Episode 20- Cyanide: toxicology and antidotes

Hello and welcome to Episode 20 of ER-Rx. This week, we have our first toxicology-related discussion and we will take a few minutes to discuss what cyanide does and which antidotes are available for patient management.

Cyanide toxicity is most commonly associated with smoke inhalation, but it can also occur in laboratory accidents, suicide attempts, and criminal activity. Cyanide exists as an inorganic salt (CN-) and also commonly as sodium cyanide (NaCN) and potassium cyanide (KCN). Sodium salts react with water to form hydrogen cyanide (HCN), which is a colorless gas with a “bitter almond” odor. Note that only 60% of the population has the gene to detect this odor.

Cyanide is found naturally in a number of plants. Also, the pits of fruits such as apricots, peaches, and cherries contain amygdalin, which when ingested is transformed to glucose, aldehyde, and cyanide—but don’t worry, you would have to eat hundreds of seeds to see any toxicity, and usually they are non-toxic if swallowed whole. Remember that cyanide is also found in nitroprusside. Each nitroprusside molecule contains 5 cyanide molecules, and if sulfate stores are depleted (as they may be in malnourished patients or those with liver disease) cyanide may accumulate and cause toxicity . This is one of the reasons we try not to use this agent anymore.

Cyanide has a very ominous history. In the 1940s it was used in German concentration camps, and cyanide pills were used in the suicides of Erwin Rommel, Eva Braun, and Heinrich Himmler. In 1978, over 900 members of the People’s Temple cult died after they “drank the Kool-Aid” which contained cyanide and other drugs. We also have cyanide to thank for the tamper-evident packaging for over-the-counter medications. This is because in 1982, someone in Chicago laced Tylenol capsules with potassium cyanide and killed 7 people.

Cyanide toxicity occurs through inhalation or ingestion as well as through the dermal and parenteral routes. The dose required to produce toxicity is dependent on formulation, duration, and route of exposure. The lethal oral dose for adults of KCN/NaCN is ~ 200 mg, and airborne concentrations of 270 ppm may be immediately fatal, but even small exposures can lead to symptoms.

Cyanide is mainly eliminated through the conversion to thiocyanate by the rhodanese enzyme, but in acute poisoning the rate-limiting step of rhodanese is the availability of sulfur donors—we’ll get back to this in a moment. This irreversible sulfation of cyanide then creates thiocyanate which is excreted in the urine.

So, how does cyanide cause toxicity? We can think of cyanide as a “chemical asphyxiant.” And a simplified way to describe the toxicity is that cyanide inhibits cytochrome oxidase, which is essential for oxidative phosphorylation and aerobic energy production, meaning that our body is unable to use oxygen, which leads to cellular hypoxia. Cyanide also causes neurotoxicity due to impaired oxygen utilization, oxidative stress, and the release of excitatory neurotransmitters. This is why the rare survivors of cyanide toxicity can have long-lasting Parkinsonian symptoms.

In terms of clinical signs, unfortunately there is no single reliable symptom or syndrome that is directly associated with acute cyanide poisoning. Cyanide causes rapid dysfunction of the CNS and cardiovascular systems, where we can see agitation, confusion, seizures, coma, respiratory collapse, and cardiovascular collapse.

On laboratory analysis we will see an anion gap metabolic acidosis with elevated lactate concentrations. We also see elevated venous oxygen saturations due to reduced oxygen consumption by our mitochondria.

Cyanide levels are not available rapidly enough to determine treatment, but you should know that levels > 3 mcg/mL lead to death, levels > 2.5 mcg/mL cause coma/respiratory depression, levels 1-2.5 mcg/mL lead do reduced consciousness, and levels of 0.5-1 mcg/mL cause tachycardia and flushing. However, a good surrogate measure of cyanide concentrations is lactate. A lactate > 8 mmol/L has a PPV of 64% and a NPV of 98% for cyanide concentrations above 1 mcg/mL. Therefore, in smoke inhalation victims, the presence of soot in the mouth or nose, along with altered mental status and hypotension, and possibly an elevated lactate level, should have you thinking about cyanide toxicity.

In terms of management, we think supportive cares initially. Controlling the airway, giving oxygen, removing clothing in case of dermal exposure, giving fluids and sodium bicarbonate if needed. Labs should include an ABG, BMP, lactate, whole blood CN level, CBC, blood gases, and carbon monoxide levels.

Antidotes are given based on clinical characteristics of cyanide toxicity discussed earlier. The first-line agent is Cyanokit, or hydroxocobalamin. This agent binds cyanide and forms cyanocobalamin (vitamin B12) which is then excreted in the urine. The dose is 5g IV over 15 minutes in adults and 70 mg/kg (max of 5 g) over 30 minutes in peds, with a repeat dose in 1-2 hours if needed. Adverse effects include transient hypotension, allergic reactions, and red discoloration of skin, mucous membranes, and urine which may last for weeks. It may also interfere with lab results for 12h-8 days (most affected are liver enzymes, bilirubin, Scr, electrolyte studies). However, the effect is transient and probably not clinically significant.

Historically, the Cyanide Antidote Kit was available, but it is no longer manufactured. This kit continued amyl nitrite, sodium nitrite, and sodium thiosulfate. The nitrites worked by generating methemoglobin—that’s right. We used to induce methemoglobinemia in these patients. This is because cyanide has a higher affinity for methemoglobin than for cytochrome oxidase. Amyl nitrite used to come in ampules which were broken and then inhaled for 15-20 seconds until IV access was available. These “amyl nitrate pearls” later became known as “poppers” and were used illicitly. You can do your own Google search on that if you want more information. Of course, the adverse effects of methemoglobinemia, hypotension, and bradycardia led to this kit becoming a less favorable option, especially in patients who also have possible carbon monoxide exposure.

The other component of this kit was sodium thiosulfate, which works by donating the sulfur necessary for the rhodanese enzyme; basically boosting our body’s own elimination pathway for cyanide. This agent can be used alone, though rarely, as it has a slow onset of action of up to 1 hour. The dose is 12.5 g IV over 10 min in adults or 400 mg/kg (with a max of 12.5 g) in peds. You can repeat ½ of the dose after 30 min if needed.

Which one of these antidotes is the best? Although there is no obvious differences in efficacy, they do have differences in their side effect profile. Since the nitrites induce methemoglobinemia and further impair oxygen transport, this can be especially dangerous in smoke-inhalation victims who also have carbon monoxide poisoning. Sodium thiosulfate is safer and is used regularly, but it does not have a rapid onset of action. Therefore, the most rapid, safe, and easy to administer agent is hydroxocobalamin.

In summary, cyanide is one of the most rapidly lethal poisons known to man. Becoming familiar with how patients with cyanide toxicity present, what their labs may show, and how antidotes work is crucial for all ER and ICU staff. I would recommend having an antidote, preferably hydroxocobalamin, readily available in your pharmacy or medication dispensing system in the ER to help expedite therapy. We always carry at least 1 vial of hydroxocobalamin in our ER. It comes with an easy-to-use instruction kit, a transfer spike, and vented tubing.

As always, thank you so much for your time. Please check out our website at errxpodcast.com, where you will find our show notes, our “Key Points,” and a full transcript of each episode.