management of cyanide toxicity in patients with burns 2015 burns
TRANSCRIPT
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7/24/2019 Management of Cyanide Toxicity in Patients With Burns 2015 Burns
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http://dx.doi.org/10.1016/j.burns.2014.06.001http://www.elsevier.com/locate/burnshttp://www.sciencedirect.com/science/journal/03054179mailto:[email protected]://dx.doi.org/10.1016/j.burns.2014.06.001http://crossmark.crossref.org/dialog/?doi=10.1016/j.burns.2014.06.001&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.burns.2014.06.001&domain=pdf -
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1. Introduction
Inhalational injury is one of the major predictors of mortality
in patients with burns [1], and is estimated to be present in
2030% ofpatients withburnswhoundergo hospitalisation [2].
Advances in fluid resuscitation, surgery and antibiotics have
improved the management of burn shock and sepsis [3], withfire and burn mortality in the USA dropping from 3.0 to 1.2 per
100,000 population in the 25-year period from 1981 to 2006 [4].
However, the management of inhalational injury remains one
of
the
greatest
challenges
of
burn
care,
and
its
presence
is
reported to double the mortality by burn [5,6].
Inhalation injury comprisesdirect thermal injury, chemical
irritation of lung parenchyma and the systemic effects of
absorptionof the toxic productsof combustion, suchas carbon
monoxide and cyanide. There is increasing evidence that
cyanide
toxicity
plays
an
important
role
in
smoke
inhalation
injury and its associated mortality [79], with smoke inhala-
tion reportedly the most common cause of cyanide toxicity
[10,11]. It is difficult to accurately determine the true incidenceof
cyanide
toxicity
due
to
smoke
inhalation
as
blood
cyanide
levelsareoften notmeasured;however, ithasbeen reported to
have been found in as many as 76% of patients with smoke
inhalation injury [9]. This paper aims to appraise the evidence
base for the pharmacological management of cyanide toxicity
in the context of smoke inhalation and burn injuries, in order
to
guide
management
in
this
clinical
setting.
2. Methods
A search of Medline (1950June 2013), EMBASE (1980June
2013) and CINAHL (1981June 2013) databaseswas undertakenusing the NHS Evidence Interface. The search terms cyanide
plus smoke inhalation, and also cyanide plus either
hydroxycobalamin, sodium thiosulphate, nitrite, or dico-
balt edetate were used.
3. Biochemistry
Cyanide
refers
to
any
substance
that
contains
the
cyano
(CN)
group. This includes inorganic cyanides with a negatively
charged cyanide ion, such as sodium cyanide, and organic
cyanides with a covalent CN group such as methyl cyanide.
Inorganic cyanides are salts of hydrocyanic acid, also knownashydrogen cyanide,andarehighly toxic.Hydrogen cyanide is
a volatile liquid that forms a colourless gas at 26 8C and has a
distinctiveodourofbitter almonds;however, 2040% ofpeople
are genetically unable to detect this [12,13]. Cyanide com-
pounds are used in the production of acrylic, rubber and
plastic;
for
industrial
processes
including
electroplating,
steel
production and metal extraction from ores; and for fumiga-
tion. In smoke inhalation injury, cyanide toxicity is thought to
occur from exposure to the products of combustion of those
cyanide-containing
synthetic
substances.
Cyanide acts by binding to the ferric ions in cytochrome c
oxidase, thus inhibiting its action in the electron transport
chain in mitochondria. This disruption of the electron
transport chain blocks cellular aerobic respiration, which
can rapidly become fatal. Whole blood cyanide levels above
0.51.0 mg/L (1940 mmol/L) are regarded as toxic [7,9,14], and
untreated levels above 2.53 mg/L (96115 mmol/L) are poten-
tially fatal [12,14].
Although the affinity of cyanide for ferric ions is strong, the
process is reversible. Cyanide disassociates from cytochrome
c oxidase by binding with sulphur transferred from endoge-nous thiosulphate by the catalyst rhodanese. The resultant
thiocyanate undergoes renal excretion. Observational studies
have shown a half-life of between 1 and 3 h [7,15].
4. Clinical features and diagnosis
Early clinical manifestations of cyanide toxicity include those
of sympathetic activation namely tachycardia, hypertension,
palpitations,
tachypnoea
and
anxiety,
as
well
as
nausea,
headache and dizziness.As the toxicity becomesmore severe,
signs include confusion, drowsiness, seizures, bradycardia,
bradypnoea, hypotension and pulmonary oedema, progres-sing
to
loss
of
consciousness,
fixed
pupils,
cardiovascular
collapse and ultimately death. The patients breath classically
smells of bitter almonds to the majority of clinicians able to
detect this odour. One study found that 67% of smoke
inhalation victims without major burns but with neurological
impairment had toxic cyanide levels above 39 mmol/L (1.0 mg/
L)
[9].
Although blood cyanide concentration can be measured, it
is not of use for diagnosis in the acute setting as few
laboratories perform the assay and results cannot be obtained
rapidly. Diagnosis is therefore clinical; however, plasma
lactate has been found to correlate with the severity of
cyanide toxicity due to lactic acidosis from the prevailinganaerobicmetabolism [7,16,17]. In victimsof smoke inhalation
with burns 10 mmol/L (90 mg/dL) has been found to be a
sensitive indicator of cyanide toxicity suggesting blood
cyanide levels >40 mmol/L (1.0 mg/L) [7].
A panel endorsed by the European Society for Emergency
Medicine recently developed algorithms for both prehospital
and in-hospital management of possible cyanide toxicity in
smoke
inhalation.
Empiric
antidotal
treatment
was
recom-
mended in the prehospital setting for those with a history of
smoke inhalation and either a Glasgow Coma Scale (GCS)
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this situation is limited and conflicting [1922]. In addition, it is
not widely available and the chamber presents a difficultenvironment
in
which
to
resuscitate
the
patient.
Several antidotes have been postulated, with differing
mechanismsof action and variable evidenceof efficacy.These
antidotes include hydroxycobalamin, sodium thiosulphate,
methaemoglobin-producing nitrites and dicobalt edetate
(Table 1).
6. Hydroxycobalamin
Hydroxycobalamin binds cyanide by substituting a hydroxyl
group for a CN group, forming cyanocobalamin, a non-toxic
substance that can be excreted by the kidneys. It is thought a5-gdose canbindblood cyanide levelsup to 40 mmol/L (1.0 mg/
L) [23]. It also has the additional effect of scavenging nitric
oxide thus raising blood pressure,which can potentially offset
the hypotension induced by the cyanide toxicity.
Hydroxycobalamin has been shown to reduce cyanide
levels in smokers [24]. In addition, animal studies by Bebarta
[2527] andRiou [28] support the efficacyofhydroxycobalamin
in reversing the effects of cyanide toxicity in swine and rat
models.
Hydroxycobalamin has been utilised in France as the first-
line antidote for cyanide toxicity for many years, and is often
administered at the scene of injury following smoke inhalation
by emergency physicians who form partof the prehospital careteam within the fire service. Fortin and Borron have published
large case series which demonstrate mean survival of 4267%
following hydroxycobalamin administration to smoke inhala-
tion victims with presumed [29] or confirmed [9] cyanide
toxicity. Borron has shown 62% and 64% survival in patients
with
blood
cyanide
concentration
over
100
mmol/L
(2.6
mg/L),
a
level usually regarded as fatal, when treated with hydroxyco-
balamin for cyanide toxicity due to smoke inhalation [9] and
other causes [30], respectively. Fortin noted statistically
significant
differences
in
mean hydroxycobalamin
dose
in
those who had cardiac arrest without recovery, cardiac arrest
with early recovery but later death and cardiac arrest with
recovery [31], and concluded thathydroxycobalamin should be
administered presumptively and as quickly as possible when
cyanide toxicity is suspected, and in the event of cardiac arrestthe
dose
should
be
increased
or
repeated
unless
a
rapid
response is observed. As there were no significant adverse
effects of hydroxycobalamin administration in any of these
case series, they conclude thathydroxycobalamin is safe touse
empirically for suspected cyanide toxicity in prehospital care.
Hydroxycobalamin has a very mild side effect profile:
transient
hypertension,
bradycardia,
headache
and
skin
and
urine discolouration have been documented but no major
adverse effects have been reported [9,2932].
A number of recent review articles have also concluded,
based on the limited efficacy data available, as well as the
more widely documented safety data, that hydroxycobalamin
is a safe and effective first-line antidote for cyanide toxicity[14,18,3339].
7. Sodium thiosulphate
Endogenous thiosulphate forms part of the bodys normal
excretion mechanism of cyanide, by transferring sulphur to
cyanide to form thiocyanate which is excreted by the kidneys,
under
the
action
of
the
catalyst
rhodanese.
Administration
of
sodium thiosulphate is thought to upregulate the bodys
natural excretion of cyanide by increasing the availability of
substrate, thus limiting toxicity. Sodium thiosulphate is
generally well tolerated with only minor side effects such asnausea, vomiting and headache being reported [3941].
Much of the evidence in the literature assesses the efficacy
of sodium thiosulphate when given in conjunction with other
antidotes [39]. Evidence for theefficacyof sodium thiosulphate
as a sole agent is confined to case reports and animal models,
and
outcomes
are
mixed.
It
has
been
shown
to
reverse
the
effects of cyanide in sheep when given at triple the standard
humandose [42],and to reverse the effectsof cyanide in rats at
standard human doses [43]. One study in a dog model
demonstrated
reduced
plasma
cyanide
levels
compared
to
the control but differences were only seen after 1 h [44]. This
apparent slow onset of action may explain why some studies
donot show clinical efficacy, as either the studyperiodmaybe
Table 1 Cyanide antidote properties.
Antidote Mechanism of action Dose and route Side effects
Hydroxycobalamin Binds cyanide directly 5 g IV over 15 min Transient hypertension, headache,
bradycardia, skin and urine
discolouration
Sodium thiosulphate Upregulates bodys
natural excretion
mechanism of formingthiocyanate
12.5 g IV over 10min Nausea and vomiting, headache
Sodium nitrite, Amyl
nitrite, 4DMAP
Convert haemoglobin to
methaemoglobin which
binds cyanide
Sodium nitrite: 300mg
IV over 520min
Amyl nitrite: 0.3 ml
ampoules crushed and
inhaled
4DMAP: 250 mg IV over
1 min
Reduction in oxygen carrying capacity
of blood, vasodilation, hypotension
Dicobalt edetate Binds cyanide directly 300 mg IV over 1 min Anaphylaxis, hypotension, cardiac
arrhythmias; more severe in absence of
cyanide toxicity
b ur ns 4 1 ( 20 15 ) 1 8 2420
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too short [45] or the severity of the cyanide toxicity so great as
to cause death before a response is seen [46].
Several literature reviews conclude that there is reasonable
evidence that sodium thiosulphate is effective in cyanide
toxicity [37,38,40]; however, the slower onset of action
compared to other antidotes is also generally accepted [37
40,47].Considering the rapidhalf-life ofcyanide, it ispostulated
that in the period prior to the onset of action of sodiumthiosulphate the cyanide would either prove fatal or reduce to
non-critical concentrations; thus, this slow onset of action
limits the usefulness of sodium thiosulphate as an antidote for
the
acute
cyanide
toxicity
seen
in
smoke
inhalation.
8. Sodium nitrite, amyl nitrite, 4DMAP
Nitrites such as sodium nitrite or amyl nitrite oxidise iron in
haemoglobin
from
ferrous
to
ferric
iron,
forming
methaemo-
globin. 4-dimethylaminopyridine (4DMAP) works by a similar
mechanism via methaemoglobin. Oxygen cannot bind to the
ferric iron in methaemoglobin, but cyanide binds preferen-tially
with
methaemoglobin
over
cytochrome
c
oxidase,
forming cyanmethaemoglobin, thus releasing cytochrome c
oxidase so that aerobic metabolism can resume.
Nitrites have been used as a cyanide antidote since their
efficacy was demonstrated in animal models in the 1930s [48
52]. These studies popularised a regime of amyl nitrite and
sodium
nitrite
given
together
with
sodium
thiosulphate.
However, 2030% of haemoglobin needs to be converted to
methaemoglobin for adequate efficacy [47], which has an
adverse effect on the oxygen carrying capacity of blood,
making this an unsafe choice in patients with smoke
inhalation injury who may also have concurrent carbon
monoxide toxicity [14,37,39,53]. In addition, nitrites causevasodilation and consequently hypotension which can wors-
en circulatory stability [53,54], a side effect which could be
particularly dangerous in patients with major burns.
9. Dicobalt edetate
Dicobalt edetate also acts by binding cyanide, and it has been
used
as
a
cyanide
antidote
for
over
100
years.
Once
again,
evidence of efficacy is derived from animal models and case
reports [41] rather than human clinical trials. It is associated
with a number of serious side effects, including anaphylaxis,
hypotension and cardiac arrhythmias [55,56]. These sideeffects may be even more pronounced if dicobalt edetate is
administered in the absenceof cyanide toxicity; therefore, it is
generally recommended that it is only used as an antidote in
severe confirmed cases of cyanide toxicity [38]. In practical
terms, this precludes it from being used as a cyanide antidote
in
patients
with
burns
with
smoke
inhalation
as
cyanide
toxicity can rarely be absolutely confirmed in these cases.
10. Choice of antidote
There are no randomised controlled human trials to evaluate
the efficacy of cyanide antidotes in the literature, only animal
models and case series. There are a number of factors to
account for this, including the relative rarity of cyanide
poisoning, the lack of a rapid test to confirm the presence of
cyanide toxicity and ethical issues which would prevent the
use of a placebo when cyanide toxicity is suspected. In the
absence of controlled human studies, these animal models
and case series become the only evidence on which we can
base our practice. The only randomised controlled trial inhumans in the literature is a safety study of hydroxycobala-
min inhealthyhuman subjects [32]; however, this providesno
information on efficacy.
There
is
evidence
of
efficacy
in
the
literature
for
every
cyanide antidote in our review; however, not all of these
antidotes appear to be suitable in the context of smoke
inhalation injury.
Antidotes such as sodium nitrite, amyl nitrite and 4DMAP,
which act by forming methaemoglobin, reduce the oxygen
carrying
capacity
of
blood.
The
coexistence
of
carbon
monoxide toxicity in smoke inhalation injury may also
simultaneously reduce the oxygen carrying capacity of blood,
making methaemoglobin-forming antidotes potentially dan-gerous
in
this
context,
and
there
have
been
reports
of
fatal
reductions in oxygen carrying capacity when sodium nitrite
has been given in the presence of carbon monoxide toxicity
[40,53]. In addition, we postulate that the reduction in
oxygenation of the blood in these vital first few hours post
injury could potentially have an adverse effect on coexisting
burns,
and
the
side
effect
of
hypotension
with
nitrite
use
could
worsen circulatory stability in patients with burn shock.
Dicobaltedetate isassociatedwith frequent andsevere side
effects such as anaphylaxis, hypotension and arrhythmias.
These side effects can be amplified when it is administered in
the absence of cyanide toxicity [57]. Consequently, its use is
usually limited to cases where cyanide toxicity has beenconfirmed such as ingestion of a known cyanide-containing
substance [40]. In the context of patients with burns with
smoke inhalation, cyanide toxicity can be suspected but
cannot be definitively confirmed in the immediate resuscita-
tion period, therefore precluding the use of dicobalt edetate as
a cyanide antidote in smoke inhalation injury.
Hydroxycobalamin and sodium thiosulphate are both
associated with a mild side-effect profile and are regarded
as
safe
to
use
in
smoke
inhalation
patients.
Sodium
thiosulphate however appears to have a slower onset of
action which may limit its usefulness as a sole agent in the
urgent reversal of severe cyanide toxicity. Sodium thiosul-
phate has traditionally been used in conjunction with othermore rapid acting antidotes [39,41], particularly sodiumnitrite
[26], and evidence in the literatureof its efficacy as a sole agent
is limited. Recent guidance on antidote availability from the
UK College of Emergency Medicine recommends that hydro-
xycobalamin be considered in smoke inhalation victims
showing
signs
associated
with
cyanide
toxicity,
and
that
sodium thiosulphate generally be used as an adjuvant to other
antidotes [58].
There has been a lack of good quality comparative studies
in
the
literature
comparing
the
relative
efficacy
of
cyanide
antidotes;however, Bebarta et al. have recently published two
randomised controlled comparative studies in a swine model
[25,26]. In the first study, hydroxycobalamin with sodium
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thiosulphate was compared to sodium nitrite with sodium
thiosulphate, and found that hydroxycobalamin with sodium
thiosulphate reversed hypotension morerapidlybut therewere
no statistically significant differences in mortality, acidosis or
lactate [25]. In the second study, hydroxycobalamin, sodium
thiosulphate and hydroxycobalamin plus sodium thiosulphate
were compared, andwhereas the cyanide toxicitywas reversed
in thehydroxycobalamin and combined groups,all the subjectsdied in the sodium thiosulphate group [26]. In addition, no
difference in outcome measures was seen in the combined
group compared to hydroxycobalamin alone. These results
suggest
that
hydroxycobalamin
is
significantly
more effective
than sodium thiosulphate for cyanide toxicity, as there was a
profound difference in survival demonstrated in this model.
Clearly, the applicability of an animal model to a human
population has its limits; however,asasimilar study inhumans
would be ethically unfeasible, increased reliance on animal
models
may be
necessary.
We therefore
recommend
that
hydroxycobalamin is used as the antidote of choice in patients
with burns with cyanide toxicity due to smoke inhalation.
11. Discussion
It has been suggested that the low flashpoint of hydrogen
cyanide of 18 8C (0 8F), which is the lowest temperature at
which cyanide will ignite, means that most hydrogen cyanide
will
combust
and
therefore
not
be
present
in
significant
levels
in smoke in adomesticfire [47]. However, the lowerflammable
limit, the minimum concentration at which a substance can
ignite, is 5.6% (56,000 ppm) which is a level immensely higher
than the immediate danger to life or health value of 50 ppm
[59], suggesting that dangerous cyanide levels could still be
present before the threshold for ignition is reached. Thehighest concentration of cyanide appears to occur in the first
few minutes following fire ignition [60,61], which may explain
why one study did not find dangerous exposure levels using
measuring devices attached to coats of firefighters who will
have arrived on scene after cyanide levels have dropped [62].
Studies of smoke inhalation victims measuring cyanide levels
at the fire scene have demonstrated blood cyanide levels
significantly higher than controls [7], with levels above
39
mmol/L
in
67%
of
victims
[9].
The necessity to use specific cyanide antidotes for blood
cyanide concentrations which in isolation are generally
regarded as toxic but not fatal has also been questioned
[47]. Although it may not be necessary to use antidotes in thissituationwhen the cyanide toxicity is an isolated injury, in the
context of a patient with burns with smoke inhalation injury
we believe that amore aggressive approachwith early use of a
specific antidote is warranted. Animal studies have shown
that in the presence of concomitant major atmospheric
oxygen
depletion,
the
fatal
dose
of
blood
cyanide
was
one
tenth of that expected [8]. Even if the cyanide toxicity alone is
not sufficient to be fatal, it could potentially confer a worse
outcome on a concomitant major burn injury. Optimal
perfusion
of
the
burnt
skin
during
the
resuscitation
period
can affect the survival of tissue in the zone of stasis [63]. We
postulate that the ischaemia and acidosis caused by cyanide
toxicity may reduce perfusion of the burnt tissue, and in
patients with major burns aggressive reversal of even mild
cyanide toxicity may improve burn tissue perfusion and
consequently could potentially indirectly improve survivalfrom
the
burn
injury.
We therefore
recommend
treatment
with hydroxycobalamin for any burn victim with a history of
smoke inhalation who has clinical features consistent with
cyanide toxicity (Fig. 1).
The clinical features suggestive of cyanide toxicity are
similar to those of carbon monoxide toxicity, and it is possible
that
clinical
features
in
a
patient
warranting
empiric
cyanide
antidote treatment are in fact attributable to carbonmonoxide
toxicity. However, we believe the risk of treatment of cyanide
toxicity in a patient with only carbon monoxide toxicity is
outweighed by the potentialbenefit of early empiric treatment
for cyanide toxicity. High-flow oxygen is indicated for both
toxins, and empiric hydroxycobalamin treatment has a safeside-effect profile even in the absence of cyanide toxicity. In
addition, a correlation between blood concentrations of
carbon monoxide and cyanide has been shown in smoke
inhalation victims [7] suggesting that most patients in actual
fact suffer toxicityof both simultaneously.The possibility that
the clinical features may be attributable to another cause
should of course always be considered when resuscitating a
patient, and it should not be assumed that cyanide toxicity is
the
sole
cause
of
the
patients
clinical
condition.
The time delay to administration of a cyanide antidote is
thought to have a significant impact on outcome [64]. Early
empiric treatment at the scene of injury with hydroxycoba-
lamin for patients suspected to have cyanide toxicity isutilised in France [9,2931]. Early administration of hydro-
xycobalamin is possible in France as prehospital care includes
a physician-led ambulance team. We postulate the earlier
intervention has an important role in improving survival, and
that feasibility studies of early empiric treatment of cyanide
toxicity
with
hydroxycobalamin
administered
at
the
scene
of
injury are warranted in other countries.
12. Conclusion
The natureof cyanide toxicity inpatientswithburnsprecludes
the possibility of randomised controlled human trials to
aConsider 10g dose in the event of cardiac arrest.
bFurther 5g dose can be given up to 10g total dose.
History of Smoke Inhalation
5g IV hydroxycobalamina 5g IV hydroxycobalaminb
100% O2
Pre-hospital:
GCS < 14 and/or cardiovascular
instability
In hospital:
Plasma lactate > 10mmol/L
Fig. 1 Flowchart for assessment and management of
cyanide
toxicity
in
patients
with
burns.
Source: Modified from Anseeuw et al. [18].
b ur ns 4 1 ( 20 15 ) 1 8 2422
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provide strong clinical evidence for the efficacy of antidotes;
therefore, pharmacological theorymust be combinedwith the
available evidence in the literature from animal models and
case series, despite the limitations of this type of evidence, in
order to determine optimal treatment strategies. Dicobalt
edetate and methaemoglobin-forming agents such as sodium
nitritehave side-effect profiles that render them unsafe to use
in patients with burns with smoke inhalation injury. There isevidence of efficacy for both hydroxycobalamin and sodium
thiosulphate and both are well tolerated; however, compara-
tive studies in the literature found hydroxycobalamin to be
substantially
more
efficacious
than
sodium
thiosulphate,
and
in addition concerns have been raised regarding the slow
onset of action of sodium thiosulphate. We therefore
recommend that hydroxycobalamin is used as the first-line
antidote of choice in patients with burns with inhalational
injury where features consistent with cyanide toxicity are
present.
In
addition,
we
suggest
that
protocols
are
developed
in the prehospital and emergency care setting that facilitate
the most timely administration of hydroxycobalamin in order
to maximise efficacy.
Conflict
of
interest
There are no conflicts of interest to declare.
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b ur ns 4 1 ( 20 15 ) 1 8 24 23
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