Cyanide Antidotes Paul Jones September 10, 2010

Objectives To review the management decisions in a case of cyanide poisoning Case presentation Clinical question to consider Case conclusion

Case Presentation Patient brought in VSA to the ED by EMS Roommate found patient collapsed on the floor and unresponsive – started CPR after calling EMS No known medical conditions Works in chemistry research lab

Case Cont’d… GCS 3 Pupils fixed and dilated ETT intubation by EMS PEA Bedside U/S shows no cardiac activity No signs of obvious injury

Case Cont’d… Ongoing CPR IV access obtained Femoral line inserted Blood drawn Epinephrine and atropine administered Sodium bicarbonate boluses given … EMS presents vial found beside patient at the scene labelled NaCN

Cyanide: Background Sources: industry, smoke inhalation Cyanide can originate from several sources: Industry (variety of salts, halogen compounds, coupled with organic moieties, nitriles), common component of smoke from burning nitrogen-containing fuels, such as many plastics – In fact, the most common current cause of cyanide poisoning is smoke inhalation. Cyanide is rapidly absorbed from the lung or gastrointestinal tract, and there is a rapid onset of symptoms involving the central nervous system (CNS) and cardiovascular systems, as well as profound metabolic acidosis. Death can occur within a few minutes. Cyanide is metabolized primarily by the enzyme rhodanese in the presence of a sulfur source in the liver, forming the relatively nontoxic metabolite thiocyanate. The body can detoxify about 0.017 mg of cyanide/kilogram/minute. These enzymatic routes are highly effective, but they are insufficient for the large quantities of cyanide encountered in poisonings due to depletion of sulfur donors. Cyanide is a potent non-competitive inhibitor of cytochrome c oxidase within the mitochondria and a number of other enzymes The mitochondria continue to be exposed to an adequate oxygen supply; however, there is impaired oxygen extraction and use. This disruption of aerobic metabolism leads to increased glycolysis by anaerobic pathways resulting in tissue hypoxia, tissue dysfunction, and ultimately death. Figure: Binding of the cytochrome oxidase within the mitochondria, resulting in abrupt cessation of cellular respiration. (1)Step 1 shows cyanide bindings to the ferric ion (Fe3+) in the cytochrome a3+ complex. (2) Step 2 illustrates that the electron transport chain is inhibited, resulting in loss of aerobic metabolism and generation of adenosine triphosphate (ATP). (3) In step 3, nitrites (NO2) react with oxyhemoglobin to form methemoglobin, which draws cyanide out of mitochrondria and forms cyanomethemoglobin. (4) In step 4, the enzyme rhodanase combines thiosulfate with cyanomethemoglobin to form the less toxic thiocyanate, which is excreted by the kidneys. (5) Finally, in step 5, methemoglobin is converted back to oxyhemoglobin by the enzyme methemoglobin reductase. A cyanide is any chemical compound that contains the cyano group (C≡N), which consists of a carbon atom triple-bonded to a nitrogen atom. Inorganic cyanides are generally salts of the anion CN−. Of the many kinds of cyanide compounds, some are gases; others are solids or liquids. Those that can release the cyanide ion CN− are highly toxic. Cyanides are produced by certain bacteria, fungi, and algae and are found in a number of foods and plants. Cyanides are found, although in small amounts, in certain seeds and stones, e.g. those of apple, mango, peach, and bitter almonds.[8] In plants, cyanides are usually bound to sugar molecules in the form of cyanogenic glycosides and defend the plant againstherbivores. Cassava roots (also called manioc), an important potato-like food grown in tropical countries (and the base from which tapioca is made), also contain cyanogenic glycosides. The most dangerous cyanides are hydrogen cyanide (HCN) and salts derived from it, such as potassium cyanide (KCN) and sodium cyanide (NaCN), among others. Source: Wiki

Cyanide: Clinical Presentation Hypoxia and acidosis Coma, hemodynamic compromise, seizures, apnea, cardiac arrest, death Acute cyanide toxicity: dizziness, headache, weakness, flushing, diaphoresis, dyspnea, hyperventilation, hyperpnea Labs: metabolic acidosis and elevated lactate, supranormal venous O2 content Exposure to high concentrations of cyanide can result in death within seconds to minutes. In cases of more prolonged onset of toxicity, signs and symptoms reflect a progressive intracellular hypoxia. The hallmark presentation is hypoxia and acidosis. Acute cyanide toxicity lacks characteristic symptoms, and the diagnosis often is missed in absence of a reasonable index of suspicion. The constellation of initial transient symptoms often mimics anxiety. The victim may complain of dizziness, headache, weakness, flushing, diaphoresis, dyspnea, hyperventilation, and hyperpnea. The victim may have an odor of bitter almonds, but only about 40–60% of the population possesses the gene necessary to detect this odor, and it is not a reliable sign. The most prominent laboratory finding in cyanide toxicity is a metabolic acidosis with dramatically elevated lactate concentrations. The shift from aerobic to anaerobic metabolism ultimately results in marked production of lactate as a profound high anion gap acidosis ensues. In the case of an unknown exposure, it is useful to check both venous and arterial blood gases for supranormal venous oxygen content or “arteriolization” of venous blood. Cyanide tests are not readily available and often require a few days for the results to be available.

Cyanide: Treatment GI Decontamination Supplemental O2 ? Hyperbaric oxygen Antidotes: Increase endogenous metabolism: Thiosulfate Cyanide chelating: Hydroxocobalamin, Dicobalt EDTA Methemoglobin generation: Nitrites, 4-DMAP CAK = Amyl nitrite + Sodium nitrite + Sodium thiosulfate Gastrointestinal decontamination measures may prove futile due to cyanide’s high potency and rapid onset of toxicity. However, some forms of cyanide may have prolonged absorption kinetics. For patients presenting within 1 hour of ingestion, it is reasonable to consider performing an orogastric lavage and administering activated charcoal in attempt to recover any amount of the cyanide. Supplemental oxygen is a crucial part of supportive care in cyanide poisoning. Ventilation with 100% oxygen increases tissue oxygen delivery. The use of hyperbaric oxygen for cyanide toxicity remains controversial. Antidotes: Mechanism: Increasing the rate of endogenous metabolism: Thiosulfate as a sulfur source for rhodanese Chelating cyanide Hydroxycobalamin (vitamin B12) – available in France 1996 and the US 2007 = higher affinity for cyanide than do tissue cytochromes, thereby competitively binding and inactivating both free and cytochrome-bound cyanide; cyanocobalamin formed is readily excreted by the kidney Dicobalt EDTA – Great Britain, France = toxcity Generating methemoglobin which competitively binds cyanide, liberating cytochrome oxidase: Nitrites 4-dimethylaminophenol (4-DMAP) – Germany = toxicity Cyanide antidote kit: Nitrites are used to induce methemoglobinemia. Amyl nitrite is administered by inhalation and generates approximately 5% methemoglobin. Sodium nitrite is given intravenously and increases methemoglobin by about 8–20%. Cyanide appears to bind preferentially to the ferric iron of methemoglobin, rather than to the ferric iron of the cytochrome in mitochondria. It is thought that an increased amount of cyanide will transfer to the extracellular space and be displaced from the cytochrome, enabling the mitochondria to reactivate electron transport. The nitrites do cause significant adverse effects, namely vasodilatation and hypotension. It is recommended to avoid nitrites in smoke inhalation victims due to the risk of worsening the oxygen-carrying–capacity deficit. The third component of the cyanide antidote kit is sodium thiosulfate. This agent enhances clearance of cyanide by acting as a sulfhydryl donor. Thiosulfate reversibly combines with cyanide in the extracellular space to form the minimally toxic and renally excreted thiocyanate. Not suitable as prophylactic agents: Excessive doses of sodium nitrite may produce methemoglobin levels capable of significantly impeding oxygen transport. This is of particular concern in fire/smoke inhalation victims, in whom other risk factors, particularly carbon monoxide exposure, may significantly increase the risk of hypoxia.

Question to Consider? Is hydroxocobalamin an effective and safe antidote to administer for suspected cyanide ingestion? CAK has traditionally been used as a first-line treatment in North America – hydroxocobalamin approved in the US in 2007

Evidence source: Difficult to find – both ethics and practicality prohibit the use of prospective randomized trials in humans treated for cyanide ingestion! See also RCT parachutes…

PICO Analysis Patients Patients with cyanide poisoning Lethal threshold = 100 µmol/L Patients Patients with cyanide poisoning = patients found in Cardiac arrest This retrospective chart review was undertaken to assess efficacy and safety of hydroxocobalamin for acute cyanide poisoning. Hospital records of the Fernand Widal and Lariboisie`re Hospitals in Paris, France were reviewed for intensive care unit admissions with cyanide poisoning for which hydroxocobalamin was used as first-line treatment from 1988 to 2003. Smoke inhalation cases were excluded. The sample included 14 consecutive patients poisoned with cyanide (12 men, 2 women; median age, 35.2 years) Of the 14 poisonings, 12 involved suicide attempts Two patients were found in cardiac arrest; 4, in shock; and 5, with severe neurological impairment (GCS score ≤ 8) Blood cyanide concentrations before administration of hydroxocobalamin exceeded the typically lethal threshold of 100 lmol/L (2.6 mg/L) in 11 of the 12 patients with available blood cyanide concentrations.

PICO Analysis Cont’d... Interventions Retrospective chart review First-line treatment: hydroxocobalamin Comparators/Confounders Time between exposure and antidote administration Environment/context in which cyanide poisoning occurs Health/medical status of the patient Adequacy of supportive measures Outcomes of Interest Survival Post-treatment neurological status Adverse events Prehospital and hospital protocols in effect during the study period specified that hydroxocobalamin be administered intravenously as soon as medically feasible at an initial dose of 5 g. The hydroxocobalamin dose could be repeated and/or a second antidote could be used in the event of incomplete or transient response. All patients were treated with hydroxocobalamin as first-line antidotal therapy!

Methodology Weaknesses Strengths Retrospective study Chart review of cases between 1988-2003 from toxicological ICU in France Weaknesses Retrospective study No comparison group Small, heterogenous sample Strengths Measured blood cyanide levels Pure cyanide poisoning – eliminates other toxins present with smoke inhalation or co-ingestions -comment on: Search Strategy Quality Assessment tools Heterogeneity testing (if any) Measures of Association reported: Odds ratios (OR), Relative Risks (RR), Absolute Risk Reductions (ARR), Weighted Mean Differences (WMD), etc.

Study Results… Hydroxocobalamin (5-20 g) was administered to 14 consecutive patients beginning a median 2.1 hours and mean 3.1 hours after cyanide ingestion or inhalation. Hydroxocobalamin was administered in both the prehospital setting and at the hospital intensive care unit in 5 patients, only in the prehospital setting in 2 patients, and only in the hospital intensive care unit in 7 patients. Hydroxocobalamin was administered as the only cyanide antidote in 9 patients; other cyanide antidotes were administered in 5 patients (sodium thiosulfate in 4 and both sodium thiosulfate and dicobalt edetate in 1) Supportive therapy included normobaric oxygen in 11 patients, cardiopulmonary resuscitation in the 2 patients found in cardiac arrest, catecholamines at the scene or upon hospital admission in 8 patients, and mechanical ventilation in 7 patients A dose of 5 g hydroxocobalamin can neutralize estimated lethal doses of cyanide of approximately 50 to 100 mg as hydrogen cyanide or 150 to 200 mg of potassium cyanide in a human adult. (SAFETY OF HYDROXOCOBALAMIN in healthy volunteers RCT). Hydroxocobalamin appears to have been particularly useful in patients treated before the onset of cardiac arrest leading to anoxic brain damage. All 4 patients who died were in cardiac or cardiorespiratory arrest before hydroxocobalamin was administered. This finding underscores the need for rapid intervention. At the same time, however, results of this study support the existence of a window of time for effective intervention for acute cyanide poisoning, particularly in cases of ingestion of cyanide salts. The median time between ingestion or inhalation of cyanide and administration of hydroxocobalamin was 2.1 hours in the sample as a whole, in which 71% of patients survived. One patient with preintervention blood cyanide concentration of 170 lmol/L, a value substantially exceeding the typically lethal threshold, survived when treated with hydroxocobalamin 4 hours after cyanide ingestion. This patient ingested acetonitrile, which causes delayed onset of cyanide poisoning. Delayed onset of cyanide poisoning might explain the lag between ingestion and antidotal treatment in this case.

Study Results… Adverse Events Caused by Hydroxocobalamin: n = 8 Chromaturia (red-colored urine): n =5 Pink-to-red skin discoloration: n = 3 Increase in HR: n =1 Elevated BP: n = 1 Not sure if we want to include the other study for further proof of this point or just include them in our references but I noticed that a dose of 5 g hydroxocobalamin can neutralize estimated lethal doses of cyanide of approximately 50 to 100 mg as hydrogen cyanide or 150 to 200 mg of potassium cyanide in a human adult. (SAFETY OF HYDROXOCOBALAMIN in healthy volunteers RCT). Also we could talk about the dose related response in terms of Chromaturia and Pink/red discolouration as well as how quickly it starts and resolves. Adverse events = any untoward medical occurrences observed within 7 days after hydroxocobalamin administration Top picture from the trial we talk about, bottom picture from RCT trial with healthy volunteers. Borron et al. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. Uhl et al. Safety of Hydroxocobalamin in Healthy Volunteers in a RCT

Study Results… Of the 14 patients, 10 (71%) survived and were discharged, and 4 (29%) died in the intensive care unit because of postanoxic injury Of the 11 patients with blood cyanide exceeding the typically lethal threshold of 100 lmol/L, 7 survived. The mean (SD) time to death was 6.3 days (range, 4-12 days) All patients who died were in cardiorespiratory arrest before they were treated with hydroxocobalamin Of the 10 surviving patients, 9 had no clinically evident neurologic sequelae, and 1 had postanoxic encephalopathy with memory impairment (This patient first received hydroxocobalamin 12 hours after he was discovered and after he had suffered cardiac arrest leading to anoxic brain damage) Of the 9 patients administered hydroxocobalamin as sole antidote, 7 survived (1 with neurological sequelae). Of the 7 patients administered hydroxocobalamin as sole antidote and having a documented blood cyanide concentration greater than 100 lmol/L, 5 survived.

Conclusions… 71% of patients survived potentially lethal cyanide poisoning after treatment with hydroxocobalamin Need for rapid intervention Builds on previous case reports Risk-benefit profile supports empiric use in both the pre-hospital and hospital settings Uhl et al. Safety of Hydroxocobalamin in Healthy Volunteers in a Randomized, Placebo-Controlled Study In this retrospective chart review, use of hydroxocobalamin as a first-line antidote was associated with survival in 10 of 14 patients (71%). Of the 11 patients with blood cyanide exceeding the typically lethal threshold, 7 (64%) survived, and only 1 of these 7 patients had clinically evident neurologic sequelae. Severe cyanide poisoning of the nature observed in most patients in this study is frequently fatal. That 71% of patients survived after treatment with hydroxocobalamin suggests that hydroxocobalamin as first-line antidotal therapy is effective and safe in acute cyanide poisoning. Hydroxocobalamin appears to have been particularly useful in patients treated before the onset of cardiac arrest leading to anoxic brain damage. All 4 patients who died were in cardiac or cardiorespiratory arrest before hydroxocobalamin was administered. This finding underscores the need for rapid intervention. At the same time, however, results of this study support the existence of a window of time for effective intervention for acute cyanide poisoning, particularly in cases of ingestion of cyanide salts. These results extend previous case reports of successful use of hydroxocobalamin to treat acute cyanide To investigate the potential adverse effects of hydroxycobalamin, Uhl et al. conducted a randomized, double-blind, placebo-controlled, ascending-dose study in 136 healthy volunteers. No significant toxicity was observed. Hydroxycobalamin has an advantage over the CAK and 4-DMAP in that it does not further compromise oxygen transport. This makes hydroxocobalamin an ideal agent for prehospital use In the RCT on healthy volunteers two subjects developed an allergic reaction to Hydroxocobalamin this would be the only serious caveat to its use, but I think since it appeared to be a relatively rare occurrence the benefit would still outweigh the risk unless someone had a known anaphylatic allergy to hydoxocobalamin From Which Cyanide Antidote - Critical Reviews in Toxicology, 2009; 39(7): 541–552 The ideal cyanide antidote would neutralize cyanide without interfering with cellular oxygen use or oxygen transport. Cyanide inactivates mitochondrial cytochrome oxidase to prevent cells from using oxygen, which is the substrate of normal cellular respiration (Mégarbane et al., 2003). Antidotes that neutralize cyanide but impair cellular oxygen use can cause harm by further impairing cellular respiration in a system that is already compromised by cyanide. Ideally, an antidote would not impair cellular respiration. In smoke- inhalation victims, concomitant carbon monoxide poisoning results in formation of non-oxygen-transporting carboxyhemoglobin. The ideal cyanide antidote would not cause further decreases in oxygen transport, particularly by methemoglobin formation. ■■ The ideal cyanide antidote would have safety and tolerability profiles conducive to use in the prehospital setting, as well as in the emergency department or intensive care unit. Because of the need to initiate treatment rapidly, cyanide antidotes must often be administered in the prehospital setting at the scene of an emergency to be effective. Resources for management of ntidoteassociated toxicities and side effects may be limited in the prehospital setting. A benign adverse-effect profile with low potential for interactions with other agents administered for the care of acute cyanide poisoning is desirable. ■■ The ideal cyanide antidote would be safe for use with victims of smoke inhalation. Smoke inhalation is the most common cause of cyanide poisoning (Walsh and Eckstein, 2004).

Case Conclusion… Cyanide Antidote Kit (CAK) retrieved Sodium nitrite and sodium thiosulfate administered intravenously Further boluses of sodium bicarbonate given No cardiac activity seen on repeat bedside U/S Time of death called after over an hour of resuscitation Suicide note and printout on cyanide poisoning found in patients apartment The nitrites oxidize some of the hemoglobin's iron from the ferrous state to the ferric state, converting the hemoglobin into methemoglobin..Treatment with nitrites is not innocuous as methemoglobin cannot carry oxygen, and methemoglobinemia needs to be treated in turn with methylene blue). Cyanide preferentially bonds to methemoglobin rather than the cytochrome oxidase, converting methemoglobin into cyanmethemoglobin. In the last step, the intravenous sodium thiosulfate converts the cyanmethemoglobin to thiocyanate, sulfite, and hemoglobin. The thiocyanate is then excreted in the urine.

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References Borron SW, Baud FJ, Megarbane B and Bismuth C. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. American Journal of Emergency Medicine (2007) 25, 551–558 Rodgers GC and Condurache CT. Antidotes and treatments for chemical warfare/terrorism agents: an evidence-based review. Clinical Pharmacology Therapeutics. 2010 Sep;88(3):318-27. Gracia R and Shepherd G. Cyanide Poisoning and Its Treatment. Pharmacotherapy 2004;24(10):1306-1310. Uhl W, Nolting A, Golor G, Rost KL and Kovar, A. Safety of Hydroxocobalamin in Healthy Volunteers in a Randomized, Placebo-Controlled Study. Clinical Toxicology, 44:17–28, 2006. Alan H. Hall AH, Saiers J and Baud F. Which cyanide antidote? Critical Reviews in Toxicology, 2009; 39(7): 541–552. Borron SW, Baud FJ, Megarbane B and Bismuth C. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. American Journal of Emergency Medicine (2007) 25, 551–558 Rodgers GC and Condurache CT. Antidotes and treatments for chemical warfare/terrorism agents: an evidence-based review. Clinical Pharmacology Therapeutics. 2010 Sep;88(3):318-27. Gracia R and Shepherd G. Cyanide Poisoning and Its Treatment. Pharmacotherapy 2004;24(10):1306-1310. Uhl W, Nolting A, Golor G, Rost KL and Kovar, A. Safety of Hydroxocobalamin in Healthy Volunteers in a Randomized, Placebo-Controlled Study. Clinical Toxicology, 44:17–28, 2006. Alan H. Hall AH, Saiers J and Baud F. Which cyanide antidote? Critical Reviews in Toxicology, 2009; 39(7): 541–552.

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