PART I – Cyanide Poisoning (aka “Doc, it hurts right here” *points to mitochondria*)
Authors: Trevor Cerbini, MD; Alec Feuerbach, MD,
Peer reviewers: Nic Anthony, MD; Wesley Chan, MD
Faculty reviewer: Sage Wiener, MD
From apple seeds to false teeth, Tylenol, and cigarettes, salad bars to kool-aid, cyanide is among the most ubiquitous deadly poisons discussed in popular culture and news outlets. Its resulting toxicity is one that we are likely to treat as Emergency Medicine providers – most commonly in victims of fires (though we should be prepared for the other nefarious presentations as well).[1]
Cyanide (CN) is a rapidly lethal toxin, producing damage to highly ATP-dependent organs like the brain and heart by inhibiting oxidative phosphorylation, thereby decreasing ATP production.[2]
Cyanide inhibits oxidative phosphorylation by binding cytochrome a3 (a part of Complex IV of the electron transport chain) [2]. Want more details on its mechanism? Check out Tox and the Hound [2] (image from Tox and the Hound)
Diagnosis:
The symptoms of CN poisoning are fairly non-specific. Often, it will take a reported exposure (or signs of exposure such as soot to the face after a fire) to clue you into its presence.[1,3] Still, it is important to be familiar with the typical, presenting symptoms.
In severe CN toxicities, unresponsiveness is the most common presentation. However, neurologic signs of toxicity can start with dizziness and generalized headache before progressing to decreased consciousness, seizures, or coma. GI symptoms include nausea and vomiting. Tachycardia can result from an initial catecholamine surge but may quickly devolve into bradycardia and, ultimately, cardiac arrest. In severe toxicity, you might also see patients present with dyspnea and tachypnea.
How about abnormalities on the skin exam? Or that bitter almond smell? Unfortunately, these board exam giveaways are rare in actual patients. In a review of 102 patients, only 11% had skin changes and 15% had an odor present.[4]
Complicating the diagnosis is the lack of timely and definitive laboratory testing. A CN level can be measured, but will typically take a day or so to come back, rendering it useless in the initial treatment of the unstable patient. Still, while not diagnostic, there is a laboratory test that can be helpful.
As previously discussed, CN produces its deadly effects by inhibiting oxidative phosphorylation. This forces the body to rely on anaerobic metabolism to produce ATP. Doing this requires the regeneration of ample NAD+ which is converted to NADH during glycolysis. When oxidative phosphorylation is occurring, NADH will donate electrons to the electron transport chain and convert back to NAD+. Without the electron transport chain, however, the only way to convert NAD+ to NADH is through the breakdown of pyruvate:
Pyruvate + NADH + H+ <==> Lactate + NAD+
In CN-poisoned patients, this reaction is rapidly trying to regenerate enough NAD+ to power the anaerobic production of ATP. This produces, as a byproduct, a buildup of lactate. For this reason, serum lactate levels can be a useful, albeit nonspecific, marker of CN poisoning. In fire victims, for example, serum lactate levels rise alongside serum CN levels [5]. In this context, a serum lactate concentration greater than 10mmol/L was found to be 87% sensitive and 94% specific for cyanide poisoning, with a positive predictive value of 95%.[5]
So, once the diagnosis of cyanide poisoning is suspected, what are the treatment options?
Treatment Options: Nitrates & Sodium Thiosulfate
The vast majority of CN-poisoned patients encountered in the ED are victims of fire, inhaling significant quantities of hydrogen cyanide (HCN) gas from the combustion of textiles and synthetic materials.
While no longer available in the United States, the Lilly Cyanide Antidote kit (Eli Lilly & Co) was the only antidote kit available for many years, consisting of amyl nitrite, sodium nitrite, and sodium thiosulfate. The amyl nitrite was prepared in small glass ampules that, when cracked, would release vapors to be sniffed by the patient. While this was performed, intravenous access would be established to administer the sodium nitrite and sodium thiosulfate.
Cyanide antidote kit. Photo credit: Russ Kerns, MD, Emergency Medicine Attending and Medical Toxicologist, Atrium Health’s Carolinas Medical Center.
Sodium thiosulfate exerts its effect by providing a sulfur group to which CN can be bound, forming sodium thiocyanate, a renally excreted, non-toxic compound.
Both amyl nitrite and sodium nitrite are strong methemoglobin inducers, oxidizing heme iron from its ferrous (Fe2+) to ferric (Fe3+) state. This action was long considered to be their primary mechanism in CN toxicity, as CN preferentially binds to methemoglobin forming cyanmethemoglobin. Further study has led investigators to believe that the major role of nitrites in CN poisoning is actually the generation of a large, available pool of nitrous oxide (NO).[6] NO competes with and displaces CN from cytochrome C oxidase, making the CN available to be bound up by sodium thiosulfate (or hydroxocobalamin).[6]
As of 2018, the US FDA no longer recognizes amyl nitrite as an approved therapy, and amyl nitrite containing cyanide antidote kits are no longer commercially available in the US. Nithiodote, an antidote kit containing sodium nitrite and sodium thiosulfate is still available. However, inducing methemoglobinemia raises safety concerns in patients who may already be suffering from decreased oxygen-carrying capacity due to exposure to other combustion by-products (such as carbon monoxide). In addition, nitrates can exacerbate CN-induced vasodilation and hypotension – a less than desired outcome in already critically ill patients.
Treatment Options: Hydroxocobalamin
At present, the most widely used antidote for victims of CN poisoning, at least in the US and Europe, is hydroxocobalamin (Cyanokit).[7] Hydroxocobalamin is as close to alchemy as it gets in medicine; hydroxocobalamin binds with cyanide, forming cyanocobalamin, also known as vitamin B12. Hydroxocobalamin literally takes a deadly poison and transforms it into a freaking VITAMIN. In contrast to nitrates, hydroxocobalamin has the added benefit of transiently raising blood pressure, likely through the scavenging of NO, improving hemodynamics in CN-poisoned patients.[8]
Figure depicting the mechanisms of action of cyanide antidotes, painstakingly crafted. Please excuse its highly technical nature.
When comparing antidotes, available evidence comes primarily from studies done in swine models of CN toxicity. No significant mortality differences were observed when comparing a combination of sodium thiosulfate with either hydroxocobalamin or sodium nitrite.[9] However, when comparing sodium thiosulfate vs hydroxocobalamin alone, 100% of the swine in the sodium thiosulfate group died, while only 1 of 12 in the hydroxocobalamin-alone group died.[10]
Treatment Options: The Future?
Other therapies have shown promise in animal models but are not yet available for human use.[11,12] One potential antidote is cobinamide, a vitamin B12 analog with two CN binding sites. Compared to hydroxocobalamin, cobinamide displays a significantly increased binding affinity for CN (by several orders of magnitude). Cobinamide can also be administered intramuscularly (whereas hydroxocobalamin is only available in intravenous formulations); this makes it an option for mass casualty incidents. Cobinamide in an auto-injector type device could be used by non-medical personnel (bystanders, police, firefighters) to provide antidotal therapy to many more patients than could be treated otherwise.
At this time, a US patent has been filed for the use of cobinamide as a CN, sulfide, or methane-thiol antidote.[13] Phase 1a dose escalation and 1b extended safety clinical trials are pending (none are registered with www.clinicaltrials.gov at the time of this blog post).[14]
Indications for Treatment
As discussed in Goldfrank’s Toxicology Emergencies, CN poisoning should be suspected in several clinical scenarios: sudden collapse of laboratory/industrial workers, fire victims with coma or acidemia, and suicide attempts or circumstances suspicious for homicide with unexplained, rapid onset of coma or acidemia.[15] In these cases, antidotal therapy along with standard supportive care (including cutaneous and gastrointestinal decontamination) should be strongly considered. Hydroxocobalamin is preferred, but antidotal availability will largely dictate your management as it pertains to the administration of specific CN reversal agents.[15]
In part II of this post (wait… there’s more?!), we will take a deep dive into all of the particulars of hydroxocobalamin, including its administration, additional indications apart from CN toxicity), impact on other lab results, and side effects. Stay tuned, nerds.
Take-Home Points
- Cyanide is a rapidly lethal mitochondrial poison.
- Rapid knockdown/unresponsiveness is a key feature of intoxication.
- In fire victims, lactate greater than 10 mmol/L is fairly sensitive and specific for CN poisoning.
- A high index of suspicion should be maintained in suggestive clinical scenarios and antidotal therapy should be provided, preferably in the form of hydroxocobalamin.
References
1) 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) Yen D, Tsai J, Wang LM, et al. The clinical experience of acute cyanide poisoning. Am J Emerg Med. 1995;13(5):524-528. doi:10.1016/0735-6757(95)90162-0
4) 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
5) Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med. 1991;325(25):1761-1766. doi:10.1056/NEJM199112193252502
6) Howland MA. Nitrites (Amyl and Sodium) and Sodium Thiosulfate. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Hoffman RS, Howland MA, Nelson LS, editors. Goldfrank’s toxicologic emergencies, 11 ed. New York: The McGraw-Hill Companies, Inc; 2019. Accessed February 12, 2022. https://accessemergencymedicine-mhmedical-com.newproxy.downstate.edu/content.aspx?bookid=2569§ionid=210264055
7) Streitz MJ, Bebarta VS, Borys DJ, Morgan DL. Patterns of cyanide antidote use since regulatory approval of hydroxocobalamin in the United States. Am J Ther. 2014;21(4):244-249. doi:10.1097/MJT.0b013e31824ea656
8) 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.doi: 10.1016/j.annemergmed.2007.01.026.
9) 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
10) 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
11) Bebarta VS, Tanen DA, Boudreau S, et al. Intravenous cobinamide versus hydroxocobalamin for acute treatment of severe cyanide poisoning in a swine (Sus scrofa) model. Ann Emerg Med. 2014;64(6):612-619. doi:10.1016/j.annemergmed.2014.02.009
12) Lee J, Mahon SB, Mukai D, et al. The Vitamin B12 Analog Cobinamide Is an Effective Antidote for Oral Cyanide Poisoning. J Med Toxicol. 2016;12(4):370-379. doi:10.1007/s13181-016-0566-4
13) Boss G, Chan A, Brenner M, Mahon S, Berbarta V. Cobinamide Compounds as a cyanide, sulfide, or methane-thiol antidote. 2019. US 2019/035353
14) Boss G. Pre-Clinical and Clinical Studies of Cobinamide, A New Cyanide Detoxifying Agent. Grantome. https://grantome.com/grant/NIH/U01-NS058030-10. Published 2022. Accessed February 7, 2022.
15) Holstege CP, Ison GE, Kirk MA. Cyanide and hydrogen sulfide. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Hoffman RS, Howland MA, Nelson LS, editors. Goldfrank’s toxicologic emergencies, 11 ed. New York: The McGraw-Hill Companies, Inc; 2019. Accessed February 12, 2022. https://accessemergencymedicine-mhmedical-com.newproxy.downstate.edu/content.aspx?bookid=2569§ionid=210264536
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