STATE-OF-THE-ART REVIEW ARTICLE

Pediatric Cyanide Poisoning: Causes, Manifestations,

Management, and Unmet Needs
Robert J. Geller, MDa,b, Claudia Barthold, MDa,b, Jane A. Saiers, PhDc, Alan H. Hall, MDd,e

aDepartment of Pediatrics and the Medical Toxicology Fellowship Program, Emory University School of Medicine, Atlanta, Georgia; bGeorgia Poison Center, Atlanta,

Georgia; cThe WriteMedicine, Inc, Chapel Hill, North Carolina; dToxicology Consulting and Medical Translating Services, Inc, Elk Mountain, Wyoming; eDepartment of
Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado

Financial Disclosure: Dr Hall is a consultant for EMD Pharmaceuticals, manufacturer of hydroxycobalamin. The other authors have indicated they have no nancial relationships relevant to this article to
disclose.

ABSTRACT
Confirmed cases of childhood exposure to cyanide are rare despite multiple
potential sources including inhalation of fire smoke, ingestion of toxic household
www.pediatrics.org/cgi/doi/10.1542/
and workplace substances, and ingestion of cyanogenic foods. Because of its peds.2006-1251
infrequent occurrence, medical professionals may have difficulty recognizing cy- doi:10.1542/peds.2006-1251
anide poisoning, confirming its presence, and treating it in pediatric patients. The
Drs Geller and Hall developed the concept
sources and manifestations of acute cyanide poisoning seem to be qualitatively for the manuscript; Drs Geller and Saiers
similar between children and adults, but children may be more vulnerable than developed the initial outline; all the
authors reviewed the literature; Dr Saiers
adults to poisoning from some sources. The only currently available antidote in the wrote the rst draft from the developed
United States (the cyanide antidote kit) has been used successfully in children but outline; and all the authors collaborated in
revisions of the manuscript and approved
has particular risks associated with its use in pediatric patients. Because hemoglo- the nal manuscript.
bin kinetics vary with age, methemoglobinemia associated with nitrite-based Key Words
antidotes may be excessive at standard adult dosing in children. A cyanide antidote cyanide, poisoning, smoke inhalation,
with a better risk/benefit ratio than the current agent available in the United States nitrite, hydroxocobalamin,
methemoglobinemia, antidotes
is desirable. The vitamin B12 precursor hydroxocobalamin, which has been used in
Accepted for publication Jun 12, 2006
Europe, may prove to be an attractive alternative to the cyanide antidote kit for Address correspondence to Robert J. Geller,
pediatric patients. In this article we review the available data on the sources, MD, Georgia Poison Center, Grady Health
System, 80 Jesse Hill Jr Dr SE, Box 26066,
manifestations, and treatment of acute cyanide poisoning in children and discuss Atlanta, GA 30303-3050. E-mail:
unmet needs in the management of pediatric cyanide poisoning. robertgeller@oz.ped.emory.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright 2006 by the
American Academy of Pediatrics

2146 GELLER et al
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C YANIDE IS AMONG the most potent and deadly poi-
sons, 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 com-
bustion 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 cy-
anide 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.3,510 Humans can also be exposed to cya-
nide 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 dis-
persed 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 in-
gestion. In this article we review the available data on
the sources, manifestations, and treatment of acute cy-
anide 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 poison-
ing in children.5,7 Additional sources described in case
reports include household or workplace substances con-
taining cyanogenic compounds, cyanogenic foods, lae-
trile, and nitroprusside (Table 1).1229 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 cya-
nide-containing or cyanogenic household substances
and ingestion of cyanogenic plants have been reported
more frequently in children than adults (Table 1).1229
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 expo-
sure, the specific cyanide compound or cyanogenic com-
pound involved, the route of exposure, treatment pro-
vided 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 mol/L), and the fatal exploration.32,33 Although the US Consumer Product
level is generally considered to exceed 2.6 to 3 mg/L
(100 115 mol/L).3,6,7,28
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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 dur-
ing 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-inhalationassociated deaths occur-
ring 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 concen-
trations 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 mol/L) and those who died
(mean concentration: 87.0 mol/L). Blood carbon mon-
oxide 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 poison-
ing and/or other causes of hypoxia may have contrib-
uted 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 sub-
stances in their mouths and/or ingest them as a means of
Safety Commission prohibits the sale of consumer prod-
ucts containing soluble cyanide salts,34 cyanide may be
PEDIATRICS Volume 118, Number 5, November 2006 2147
 TABLE 1 Summary of Case Reports of Pediatric Cyanide Poisoning From Causes Other Than Smoke Inhalation

2148
Reference Age/Gender Source/Cause of Cyanide Signs and Symptoms Blood Cyanide Intervention Outcome
Poisoning Concentrationa
Ingestion of substances containing
acetonitrile
Caravati and Litovitz12 (1988) 16 mo/boy Acetonitrile-containing false- Vomiting, respiratory distress; found None Died

GELLER et al
Caravati and Litovitz12 (1988)
Geller et al13 (1991)
Kurt et al14 (1991)
Losek et al15 (1991)
ngernail remover dead in bed the morning after
ingesting the product
2 y/boy Acetonitrile-containing false- Vomiting, coma, respiratory distress,
ngernail remover shock 8 h after ingestion
3 y/boy Acetonitrile-containing false- No noticeable symptoms on
ngernail remover presentation to the emergency
department 30 min after
ingestion; 13 h after ingestion
(and after gastric lavage and
administration of activated
charcoal on emergency
department admission), the
patient vomited; 16 h after
ingestion, confusion, vomiting,
abnormal venous blood
hemoglobin desaturation
2 y/girl Acetonitrile-containing false- Vomiting, seizures, coma 14 h after
ngernail remover ingesting the product; marked
hypoxia and acidosis; no odor of
bitter almonds
23 mo/boy Acetonitrile-containing false- Vomiting, 6 h after ingestion;
ngernail remover otherwise normal; beginning
24 h after ingestion, altered
responsiveness (staring episodes,
3.1 g/mL 12 h after
ingestion
6.0 g/mL 12 h after Oxygen, intravenous uids Survived with no sequelae
ingestion
124 g/dL 3 h and 45 min Gastric lavage and activated Survived with no sequelae
after ingestion charcoal 30 min after
ingestion (while patient
was asymptomatic);
sodium thiosulfate 16 h
after ingestion
70.1 mol/L 14 h after Oxygen; cyanide antidote Survived with no sequelae
ingestion kit (inhaled amyl nitrite
followed by sodium
nitrite and sodium
thiosulfate); activated
charcoal
2.1 g/mL 12 h after Amyl nitrite, sodium Survived with no sequelae
ingestion; 3.8 g/mL thiosulfate
25 h after ingestion

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Ingestion of other household and
workplace substances
Berlin16 (1970)
Krieg and Saxenal17 (1987)
17 mo/boy Ingestion of Drabkins solution
containing 50 mg of
potassium cyanide, 200 mg
of potassium ferrocyanide,
and 1 g of sodium
bicarbonate in 1 liter
2.5 y/girl Ingestion of metal-cleaning
solution containing cyanide
salt
not responding to mother), low
oxygen saturation; no odor of
bitter almonds
Asymptomatic on arrival at the
emergency department 30 min
after ingestion; after
administration of antidote,
vomiting, apneic spells,
generalized seizure; cardiac arrest
Unresponsive, unconscious,
hypotension, tachycardia; odor of
bitter almonds present
Postmortem blood cyanide Amyl nitrite, sodium nitrite, Died; the authors attributed
concentration 10 sodium thiosulfate; the death to sodium
g% oxygen; diazepam for nitrite-induced
seizure; sodium methemoglobinemia.
bicarbonate; methylene
blue
Not reported Cyanide antidote kit (amyl Survived with no sequelae
nitrite, sodium nitrite,
sodium thiosulfate)
 TABLE 1 Continued
Reference
Ingestion of cyanogen-containing
food
Dawood18 (1969)
Cheok19 (1978)
Cheok19 (1978)
Akintonwa and Tunwashe20 (1992)
Akintonwa and Tunwashe20 (1992)
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Arifn et al21 (1992)
Espinoza et al22 (1992)
PEDIATRICS Volume 118, Number 5, November 2006
2149
Age/Gender Source/Cause of Cyanide Signs and Symptoms Blood Cyanide Intervention Outcome
Poisoning Concentrationa
3.5 y/girl Ingestion of cooked wild Vomiting 5 h after ingestion, Not reported. Analysis of Sodium bicarbonate Survival with no sequelae
tapioca frothing around the mouth; on the specimen of
admission to the hospital, the girl uncooked tapioca tuber
was in shock, acidotic, drowsy, showed 0.0094% (wt/
hypotensive, irritable, breathless, wt) hydrogen cyanide;
pale; pupils were dilated and the authors
nonreactive characterized this
amount as being
moderately to severely
poisonous
2.5 y/boy Ingestion of tapioca cake Vomiting, drowsiness, weakness 9 Not reported Sodium bicarbonate; Survived with no sequelae
h after ingestion sodium thiosulfate
1.5 y/girl Ingestion of tapioca cake Vomiting, drowsiness, weakness, Not reported; analysis of Gastric lavage; oxygen; Survived with no sequelae
dyspnea, cyanosis a few hours the cooked tapioca, the sodium bicarbonate;
(time not specied) after upper tuber of sodium thiosulfate
ingestion uncooked tapioca, and
the lower tuber of
uncooked tapioca
revealed 3, 15, and 28
ppm cyanide,
respectively
8 y/boy Ingestion of a cassava-based Coma Blood and urine Supportive therapy (not Died of cardiorespiratory
meal concentrations: 0.85 and specied) arrest
0.56 mg/L, respectively
17 y/girl Ingestion of a cassava-based Dizziness, headache, vomiting Blood and urine Not specied Died of cardiorespiratory
meal progressing to shock with acute concentrations: 1.35 and arrest
renal failure 0.40 mg/L, respectively
Siblings Ingestion of tapioca blocks
6 y/girl Vomiting and diarrhea 10 h after 4 g/mL (the authors Gastric lavage, oxygen, Survival with no sequelae
ingestion; otherwise normal suggested that this intravenous dextrose
value was erroneously saline
high)
1.5 y/girl Abdominal cramps, nausea, Not reported Not treated Died en route to the
diarrhea, vomiting 6.5 h after hospital
ingestion
8 y/girl Vomiting Not reported Not treated Survived with no sequelae
8 children 811 y/boys Ingestion of rhizomes of bitter Vomiting, excessive weakness, Not reported 100% oxygen to all 8 All 8 survived with no
cassava respiratory failure, bradycardia, children; Sodium nitrite sequelae
hypotension, cardiovascular followed by sodium
collapse; generalized seizures in thiosulfate to 4 children;
2 children; bright cherry-red hydroxocobalamin to 4
blood when samples for blood children
gases were obtained
 TABLE 1 Continued

2150
Reference Age/Gender Source/Cause of Cyanide Signs and Symptoms Blood Cyanide Intervention Outcome
Poisoning Concentrationa
Ruangkanchanasetr et al23 (1999) 4 y/girl Ingestion of boiled cassava Vomited and went unconscious 9 h 0.56 g/mL 19 h after Intubation with ventilatory Survived with no sequelae
after ingestion; on arrival at the ingestion support; gastric lavage
hospital, the girl was stuporous and activated charcoal;

GELLER et al
but responsive to pain stimuli; sodium nitrate and
19 h after ingestion, hypocapnia sodium thiosulfate and
and lactic academia were supportive treatment
present 19 h after ingestion
Ruangkanchanasetr et al23 (1999) 1.5 y/boy Ingestion of boiled cassava Vomited and went unconscious 9 h 0.32 g/mL 23 h after Mechanical ventilation with Survived with no sequelae
after ingestion; on arrival at the ingestion hyperventilation and
hospital, stupor, spasticity, and circulatory support by
hypoventilation with cyanosis intravenous uid loading,
were noted; 23 h after ingestion, dopamine, and
had bitter-almond breath, dobutamine; gastric
respiratory alkalosis, mild lactic lavage
acidemia
Chang et al24 (2004) 3 children Ingestion of Cycas seeds
14 y/boy Asymptomatic Not reported Not reported Survived with no sequelae
(all cases)
7 y/girl Vomiting, headache, dizziness, Not reported Not reported
weakness
10 y/girl Vomiting, abdominal pain, diarrhea Not reported Not reported
Nitroprusside for surgical
hypotension
Davies et al25 (1975) 14 y Nitroprusside 400 mg for Tachyphylaxis and acidosis 80 min 140 mol/L (authors Supportive care Died
surgical hypotension after administration of suggested the presence
nitroprusside of an abnormality of
cyanide metabolism)
Pershau et al26 (1977) 14 y Nitroprusside 130 mg for Acidosis and tachyphylaxis 5 h after Not reported Supportive care Survived with no sequelae
surgical hypotension administration of nitroprusside

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Laetrile
Humbert et al27 (1977) 11 mo/girl Laetrile tablets Coma Not reported Hospital treatment Died
Ortega and Creek28 (1978) 2 y and 10 mo/boy Laetrile enema for cancer Vomiting and diarrhea after second 214 g/dL 5 h after Oxygen therapy and Survived with no sequelae
treatment daily enema; after the third daily admission to the intravenous hydration
enema, lethargy, hospital after the third
unresponsiveness, tachypnea, daily enema
cyanosis
Hall et al29 (1986) 4 y/boy Laetrile tablets ingested Over the 1.5 h after ingestion, 16.2 g/mL 5 h after Initially, diazepam for Survived with no sequelae
shortly after a meal of fresh progressively increasing lack of ingestion seizures, 100% oxygen,
fruits, vegetables, and responsiveness, seizures; on gastric lavage, amyl
peanuts arrival at hospital, the boy was nitrite; 6 h after ingestion,
hypotensive, pupils widely sodium nitrite and
dilated but responsive, acidotic; sodium thiosulfate
no bitter-almond smell noted
a Reported in the units used in the original publication
accessible from industrial sources, as are some cyano-
genic compounds that may also be contained in products
marketed for consumer use. This risk is illustrated by
several cases of cyanide poisoning from acetonitrile-con-
taining false-fingernail remover. Acetonitrile is used as a
solvent in industrial and laboratory settings and is some-
times 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 med-
ical literature (Table 1).1215
As would be expected from a cyanogenic compound
requiring metabolic activation to be converted to cya-
nide, the onset of acetonitrile-associated cyanide toxicity
typically occurs after a delay. This observation is consis-
tent 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 poten-
tially highly toxic acetonitrile-containing cosmetics, par-
ticularly false-fingernail removers, with less-toxic ace-
tone-containing fingernail-polish removers. In one
reported case, a 16-month-old boy who had ingested
acetonitrile-containing fingernail remover was mistak-
enly assumed to have ingested acetone-containing fin-
gernail 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 aceto-
nitrile poisoning is compounded by the initial similarity
TABLE 2 Cyanogenic Glycosides in Major Edible Plants
Cyanogenic Glycosides
Common Name
Amygdalin Almonds
Dhurrin Sorghum
Linamarin Cassava
Lima beans
Lotaustralin Cassava
Lima beans
Prunasin Stone fruits
Taxiphyllin Bamboo shoots
Source: Speijers G. Cyanogenic glycosides. Available at: www.inchem.org/documents/jecfa/jecmono/v30je18.htm.
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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 poison-
ing, 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 cy-
anide poisoning, vomiting was the first symptom of tox-
icity and heralded the development of severe toxicity
(Table 1).1215 However, vomiting is common from many
causes and is not sufficient by itself to dictate the admin-
istration 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 pedi-
atric poisoning. Cases of pediatric cyanide poisoning
from ingestion of Drabkins 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 in-
cluding 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 inges-
tion 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 impor-
tant parts of the diet.
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 -glucosidase or -glucosidase liberated
from the cassava plant itself.36 Numerous cases of acute
Plant Source
Latin Name
Prunus amygdalus
Sorghum album
Sorghum bicolor
Manihot esculenta
Manihot carthaginensis
Phaseolus lunatus
M carthaginensis
P lunatus
Prunus spp such as Prunus avium,
Prunus padus, Prunus persica,
Prunus macrophylla
Bambusa vulgaris
PEDIATRICS Volume 118, Number 5, November 2006 2151
cyanide poisoning after ingestion of cassava have been
reported in children in tropical countries.18,19,2024 Cassava
poisoning in adults has also been reported, but pediatric
poisoning may be more frequent and severe (as dis-
cussed below in Manifestations of Acute Cyanide Poi-
soning). 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 parapare-
sis.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 -glucosidase emulsin,
which catalyzes amygdalin hydrolysis.41 Chewing apricot
pits releases emulsin and increases the toxicity of cya-
nide. Swallowing 1 or 2 whole stone fruit pits usually
does not result in cyanide poisoning, because the amyg-
dalin and the -glucosidase enzyme are located in dif-
ferent 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 amyg-
dalin, 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
-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 pro-
ducing controlled hypotension to reduce bleeding during
surgery. Within minutes of intravenous infusion, so-
dium 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 ecolog-
ical 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 contami-
2152 GELLER et al
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nated fish from the river, cyanide levels and other con-
firmatory 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 by-
products such as lactic acid over the production of cel-
lular energy in the form of adenosine triphosphate
(ATP). Accordingly, clinical manifestations of acute cy-
anide 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.
After intense exposure, rapid death may ensue. After
less severe exposure, early manifestations include weak-
ness, malaise, confusion, headache, dizziness, and short-
ness of breath. Later manifestations include nausea and
vomiting, hypotension, generalized seizures, coma, ap-
nea, cardiac arrhythmias, and death attributed to cardio-
respiratory arrest. Additional physical findings some-
times 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 ele-
vated venous oxygen levels, cyanosis is typically not
present in spontaneously breathing or artificially venti-
lated patients. A patients breath may have a bitter,
almond-like odor attributed to excretion of unmetabo-
lized cyanide; however, this odor is often undetect-
able.4648
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
TABLE 3 Signs and Symptoms of Cyanide Poisoning
System Sign or Symptom
Dermatologic Cherry-red color of skin
Neurologic Headache, agitation, disorientation, confusion,
weakness, malaise, dizziness, lethargy, seizures,
coma, cerebral death
Cardiovascular Hypotension, tachycardia or bradycardia, ST-T
wave changes, dysrhythmias, atrioventricular
block, cardiovascular collapse
Respiratory and metabolic Tachypnea or apnea, venous hyperoxemia, red
venous blood, increased mixed venous oxygen
content and decreased oxygen consumption
resulting in narrow arteriovenous oxygen
differential
Acidosis, elevated blood lactate, elevated lactate/
pyruvate ratio
Gastrointestinal Nausea, vomiting, abdominal pain
Other Bitter-almond breath in some patients
Sources: Ruangkanchanasetr S, Wananukul V, Suwanjutha S. J Med Assoc Thai. 1999;82(suppl
1):S162S171; Megarbane B, Delahaye A, Goldgran-Toledano D, Baud FJ. J Chin Med Assoc.
2003;66:193203; and Dart RC, Bogdan GM. Frontline First Responder. 2004;2:19 22.
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 vic-
tims, 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 doc-
ument 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 suscep-
tible 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 impair-
ment, respiratory distress, and cardiovascular compro-
mise; the occasional presence of bitter-almond breath
and bright-red venous blood; and metabolic acidosis
(Table 1).1229,51
Factors that could render children more vulnerable
than adults to cyanide poisoning include higher respira-
tory 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 inges-
tion 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 cyano-
genic foods has been attributed to childrens lower body
mass and, in cassava poisoning, to the childrens higher
gastric acidity than that of adults.18,19,21 Cyanide in cas-
sava exists both in a free form and in combination with
the glycosides linamarin and lotaustralin. However,
nonage-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
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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
mol/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 chil-
dren and adults entails removal of the victim from the
source of cyanide in inhalation exposure, gastric decon-
tamination with aspiration of gastric contents, and ad-
ministration of activated charcoal in the event of poison-
ing by ingestion (if care for the victim begins soon after
ingestion). Ensuing supportive care includes 100% ox-
ygen, cardiopulmonary resuscitation if necessary, and an
appropriate antidote (Table 4).44,45,54 Because cyanide
toxicity can culminate quickly in death, rapid interven-
tion is crucial and is usually undertaken on the basis of
a presumptive diagnosis before confirmatory blood cya-
nide concentrations are available.
The cyanide antidote kit is the only cyanide antidote
currently commercially available in the United States,
although other antidotes are available in other coun-
tries.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 ni-
trite and sodium thiosulfate. The nitrite moieties from
amyl nitrite and sodium nitrite oxidize hemoglobin to
TABLE 4 Management of Acute Cyanide Poisoning
Supportive measures
Removal of victim from source of exposure (in cases of inhalation)
Gastric aspiration (in cases of ingestion, if able to be started soon after
ingestion)
Activated charcoal (in cases of ingestion, if able to be started soon after
ingestion)
100% oxygen
Cardiopulmonary support and/or resuscitation
Sodium bicarbonate to correct metabolic acidosis
Anticonvulsants, epinephrine, antidysrhythmic agents as needed
Antidotes available in the US as of January 2006
Cyanide antidote kit (only antidote currently available in the US)
Includes amyl nitrite sodium nitrite sodium thiosulfate
May cause excessive methemoglobinemia, particularly in smoke-inhalation
victims and pediatric patients
Antidotes licensed in other countries as of January 2006
Dicobalt EDTA (Kelocyanor)
Hydroxocobalamin (Cyanokit)
4-Dimethylaminophenol (DMAP)
Sources: Megarbane B, Delahaye A, Goldgran-Toledano D, Baud FJ. J Chin Med Assoc. 2003;66:
193203; Dart RC, Bogdan GM. Frontline First Responder. 2004;2:19 22; and Lambert RJ, Kindler
BL, Schaeffer DJ. Ann Emerg Med. 1988;17:595598
PEDIATRICS Volume 118, Number 5, November 2006 2153
create methemoglobin, which competes with cyto-
chrome oxidase for the cyanide ion. Binding of cyanide
to methemoglobin frees the cytochrome oxidase neces-
sary for aerobic cellular respiration. The extent of met-
hemoglobinemia required to achieve the desired thera-
peutic benefit is uncertain; a prudent strategy is to use
the lowest amount of methemoglobinemia that reverses
the cyanide-induced clinical findings.55 Another mecha-
nism 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 thiocya-
nate.
Incongruously, the methemoglobinemia induced by
the nitrites in the cyanide antidote kit itself can be dan-
gerous 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 met-
hemoglobinemia 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 an-
tidote kit demonstrated methemoglobin levels of 7.9%
to 13.4%, and their total reduction in oxygen-carrying
capacity caused by carbon monoxide, cyanide, and met-
hemoglobinemia never exceeded 21%.59 These values
were not considered dangerous.
Nitrite-induced methemoglobinemia may pose a par-
ticular danger for victims of cyanide poisoning from
smoke inhalation (probably the most common cause of
cyanide poisoning in children) because of the likely pres-
ence of carboxyhemoglobinemia secondary to concom-
itant carbon monoxide poisoning.10,57,60,61 Like methemo-
globinemia, 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 patients
condition. This possibility raises concern about the use of
the cyanide antidote kit in the management of smoke-
inhalationassociated cyanide poisoning, particularly in the
prehospital setting.10,62
To avoid the complications of methemoglobinemia
associated with nitrites, sodium thiosulfate has been rec-
ommended for use as a sole agent (without nitrites) for
cyanide toxicity to enhance rhodanase activity.63,64 Ad-
vocates of this therapeutic regimen contend that the
enhanced safety of this approach outweighs the poten-
tially slower reduction of cyanide level in the body.65
Nitrite-induced methemoglobinemia can pose a par-
ticular safety hazard to young children, because hemo-
globin kinetics vary with age. A proportion of hemoglo-
bin 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 hemoglo-
bin.66 In addition, infants and very young children have
2154 GELLER et al
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significantly reduced activity of methemoglobin reduc-
tase (the enzyme responsible for converting methemo-
globin) compared with normal adults back to normal
hemoglobin.66,67 These factors render young children es-
pecially susceptible to excessive nitrite-induced methe-
moglobinemia.
The dangers of excessive nitrite-induced methemo-
globinemia in childhood are illustrated by the case of a
17-month-old who died after administration of the cy-
anide 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 g/dL (0.01 mg/L), the patients 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 potas-
sium 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 esti-
mated at up to 92%, well above the 70% that is considered
potentially lethal. The author suggested that the adult dos-
ing schedule for treatment of cyanide poisoning with the
cyanide antidote kit is potentially lethal for children weigh-
ing 25 kg because of their weight and the lower hemo-
globin concentrations often observed.16
Besides excessive methemoglobinemia, other prob-
lems with the cyanide antidote kit include complicated
administration procedures, the need to administer mul-
tiple components, and the potential for profound vaso-
dilation associated with syncope, hypotension, tachycar-
dia, 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 espe-
cially pronounced because of the concomitant exposure
to carbon monoxide in many cases. Risk/benefit con-
cerns 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 presump-
tive cases of poisoning creates the potential risk of exac-
erbating patient status by inducing antidote adverse ef-
fects 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, urti-
caria, anaphylactic shock, hypotension, and ventricular
arrhythmias.6870
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 detoxi-
fies cyanide by binding it to form cyanocobalamin (vita-
min B12), a nontoxic compound excreted in the urine.44
With human fibroblasts in vitro incubated in a cya-
nide solution, addition of hydroxocobalamin decreased
intracellular cyanide concentrations by 75% and re-
sulted in formation of intracellular cyanocobalamin, a
finding suggesting that hydroxocobalamin penetrates
cells and can act intracellularly.72 In experimental ani-
mals, hydroxocobalamin crosses the blood-brain barrier
and enters the cerebrospinal fluid from the blood circu-
lation.73 It has been shown to be an efficacious cyanide
antidote in mice, rabbits, guinea pigs, dogs, and ba-
boons.7485 Preclinical studies in normal human volun-
teers 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 in-
halation, industrial exposure to cyanide gas, and inges-
tion of cyanide salts.44,75,8796 Hydroxocobalamin has also
been used in other countries including Sweden, Den-
mark, Spain, Japan, and Hong Kong.97101 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 prehos-
pital mortality rate of 27% (11 of 41) and an in-hospital
mortality rate of 23% (7 of the 30 hospitalized chil-
dren).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 hydroxocobal-
amin.
Espinoza et al22 reported 8 pediatric patients (aged
8 11 years) with suspected acute cyanide poisoning
from improperly prepared bitter cassava (Manihot escu-
lenta). These children had vomiting, weakness, respira-
tory failure, bradycardia, hypotension, and cardiovascu-
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lar 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 dex-
trose 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 hydr-
oxocobalamin are lacking. Although safety and tolera-
bility of hydroxocobalamin in children have not been
systematically studied, its use without adverse effects has
been reported in pediatric patients.91,102 The most com-
mon adverse effects in patients regardless of agetran-
sient interference with colorimetric clinical laboratory
tests and transient reddish-brown discoloration of the
urine and mucous membranesseem 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 sub-
stances, 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 sus-
ceptible to the dangers of nitrite-induced methemoglo-
binemia caused by administration of the cyanide anti-
dote kit, the only currently available antidote in the
United States. The vitamin B12 precursor hydroxocobal-
amin 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.
PEDIATRICS Volume 118, Number 5, November 2006 2155
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IN NEW JERSEY, MOUNTING COSTS FOR MEDICAL SCHOOL INQUIRY DRAW CRITICISM

The federal monitor appointed to investigate wasteful spending at New

Jerseys troubled state medical and dental school has submitted a $5.8 million
bill for his first six months on the job, according to state billing records. That
figure is higher than the amount of financial wrongdoing that prompted the
inquiry, and has spurred criticism from some board members and state
officials who say the charges are excessive. Herbert J. Stern, a former federal
judge, was assigned to investigate the University of Medicine and Dentistry of
New Jersey in December after school administrators acknowledged that they
had over-billed Medicaid by nearly $5 million. Since then, Mr. Stern has
charged the state $199,600 for 436 hours of work on the case, while a team
of seven lawyers in his firm has billed the university $992,787. In addition, an
assortment of subcontractors have added to the costincluding the auditing
of the accounting firm J. H. Cohn, which has charged $3.6 million, and the
accounting firm Sobel & Company, which has billed for $535,956.
Kocieniewski D. New York Times. August 9, 2006
Noted by JFL, MD

2158 GELLER et al
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Pediatric Cyanide Poisoning: Causes, Manifestations, Management, and Unmet
Needs
Robert J. Geller, Claudia Barthold, Jane A. Saiers and Alan H. Hall
Pediatrics 2006;118;2146
DOI: 10.1542/peds.2006-1251
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2006 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Pediatric Cyanide Poisoning: Causes, Manifestations, Management, and Unmet
Needs
Robert J. Geller, Claudia Barthold, Jane A. Saiers and Alan H. Hall
Pediatrics 2006;118;2146
DOI: 10.1542/peds.2006-1251

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/118/5/2146.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2006 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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