Acute Cyanide Toxicity: Mechanisms and Manifestations

C Y A N I D E S U P P L E M E N T

Author: Lewis Nelson, MD, New York, NY

Lewis Nelson, Director, Fellowship in Medical Toxicology, New YorkUniversity School of Medicine, New York City Poison ControlCenter, New York, NY.

For correspondence, write: Lewis Nelson, MD, New York CityPoison Control Center, 455 First Avenue, Room 123, New York,NY 10016; E-mail: lnelson@pol.net.

J Emerg Nurs 2006;32:S8-11.

0099-1767/$32.00

Copyright n 2006 by the Emergency Nurses Association.

doi: 10.1016/j.jen.2006.05.012

S8

yanide is a multifaceted poison—toxicant in fire

Csmoke; agent of suicide, murder, and terrorism;

and industrial and occupational hazard. As it ex-

ists in gas, liquid, and solid forms, it can cause human

toxicity via multiple routes including inhalation, ingestion,

parenteral administration, and dermal or conjunctival con-

tact.1 One of the most rapidly acting and deadly of poi-

sons, cyanide can kill within seconds or minutes to hours

of exposure depending on the route and length of exposure

as well as the ‘‘dose’’ received. How does cyanide cause

such potent and rapid toxicity? An understanding of the

mechanisms of cyanide toxicity can enhance the ability of

the emergency nurse to provide care for cyanide-poisoned

patients. This article discusses the mechanisms of cyanide

toxicity and relates the cellular and tissue effects of cyanide

to clinical manifestations of cyanide poisoning.

Endogenous Pathways for Cyanide Detoxification

Most humans are exposed to very low concentrations of

cyanide from natural sources such as cyanogenic foods and

man-made sources such as cigarette smoke.2 For example,

cyanide concentrations in whole blood are approximately

2.5-fold higher, on average, in cigarette smokers than in

nonsmokers.3 Given that cyanide occurs naturally in the

environment, the presence of endogenous mechanisms of

detoxification of cyanide in humans and many animals is

not surprising.4 The primary endogenous mechanism of cya-

nide detoxification is metabolism in the liver by rhodanese

to thiocyanate, which is a nontoxic compound excreted in

the urine (Figure 1).4-6 Minor routes of metabolism include

binding of cyanide to hydroxocobalamin (vitamin B12a) to

form cyanocobalamin (vitamin B12, or cyanocobalamin),

JOURNAL OF EMERGENCY NURSING 32:4S August 2006

Cyanide

Cyanocobalamin

Stable nontoxic compounds

Thiocyanate

Unchanged cyanide

Elimination in urineElimination in urinebreath, sweatbreath, sweat

RhodaneseRhodanese

HydroxocobalaminHydroxocobalamin

FIGURE 1

Main endogenous means of detoxifying and

eliminating cyanide.4,5

Anaerobic Metabolism

Fe2+

Fe3+

2H+ + / 02 H20

and

Cytochrome oxidase

AerobicMetabolism

02 Use

Cell Death

Fe2+

Normal Cellular Respiration

metabolic acidosisLactic acid/

Fe3+-HCN

+2

Oxidative metabolismresponsible

for generating ATP

Impaired Respiration in aCyanide-Poisoned Cell

12

FIGURE 2

Cyanide inactivates mitochondrial cytochrome oxidase to

inhibit cellular respiration.5,7

C Y A N I D E S U P P L E M E N T / N e l s o n

which is excreted in urine; and oxidation of cyanide to

thiocyanate and other stable nontoxic compounds through

various enzymatic and nonenzymatic pathways.4,5 These en-

dogenous mechanisms can detoxify only very small amounts

of cyanide—0.017 mg of cyanide per kg of body weight per

minute in the average person.4

Small amounts of cyanide that are not detoxified can

be excreted unmetabolized in breath, urine, and sweat.2,5

Unmetabolized cyanide has a bitter almond-like odor that

is sometimes detected on the breath or in gastric contents

of cyanide-poisoned patients. However, the ability to smell

this odor is genetically determined, and up to 50% of the

population lacks the relevant gene.6

Mechanisms of Cyanide Toxicity

The endogenous metabolic pathways for cyanide are rap-

idly and easily overcome in the event of cyanide poisoning.

Cyanide might have multiple toxic mechanisms, some of

which have not been established with certainty. The best-

established and probably most important toxic action of

cyanide is incapacitation of the cell’s mechanism for using

oxygen resulting in chemical asphyxiation (i.e., effective ox-

ygen deprivation).1

Cyanide prevents cells from using oxygen by inhibit-

ing the oxidative function of mitochondrial cytochrome

oxidase, an enzyme in the electron transport chain that is

integral to production of aerobic energy for cellular func-

tion.1 Cytochrome oxidase normally converts oxygen to

August 2006 32:4S

water at the end of the electron transport chain. This

oxidative metabolism via the electron transport chain is

responsible for creating large amounts of adenosine tri-

phosphate (ATP) from reducing equivalents (e.g., nicotine

adenine dinucleotide, or NADH) derived from interme-

diary metabolism (e.g., Kreb cycle). ATP is the primary

source of cellular energy (Figure 2).5,7 Cyanide, which has

a chemical structure similar to that of oxygen, binds to the

ferric iron portion of cytochrome oxidase. The binding of

cyanide inhibits the ability of cytochrome oxidase to use

oxygen and thereby reduces production of ATP. Thus,

cyanide prevents the proper functioning of the mito-

chondria. Because their oxygen-utilization mechanism is

disabled, cells are forced to rely on anaerobic (or oxygen-

independent) metabolism instead of aerobic metabolism.

Whereas aerobic metabolism produces a large amount of

ATP via the electron transport chain, anaerobic metab-

olism produces only a tiny amount. The reduced avail-

ability of ATP results in cellular dysfunction and death.

In addition, cyanide affects multiple neurotransmitter sys-

tems, including dopaminergic, GABAergic, and glutama-

tergic pathways, either directly or indirectly through changes

in ion regulation.8 Effects of cyanide on these or other neu-

rotransmitter systems could cause or potentiate cyanide

JOURNAL OF EMERGENCY NURSING S9

C Y A N I D E S U P P L E M E N T / N e l s o n

toxicity. However, any such effects are thought to be less

important than disruption of cellular aerobic metabolism in

producing acute toxicity.

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Cyanide poisoning is caused bythe inability of cells to use oxygen ratherthan by deficient oxygen deliveryor supply.

Manifestations of Acute Cyanide Poisoning

As cells of all tissues rely on oxygen and ATP, all body sys-

tems are affected by acute cyanide poisoning. Those such

as the heart and brain, which require a large, continuous

supply of oxygen and ATP for normal function, are most

susceptible.1 The broad-ranging clinical manifestations of

acute cyanide poisoning mainly ref lect the nonspecific ef-

fects of chemical asphyxiation.4 Early signs and symptoms

of acute cyanide poisoning ref lect ref lexive attempts of

the respiratory, neurologic, and cardiovascular systems to

overcome tissue hypoxia. Transient increases in blood pres-

sure and heart rate, hyperventilation, shortness of breath,

palpitations, and headache are common early signs and

symptoms of acute cyanide poisoning. Late symptoms or

symptoms of severe poisoning ref lect neurologic, respira-

tory, and cardiovascular depression as tissues fail to com-

pensate for their inability to use oxygen. Stupor, coma,

seizures, hemodynamic shock, and cardiorespiratory arrest

are common signs of late or severe poisoning.

Hypoxia-associated brain damage might cause a neuro-

logical syndrome that can first develop days to weeks after

acute cyanide poisoning and recovery.9,10 The frequency

of this sequela, characterized by impaired motor reaction;

reduced verbal f luency; and symptoms such as dystonia

and bradykinesia, is not known. This syndrome is associ-

ated with abnormalities on brain scans in the nigrostriatal

dopaminergic system and temporo-parieto-occipital and

cerebellar cortices.9,11,12 Although these abnormalities are

plausibly secondary to hypoxia, they might also result from

direct cellular injury by cyanide.1

Cyanide poisoning is caused by the inability of cells to

use oxygen rather than deficient oxygen delivery or sup-

ply. In this respect, cyanide differs from carbon monoxide,

J

which also disrupts oxygen delivery to the tissues. Carbon

monoxide binds to hemoglobin to prevent the binding of

oxygen whereas cyanide does not. Cyanide’s incapacitation

of cellular oxygen utilization in fact is associated with an

excess of blood oxygen. Because cyanide-poisoned cells are

unable to extract oxygen from arterial blood, venous blood

is often nearly as oxygenated as arterial blood. The presence

of oxygenated blood with its characteristic bright-red color

explains the findings of cherry-red complexion and bright-

red retinal veins in some cyanide-poisoned patients as well

as the frequent failure to observe cyanosis, a sign of poorly

oxygenated blood, in early acute cyanide poisoning.7,13 Oxy-

genated venous blood also accounts for the characteristic

laboratory finding on blood gas analysis of elevated venous

oxygen with reduced arteriovenous oxygen saturation dif-

ference (b10 mm Hg) in patients with severe acute cya-

nide poisoning.

Anaerobic metabolism causes a rise in plasma lactate

concentration, one of the hallmark laboratory findings in

acute cyanide poisoning.1,5 The plasma lactate concentra-

tion in acute cyanide poisoning often exceeds 8 mmol/L

compared with the normal range of 0.5 to 2.2 mmol/L.14

The process that produces the lactate abnormalities also

produces metabolic acidosis, another characteristic labo-

ratory abnormality in acute cyanide poisoning, defined by

an arterial blood pH of less than 7.35 with a plasma bi-

carbonate concentration of less than 22 mmol/L. The pro-

found acidemia also contributes to cellular death.

The rate of progression of toxicity and its severity are

affected by the form of cyanide and the route, concentra-

tion, and duration of exposure.1 Exposure to high concen-

trations of cyanide for even a brief period produces severe

toxicity whereas prolonged low-level exposure typically pro-

duces minimal to moderate toxicity. Inhalation exposure

to hydrogen cyanide and other cyanide gases can be rapidly

toxic or lethal because of fast diffusion of cyanide across

alveolar membranes and its direct distribution to organs.1

Likewise, intravenous administration can be toxic or lethal

within seconds because of fast, direct exposure of target or-

gans to cyanide. Time to severe toxicity is generally less

rapid and more variable with oral ingestion. Clinical effects

may become manifest within minutes with orally ingested

salts and in minutes to hours with cyanogenic compounds

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C Y A N I D E S U P P L E M E N T / N e l s o n

such as amygdalin or nitriles, which generate cyanide when

they are metabolized.

Antidotal Therapy

The only cyanide antidote currently available in the United

States is the Cyanide Antidote Kit (or Cyanide Antidote

Package), a 3-component kit of amyl nitrite, sodium ni-

trite, and sodium thiosulfate. A second cyanide antidote,

hydroxocobalamin, is anticipated to be introduced soon in

the United States. These antidotes differ in their mecha-

nisms of action. An in-depth discussion of the types and

mechanisms of antidotal therapy is presented in Borron’s

article, Recognition and Treatment of Acute Cyanide Poison-

ing,15 in this supplement.

Conclusions

Tissue hypoxia caused by cyanide’s incapacitation of the

oxygen-utilization mechanism of the cell produces many of

the clinical signs and symptoms and the laboratory findings

in acute cyanide poisoning. Cyanide toxicity affects all body

systems, producing profound effects on the heart and brain as

toxicity progresses. Progression and severity of toxicity vary

according to route, concentration, and duration of exposure.

Acknowledgment

The author acknowledges the assistance of Jane Saiers, PhD, inwriting this manuscript. Dr. Saiers’ work was funded by EMDPharmaceuticals.

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