PEDIATRICS Vol. 118 No. 5 November 2006, pp. 2146-2158 (doi:10.1542/peds.2006-1251)
STATE-OF-THE-ART REVIEW ARTICLE |
Pediatric Cyanide Poisoning: Causes, Manifestations, Management, and Unmet Needs
a Department of Pediatrics and the Medical Toxicology Fellowship Program, Emory University School of Medicine, Atlanta, Georgia
b Georgia Poison Center, Atlanta, Georgia
c The WriteMedicine, Inc, Chapel Hill, North Carolina
d Toxicology Consulting and Medical Translating Services, Inc, Elk Mountain, Wyoming
e Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado
ABSTRACT
Confirmed cases of childhood exposure to cyanide are rare despite multiple potential sources including inhalation of fire smoke, ingestion of toxic household and workplace substances, and ingestion of cyanogenic foods. Because of its infrequent occurrence, medical professionals may have difficulty recognizing cyanide poisoning, confirming its presence, and treating it in pediatric patients. The sources and manifestations of acute cyanide poisoning seem to be qualitatively similar between children and adults, but children may be more vulnerable than adults to poisoning from some sources. The only currently available antidote in the United States (the cyanide antidote kit) has been used successfully in children but has particular risks associated with its use in pediatric patients. Because hemoglobin kinetics vary with age, methemoglobinemia associated with nitrite-based antidotes may be excessive at standard adult dosing in children. A cyanide antidote with a better risk/benefit ratio than the current agent available in the United States is desirable. The vitamin B12 precursor hydroxocobalamin, which has been used in Europe, may prove to be an attractive alternative to the cyanide antidote kit for pediatric patients. In this article we review the available data on the sources, manifestations, and treatment of acute cyanide poisoning in children and discuss unmet needs in the management of pediatric cyanide poisoning.
Key Words: cyanide • poisoning • smoke inhalation • nitrite • hydroxocobalamin • methemoglobinemia • antidotes
Cyanide is among the most potent and deadly poisons, and sources of potential human exposure to it are numerous.1, 2 Existing in gaseous, solid, and liquid forms, cyanide is used in many industries, found in certain household substances, and produced by the combustion of common materials such as fabrics containing nylon, silk, or wool and many plastics such as melamine, polyurethane, and polyacrylonitrile.3, 4 The release of cyanide and cyanogenic compounds (such as nitriles) from combustion of such products is the most common source of human exposure to cyanide and may be second only in importance to carbon monoxide as a toxicant in these circumstances.3, 5–10 Humans can also be exposed to cyanide by eating cyanogenic foods, such as the tropical root cassava, that contain cyanogenic glycosides that liberate cyanide when metabolized in the body. Additional sources of cyanide exposure include metabolites of the antihypertensive drug nitroprusside, suicide attempts, and malicious acts such as murder attempts or terrorist attacks.11 Cyanide is a potential chemical weapon for use by terrorists because it can be easily obtained and dispersed and may be rapidly incapacitating or even lethal.
Causes and manifestations of acute cyanide poisoning have not been systematically described in children, and little is known about the benefits and risks of antidotes and other aspects of intervention in pediatric patients. The information on these topics comes predominantly from case reports of pediatric cyanide poisoning by ingestion. In this article we review the available data on the sources, manifestations, and treatment of acute cyanide poisoning in pediatric patients and discuss unmet needs in the management of this condition.
SOURCES OF ACUTE CYANIDE POISONING IN CHILDREN
Fire smoke is a common source of acute cyanide poisoning in children.5, 7 Additional sources described in case reports include household or workplace substances containing cyanogenic compounds, cyanogenic foods, laetrile, and nitroprusside (Table 1). 12–29 The sources of acute cyanide toxicity are similar between children and adults, although their relative frequency of poisoning varies with age. Acute poisonings by ingestion of cyanide-containing or cyanogenic household substances and ingestion of cyanogenic plants have been reported more frequently in children than adults (Table 1).12–29
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The amount of cyanide in the blood that is likely to prove toxic is imprecise and depends heavily on when the sample is drawn in comparison to the time of exposure, the specific cyanide compound or cyanogenic compound involved, the route of exposure, treatment provided before sampling (if any), and sample handling between collection and analysis. In adults, the blood cyanide level that is regarded as "toxic" is generally considered to be
1 mg/L (39 µmol/L), and the "fatal" level is generally considered to exceed 2.6 to 3 mg/L (100–115 µmol/L).3, 6, 7, 28
Inhalation of Fire Smoke
Approximately one fourth of the 
4000 fire- and burn-related deaths each year in the United States occur in children younger than 15 years.30 In children, as in adults, the majority of fire-related deaths are attributed to smoke inhalation rather than burns.30 Children were among the smoke-inhalation fatalities in the widely publicized apartment fires in the Paris, France, area during 2005.31 In one apartment fire in August 2005, 14 of 17 fatalities were of children. In a second apartment fire also in August 2005, 4 of the 7 fatalities were of children. Children also died in a third apartment fire in September 2005.
Cyanide is an important contributor to death by smoke inhalation and is present in the blood of fire victims (regardless of age) in most cases.3, 6, 7 In a meta-analysis of smoke-inhalation–associated deaths occurring in 7 major fire incidents from 1971 to 1990, cyanide was found in the victims' blood in each study in which it was measured.3 Carboxyhemoglobin levels correlated poorly with blood concentrations of carbon monoxide. The percentage of fatalities having lethal blood concentrations of cyanide ranged from 33% to 87% in the meta-analysis. In one fire scene, for example, toxic blood concentrations of cyanide were documented in 87% of victims, although only 72% had a carboxyhemoglobin level exceeding 30%, a finding suggested by incomplete data from other scenes as well and suggesting a cause of death other than carbon monoxide in these victims. Consistent with the results of this meta-analysis, other studies have found cyanide in the blood of 62% to 77% of victims who died.6, 7
Elevated blood cyanide concentrations have been found in children exposed to fire smoke. In a seminal study of the role of cyanide in smoke-inhalation injury and death, 30 of the 109 victims of smoke inhalation in residential fires in Paris were younger than 14 years.9 Among those 30 children, 13 died and 17 survived. Cyanide was present in both children who survived (mean concentration: 27.4 µmol/L) and those who died (mean concentration: 87.0 µmol/L). Blood carbon monoxide concentrations were below the lethal level in some children who survived and some who died, a result suggesting, when considered in conjunction with the presence of cyanide in their blood, that cyanide poisoning and/or other causes of hypoxia may have contributed to their death.
Ingestion of Household or Workplace Substances Containing Cyanogenic Compounds
Accidental ingestion of household substances containing poisons often involves young children, who place substances in their mouths and/or ingest them as a means of exploration.32, 33 Although the US Consumer Product Safety Commission prohibits the sale of consumer products containing soluble cyanide salts,34 cyanide may be accessible from industrial sources, as are some cyanogenic compounds that may also be contained in products marketed for consumer use. This risk is illustrated by several cases of cyanide poisoning from acetonitrile-containing false-fingernail remover. Acetonitrile is used as a solvent in industrial and laboratory settings and is sometimes present in cosmetics. Its toxicity is attributed to its metabolism to inorganic cyanide. Five case reports of pediatric cyanide poisoning from acetonitrile-containing false-fingernail remover have been reported in the medical literature (Table 1).12–15
As would be expected from a cyanogenic compound requiring metabolic activation to be converted to cyanide, the onset of acetonitrile-associated cyanide toxicity typically occurs after a delay. This observation is consistent with the pharmacokinetic properties of acetonitrile, which is metabolized slowly to inorganic cyanide via hepatic microsomal enzymes.12 In these pediatric cases, manifestations of toxicity were first observed 6 to 14 hours after ingestion of acetonitrile (Table 1). A similar delay between exposure and onset of toxicity has been observed in adults.35 The failure to observe symptoms of toxicity in the initial minutes and hours after acetonitrile exposure should not be interpreted as the absence of toxicity.
Health care providers should not confuse the potentially highly toxic acetonitrile-containing cosmetics, particularly false-fingernail removers, with less-toxic acetone-containing fingernail-polish removers. In one reported case, a 16-month-old boy who had ingested acetonitrile-containing fingernail remover was mistakenly assumed to have ingested acetone-containing fingernail polish remover.12 Because cyanide poisoning was not suspected, no treatment for it was given; the child died. This incident underscores the risk of sound-alike and look-alike products and emphasizes the importance of specifically ascertaining the exact toxin involved.
This potential confusion between acetone and acetonitrile poisoning is compounded by the initial similarity of their early features, including vomiting, lethargy, slurred speech, ataxia, stupor, coma, and respiratory depression.15 Delayed vomiting, although not typically a major clinical indicator of most cases of cyanide poisoning, may be important in alerting health care providers to acetonitrile toxicity in exposed children.13 In each of the reported pediatric cases of acetonitrile-associated cyanide poisoning, vomiting was the first symptom of toxicity and heralded the development of severe toxicity (Table 1).12–15 However, vomiting is common from many causes and is not sufficient by itself to dictate the administration of a cyanide antidote in the absence of other supporting evidence of cyanide toxicity from history and clinical laboratory studies.
In addition to cosmetics and other products used in the household, workplace substances containing cyanide or cyanogenic compounds are potential sources of pediatric poisoning. Cases of pediatric cyanide poisoning from ingestion of Drabkin's solution (used in medical laboratories)16 and a metal cleaning solution17 have been reported.
Ingestion of Cyanogenic Foods
Cyanogenic compounds are found in several foods including almonds, the pits of stone fruits, lima beans, and cassava (Table 2). 36 When these foods are ingested in large quantities or without adequate preparation, they can cause cyanide toxicity. Cyanide poisoning by ingestion of cyanogenic foods seems to occur very rarely in the United States, where they are not major components of the diet, but it is reported more frequently in children in tropical countries, where such foods are more important parts of the diet.
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Roots and/or leaves of the cyanogenic plant cassava (or tapioca) are a staple food for millions of people in the tropics. Cassava contains glycosides (Table 2), which are hydrolyzed to glucose, hydrogen cyanide, and acetone by intestinal ß-glucosidase or ß-glucosidase liberated from the cassava plant itself.36 Numerous cases of acute cyanide poisoning after ingestion of cassava have been reported in children in tropical countries.18, 19, 20–24 Cassava poisoning in adults has also been reported, but pediatric poisoning may be more frequent and severe (as discussed below in "Manifestations of Acute Cyanide Poisoning"). Frequent ingestion of cassava over the long-term, particularly in the presence of protein-calorie malnutrition, is also associated with chronic poisoning syndromes such as tropical ataxic neuropathy (lesions of skin, mucous membranes, optic and auditory nerves, spinal cord, peripheral nerves) and konzo, a relatively sudden-onset upper motor neuron spastic paraparesis.20, 37, 38 The exact mechanisms by which tropical ataxic neuropathy and konzo occur remain obscure.
Cyanogenic compounds are also present in the pits of stone fruits such as peaches and apricots (Table 2).36 Multiple cases of pediatric cyanide poisoning from eating large quantities of cooked and/or ground apricot pits have been reported.39, 40 Apricot pits contain amygdalin, which is hydrolyzed to hydrogen cyanide, glucose, and benzaldehyde, as well as the ß-glucosidase emulsin, which catalyzes amygdalin hydrolysis.41 Chewing apricot pits releases emulsin and increases the toxicity of cyanide. Swallowing 1 or 2 whole stone fruit pits usually does not result in cyanide poisoning, because the amygdalin and the ß-glucosidase enzyme are located in different parts of the pit and do not interact to release cyanide.
Other Causes of Cyanide Poisoning in Children
Pediatric cyanide poisoning has also been reported after administration of laetrile, which has been promoted by its advocates as a cancer preventative and cure despite lack of accepted evidence of efficacy.29 Laetrile is amygdalin, the glycoside naturally present in pits of apricots and other stone fruits and nuts (Table 2).36 Like the cyanogenic glycosides in cassava, amygdalin liberates cyanide when hydrolyzed by intestinal or plant-derived ß-glucosidase.28
Cases of acute cyanide poisoning secondary to use of nitroprusside have also been reported in children.25, 26 Sodium nitroprusside is indicated for reduction of blood pressure in patients in hypertensive crises and for producing controlled hypotension to reduce bleeding during surgery. Within minutes of intravenous infusion, sodium nitroprusside is converted to free cyanide, with the production of 44 mg of free cyanide for every 100 mg of sodium nitroprusside infused.42
Acute poisoning in 127 children aged 2 months to 17 years was attributed to cyanide toxicity after an ecological accident resulting in spilling of acetone cyanohydrin and ammonia water into the Siret River in Romania in January 2001.43 Nursing infants whose mothers ingested contaminated fish also developed symptoms. Although the poisoning was attributed to ingestion of contaminated fish from the river, cyanide levels and other confirmatory data are not available.
MANIFESTATIONS OF ACUTE CYANIDE POISONING
Cyanide prevents cellular use of oxygen by inactivating mitochondrial cytochrome oxidase and thereby causing cells to switch from aerobic to anaerobic metabolism.44 Anaerobic metabolism favors production of toxic byproducts such as lactic acid over the production of cellular energy in the form of adenosine triphosphate (ATP). Accordingly, clinical manifestations of acute cyanide poisoning are often nonspecific and mainly reflect oxygen deprivation of the heart and brain (Table 3). 23, 44, 45 The frequency of any specific clinical effect in cyanide poisoning is generally unclear; therefore, it is difficult to diagnose cyanide poisoning on the basis of any one finding.
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After intense exposure, rapid death may ensue. After less severe exposure, early manifestations include weakness, malaise, confusion, headache, dizziness, and shortness of breath. Later manifestations include nausea and vomiting, hypotension, generalized seizures, coma, apnea, cardiac arrhythmias, and death attributed to cardiorespiratory arrest. Additional physical findings sometimes include cherry-red discoloration of the skin and red retinal veins and arteries arising from the inability of cells to extract oxygen from the blood. Because of elevated venous oxygen levels, cyanosis is typically not present in spontaneously breathing or artificially ventilated patients. A patient's breath may have a bitter, almond-like odor attributed to excretion of unmetabolized cyanide; however, this odor is often undetectable.46–48
Elevated oxygen content of venous blood is often present in cyanide poisoning but not highly specific for it.49 Lactic acidosis was shown in a sample of 11 patients to be highly sensitive and moderately specific for cyanide poisoning. A plasma lactate level of 72 mg/dL (8 mmol/L) was 94% sensitive and 70% specific for a blood cyanide level of 1.0 mg/L in a series of adults exposed solely to cyanide.50 In a series of smoke-inhalation victims, the lactate value of 10 mmol/L proved to be a better cutoff value.9 Although cyanide concentrations in whole blood are also elevated in acute poisoning, the long time required for results of this test to return limits its clinical utility. Nevertheless, in cases of suspected cyanide toxicity, blood levels should be obtained to document the poisoning.
The time between exposure to cyanide and the onset of toxicity depends on the form of cyanide and the route and concentration of exposure.1, 44, 45 Exposure to cyanide gas at high concentrations can result in death within seconds to minutes, but toxicity develops over minutes to hours after ingestion or dermal exposure. Cyanide salts and cyanogenic compounds also typically cause delayed onset of effects.
Whether children and adults are differentially susceptible to cyanide poisoning has not been systematically studied. Manifestations of cyanide poisoning seem to be qualitatively similar between children and adults.51 In children, as in adults, acute cyanide poisoning has been characterized by varying degrees of neurologic impairment, respiratory distress, and cardiovascular compromise; the occasional presence of bitter-almond breath and bright-red venous blood; and metabolic acidosis (Table 1).12–29, 51
Factors that could render children more vulnerable than adults to cyanide poisoning include higher respiratory rates, which might contribute to greater systemic toxicity from inhalation exposure, and lower body mass and immature metabolic mechanisms, which might make children more susceptible than adults to toxicity from small amounts of poison.52, 53 Young organs can be particularly sensitive to toxicants during critical periods of structural and functional development, the timing of which depends on the organ system.51 Children seem to be more susceptible than adults to poisoning by ingestion of cyanogenic foods including cassava and apricot pits,18, 19, 21, 51 often developing more severe toxicity than adults concurrently ingesting cassava. The apparently greater vulnerability of children to poisoning by cyanogenic foods has been attributed to children's lower body mass and, in cassava poisoning, to the children's higher gastric acidity than that of adults.18, 19, 21 Cyanide in cassava exists both in a free form and in combination with the glycosides linamarin and lotaustralin. However, non–age-related factors, such as ingestion of different amounts or parts of cyanogenic plants, might also have contributed to the differential toxicity.
Data from the Paris study described above9 support the concern of greater vulnerability of children than adults to cyanide poisoning from inhalation of fire smoke. In smoke-inhalation victims, the fatality rate was slightly higher among patients younger than 14 years than among older patients (43% vs 38%). Mean blood cyanide concentrations of victims who died were lower among patients younger than 14 years than they were among older patients (87.0 ± 76.1 vs 129.0 ± 93.1 µmol/L, respectively; 2.62 ± 0.16 vs 3.35 ± 2.42 mg/L, respectively) (differences not statistically tested).
CYANIDE ANTIDOTES
Management of acute cyanide poisoning in both children and adults entails removal of the victim from the source of cyanide in inhalation exposure, gastric decontamination with aspiration of gastric contents, and administration of activated charcoal in the event of poisoning by ingestion (if care for the victim begins soon after ingestion). Ensuing supportive care includes 100% oxygen, cardiopulmonary resuscitation if necessary, and an appropriate antidote (Table 4). 44, 45, 54 Because cyanide toxicity can culminate quickly in death, rapid intervention is crucial and is usually undertaken on the basis of a presumptive diagnosis before confirmatory blood cyanide concentrations are available.
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The cyanide antidote kit is the only cyanide antidote currently commercially available in the United States, although other antidotes are available in other countries.45 The cyanide antidote kit is composed of amyl nitrite, sodium nitrite, and sodium thiosulfate. Amyl nitrite, contained in ampoules intended to be crushed and the contents inhaled, is administered to stabilize the victim before intravenous administration of sodium nitrite and sodium thiosulfate. The nitrite moieties from amyl nitrite and sodium nitrite oxidize hemoglobin to create methemoglobin, which competes with cytochrome oxidase for the cyanide ion. Binding of cyanide to methemoglobin frees the cytochrome oxidase necessary for aerobic cellular respiration. The extent of methemoglobinemia required to achieve the desired therapeutic benefit is uncertain; a prudent strategy is to use the lowest amount of methemoglobinemia that reverses the cyanide-induced clinical findings.55 Another mechanism by which nitrites might achieve their therapeutic benefits involves induced alterations in the nitric-oxide redox pathway.56 Sodium thiosulfate serves as a sulfur donor that increases the rate of rhodanase-catalyzed transformation of cyanide to much less toxic thiocyanate.
Incongruously, the methemoglobinemia induced by the nitrites in the cyanide antidote kit itself can be dangerous and even lethal.10, 16, 45, 57, 58 Methemoglobinemia reduces the amount of hemoglobin available to transport oxygen to the cells. In some cases, nitrite-induced methemoglobinemia can be excessive, even to the extent of likely fatal reduction in the oxygen-carrying capacity of the blood.16 However, a study of 4 critically ill adult smoke-inhalation patients treated with the cyanide antidote kit demonstrated methemoglobin levels of 7.9% to 13.4%, and their total reduction in oxygen-carrying capacity caused by carbon monoxide, cyanide, and methemoglobinemia never exceeded 21%.59 These values were not considered dangerous.
Nitrite-induced methemoglobinemia may pose a particular danger for victims of cyanide poisoning from smoke inhalation (probably the most common cause of cyanide poisoning in children) because of the likely presence of carboxyhemoglobinemia secondary to concomitant carbon monoxide poisoning.10, 57, 60, 61 Like methemoglobinemia, carboxyhemoglobinemia reduces the amount of hemoglobin available to transport oxygen to the cells. The additive effects of nitrite-induced methemoglobinemia and carboxyhemoglobinemia can exacerbate the patient's condition. This possibility raises concern about the use of the cyanide antidote kit in the management of smoke-inhalation–associated cyanide poisoning, particularly in the prehospital setting.10, 62
To avoid the complications of methemoglobinemia associated with nitrites, sodium thiosulfate has been recommended for use as a sole agent (without nitrites) for cyanide toxicity to enhance rhodanase activity.63, 64 Advocates of this therapeutic regimen contend that the enhanced safety of this approach outweighs the potentially slower reduction of cyanide level in the body.65
Nitrite-induced methemoglobinemia can pose a particular safety hazard to young children, because hemoglobin kinetics vary with age. A proportion of hemoglobin in infants and young children is available in the form of fetal hemoglobin, which is oxidized more easily by nitrites to form methemoglobin than is adult hemoglobin.66 In addition, infants and very young children have significantly reduced activity of methemoglobin reductase (the enzyme responsible for converting methemoglobin) compared with normal adults back to normal hemoglobin.66, 67 These factors render young children especially susceptible to excessive nitrite-induced methemoglobinemia.
The dangers of excessive nitrite-induced methemoglobinemia in childhood are illustrated by the case of a 17-month-old who died after administration of the cyanide antidote kit for ingestion of potassium cyanide.16 The cyanide antidote kit, which was given according to the published adult dosing schedule, seems to have been a more important contributor to this death than cyanide. At 10 µg/dL (0.01 mg/L), the patient's blood cyanide concentration, determined a posteriori on the basis of samples taken shortly after ingestion, was substantially under the lethal range. Furthermore, the amount of potassium cyanide ingested was estimated at between 1/50th and 1/140th of the published lethal dose. On the other hand, the cumulative amount of hemoglobin estimated a posteriori to have been oxidized to methemoglobin by nitrites administered during antidotal treatment was estimated at up to 92%, well above the 70% that is considered potentially lethal. The author suggested that the adult dosing schedule for treatment of cyanide poisoning with the cyanide antidote kit is potentially lethal for children weighing <25 kg because of their weight and the lower hemoglobin concentrations often observed.16
Besides excessive methemoglobinemia, other problems with the cyanide antidote kit include complicated administration procedures, the need to administer multiple components, and the potential for profound vasodilation associated with syncope, hypotension, tachycardia, dizziness, and nausea and vomiting.45 In children, and in smoke-inhalation victims in particular, the risks of administering the cyanide antidote kit might be especially pronounced because of the concomitant exposure to carbon monoxide in many cases. Risk/benefit concerns are also affected by the need to initiate antidotal treatment rapidly on the basis of a presumptive diagnosis of cyanide poisoning. Use of the antidote for presumptive cases of poisoning creates the potential risk of exacerbating patient status by inducing antidote adverse effects when the presumptive diagnosis of cyanide poisoning is incorrect.
Dicobalt edetate (Kelocyanor) also has been shown to be effective in the treatment of cyanide poisoning in humans, although it is not approved in the United States. In the United Kingdom, it is a treatment of choice for cyanide poisoning, provided that cyanide toxicity is definitely present. Some free cobalt ions are always present in solutions of dicobalt edetate. These cobalt ions are toxic, and the use of dicobalt edetate in the absence of cyanide will lead to serious cobalt toxicity. Animal data suggest a protective role of glucose against this cobalt toxicity, so glucose should probably be given at the same time as dicobalt edetate. Serious adverse effects recorded from dicobalt edetate include vomiting, urticaria, anaphylactic shock, hypotension, and ventricular arrhythmias.68–70
The need for a cyanide antidote with a better risk/benefit ratio than the current option in the United States is increasingly recognized.10, 11, 71 In an attempt to meet this need, the vitamin B12 precursor hydroxocobalamin is being studied for possible introduction in the United States as a cyanide antidote. Hydroxocobalamin detoxifies cyanide by binding it to form cyanocobalamin (vitamin B12), a nontoxic compound excreted in the urine.44
With human fibroblasts in vitro incubated in a cyanide solution, addition of hydroxocobalamin decreased intracellular cyanide concentrations by 75% and resulted in formation of intracellular cyanocobalamin, a finding suggesting that hydroxocobalamin penetrates cells and can act intracellularly.72 In experimental animals, hydroxocobalamin crosses the blood-brain barrier and enters the cerebrospinal fluid from the blood circulation.73 It has been shown to be an efficacious cyanide antidote in mice, rabbits, guinea pigs, dogs, and baboons.74–85 Preclinical studies in normal human volunteers have shown safety and efficacy in clearing the blood of the small amounts of cyanide detectable in heavy smokers.86
Licensed as a cyanide antidote in France in 1996, hydroxocobalamin has been used to treat known or suspected cyanide poisoning associated with smoke inhalation, industrial exposure to cyanide gas, and ingestion of cyanide salts.44, 75, 87–96 Hydroxocobalamin has also been used in other countries including Sweden, Denmark, Spain, Japan, and Hong Kong.97–101 It has been administered to pediatric patients as well as adults. The licensed pediatric dose in France is 70 mg/kg.
In a recently reported study of 41 French children (median age: 5 years) with fire smoke inhalation, the total mortality rate was 44% (18 of 41), with a prehospital mortality rate of 27% (11 of 41) and an in-hospital mortality rate of 23% (7 of the 30 hospitalized children).91 Prehospital administration of hydroxocobalamin was associated with only a 4% mortality rate in children not found in cardiac arrest. Of 23 children not found in cardiac arrest at the fire scene, 70% (16 of 23) had loss of consciousness, 74% (17 of 23) were intubated at the scene, all 23 (100%) were hospitalized, and there was 1 fatality. The mortality rate in children found in cardiac arrest was 94% (only 1 of 18 survived: 11 died at the scene, and 6 died in the intensive care unit) despite supportive care and administration of hydroxocobalamin.
Espinoza et al22 reported 8 pediatric patients (aged 8–11 years) with suspected acute cyanide poisoning from improperly prepared bitter cassava (Manihot esculenta). These children had vomiting, weakness, respiratory failure, bradycardia, hypotension, and cardiovascular collapse. Two had generalized seizures. The 4 most acutely ill children were each treated with limited supplies of sodium nitrite/sodium thiosulfate. The 4 other children were treated with 500 mg of hydroxocobalamin in a dextrose solution. All children improved within a few minutes of antidote administration, remained asymptomatic, and were discharged from the hospital the following day with normal cardiovascular and neurologic assessments.
Pediatric pharmacokinetic and safety data on hydroxocobalamin are lacking. Although safety and tolerability of hydroxocobalamin in children have not been systematically studied, its use without adverse effects has been reported in pediatric patients.91, 102 The most common adverse effects in patients regardless of age—transient interference with colorimetric clinical laboratory tests and transient reddish-brown discoloration of the urine and mucous membranes—seem not to be clinically significant and are attributed to the red color of the hydroxocobalamin molecule.71, 103 Elevation in blood pressure and rash have been observed in ongoing clinical trials of hydroxocobalamin. Other allergic reactions to hydroxocobalamin (primarily with a long-term low dose for indications other than cyanide poisoning) have been occasionally observed104, 105 but have not been reported in the relatively small number of children treated to date. On the basis of available data, hydroxocobalamin seems to constitute a useful alternative to the cyanide antidote kit for acute cyanide poisoning in pediatric patients. However, additional data about the risks and benefits of hydroxocobalamin and other potential cyanide antidotes are needed, particularly in children.
CONCLUSIONS
Acute exposure to cyanide from inhalation of fire smoke, ingestion of toxic household and workplace substances, ingestion of cyanogenic foods, and other sources has caused morbidity and mortality in children. Children may be more vulnerable than adults to some sources of cyanide poisoning. Children also seem to be more susceptible to the dangers of nitrite-induced methemoglobinemia caused by administration of the cyanide antidote kit, the only currently available antidote in the United States. The vitamin B12 precursor hydroxocobalamin constitutes a potentially useful alternative to the cyanide antidote kit for known or suspected cyanide poisoning in children, but additional information about its dosing, pharmacokinetics, and risks and benefits in children is still needed. If its efficacy and generally good tolerability reported in European data in adult patients are confirmed, hydroxocobalamin could prove useful in prehospital and inpatient management of pediatric smoke-inhalation victims as well as victims of cyanide poisoning from other sources.
FOOTNOTES
Accepted Jun 12, 2006.
Address correspondence to Robert J. Geller, MD, Georgia Poison Center, Grady Health System, 80 Jesse Hill Jr Dr SE, Box 26066, Atlanta, GA 30303-3050. E-mail: robert_geller{at}oz.ped.emory.edu
Financial Disclosure: Dr Hall is a consultant for EMD Pharmaceuticals, manufacturer of hydroxycobalamin. The other authors have indicated they have no financial relationships relevant to this article to disclose.
Drs Geller and Hall developed the concept for the manuscript; Drs Geller and Saiers developed the initial outline; all the authors reviewed the literature; Dr Saiers wrote the first draft from the developed outline; and all the authors collaborated in revisions of the manuscript and approved the final manuscript.
REFERENCES
1. World Health Organization. Hydrogen Cyanide and Cyanides: Human Health Aspects. Geneva, Switzerland: World Health Organization; 2004. Concise International Chemical Assessment Document 61
2. Baskin SI, Brewer TG. Chapter 10: cyanide poisoning. Available at: www.bordeninstitute.army.mil/cwbw/Ch10.pdf. Accessed June 10, 2006
3. Alarie Y. Toxicity of fire smoke. Crit Rev Toxicol. 2002;32 :259 –289[CrossRef][Web of Science][Medline]
4. Betol E, Mari F, Orzalesi G, Volpato I. Combustion products from various kinds of fires: toxicological hazards from smoke exposure. Forensic Sci Int. 1983;22 :111 –116[CrossRef][Web of Science][Medline]
5. Riordan M, Rylance G, Berry K. Poisoning in children 5: rare and dangerous poisons.
Arch Dis Child. 2002;87
:407
–410
6. Yeoh MJ, Braitberg G. Carbon monoxide and cyanide poisoning in fire-related deaths in Victoria, Australia. J Toxicol Clin Toxicol. 2004;42 :855 –863[CrossRef][Web of Science][Medline]
7. Barillo DJ, Goode R, Esch R. Cyanide poisoning in victims of fire: analysis of 364 cases and review of the literature. J Burn Care Rehabil. 1994;15 :46 –57[Medline]
8. Lundquist P, Rammer L, Sorbo B. The role of hydrogen cyanide and carbon monoxide in fire casualties: a prospective study. Forensic Sci Int. 1989;43 :9 –14[CrossRef][Web of Science][Medline]
9. Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med. 1991;325 :1761 –1766[Abstract]
10. Walsh DW, Eckstein M. Hydrogen cyanide in fire smoke: an underappreciated threat. EMS Mag. 2004;(October):160 –163
11. Eckstein M. Cyanide as a chemical terrorism weapon. JEMS. 2004;29(8 suppl) :22 –31
12. Caravati EM, Litovitz TL. Pediatric cyanide intoxication and death from an acetonitrile-containing cosmetic.
JAMA. 1988;260
:3470
–3473
13. Geller RJ, Ekins BR, Iknoian RC. Cyanide toxicity from acetonitrile-containing false nail remover. Am J Emerg Med. 1991;9 :268 –270[CrossRef][Web of Science][Medline]
14. Kurt TL, Day LC, Reed G. Cyanide poisoning from glue-on nail remover. Am J Emerg Med. 1991;9 :271 –272[CrossRef][Web of Science][Medline]
15. Losek JD, Rock AL, Boldt RR. Cyanide poisoning from a cosmetic nail remover.
Pediatrics. 1991;88
:337
–340
16. Berlin CM. The treatment of cyanide poisoning in children.
Pediatrics. 1970;46
:793
–796
17. Krieg A, Saxena K. Cyanide poisoning from metal cleaning solutions. Ann Emerg Med. 1987;16 :582 –584[CrossRef][Web of Science][Medline]
18. Dawood MY. Acute tapioca poisoning in a child. J Singapore Paediatr Soc. 1969;11 :154 –158[Medline]
19. Cheok SS. Acute cassava poisoning in children in Sarawak. Trop Doct. 1978;8 :99 –101[Web of Science][Medline]
20. Akintonwa A, Tunwashe OL. Fatal cyanide poisoning from cassava-based meal.
Hum Exp Toxicol. 1992;11
:47
–49
21. Ariffin WA, Choo KE, Karnaneedi S. Cassava (ubi kayu) poisoning in children. Med J Malaysia. 1992;47 :231 –234[Medline]
22. Espinoza OB, Perez M, Ramirez MS. Bitter cassava poisoning in eight children: a case report. Vet Hum Toxicol. 1992;34 :65[Web of Science][Medline]
23. Ruangkanchanasetr S, Wananukul V, Suwanjutha S. Cyanide poisoning, 2 case reports and treatment review. J Med Assoc Thai. 1999;82(suppl 1) :S162 –S171
24. Chang SS, Chan YL, Wu ML, et al. Acute Cycas seed poisoning in Taiwan. J Toxicol Clin Toxicol. 2004;42 :49 –54[CrossRef][Web of Science][Medline]
25. Davies DW, Kadar D, Steward DJ, Munro IR. A sudden death associated with the use of sodium nitroprusside for induction of hypotension during anaesthesia. Can Anaesth Soc J. 1975;22 :547 –552[Web of Science][Medline]
26. Pershau RA, Modell JH, Bright RW, Shirley PD. Suspected sodium nitroprusside-induced cyanide intoxication.
Anesth Analg. 1977;56
:533
–537
27. Humbert JR, Tress JH, Braico KT. Fatal cyanide poisoning: accidental ingestion of amygdalin. JAMA. 1977;238 :482[CrossRef][Web of Science][Medline]
28. Ortega JA, Creek JE. Acute cyanide poisoning following administration of laetrile enemas. J Pediatr. 1978;93 :1059 –1067[Web of Science][Medline]
29. Hall AH, Linden CH, Kulig K, Rumack BH. Cyanide poisoning from laetrile ingestion: role of nitrite therapy.
Pediatrics. 1986;78
:269
–272
30. American Academy of Pediatrics, Committee on Injury and Poison Prevention. Reducing the number of deaths and injuries from residential fires.
Pediatrics. 2000;105
:1355
–1357
31. CNN International. Paris apartment fire kills 7. Available at: http://edition.cnn.com/2005/WORLD/europe/08/30/france.fire. Accessed February 10, 2006
32. Herranz M, Clerigue N. Poisoning in children: methaemoglobinaemia [in Spanish]. An Sist Sanit Navar. 2003;26(suppl 1) :209 –213
33. Michael JB, Sztanjnkrycer MD. Deadly pediatric poisons: nine common agents that kill at low doses. Emerg Med Clin North Am. 2004;22 :1019 –1050[CrossRef][Web of Science][Medline]
34. US Consumer Product Safety Commission Office of Compliance. Requirements under the Federal Hazardous Substances Act: labeling and banning requirements for chemicals and other hazardous substances. 15 UCS 1261 and 16 CFR Part 1500 (August 2002)
35. Turchen SG, Manoguerra AS, Whitney C. Severe cyanide poisoning from the ingestion of acetonitrile-containing cosmetic. Am J Emerg Med. 1991;9 :264 –267[CrossRef][Web of Science][Medline]
36. Speijers G. Cyanogenic glycosides. Available at: www.inchem.org/documents/jecfa/jecmono/v30je18.htm. Accessed June 10, 2006
37. Tylleskär T, Banea M, Bikangi N, Fresco L, Persson LA, Rosling H. Epidemiological evidence from Zaire for a dietary etiology of konzo, an upper motor neuron disease. Bull World Health Organ. 1991;69 :581 –589[Web of Science][Medline]
38. Mayambu B. Cassava Processing: Dietary Cyanide Exposure and Konzo in Zaire [masters thesis]. Uppsala, Sweden: Uppsala University; 1993
39. Sayre JW, Kaymakcalan S. Cyanide poisoning from apricot seeds among children in Central Turkey. N Engl J Med. 1964;270 :1113 –1118[Web of Science][Medline]
40. Lasch EE, El Shawa R. Multiple cases of cyanide poisoning by apricot kernels in children from Gaza.
Pediatrics. 1981;68
:5
–7
41. Suchard JR, Wallace KL, Gerkin RD. Acute cyanide toxicity caused by apricot kernel ingestion. Ann Emerg Med. 1998;32 :742 –744[CrossRef][Web of Science][Medline]
42. Schulz V. Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and thiocyanate. Clin Pharmacokinet. 1984;9 :239 –251[Web of Science][Medline]
43. Iordache C, Azoicai D, Cristea A, et al. Ecological accident on the Siret river: an episode of cyanide poisoning in children [in Romanian]. Rev Med Chir Soc Med Nat Iasi. 2002;107 :319 –323[Medline]
44. Mégarbane B, Delahaye A, Goldgran-Tolédano D, Baud FJ. Antidotal treatment of cyanide poisoning. J Chin Med Assoc. 2003;66 :193 –203[Medline]
45. Dart RC, Bogdan GM. Acute cyanide poisoning: causes, consequences, recognition and management. Frontline First Responder. 2004;2 :19 –22
46. Gonzalez ER. Cyanide evades some noses, overpowers others.
JAMA. 1982;248
:2211
47. Kirk RL, Stenhouse NS. Ability to smell solutions of potassium cyanide. Nature. 1953;171 :698 –699[Medline]
48. Schragg TA, Albertson TE, Fisher CJ Jr. Cyanide poisoning after bitter almond ingestion. West J Med. 1982;136 :65 –69[Web of Science][Medline]
49. Mutlu GM, Leikin JB, Oh K, Factor P. An unresponsive biochemistry professor in the bathtub. Chest. 2002;122 :1073 –1076[CrossRef][Web of Science][Medline]
50. Baud FJ, Borron SW, Mégarbane B, et al. Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning. Crit Care Med. 2002;30 :2044 –2050[CrossRef][Web of Science][Medline]
51. Agency for Toxic Substances and Diseases Registry. Toxicological Profile for Cyanide. Atlanta, GA: US Department of Health and Human Services; 2004
52. Lynch EL, Thomas TL. Pediatric considerations in chemical exposures: are we prepared? Pediatr Emerg Care. 2004;20 :198 –208[CrossRef][Web of Science][Medline]
53. Morris-Kukoski CL, Egland AG. Toxicity, deadly in a single dose. Available at: www.emedicine.com/ped/topic2726.htm. Accessed June 10, 2006
54. Lambert RJ, Kindler BL, Schaeffer DJ. The efficacy of superactivated charcoal exposed to a lethal oral dose of potassium cyanide. Ann Emerg Med. 1988;17 :595 –598[CrossRef][Web of Science][Medline]
55. Pearce LL, Bominaar EL, Hill NC, Peterson J. Reversal of cyanide inhibition of cytochrome c oxidase by the auxiliary substrate nitric oxide: an endogenous antidote to cyanide poisoning?
J Biol Chem. 2003;278
:52139
–52145
56. Johnson WS, Hall AH, Rumack BH. Cyanide poisoning successfully treated without therapeutic methemoglobin levels. Am J Emerg Med. 1998;7 :437 –440[CrossRef]
57. Hall AH, Kulig KW, Rumack BH. Suspected cyanide poisoning in smoke inhalation: complications of sodium nitrite therapy. J Toxicol Clin Exp. 1989;9 :3 –9[Medline]
58. van Heijst AN, Douze JMC, van Kesteren RG, van Bergen JE, van Dijk A. Therapeutic problems in cyanide poisoning. Clin Toxicol. 1987;25 :383 –398
59. Kirk MA, Gerace R, Kulig KW. Cyanide and methemoglobin kinetics in smoke inhalation victims treated with the cyanide antidote kit. Ann Emerg Med. 1993;22 :1413 –1418[CrossRef][Web of Science][Medline]
60. Jones J, McMullen MJ, Dougherty J. Toxic smoke inhalation: cyanide poisoning in fire victims. Am J Emerg Med. 1987;5 :317 –321[CrossRef][Medline]
61. Becker CE. The role of cyanide in fires. Vet Hum Toxicol. 1985;27 :487 –490[Web of Science][Medline]
62. Gracia R, Shepherd G. Cyanide poisoning and its treatment. Pharmacotherapy. 2004;24 :1358 –1365[CrossRef][Web of Science][Medline]
63. Kerns W II, Isom G, Kirk MA. Cyanide and hydrogen sulfide. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Howland MA, Hoffman RJ, Nelson LS, eds. Goldfrank's Toxicologic Emergencies. 7th ed, San Francisco, CA: McGraw-Hill; 2002;1498–1514
64. Chen KK, Rose RL, Clowes GHA. Methylene blue, nitrites, and sodium thiosulphate against cyanide poisoning. Proc Soc Exp Biol Med. 1933;3 :250 –251
65. Sylvester D, Hayton WL, Morgan RL, Way JL. Effects of thiosulfate on cyanide kinetics in dogs. Toxicol Appl Pharmacol. 1983;69 :265 –271[CrossRef][Web of Science][Medline]
66. Agency for Toxic Substances and Disease Registry. Case Studies in Environmental Medicine: Nitrate/Nitrite Toxicity. Atlanta, GA: US Department of Health and Human Services; 2001. ATSDR publication No. ATSDR-HE-CS-2002-0007
67. Nilsson A, Engberg G, Henneberg S, Danielson K, De Verdier CH. Inverse relationship between age-dependent erythrocyte activity of methaemoglobin reductase and prilocaine-induced methaemoglobinaemia during infancy.
Br J Anaesth. 1990;64
:72
–76
68. Hilmann B, Bardham KD, Bain JTB. The use of dicobalt edetate (Kelocyanor) in cyanide poisoning. Postgrad Med J. 1974;50 :171 –174[Medline]
69. Naughton M. Acute cyanide poisoning. Anaesth Intensive Care. 1974;2 :351 –356[Medline]
70. Evans CL. Cobalt compounds as antidotes for hydrocyanic acids. Br J Pharmacol. 1964;23 :455 –475[Medline]
71. Sauer SW, Keim ME. Hydroxocobalamin: improved public health readiness for cyanide disasters. Ann Emerg Med. 2001;37 :635 –641[CrossRef][Web of Science][Medline]
72. Astier A, Baud FJ. Complexation of intracellular cyanide by hydroxocobalamin using a human cellular model. Hum Exp Toxicol. 1996;15 :19 –25[Medline]
73. van den Berg MP, Merkus P, Romeijn SG, Verhoef JC, Merkus FW. Hydroxocobalamin uptake into the cerebrospinal fluid after nasal and intravenous delivery in rats and humans. J Drug Target. 2003;11 :325 –331[CrossRef][Web of Science][Medline]
74. Mushett CW, Kelly KL, Boxer GE, Richards JC. Antidotal efficacy of vitamin B12 (hydroxo-cobalamin) in experimental cyanide poisoning. Proc Soc Exp Biol Med. 1952;81 :234 –237[CrossRef][Medline]
75. Hantson P, Benaissa L, Baud F. Smoke poisoning [in French]. Presse Med. 1999;28 :1949 –1954[Web of Science][Medline]
76. Pill J, Engeser P, Hobel M, Kreye VA. Sodium nitroprusside: comparison of the antidotal effect of hydroxocobalamin and sodium thiosulfate in rabbits. Dev Toxicol Environ Sci. 1980;8 :423 –426[Medline]
77. Mizoule J. Study of the Action of Hydroxocobalamin in Regards to Cyanide Poisoning [doctoral thesis; in French]. Paris, France: Faculte de Pharmacie de l'Universite de Paris; 1966:1 –178
78. Faure J, Vincent M, Benabid AL, Chirossel JP, Levy JC, Yacoub M. Hydroxocobalamin treatment of hypercyanemia and hypercyanuria following sciatic nerve compression in rabbits [in French]. C R Seances Soc Biol Fil. 1977;171 :1221 –1226[Web of Science][Medline]
79. Vincent M, Vincent F, Marka C, Faure J. Cyanide and its relationship to nervous suffering: physio-pathological aspects of intoxication. Clin Toxicol. 1981;18 :1519 –1527[Web of Science][Medline]
80. Posner MA, Rodkey FL, Tobey RE. Nitroprusside-induced cyanide poisoning: antidotal effect of hydroxocobalamin. Anesthesiology. 1976;44 :330 –335[Web of Science][Medline]
81. Krapez JR, Vesey CJ, Adams L, Cole PV. Effects of cyanide antidotes used with sodium nitroprusside infusions: sodium thiosulphate and hydroxocobalamin given prophylactically to dogs.
Br J Anaesth. 1981;53
:793
–804
82. Rose CL, Worth RM, Chen KK. Hydroxo-cobalamine and acute cyanide poisoning in dogs. Life Sci. 1965;4 :1785 –1798[CrossRef][Medline]
83. Ivankovich AD, Braverman B, Kanuru RP, Heyman HJ, Paulissian R. Cyanide antidotes and methods of their administration in dogs: a comparative study. Anesthesiology. 1980;52 :210 –216[Web of Science][Medline]
84. Paulet G, Olivier M. On the subject of the therapeutic value of hydroxocobalamin in cyanide poisoning [in French]. Ann Pharm Fr. 1963;21 :133 –137[Web of Science][Medline]
85. Paulet G. On the subject of the treatment of cyanide poisoning with the cobalt chelates [in French]. Urgence Med Chir. 1965;II :611 –613
86. Forsyth JC, Mueller PD, Becker CE, et al. Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. J Toxicol Clin Toxicol. 1993;31 :277 –294[Web of Science][Medline]
87. Borron S, Mégarbane B, Baud FJ. Hydroxocobalamin is an effective antidote in severe acute cyanide poisoning in man [abstract]. Int J Toxicol. 2004;23 :399 –400
88. Bromley J, Hughes BG, Leong DC, Buckley NA. Life-threatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C.
Ann Pharmacother. 2005;39
:1566
–1569
89. Fortin JL, Waroux S, Ruttimann M, Astaud C, Kowalski JJ. Hydroxocobalamin for poisoning caused by ingestion of potassium cyanide: a case study [abstract]. Clin Toxicol. 2005;43 :731
90. Weng TI, Fang CC, Lin SM, Chen WJ. Elevated plasma cyanide level after hydroxocobalamin infusion for cyanide poisoning. Am J Emerg Med. 2004;22 :492 –493[CrossRef][Web of Science][Medline]
91. Haouach H, Fortin JL, LaPostolle F. Prehospital use of hydroxocobalamin in children exposed to fire smoke [abstract]. Ann Emerg Med. 2005;46 :S30 . Abstract 102
92. Borron SW, Baud FJ. Acute cyanide poisoning: Clinical spectrum, diagnosis, and treatment. Arh Hig Rada Toksikol. 1996;47 :307 –322[Medline]
93. Bismuth C, Cantineau JP, Pontal P, Baud F, Garnier R, Poulos L. Priority of oxygenation in cyanide poisoning: regarding 25 cases [in French]. Presse Med. 1984;13 :2493 –2497[Web of Science][Medline]
94. Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med. 1987;5 :115 –121[CrossRef][Medline]
95. Borron SW, Barriot P, Imbert M, Baud FJ. Hydroxocobalamin for empiric treatment of smoke inhalation-associated cyanide poisoning: results of a prospective study in the prehospital setting [abstract]. Ann Emerg Med. 2005;46(3 suppl) :S77 . Abstract 275
96. Fortin JL, Ruttiman M, Domanski L, Kowalski JJ. Hydroxocobalamin: treatment for smoke inhalation-associated cyanide poisoning: meeting the needs of fire victims. JEMS. 2004;29(8 suppl) :18 –21
97. Santiago I. Gas poisoning [in Spanish]. An Sist Sanit Navar. 2003;26(suppl 1) :173 –180
98. Lau FL. Emergency management of poisoning in Hong Kong. Hong Kong Med J. 2000;6 :288 –292[Medline]
99. Kukori Y, Endo Y, Madono K, et al. Antidotes not approved in Japan: imported antidotes for the Kyushu/Okinawa Summit [in Japanese]. Jpn J Toxicol. 2001;14 :259 –267
100. Møeller S, Hemmingsen C. Science and practice: case reports—cyanide poisoning [in Danish]. Ugeskr Laeger. 2003;165 :2579 –2580[Medline]
101. Personne M, Kulling P. Vitamin B12 variant for cyanide poisoning: hydroxocobalamin, new effective antidote [in Swedish]. Lakartidningen. 1997;94 :877 –878[Medline]
102. Breton D, Jouvet P, de Blic J, Delacourt C, Hubert P. Toxicity of fire smoke: Regarding two pediatric cases [in French]. Arch Fr Pediatr. 1993;50 :43 –45[Web of Science][Medline]
103. Curry SC, Connor DA, Raschke RA. Effect of the cyanide antidote hydroxocobalamin on commonly ordered serum chemistry studies. Ann Emerg Med. 1994;24 :65 –67[Web of Science][Medline]
104. Heyworth-Smith D, Hogan PG. Allergy to hydroxycobalamin, with tolerance of cyanocobalamin. Med J Aust. 2002;177 :162 –163[Web of Science][Medline]
105. Branco-Ferreira M, Clode MH, Pereira-Barbosa MA, Palma-Carlos AG. Anaphylactic reaction to hydroxycobalamin. Allergy. 1997;52 :118 –119[Web of Science][Medline]
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