ReviewManagement of cyanide toxicity in patients with burns
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], [8], [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.
Section snippets
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.
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 °C and has a distinctive odour of bitter almonds; however, 20–40% of people are
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
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 this situation is limited
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 μmol/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
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
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
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
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
Discussion
It has been suggested that the low flashpoint of hydrogen cyanide of −18 °C (0 °F), 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
Conclusion
The nature of cyanide toxicity in patients with burns precludes the possibility of randomised controlled human trials to 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
Conflict of interest
There are no conflicts of interest to declare.
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