Management of cyanide toxicity in patients with burns

JBUR-4389; No. of Pages 7 burns xxx (2014) xxx–xxx

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Review

Management of cyanide toxicity in patients with burns Louise MacLennan *, Naiem Moiemen UK Healing Foundation Centre for Burns Research, Queen Elizabeth Hospital Birmingham, Birmingham, UK

article info

abstract

Article history:

The importance of cyanide toxicity as a component of inhalational injury in patients with

Accepted 4 June 2014

burns is increasingly being recognised, and its prompt recognition and management is vital

Keywords:

by a lack of randomised controlled trials in humans, and in addition consideration must be

Cyanide

given to the concomitant pathophysiological processes in patients with burns when inter-

for optimising burns survival. The evidence base for the use of cyanide antidotes is limited

Inhalation injury

preting the literature. We present a literature review of the evidence base for cyanide

Burns

antidotes with interpretation in the context of patients with burns. We conclude that

Hydroxycobalamin

hydroxycobalamin should be utilised as the first-line antidote of choice in patients with

Sodium thiosulphate

burns with inhalational injury where features consistent with cyanide toxicity are present. # 2014 Elsevier Ltd and ISBI. All rights reserved.

Sodium nitrite Dicobalt edetate

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Introduction . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . Biochemistry . . . . . . . . . . . . . . . . . . . Clinical features and diagnosis . . . . . Management . . . . . . . . . . . . . . . . . . . Hydroxycobalamin. . . . . . . . . . . . . . . Sodium thiosulphate . . . . . . . . . . . . . Sodium nitrite, amyl nitrite, 4DMAP . Dicobalt edetate. . . . . . . . . . . . . . . . . Choice of antidote . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: UK Healing Foundation Centre for Burns Research, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, United Kingdom. Tel.: +44 7738 399472. E-mail address: [email protected] (L. MacLennan). http://dx.doi.org/10.1016/j.burns.2014.06.001 0305-4179/# 2014 Elsevier Ltd and ISBI. All rights reserved.

Please cite this article in press as: MacLennan L, Moiemen N, Management of cyanide toxicity in patients with burns. Burns (2014), http:// dx.doi.org/10.1016/j.burns.2014.06.001

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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 20–30% of patients with burns who undergo hospitalisation [2]. Advances in fluid resuscitation, surgery and antibiotics have improved the management of burn shock and sepsis [3], with fire 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 comprises direct thermal injury, chemical irritation of lung parenchyma and the systemic effects of absorption of the toxic products of combustion, such as carbon monoxide and cyanide. There is increasing evidence that cyanide toxicity plays an important role in smoke inhalation injury and its associated mortality [7–9], with smoke inhalation reportedly the most common cause of cyanide toxicity [10,11]. It is difficult to accurately determine the true incidence of cyanide toxicity due to smoke inhalation as blood cyanide levels are often not measured; however, it has been 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 (1950–June 2013), EMBASE (1980–June 2013) and CINAHL (1981–June 2013) databases was undertaken using the NHS Evidence Interface. The search terms ‘cyanide’ plus ‘smoke inhalation’, and also ‘cyanide’ plus either ‘hydroxycobalamin’, ‘sodium thiosulphate’, ‘nitrite’, or ‘dicobalt 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 known as hydrogen cyanide, and are highly toxic. Hydrogen cyanide is a volatile liquid that forms a colourless gas at 26 8C and has a distinctive odour of bitter almonds; however, 20–40% of people are genetically unable to detect this [12,13]. Cyanide compounds are used in the production of acrylic, rubber and plastic; for industrial processes including electroplating, steel production and metal extraction from ores; and for fumigation. 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 0.5–1.0 mg/L (19–40 mmol/L) are regarded as toxic [7,9,14], and untreated levels above 2.5–3 mg/L (96–115 mmol/L) are potentially 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 endogenous 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 becomes more severe, signs include confusion, drowsiness, seizures, bradycardia, bradypnoea, hypotension and pulmonary oedema, progressing to loss of consciousness, fixed pupils, cardiovascular collapse and ultimately death. The patient’s 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 prevailing anaerobic metabolism [7,16,17]. In victims of smoke inhalation with burns <15% total body surface area (TBSA), a plasma lactate level >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 recommended in the prehospital setting for those with a history of smoke inhalation and either a Glasgow Coma Scale (GCS) <14 or abnormal haemodynamics; and in the hospital setting for those with a history of smoke inhalation and a lactate above 90 mg/dL (10 mmol/L) [18].

5.

Management

Management of cyanide toxicity in patients with burns with smoke inhalation injury includes both supportive measures and specific antidotes. Supportive measures include high-flow oxygen, monitoring of vital signs including cardiac monitoring, circulatory support, mechanical ventilation and correction of metabolic acidosis with sodium bicarbonate. Hyperbaric oxygen has been advocated as a potential adjunct for cyanide toxicity; however, the evidence for its efficacy in

Please cite this article in press as: MacLennan L, Moiemen N, Management of cyanide toxicity in patients with burns. Burns (2014), http:// dx.doi.org/10.1016/j.burns.2014.06.001

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Table 1 – Cyanide antidote properties. Antidote

Mechanism of action

Hydroxycobalamin

Binds cyanide directly

5 g IV over 15 min

Sodium thiosulphate

Upregulates body’s natural excretion mechanism of forming thiocyanate Convert haemoglobin to methaemoglobin which binds cyanide

12.5 g IV over 10 min

Sodium nitrite, Amyl nitrite, 4DMAP

Dicobalt edetate

Binds cyanide directly

Dose and route

Sodium nitrite: 300 mg IV over 5–20 min Amyl nitrite: 0.3 ml ampoules crushed and inhaled 4DMAP: 250 mg IV over 1 min 300 mg IV over 1 min

this situation is limited and conflicting [19–22]. In addition, it is not widely available and the chamber presents a difficult environment in which to resuscitate the patient. Several antidotes have been postulated, with differing mechanisms of action and variable evidence of 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 a 5-g dose can bind blood cyanide levels up 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 [25–27] and Riou [28] support the efficacy of hydroxycobalamin in reversing the effects of cyanide toxicity in swine and rat models. Hydroxycobalamin has been utilised in France as the firstline antidote for cyanide toxicity for many years, and is often administered at the scene of injury following smoke inhalation by emergency physicians who form part of the prehospital care team within the fire service. Fortin and Borron have published large case series which demonstrate mean survival of 42–67% following hydroxycobalamin administration to smoke inhalation 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 hydroxycobalamin 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 that hydroxycobalamin should be

Side effects Transient hypertension, headache, bradycardia, skin and urine discolouration Nausea and vomiting, headache

Reduction in oxygen carrying capacity of blood, vasodilation, hypotension

Anaphylaxis, hypotension, cardiac arrhythmias; more severe in absence of cyanide toxicity

administered presumptively and as quickly as possible when cyanide toxicity is suspected, and in the event of cardiac arrest the 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 that hydroxycobalamin is safe to use 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 [9,29–32]. 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 [14,18,33–39].

7.

Sodium thiosulphate

Endogenous thiosulphate forms part of the body’s 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 body’s 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 as nausea, vomiting and headache being reported [39–41]. Much of the evidence in the literature assesses the efficacy of sodium thiosulphate when given in conjunction with other antidotes [39]. Evidence for the efficacy of 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 human dose [42], and to reverse the effects of 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 do not show clinical efficacy, as either the study period may be

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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 rapid half-life of cyanide, it is postulated that in the period prior to the onset of action of sodium thiosulphate 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 methaemoglobin. 4-dimethylaminopyridine (4DMAP) works by a similar mechanism via methaemoglobin. Oxygen cannot bind to the ferric iron in methaemoglobin, but cyanide binds preferentially 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, 20–30% 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 cause vasodilation and consequently hypotension which can worsen 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 side effects may be even more pronounced if dicobalt edetate is administered in the absence of 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 in humans in the literature is a safety study of hydroxycobalamin in healthy human subjects [32]; however, this provides no 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 dangerous 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. Dicobalt edetate is associated with frequent and severe 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 been confirmed 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 resuscitation 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 thiosulphate has traditionally been used in conjunction with other more rapid acting antidotes [39,41], particularly sodium nitrite [26], and evidence in the literature of its efficacy as a sole agent is limited. Recent guidance on antidote availability from the UK College of Emergency Medicine recommends that hydroxycobalamin 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 more rapidly but there were no statistically significant differences in mortality, acidosis or lactate [25]. In the second study, hydroxycobalamin, sodium thiosulphate and hydroxycobalamin plus sodium thiosulphate were compared, and whereas the cyanide toxicity was reversed in the hydroxycobalamin and combined groups, all the subjects died 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, as a similar study in humans 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 a domestic fire [47]. However, the lower flammable 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. The highest 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 this situation when the cyanide toxicity is an isolated injury, in the context of a patient with burns with smoke inhalation injury we believe that a more aggressive approach with 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

History of Smoke Inhalation

100% O2 Pre-hospital:

In hospital:

GCS < 14 and/or cardiovascular instability

Plasma lactate > 10mmol/L

5g IV hydroxycobalamina

5g IV hydroxycobalaminb

a

Consider 10g dose in the event of cardiac arrest.

b

Further 5g dose can be given up to 10g total dose.

Fig. 1 – Flowchart for assessment and management of cyanide toxicity in patients with burns. Source: Modified from Anseeuw et al. [18].

patients with major burns aggressive reversal of even mild cyanide toxicity may improve burn tissue perfusion and consequently could potentially indirectly improve survival from 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 carbon monoxide toxicity. However, we believe the risk of treatment of cyanide toxicity in a patient with only carbon monoxide toxicity is outweighed by the potential benefit of early empiric treatment for cyanide toxicity. High-flow oxygen is indicated for both toxins, and empiric hydroxycobalamin treatment has a safe side-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 toxicity of 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 patient’s 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 hydroxycobalamin for patients suspected to have cyanide toxicity is utilised in France [9,29–31]. Early administration of hydroxycobalamin 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 nature of cyanide toxicity in patients with burns precludes the possibility of randomised controlled human trials to

Please cite this article in press as: MacLennan L, Moiemen N, Management of cyanide toxicity in patients with burns. Burns (2014), http:// dx.doi.org/10.1016/j.burns.2014.06.001

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provide strong clinical evidence for the efficacy of antidotes; therefore, pharmacological theory must be combined with 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 nitrite have side-effect profiles that render them unsafe to use in patients with burns with smoke inhalation injury. There is evidence of efficacy for both hydroxycobalamin and sodium thiosulphate and both are well tolerated; however, comparative 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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