Cyanide exposure is associated with smoke inhalation, laboratory mishaps, industrial incidents, suicide attempts, and criminal activity.39,113 Cyanide is a chemical group that consists of one atom of carbon bound to one atom of nitrogen by three molecular bonds (C≡N). Inorganic cyanides (also known as cyanide salts) contain cyanide in the anion form (CN–) and are used in numerous industries, such as metallurgy, photographic developing, plastic manufacturing, fumigation, and mining. Common cyanide salts include sodium cyanide (NaCN) and potassium cyanide (KCN). Sodium salts react readily with water to form hydrogen cyanide. Organic compounds that have a cyano group bonded to an alkyl residue are called nitriles. For example, methyl cyanide is also known as acetonitrile (CH3CN). Hydrogen cyanide (HCN) is a colorless gas at standard temperature and pressure with a reported bitter odor. Cyanogen gas, a dimer of cyanide, reacts with water and breaks down into the cyanide anion. Cyanogen chloride (CNCl) is a colorless gas that is easily condensed; it is a listed agent by the Chemical Weapons Convention.
Many plants, such as the Manihot spp, Linum spp, Lotus spp, Prunus spp, Sorghum spp, and Phaseolus spp contain cyanogenic glycosides.111 The Prunus species consisting of apricots, bitter almond, cherry, and peaches have pitted fruits containing the glucoside amygdalin. When ingested, amygdalin is biotransformed by intestinal β-d-glucosidase to glucose, aldehyde, and cyanide (Fig. 126–1). Laetrile, which contains amygdalin, was inappropriately suggested to have antineoplastic properties despite a lack of evidence to support such claims.83 When laetrile was administered by intravenous infusion, amygdalin bypassed the necessary enzymes in the gastrointestinal tract to liberate cyanide and did not cause toxicity. However, ingested laetrile can cause cyanide poisoning. Despite data demonstrating its lack of utility in the treatment of cancer, it still is available via the Internet.
Biotransformation of cyanogens (A) acetonitrile and (B) amygdalin to cyanide.
Cassava (Manihot esculenta) root is a major source of food for millions of people in the tropics. It is a hardy plant that can remain in the ground for up to 2 years and needs relatively little water to survive. Because the shelf life of a cassava root is short once it is removed from the stem, cassava root must be processed and sent to market as soon as it is harvested. However, proper processing must occur to assure the food’s safety. Processed cassava is called Gari. Linamarin (2-hydroxyixo-buty-nitrite-β-d-glycoside) is the major cyanogenic glycoside in cassava roots. It is hydrolyzed to hydrogen cyanide and acetone in two steps during the processing of cassava roots.124 Soaking peeled cassava in water for a single day releases approximately 45% of the cyanogens, whereas soaking for 5 days causes 90% loss. If processing is inefficient, linamarin and cyanohydrin, the immediate product of hydrolysis of linamarin, remain in the food.92 Consumed linamarin is hydrolyzed to cyanohydrin by β-glucosidases of the microorganisms in the intestines. Cyanohydrin present in the food and formed from linamarin then dissociates spontaneously to cyanide in the alkaline pH of the small intestines.
Iatrogenic cyanide poisoning may occur during use of nitroprusside for the management of hypertension. Each nitroprusside molecule contains five cyanide molecules, which are slowly released in vivo. If endogenous sulfate stores are depleted, as in the malnourished or postoperative patient, cyanide may accumulate even with therapeutic nitroprusside infusion rates (2–10 μg/kg/min).
In 1782, the Swedish chemist Carl Wilhelm Scheele first isolated hydrogen cyanide. He reportedly died from the adverse health effects of cyanide poisoning in 1786. Napoleon III was the first to employ hydrogen cyanide in chemical warfare, and it was subsequently used on World War I battlefields. During World War II, hydrocyanic acid pellets (brand name Zyklon B) caused more than one million deaths in Nazi gas chambers at Auschwitz, Buchenwald, and Majdanek. In 1978, KCN was used in a mass suicide led by Jim Jones of the People’s Temple in Guyana, resulting in 913 deaths. Other notorious suicide cases include Wallace Carothers, Herman Goring, Heinrich Himmler, and Ramon Sampedro. In 1982, seven deaths resulted from consumption of cyanide-tainted acetaminophen in Chicago that subsequently lead to the requirement of tamper-resistant pharmaceutical packaging. Numerous copycat murders subsequently have occurred using cyanide-tainted capsules, with the last high-profile case occurring in 2010 involving an Ohio emergency medicine physician who murdered his wife with a cyanide-laden calcium capsule.14 Cyanide has also been used for illicit euthanasia.20
Cyanide poisoning accounted for 1148 exposures reported to the American Association of Poison Control Centers from 2007 to 2011 (Chap. 136).24 One study of poison center data found that 8.3% of intentional overdose cases died and another 9% developed cardiac arrest but survived; 74% did not receive an antidote, most likely due to the failure of the initial treatment team to recognize the poisoning.13 The majority of reported cyanide exposures are unintentional. These events frequently involve chemists or technicians working in laboratories where cyanide salts are common reagents.19 The potential for cyanide poisoning also exists following smoke inhalation, especially following the combustion of materials such as wool, silk, synthetic rubber, and polyurethane.8,30,108 Ingestion of cyanogenic chemicals (ie, acetonitrile, acrylonitrile, and proprionitrile) is another source of cyanide poisoning.115 Acetonitrile (C2H3N) and acrylonitrile (C3H3N) are themselves nontoxic, but biotransformation via cytochrome P450 liberates cyanide (Fig. 126–1).126
The dose of cyanide required to produce toxicity is dependent on the form of cyanide, the duration of exposure, and the route of exposure. However, cyanide is an extremely potent toxin with even small exposures leading to life-threatening symptoms. For example, an adult oral lethal dose of KCN is approximately 200 mg. An airborne concentration of 270 ppm (μg/mL) of hydrogen cyanide (HCN) may be immediately fatal, and exposures >110 ppm for more than 30 minutes are generally considered lifethreatening. The current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) for both hydrogen cyanide and cyanogen is 10 ppm as an 8-hour time-weighted average (TWA) concentration. The Immediately Dangerous to Life or Health (IDLH) value for hydrogen cyanide is 50 ppm.
Acute toxicity occurs through a variety of routes, including inhalation, ingestion, dermal, and parenteral. Hydrogen cyanide readily crosses membranes because it has a low molecular weight (27 Da) and is nonionized. After absorption and dissolution in blood, cyanide exists in equilibrium as the cyanide anion (CN–) and undissociated HCN. Hydrogen cyanide is a weak acid with a pKa of 9.21. Therefore, at physiologic pH 7.4 it exists primarily as HCN. Rapid diffusion across alveolar membranes followed by direct distribution to target organs accounts for the rapid lethality associated with HCN inhalation.
Cyanide is eliminated from the body by multiple pathways. The major route for detoxification of cyanide is the enzymatic conversion to thiocyanate. Two sulfurtransferase enzymes, rhodanese (thiosulfate-cyanide sulfurtransferase) and β-mercaptopyruvate-cyanide sulfurtransferase, catalyze this reaction. The primary pathway for metabolism is rhodanese, which is widely distributed throughout the body and has the highest concentration in the liver. This enzyme catalyzes the transfer of a sulfane sulfur from a sulfur donor, such as thiosulfate to cyanide to form thiocyanate. In acute poisoning, the limiting factor in cyanide detoxification by rhodanese is the availability of adequate quantities of sulfur donors. The endogenous stores of sulfur are rapidly depleted, and cyanide metabolism slows. Hence, the efficacy of sodium thiosulfate as an antidote stems from its normalization of the metabolic inactivation of cyanide. The sulfation of cyanide is essentially irreversible, and the sulfation product thiocyanate has relatively little inherent toxicity. Thiocyanate is eliminated in urine. A number of minor pathways of metabolism (<15% of total) account for cyanide elimination, including conversion to 2-aminothiazoline-4-carboxylic acid, incorporation into the 1-carbon metabolic pool, or in combination with hydroxycobalamin to form cyanocobalamin.
Limited human data regarding the cyanide elimination half-life are available. Elimination appears to follow first-order kinetics,73 although it varies widely in reports (range 1.2–66 hours).8,51,73 Disparity in values may result from the number of samples used to perform calculations and the effects of antidotal treatment. The volume of distribution of the cyanide anion varies according to species and investigator, with 0.075 L/kg reported in humans.34
Cyanide is an inhibitor of multiple enzymes, including succinic acid dehydrogenase, superoxide dismutase, carbonic anhydrase, and cytochrome oxidase.80,87 Cytochrome oxidase is an iron containing metalloenzyme essential for oxidative phosphorylation and, hence, aerobic energy production. It functions in the electron transport chain within mitochondria, converting catabolic products of glucose into adenosine triphosphate (ATP). Cyanide induces cellular hypoxia by inhibiting cytochrome oxidase at the cytochrome a3 portion of the electron transport chain (Fig. 126–2).95,128 Hydrogen ions that normally would have combined with oxygen at the terminal end of the chain are no longer incorporated. Thus, despite sufficient oxygen supply, oxygen cannot be utilized, and ATP molecules are no longer formed.78 Unincorporated hydrogen ions accumulate, contributing to acidemia.
Pathway of cyanide and hydrogen sulfide toxicity and detoxification.
Hyperlactemia occurs following cyanide poisoning because of failure of aerobic energy metabolism. During aerobic conditions, when the electron transport chain is functional, lactate is converted to pyruvate by mitochondrial lactate dehydrogenase. In this process, lactate donates hydrogen moieties that reduce nicotinamide adenine dinucleotide (NAD+) to NADH. Pyruvate then enters the tricarboxylic acid cycle, with resulting ATP formation. When cytochrome a3 within the electron transport chain is inhibited by cyanide, there is a relative paucity of NAD+ and predominance of NADH, favoring the reverse reaction, in which pyruvate is converted to lactate.
Cyanide is also a potent neurotoxin. Cyanide exhibits a particular affinity for regions of the brain with high metabolic activity. Central nervous system (CNS) injury occurs via several mechanisms, including impaired oxygen utilization, oxidant stress, and enhanced release of excitatory neurotransmitters. Cranial imaging of survivors of cyanide poisoning reveals that injury occurs in the most oxygen-sensitive areas of the brains, such as the basal ganglia, cerebellum, and sensorimotor cortex.
Cyanide enhances N-methyl-d-aspartate (NMDA) receptor activity and directly activates the NMDA receptor, which increases release of glutamate and inhibits voltage-dependent magnesium blockade of the NMDA receptor. This NMDA receptor stimulation results in Ca2+ entry into the cytosol of neurons. Cyanide also activates voltage-sensitive calcium channels64 and mobilizes Ca2+ from intracellular stores.81,98 As a result, cytosolic Ca2+ rises and activates a series of biochemical reactions that lead to the generation of reactive oxygen species and nitrous oxide.70,84,106 These reactive oxygen species initiate peroxidation of cellular lipids, which, together with cyanide-induced inhibition of the respiratory chain, adversely affect mitochondrial function, initiating cytochrome c release and execution of apoptosis, necrosis, and subsequent neurodegeneration.6,64,97,107 Experimental studies demonstrate that NMDA inhibitors such as dextrorphan and dizocilpine, antioxidants, and cyclooxygenase inhibitors all protect neurons against cyanide-induced damage.61,77,125
Sulfurtransferase metabolism via rhodanese is crucial for detoxification. However, the aforementioned cyanide-induced metabolic derangement may decrease enzyme detoxification. Decreased ATP and reactive oxygen species and increased cytosolic Ca2+ stimulate protein kinase C activity, which in turn inactivates rhodanese.3
Acute Exposure to Cyanide.
The amount, duration of exposure, route of exposure, and premorbid condition of the individual influence the time to onset and severity of illness. A critical combination of these factors overwhelms endogenous detoxification pathways, allowing cyanide to diffusely affect cellular function within the body. No reliable pathognomonic symptom or toxic syndrome is associated with acute cyanide poisoning.47 The initial clinical effects of acute cyanide poisoning may be nonspecific, generalized, and nondiagnostic, thereby making the correct diagnosis difficult to obtain. Clinical manifestations reflect rapid dysfunction of oxygen-sensitive organs, with central nervous and cardiovascular findings predominating. The time to onset of symptoms typically is seconds with inhalation of gaseous HCN or intravenous injection of a water soluble cyanide salt and several minutes following ingestion of an inorganic cyanide salt. The clinical effects of cyanogenic chemicals often are delayed, and the time course varies among individuals (ranging from 3–24 hours), depending on their rate of biotransformation.115 Clinically apparent cyanide toxicity may occur within hours to days of initiating nitroprusside infusion, although concurrent administration of thiosulfate or hydroxocobalamin may prevent toxicity (Chap. 63).104
CNS signs and symptoms are typical of progressive hypoxia and include headache, anxiety, agitation, confusion, lethargy, nonreactive dilated pupils seizures, and coma. A centrally mediated tachypnea occurs initially, followed by bradypnea and apnea.
Cardiovascular responses to cyanide are complex. Studies of isolated heart preparations and intact animal models show that the principal cardiac insult is slowing of rate and loss of contractile force.7 Several reflex mechanisms, including catecholamine release and central vasomotor activity, may modulate myocardial performance and vascular response in patients with cyanide poisoning.71 In laboratory investigations, a brief period of increased inotropy caused by reflex compensatory mechanisms occurs before myocardial depression. Clinically, an initial period of tachycardia and hypertension may occur, followed by hypotension with reflex tachycardia, but the terminal event is consistently bradycardia and hypotension. Ventricular dysrhythmias do not appear to be an important factor.
Pulmonary edema may be found at necropsy.47 Inhalation of HCN may be associated with mild corrosive injury to the respiratory tract mucosa.
Gastrointestinal toxicity may occur following ingestion of inorganic cyanide and cyanogens and includes abdominal pain, nausea, and vomiting. These symptoms are caused by hemorrhagic gastritis, which is frequently identified on necropsy, and are thought to be secondary to the corrosive nature of cyanide salts. However, if death occurs rapidly, this gastritis may not be seen at autopsy because development of inflammation occurs over time.47 Following ingestion, a smell of bitter almonds should not be relied upon to be emitted from the gastrointestinal system as health care providers in nearly all case reports published do not mention this finding.63
Cutaneous manifestations may vary. Traditionally, a cherry-red skin color is described as a result of increased venous hemoglobin oxygen saturation, which results from decreased utilization of oxygen at the tissue level. This phenomenon may be more evident on funduscopic examination, where veins and arteries may appear similar in color. Despite the inference in the name, cyanide does not directly cause cyanosis. The occurrence of cyanosis is commonly reported in published case reports and is likely due to cardiovascular collapse and subsequent poor perfusion.122
Delayed Clinical Manifestations of Acute Exposure.
Survivors of serious, acute poisoning may develop delayed neurologic sequelae. Parkinsonian symptoms, including dystonia, dysarthria, rigidity, and bradykinesia, are most common. Symptoms typically develop over weeks to months, but subtle findings can be present within a few days. Head computerized tomography and magnetic resonance imaging consistently reveal basal ganglia damage to the globus pallidus, putamen, and hippocampus, with radiologic changes appearing several weeks after onset of symptoms. Whether delayed manifestations result from direct cellular injury or secondary hypoxia is unclear. Extrapyramidal manifestations may progress or resolve. Response to pharmacotherapy with antiparkinsonian agents is generally disappointing.
Chronic Exposure to Cyanide.
Chronic exposure to cyanide may result in insidious syndromes, including tobacco amblyopia, tropical ataxic neuropathy, and Leber hereditary optic neuropathy. Tobacco amblyopia is a progressive loss of visual function that occurs almost exclusively in men who smoke cigarettes. Affected smokers have lower serum cyanocobalamin and thiocyanate concentrations than unaffected smoking counterparts, suggesting a reduced ability to detoxify cyanide. Cessation of smoking and administration of hydroxocobalamin often reverses symptoms. Tropical ataxic neuropathy is a demyelinating disease associated with improperly processed cassava consumption.91,112 Neurologic manifestations include Parkinson disease, spastic paraparesis, sensory ataxia, optic atrophy, and sensorineural hearing loss.122 Concomitant dermatitis and glossitis suggest an association of high dietary cassava with low vitamin B12 intake. Elevated thiocyanate concentrations in affected individuals further implicate cyanide as the etiology. Removal of dietary cassava and institution of vitamin B12 therapy alleviates symptoms. Leber hereditary optic atrophy, a condition of subacute visual failure affecting men, is thought to be caused by rhodanese deficiency.42
Chronic exposure to cyanide is associated with thyroid disorders.1 Thiocyanate is a competitive inhibitor of iodide entry into the thyroid, thereby causing the formation of goiters and the development of hypothyroidism. Chronic exposure to cyanide in animals is associated with hydropic degeneration in hepatocytes and epithelial cells of the renal proximal tubules; however, these morphologic lesions are not linked to functional alternations.111
Because of nonspecific symptoms and delay in laboratory cyanide confirmation, the clinician must rely on historical circumstances and some initial findings to raise suspicion of cyanide poisoning and institute therapy (Table 126–1).
TABLE 126–1.Cyanide Poisoning: Emergency Management Guidelines ||Download (.pdf) TABLE 126–1. Cyanide Poisoning: Emergency Management Guidelines
|When to suspect cyanide |
Sudden collapse of laboratory or industrial worker
Fire victim with coma or academia
Suicide with unexplained coma or academia
Ingestion of artificial nail remover
Ingestion of seeds or pits from Prunus species
Patient with altered mental status, acidemia, and tachyphylaxis to nitroprusside
|Supportive care |
Control airway, ventilate, and give 100% oxygen
Crystalloids and vasopressors for hypotension
Administer sodium bicarbonate; titrate according to ABG and serum HCO3
Initial adult dose: 5 g IV over 15 minutes; pediatric dose 70 mg/kg up to 5 g
2) Cyanide Antidote Kit
Amyl nitrite pearls are included in the kit for prehospital use. For hospital management, sodium nitrite is the preferred methemoglobin inducer and is given in lieu of the pearls.
Give sodium nitrite (NaNO2) as a 3% solution over 2–4 minutes IV: Adult dose: 10 mL (300 mg)
Caution: Monitor blood pressure frequently, and treat hypotension by slowing infusion rate and giving crystalloids and vasopressors. Obtain methemoglobin level 30 minutes after dose, and consider possible excessive methemoglobin formation if patient deteriorates during therapy. Withhold nitrites if COHb is suspected to be present.
Give sodium thiosulfate (NaS2O3) as a 25% solution IV:
Adult dose: 50 mL (12.5 g)
Pediatric dose: 1.65 mL/kg up to 50 mL
Protect health care provider from contamination
Cutaneous: Carefully remove all clothing and flush the skin
Ingestion: Oro- or nasogastric lavage and instill 1 g/kg activated charcoal
Arterial blood gas
Electrolytes and glucose
Whole-blood cyanide concentration (for later confirmation only)
Laboratory findings suggestive of cyanide poisoning reflect the known metabolic abnormalities, which include metabolic acidosis, elevated lactate concentration, and increased anion gap. Elevated venous oxygen saturation results from reduced tissue extraction.65 A venous oxygen saturation >90% from superior vena cava or pulmonary artery blood indicates decreased oxygen utilization. This finding is not specific for cyanide and could represent cellular poisoning from other agents such as carbon monoxide, clenbuterol, hydrogen sulfide, and sodium azide, or medical conditions such as sepsis high-output cardiac syndromes and left to right intracardiac shunts.
Hyperlactatemia is found in numerous critical illnesses and typically is a nonspecific finding. However, a significant association exists between blood cyanide and serum lactate concentrations.9,10 ABG analysis of whole blood may provide additional information. Arterial pH correlates inversely with cyanide concentration.10 The finding of a narrow arterial–venous oxygen difference also may suggest cyanide toxicity.
Cyanide results in nonspecific electrocardiographic (ECG) findings.40 Rhythm disturbances such as sinus tachycardia, bradydysrhythmias, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation are all reported, as are elevation or depression of the ST segment, shortened ST segments, and fusion of the T wave into the QRS complex.
Blood cyanide concentration determination can confirm toxicity, but this determination is not available in a sufficiently rapid manner to affect initial treatment. Whole blood or serum can be analyzed, with most reports utilizing whole blood for cyanide detection. In mammals, including primates, whole-blood concentrations are twice serum concentrations as a result of cyanide sequestration in red blood cells. Background whole-blood concentrations in nonsmokers range between 0.02 and 0.5 μg/mL.52,59 Higher blood concentrations suggest toxicity. Coma and respiratory depression are associated with whole blood concentrations >2.5 μg/mL and death with concentrations >3 μg/mL. Detecting urinary cyanide is difficult, and urinary thiocyanate is a more readily detectable and useful marker of cyanide exposure. Serum thiocyanate concentrations are of little value in assessing patients with acute poisoning because of little correlation with symptoms but are useful in confirming exposure.
A semiquantitative assay that uses calorimetric paper test strips may immediately detect cyanide. Cyantesmo test strips currently are used by water treatment facilities to detect cyanide. An investigation of the utility of these strips in clinical practice found that the test strips incrementally increased to a deep blue color over a progressively longer portion of the test strip with increasing concentrations of cyanide in the blood.102 These strips accurately and rapidly detected, in a semiquantifiable manner, CN concentrations >1 μg/mL.
Because cyanide poisoning is rare, it is easy to overlook the diagnosis unless there is an obvious history of exposure. Thus, the most critical step in treatment is considering the diagnosis in high-risk situations (Table 126–1) and initiating empiric therapy with 100% oxygen and either hydroxycobalamin or the cyanide antidote kit. The initial care (Table 126–1) of the cyanide-poisoned patient begins by directing attention to airway patency, ventilatory support, and oxygenation. Acidemia should be treated with adequate ventilation and sodium bicarbonate administration.
Intravenous access should be rapidly obtained and blood samples sent for renal function, glucose, and electrolyte determinations. A whole-blood cyanide concentration can be obtained for later confirmation of exposure. ABG analysis and serum lactate concentration will help assess acid–base status. Initiation of crystalloid and infusion of vasopressor for hypotension are warranted.
First responders should exercise extreme caution when entering potentially hazardous areas such as chemical plants and laboratories where a previously healthy person is “found down.” Exposure to cyanide may occur by multiple routes, including ingestion, inhalation, dermal, and parenteral. For patients with inhalation exposure, removal from the area of exposure is critical. Further decontamination is generally unnecessary. Decontamination of the cyanide-poisoned patient occurs concurrently with initial resuscitation. The health care provider should always be protected from potential dermal contamination by using personal protective devices such as water-impervious gowns, gloves, and eyewear. For patients with cutaneous exposure, remove their clothing, brush any powder off the skin, and flush the skin with water. Particular attention should be given to open wounds because CN– or HCN is readily absorbed through abraded skin.
Instillation of activated charcoal often is considered ineffective because of low binding of cyanide (1 g activated charcoal only adsorbs 35 mg cyanide). However, a potentially lethal oral dose of cyanide (ie, a few hundred milligrams) is within the adsorptive capacity of a typical 1 g/kg dose of activated charcoal. Prophylactic activated charcoal administration improved survival in animals given an LD100 dose of KCN.74 Based on the potential benefits and minimal risks, activated charcoal may be considered in the patient with an intact protected airway.
Although either hydroxocobalamin or the cyanide antidote kit can be administered as soon as cyanide poisoning is suspected, hydroxocobalamin is preferred. Hydroxocobalamin is a metalloprotein with a central cobalt atom that complexes cyanide, forming cyanocobalamin (vitamin B12). Cyanocobalamin is eliminated in the urine or releases the cyanide moiety at a rate sufficient to allow detoxification by rhodanese. One molecule of hydroxocobalamin binds one molecule of cyanide, yielding a molecular weight binding ratio of 50:1. The US-approved adult starting dose is 5 g administered by intravenous infusion over 15 minutes. Depending upon the severity of the poisoning and the clinical response, a second dose of 5 g may be administered by intravenous infusion for a total dose of 10 g. Hydroxocobalamin has few adverse effects, which include allergic reaction and a transient reddish discoloration of the skin, mucous membranes, and urine.25,21,53 No hemodynamic adverse effects other than a potential mild transient rise of blood pressure are observed16,105 (Antidotes in Depth: A41).
The cyanide antidote kit contains amyl nitrite, sodium nitrite, and sodium thiosulfate. Both thiosulfate and nitrite individually have antidotal efficacy when given alone in animal models of cyanide poisoning, but they have even greater benefit when they are given in combination.80 Thiosulfate donates the sulfur atoms necessary for rhodanese-mediated cyanide biotransformation to thiocyanate. The mechanism of nitrite is less clear. Traditional rationale relies on the ability of nitrite to generate methemoglobin. Because cyanide has a higher affinity for methemoglobin than for cytochrome a3, cytochrome oxidase function is restored. However, improved hepatic blood flow and nitric oxide formation are alternate explanations (Antidotes in Depth: A39 and A40). Amyl nitrite is contained within glass pearls that are crushed and intermittently inhaled or intermittently introduced into the ventilator system to initiate methemoglobin formation. The amyl nitrite pearls are reserved for cases where intravenous access is delayed or not possible. Intravenous sodium nitrite is preferred and is supplied as a 10-mL volume of 3% solution (300 mg). Adverse effects of nitrites include excessive methemoglobin formation and, because of potent vasodilation, hypotension and tachycardia. Avoiding rapid infusion, monitoring blood pressure, and adhering to dosing guidelines will limit adverse effects. Because of the potential for excessive methemoglobinemia during nitrite treatment, pediatric dosing guidelines are available (Table 126–2). Sodium thiosulfate is the second component of the cyanide antidote kit. It is supplied as 50 mL of 25% solution (12.5 g). It is a substrate for the reaction catalyzed by rhodanese that is essentially irreversible, converting a highly toxic entity to a relatively harmless compound. However, thiocyanate does have its own toxicity in the presence of kidney failure, including abdominal pain, vomiting, rash, and CNS dysfunction. Thiosulfate itself is not associated with significant adverse reactions. The pediatric dose of thiosulfate is adjusted for weight.
TABLE 126–2.Cyanide Management: Pediatric Sodium Nitrite Guidelinesa ||Download (.pdf) TABLE 126–2. Cyanide Management: Pediatric Sodium Nitrite Guidelinesa
|Hemoglobin (g) ||NaNO2 (mg/kg) ||3% NaNO2 solution (mL/kg) |
|7.0 ||5.8 ||0.19 |
|8.0 ||6.6 ||0.22 |
|9.0 ||7.5 ||0.25 |
|10.0 ||8.3 ||0.27 |
|11.0 ||9.1 ||0.30 |
|12.0 ||10.0 ||0.33 |
|13.0 ||10.8 ||0.36 |
|14.0 ||11.6 ||0.39 |
In Europe, 4-dimethylaminophenol (4-DMAP), rather than sodium nitrite, is the methemoglobin-inducer of choice.54 It generates methemoglobin more rapidly than sodium nitrite, with peak methemoglobin concentrations at 5 minutes after 4-DMAP rather than 30 minutes after sodium nitrite. The dose of 4-DMAP is 3 mg/kg and is coadministered with thiosulfate. As with sodium nitrite, its major adverse effect is excessive methemoglobin formation and potential for hypotension. Cobalt in the form of dicobalt edetate has been used as a cyanide chelator, but its usefulness is limited by serious adverse effects such as hypotension, cardiac dysrhythmias, decreased cerebral blood flow, and angioedema.22,86 The cobalamin precursor cobinamide has been used both prophylactically and therapeutically to treat experimental cyanide toxicity, and when given at high enough doses, it has rescued animals from cyanide-induced apnea and coma.23 Cobalamin has been used in France to treat human cyanide exposure, either alone or combined with sodium thiosulfate. Cobinamide is an investigational treatment that has a much greater affinity for cyanide ion than cobalamin.29 Hyperbaric oxygen has been considered in the past, but recent evidence suggests no benefit in cyanide poisoning.76
In animal models, the antioxidant vitamins A, C, and E diminish the extent of tissue damage caused by subacute cyanide intoxication.89 This is especially important in the tropics, where the majority of dietary staples are cyanophoric crops such as cassava.
Patients who do not survive cyanide poisoning are suitable organ donors. Heart, liver, kidney, pancreas, cornea, skin, and bone have been successfully transplanted following cyanide poisoning.41