Cyanide poisoning

INTRODUCTION — Cyanide is a mitochondrial toxin that is among the most rapidly lethal poisons known. Used in both ancient and modern times as a method of execution, cyanide causes death within minutes to hours of exposure. Though significant cyanide poisoning is uncommon, it must be recognized rapidly to ensure prompt administration of a lifesaving antidote and supportive treatment. A summary table to facilitate emergency management is provided (table 1).

This topic review will discuss the toxicity and management of cyanide poisoning. A general approach to the poisoned patient is found separately.

●(See "General approach to drug poisoning in adults".)

●(See "Initial management of the critically ill adult with an unknown overdose".)

●(See "Approach to the child with occult toxic exposure".)

EPIDEMIOLOGY AND SOURCES OF EXPOSURE — Approximately 150 to 200 single-substance non-rodenticide cyanide exposures involving two to four fatalities are reported annually to United States regional poison control centers [1-4]. Also, approximately 150 to 200 administrations of cyanide antidotes (eg, hydroxocobalamin, sodium thiosulfate) are reported annually to United States regional poison control centers. Cyanide poisoning may result from a broad range of exposures (table 2).

●Fire-related – In industrialized countries, the most common cause of cyanide poisoning is domestic fires [5]. Cyanide can be liberated during the combustion of products containing both carbon and nitrogen. These products include wool, silk, polyurethane (insulation/upholstery), polyacrylonitriles (plastics), melamine resins (household goods), and synthetic rubber [6-8]. Vehicular fires can also expose victims to cyanide. Toxicologic evaluation of passengers following the 1985 explosion of a Boeing 737 during takeoff in Manchester, England, revealed that 20 percent of the 137 victims who escaped had dangerously elevated levels of carbon monoxide, while 90 percent had dangerously elevated levels of cyanide [9]. Overall, it is reported that significant levels of cyanide are present in up to 35 percent of all fire victims [10].

●Industrial – Worldwide industrial consumption of cyanide is estimated to be 1.5 million tons per year, and occupational exposures account for a significant number of cyanide poisonings [11]. Metal extraction in mining, electroplating in jewelry production, photography, plastics and rubber manufacturing, hair removal from hides, and rodent pesticide and fumigants have all been implicated in cyanide poisonings. Skin contact with cyanide salts can result in burns, which allow for enhanced absorption of cyanide through the skin. The combination of cyanide salts and acid, as utilized in electroplating, results in the release of cyanide gas, which can lead to lethal inhalational exposures. Splashes of cyanide solutions can result in dermal as well as mucosal absorption [5,12].

●Medical – Cyanide exposures can result from alternative and standard medical treatments. Amygdalin (trade name Laetrile), a substance derived from apricot and peach kernels and introduced as an antineoplastic agent in the 1950s, can cause severe cyanide toxicity [13-15]. The drug is alleged to kill cancer cells selectively via its metabolite, hydrocyanic acid. Laetrile is available as a 500 mg oral tablet that contains 30 to 150 mg of amygdalin [16]. Intestinal beta-d-glucosidase digests the amygdalin, releasing hydrogen cyanide (HCN). This enzymatic reaction explains why only gastrointestinal exposure, in contrast to intravenous (IV) administration, results in toxicity [13].

Sodium nitroprusside, a medication used in the treatment of hypertensive emergencies, contains five cyanide groups per molecule. Toxic levels of cyanide may be reached in patients who receive prolonged infusions of sodium nitroprusside, in patients with chronic renal failure, or in pediatric patients [17,18]. Treatment for 3 to 10 hours with 5 to 10 mcg/kg per minute has resulted in fatalities [19]. Methods for preventing nitroprusside-induced cyanide poisoning include using silver foil on IV tubing (preventing light from decomposing the nitroprusside molecule), using maximal infusion rates of 2 mcg/kg per minute, and adding sodium thiosulfate to the nitroprusside solution [20]. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Nitroprusside'.)

●Diet – The family Rosaceae, which includes the bitter almond, cherry laurel, apricot, plum, peach, pear, and apple, is responsible for many reported cyanide poisonings. These foods all contain cyanogenic glycosides, such as amygdalin, in their pits and seeds. The common (ie, sweet) almond does not cause cyanide intoxication. Other foods containing possible cyanogens include cassava root, bamboo shoots, and soy [21].

●Other – Ingestion of cyanide salts, such as potassium cyanide and sodium cyanide, continues to be a method of both suicide and homicidal/terrorist acts [22]. Miscellaneous exposure to cyanide may occur during illicit synthesis of phencyclidine, ingestion of acetonitrile (artificial nail polish remover), and cigarette smoking. Because of the natural cyanide found in tobacco, cigarette smokers have more than 2.5 times the mean whole blood cyanide level of nonsmokers (table 1) [23].

PATHOPHYSIOLOGY — In normal cellular metabolism, most adenosine triphosphate (ATP) is generated from oxidative phosphorylation. An important part of this process is the shuttling of electrons through the mitochondrial cytochrome complex (also known as the electron transport chain) (figure 1).

Cyanide avidly binds to the ferric ion (Fe3+) of cytochrome oxidase a3, inhibiting this final enzyme in the mitochondrial cytochrome complex. When this enzyme's activity is blocked, oxidative phosphorylation ceases. The cell must then switch to anaerobic metabolism of glucose to generate ATP.

Anaerobic metabolism leads to the formation of lactic acid and the development of metabolic acidosis. Hydrogen ions produced by ATP hydrolysis are no longer consumed in aerobic ATP production, exacerbating this acidosis [24]. Serum bicarbonate decreases as it buffers excess acid, leading to an increased anion gap.

Despite an ample oxygen supply, cells cannot utilize oxygen because of their poisoned electron transport chain. This functional (or "histotoxic") hypoxia is particularly deleterious to the cardiovascular and central nervous systems (especially the basal ganglia).

A number of other mechanisms may exacerbate brain injury. Cyanide's nonspecific inhibition of antioxidants (such as catalase, glutathione reductase, and superoxide dismutase) results in the accumulation of toxic oxygen free radicals. Cyanide stimulates N-methyl-D-aspartate (NMDA) receptors, inducing apoptotic cell death. It also inhibits glutamic acid decarboxylase, the enzyme responsible for the formation of the inhibitory neurotransmitter gamma–aminobutyric acid (GABA) from glutamic acid. Consequently, cyanide increases the risk of seizures as GABA levels fall [25-27].

Although cyanide has a primary affinity for Fe3+, a small amount may bind to the ferrous ion (Fe2+) of hemoglobin, forming cyanohemoglobin, which is unable to transport oxygen, thereby further exacerbating tissue hypoxia [19].

KINETICS AND METABOLISM — Cyanide is rapidly absorbed through the respiratory tract and mucous membranes, and it can also be absorbed through the gastrointestinal tract and skin [28]. Symptoms and signs of poisoning begin at blood cyanide concentrations of approximately 40 micromol/L [29]. Once absorbed, cyanide is quickly distributed in the body with an estimated volume of distribution of 1.5 L/kg. Approximately 60 percent is protein bound [10].

In vivo, cyanide metabolism and neutralization involve a number of mechanisms. The most important is the detoxification of cyanide via rhodanese. Rhodanese is an enzyme found abundantly in many tissues, particularly the liver and muscle [28]. Thiosulfate serves as a sulfur donor in the reaction catalyzed by rhodanese that converts cyanide to thiocyanate, a water-soluble molecule excreted in the urine [5].

A minor pathway for cyanide detoxification involves hydroxocobalamin, the precursor to vitamin B12. Circulating hydroxocobalamin combines with cyanide to form cyanocobalamin, which is safely excreted in the urine. Finally, a small amount of unmetabolized cyanide is eliminated through urine, sweat, and expiration [5].

CLINICAL PRESENTATION

Acute exposure — Clinical features of cyanide poisoning are dependent upon the route, source, and severity of exposure. Central nervous system and cardiovascular system dysfunction are most prominent. Symptoms and signs can include the following:

●Central nervous system – Headache, anxiety, confusion, vertigo, loss of consciousness, seizures

●Cardiovascular – Initially tachycardia and hypertension, then bradycardia and hypotension, and dysrhythmias [30]

●Respiratory – Initial tachypnea then bradypnea, pulmonary edema

●Gastrointestinal – Vomiting, abdominal pain

●Skin – Flushing ("cherry-red" color), cyanosis, irritant dermatitis (itching, erythema, edema, vesicles resulting from skin exposure) [31]

●Renal – Renal failure

●Hepatic – Hepatic necrosis

●Miscellaneous – Rhabdomyolysis, bright red venules seen on funduscopy, bitter almond or unusual odor [30,32,33]

Because cyanide poisoning impairs the utilization of oxygen by tissues, the venous oxyhemoglobin concentration is high, resulting in a bright red appearance to venous blood. On physical examination, this may manifest as a "cherry-red" color to the skin. However, this sign is present in a minority of cyanide-toxic patients. According to a review of 102 cases, a "cherry-red" skin color was found in only 11 percent of patients [33]. Normal skin color and cyanosis were more common skin findings.

The severity of symptoms depends on the route, dose, and duration of cyanide poisoning (table 3). After inhaling hydrogen cyanide (HCN), the victim may detect a bitter almond odor (discernible to approximately 60 percent of the population) [32]. Initially, inhalation of small amounts of HCN causes headache, anxiety, nausea, and a metallic taste [12]. In contrast, cyanogen chloride exposure predominantly results in eye and mucous membrane irritation and then pulmonary symptoms, namely bronchorrhea, cough, and dyspnea [26]. Inhalation of 100 ppm for 30 minutes or 300 ppm for five minutes is usually fatal [12].

While toxicity from inhalational exposure begins within seconds, toxicity from ingestion or dermal exposure is delayed from minutes to hours, depending on the extent of exposure. Ingestion of cyanide salts results in gastric irritation, frequently causing vomiting and abdominal pain [19].

Inhalational exposure to HCN gas at concentrations of approximately 200 parts per million will likely result in instantaneous death. However, lower concentrations over longer periods can also result in severe symptoms and death [34]. The average lethal dose from oral exposure is 1.52 mg/kg [34]. The lethal dermal exposure is estimated to be 100 mg/kg (table 3) [10].

Delayed sequelae — Survivors of severe cyanide poisoning may develop delayed-onset Parkinsonism or other neurologic sequelae. The basal ganglia are particularly sensitive to cyanide toxicity [32]. Basal ganglia injury may be due to either direct cellular injury or secondary to hypoxic effects. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain may demonstrate radiologic changes several weeks after the exposure. Resolution of symptoms is variable, and treatment is supportive.

Chronic cyanide exposure — Chronic cyanide exposure results in vague symptoms such as headache, dysgeusia (abnormal taste), vomiting, chest pain, abdominal pain, and anxiety [12]. There are at least three insidious syndromes associated with chronic, low-level cyanide exposure: tobacco amblyopia, tropical ataxic neuropathy, and Leber hereditary optic neuropathy.

Tobacco amblyopia occurs predominantly in male cigarette smokers and manifests as progressive visual loss. It may result from an inherent inability to detoxify cyanide, and symptoms may reverse following smoking cessation or hydroxocobalamin (Cyanokit) administration.

Tropical ataxic neuropathy is a demyelinating condition associated with excessive cassava consumption, usually in the poor and malnourished. The cassava plant contains a cyanogen, linamarin, which may be ingested if preparation of the plant is inadequate. Signs and symptoms of tropical ataxic neuropathy include paresthesias, ataxia, hearing loss, and optic atrophy. Vitamin B12 deficiency may contribute to the condition. Cessation of dietary cassava and administration of vitamin B12 ameliorate symptoms.

Leber hereditary optic neuropathy is a rare, gradual loss of central vision that appears to be due to a defect in cyanide metabolism. A deficiency of rhodanese is one proposed mechanism.

LABORATORY EVALUATION

General testing — Routine laboratory evaluation in the potentially poisoned patient should include the following:

●Point-of-care (eg, fingerstick) glucose concentration to rule out hypoglycemia as the cause of any alteration in mental status

●Acetaminophen and salicylate concentrations to rule out these common co-ingestions

●Electrocardiogram (ECG) to rule out conduction system poisoning by drugs that affect the QRS or QTc intervals

●Pregnancy test in female patients of childbearing age

Specific testing — Specific testing in cases of potential cyanide poisoning should also include the following:

●Basic blood chemistries (eg, Na+, Cl-, K+, HCO3-) and arterial or venous blood gas to assess for anion gap metabolic acidosis

●Blood lactate concentration to confirm hyperlactatemia

●Central venous blood gas, if possible, to assess venous-arterial partial pressure of oxygen (PO₂) gradient

●Carboxyhemoglobin and methemoglobin levels (measured by co-oximetry), particularly if there is any concern for concomitant carbon monoxide exposure (eg, house or vehicle fire) or exposure to drugs that produce methemoglobinemia (table 1) (see "Carbon monoxide poisoning" and "Inhalation injury from heat, smoke, or chemical irritants")

Of note, treatment with hydroxocobalamin affects a number of laboratory tests. (See 'Hydroxocobalamin' below.)

Anion gap acidosis — A severe metabolic acidosis with an increased anion gap is expected in cyanide poisoning. In addition to its inhibitory effects on cellular respiration, cyanide can induce cardiovascular collapse and seizures, which exacerbate anion gap metabolic acidosis. (See 'Pathophysiology' above.)

Lactate — Cyanide-poisoned patients have an elevated blood lactate concentration. A retrospective study of 11 intensive care unit patients with cyanide poisoning found that plasma lactate concentrations correlated closely with the severity of cyanide toxicity [35]. There were significant inverse correlations between lactate and systolic blood pressure, respiratory rate, and arterial pH. In fact, lactate concentrations of 10 mmol/L or greater have been shown to be both sensitive and specific for cyanide poisoning in smoke inhalation victims [36]. Consequently, a normal serum lactate should lead the clinician to entertain other diagnoses, while serial lactate measurements can be used to monitor the progress of patients being treated for cyanide poisoning. Of note, a significant delay in laboratory processing of the patient's blood sample may cause an artificial elevation in lactate concentration.

Venous PO2 — A narrowing of the venous-arterial PO₂ gradient (ie, venous hyperoxia) may be seen in the cyanide-poisoned patient [37]. Cyanide inhibits cellular oxidative phosphorylation, resulting in a marked decrease in peripheral tissue oxygen extraction from the blood. This results in elevated central venous oxygenation. On examination, the skin may appear flushed and the venules in the retina bright red. Laboratory evaluation may reveal a decreased arterial–venous oxygen gradient. Clinicians should keep in mind that a decreased oxygen gradient is nonspecific and can result from other inhibitors of oxidative phosphorylation, such as carbon monoxide, hydrogen sulfide, and azides.

Cyanide concentration (level) — Blood cyanide concentrations may be obtained for diagnostic confirmation, but results are not available in time to be clinically useful. Even when available, the results of direct testing may be unreliable as both proper storage conditions and prompt blood draws are required. Furthermore, blood cyanide concentrations do not correlate directly with survival. Nonetheless, blood cyanide concentrations of 0.5 to 1 mg/L (12 to 23 micromol/L) generally correlate with tachycardia and flushing, 1 to 2.5 mg/L (23 to 58 micromol/L) with obtundation, 2.5 to 3 mg/L (58 to 69 micromol/L) with coma, and greater than 3 mg/L (>69 micromol/L) with death [26].

Cyantesmo test strips are colorimetric strips used in the testing of wastewater and during autopsies. One in vitro study assessed the ability of these strips to detect cyanide in simulated samples [38] and found they were accurate only at markedly elevated cyanide levels. Additional work is needed before this test can be considered for routine clinical use.

Given the limitations of cyanide concentration testing, antidotal treatment should be administered empirically based on the clinical presentation, and blood cyanide levels should serve mainly as confirmation.

DIAGNOSIS — Cyanide poisoning is an uncommon entity. Therefore, making the diagnosis requires that the clinician maintain a high index of suspicion based on the history and clinical presentation. Patients who are victims of fires or reported ingestions, are exposed at work, or have recently been treated with sodium nitroprusside should all be considered potentially poisoned with cyanide. When a clear history is unavailable, clinicians should consider any patient with altered mental status and a metabolic acidosis of unknown etiology a possible victim of cyanide poisoning. Blood cyanide concentrations may not correlate with toxicity, and results are rarely available in time to guide the clinical management of acutely poisoned patients.

DIFFERENTIAL DIAGNOSIS — Carbon monoxide poisoning is similar to cyanide in presentation. (See "Carbon monoxide poisoning".)

Due to cyanide's wide range of possible symptoms and signs, the clinician must consider a number of potential diagnoses, including those listed below. Generally, the diagnosis is made based on a history of exposure and a consistent clinical presentation, since very few of these intoxicants have a rapidly available diagnostic test. If the diagnosis is in doubt, clinicians should seek assistance from a medical toxicologist or regional poison center. (See 'Additional resources' below.)

A patient with altered mental status, seizures, hypotension, and lactic acidosis may be poisoned with:

●Tricyclic antidepressants (see "Tricyclic antidepressant poisoning")

●Isoniazid (see "Isoniazid: An overview")

●Organophosphates (see "Organophosphate and carbamate poisoning")

●Salicylates (see "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation")

●Methemoglobin producing agents (see "Methemoglobinemia")

●Strychnine (see "Strychnine poisoning")

A patient who suddenly collapsed after exposure to a gas may be poisoned with:

●Carbon monoxide (see "Carbon monoxide poisoning")

●Hydrogen sulfide gas

●Phosphine

●Arsine (see "Chemical terrorism: Rapid recognition and initial medical management")

●Asphyxiants (eg, methane)

Also, exposure to cyanogen chloride can mimic exposure to any chemical irritant (eg, chlorine) [32].

MANAGEMENT — Untreated cyanide poisoning is rapidly lethal. If clinical history and examination are suggestive of cyanide poisoning, antidotal therapy must be given immediately, barring any contraindications. Management should also include resuscitation and decontamination. A summary table to facilitate emergency management is provided (table 1). (See 'Treatment with antidotes' below.)

Care must be taken when evaluating victims of smoke inhalation. Carbon monoxide poisoned patients present similarly to those also poisoned by cyanide, and clinicians may focus on easily obtained carboxyhemoglobin levels, inadvertently neglecting to manage co-existent cyanide toxicity [21]. Cyanide toxicity should be considered in all smoke inhalation patients with two or more of the following: carbonaceous material in the oropharynx, neurologic dysfunction, metabolic acidosis on arterial blood gas, and serum lactate >8 mmol/L [39]. (See "Inhalation injury from heat, smoke, or chemical irritants".)

The recognition and management of cyanide poisoning can be difficult, and clinicians should seek assistance from a medical toxicologist or a regional poison center if they have any questions or concerns. (See 'Additional resources' below.)

Resuscitation — First, clinicians must stabilize the patient's airway, breathing, and circulation. The patient's airway should be secured as necessary, and high-flow oxygen should be given regardless of pulse oximetry readings. Rescue breaths are contraindicated in cyanide poisoning due to the risk of exposure to the provider of cardiopulmonary resuscitation (CPR) [19]. Otherwise, CPR should be provided as per advanced cardiac life support protocols. (See "Advanced cardiac life support (ACLS) in adults" and "Adult basic life support (BLS) for health care providers" and "Pediatric basic life support (BLS) for health care providers".)

In unresponsive patients, point-of-care testing of serum glucose should be performed and, if hypoglycemic, supplemental dextrose should be administered. Naloxone should be administered if opioid toxicity is suspected. Thiamine is a benign antidote, and its administration should be considered, particularly in patients with a history of alcohol abuse. (See "Stupor and coma in adults".)

Seizures associated with cyanide poisoning are treated with benzodiazepines. Hypotension is treated with fluids and vasopressors as needed. Comorbid conditions and concurrent exposures are treated as necessary. Detailed discussions of the general management of the poisoned patient are provided separately. (See "Initial management of the critically ill adult with an unknown overdose" and "General approach to drug poisoning in adults".)

Decontamination — Patients poisoned by cyanide through inhalation or topical exposure must be rapidly removed from the source and their clothing taken off and appropriately discarded. In dermal exposures, wounds must be cleansed with soap and water to prevent further absorption. Rescuers should wear protective suits and respirators until proper decontamination is completed [40]. (See "Topical chemical burns: Initial evaluation and management".)

Gastrointestinal decontamination should be performed rapidly in cases of oral ingestion, as cyanide is quickly absorbed. Although laboratory studies have demonstrated that cyanide binds poorly to activated charcoal (AC), animal studies report decreased mortality among rats given AC after lethal potassium cyanide ingestions [41]. Therefore, we recommend administration of a single dose of AC (50 g in adults; 1 g/kg, up to 50 g maximum, in children). There is no evidence to support use of multiple doses of AC or cathartics such as magnesium citrate or sorbitol. AC should be withheld in non-intubated patients with depressed mental status. (See "Gastrointestinal decontamination of the poisoned patient".)

Orogastric lavage is not generally recommended. It should only be attempted if ingestion is recent and a large amount of cyanide is thought to be present in the upper gastrointestinal tract [42].

Antidotes: Concepts and available therapies — If clinical history and examination are suggestive of cyanide poisoning, antidotal therapy must be given immediately, barring any contraindications. (See 'Treatment with antidotes' below.)

Antidotal treatment of cyanide poisoning involves three possible strategies: binding of cyanide, induction of methemoglobinemia, and use of sulfur donors.

Direct cyanide binding — One strategy for cyanide neutralization involves direct binding of cyanide, preferably using hydroxocobalamin (Cyanokit). Dicobalt edetate also binds cyanide but can cause severe side effects.

Hydroxocobalamin — Hydroxocobalamin, a precursor of vitamin B12, contains a cobalt moiety that avidly binds to intracellular cyanide (with greater affinity than cytochrome oxidase), forming cyanocobalamin [43]. This molecule is stable and readily excreted in the urine. Because hydroxocobalamin acts rapidly, does not adversely affect tissue oxygenation, and is relatively safe, many investigators recommend it be used as the first-line agent in cyanide poisoning whenever it is available, and we concur with this approach [44,45].

The dose of hydroxocobalamin is 70 mg/kg (typical adult dose is 5 g) given intravenously (IV). This dose is effective for the majority of adult patients when cyanide exposure occurs by inhalation (eg, smoke inhalation). A second full dose may be given depending upon the severity of poisoning or the clinical response to treatment. Additional doses of hydroxycobalamin may be necessary in cases of severe poisoning (eg, oral ingestion) and for patients presenting in extremis. Although optimum pediatric dosing is not well established, some recommend 70 mg/kg IV (maximum dose 5 g) [26]. The half-life is 24 to 48 hours. In France, hydroxocobalamin is commonly used in conjunction with sodium thiosulfate, a combination shown to be effective and safe in severe cyanide poisoning [10,46-48].

Hydroxocobalamin, when given at the recommended dose, may cause a temporary reddish discoloration of the skin, plasma, urine, and mucous membranes [49,50]. These changes last for approximately two to three days, altering the laboratory values of tests performed using co-oximetry or spectrophotometry. Blood tests that may be affected include creatinine, lactate, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), bilirubin, and magnesium [21,51-53]. Common urinalysis tests may also be affected (eg, glucose, protein, ketones, and leukocyte and erythrocyte counts).

As IV infusion of hydroxocobalamin interferes with co-oximetry measurements of total hemoglobin, carboxyhemoglobin, methemoglobin, and oxyhemoglobin, the assessment of smoke inhalation victims (who may suffer from simultaneous cyanide and carbon monoxide poisoning) is complicated by hydroxocobalamin administration [54,55].

Overall, hydroxocobalamin is safe and effective [43,56]. In a study of smoke inhalation victims who received hydroxocobalamin in the pre-hospital setting, survival was 74 percent (28/42) and 62 percent (8/13) in patients with blood cyanide concentrations of 1.7 to 4.3 mg/L (39 to 99 micromol/L) and >4.3 mg/L (100 micromol/L, which is typically fatal), respectively [46]. In patients with confirmed cyanide toxicity and neurologic impairment, 51 percent (21/41) had neurologic improvement after hydroxocobalamin administration. All 15 patients who had cardiac arrest had hemodynamic improvement after hydroxocobalamin administration, but only 13 percent (2/15) survived to hospital discharge. In another study of smoke inhalation victims who received hydroxocobalamin in the pre-hospital setting, 42 percent (30/72) survived [47]. In 38 patients who had cardiac arrest, 21 (55 percent) had a return of spontaneous circulation, and in the 12 patients who were hypotensive, nine (75 percent) had improvement in blood pressure. One study of heavy cigarette smokers found that hydroxocobalamin decreased blood cyanide concentrations by 59 percent [57]. In a study of dogs administered cyanide, mortality was 21 percent after hydroxocobalamin 75 mg/kg and zero after hydroxocobalamin 150 mg/kg compared with 82 percent in dogs given placebo [58].

In one study of hydroxocobalamin administration in adults, adverse effects from high doses included rash, headache, nausea, chest discomfort, decreased lymphocyte percentage, and dysphagia [59]. At the recommended dose, both transient hypertension and slowing of the heart rate have been reported [10,52,57].

Dicobalt edetate — Dicobalt edetate is an IV chelator of cyanide, with a rapid onset of action, used primarily in the United Kingdom (it is not approved by the US Food and Drug Administration [FDA]). The dose is 20 mL of a 1.5% solution given over one minute. Although its use has been associated with multiple severe side effects including seizures, anaphylaxis, hypotension, and cardiac dysrhythmias [5]; a systematic review reports that this antidote is efficacious and that adverse effects may be less severe than previously thought [60]. Adverse effects appear to be more prominent when evidence of cyanide toxicity is mild or absent. Published cases of dicobalt edetate as an antidote for cyanide poisoning are limited [60], and additional experience with this antidote is needed to determine its safety and efficacy.

Induction of methemoglobinemia — Another antidotal strategy involves the induction of methemoglobin. The formation of methemoglobin entails the oxidation of the ferrous (Fe2+) moiety in hemoglobin to the ferric (Fe3+) form. This provides an attractive alternative binding site for cyanide, in direct competition with the site on the cytochrome complex. When cyanide binds methemoglobin, a relatively less toxic cyanmethemoglobin is formed [19].

The induction of methemoglobinemia can be accomplished by the administration of either sodium nitrite or dimethylaminophenol (4-DMAP; not approved by the FDA). Nitrites should be avoided in pregnant patients. Sodium nitrite 300 mg is administered IV and typically induces a 15 to 20 percent methemoglobinemia [59], but the response can be quite variable. This degree of methemoglobinemia is tolerated by most patients. However, methemoglobin shifts the oxygen-hemoglobin dissociation curve to the left, further hindering oxygen delivery to tissues (figure 2). Therefore, a decreased dose is used for patients with anemia because of potential adverse effects due to the formation of methemoglobin.

The appropriate dose of sodium nitrite given to patients with anemia can be adjusted according to the patient's hemoglobin. A medical toxicologist or regional poison center should be consulted for appropriate dosing. Approximate initial dosing is as follows:

●Hemoglobin 7 g/dL, dose is 0.19 mL/kg of 3% sodium nitrite

●Hemoglobin 8 g/dL, dose is 0.22 mL/kg of 3% sodium nitrite

●Hemoglobin 9 g/dL, dose is 0.25 mL/kg of 3% sodium nitrite

●Hemoglobin 10 g/dL, dose is 0.27 mL/kg of 3% sodium nitrite

●Hemoglobin 11 g/dL, dose is 0.30 mL/kg of 3% sodium nitrite

Patients receiving nitrites may develop hypotension and tachycardia [19]. These side effects are somewhat rate dependent. Arthralgias, myalgias, vomiting, and psychosis may also occur.

Prior to the availability of hydroxocobalamin (the preferred treatment for cyanide poisoning), in the United Sates, induction of methemoglobin was accomplished using the Cyanide Antidote Kit. The components of the now discontinued kit included amyl nitrite, sodium nitrite, and sodium thiosulfate. The Cyanide Antidote Kit has been replaced with copackaged sodium nitrite and sodium thiosulfate (Nithiodote), which may be needed if hydroxocobalamin is unavailable. Sodium nitrite and sodium thiosulfate are also available separately. Treatment with sodium nitrite is contraindicated in cases of concurrent carbon monoxide toxicity because it further impairs oxygen delivery.

In addition to inducing a methemoglobinemia, nitrites may provide benefit by causing vasodilation. Nitrites release nitrous oxide, a vasodilator, leading to increased blood flow to the liver and other organs, thereby enhancing the metabolism of cyanide. This proposed effect is supported by the success of other vasodilators in protecting the body from cyanide toxicity [26,61]. In an animal experiment, nitrite treatment alone provided a protective effect and tripled the dose of cyanide needed to cause death [26].

4-DMAP, an agent introduced in Germany, is another inducer of methemoglobin. 4-DMAP is given in a dose of 5 mL of a 5% solution IV over one minute. It is potent and rapidly acting, achieving peak levels of methemoglobin within five minutes of administration. The potency of 4-DMAP, which can require methylene blue to reverse the extent of methemoglobinemia, is problematic. Methylene blue, the recommended reversal agent for methemoglobinemia, should be avoided in the setting of cyanide poisoning because its use can release free cyanide [62]. Other potential adverse effects of 4-DMAP include reticulocytosis, nephrotoxicity, and hemolysis [5]. (See "Methemoglobinemia".)

Of special note, patients who are victims of fires may be suffering from both carbon monoxide and cyanide toxicity. Carboxyhemoglobin causes the oxygen-hemoglobin dissociation curve to be shifted to the left, creating tissue hypoxia. In these patients, the induction of methemoglobinemia could be lethal [63]. (See "Carbon monoxide poisoning" and "Inhalation injury from heat, smoke, or chemical irritants".)

Sulfur donors — A third antidotal strategy involves maximizing the availability of sulfur donors for rhodanese, a ubiquitous enzyme that detoxifies cyanide by transforming it to thiocyanate. Thiocyanate is then renally excreted. The therapeutic sulfur donor of choice is sodium thiosulfate.

In theory, a 3:1 ratio of sodium thiosulfate to cyanide is required for complete detoxification. The standard adult dose of sodium thiosulfate is 50 mL of a 25% solution, or 12.5 g [19,26]. The onset of action may be slow (up to 30 minutes). Because thiocyanate levels of 10 mg/dL or higher may cause psychosis, arthralgias, vomiting, and myalgias, patients with renal failure may require hemodialysis to remove it from the bloodstream [10]. However, in most patients, sodium thiosulfate is safe and well tolerated.

In an animal experiment, thiosulfate treatment alone also provided a protective effect and quadrupled the dose of cyanide needed to cause death [26]. In combination, however, nitrites (lone treatment tripled the lethal dose of cyanide) and thiosulfate increased the dose of cyanide required to cause death 13-fold suggesting synergy between the two treatments.

The efficacy of dimethyl trisulfide (DMTS) for treating cyanide poisoning has been investigated in animal studies. DMTS is a plant-based sulfur donor that enhances cyanide clearance, has minimal side effects, and appears to be effective when administered intramuscularly [64,65]. A study of DMTS in vitro and in vivo (mouse model) revealed that DMTS penetrates the blood-brain barrier, which would afford protection against central nervous system damage [66].

Adjunct treatment with hyperbaric oxygen — The results of two animal studies suggest that hyperbaric oxygen (HBO), used in combination with antidotal therapy, is an effective treatment for cyanide toxicity [67,68]. One study found that HBO may facilitate transport of cyanide from tissue to blood, theoretically enhancing detoxification [67]. The other reported improved respiratory status and a decreased surge in brain lactate with HBO therapy [68]. However, due to inconsistent findings in the literature overall, the use of HBO therapy in cyanide poisoning remains controversial. Further research and controlled studies in humans are needed.

Treatment with antidotes

Overall recommendations and risks of nitrite therapy — Cyanide poisoning is rare but requires decisive action when present. We recommend treatment with hydroxocobalamin whenever it is available.

In hospitals where hydroxocobalamin is unavailable, treatment with nitrites may be lifesaving. When the history and clinical findings strongly suggest cyanide toxicity, and hydroxocobalamin is not available, we recommend prompt treatment with both nitrites and sodium thiosulfate. In such cases, the benefit of therapy outweighs the risks of methemoglobinemia. Patient assessment must be performed carefully, as induction of 20 to 30 percent methemoglobinemia in a patient who is critically ill from an etiology other than cyanide poisoning can cause significant patient morbidity or mortality. Methemoglobinemia can be harmful in anemic patients, who have little reserve. Nitrites should be avoided in pregnant patients and patients with carbon monoxide poisoning. (See 'Induction of methemoglobinemia' above.)

Suspected cyanide intoxication — Availability of treatment varies by region and hospital. Immediately below is a series of antidotal management recommendations, based upon treatment availability, for patients with suspected cyanide intoxication:

Hydroxocobalamin available

●For patients in locations where hydroxocobalamin is available, it is the preferred treatment. We recommend giving:

•Hydroxocobalamin 5 g (adults) or 70 mg/kg IV (pediatric patients, maximum 5 g)

●If the patient does not have rapid clinical improvement after the initial dose, we recommend repeating the dose. A second dose can be given 10 to 15 minutes after completion of the first dose.

●In extreme cases where no clinical improvement occurs after two doses of hydroxocobalamin, it is reasonable to give a third dose of hydroxocobalamin and sodium thiosulfate (25% solution) 50 mL (12.5 g) IV for adults or 1.65 mL/kg IV (412.5 mg/kg) IV for pediatric patients (maximum 12.5 g). In this situation, sodium thiosulfate should be administered via a separate IV line from the one used to give hydroxocobalamin.

Hydroxocobalamin not available

●For patients without contraindication to nitrites and in locations where hydroxocobalamin is not available, we recommend treatment as follows [61]:

Adult:

•Sodium nitrite (3% solution) 10 mL IV (300 mg) at 2.5 to 5 mL per minute

and

•Sodium thiosulfate (25% solution) 50 mL IV (12.5 g) immediately following sodium nitrite administration

Pediatric:

•Sodium nitrite (3% solution) 0.2mL/kg (6 mg/kg) IV at 2.5 to 5 mL per minute, not to exceed 10 mL (300mg)

and

•Sodium thiosulfate (25% solution) 1.65 mL/kg (412.5 mg/kg) IV (maximum dose 12.5 g or 50 mL) given immediately following sodium nitrite administration

Hydroxocobalamin not available and nitrites contraindicated — For patients with contraindications to nitrites or with smoke inhalation (pending test results for carboxyhemoglobin) in locations where hydroxocobalamin is not available, we recommend sodium thiosulfate monotherapy:

•Sodium thiosulfate (25% solution) 50 mL (12.5 g) IV for adults or 1.65 mL/kg IV (412.5 mg/kg) for pediatric patients (maximum 12.5 g)

Treatment with sodium nitrite is contraindicated in cases of potential carbon monoxide toxicity (eg, from a fire), until such toxicity has been excluded, because it further impairs oxygen delivery.

Only alternative therapies available — In locations where 4-DMAP or dicobalt edetate is available, there are no contraindications to either drug, and neither hydroxocobalamin nor sodium nitrite is available, we recommend administering:

●4-DMAP (5% solution) 5 mL IV over one minute or

●If 4-DMAP is unavailable and only if cyanide poisoning is highly suspected or confirmed, give dicobalt edetate (1.5% solution) 20 mL IV over one minute

Empiric treatment for smoke inhalation — Clinicians should consider the possibility of cyanide toxicity and maintain a low threshold for initiating treatment in victims of smoke inhalation. Frequently, victims of house fires have a depressed level of consciousness, which may be caused by cyanide, carbon monoxide, other inhaled or ingested toxins, traumatic shock, or head injury. The pathophysiology and general management of smoke inhalation is discussed separately. (See "Inhalation injury from heat, smoke, or chemical irritants".)

We suggest that empiric treatment for cyanide toxicity be initiated in victims of smoke inhalation with an unexplained metabolic acidosis and increased blood lactate concentration or a low or declining end-tidal carbon dioxide (EtCO₂) level. If these measurements are unavailable, we suggest treatment be initiated in any patient demonstrating a depressed level of consciousness, cardiac arrest, or hemodynamic decompensation [69].

The preferred antidotal treatment in this setting is identical to that for suspected cyanide poisoning:

●Hydroxocobalamin 5 g (adults) or 70 mg/kg IV (pediatric patients, maximum 5 g)

Treatment with sodium nitrite is contraindicated in cases of potential carbon monoxide toxicity (eg, from a fire), until such toxicity has been excluded, because it further impairs oxygen delivery. (See 'Induction of methemoglobinemia' above.)

Blood lactate and EtCO₂ monitoring may provide useful information when determining management of smoke inhalation victims. Cyanide toxicity poisons mitochondria, forcing cells to use anaerobic metabolism. This results in a metabolic acidosis with a high lactate concentration and a compensatory drop in EtCO₂. (See 'Pathophysiology' above and "Carbon dioxide monitoring (capnography)".)

Of note, hydroxocobalamin administration can interfere with carboxyhemoglobin measurements, causing the carboxyhemoglobin values obtained from co-oximetry to be inaccurate. (See "Carbon monoxide poisoning", section on 'Diagnosis'.)

PEDIATRIC CONSIDERATIONS — The pathophysiology and clinical manifestations of acute cyanide poisoning are similar for children and adults [70]. However, pediatric patients appear to be more vulnerable to cyanide poisoning from smoke inhalation. This is thought to be due to their immature metabolism, lower body mass, and higher respiratory rate. (See 'Clinical presentation' above.)

As young children have higher concentrations of fetal hemoglobin and less methemoglobin reductase than adults, induced methemoglobinemia can reduce oxygen-carrying capacity to dangerously low levels. Therefore, hydroxocobalamin is the preferred treatment for cyanide intoxication, and it is considered safe in children [71]. Although optimum pediatric dosing is not well established, some recommend 70 mg/kg intravenously (IV; maximum 5 g) [26,71].

The major concern in children with cyanide poisoning involves management using sodium nitrite when hydroxocobalamin is unavailable. To avoid dangerously high methemoglobin levels, sodium nitrite should be dosed according to the patient's hemoglobin. A medical toxicologist or regional poison center should be consulted for dosing details and assistance with management. The approximate initial dose of sodium nitrite, to be given no faster than 5 mL per minute, is as follows [12]:

●Hemoglobin 7 g/dL, dose is 0.19 mL/kg of 3% sodium nitrite

●Hemoglobin 8 g/dL, dose is 0.22 mL/kg of 3% sodium nitrite

●Hemoglobin 9 g/dL, dose is 0.25 mL/kg of 3% sodium nitrite

●Hemoglobin 10 g/dL, dose is 0.27 mL/kg of 3% sodium nitrite

●Hemoglobin 11 g/dL, dose is 0.30 mL/kg of 3% sodium nitrite

●Hemoglobin 12 g/dL, dose is 0.33 mL/kg of 3% sodium nitrite

●Hemoglobin 13 g/dL, dose is 0.36 mL/kg of 3% sodium nitrite

●Hemoglobin 14 g/dL, dose is 0.39 mL/kg of 3% sodium nitrite

Point-of-care hemoglobin testing makes this approach easier to perform. In emergency departments where a rapid hemoglobin level is difficult to obtain, pediatric patients can be dosed based on their weight. The recommended pediatric dose of sodium nitrite is 0.2 mL/kg (6 mg/kg) of a 3% solution IV. The dose should not exceed 10 mL and should not be given at a rate greater than 5 mL per minute to avoid significant hypotension.

Sodium thiosulfate is given as 412.5 mg/kg IV (1.65 mL/kg of a 25% solution, up to a maximum of 12.5 g [50 mL]) [61]. For pediatric patients, we use a higher dose of sodium thiosulfate than what is included in United States prescribing information. Sodium thiosulfate appears to cause fewer adverse effects than sodium nitrite and is considered safe for use in children [12,19]. Gastrointestinal symptoms and localized burning at the injection site were noted in one volunteer study [57].

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Chemical terrorism".)

SUMMARY AND RECOMMENDATIONS

●Lethality and emergency management table – Cyanide is among the most rapidly lethal poisons known. Tissue hypoxia is the key feature. A summary table to facilitate emergency management of cyanide exposure is provided (table 1). Clinicians should seek immediate assistance from a medical toxicologist or a regional poison center. (See 'Additional resources' above and 'Pathophysiology' above.)

●Sources of exposure – Cyanide poisoning may result from a broad range of exposures (table 2). In industrialized countries, the most common cause is domestic fires. Other causes include industrial exposure (eg, mining, electroplating, plastic manufacturing), standard and alternative medical treatments (eg, nitroprusside, laetrile), and certain foods (eg, Rosaceae family). (See 'Epidemiology and sources of exposure' above.)

●Clinical features – Clinical features can vary widely with the route, duration, and intensity of exposure. Toxicity from parenteral exposure begins within seconds; toxicity from an ingestion or dermal exposure is delayed from minutes to hours (table 3). Central nervous system and cardiovascular system dysfunction are most prominent, but all organ systems can be affected. Symptoms and signs of acute toxicity and delayed sequela are described above. (See 'Clinical presentation' above.)

Decreased utilization of oxygen by tissues causes the venous oxyhemoglobin concentration to be high, making venous blood appear bright red. Therefore, despite hypotension, apnea, and/or bradycardia, the patient does not appear cyanotic.

●Diagnosis – No definitive diagnostic test is readily available; diagnosis is made clinically. Victims of fires, patients with reported ingestions or recently treated with nitroprusside, and industrial workers exposed to cyanide are all potentially cyanide poisoned. When a history is unavailable, clinicians should consider any patient with altered mental status and a severe anion gap metabolic acidosis of unknown etiology a possible cyanide poisoning. (See 'Diagnosis' above and "Simple and mixed acid-base disorders".)

●Diagnostic testing – General laboratory evaluation of suspected cyanide poisoning should include point-of-care (eg, fingerstick) glucose, acetaminophen and salicylate concentrations, electrocardiogram (ECG), and a pregnancy test in female patients of childbearing age. (See 'Laboratory evaluation' above.)

In addition, the following studies should be obtained:

•Basic chemistries (Na+, Cl-, K+, HCO3-) and arterial blood gas to assess for anion gap metabolic acidosis.

•Blood lactate to confirm lactic acidosis and assess severity of exposure.

•Central venous blood gas, if possible, to assess for a diminished venous-arterial partial pressure of oxygen (PO₂) gradient.

•Carboxyhemoglobin and methemoglobin levels (measured by co-oximetry), particularly if there is any concern for concomitant carbon monoxide exposure (eg, house or vehicle fire) or exposure to drugs that produce methemoglobinemia (table 4). Intravenous (IV) infusion of hydroxocobalamin interferes with co-oximetry measurements of total hemoglobin, carboxyhemoglobin, methemoglobin, and oxyhemoglobin. (See 'Laboratory evaluation' above and "Inhalation injury from heat, smoke, or chemical irritants".)

●Resuscitation – The clinician's first responsibility is to stabilize the patient's airway, breathing, and circulation. Mouth-to-mouth resuscitation is contraindicated due to the potential for provider exposure. Otherwise, cardiopulmonary resuscitation should be provided as per standard protocols. (See "Advanced cardiac life support (ACLS) in adults" and 'Resuscitation' above.) 

●Decontamination – Patients poisoned by inhalation or topical exposure must rapidly be extricated from the source and their clothing removed and appropriately discarded. In dermal exposures, wounds must be cleansed with soap and water to prevent further absorption. Rescuers should wear protective suits and respirators until decontamination is completed. (See 'Decontamination' above.)

Gastrointestinal decontamination should be performed as quickly as possible in cases of oral ingestion. We recommend that a single dose of activated charcoal (AC) be administered (Grade 2C); the typical dose is 50 g in adults and 1 g/kg in children. There is no role for multiple-dose AC or cathartics (eg, sorbitol). AC is not given to patients unable to protect their airway unless tracheal intubation is performed first. (See 'Decontamination' above and "Gastrointestinal decontamination of the poisoned patient".)

●Antidote treatment – Based upon treatment availability, we recommend antidotal therapy as outlined below. (See 'Treatment with antidotes' above.)

Hydroxocobalamin available – Whenever it is available, we recommend treatment with hydroxocobalamin for suspected cyanide poisoning (Grade 1B). The dose of hydroxocobalamin is 5 g (adults) or 70 mg/kg IV (pediatric patients, maximum 5 g). A second or third dose may be needed if the response to the first is inadequate. (See 'Hydroxocobalamin' above and 'Hydroxocobalamin available' above.)

Hydroxocobalamin not available – If hydroxocobalamin is not available and the patient is without contraindication to treatment with nitrites (eg, pregnancy, possible carbon monoxide poisoning), we recommend treatment with nitrites and sodium thiosulfate (Grade 1C). Dosing is as follows (see 'Induction of methemoglobinemia' above and 'Hydroxocobalamin not available' above):

Adult:

•Sodium nitrite (3% solution) 10 mL IV (300 mg) at 2.5 to 5 mL per minute

and

•Sodium thiosulfate (25% solution) 50 mL IV (12.5 g) immediately following sodium nitrite administration

Pediatric:

•Sodium nitrite (3% solution) 0.2mL/kg (6 mg/kg) IV at 2.5 to 5 mL per minute; not to exceed 10mL (300 mg)

and

•Sodium thiosulfate (25% solution) 1.65 mL/kg (412.5 mg/kg) IV (maximum dose 12.5 g or 50 mL) given immediately following sodium nitrite administration

Hydroxocobalamin not available and nitrites contraindicated – For patients with contraindications to nitrites or with smoke inhalation (pending test results for carboxyhemoglobin), in locations where hydroxocobalamin is not available, we recommend administering sodium thiosulfate only (Grade 1C). Dosing is as above. Treatment with sodium nitrite is contraindicated in cases of potential carbon monoxide toxicity (eg, from a fire), until such toxicity has been excluded, because it further impairs oxygen delivery. (See 'Sulfur donors' above and 'Hydroxocobalamin not available and nitrites contraindicated' above.)