Review of Literature on Cyanide Poisoning and Treatment
Item
- Title
- Review of Literature on Cyanide Poisoning and Treatment
- Date
- 1986
- extracted text
-
52
A
«
Part
REVIEW
SYMPTOMS ;
OF
II
LITERATURE ON CYANIDE
AND TREATMENT
POISONING
Early stages of acute poisoning resembles
an anxiety state with headache, giddiness, excitement
and tachycardia. Tachypnoea is a sign of low cyanide
concentrations. In severe poisoning drowsiness, coma
and convulsions precede death. Reduced oxygen consump
tion diminishes the arteriovenous oxygen content differ
ence, rendering the retinal artery and vein a similar
Palpitations, hypotension, pulmonary oedema and
hypoxic ECG changes can occur and a smell of burnt or
bitter almonds may be detected on the breath.
(The
colour.
ability to detect such a smell is, however, genetically
determined and lacking in a large fraction of the popula. .
6 In one test 3 out of 5 pathologists and 9 out of
tion.
11 members of a biochemistry department could not identify
2
cyanide by smell. )
Clinical abnormalities can occur when cyanide exposure is
high or when there is abnormality of detoxification or
when there is a combination of both factorsn Abnormalit
ies in detoxification may ar se from paucity of substrate
arising from malnutrition. Such situations can give rise
to tobacco amblyopia, Leber's hereditary optic atrophy,
inherited optic atrophy and subacute combined degeneration
4*
of the cord.
LETHAL DOSAGE AND.BLOOD CONCENTRATIONS ; The minimum
lethal dose is 0.5 mg/kg of body weight and the minimum
lethal concentration in air is 0.2 - 0.3 mg/1 (200 - 300
7*
ppm).
Oral ingestion of 250 mg of cyanide salt is
usually fatal within minutes as is inhalation of 50 ml
(1.85 mmol) of HCN gas.
A blood cyanide lezel of greater than 0.2 microgram/ml
is considered toxa a. Acute toxicity may occur as blood
cyanide concentrations approach 0.5 micrograms/ml.
Fatalities are usually associated with concentrations
exceeding 1.0 micragram per ml (John D. Bauert Casarette
Sc Doull).
* See also additional notes at the end.
s 2
TOXIC ACTION ;
2
Cyanide has a high affinity for the
ferricJLon of cytochrome oxidase (a^) within the mitochon
dria. By combining with the aa^ complex, cyanide prevents
02 from reoxidizing reduced cytochrome a^ thus inhibiting
electron transfer and preventing both oxidative phospho
rylation and oxygen utilisation and cellular respiration
(for conversion of glucose to energy).
As a result of the
inhibition of oxidative phosphorylation, mitochondrial 02
utilisation ceases and arteriovenous 02 differences are
abolished. The loss of ATP generation in the mitochondrial
electron transport chain evokes anaerobic metabolism
(Pasteur effect). This increases lactic acid generation
leading to lactic acidosis. The buffering of lactic acid
leads to a progressive fall in plasma bicarbonate concent
ration. All organs are affected; eventually there is cent2
ral nervous system anoxia and finally, death.
Cyanide may also have a direct, though reversible, toxic
2
effect on pancreatic P cells resulting in hyperglycaemia.
DETOXIFICATION s
The major pathway for detoxification is
the formation of thiocyanate from the combination of sul
phur with the cyanide-cytochrome complex by the enzyme
thiocyanate oxidase in the liver. The respiratory enzyme
is released and thiocyanate undergoes renal excretion.
The rate limiting step is the production of sulphur from
the limited body store of thiosulphate by the rhodenase
catalysed reaction which may also explain recurrent and
prolonged toxic symptoms despite antidotal therapy. 1t10
to alternative pathway is the conversion of hydroxocobal
amin (Vitamin B.iza
o ) by cyanide ions to cyanocobalamin
(Vitamin B^2) , which undergoes renal excretion, and to
1
hydrogen cyanide which is excreted via the lungs.
ANTIDOTES ; The intrinsic toxicity of antidotes should be
carefully considered in case the diagnosis of cyanide
poisoning proves to be erroneous. It must also be borne
in mind that as of 1977 in only 4 out of 61 cases reported
in the last 100 years, was the magnitude of poisoning by
cyanide documented quantitatively, and that inferences of
a causal relationship between antidotal use and successful
2
outcome were till 1977 based on such data,
The situation
has improved somewhat subsequently.
1
3
SODIUM NITRITE z
3 S
This oxidises nearly 30 - 35% of blood
haemoglobin with a ferrous (2‘) ion to methaemoglobin
(M-Hb) with a ferric (3*) ion which has a greater attrac
tion for free ON" ions than does cytoch ome oxidase. M-Hb
thus binds the CN~ ion to form cyanomethaemoglobin thereby
decreasing CN~ combination with cytochrome oxidase.
The
weak CN-MHb bond allows the slow release of cyanide within
the liver, where increased sulphur requirements for detoxi
fication are met by exogenous thiosulphate which has slower
tissue penetration than cyanide. Normal M-Hb blood levels
are 1%, and 300 mg of sodium nitrite will produce a level
of 10% when cyanosis will appear.
The optimum cheraputic
M-Hb level of 25% may be increased to 40% if symptoms of
cyanide poisoning are severe.
1
anoxia, coma and death.
Greater levels may produce
Although attended with low allergy risk, sodium nitrite
has considerable intrinsic toxicity and its use in patients
with cardiovascular collapse or vascular haemorrhage is
hazardous. It involves a large sodium load and presents
problems in monitoring therapy whilst maintaining near
died
toxic levels of M-Hb. A child treated with nitrite,because
of overwhelming methaemoglobinemia. 2
Recent observation, 4,5 that the antidotal combination of
sodium nitrite and thiosulphate with or without M-Hb forma
tion were equally effective against cyanide poisoning has
triggered investigations which seem to indicate that the
antidotal action of sodium nitrite is due to vasogenic
action rather than methaemoglobin formation.
SODIUM THIOSULPHATE s It combines with cyanide in the
presence of the enzyme thiosulphate transulphurase
(rhodanase) and
to produce relatively nontoxic thio
cyanate. It is relatively nontoxic although impurities
in production may produce allergic reaction in 1 out of
1000 or 10000 persons. As a single agent its efficacy is
,
,
in acute poisoning
about that of sodium nitrite but accepted practice/is to
use it in combination with sodium nitrite, which increases
its efficacy, in those patients for whom the diagnosis of
■1
overwhelming cyanide poisoning is clearly established.
sodium thiosulphate < cyanomethaemoglobin
rhodanase
methaemoglobin -F thiocyanate
^thiocyanate oxidase^
4
OXYGEN :
:: o
Inhalation of 100% oxygen increases arterial
PO2 and increases tissue O2 delivery.
It may reverse the
binding of cyanide with cytochrome oxidase and may also
help increase the conversion of cyanide to thiocyanate by
thiosulphate.2 Oxygen can markedly enhance the efficacy
of the nitrite - thiosulphate combination, so that oxygen
should be made an integral part of antidotal combination
3
Oxygen toxicity is unlikely
in cyanide poisoning therapy,
1
with use over periods less than 48 hours.
HYDROXOCOBALAMIN (VITAMIN B10=s
z a ) s It combines with cyanide
forming cyanocobalamin (Vitamin B^) but has limited pro
tein binding and a short half-life of 5. min.1 It has the
overwhelming advantage that it is essentially nontoxic
although in large doses it may produce facial acne, Thus
even in the face of erroneous diagnosis or dosage, the
patient is not at increased risk because of therapy.
It
has been called the most promising antidote.
For maximum
effect it must be given in equimolar proportions that are
7
approximately 50 times the ingested amount of cyanide.
There seems to be disagreement over its use in combination
with sodium thiosulphate.
In reference 1 we find the state
ment that it is inactivated when mixed with soduum thiosul
phate, whereas in reference 2 we find the ’assertion that
in animal studies this agent is found to be especially
useful when combined with thiosulphate.
COBALT EDETATE s It rapidly chelates free plasma and tissue
bound cyanide producing cobalticyanide and monocobalt which
are excreted within 24 hours renally. While not free from
side effects, it can be employed in severe poisoning with
out close biochemical monitoring or reduction in oxygen
carrying capacity.1 High concentrations of cobalt salts
have their own intrinsic toxicity, therefore, great caution
o
must be exercised in their use.
A simple chemical test on gastric aspirates to establish
oral cyanide poisoning is described in reference 2. A
detailed description of the mechanisms of cyanide toxicity
and antagonisms is given in reference 5. deference 8 deals
wiuh the treatment of cyanide poisoning by the administra
tion of 4-dimethyl-aminophenol (DMAP) whose action is
similar to th ar of sodium nitrite in that it helps in the
oxidation of the ferrous form of blood haemoglobin to
}
2 S
5
S 3
3
3-5
to methaemoglobin. Use of pyruvate , mere atopyruv ate
3
and chlorpromazine as antidotes is also described in
the lite mature.
ADDITIONAL NOTES s
The current OSHA exposure limit to
hydrogen cyanide is 10 ppm (eight-hour time-weighted
average) although a reduction to 5 ppm has been recommend
ed. Short-term inhalation of air levels of 50 ppm HCN
causes acute symptoms of gastric and respiratory tract
disturbance; 130 ppm can be lethal.
Lower doses, in the
range of 10 to 20 ppm can cause complaints similar to
those experienced at 50 ppm although longer exposure times
9
may be required to elicit them.
It has been suggested that vitamin
o may be a protective
j. z
factor in cyanide neurotoxic effects, Long-term cyanide
intoxication leads to thyroid enlargement and interferes
i
with iodine metabolism.
It can also lead to weight loss,
easy fatigue and sleep disturbance. It must be remembered
that cyanide exposure inhibits a wide variety of enzyme
systems in addition to the cytochrome oxidase system.
Reference 11 contains a detailed account of the treatment
of an episode of acute acrylonitrile poisoning. This is
an important paper as it documents that a single incidence
of acute cyanide poisoning can give rise to recurrent cya
nide toxicity.
As a result of this recurrence the patient
required 15 treatments vzith sodium nitrite and sodium thio
sulphate during a 72 hour period, along with additional
therapy involving hydroxocobalamin and supplemental 0 2'
with constant monitoring of methaemoglobin levels, This
case emphasizes that prolonged treatment of cyanide poison
ing may be required and that many doses of sodium nitrite
and sodium thiosulphate can be given safely over a prolong
ed period vzith adequate monitoring.
3 o
6
2 s
POTENTIAL TOXICITY
AGENT
MECHANISM
Sodium
nitrite
NaNO2-:-Hb
M-Hb
M-Hb-rCN
CyanoM-Hb
Tachycardia, vomiting,
hypotension, severe
me thaemoglobinemi a,
hypoxi a, vascular
collapse
Sodium
thiosulphate
Na2S2O2-:-CN (rhodanase) none known
Oxygen
more 02 in arterial
blood
more 02 in tissues
Oxygen toxicity unlikely
when used for less than
48 hours
may reverse CN*" bind
ing with cytochrome
potentiates activity
of sodium thiosul
phate
Hydroxocobalamin
OH-B12 4- CN
Cobalt salts
chelates cyanide
CN-B12 none known
significant loss of
Ca' ' , Mg' ' z plus
intense purgation,
cardiac toxicity
i
7
2 2
upTaYke of cyanide,
2 2
(per
PERCUTANEOUS
r
i
excreted renally
HCN in expired air
/
/ HCNO--------- > C02
cobalticyanide
Al------
! cobalt edetate j
/jhydroxocobalaminj
h------
CN /
CYANOGENIC
POOL
cynaocobalamin
excreted renally
cyanomet
haemoglobin
K cyanocytochrorne
oxidase
1 !■
methaemoglobin
cytochrome
oxidase
I
sodium /
nitrite?
fDMAP|‘
I
|
o
i
IQ
V
HbFe
•H
rd
o
(!)
0)
w
c
-P
nJ
G
rd
TJ
O
b.
0^
i*~
-
\K
Hb°2
o
o
—t
i Sodium
' thiosulphate| ?
■H
X
H
^1/ 'J,
MX
SCN~
THIOCYANATE
FAiTS
OF
CYANIDE
/Adapted from:
Williams R.T., Detoxification
Wiley, Nev; York 1953, pp 393.
■
L
ION_.JN
.^excreted
renally
THE
BODY
Mechanisms, -2nd Ed,
(98%)
I
I
8
REFERENCES
TO
PART
2 2
II
1.
C.G. Peters, J.V.B# Mundy and P.R. Rayner,
"Acute Cyanide Poisoning”, Anaesthesia 37, 582 (1982).
2.
D.L. Graham, D. Laman, J. Theodore and E.D. Robin,
•’’Acute Cyanide Poisoning Complicated by Lactic
Acidosis and Pulmonary Edema”, Arch. Intern. Med.
1.37, 1051 (1977) .
3.
J.L. Way, "Cyanide Antagonism", Fundam. Appl.
Toxicol. 3,383 (1933).
4.
J. Wilson, "Cyanide in Human Disease, a Review of
Clinical and Laboratory Evidence", Fundam. Appl.
Toxicol. .3/397 (1983).
5.
J.L. Way, D. Silvester, R.L. Morgan, G.E. Isom,
G.E. Burrows, C.B. Tamulinas and J.L. Way, "Recent
Perspectives on the Toxicodynamic Basis of Cyanide
Antagonism”, Fundam. Appl. Toxicol. 4,S231(1984).
6.
D.j. Holland, "Cyanide Poisonings an uncommon
encounter”, J. Smerg. Nursing 9,138 (1983).
7.
G.S. Birse, ’’Cyanide Poisoning”, JAOA 83,811 (1983) .
8,
N.P. Weger, “Treatment of Cyanide Poisoning with
4-Dimethy1-aminophenol (DMAP) - Experimental and
Clinical Overview”, Fundam. Appl. Toxicol. _3,387 (1983) .
9.
P. Blanc and D. Hryhorczuk, "Cyanide Intoxication
among Silver-Reclaiming Workers", JAMA 253,367(1985).
10.
J.E. Cottrell, "Prevention of nitroprusside induced
cyanide toxicity with hydroxocobalamin”, New England
Journal of Medicine 298, 809(1978).
11.
R.A. Vogel and W.M. Kirkendal, "Acrylonitrile
(vinyl cyanide) poisoning; a case report",
Texas Medicine .80/48 (1984) .
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