from enclosed-space fires. Hydroxocobalamin has been used in Europe as a cyanide antidote since 1996 where it is recognized as the “primary” antidote to cyanide. A 2018 expert consensus report determined that hydroxocobalamin was the preferred cyanide antidote over sodium nitrite/sodium thiosulfate because of its wider indications, ease of use, and anticipated safety in widespread use. Because hydroxocobalamin does not cause hypotension or methemoglobinemia, it is reasonable to administer it before confirming cyanide exposure in the pre-hospital setting, eg, by paramedics/first responders.
- The combustion of synthetic materials in enclosed-space domestic fires produces toxic gas, of which hydrogen cyanide is an important component
- Most domestic fire deaths are due to smoke inhalation
- Cyanide is a cellular asphyxiant and symptoms of suspected cyanide toxicity include altered mental status, soot around mouth/nose, carbonaceous sputum, cardiac abnormalities, low blood pressure, apnea, and elevated blood lactate level
- Two cyanide antidotes are approved for use in the United States: sodium thiosulfate/sodium nitrite (administered consecutively or sodium thiosulfate solely) and hydroxocobalamin
- Both antidotes are effective; however, concerns regarding possible adverse events with sodium thiosulfate/sodium nitrite limit usefulness as a prophylaxis
- Hydroxocobalamin does not affect oxygenation and is considered safe for most patients; although renal function should be monitored due to the (rare) risk of kidney injury. Hydroxocobalamin is widely used in the United States and is the “first line” choice in Europe where it is often carried by first responders/emergency services
- Guidelines for pre-hospital admission of cyanide antidotes are lacking but are in development. In the meantime, prompt administration to at-risk smoke inhalation/fire victims is recommended when clinically indicated
- Haynes H.J.G. 2017. Fire Loss in the United States during 2016. National Fire Protection Association. Fire Analysis and Research Division. Quincy, MA.
- Hanley ME, Murphy-Lavoire HM. 2018. Hyperbaric, cyanide toxicity. In: StatPearls [Internet]. Treasure Island, FL: StatsPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482265/. Accessed February 11, 2019.
- Federal Emergency Management Agency (FEMA). Civilian Fire Fatalities in Residential Buildings (2013-2015). US Fire Administration National Fire Data Center Topical Report Series. 2017;18:1-13. Emmitsburg, MD. https://www.usfa.fema.gov/downloads/pdf/statistics/v18i4.pdf. Accessed February 11, 2019.
- Alaire Y. Toxicity of fire smoke. Crit Rev Toxicol. 2002;32:259-289.
- Barillo DJ. Diagnosis and treatment of cyanide toxicity. J Burn Care Res. 2009;30:148-163.
- Moudgil R, Michelakis ED Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol. 2005;98:390-403.
- Agency for Toxic Substances and Disease Registry (ATSDR). 2006. Toxicological profile for Cyanide. Atlanta, GA: US Department of Health and Human Services, Public Health Service. https://www.atsdr.cdc.gov/toxprofiles/tp8-c1.pdf. Accessed August 6, 2018.
- Occupational Safety and Health Administration (OSHA). 1999. Hydrogen cyanide. US Department of Labor. Occupational Safety and Health Administration. Code of Federal Regulations. 29 CFR 1910.1000. TableZ-1. Part Z, Toxic and Hazardous Substances. http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=9992. Accessed August 6, 2018.
- National Institute for Occupational Safety and Health (NIOSH). 2005. Hydrogen cyanide. NIOSH pocket guide to chemical hazards. National Institute for Occupational Safety and Health. http://www.cdc.gov/niosh/npg/npgd0333.html. Accessed August 6, 2018.
- Grabowska T, Skowronek R, Nowicka J, et al. Prevalence of hydrogen cyanide and carboxyhaemoglobin in victims of smoke inhalation during enclosed-space fires: a combined toxicological risk. Clin Toxicol (Phila). 2012;50:759-763.
- Stoll S, Roider G, Keil W. Concentration of cyanide in blood samples of corpses after smoke inhalation of varying origin. Int J Leg Med. 2017;131:123-129.
- Jones J, McMullen MJ, Dougherty J. Toxic smoke inhalation: cyanide poisoning in fire victims. Am J Emerg Med. 1987;5: 317-321.
- Logue BA, Stutelberg MW, Manandhar E, et al. Rapid field-usable cyanide sensor development for blood and saliva. Brookings, SD: South Dakota State University; 2014. http://www.dtic.mil/dtic/tr/fulltext/u2/a621259.pdf. Accessed February 11, 2019.
- Gagliano M, Phillips CR, Bernocco S, et al. Air Management for the Fire Service. La Mirada, CA: Fire Engineering Books; 2008.
- Kaplan HL, Hartzell GE. Modeling of toxicological effects of fire gases: Incapacitating effects of narcotic fire gases. J Fire Sci. 1984;4:286-305.
- CYANOKIT® (single 5-g vial) [package insert]. Columbia, MD: Meridian Medical Technologies, Inc. 2017.
- Dart RC, Goldfrank LR, Erstad BL, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2018;71:314-325.
- Gracia R, Shepherd G. Cyanide poisoning and its treatment. Pharmacotherapy. 2004;24:1358-1365.
- Anseeuw K, Delvau N, Burillo-Putze G, et al. Antidotes for cyanide poisoning. Eur J Emerg Med. 2013;20:66-67.
- Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol. 2009;39:541-552.
- Lam KK, Lau FL. An incident of hydrogen cyanide poisoning. Am J Emerg Med. 2000;18:172-175.
- Chin RG, Calderon Y. Acute cyanide poisoning: a case report. J Emerg Med. 2000;18:441-445.
- Goodhart GL. Patient treated with antidote kit and hyperbaric oxygen survives cyanide poisoning. South Med J. 1994;87:814-816.
- Turchen SG, Manoguerra AS, Whitney C. Severe cyanide poisoning from the ingestion of an acetonitrile-containing cosmetic. Am J Emerg Med. 1991;9:264-267.
- Lavon O, Bentur Y. Does amyl nitrite have a role in the management of pre-hospital mass casualty cyanide poisoning? Clin Toxicol (Phila). 2010;48:477-484
- Baskin SI, Horowitz AM, Nealley EW. The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning. J Clin Pharmacol. 1992;32:368-375.
- Petrikovics I, Budai M, Kovacs K, et al. Past, present and future of cyanide antagonism research: From the early remedies to the current therapies. World J Methodol. 2015;5:88-100.
- Fortin, J-L., Giocanti J-P, Ruttimann M, et al. Prehospital administration of hydroxocobalamin for smoke inhalation-associated cyanide poisoning: 8 years of experience in the Paris Fire Brigade. Clin. Toxicol. 2006;44:37-44.
- Borron SW, Baud FJ, Barriot P, et al. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med. 2007;49:794-801.
- Borron SW, Baud FJ, Mégarbane B, et al. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. Am J Emerg Med. 2007;25:551-558.
- Baud F. Efficacy and safety of antidotes for acute poisoning by cyanides. Brussels, Belgium 2013 No. Technicial Report No. 121. http://www.ecetoc.org/publication/tr-121-efficacy-and-safety-of-antidotes-for-acute-poisoning-by-cyanides/. Accessed February 11, 2019.
- Nyguyen L, Afshari A, Kahn SA, et al. Utility and outcomes of hydroxocobalamin use in smoke inhalation patients. Burns. 2017;43:107-113.
- Legrand M, Thibault M, Daudon M, et al. Risk of oxalate nephropathy with the use of cyanide antidote hydroxocobalamin in critically ill burn patients. Intensive Care Med. 2016;42:1080-1081.
- Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med. 1991;325:1761-1766.
- Baud FJ, Haidar MK, Jouffroy R, et al. Determinants of lactic acidosis in acute cyanide poisonings. Crit Care Med. 2018;46:e523-e529.
- Agency for Toxic Substances & Disease Registry. Medical Management Guidelines for Hydrogen Cyanide (HCN) Cas# 74-90-8, UN#1051. https://www.atsdr.cdc.gov/mmg/mmg.asp?id=1073&tid=19#bookmark03. Accessed 8 August 2018.
Adapted from Medscape CME 2019