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Clinical toxicology of cyanide

Article  in  Annals of Emergency Medicine · October 1986

DOI: 10.1016/S0196-0644(86)80131-7 · Source: PubMed

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Alan H Hall Barry H Rumack

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SPECIAL CONTRIBUTION
cyanide, clinical toxicology;
poisoning, cyanide

Clinical Toxicology of Cyanide

Cyanide poisoning causes a high incidence of severe symptomatology and Alan H Hall, MD
fatality. There are numerous sources of potential cyanide exposure. Without Barry H Rumack, MD
the history of cyanide exposure, diagnosis is often difficult. Treatment with Denver, Colorado
supportive measures and available specific and efficacious antidotes fre-
quently allows survival. The toxicology of cyanide, including sources, From the Rocky Mountain Poison and
clinical features, diagnosis, and treatment, is reviewed. [Hail AH, Rumack Drug Center, University of Colorado
BH: Clinical toxicology of cyanide. Ann Emerg Med September 1986;15: Health Sciences Center, Denver Generat
Hospital, Denver, Colorado,
1067-1074.]
Received for publication February 14,
INTRODUCTION 1986. Revision received May 19, 1986.
Cyanide is one of the few poisons for which specific antidotes exist. Inha- Accepted for publication June 5, 1986.
lation or ingestion of cyanide can produce a dramatic and severe poisoning
leading rapidly to death. Subacute and chronic exposures also have been re- Presented at the UAEM/IRIEM Research
ported to cause adverse effects. Although cyanide poisoning is encountered Symposium on Toxicology in San
infrequently, these factors serve to pique continued clinical interest in this Francisco, California, February 1986.
agent.
Cyanide produces a histotoxic (intracellular) hypoxic poisoning by the Address for reprints: Barry H Rumack,
binding of the cyanide ion to the ferric (Fe +3) iron of mitochondrial MD, Rocky Mountain Poison and Drug
cytochrome oxidase. This causes an almost total inhibition of cytochrome Center, 645 Bannock Street, Denver,
Colorado 80204-4507.
oxidase activity, which leads to anaerobic metabolism with severely de-
creased ATP production and lactic acid accumulation.
Diagnosis is difficult without the history of cyanide exposure. There are no
readily available cyanide assays that will confirm the poisoning within the
time needed to treat an acutely poisoned patient.
Even when the diagnosis has been made, the use of antidotes and hyper-
baric oxygen therapy remains controversial.

SOURCES OF CYANIDE
Hydrocyanic acid or its salts are used in numerous industrial processes,
including precious metal extraction and electroplating (Figure 1).l,2 Although
there are only three producers of cyanide worldwide - - Dupont in America,
ICI in England, and Degussa in West Germany - - the agent is widely avail-
able. Investigators of the 1982 Chicago cyanide-Tylenol® tampering incident
identified more than 65 legitimate cyanide users in the Chicago area alone. 3
Cyanide may be released from various compounds by chemical reactions
or pyrolysis (Figure 2). Some smoke inhalation victims have significant blood
cyanide levels (Table 1).4-6 Cigarette smokers have been found to have mean
whole blood cyanide levels of about 0.41 ~g/mL, more than 2.5 times the
mean for nonsmokers. 7
Potassium cyanide crystals may be used in "coyote gitter" animal traps
involving a meat-wrapped explosive shell. When an animal bites into the
meat, the shell explodes, producing both cyanide poisoning and blast injury.
Stepping or pulling on the device may also detonate the shell, and can expose
curious children or unwary hunters.
Natural sources of cyanide include amygdalin and similar cyanogenic sub-
stances found in a wide variety of plants (Figure 3). These have been known
since antiquity. The ancient Egyptian "penalty of the peach" and the Roman
"cherry death" are examples of the use of cyanogenic plants for judicial ex-
ecutions. Human ingestion of cyanogenic plants is relatively common, but

15:9 September 1986 Annals of Emergency Medicine 1067/115

CYANIDE TOXICOLOGY
Hall & Rumack

FIGURE 1. Processes that may involve

cyanide (adapted from Rumack31). Almond extract preparation Calcium cyanide (CaCN2)
Chemical synthesis Acrylonitrile (CH2CHCN)
FIGURE 2. Chemical compounds that
release cyanide by pyrolysis or chem- Dry synthesis Acetonitrile (CH3CN)
ical reaction (adapted from Rumack31). Electroplating of metals Cyanogen (NCCN)
Executions Cyanogen halide (CNCI, CNBr)
FIGURE 3. Plants containing cyano- 2
gens (adapted from Rumack31). Extraction of gold or silver
Fumigants (ships, grain
acute toxicity is rare. Apricot pits, 8 elevators, buildings)
bitter almonds, 9 and chokecherries lo Hair removal from hides Apple (seeds)
have been reported to cause cyanide Greenhouses Bamboo (sprouts of some species)
poisoning in America.
Laetrile, a supposed antineoplastic Illicit PCP manufacture Cassava (beans and roots)
agent, has produced a number of acute Incomplete combustion Christmas berry
and subacute cyanide poisonings. 11-13 Blast furnace Crab apple (seeds)
Laetrile is usually amygdalin obtained Coke furnace
from apricot or peach pits, and it can
Cycad nut
Film fires
release cyanide when metabolized by House fires Elderberry (leaves and shoots)
a B-glucosidase in the emulsin en- Hydrangea (leaves and buds)
zyme complex. 14 Metal coating, cleaning, or
polishing Jetberry bush (jet bead)
INCIDENCE OF CYANIDE Metal tempering (heat Lima beans
POISONING treatment) Linum species
Between 1926 and 1947, death rates Photography (flax, yellow pine flax)
from cyanide poisoning in America Pear (seeds)
r a n g e d b e t w e e n 79 and 416 per
Plastic processing
10,000,000 population. 15 The highest Pseudomonas aeruginosa Prunus species
death rates were recorded during the interaction in burn patients (leaves, bark, and
early 1930s, with a gradual decline seeds may contain amygdalin)
thereafter through 1947. The availabil- Cherry laurel
ity of the Lilly Cyanide Antidote kit ® Western chokecherry
may have contributed to this decreas- dote kit is also used by some clini- Mountain mahogany
ing death rate. Intensive supportive cians for hydrogen sulfide poisoning, Pin cherry
care with artificial respiration and these numbers cannot be assumed to Wild black cherry
100% supplemental oxygen also be- be representative of the incidence of Chokecherry (stone fruit)
came common during this time. severe cyanide poisoning. Plum
Data on cyanide exposures reported Life-threatening cyanide poisoning Bitter almond
to the American Association of Poison is infrequent. It is, however, a treat- Peach
Control Centers (AAPCC) National able condition requiring immediate Apricot
Data Collection System by participat- recognition and therapy with specific Sorghum species
ing poison centers in 1983 and 1984 measures. Johnson grass
are s h o w n (Table 2). t6,17 In t h i s Sorghum
database, there were 105 cyanide ex- CLINICAL FEATURES & Sudan grass
posures in 1983 and 232 in 1984, repre- PRESENTATION Arrow grass
N u m e r o u s signs and s y m p t o m s 3
s e n t i n g (respectively) 0.03% and
0.01% of total calls. Of these, 12 pa- may be associated with cyanide poi-
tients in 1983 and 10 in 1984 experi- soning. Expected clinical responses to
enced major s y m p t o m s (potentially various concentrations of hydrogen does not develop until the stage of cir-
life-threatening, lasted more than 24 cyanide gas are shown (Table 3). culatory collapse and apnea. The pre-
hours, r e s u l t e d in p e r m a n e n t se- The initial clinical picture is usu- sentation of severe hy-poxic symptoms
quelae). There were three deaths in ally one of hyperpnea and central ner- in the absence of cyanosis should raise
1983 and five in 1984. Cyanogenic vous system stimulation. Early signs clinical suspicion of cyanide poison-
p l a n t exposures were m u c h m o r e of dyspnea, palpitations, headache, ing.
common (608 in 1983, 2,216 in 1984), and giddiness may be misinterpreted
but resulted in only eight major ef- as hyperventilation syndrome with Associated Syndromes
fects and no deaths during the two anxiety. Vomiting, bradycardia, hypo- Several disease states, including de-
years.16,17 tension, coma, convulsions, and apnea myelinating nervous syndromes, are
The Lilly Cyanide Antidote Kit ® are late signs.IS, 19 The electrocardio- associated with chronic exposure to
was listed in the AAPCC reports as gram may show erratic rhythms, with low doses of cyanide or cyanogensY
being used 27 times in 1983 and 102 hypoxic changes and various degrees Demyelinating syndromes have also
times in 1984.16,17 Because the so- of atrioventricular block followed by been described after acute cyanide poi-
dium nitrite component of the anti- asystole. 2o Cyanosis is a late sign, and soning,22, ~3 but have been considered
116/1068 Annals of Emergency Medicine 15:9 September 1986
 crystals of FeSO4 and four to five
TABLE 1. Whole blood cyanide levels in smoke inhalation victims drops of 20% NaOH are added to 5
mL of gastric contents. The mixture is
boiled and cooled. Then eight to ten
Author No. Patients Whole Blood CN Levels drops of 10% HC1 are added. If cyanide
(l~g/mL) is present the reaction produces ferro-
Range Mean cyanide, indicated by development of
Clark et al, 19814 36 0.05-3.3 0.68 a green-blue colon Barbiturates, ben-
zodiazepines, phenothiazines, and tri-
Symington et al, 19785 73 0 -3.38 0.42 cyclic antidepressants are examples of
Hart et al, 19856 5 0.35-3.9 1.62 c o m m o n ingestants that m a y give
false-positive results, gl
Cyanide m a y be q u a n t i t a t e d in
whole blood, urine, gastric contents,
TABLE 2. American Association of Poison Control Centers National Data and tissue. Plasma thiocyanate (an in-
Collection System cyanide poisoning data 16,17 dication of the amount of endogenous
detoxification of cyanide by the natu-
rally occurring enzyme, rhodanase)
1983 1984 may also be measured.7 The usual
N % N % technique is a colorimetric diffusion
Total calls 332,012 100 743,611 100 method, although measurement by
specific electrode can be obtained
Use of Lilly Antidote Kit* 27 -- 102 --
from some laboratories, g2
Cyanide exposures Whole blood cyanide levels usually
(excluding rodenticides)l- 105 0.03 232 0.01 take from several hours to days to ob-
Major effect tain, and have had a limited place in
(% of cyanide exposures) 12 11.4 10 4.3 the diagnosis and m a n a g e m e n t of
Deaths acute poisoning. A recently developed
(% of cyanide exposures) 3 2.9 5 2.2 automated microdistillation assay can
give whole blood or plasma cyanide
Cyanogenic plant exposures 608 0.18 2,216 0.29 results in less than half an hour, but it
Major effect is not yet generally available, g3
(% of cyanide exposures) 7 1.2 1 0.05 Whole blood cyanide is the com-
Death monly reported value. Most of the
(% of cyanide exposures) 0 0 0 0 cyanide present in blood is found in
erythrocytes, with a ratio of at least
*Lilly antidote kit is also utilized by some clinicians for hydrogen sulfide poisoning. 10:1 of erythrocytes to plasma, gl
These numbers therefore cannot be used as accurate markers for the number of
severe acute cyanide poisonings. Cyanide levels are reported in vari-
ous traditional units (~g/mL, ~g/dL,
tRodenticide data are not separated into cyanide/noncyanide categories. mg/L, mg/dL) and in Systeme Interna-
tional (SI) units of ~mol/L. The fol-
lowing formulae may be used to inter-
to be nonspecific lesions from gener- E1 Ghawabi et a130 found that more convert traditional units and SI units:
alized anoxia. 24 than half the workers using cyanates ~g/mL = p~mol/L x 0.026
Increased incidences of optic atro- in an electroplating facility had thy- ~mol/L = p~g/mL + 0.026
phy and Nigerian nutritional ataxic roid enlargement and increased I 131 Whole blood cyanide levels and ex-
neuropathy have been described in uptake. Elevated lymphocyte and he- pected s y m p t o m a t o l o g y are shown
countries in which cyanogenic plants moglobin counts were found in all (Table 4). This correlation is subject to
(particularly cassava) make up a large workers, and two developed toxic psy- error and misinterpretation. In some
part of the diet.2s, 26 The relationship choses similar to those induced by cases, cyanide levels have been ob-
of the chronic consumption of cyano- bromides, go Abnormal thyroid func- tained only after prolonged intensive
genic plants to these nervous disorders tions, folate, and vitamin B12 levels supportive treatment or at post-mor-
r e m a i n s c i r c u m s t a n t i a l . 27 M o n t - were found among workers using a tem examination hours to days after
gomery27 has noted that achlorhydria cyanide extracting process to recover exposure. Reports of very low "lethal
and dietary vitamin B12 deficiencies silver from used x-ray and photo- levels" come from such cases, g4 Before
also are associated with these neu- graphic film. 2 The relationship of interpreting any cyanide blood level,
ropathies. these findings to cyanide exposure is the elapsed time since the exposure
Elevated whole blood cyanide and not well defined. must be considered. Physiologic de-
thiocyanate levels found in smokers 7 toxification and excretion of cyanide
have been associated with tobacco C L I N I C A L LABORATORY I N may be enhanced by the administra-
amblyopia and Leber's hereditary op- CYANIDE P O I S O N I N G tion of sodium thiosulfate, and must
tic atrophy. 28 Vitamin B12 therapy has The Lee-Jones test is a qualitative also be considered when reviewing
sometimes produced improvement in evaluation for the presence of cyanide cyanide blood levels. For reasons that
these conditions. 29 in gastric aspirate or vomitus. A few have n o t been f u l l y d e l i n e a t e d ,

15:9 September 1986 Annals of Emergency Medicine 1069/1 t 7

CYANIDE TOXICOLOGY
Hall & Rumack

cyanide disappears rather rapidly from

stored blood specimens. A delay be- TABLE 3. Air cyanide concentrations and expected responses*
tween venipuncture and analysis may
cause a falsely low value to be re-
ported by the laboratory.7 Concentration
Response mg/m3 ppm
D I A G N O S I S OF CYANIDE Fatal immediately 300 270
POISONING
The sodium nitrite antidote cur- Fatal in 10 min 200 181
rently in use in the United States is Fatal in 30 min 150 135
not without inherent toxicity. It is de- Fatal within 1/2 to 1 hr or more,
sirable to have a relatively firm diag- dangerous to life 120-150 110-135
nosis before administering this agent.
No immediate or late effects
The h i s t o r y is m o s t i m p o r t a n t ;
with exposure for 1/3 to 1 hr 50-60 45-54
however, inhaled or ingested cyanide
produces rapid coma, convulsions, ap- Mild symptoms with several
nea, and cardiac depression. In some hours exposure 20-40 18-36
occupational accidents, the history of *Adapted from Rumack.31
the type of industrial activity may
suggest cyanide (Figure 1). Patients in-
volved in closed-space fires who have
suffered smoke inhalation may have TABLE 4. Cyanide levels and associated symptoms*
significant cyanide poisoning as well
as particulate and carbon monoxide Whole Blood Cyanide Symptoms
inhalation. 4-6 The history of burning
plastic or polyurethane materials sug- i~g/mL i~mol/L
gests the possibility of a cyanide poi- 0.2-0.5 8-20 None
soning component. 0,5-1.0 20-38 Tachycardia, flushing
The traditional "bitter almonds"
odor of cyanide on a patient's breath 1.0-2.5 48-95 Depressed level of
or in gastric washings cannot be ap- consciousness
preciated by a large proportion of the 2.5-3.0 95-114 Coma
population, but can be a valuable diag- 3.0 114 Death
nostic clue. Although difficult to as-
*Adapted from Rumack.31
sess, on funduscopic examination the
retinal veins and arteries m a y be
noted to approach being equally red.
Signs and symptoms of severe hypoxia TABLE 5. Screening laboratory values and expected results
in patients who do not appear cyanot- in cyanide poisoning
ic should suggest the diagnosis.
An elevated anion gap metabolic
acidosis is usually present in acute Laboratory Examination Expected Result
poisoning, but is not specific. Convul- Arterial blood gases Metabolic acidosis
sions alone may produce this laborato- Normal PO 2
ry picture. Animal data indicate that
Serum electrolytes Elevated anion gap
the presence of an elevated central
Na - (CI + CO2) = greater than 12
venous %0 2 s a t u r a t i o n and a de-
creased arterial-central venous %02 Calculated arterial %
saturation difference on room air sug- 0 2 saturation Normal*
gests cyanide poisoning.35 Measured arterial %
Some cyanide binds to the ferrous 02 saturation Decreased*
(Fe +2) iron of normal hemoglobin. 36 Arterial - - central venous Decreased (arterial and central venous %
This cyanhemoglobin cannot trans- % 02 saturation difference 0 2 saturation approach each other,
port oxygen. The presence of signifi- central venous % 02 saturation greater
cant amounts of cyanhemoglobin may than 70%)
be indicated by a decrease in the mea-
sured arterial %02 saturation (mea- *The "% 0 2 saturation gap" (% 0 2 saturation difference of 5 may be of
significance),
sured directly with a co-oximeter),
while the calculated %0 2 saturation
(derived from a nomogram using mea-
sured P0 2 and total h e m o g l o b i n mal (non-oxygen-transporting) hemo- globins include carbon monoxide (car-
values) remains normal. This "02 sat- globin if the difference between the boxyhemoglobin) and methemoglo-
uration gap" is suggestive of the pres- two values is five or greater. Other bin-inducing agents (methemoglobin).
ence of a poison producing an abnor- poisons producing abnormal hemo- Carbon monoxide is excluded with a
118/1070 Annals of Emergency Medicine 15:9 September 1986
 FIGURE 4. How to administer the
Children Lilly Cyanide Antidote Kit ® (adapted
from Rumack31).
1. Amyl nitrite inhaler - - crack and inhale 30 sec/min.
2. Administration of IV sodium nitrite and sodium thiosulfite:
3% dromes, have been reported.22, 23
Hb NaNO 2 25% Na2S203
CYANIDE POISONING FROM
(g/lO0 mL) (mL/kg) (mL/kg)
LAETRILE
7 0.19 0.95 Despite any evidence of efficacy,
8 0.22 1.10 laetrile enjoyed popularity as an anti-
9 0.25 1.25
neoplastic agent in the 1970s and early
1980s.14, 39 Laetrile is m o s t o f t e n
10 0.27 1.35 amygdalin (D-mandelonitrile-B-D-
11 0.30 1.50 glucoside-6-B-glucoside) in varying
12 0.33* 1.65* concentrations. 4o With intravenous
a d m i n i s t r a t i o n , a l m o s t all of the
13 O.36 1.80 amygdalin is excreted unchanged in
14 0.39 1.95 the urine and no cyanide poisoning is
produced. 4o Ingested with foods con-
3. May repeat at 1/2 dose once.
taming the enzyme complex emulsin
4. Monitor methemoglobin to keep level less than 30%. (many fresh fruits and vegetables, cer-
tain nuts, pits of stone fruits), amyg-
*Doses in mL/kg of sodium nitrite and sodium thiosulfate for the average dalin is broken down by a B-glucosi-
child. dase to benzaldehyde, glucose, and
Adults hydrogen cyanide. 14 N i n e cases of
1. Amyl nitrite inhaler - - crack and inhale 30 sec/min. cyanide poisoning, including t w o
deaths, from laetrile ingestion were re-
2. Sodium nitrite - - 10 mL IV (NaNO2: 10-mL ampule, 300 mg, 30 mg/ ported b e t w e e n 1977 and 1983.12 ,
mL). 13,41-47
Parenteral laetrile preparations con-
3. Sodium thiosulfate - - 50 mL IV (Na2S203: 50-mL ampule, 12.5 g, 250 tam between 8.3 and 57.9 mg/mL of
mg/mL).
cyanide, and tablets may have from
4. May repeat at 1/2 dose once. 2.7 to 51.5 mg/g of cyanide. 4s A poten-
tially lethal adult dose of hydrocyanic
4 acid is 100 m g . 34 It could take only
small amounts of amygdalin to pro-
duce serious poisoning or death when
carboxyhemoglobin level and methe- tying shortly after an ingestion, can ingested w i t h e m u l s i n - c o n t a i n i n g
moglobinemia by the absence of cen- significantly decrease absorption of foodstuffs.
tral cyanosis, a bedside test utilizing a the poison. Provision of intensive sup- Inhalation of hydrogen cyanide gas
drop of the patient's blood compared portive care measures, including 100% or ingestion of salts of cyanide pro-
to a normal control, and measured supplemental oxygen and assisted res- duce a rapid onset of symptoms. 49
methemoglobin levels. piration, control of seizures with anti- Amygdalin ingestion from either
Hydrogen sulfide produces similar convulsants, correction of acidosis laetrile or plant sources, in contrast,
l a b o r a t o r y findings. T h e only dif- with sodium bicarbonate, and support produces delayed symptoms with on-
ference in t r e a t m e n t r e c o m m e n d a - of pulse and blood pressure with fluid set from 1Y~ to 2 hours and a some-
tions is the inefficacy of sodium thio- infusion, atropine, or vasopressors, are what slower progression,9,so allowing
sulfate. A d m i n i s t r a t i o n of sodium important measures that alone may the clinician more time for diagnosis
thiosulfate in recommended doses to a allow survival in less severe c a s e s . 24,37 and intervention and increasing the
patient with hydrogen sulfide poison- Specific antidote administration can potential for a favorable outcome.
ing, however, will do no harm. enhance survival in more severe poi-
Expected screening laboratory sonings.lS, 3s Some authors have stated TREATMENT OF CYANIDE
values in acute cyanide poisoning are that survival can be obtained with ad- POISONING
listed (Table 5). m i n i s t r a t i o n of the Lilly Cyanide In America, the only available spe-
Antidote kit ® as long as any cardiac cific cyanide antidotes are found in
PROGNOSIS & SEQUELAE activity persists, is the Lilly Cyanide A n t i d o t e kit ®,
The a m o u n t , form, and route of While most patients who survive an which contains amyl nitrite perles for
cyanide exposure, and the type and episode of acute cyanide poisoning inhalation and 10% sodium nitrite
rapidity of treatment determine the will be free of sequelae, manifes- and 25% sodium thiosulfate solutions
prognosis for survival w i t h o u t se- t a t i o n s of anoxic encephalopathy, for intravenous administration. Pro-
quelae. Removing the patient from ex- including disordered m e m o r y and posed for use by Chen et al sl in the
posure to hydrogen cyanide gas in in- m a t h e m a t i c a l abilities, personality 1930s, this c o m b i n a t i o n has b e e n
halational exposures, or gastric emp- changes, and e x t r a p y r a m i d a l syn- shown to be effective in both animal

15:9 September 1986 Annals of Emergency Medicine 1071/119

I
CYANIDE TOXICOLOGY
Hall & Rumack
e x p e r i m e n t s and h u m a n poison-
ings.15,38
A protocol for administration of the
kit is shown (Figure 4). An average
child requires 0.33 mL/kg of 10% so-
dium nitrite and 1.65 mL/kg of 25%
sodium thiosulfate. The usual adult
dose is 1 ampule (10 mL, 300 mg) of
sodium nitrite and 1 ampule (50 mL,
12.5 g) of sodium thiosulfate. It is de-
sirable to m o n i t o r m e t h e m o g l o b i n
levels to guide administration of the
sodium nitrite. Methemoglobin levels
should be m a i n t a i n e d at less than
40%. 24 A single therapeutic dose of
sodium nitrite has been said to pro-
duce a methemoglobin level of 20% or
less. is When methemoglobin levels
cannot be obtained, repeat doses of
the sodium nitrite and thiosulfate at
one-half the original dose m a y be
given half an hour after the first ad-
ministration when there is inadequate
clinical response.
The sodium nitrite component of
the kit may produce toxicity when ad-
ministered incorrectly. Too rapid ad-
ministration can cause excessive vaso-
dilatation and hypotension. 24 This
may be avoided by slow intravenous
a d m i n i s t r a t i o n w i t h careful blood
pressure monitoring. Excessive methe-
m o g l o b i n i n d u c t i o n is f r e q u e n t l y
mentioned as a serious complication.
The only reported case of toxicity
from excessive m e t h e m o g l o b i n e m i a
in the 50-year history of use of the
Lilly kit involved a fatality in a young
child without serious cyanide poison-
ing who was given two adult doses of
sodium nitrite, s2 Use of proper doses
and monitoring methemoglobin levels
can prevent this complication.
The induction of methemoglobin-
emia has classically been considered
the mechanism of action of the ni-
trites. Methemoglobin (Fe + 3 ) h a s a
greater affinity for cyanide than does
the ferric iron (Fe +3) m o i e t y of
cytochrome oxidase and will exchange
cyanide from the respiratory enzyme,
freeing it to take up its normal ac-
tivity. Aerobic metabolism may then
proceed with cessation of lactic acid
production and generation of normal
amounts of ATP As the cyanide dis-
sociates from methemoglobin, it is
m e t a b o l i z e d by t h e e n d o g e n o u s
e n z y m e rhodanase and complexed
with sulfur from sodium thiosulfate
to produce essentially nontoxic thio-
cyanate w h i c h is excreted in the
urine.
This antidotal mechanism has been
120/1072
questioned by Way et al, s3 who pre-
treated cyanide-poisoned animals with
m e t h y l e n e blue, precluding attain-
m e n t of significant methemoglobin
levels. Sodium nitrite was equally
efficacious against cyanide poisoning
in the absence of m e t h e m o g l o b i n -
emia. A local vasodilatation or other
mechanisms may account for the anti-
dotal efficacy of the nitrites, s3
The use of antidotes in cyanide poi-
soning has been questioned. 54 Sup-
portive care only has produced some
survivals.24, 37 The highest reported
whole blood cyanide level in a sur-
vivor treated only with supportive
measures was 2.9 p~g/mL.24 Survival
after supportive treatment and anti-
dote has been reported in patients
with whole blood cyanide levels of
3.85 and 6.10 ~g/mL.38, 46 It is possible
that the a d m i n i s t r a t i o n of specific
antidotes may allow survival from
more severe poisoning.
Hyperbaric oxygen has been pro-
posed as a treatment for cyanide poi-
soning, although evidence supporting
the use of this m o d a l i t y is incon-
clusive. One animal study by Way et
al 5s did not show a more efficacious
effect of hyperbaric oxygen as com-
pared to 100% normobaric oxygen.
Data from Takano et a156 did show
improved efficacy w i t h hyperbaric
oxygen. One h u m a n survival f r o m
cyanide poisoning after t r e a t m e n t
with both the Lilly kit and hyperbaric
oxygen has been reported.S7 Another
patient succumbed despite both anti-
dote and hyperbaric oxygen. 38 Five
smoke inhalation victims treated with
both the Lilly kit and hyperbaric oxy-
gen had rapid decreases in w h o l e
blood cyanide levels from a mean of
1.62 p,g/ml (0.35 to 3.9) to less than
0.15 p,g/ml. 6 Four of these patients
with carbon monoxide and cyanide
poisoning survived. 6 When available,
it would currently seem appropriate to
administer hyperbaric oxygen to cya-
nide poisoning victims who do not
have a d e q u a t e oxygen clinical re-
sponse to supportive measures, 100%
n o r m o b a r i c oxygen, and antidote.
However, current mixed evidence does
not allow this recommendation to be
viewed as a standard of practice.
Alternate antidotes are available in
Europe. Kelocyanor ® (dicobalt-EDTA)
chelates cyanide as cobalticyanide and
is in use in Britain and France. 24 This
agent can produce severe hypertension
and cardiac arrhythmias when given
in the absence of cyanide. Hydroxy-
Annals of Emergency Medicine
cobalamin (vitamin B12a) has been
used for more than 15 years in France.
Low doses have been used in the Unit-
ed States experimentally to prevent
cyanide accumulation during nitro-
prusside administration, s8 Hydroxy-
cobalamin is administered in a 4-g
dose combined with 8 g of sodium
thiosulfate in France. 23 In this dosage
form, the hydroxycobalamin/sodium
thiosulfate cyanide antidote has been
recently designated an orphan drug by
the Food and Drug Administration.
Clinical trials are not yet in progress
in America. The formulation of hy-
droxycobalamin currently available in
the United States is an intramuscular
preparation of 1 mg/mL for the treat-
ment of pernicious anemia. It would
take an impossible 4,000 ampules (4
L) of the available preparation to pro-
vide a sufficient antidotal dose in
a c u t e cyanide p o i s o n i n g . 24 Kelo-
cyanor ® and hydroxycobalamin are
often administered together in France,
as they have different mechanisms of
action and thus additive antidotal
efficacy. 32 Hydroxycobalamin is es-
s e n t i a l l y d e v o i d of a d v e r s e ef-
fects.22,23,32,36
CONCLUSION
Although cases of acute poisoning
fortunately are very rare, cyanide re-
mains one of the few toxic agents
w i t h specific antidotes. There are
many sources for possible exposure.
With the increased use of plastic
building materials, the potential haz-
ards of cyanide poisoning as a compo-
nent of smoke inhalation in closed-
space fires can be expected to in-
crease.
Initial supportive measures should
include provision of 100% supplemen-
tal oxygen with artificial ventilation,
correction of acidosis with sodium bi-
carbonate, seizure control with anti-
convulsants, and support of pulse and
blood pressure with atropine, fluid ad-
ministration, and vasopressors.
Treatment with the antidotes found
in the Lilly Cyanide Antidote kit ®
may allow survival in more serious
poisonings. Other antidotes are not
currently available in America.
Hyperbaric oxygen should be con-
sidered for patients who fail to devel-
op an adequate clinical response to
supportive m e a s u r e s and antidotal
therapy.
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15:9 September 1986
autonomic functioning, behavior, and feelings. This abstinence or
withdrawal syndrome has two phases, the first lasting 4 to 10
weeks and the second lasting at least 26 weeks. In general, other
opioid drugs produce similar effects; however, some common
opioids, such as meperidene, propoxyphene, codeine, pentazocine
and methadone, have additional pharmacologic effects that are
responsible for additional toxic manifestations.
Experimental Amitriptyline Intoxication:
Treatment of Cardiac Toxicity by
Administration of Sodium Bicarbonate
Betty Sasyniuk, PhD (presenter), V Jhamandas, M Valois,
Department of Pharmacology, Faculty of Medicine, McGill
University, Montreal, Canada
Overdose with amitriptyline and other tricyclic antidepres-
sants may result in ventricular conduction abnormalities as well
as severe ventricular arrhythmias. The arrhythmic effects of
these compounds may be attributed to their direct local anesthet-
ic actions in blocking sodium channels in cardiac membranes.
Thus tricyclic-induced ventricular arrhythmias usually do not re-
spond well to therapy with standard Class I antiarrhythmic
drugs, which also have direct local anesthetic action and may in
fact be potentiated by them. We produced cardiac toxicity in dogs
by pretreating the animals with oral doses of 60 mg/kg amitrip-
tyline 24 hours previously followed by an additional oral dose of
30 mg/kg and an intravenous infusion if necessary. ECG and
blood pressure were monitored continuously following the sec-
ond oral dose. Administration of amitriptyline produced sinus
tachycardia and marked QRS widening followed by ventricular
tachyarrhythmias. Toxicity was associated with total serum drug
concentrations greater than 2,000 ng/mL [both parent Compound
and metabolite}. During toxicity 1 to 2 mEq/kg of sodium bicar-
bonate were administered over 0.5 to 2 minutes. Sodium bicar-
bonate, when effective, rapidly converted the ventricular tachy-
cardia to normal sinus rhythm and reduced the amitriptyline-
induced conduction slowing. Reversion to normal sinus rhythm
was accompanied by a transient increase in both systolic and di-
astolic blood pressure and a slowing of the sinus rate. Admin-
istration of sodium bicarbonate was accompanied by increases in
arterial pH from 7.38 -+ 0.03 to 7.50 -+ 0.03, increases in plasma
HCO3 from 20.3 +- 2.7 to 30.4 -+ 4.0 mEq/L, and decreases in
serum potassium from 3.6 +_ 0.2 to 2.8 _+ 0.1 mM. Duration of
sodium bicarbonate effect was 10 to 20 minutes. Repetition of
treatment was equally effective. Duration of effect appeared to
parallel the duration of the pH change. In vitro studies in cardiac
Purkinje fibers exposed to 500 ng/mL amitriptyiine suggest that
reversal of amitriptyline-inducedcardiac membrane effects by so-
dium bicarbonate may be attributed both to alkalinization and to
increases in extracellular sodium concentration. Both diminish
the local anesthetic action of amitriptyline, resulting in less so-
dium channel block. The direct depressant effect of amitriptyline
on conduction is frequency dependent, and thus would be expect-
ed to be potentiated by the indirect anticholinergic-mediated
sinus tachycardia which accompanies toxicity. Thus counteract-
ing the sinus tachycardia with either propranolol or physostig-
mine reduces the direct cardiotoxic effect of the drug, but may
exacerbate the hypotensive effects. Our results suggest that al-
kalinization with sodium bicarbonate, coupled with interven-
tions which slow the sinus rate, may provide a rational
therapeutic approach for the treatment of tricyclic-induced car-
diac toxicity.
0 Management of Poisoning Associated
with "Newer" Antidepressant Agents
Kenneth Kulig, MD, Director, Clinical Toxicology Fellowship
Program; Associate Director, Rocky Mountain Poison and Drug
Center, Denver, Colorado
15:1 January 1986 Annals of EmergencyMedicine
Four cyclic antidepressants - - maprotiline, amoxapine,
trazodone, and nomifensine - - have been released by the FDA in
the last five years. Each has been reported to result in different
toxicity after overdose when compared to the prototype tricyclic
antidepressants. The importance of this can easily be seen by re-
viewing the mortality statistics for tricyelics. American and Eu-
ropean literature and experience will be reviewed to evaluate the
toxicity of the newer cyclic antidepressants when taken as an
overdose, and management strategies will be discussed.
1 Immunological Approach to Poisoning
Douglas E Rollins, MD, PhD, Associate Professor of Medicine and
Pharmacology, University of Utah, Salt Lake City, Utah
Increasingly the approach to the diagnosis and management of
poisoning is involving the use of sophisticated analytical meth-
ods and treatment modalities. Recent advances in immunology
are among the newer techniques being applied to the poisoned
patient. This presentation focuses on three areas: 1) the use of
immunology and newer cell biology techniques in the diagnosis
of drug toxicity; 2} the use of antibodies and antibody fragments
as immunotherapy; and 3) the use of antibodies in extracorporeal
perfusion systems to remove drugs from the body. Immunoassays
have been used for many years in the diagnosis of drug overdoseS,
and with the discovery of monoclonal antibodies, they will con-
tinue to be the main line for such diagnostic techniques in the
future. Radioreceptor-ligand assay should be explored as a meth-
od to measure drugs in body fluids of poisoned patients. Anti-
bodies also may be used therapeutically to neutralize the effects
of drugs or toxins. Digoxin F(ab) fragments are now being used to
treat digoxin overdose. Immunotherapy also is being explored for
the toxicities of other drugs, including phencyclidine and the tri-
cyclic antidepressants. A third area currently being explored is
the removal of drugs via extracorporeal profusion of antidrug
antibodies immobilized on a solid support. These techniques, in
concert with the production of antibodies by genetic engineering,
will significantly change the practice of clinical toxicology in the
near future.
2 Clinical Toxicology of Cyanide: North
American Clinical Experiences
Alan H Hall, MD, Barry H Rumack, MD, Michael I Schaffer, MD,
Christopher H Linden, MD, Rocky Mountain Poison Center,
Denver, Colorado
Cyanide is one of the few agents that both produce a rapid, life-
threatening poisoning and have specific antidotes. During the
1982 Chicago cyanide tampering incident, at least 65 legitimate
users of cyanide were identified in the Chicago area alone. Nu-
merous laboratory and industrial procedures utilize cyanide salts.
Hydrogen cyanide gas is used as a fumigant. Pyrolysis can release
cyanide from various cyanogenic compounds. Natural cyanogens
from sources such as bitter almonds and the pits o~ stone fruits
occasionally cause poisoning. Cyanide may also be released from
laetrile and nitroprusside. The pathophysiology of cyanide poi-
soning is inhibition of mitochondrial cytochrome oxidase, result-
ing in anaerobic metabolism, decreased ATP production, and lac-
tic acidosis. Clinical symptoms range from agitation and anxiety
to coma, seizures, apnea, bradycardia, hypotension, and death.
Whole blood cyanide levels take hours to obtain and are not
useful for management of the acutely poisoned patient. An ele-
vated anion gap metabolic acidosis is usually present. The bind-
ing of some cyanide to hemoglobin (Fe+ +) can produce a "%02
saturation gap" between measured arterial %02 saturation and
calculated arterial %O2 saturation. A difference between these
values of 5 points is possibly significant. Animal experiments
have shown a narrowing of the A-V %02 saturation difference
93/151
 UAEM/IRIEM ABSTRACTS
(central venous %02 saturation greater than 70% and approach-
ing the arterial value). Bedside tests, such as the Lee-Jones reac-
tion on gastric contents, may give diagnostic clues, but there are
many interferences from commonly ingested agents. The prog-
nosis in cyanide poisoning is generally good if the patient reaches
medical care before sustaining a cardiac arrest. Patients usually
either succumb or fully recover. Isolated patients have had per-
sistent encephalopathic sequelae. Unique North American
clinical experiences with cyanide poisoning have included the
1982 Chicago cyanide tampering incident, recent autopsy data
from the Cook County (Illinois) Institute of Forensic Medicine,
and cyanide poisoning from the use of laetrile as an anti-
neoplastic agent. The Chicago tampering incident involved re-
placement of acetaminophen with cyanide in Extra Strength
Tylenol ® capsules. Seven persons died in this bizarre incident,
Post-mortem cyanide levels were obtained from five of the vic-
tims. Multiple blood and urine cyanide and thiocyanate levels
were obtained from one victim who survived for nearly 40 hours.
Tainted capsules remaining in bottles used by the victims were
analyzed and found to contain between 117 and 858 mg/capsule
of potassium cyanide. Autopsy data from the Cook County In-
stitute of Forensic Medicine for the period March 1984 to January
1985 revealed eight fatalities (0.2% of all reported deaths) due to
cyanide poisoning. Various blood, urine, and tissue cyanide levels
were obtained. Between 1977 and 1983, nine cases of cyanide poi-
soning from laetrile were reported in the North American liter-
ature. Two of these victims died. The only antidotes currently
available for cyanide poisoning in the United States are amyl ni-
trite, sodium nitrite, and sodium thiosulfate in the Lilly Cyanide
Antidote Kit ®. Other antidotes available in Europe are dicobalt
EDTA (Kelocyanor ®) and the combination hydroxycobalamin/
sodium thiosulfate. The hydroxycobalamin/sodium thiosulfate
combination recently has been designated an orphan drug by the
Food and Drug Administration. Hyperbaric oxygen has been pro-
posed as a treatment for cyanide poisoning. While animal re-
search has shown equivocal efficacy, anecdotal clinical experi-
ence indicates that hyperbaric oxygen should be used in those
patients not having a satisfactory clinical response to other sup-
portive measures and antidote.
3 Organophosphate Insecticides
Lester M Haddad, MD, Director, Emergency Department,
Washington County Hospital (MIEMSS Trauma/Regional Center),
Hagerstown, Maryland; Clinical ASsistant Professor, Department of
Emergency Medicine, Georgetown University Hospital,
Washington, DC
The organophosphate insecticides have replaced DDT and the
organochlorine insecticides as the agricultural agent of choice.
Because of their unstable chemical structure, they disintegrate
into harmless radicals within days after application, and do not
persist in body tissue or the environment [as does DDT). The
concept that a chemical can penetrate the intact skin without
producing sensation, or that such a small quantity of chemical
can be fatal, is simply not grasped by the general public, and
herein lies the danger of the highly toxic organophosphate insec-
ticides. The basic science of the human autonomic nervous sys-
tem comes into focus with organophosphate poisoning, as acetyl-
cholinesterase is inhibited. The clinical presentation of organo-
phosphate poisoning, clinical guidelines to therapy with the
physiologic antidote atropine and the specific biochemical anti-
dote pralidoxime; unusual clinical presentations; and complica-
tions will be reviewed.
Free Radicals and Environmental Toxins
14
152/94 Annals of Emergency Medicine
View publication stats
Steven D Aust, PhD, Professor, Department of Biochemistry,
Center for the Study of Active Oxygen in Biology and Medicine,
Michigan State University, East Lansing, Michigan
Some chemicals that contaminate our environment exert their
toxic effects by virtue of their ability to form free radicals. In the
absence of sufficient quenching reactions, these reactive radicals
can attack biomolecules, resulting in their oxidative degradation.
Biological membranes which contain polyunsaturated fatty acids
are most susceptible to oxidative degradation (lipid peroxidation),
although oxidation of DNA may have more severe biological con-
sequences. Free radical species can be generated by at least two
mechanisms in vivo. The first, of which carbon tetrachloride is
the classic example, is the biotransformation of the chemical to a
free radical species. Metabolism of CC14 to the trichloromethyl
radical by the hepatic mixed-function oxidase system results in
the initiation of lipid peroxidation, protein-lipid cross linkages
and trichloromethyl adducts with DNA, protein, and lipid. The
second mechanism for forming free radicals involves their reduc-
tion to less stable free radical intermediates which are oxidized
by molecular oxygen to give superoxide (O2-~. In the presence of
transition metals such as iron, O2 ~ can be converted to other
oxygen radical species such as the hydroxyl radical (.OH), an ex-
tremely powerful oxidant capable of cleaving DNA, oxidizing
protein, and initiating lipid peroxidation. Under many condi-
tions, lipid peroxidation appears not to be initiated by .OH, but
rather by an iron-oxygen complex. Regardless of the identity of
the initiating species, transition metals are required for most of
the deleterious reactions of oxygen. Superoxide and certain
organic radicals have been found to release iron from ferritin.
5 Emergency Department Response to
Radiation Accidents
Robert C Ricks, PhD, Director, Radiation Emergency Assistance
Center/Training Site (REAC/TS), Oak Ridge Associated
Universities, Oak Ridge, Tennessee
Perceptions regarding medical management of the radiation ac-
cident victim often are obscured by misunderstanding, fear, or
uncertainty. Emergency physicians and nurses may feel that ul-
traspecial facilities, equipment, and resources are needed to as-
sess and care for the radiation accident victim while providing
minimal risk to responders. This presentation will describe a
proper response protocol, with emphasis on adaptation of every-
day procedures to meet the patient's needs as well as the struc-
ture of a radioiogical emergency response team. Aspects of facili-
ty preparation, patient reception/triage, contamination control,
radiological monitoring, decontamination, and post-emergency
patient transfer will be covered. Decontamination procedures
covered will include those for intact skin, hair, eyes, wounds, and
internally deposited radionuclides. The difference between han-
dling the patient exposed to radiation and the patient contami-
nated with radioactive material will be demonstrated. Physical
and biological samples needed to assess status of both exposed
and contaminated patients will be presented. Appropriate case
histories drawn from the REAC/TS Registry files documenting
worldwide radiation accident history will be reviewed. Finally,
questions most frequently asked by emergency medical re-
sponders regarding their involvement in radiation accidents will
be reviewed, with emphasis on whether there is a medical emer-
gency following a radiation accident. [This abstract is based on
work performed under Contract No. DE-ACOS-760R00033 be-
tween the Department of Energy, Office of Health and Environ-
mental Research, and Oak Ridge Associated Universities.]
6 New Concepts of Radiation Accidents m
Biology
Eugene L Saenger, MD, EL Saenger Radioisotope Laboratory,
15:1 January 1986