Keracunan Akut Dan Antidotumnya 2

DOI: 10.1542/peds.2006-1251 2006;118;2146-2158 Pediatrics

Robert J. Geller, Claudia Barthold, Jane A. Saiers and Alan H. Hall Needs

Pediatric Cyanide Poisoning: Causes, Manifestations, Management, and Unmet

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STATE-OF-THE-ART REVIEW ARTICLE

Pediatric Cyanide Poisoning: Causes, Manifestations,Management, and Unmet NeedsRobert 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 ofPreventive 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 financial relationships relevant to this article todisclose.

ABSTRACT

Confirmed cases of childhood exposure to cyanide are rare despite multiplepotential sources including inhalation of fire smoke, ingestion of toxic householdand workplace substances, and ingestion of cyanogenic foods. Because of itsinfrequent occurrence, medical professionals may have difficulty recognizing cy-anide poisoning, confirming its presence, and treating it in pediatric patients. Thesources and manifestations of acute cyanide poisoning seem to be qualitativelysimilar between children and adults, but children may be more vulnerable thanadults to poisoning from some sources. The only currently available antidote in theUnited States (the cyanide antidote kit) has been used successfully in children buthas particular risks associated with its use in pediatric patients. Because hemoglo-bin kinetics vary with age, methemoglobinemia associated with nitrite-basedantidotes may be excessive at standard adult dosing in children. A cyanide antidotewith a better risk/benefit ratio than the current agent available in the United Statesis desirable. The vitamin B12 precursor hydroxocobalamin, which has been used inEurope, may prove to be an attractive alternative to the cyanide antidote kit forpediatric patients. In this article we review the available data on the sources,manifestations, and treatment of acute cyanide poisoning in children and discussunmet needs in the management of pediatric cyanide poisoning.

www.pediatrics.org/cgi/doi/10.1542/peds.2006-1251

doi:10.1542/peds.2006-1251

Drs Geller and Hall developed the conceptfor the manuscript; Drs Geller and Saiersdeveloped the initial outline; all theauthors reviewed the literature; Dr Saierswrote the first draft from the developedoutline; and all the authors collaborated inrevisions of the manuscript and approvedthe final manuscript.

KeyWordscyanide, poisoning, smoke inhalation,nitrite, hydroxocobalamin,methemoglobinemia, antidotes

Accepted for publication Jun 12, 2006

Address correspondence to Robert J. Geller,MD, Georgia Poison Center, Grady HealthSystem, 80 Jesse Hill Jr Dr SE, Box 26066,Atlanta, GA 30303-3050. E-mail:robert�geller@oz.ped.emory.edu

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CYANIDE 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 liquidforms, cyanide is used in many industries, found incertain household substances, and produced by the com-bustion of common materials such as fabrics containingnylon, 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) fromcombustion of such products is the most common sourceof human exposure to cyanide and may be second onlyin importance to carbon monoxide as a toxicant in thesecircumstances.3,5–10 Humans can also be exposed to cya-nide by eating cyanogenic foods, such as the tropical rootcassava, that contain cyanogenic glycosides that liberatecyanide when metabolized in the body. Additionalsources of cyanide exposure include metabolites of theantihypertensive drug nitroprusside, suicide attempts,and malicious acts such as murder attempts or terroristattacks.11 Cyanide is a potential chemical weapon for useby terrorists because it can be easily obtained and dis-persed and may be rapidly incapacitating or even lethal.

Causes and manifestations of acute cyanide poisoninghave not been systematically described in children, andlittle is known about the benefits and risks of antidotesand other aspects of intervention in pediatric patients.The information on these topics comes predominantlyfrom case reports of pediatric cyanide poisoning by in-gestion. In this article we review the available data onthe sources, manifestations, and treatment of acute cy-anide poisoning in pediatric patients and discuss unmetneeds in the management of this condition.

SOURCES OF ACUTE CYANIDE POISONING IN CHILDRENFire smoke is a common source of acute cyanide poison-ing in children.5,7 Additional sources described in casereports include household or workplace substances con-taining cyanogenic compounds, cyanogenic foods, lae-trile, and nitroprusside (Table 1).12–29 The sources ofacute cyanide toxicity are similar between children andadults, although their relative frequency of poisoningvaries with age. Acute poisonings by ingestion of cya-nide-containing or cyanogenic household substancesand ingestion of cyanogenic plants have been reportedmore frequently in children than adults (Table 1).12–29

The amount of cyanide in the blood that is likely toprove toxic is imprecise and depends heavily on whenthe 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 handlingbetween collection and analysis. In adults, the bloodcyanide level that is regarded as “toxic” is generallyconsidered to be �1 mg/L (39 �mol/L), and the “fatal”level is generally considered to exceed 2.6 to 3 mg/L(100–115 �mol/L).3,6,7,28

Inhalation of Fire SmokeApproximately one fourth of the �4000 fire- and burn-related deaths each year in the United States occur inchildren younger than 15 years.30 In children, as inadults, the majority of fire-related deaths are attributedto smoke inhalation rather than burns.30 Children wereamong the smoke-inhalation fatalities in the widelypublicized apartment fires in the Paris, France, area dur-ing 2005.31 In one apartment fire in August 2005, 14 of17 fatalities were of children. In a second apartment firealso in August 2005, 4 of the 7 fatalities were of children.Children also died in a third apartment fire in September2005.

Cyanide is an important contributor to death bysmoke inhalation and is present in the blood of firevictims (regardless of age) in most cases.3,6,7 In a meta-analysis of smoke-inhalation–associated deaths occur-ring in 7 major fire incidents from 1971 to 1990, cyanidewas found in the victims’ blood in each study in which itwas measured.3 Carboxyhemoglobin levels correlatedpoorly with blood concentrations of carbon monoxide.The percentage of fatalities having lethal blood concen-trations of cyanide ranged from 33% to 87% in themeta-analysis. In one fire scene, for example, toxic bloodconcentrations of cyanide were documented in 87% ofvictims, although only 72% had a carboxyhemoglobinlevel exceeding 30%, a finding suggested by incompletedata from other scenes as well and suggesting a cause ofdeath other than carbon monoxide in these victims.Consistent with the results of this meta-analysis, otherstudies have found cyanide in the blood of 62% to 77%of victims who died.6,7

Elevated blood cyanide concentrations have beenfound in children exposed to fire smoke. In a seminalstudy of the role of cyanide in smoke-inhalation injuryand death, 30 of the 109 victims of smoke inhalation inresidential 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 somechildren who survived and some who died, a resultsuggesting, when considered in conjunction with thepresence 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 ContainingCyanogenic CompoundsAccidental ingestion of household substances containingpoisons often involves young children, who place sub-stances in their mouths and/or ingest them as a means ofexploration.32,33 Although the US Consumer ProductSafety Commission prohibits the sale of consumer prod-ucts containing soluble cyanide salts,34 cyanide may be

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TABLE1

Summaryof

PediatricCyan

ingFrom

Causes

SmokeInha

lation

Reference

Age/Gender

Source/Cause

ofCyanide

Poison

Symptom

sBloodCyanide

Concentrationa

Interventio

nOutcome

Ingestionofsubstancescontaining

acetonitrile

CaravatiandLitovitz

12(1988)

16mo/boy

Acetonitrile-containingfalse-

fingernailrem

Vomiting,respiratorydistress;found

inbedthemorning

ingestingtheproduct

�g/mL12

hafter

ingestion

CaravatiandLitovitz

12(1988)

2y/boy

fingernailrem

Vomiting,com

a,respiratorydistress,

shock8hafteringestion

�g/mL12

hafter

ingestion

Oxygen,intravenous

fluids

Survived

nosequelae

Gelleretal13(1991)

3y/boy

fingernailrem

Nonoticeablesymptom

presentationtotheem

ergency

departm

ent30minafter

ingestion;13

hafteringestion

aftergastriclavage

administrationofactivated

charcoalon

emergency

departm

entadm

ission),the

patientvomited;16

hafter

ingestion,confusion,vomiting,

abnorm

alvenous

hemoglobindesaturation

�g/dL

3hand45

afteringestion

Gastric

lavage

andactivated

charcoal30

minafter

ingestion(whilepatient

wasasym

atic);

sodium

thiosulfate16

hafteringestion

Survived

nosequelae

Kurtetal14(1991)

2y/girl

fingernailrem

Vomiting,seizures,coma14

hafter

ingestingtheproduct;marked

hypoxiaandacidosis;no

odorof

bitteralmonds

�mol/L14

hafter

ingestion

Oxygen;cyanideantidote

kit(inhaledam

ylnitrite

followed

bysodium

nitriteandsodium

thiosulfate);activated

charcoal

Survived

nosequelae

Loseketal15(1991)

23mo/boy

fingernailrem

Vomiting,6

hafteringestion;

otherwise

al;beginning

24hafteringestion,altered

responsiveness(staringepiso

notrespondingtomother),low

oxygen

saturation;no

odorof

bitteralmonds

�g/mL12

hafter

ingestion;3.8

�g/mL

25hafteringestion

Amylnitrite,sodium

thiosulfate

Survived

nosequelae

Ingestionofotherhouseholdand

workplace

substances

Berlin1

6(1970)

17mo/boy

IngestionofDrabkin’ssolution

containing

50mgof

potassiumcyanide,200mg

ofpotassiumferro

cyanide,

and1gofsodium

bicarbonatein1liter

aticon

arrivalatthe

emergencydepartm

ent30min

afteringestion;after

administrationofantidote,

vomiting,apneicspells,

generalized

seizure;cardiacarrest

Postmortembloodcyanide

concentration

Amylnitrite,sodiumnitrite,

sodium

thiosulfate;

oxygen;diazepamfor

seizure;sodium

bicarbonate;methylene

Died;theauthorsattributed

thedeathtosodium

nitrite-induced

methemoglobinemia.

KriegandSaxenal17(1987)

2.5y/girl

Ingestionofmetal-cleaning

solutioncontaining

cyanide

Unresponsive,unconscious,

hypotension,tachycardia;odorof

bitteralmonds

present

Notreported

Cyanideantidotekit(am

ylnitrite,sodiumnitrite,

sodium

thiosulfate)

Survived

nosequelae

TABLE1

Continue

Reference

Age/Gender

Source/Cause

ofCyanide

Poison

Symptom

sBloodCyanide

Concentrationa

Interventio

nOutcome

Ingestionofcyanogen-containing

8(1969)

3.5y/girl

Ingestionofcooked

tapioca

Vomiting

5hafteringestion,

frothingaround

themouth;on

admissiontothehospital,thegirl

wasinshock,acidotic,drowsy,

hypotensive,irritable,breathless,

pale;pupilsweredilatedand

nonreactive

Notreported.An

alysisof

thespecimen

ofuncooked

tapiocatuber

ed0.0094%(wt/

wt)hydrogen

cyanide;

theauthors

characterized

amountasbeing

moderatelytoseverely

Sodium

bicarbonate

Survivalwith

nosequelae

Cheok1

9(1978)

2.5y/boy

Ingestionoftapiocacake

Vomiting,drowsin

ess,weakness�

9hafteringestion

Notreported

Sodium

bicarbonate;

sodium

thiosulfate

Survived

nosequelae

Cheok1

9(1978)

1.5y/girl

Ingestionoftapiocacake

Vomiting,drowsin

ess,weakness,

dyspnea,cyanosisafewhours

(timenotspecified)after

ingestion

Notreported;analysisof

thecooked

tapioca,the

uppertuberof

uncooked

tapioca,and

thelowertuberof

uncooked

tapioca

revealed

3,15,and

28ppmcyanide,

respectively

Gastric

lavage;oxygen;

sodium

bicarbonate;

sodium

thiosulfate

Survived

nosequelae

Akintonw

aandTunw

20(1992)

8y/boy

Ingestionofacassava-based

Bloodandurine

concentrations:0.85and

mg/L,respectively

Supportivetherapy(not

specified)

Diedofcardiorespiratory

arrest

Akintonw

aandTunw

20(1992)

17y/girl

Ingestionofacassava-based

Dizziness,headache,vomiting

progressingtoshockwith

renalfailure

Bloodandurine

concentrations:1.35and

mg/L,respectively

Notspecified

Diedofcardiorespiratory

arrest

Ariffinetal21(1992)

Siblings

Ingestionoftapiocablocks

6y/girl

Vomiting

anddiarrhea

hafter

ingestion;otherwise

�g/mL(th

eauthors

suggestedthatthis

valuewaserroneously

Gastric

lavage,oxygen,

intravenous

dextrose

saline

Survivalwith

nosequelae

1.5y/girl

Abdominalcram

ps,nausea,

diarrhea,vom

�6.5hafter

ingestion

Notreported

Nottreated

Dieden

routetothe

hospital

8y/girl

Vomiting

Notreported

Nottreated

Survived

nosequelae

Espinozaetal22(1992)

8children8–11

y/boys

Ingestionofrhizom

esofbitter

cassava

Vomiting,excessiveweakness,

respiratoryfailure,bradycardia,

hypotension,cardiovascular

collapse;generalized

seizuresin

2children;brightcherry-red

bloodwhensamplesforblood

gasesw

ereobtained

Notreported

oxygen

toall8

children;Sodium

nitrite

followed

bysodium

thiosulfateto4children;

hydroxocobalam

children

survived

nosequelae

TABLE1

Continue

Reference

Age/Gender

Source/Cause

ofCyanide

Poison

Symptom

sBloodCyanide

Concentrationa

Interventio

nOutcome

Ruangkanchanasetretal23(1999)

4y/girl

Ingestionofboiledcassava

Vomitedandwentunconscious

afteringestion;on

arrivalatthe

hospital,thegirlwasstuporous

butresponsivetopainstimuli;

19hafteringestion,hypocapnia

andlacticacadem

iawere

present

�g/mL19

hafter

ingestion

Intubationwith

ventilatory

support;gastric

lavage

andactivated

charcoal;

sodium

nitrateand

sodium

thiosulfateand

supportivetreatment

19hafteringestion

Survived

nosequelae

Ruangkanchanasetretal23(1999)

1.5y/boy

Ingestionofboiledcassava

Vomitedandwentunconscious

afteringestion;on

arrivalatthe

hospital,stupor,spasticity,and

hypoventilationwith

cyanosis

werenoted;23

hafteringestion,

hadbitter-almondbreath,

respiratoryalkalosis,m

ildlactic

acidem

�g/mL23

hafter

ingestion

Mechanicalventilationwith

hyperventilationand

circulatorysupportby

intravenous

fluidloading,

dopamine,and

dobutamine;gastric

lavage

Survived

nosequelae

Changetal24(2004)

3children

IngestionofCycasseeds

14y/boy

Notreported

Survived

nosequelae

(allcases)

7y/girl

Vomiting,headache,dizziness,

weakness

Notreported

10y/girl

Vomiting,abdom

inalpain,diarrh

eaNotreported

Notreported

Nitroprussideforsurgical

hypotension

Daviesetal25(1975)

Nitroprusside400mgfor

surgicalhypotension

Tachyphylaxisand

acidosis80

afteradm

inistrationof

prussid

�mol/L(authors

suggestedthepresence

abnorm

ofcyanidemetabolism

Supportivecare

Pershauetal26(1977)

Nitroprusside130mgfor

surgicalhypotension

Acidosisandtachyphylaxis5

hafter

administrationofnitro

prussid

eNotreported

Supportivecare

Survived

nosequelae

Laetrile

bertetal27(1977)

11mo/girl

Laetriletablets

Notreported

Hospitaltreatment

Ortega

andCreek2

8(1978)

2yand10

mo/boy

Laetrileenem

aforcancer

treatment

Vomiting

anddiarrhea

aftersecond

dailyenem

a;afterthe

a,lethargy,

unresponsiveness,tachypnea,

cyanosis

�g/dL

5hafter

admissiontothe

hospitalafterthe

dailyenem

Oxygentherapyand

intravenous

hydration

Survived

nosequelae

Halletal29(1986)

4y/boy

Laetriletabletsingested

shortly

aftera

mealoffresh

fruits,vegetables,and

peanuts

Overthe

1.5hafteringestion,

progressivelyincreasin

glackof

responsiveness,seizures;on

arrivalathospital,theboywas

hypotensive,pupilswidely

dilatedbutresponsive,acidotic;

nobitter-almondsm

ellnoted

�g/mL5hafter

ingestion

Initially,diazepamfor

seizures,100%oxygen,

gastric

lavage,amyl

nitrite;6

hafteringestion,

sodium

nitriteand

sodium

thiosulfate

Survived

nosequelae

aReportedintheunits

intheoriginalpublication

accessible from industrial sources, as are some cyano-genic compounds that may also be contained in productsmarketed for consumer use. This risk is illustrated byseveral cases of cyanide poisoning from acetonitrile-con-taining false-fingernail remover. Acetonitrile is used as asolvent in industrial and laboratory settings and is some-times present in cosmetics. Its toxicity is attributed to itsmetabolism to inorganic cyanide. Five case reports ofpediatric cyanide poisoning from acetonitrile-containingfalse-fingernail remover have been reported in the med-ical literature (Table 1).12–15

As would be expected from a cyanogenic compoundrequiring metabolic activation to be converted to cya-nide, the onset of acetonitrile-associated cyanide toxicitytypically occurs after a delay. This observation is consis-tent with the pharmacokinetic properties of acetonitrile,which is metabolized slowly to inorganic cyanide viahepatic microsomal enzymes.12 In these pediatric cases,manifestations of toxicity were first observed 6 to 14hours after ingestion of acetonitrile (Table 1). A similardelay between exposure and onset of toxicity has beenobserved in adults.35 The failure to observe symptoms oftoxicity in the initial minutes and hours after acetonitrileexposure should not be interpreted as the absence oftoxicity.

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 onereported case, a 16-month-old boy who had ingestedacetonitrile-containing fingernail remover was mistak-enly assumed to have ingested acetone-containing fin-gernail polish remover.12 Because cyanide poisoning wasnot suspected, no treatment for it was given; the childdied. This incident underscores the risk of sound-alikeand look-alike products and emphasizes the importanceof specifically ascertaining the exact toxin involved.

This potential confusion between acetone and aceto-nitrile poisoning is compounded by the initial similarity

of their early features, including vomiting, lethargy,slurred speech, ataxia, stupor, coma, and respiratorydepression.15 Delayed vomiting, although not typically amajor clinical indicator of most cases of cyanide poison-ing, may be important in alerting health care providersto acetonitrile toxicity in exposed children.13 In each ofthe 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).12–15 However, vomiting is common from manycauses and is not sufficient by itself to dictate the admin-istration of a cyanide antidote in the absence of othersupporting evidence of cyanide toxicity from history andclinical laboratory studies.

In addition to cosmetics and other products used inthe household, workplace substances containing cyanideor cyanogenic compounds are potential sources of pedi-atric poisoning. Cases of pediatric cyanide poisoningfrom ingestion of Drabkin’s solution (used in medicallaboratories)16 and a metal cleaning solution17 have beenreported.

Ingestion of Cyanogenic FoodsCyanogenic compounds are found in several foods in-cluding almonds, the pits of stone fruits, lima beans, andcassava (Table 2).36 When these foods are ingested inlarge quantities or without adequate preparation, theycan cause cyanide toxicity. Cyanide poisoning by inges-tion of cyanogenic foods seems to occur very rarely inthe United States, where they are not major componentsof the diet, but it is reported more frequently in childrenin 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 thetropics. Cassava contains glycosides (Table 2), which arehydrolyzed to glucose, hydrogen cyanide, and acetoneby intestinal �-glucosidase or �-glucosidase liberatedfrom the cassava plant itself.36 Numerous cases of acute

TABLE 2 Cyanogenic Glycosides in Major Edible Plants

Cyanogenic Glycosides Plant Source

Common Name Latin Name

Amygdalin Almonds Prunus amygdalusDhurrin Sorghum Sorghum album

Sorghum bicolorLinamarin Cassava Manihot esculenta

Manihot carthaginensisLima beans Phaseolus lunatus

Lotaustralin Cassava M carthaginensisLima beans P lunatus

Prunasin Stone fruits Prunus spp such as Prunus avium,Prunus padus, Prunus persica,Prunus macrophylla

Taxiphyllin Bamboo shoots Bambusa vulgaris

Source: Speijers G. Cyanogenic glycosides. Available at: www.inchem.org/documents/jecfa/jecmono/v30je18.htm.

cyanide poisoning after ingestion of cassava have beenreported in children in tropical countries.18,19,20–24 Cassavapoisoning in adults has also been reported, but pediatricpoisoning 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-caloriemalnutrition, is also associated with chronic poisoningsyndromes such as tropical ataxic neuropathy (lesions ofskin, mucous membranes, optic and auditory nerves,spinal cord, peripheral nerves) and konzo, a relativelysudden-onset upper motor neuron spastic parapare-sis.20,37,38 The exact mechanisms by which tropical ataxicneuropathy and konzo occur remain obscure.

Cyanogenic compounds are also present in the pits ofstone fruits such as peaches and apricots (Table 2).36

Multiple cases of pediatric cyanide poisoning from eatinglarge quantities of cooked and/or ground apricot pitshave been reported.39,40 Apricot pits contain amygdalin,which is hydrolyzed to hydrogen cyanide, glucose, andbenzaldehyde, as well as the �-glucosidase emulsin,which catalyzes amygdalin hydrolysis.41 Chewing apricotpits releases emulsin and increases the toxicity of cya-nide. Swallowing 1 or 2 whole stone fruit pits usuallydoes 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 releasecyanide.

Other Causes of Cyanide Poisoning in ChildrenPediatric cyanide poisoning has also been reported afteradministration of laetrile, which has been promoted byits advocates as a cancer preventative and cure despitelack of accepted evidence of efficacy.29 Laetrile is amyg-dalin, the glycoside naturally present in pits of apricotsand other stone fruits and nuts (Table 2).36 Like thecyanogenic glycosides in cassava, amygdalin liberatescyanide when hydrolyzed by intestinal or plant-derived�-glucosidase.28

Cases of acute cyanide poisoning secondary to use ofnitroprusside have also been reported in children.25,26

Sodium nitroprusside is indicated for reduction of bloodpressure in patients in hypertensive crises and for pro-ducing controlled hypotension to reduce bleeding duringsurgery. Within minutes of intravenous infusion, so-dium nitroprusside is converted to free cyanide, with theproduction of �44 mg of free cyanide for every 100 mgof sodium nitroprusside infused.42

Acute poisoning in 127 children aged 2 months to 17years was attributed to cyanide toxicity after an ecolog-ical accident resulting in spilling of acetone cyanohydrinand ammonia water into the Siret River in Romania inJanuary 2001.43 Nursing infants whose mothers ingestedcontaminated fish also developed symptoms. Althoughthe poisoning was attributed to ingestion of contami-

nated fish from the river, cyanide levels and other con-firmatory data are not available.

MANIFESTATIONS OF ACUTE CYANIDE POISONINGCyanide prevents cellular use of oxygen by inactivatingmitochondrial cytochrome oxidase and thereby causingcells 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 reflectoxygen deprivation of the heart and brain (Table3).23,44,45 The frequency of any specific clinical effect incyanide poisoning is generally unclear; therefore, it isdifficult to diagnose cyanide poisoning on the basis ofany one finding.

After intense exposure, rapid death may ensue. Afterless severe exposure, early manifestations include weak-ness, malaise, confusion, headache, dizziness, and short-ness of breath. Later manifestations include nausea andvomiting, 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 andred retinal veins and arteries arising from the inability ofcells to extract oxygen from the blood. Because of ele-vated venous oxygen levels, cyanosis is typically notpresent in spontaneously breathing or artificially venti-lated patients. A patient’s breath may have a bitter,almond-like odor attributed to excretion of unmetabo-lized cyanide; however, this odor is often undetect-able.46–48

Elevated oxygen content of venous blood is oftenpresent in cyanide poisoning but not highly specific forit.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 skinNeurologic Headache, agitation, disorientation, confusion,

weakness, malaise, dizziness, lethargy, seizures,coma, cerebral death

Cardiovascular Hypotension, tachycardia or bradycardia, ST-Twave changes, dysrhythmias, atrioventricularblock, cardiovascular collapse

Respiratory and metabolic Tachypnea or apnea, venous hyperoxemia, redvenous blood, increased mixed venous oxygencontent and decreased oxygen consumptionresulting in narrow arteriovenous oxygendifferential

Acidosis, elevated blood lactate, elevated lactate/pyruvate ratio

Gastrointestinal Nausea, vomiting, abdominal painOther Bitter-almond breath in some patients

Sources: Ruangkanchanasetr S, Wananukul V, Suwanjutha S. J Med Assoc Thai. 1999;82(suppl1):S162–S171; Megarbane B, Delahaye A, Goldgran-Toledano D, Baud FJ. J Chin Med Assoc.2003;66:193–203; and Dart RC, Bogdan GM. Frontline First Responder. 2004;2:19–22.

to be highly sensitive and moderately specific for cyanidepoisoning. A plasma lactate level of �72 mg/dL (�8mmol/L) was 94% sensitive and 70% specific for a bloodcyanide level of �1.0 mg/L in a series of adults exposedsolely to cyanide.50 In a series of smoke-inhalation vic-tims, the lactate value of 10 mmol/L proved to be abetter cutoff value.9 Although cyanide concentrations inwhole blood are also elevated in acute poisoning, thelong time required for results of this test to return limitsits clinical utility. Nevertheless, in cases of suspectedcyanide toxicity, blood levels should be obtained to doc-ument the poisoning.

The time between exposure to cyanide and the onsetof toxicity depends on the form of cyanide and the routeand concentration of exposure.1,44,45 Exposure to cyanidegas at high concentrations can result in death withinseconds to minutes, but toxicity develops over minutesto hours after ingestion or dermal exposure. Cyanidesalts and cyanogenic compounds also typically causedelayed onset of effects.

Whether children and adults are differentially suscep-tible to cyanide poisoning has not been systematicallystudied. Manifestations of cyanide poisoning seem to bequalitatively similar between children and adults.51 Inchildren, as in adults, acute cyanide poisoning has beencharacterized by varying degrees of neurologic impair-ment, respiratory distress, and cardiovascular compro-mise; the occasional presence of bitter-almond breathand bright-red venous blood; and metabolic acidosis(Table 1).12–29,51

Factors that could render children more vulnerablethan adults to cyanide poisoning include higher respira-tory rates, which might contribute to greater systemictoxicity from inhalation exposure, and lower body massand immature metabolic mechanisms, which mightmake children more susceptible than adults to toxicityfrom small amounts of poison.52,53 Young organs can beparticularly sensitive to toxicants during critical periodsof structural and functional development, the timing ofwhich depends on the organ system.51 Children seem tobe more susceptible than adults to poisoning by inges-tion of cyanogenic foods including cassava and apricotpits,18,19,21,51 often developing more severe toxicity thanadults concurrently ingesting cassava. The apparentlygreater vulnerability of children to poisoning by cyano-genic foods has been attributed to children’s lower bodymass and, in cassava poisoning, to the children’s highergastric acidity than that of adults.18,19,21 Cyanide in cas-sava exists both in a free form and in combination withthe glycosides linamarin and lotaustralin. However,non–age-related factors, such as ingestion of differentamounts or parts of cyanogenic plants, might also havecontributed to the differential toxicity.

Data from the Paris study described above9 supportthe concern of greater vulnerability of children thanadults to cyanide poisoning from inhalation of fire

smoke. In smoke-inhalation victims, the fatality rate wasslightly higher among patients younger than 14 yearsthan among older patients (43% vs 38%). Mean bloodcyanide concentrations of victims who died were loweramong patients younger than 14 years than they wereamong 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 ANTIDOTESManagement of acute cyanide poisoning in both chil-dren and adults entails removal of the victim from thesource 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 afteringestion). Ensuing supportive care includes 100% ox-ygen, cardiopulmonary resuscitation if necessary, and anappropriate antidote (Table 4).44,45,54 Because cyanidetoxicity can culminate quickly in death, rapid interven-tion is crucial and is usually undertaken on the basis ofa presumptive diagnosis before confirmatory blood cya-nide concentrations are available.

The cyanide antidote kit is the only cyanide antidotecurrently commercially available in the United States,although other antidotes are available in other coun-tries.45 The cyanide antidote kit is composed of amylnitrite, sodium nitrite, and sodium thiosulfate. Amylnitrite, contained in ampoules intended to be crushedand the contents inhaled, is administered to stabilize thevictim before intravenous administration of sodium ni-trite and sodium thiosulfate. The nitrite moieties fromamyl nitrite and sodium nitrite oxidize hemoglobin to

TABLE 4 Management of Acute Cyanide Poisoning

Supportive measuresRemoval of victim from source of exposure (in cases of inhalation)Gastric aspiration (in cases of ingestion, if able to be started soon afteringestion)

Activated charcoal (in cases of ingestion, if able to be started soon afteringestion)

100% oxygenCardiopulmonary support and/or resuscitationSodium bicarbonate to correct metabolic acidosisAnticonvulsants, epinephrine, antidysrhythmic agents as needed

Antidotes available in the US as of January 2006Cyanide antidote kit (only antidote currently available in the US)Includes amyl nitrite � sodium nitrite � sodium thiosulfateMay cause excessive methemoglobinemia, particularly in smoke-inhalationvictims and pediatric patients

Antidotes licensed in other countries as of January 2006Dicobalt EDTA (Kelocyanor)Hydroxocobalamin (Cyanokit)4-Dimethylaminophenol (DMAP)

Sources: Megarbane B, Delahaye A, Goldgran-Toledano D, Baud FJ. J Chin Med Assoc. 2003;66:193–203; Dart RC, Bogdan GM. Frontline First Responder. 2004;2:19–22; and Lambert RJ, KindlerBL, Schaeffer DJ. Ann Emerg Med. 1988;17:595–598

create methemoglobin, which competes with cyto-chrome oxidase for the cyanide ion. Binding of cyanideto 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 usethe lowest amount of methemoglobinemia that reversesthe cyanide-induced clinical findings.55 Another mecha-nism by which nitrites might achieve their therapeuticbenefits involves induced alterations in the nitric-oxideredox pathway.56 Sodium thiosulfate serves as a sulfurdonor that increases the rate of rhodanase-catalyzedtransformation of cyanide to much less toxic thiocya-nate.

Incongruously, the methemoglobinemia induced bythe nitrites in the cyanide antidote kit itself can be dan-gerous and even lethal.10,16,45,57,58 Methemoglobinemiareduces the amount of hemoglobin available to transportoxygen to the cells. In some cases, nitrite-induced met-hemoglobinemia can be excessive, even to the extent oflikely fatal reduction in the oxygen-carrying capacity ofthe blood.16 However, a study of 4 critically ill adultsmoke-inhalation patients treated with the cyanide an-tidote kit demonstrated methemoglobin levels of 7.9%to 13.4%, and their total reduction in oxygen-carryingcapacity caused by carbon monoxide, cyanide, and met-hemoglobinemia never exceeded 21%.59 These valueswere not considered dangerous.

Nitrite-induced methemoglobinemia may pose a par-ticular danger for victims of cyanide poisoning fromsmoke inhalation (probably the most common cause ofcyanide 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 amountof hemoglobin available to transport oxygen to the cells.The additive effects of nitrite-induced methemoglobinemiaand carboxyhemoglobinemia can exacerbate the patient’scondition. This possibility raises concern about the use ofthe cyanide antidote kit in the management of smoke-inhalation–associated cyanide poisoning, particularly in theprehospital setting.10,62

To avoid the complications of methemoglobinemiaassociated with nitrites, sodium thiosulfate has been rec-ommended for use as a sole agent (without nitrites) forcyanide toxicity to enhance rhodanase activity.63,64 Ad-vocates of this therapeutic regimen contend that theenhanced 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 formof fetal hemoglobin, which is oxidized more easily bynitrites to form methemoglobin than is adult hemoglo-bin.66 In addition, infants and very young children have

significantly reduced activity of methemoglobin reduc-tase (the enzyme responsible for converting methemo-globin) compared with normal adults back to normalhemoglobin.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 a17-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 accordingto the published adult dosing schedule, seems to havebeen a more important contributor to this death thancyanide. At 10 �g/dL (0.01 mg/L), the patient’s bloodcyanide concentration, determined a posteriori on the basisof samples taken shortly after ingestion, was substantiallyunder the lethal range. Furthermore, the amount of potas-sium cyanide ingested was estimated at between 1/50thand 1/140th of the published lethal dose. On the otherhand, the cumulative amount of hemoglobin estimated aposteriori to have been oxidized to methemoglobin bynitrites administered during antidotal treatment was esti-mated at up to 92%, well above the 70% that is consideredpotentially lethal. The author suggested that the adult dos-ing schedule for treatment of cyanide poisoning with thecyanide 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 complicatedadministration 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 risksof administering the cyanide antidote kit might be espe-cially pronounced because of the concomitant exposureto carbon monoxide in many cases. Risk/benefit con-cerns are also affected by the need to initiate antidotaltreatment rapidly on the basis of a presumptive diagnosisof 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 cyanidepoisoning is incorrect.

Dicobalt edetate (Kelocyanor) also has been shown tobe effective in the treatment of cyanide poisoning inhumans, although it is not approved in the UnitedStates. In the United Kingdom, it is a treatment of choicefor cyanide poisoning, provided that cyanide toxicity isdefinitely present. Some free cobalt ions are alwayspresent in solutions of dicobalt edetate. These cobalt ionsare toxic, and the use of dicobalt edetate in the absenceof cyanide will lead to serious cobalt toxicity. Animaldata suggest a protective role of glucose against thiscobalt toxicity, so glucose should probably be given at

the same time as dicobalt edetate. Serious adverse effectsrecorded from dicobalt edetate include vomiting, urti-caria, anaphylactic shock, hypotension, and ventriculararrhythmias.68–70

The need for a cyanide antidote with a better risk/benefit ratio than the current option in the United Statesis increasingly recognized.10,11,71 In an attempt to meetthis need, the vitamin B12 precursor hydroxocobalaminis being studied for possible introduction in the UnitedStates 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 decreasedintracellular cyanide concentrations by 75% and re-sulted in formation of intracellular cyanocobalamin, afinding suggesting that hydroxocobalamin penetratescells and can act intracellularly.72 In experimental ani-mals, hydroxocobalamin crosses the blood-brain barrierand enters the cerebrospinal fluid from the blood circu-lation.73 It has been shown to be an efficacious cyanideantidote in mice, rabbits, guinea pigs, dogs, and ba-boons.74–85 Preclinical studies in normal human volun-teers have shown safety and efficacy in clearing theblood of the small amounts of cyanide detectable inheavy smokers.86

Licensed as a cyanide antidote in France in 1996,hydroxocobalamin has been used to treat known orsuspected cyanide poisoning associated with smoke in-halation, industrial exposure to cyanide gas, and inges-tion of cyanide salts.44,75,87–96 Hydroxocobalamin has alsobeen used in other countries including Sweden, Den-mark, Spain, Japan, and Hong Kong.97–101 It has beenadministered to pediatric patients as well as adults. Thelicensed 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, thetotal mortality rate was 44% (18 of 41), with a prehos-pital mortality rate of 27% (11 of 41) and an in-hospitalmortality rate of 23% (7 of the 30 hospitalized chil-dren).91 Prehospital administration of hydroxocobalaminwas associated with only a 4% mortality rate in childrennot found in cardiac arrest. Of 23 children not found incardiac arrest at the fire scene, 70% (16 of 23) had lossof consciousness, 74% (17 of 23) were intubated at thescene, all 23 (100%) were hospitalized, and there was 1fatality. The mortality rate in children found in cardiacarrest was 94% (only 1 of 18 survived: 11 died at thescene, and 6 died in the intensive care unit) despitesupportive care and administration of hydroxocobal-amin.

Espinoza et al22 reported 8 pediatric patients (aged8–11 years) with suspected acute cyanide poisoningfrom improperly prepared bitter cassava (Manihot escu-lenta). These children had vomiting, weakness, respira-tory failure, bradycardia, hypotension, and cardiovascu-

lar collapse. Two had generalized seizures. The 4 mostacutely ill children were each treated with limited suppliesof sodium nitrite/sodium thiosulfate. The 4 other childrenwere treated with 500 mg of hydroxocobalamin in a dex-trose solution. All children improved within a few minutesof antidote administration, remained asymptomatic, andwere discharged from the hospital the following day withnormal 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 beensystematically studied, its use without adverse effects hasbeen reported in pediatric patients.91,102 The most com-mon adverse effects in patients regardless of age—tran-sient interference with colorimetric clinical laboratorytests and transient reddish-brown discoloration of theurine and mucous membranes—seem not to be clinicallysignificant and are attributed to the red color of thehydroxocobalamin molecule.71,103 Elevation in bloodpressure and rash have been observed in ongoing clinicaltrials of hydroxocobalamin. Other allergic reactions tohydroxocobalamin (primarily with a long-term low dosefor indications other than cyanide poisoning) have beenoccasionally observed104,105 but have not been reported inthe relatively small number of children treated to date.On the basis of available data, hydroxocobalamin seemsto constitute a useful alternative to the cyanide antidotekit for acute cyanide poisoning in pediatric patients.However, additional data about the risks and benefits ofhydroxocobalamin and other potential cyanide antidotesare needed, particularly in children.

CONCLUSIONSAcute exposure to cyanide from inhalation of firesmoke, ingestion of toxic household and workplace sub-stances, ingestion of cyanogenic foods, and other sourceshas caused morbidity and mortality in children. Childrenmay be more vulnerable than adults to some sources ofcyanide 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 theUnited States. The vitamin B12 precursor hydroxocobal-amin constitutes a potentially useful alternative to thecyanide antidote kit for known or suspected cyanidepoisoning in children, but additional information aboutits dosing, pharmacokinetics, and risks and benefits inchildren is still needed. If its efficacy and generally goodtolerability reported in European data in adult patientsare confirmed, hydroxocobalamin could prove useful inprehospital and inpatient management of pediatricsmoke-inhalation victims as well as victims of cyanidepoisoning from other sources.

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IN NEW JERSEY, MOUNTING COSTS FORMEDICAL SCHOOL INQUIRY DRAW CRITICISM

”The federal monitor appointed to investigate wasteful spending at NewJersey’s troubled state medical and dental school has submitted a $5.8 millionbill for his first six months on the job, according to state billing records. Thatfigure is higher than the amount of financial wrongdoing that prompted theinquiry, and has spurred criticism from some board members and stateofficials who say the charges are excessive. Herbert J. Stern, a former federaljudge, was assigned to investigate the University of Medicine and Dentistry ofNew Jersey in December after school administrators acknowledged that theyhad over-billed Medicaid by nearly $5 million. Since then, Mr. Stern hascharged the state $199,600 for 436 hours of work on the case, while a teamof seven lawyers in his firm has billed the university $992,787. In addition, anassortment of subcontractors have added to the cost—including the auditingof the accounting firm J. H. Cohn, which has charged $3.6 million, and theaccounting firm Sobel & Company, which has billed for $535,956.”

Kocieniewski D. New York Times. August 9, 2006Noted by JFL, MD

DOI: 10.1542/peds.2006-1251 2006;118;2146-2158 Pediatrics

Robert J. Geller, Claudia Barthold, Jane A. Saiers and Alan H. Hall Needs

Pediatric Cyanide Poisoning: Causes, Manifestations, Management, and Unmet

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