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doi: 10.1111/j.1742-6723.2012.01538.x

Emergency Medicine Australasia (2012) 24, 225238

REVIEW ARTICLE

Review article: Management of cyanide poisoning

emm_1538 225..238

Michael C Reade,1,4,5 Suzanne R Davies,1 Peter T Morley,1,2 Jennifer Dennett1,3 and Ian C Jacobs,1,6 on behalf of the Australian Resuscitation Council 1 Australian Resuscitation Council, Royal Australasian College of Surgeons, College of Surgeons Gardens, 2 Royal Melbourne Hospital and University of Melbourne, Melbourne, 3Central Gippsland Health Service, Sale, Victoria, 4Australian Defence Force, Canberra, Australian Capital Territory, 5University of Queensland, Brisbane, 6University of Western Australia, Perth, Western Australia, Australia

Abstract
Cyanide poisoning is uncommon, but generates interest because of the presumed utility of an antidote immediately available in those areas with a high risk of cyanide exposure. As part of its regular review of guidelines, the Australian Resuscitation Council conducted a systematic review of the human evidence for the use of various proposed cyanide antidotes, and a narrative review of the relevant pharmacological and animal studies. There have been no relevant comparative or placebo-controlled human trials. Nine case series were identied. Treatment with hydroxocobalamin was reported in a total of 361 cases. No serious adverse effects of hydroxocobalamin were reported, and many patients with otherwise presumably fatal poisoning survived. Sodium thiosulphate use was reported in two case series, similarly with no adverse effects. Treatment with a combination of sodium nitrite, amyl nitrite and sodium thiosulphate was reported in 74 patients, with results indistinguishable from those of hydroxocobalamin and sodium thiosulphate. No case series using dicobalt edetate or 4-dimethylaminophenol were identied, but successful use in single cases has been reported. Hydroxocobalamin and sodium thiosulphate differ from alternatives in having negligible adverse effects, and on the basis of current evidence are the antidotes of choice. The indications for the use of an antidote, the requirements for supportive care and a recommended approach for workplaces where there is a risk of cyanide poisoning are presented.
Key words: antidote, cyanide, poisoning, resuscitation. mitochondrial oxygen utilization. Cyanide can cause poisoning by:4 Inhalation of cyanide-containing gas (such as hydrogen cyanide or cyanogen chloride) or dust containing solid or liquid cyanide. Typical sources are industrial (e.g. in gold and silver mining, acrylic manufacturing, electroplating, jewellery

Introduction
Poisoning by plants containing cyanide has been known for millennia, but the rst published description of cyanide poisoning (due to bitter almonds) was by Wepfer in 1679.13 Compounds containing cyanide ions (CN-) are rapidly acting poisons that interfere with
Correspondence:

Professor Michael C Reade, Level 9, Health Sciences Building, Royal Brisbane and Womens Hospital, Herston, Qld 4029, Australia. Email: m.reade@uq.edu.au or michael.reade@defence.gov.au Michael C Reade, MBBS, MPH, DPhil, FANZCA, FCICM, Professor of Military Surgery and Medicine; Suzanne Davies, BAppSc, MPH, Research Ofcer; Peter Morley, MBBS, FRACP, FANZCA, FCICM, Director of Medical Education; Jennifer Dennett, BAppSc(Education), MNursing, MRCNA, Nursing Unit Manager; Ian Jacobs, BAppSc, DipEd, PhD, RN, FRCNA, FACAP, Winthrop Professor of Resuscitation and Pre-Hospital Care.
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MC Reade et al.

manufacturing, steel fabrication and vermin eradication), or (possibly5) combustion of plastics, acrylics, synthetic rubber, carpeting or upholstery in enclosed spaces Skin absorption of cyanide-containing liquids, such as hydrogen cyanide at room temperature, typically in the industrial settings listed above Ingestion of cyanide compounds, either acutely (either with suicidal intent or accidentally) or over time (e.g. in foods containing cyanogenic glycosides, such as cassava root, apricot seeds and bitter almonds) Metabolism of sodium nitroprusside when administered as an i.v. vasodilator at high doses over a prolonged period The most common source of cyanide exposure is smoke inhalation from residential or industrial res, although whether the low levels of cyanide typically inhaled are sufcient to cause clinically important poisoning is unclear.5 Three pharmaceuticals (sodium nitrite, sodium thiosulphate and dicobalt edetate) are approved by the Australian Therapeutic Goods Administration (TGA) as cyanide antidotes. Many Australian organizations,6 government departments7,8 and Poisons Information Services9 have written guidelines that list these and other substances as part of an overall strategy, but there is considerable variability in recommended approaches. Although industrial cyanide poisoning is rare in the developed world10 (presumably because of good work practices), maintaining a supply of a cyanide antidote that might never be used is a signicant expense. Moreover, some of the recommended antidotes are themselves poisonous, which could make inappropriate use a greater risk than cyanide poisoning itself. No Australian or international authority has published a detailed evidence-based cyanide poisoning guideline resulting from a systematic review of the literature. In 1996, the Australian Resuscitation Council (ARC) published a Basic Life Support guideline for the management of cyanide toxicity11 that gave general rst-aid advice but no recommendation on a particular cyanide antidote. As part of its regular update of guidelines, the ARC conducted a systematic review of cyanide poisoning management. We aimed to answer the question in adult patients with conrmed severe cyanide poisoning (including cardiac arrest due to cyanide poisoning), does any intervention, as opposed to standard care, improve survival?. In addition, we sought literature reporting evidence from animal studies, the clinical features of cyanide poisoning and the indications for the administration of a cyanide antidote. 226

Methods
In November 2010, we performed a systematic literature review of English language publications indexed in MEDLINE, using the search terms (cyanides OR cyanogens OR nitriles OR azides OR cyanogenic glycosides OR nitriles OR azides) AND (antidote OR hydroxocobalamin OR sodium nitrite OR thiosulfate OR antidote OR cyanokit). In addition, we searched the Cochrane library by text word for cyanide, EMBASE for keywords cyanide poisoning AND (antidote OR hydroxocobalamin), Scopus using both backward and forward strategies, and Google Scholar for text words contained in unpublished documents. We excluded case reports of intoxications in which no conclusion could be drawn regarding the efcacy of an intervention. We manually inspected reference lists of all relevant articles. We classied identied studies using the Australian National Health and Medical Research Council Evidence Hierarchy,12 and made treatment recommendations according to ARC criteria.13 We also performed non-systematic literature reviews for relevant animal and cellular studies, for any consensus statements on the indications for the administration of a cyanide antidote and for reports of the clinical features of cyanide poisoning. In February 2011, we searched the Australian Register of Therapeutic Goods12 and online pharmaceutical catalogues in order to determine the Australian availability of the various described antidotes to cyanide.

Results
Clinical features of cyanide poisoning
Early features of cyanide poisoning are irritation of oral mucous membranes (if ingested), sympathetic activation leading to anxiety, tachycardia and/or arrhythmia, tachypnoea and hypertension, followed by headache, confusion, dyspnoea, hypotension and bradycardia.4,14 Later features (which can occur in rapid succession, depending on the dose) include neurological symptoms (reduced consciousness, seizure, opisthotonos or trismus), pulmonary oedema and cardiac arrest.4 The expired gas from a patient with cyanide poisoning is classically described as having a bitter almond smell, as do many cyanide-containing compounds. However, the diagnostic sensitivity of this characteristic is low, as 18% of men and 4% of women are unable to perceive

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Management of cyanide poisoning

this smell,15 a ratio that implies a sex-linked recessive trait. The other widely quoted feature of cyanide poisoning, bright-red (cherry) discolouration of the skin and mucous membranes, is based on the theory that decreased tissue oxygen utilization will increase oxyhaemoglobin in venous blood. However, this degree of cyanide toxicity is likely to cause circulatory failure, which would prevent such colouration.4 As oxidative phosphorylation is blocked, increased glycolysis leads to lactic acidosis, the degree of which correlates with the severity of the poisoning.16 Chronic cyanide poisoning (i.e. long-term exposure to sub-lethal concentrations of cyanide) can be more insidious, with headaches, weakness, chest and abdominal pain, itch and rash.17

mechanism of action is redistribution of cyanide from the intracellular to intravascular compartments,28,29 although this effect could not be detected in a clinical trial of 25 patients.30 Oxygen signicantly enhanced the antidotal effect of sodium nitrite and sodium thiosulphate (in combination) in rats, but hyperbaric oxygen was no more effective than normobaric 100% oxygen.31 On balance, although the mechanism remains unclear, it appears reasonable to treat victims of cyanide poisoning with 100% oxygen. Without studies comparing supportive care alone to the use of an antidote, no conclusion can be drawn other than that the potential adverse effects of any antidote must be weighed against the possibility that the patient might recover with supportive care alone.

Supportive therapy for cyanide poisoning

The majority of deaths due to exposure to high concentrations of cyanide are likely to occur before hospital arrival. Although prehospital administration of specic cyanide antidotes might possibly assist victims of cyanide poisoning, patients in cardiorespiratory arrest can undoubtedly benet from basic and advanced life support according to ARC guidelines.18 There is, however, a risk of cyanide toxicity to rescuers performing expired air resuscitation of cyanide-poisoned victims,19,20 and with the exception of victims of smoke inhalation (who are unlikely to have high levels of expired cyanide gas, as discussed below), mouth-tomoth ventilation should not be attempted. Several published case reports demonstrate that survival is possible after substantial cyanide poisoning treated with supportive care alone. For example, nine patients simultaneously poisoned in an industrial accident, with blood levels of cyanide considered lethal, had supportive therapy alone. All survived.21 Numerous other case reports2224 conrm this is possible. Supportive care in this context included the full spectrum of intensive care interventions, including mechanical ventilation, circulatory support and renal replacement therapy. Of note, only one patient in all of these reports suffered cardiac arrest, suggesting either supportive care instituted early was sufcient to prevent this, or that these patients had in fact not ingested a lethal amount of cyanide. One element of supportive care thought at times to be particularly benecial is oxygen administration. On the basis of animal experiments, oxygen,25 and also hyperbaric oxygen,26 have been advocated as adjuncts to chemical cyanide antidotes. Any benet appears not to be mediated by reactivation of cytochrome oxidase or acceleration of rhodenase detoxication.27 A postulated

Postulated cyanide antidotes

Four types of cyanide antidotes are described in the literature, grouped according to their modes of action. They are classied as: substances that increase the metabolism of cyanide (sodium thiosulphate, a ratelimiting substrate in the endogenous metabolic pathway for cyanide); substances that bind to cyanide (hydroxocobalamin [vitamin B12a] and dicobalt edetate); substances that produce methaemoglobin, which reacts with cyanide to form non-toxic cyanomethaemoglobin (sodium nitrite, amyl nitrite and 4-dimethylaminophenol [4-DMAP]); and substances that might possibly reduce the absorption of ingested cyanide (ferrous sulphate dissolved in aqueous citric acid and aqueous sodium carbonate: Solutions A and B). Only sodium thiosulphate, sodium nitrite and dicobalt edetate are listed on the Australian Register of Therapeutic Goods for the treatment of cyanide poisoning.32 Hydroxocobalamin is listed in the 1 mg/mL parenteral form used to treat pernicious anaemia and optic neuropathy, but not the 2.5 g form studied as a cyanide antidote. Hydroxocobalamin 2.5 g and amyl nitrite are available from Australian suppliers through the TGA Special Access Scheme.

Review of available cyanide antidotes: case series and pharmacodynamic and animal studies
Amyl nitrite

Nitrite-based cyanide antidotes oxidize haemoglobin to methaemoglobin, which complexes with cyanide to form non-toxic cyanomethaemoglobin. However, 2030% methaemoglobin is required to optimally bind cyanide,5 a level capable of signicantly impeding 227

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oxygen transport. Nitrites also typically cause vasodilation and hypotension.5 Amyl nitrite was the rst postulated cyanide antidote, in 1888.33 Its use is attractive for rst aid, as it is inhaled from a crushed capsule. However, it produces only about 7% methaemoglobin, which is probably insufcient to bind a lethal dose of cyanide.4 Amyl nitrite apparently reversed the cardiac and respiratory effects of cyanide in 24 of 30 dogs studied.34 These effects were observed before the generation of methaemoglobin, suggesting vasodilation and increased cardiac output as an alternative mechanism of action. Amyl nitrite treatment of cyanide-exposed mice resulted in a signicant increase in the number of survivors.35 Amyl nitrite increased the median lethal subcutaneous dose of sodium cyanide in dogs from 5.36 to 24.5 mg/kg.36 However, levels of methaemoglobin achieved in humans might be substantially less than in these experimental conditions,4 and a systematic review in 201037 found little evidence of efcacy from comparative studies, and no comparative studies in humans, but frequent reports of adverse reactions (such as hypotension, syncope, excessive methaemoglobinaemia causing hypoxia and haemolysis in patients with glucose-6phosphate deciency). As a drug of abuse,38 it must be appropriately secured to prevent theft. This review37 concluded that the use of amyl nitrite could not be justied.

to adverse effect has not been dened in humans.42 The dose recommended in the TGA-approved product information43 is 300 mg (in a typical adult, approximately 4 mg/kg, the same weight-adjusted dose as for children) at 75150 mg/min, with half the initial dose repeated at 30 min if required and with adjustment to maintain methaemoglobin levels 40%. Caution is particularly required in patients with smoke inhalation, as the methaemoglobin produced by such a dose of sodium nitrite, in combination with carboxyhaemoglobin, has been observed to precipitate ultimately fatal levels of nonoxygen-transporting haemoglobin.44 Similarly, the effect of methaemoglobin on oxygen transport will be magnied in anaemic patients.
4-Dimethylaminophenol

Sodium nitrite

4-Dimethylaminophenol produces a more rapid rise in methaemoglobin than sodium nitrite,4,45 and is a commonly used cyanide antidote in Germany.41,45 When 4-DMAP was given intravenously to dogs 1 min after poisoning with a lethal dose of potassium cyanide, all the animals survived.46 Eighteen case reports of the use of 4-DMAP have been summarized.4 In these 18 cases, there were seven deaths; 10 patients recovered, but one patient had ongoing CNS impairment. 4-DMAP can cause tissue necrosis or phlebitis at the site of injection, nephrotoxicity,45 and in 6 of the 18 case reports, substantial methaemoglobinaemia (up to 77%) was observed.4
Dicobalt edetate

The rst antidote strategy based on an understanding of biochemical mechanisms was described by Chen et al. in 1934,39 who suggested a combination of amyl nitrite, sodium nitrite and sodium thiosulphate based on results from animal studies. Sodium nitrite, at a minimum dose of 5 mg/kg, was shown to be an effective antidote for experimental cyanide poisoning in dogs, whereas 200 mg/kg was efcacious in rabbits.4 However, there is very little other animal or clinical evidence in support of this approach.5 Animal and human experiments evaluating sodium nitrite nd it produces higher methaemoglobin levels than amyl nitrite, but that this is accompanied by problematic hypotension.4 A study of 24 pigs poisoned with i.v. cyanide and subsequently treated with sodium thiosulphate and either hydroxocobalamin or sodium nitrite found no difference in mortality or biochemical parameters but faster normalization of blood pressure with hydroxocobalamin.40 Intravenous sodium nitrite can cause severe hypotension, cardiovascular instability and hypoxia in a dosedependent manner,5,41 although the relationship of dose 228

Cobalt compounds were rst advocated as cyanide antidotes in 1894.4 The cobalt atom in dicobalt edetate binds to cyanide. Until withdrawing all advice on cyanide antidotes in 1996,47 dicobalt edetate (along with amyl nitrite) was the antidote recommended by the UK government.47 Dicobalt edetate has only been comparatively evaluated in animal studies. In the 1950s and 1960s, Paulet published results of an extensive series of animal experiments investigating various cobalt compounds,4 and subsequently reported that dicobalt edetate was more effective than a combination of sodium nitrite and thiosulphate.48 Comparisons in dogs found dicobalt edetate effective, but inferior to 4-DMAP.46,49 Dicobalt edetate has been used in numerous human cases in which patients survived.4 The utility of dicobalt edetate is limited by its serious adverse effects, which include vomiting, urticaria, anaphylactic shock, hypotension and ventricular arrhythmias.50,51 These harmful effects might be more common and severe in the absence of

2012 The Authors EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

Management of cyanide poisoning

cyanide.4 There is evidence from animal experiments that glucose protects against cobalt toxicity, and it is recommended that this be simultaneously administered. Because of its toxicity, the TGA-approved product information mandates dicobalt edetate only be used in cases of conrmed cyanide poisoning when a patient has lost consciousness.52
Sodium thiosulphate

and practice, which made withdrawal of the antidote difcult to achieve. Solutions A and B are no longer recommended as a practical antidote.64
Hydroxocobalamin (vitamin B12a)

Physiological levels of cyanide are metabolized to thiocyanate by the enzyme rhodanese, which requires thiosulphate as a substrate. The bodys reserve of thiosulphate is limited,4,53 suggesting supplementation might be benecial in cyanide poisoning. However, rhodanese is located within mitochondria, and thiosulphate penetrates cell and mitochondrial membranes poorly.4 This might explain why sodium thiosulphate appears to act more slowly than other antidotes.5,54 Studies in rabbits55 and dogs56 found sodium thiosulphate was an effective antidote to cyanide produced by high levels of sodium nitroprusside. By augmenting the endogenous capacity to metabolize cyanide, sodium thiosulphate treats cyanide poisoning by a different mechanism, implying its effect could be additive to that of other antidotes. Most published animal studies4,57,58 have used sodium thiosulphate in combination with other antidotes. However, there is evidence that thiosulphate alone is effective,59 particularly in the context of sodium nitroprusside administration.56,60 In a pharmacodynamic study, the use of sodium nitroprusside at 5 mg/ kg/min for 10 h, 10 mg/kg/min for 4 h or 20 mg/kg/min for 1.5 h caused potentially toxic levels of cyanide,61 and this was prevented by sodium thiosulphate. For this reason, sodium thiosulphate has been recommended as prophylaxis against cyanide toxicity when nitroprusside is required at high doses.4 Sodium thiosulphate can cause local skin and muscle pain at the infusion site,62 nausea, vomiting, headache and disorientation,45 but life-threatening adverse effects have not been reported.4
Solutions A and B

Hydroxocobalamin was rst reported to be a promising cyanide antidote in experimental cyanide poisoning in mice in 1952.65 Hydroxocobalamin prevented metabolic acidosis and reduced blood cyanide concentrations in baboons infused with a high rate of sodium nitroprusside.66 Similar results were found in humans.67 Hydroxocobalamin also safely reduced the low blood cyanide concentrations found in heavy smokers.62 No signicant toxic effects of hydroxocobalamin have been reported in animal studies or humans.4 Minor reported adverse effects include transient hypertension and bradycardia,62 red-orange urine discolouration, transient headache and mild allergic reactions that were readily treated.68 Serum pigmentation caused by hydroxocobalamin interferes with photometric biochemical assays, such as measurements of carboxyhaemoglobin (particularly relevant in the differential diagnosis of the effects of smoke inhalation) and methaemoglobin,69 lactate, and many other commonly measured haematological and biochemical indices.70 Ideally, and especially if the diagnosis is unclear, blood should be taken for analysis before hydroxocobalamin is administered. A further problem caused by hydroxocobalamins pigment is false triggering of the sensor that detects blood leakage across the articial kidney membrane during dialysis. This problem has been circumvented by recalibrating this sensor using a continuous renal replacement machine.71

Systematic review of studies reporting use of cyanide antidotes in humans

The results of the systematic review are shown in Figure 1. There have been no comparative or placebocontrolled human trials evaluating treatment strategies for severe cyanide poisoning. Table 1 summarizes the nine relevant studies identied. All are small uncontrolled case series (National Health and Medical Research Council level IV). None provides denitive evidence of the superiority of one approach over another, or over supportive care alone. Meaningful comparisons of survival rates are impossible, as the severity of many of the poisonings is not described. Seven of the nine case series described, totalling reports of 361 patients (mostly smoke exposure victims), report treatment with 229

Solutions A and B (ferrous sulphate in aqueous citric acid and aqueous sodium carbonate) had previously been recommended as an oral antidote to cyanide ingestion. When reviewed in 1988,63 only very limited, unpublished animal evidence was found. If effective at all, it is likely that solutions A and B have to be given within seconds of cyanide ingestion. The review authors noted that the main basis for recommendations was custom

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Figure 1.

Results of the systematic search for relevant literature.

hydroxocobalamin. In two papers,73,78 this was in combination with sodium thiosulphate. Three of the nine case series,36,74,79 reporting 74 patients, describe treatment with amyl nitrite, sodium nitrite and sodium thiosulphate in combination. One report74 describes four patients treated with each approach, in which all eight patients survived. The most important conclusion that can be drawn with any certainty from this systematic review is that it is possible to survive cardiorespiratory arrest due to cyanide poisoning if given an antidote: of 136 reported patients in cardiac arrest, 16 (11.8%) survived to hospital discharge. Interestingly, the rate of initial response was much higher: 50 out of 97 patients (51.5%) had transient return of spontaneous circulation.

Indications for the use of a cyanide antidote

Cardiorespiratory collapse, combined with either a high blood cyanide level or obvious evidence of cyanide poisoning, is a clear indication for use of an antidote. Under these circumstances, the use of antidotes with even 230

narrow therapeutic indices would appear reasonable. However, the indication for use of a cyanide antidote is less clear when smaller quantities are ingested, in patients without cardiorespiratory collapse, or where the diagnosis is unclear. Under these circumstances, it is logical to avoid the more toxic antidotes, and this is reected in the TGA-approved product information for dicobalt edetate.52 Unlike other strategies, hydroxocobalamin and sodium thiosulphate have few adverse effects, justifying their use in lesser degrees of cyanide poisoning as well as in the prophylaxis of possible cyanide toxicity due to high-rate sodium nitroprusside. The most problematic possible indication for use of a cyanide antidote is with smoke inhalation, the commonest cause of cyanide exposure. Such patients often present with metabolic acidosis, but this is more likely to be caused by under-resuscitation, carbon monoxide poisoning or missed traumatic injury than by cyanide poisoning.5 Cyanide exposure during house res was measured in samples obtained from devices on reghters coats.80 Only 27 of 253 samples contained hydrogen cyanide, with a maximum concentration (3.6 p.p.m.) well

2012 The Authors EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

Table 1.
Interventions Results Relevant conclusion Study quality Fair

Summary of studies identied

Reference

Study design

Patients studied

Borron et al.72 Hydroxocobalamin 5 g repeated up to 15 g at the discretion of the treating physician Hydroxocobalamin appears safe to use in the prehospital context. No information on efcacy can be inferred.

Prospective case series

69 patients with altered consciousness due to suspected cyanide poisoning after smoke inhalation who survived to hospital admission

Borron et al.73 Hydroxocobalamin 520 g, with a mixture of prehospital and hospital administration. Some patients received sodium thiosulphate (5/14) or dicobalt edetate (1/14)

Retrospective case series

14 patients admitted to ICU with non-smoke-related cyanide poisoning (12/14 ingested; 1/14 inhaled cyanide gas, 1/14 unknown) for whom hydroxocobalamin was used as rst-line treatment

2/15 who had a cardiorespiratory arrest at the scene survived to hospital discharge. 28/42 patients with conrmed cyanide poisoning (cyanide levels 39 mmol/L) treated with hydroxocobalamin survived. 19/69 patients treated with hydroxocobalamin had benign adverse effects (including chromaturia, skin discolouration, erythema and hypertension). No allergic reactions were reported. 10/14 patients survived to discharge. 7/11 with a typically lethal (>100 mmol/L) level of cyanide survived. The most common hydroxocobalamin-attributed adverse events were chromaturia and pink skin discoloration. Poor

Chen et al.36

Retrospective case series

Amyl nitrite sodium nitrite thiosulphate

Case series only, with most patients surviving.

It is possible to survive cardiorespiratory arrest due to cyanide poisoning when hydroxocobalamin is used. Hydroxocobalamin appears safe and might be effective. The rate of survival was higher than expected with only supportive care, but whether this was due to hydroxocobalamin, the other antidotes used, selection bias in that patients had to survive until ICU admission to be included, or chance, is unclear. Note this is the single clinical paper before 1995 that supported the widespread use of nitrites.

Poor

Espinoza et al.74 Due to a shortage of antidote, 4 received hydroxocobalamin and 4 sodium nitrite and thiosulphate

Retrospective case series

All 8 children survived to hospital discharge, neurologically intact.

Fair

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Hydroxocobalamin 5 g for adults and 70 mg/kg for children, with the option to administer a second dose for incomplete response 30 patients survived, 42 died (17 at the re scene) and outcome was unknown in 29. Of 38 patients found in cardiac arrest, 21 had return of spontaneous circulation during prehospital care, but 19/21 died during hospitalization. Two adverse events red or pink coloration of urine or skin (n = 5) and cutaneous rash (n = 1) were assessed as being possibly related to hydroxocobalamin. Hydroxocobalamin might be equally as effective as sodium nitrite + sodium thiosulphate, although the contribution of indication bias to outcome is unclear. Hydroxocobalamin appears safe to use in the prehospital context. Given the 29 patients with unknown outcomes, survival after an unquantied degree of cyanide intoxication and in the context of other injuries (e.g. burns in at least 53%) when treated with hydroxocobalamin could be as low as 30% or as high as 58%. It is possible to survive cardiorespiratory arrest due to cyanide poisoning when hydroxocobalamin is used, but immediate return of circulation is often followed by delayed death. Poor

Fortin et al.75

Retrospective case series

49 patients with cyanide poisoning of various types. No quantication of cyanide levels was made 8 children with cyanide poisoning due to bitter cassava ingestion, all with hypotension, bradycardia and respiratory failure 101 patients administered hydroxocobalamin for suspected cyanide poisoning after smoke inhalation

Management of cyanide poisoning

231

232
Interventions Results Relevant conclusion Study quality Fair Hydroxocobalamin 2.55 g (less in children) with the option to administer a second dose for incomplete response 135/161 patients had a cardiac complication (61/161 cardiac arrest, 57/161 rhythm disorder, 12/161 repolarization disorder, 5/161 conduction disorder). The abstract states higher doses of the antidote seem to be associated with a superior outcome in patients with initial cardiac arrest, but this is based on simple univariate analysis; there is no quantitative multivariable analysis in the paper to support this statement. 5/59 pts found in cardiac arrest survived to hospital discharge (30 died at the scene and a further 24 died in hospital). It is possible to survive cardiorespiratory arrest due to cyanide poisoning when hydroxocobalamin is used. Hydroxocobalamin rapidly and effectively removes cyanide from the circulation. No comment can be made regarding patient outcome benet, or the comparative efcacy of other agents. Fair Hydroxocobalamin appears safe. Higher doses might possibly be associated with less severe cardiac complications of cyanide poisoning, but only indirect and questionable information on efcacy can be inferred from these data. Hydroxocobalamin 5 g given within 30 min of exposure, with blood sampled for cyanide before and after cyanocobalamin treatment Serum cyanocobalamin levels after administration of hydroxocobalamin correlated closely with pretreatment serum cyanide levels up to 40 mmol/L serum cyanide. In one patient with initial blood cyanide concentration of 96 mmol/L, plasma cyanocobalamin concentration doubled after a second 5 g dose of hydroxocobalamin. This suggests 5 g hydroxocobalamin can bind all available cyanide ions for blood cyanide concentrations up to about 40 mmol/L. Beyond this, more hydroxocobalamin must be given. 7/24 patients with initial cardiorespiratory arrest survived. Other clinical features of cyanide poisoning are described. The clinical features of cyanide poisoning are described. 16 patients presented with severe symptoms, 8 survived. All of the 8 survivors presenting with severe symptoms received the Lilly Cyanide Antidote Kit, including 4/8 with severe metabolic acidosis, coma, and respiratory failure. 8/16 severely affected patients died, of whom 6 received the antidote and 2 did not. The effect of the antidote on mortality was not signicant. It is possible to survive cardiorespiratory arrest due to cyanide poisoning. Poor A variety of antidotes, including hydroxocobalamin, dicobalt edetate and sodium thiosulphate; also supportive treatment with mechanical ventilation alone 16/21 patients received Lilly Cyanide Antidote Kit, containing amyl nitrite for inhalation and 3% sodium nitrite and 25% sodium thiosulphate solutions No information on the efcacy or safety of amyl nitrite, sodium nitrite and sodium thiosulphate can be inferred. There is insufcient detail about the severity of the cyanide poisoning prevented any assessment of the treatment for acute cyanide poisoning. Poor

Table 1.

(Continued)

MC Reade et al.

Reference

Study design

Patients studied

Fortin et al.76

Retrospective case series

161 re survivors with suspected or conrmed cyanide poisoning

Houeto et al.77

Prospective case series

12 patients treated with hydroxocobalamin for suspected cyanide poisoning due to smoke inhalation

Pontal et al.78

Retrospective case series

24 dissimilar cases of non-fatal cyanide poisoning

Yen et al.79

Retrospective case series

21 patients with conrmed or suspected cyanide poisoning (20 with oral ingestion, 1 with inhalational exposure)

2012 The Authors EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

All studies identied are National Health and Medical Research Council class IV evidence.12 The quality of each study has also been assessed as good, fair or poor on the Australian Resuscitation Council scale13 (good the methodological quality of the study is high with the likelihood of any signicant bias being minimal; fair the methodological quality of the study is reasonable with the potential for signicant bias being likely; poor the methodological quality of the study is weak possessing considerable and signicant biases).

Management of cyanide poisoning

Table 2. Antidote

Cost (in February 2011) and shelf life of various cyanide antidotes Cost A$2838 for 2 2.5 g NB. A 1 mg ampoule Pharmaceutical Benets Scheme subsidized for the treatment of pernicious anaemia is A$15.8743 A$696.9243 for 20 mL 1.5% A$787.5043 for 10 300 mg in 10 mL or A$2 631.5843 for 5 300 mg in 10 mL A$203.5084 for 50 mL 25% A$174.2484 for 6 0.6 mL Not marketed in Australia
84

Shelf life 3 years4,41

Hydroxocobalamin

Dicobalt edetate Sodium nitrite Sodium thiosulphate Amyl nitrite 4-Dimethylaminophenol

3 years4,41 5 years4,41 5 years41 6 months85 to 2 years4 3 years4

below the recommended short-term exposure limit (15 p.p.m.). Conversely, 11 of 138 patients with rerelated deaths in Victoria, Australia had potentially fatal blood cyanide levels.81 Blood cyanide levels might be impossible to obtain before a treatment decision is required, necessitating clinical judgment. Although there are no immediately available denitive laboratory tests for cyanide toxicity, a number of indices are highly suggestive. Smoke inhalation patients with a carboxyhaemoglobin level >10% are particularly likely to have inhaled a dangerous quantity of cyanide.81 In the context of smoke inhalation without severe burns, a plasma lactate >10 mmol/L had a sensitivity of 87% and specicity of 94% for clinically signicant cyanide poisoning.82 An increase in the central venous partial pressure of oxygen and per cent oxygen saturation measured by blood gas analysers, such that these approach measured arterial values, has also been described.83 In one study, 42 of 69 patients with smoke inhalation and neurological impairment had poisonous blood levels of cyanide. All 69 were treated with hydroxocobalamin, and 28 of the 42 with cyanide poisoning survived.72 Although there is insufcient evidence to recommend routine use of a cyanide antidote in patients with possible cyanide poisoning caused by smoke inhalation, the presence of neurological impairment or elevated carboxyhaemoglobin or lactate levels at least suggests one of the low-risk antidotes should be considered after other more likely causes such as carbon monoxide poisoning have been appropriately managed.

never used. If a workplace chooses to keep a cyanide antidote in its cyanide emergency kit, the cost will also be determined by the shelf life, which is also shown. Analysing acquisition costs alone and assuming recommended doses, dicobalt edetate is 2.8 times, hydroxocobalamin is 11.2 times, and sodium thiosulphate 0.8 times the cost of amyl + sodium nitrite.

Prehospital availability and use of cyanide antidotes

The majority of patients reported in papers identied in the systematic review were treated with cyanide antidotes before arrival in hospital. It would seem intuitively obvious that earlier antidote administration will lead to better outcomes. This might not be true in cases of equivocal diagnosis if using antidotes that are themselves toxic, but as noted above, hydroxocobalamin and sodium thiosulphate appear sufciently safe. However, the community incidence of cyanide poisoning (ignoring the possibly much larger number of exposures due to smoke inhalation) is low: for example, only 257 of 2.8 million exposures to poisons reported to US poison control centres in 2004 were due to cyanide.86 Given their cost, this argues against universally equipping prehospital emergency medical services with cyanide antidotes. However, workplaces with a particular risk of cyanide exposure and perhaps hospitals serving a high concentration of industries in which cyanide is used are logical places to stock this resource. No rm conclusion can be drawn from the literature as to whether emergency medical services should stock cyanide antidotes for use in victims of smoke inhalation. If transport times to hospitals specializing in burns care are short, only stocking cyanide antidotes in such centres would seem a reasonable approach. 233

Cost and stability in storage

Representative retail costs of the various cyanide antidotes are listed in Table 2. Because of the infrequency of cyanide poisoning, most cyanide antidote vials are

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Recommendations
The ARC recommends that the contents of an industrial workplace cyanide emergency kit should be determined by a qualied occupational health assessor, taking into account the nature of the cyanide threat, the training of workplace rst aiders and the proximity of external assistance (Appendix S1). Possible inclusions are: Equipment for articial respiration, including oropharyngeal airways, laryngeal mask airways, equipment for endotracheal intubation, a self-inating bag-valvemask apparatus and a supply of medical oxygen sufcient to provide 100% inspired oxygen to the victim A tourniquet, i.v. cannulae, syringes and needles A cyanide antidote The sparse published human efcacy and safety evidence that exists supports the use of hydroxocobalamin with or without sodium thiosulphate, or sodium thiosulphate alone, for conrmed or suspected cyanide poisoning. The onset of action of sodium thiosulphate appears slower than that of hydroxocobalamin. The ARC therefore recommends that adult patients with suspected severe cyanide poisoning (including those in cardiac arrest) should receive immediate parenteral hydroxocobalamin, 5 g over 15 min with repeat dosing up to 15 g. Paediatric doses should be adjusted according to weight: 70 mg/kg over 15 min, repeated twice if necessary.87 This is a considerably larger dose than contained in parenteral vitamin B12a preparations designed for other indications. The ARC therefore recommends that a workplace cyanide emergency kit contains at least 2 2.5 g ampoules of hydroxocobalamin (marketed as Cyanokit84), if an antidote is to be stocked. However, in February 2011, Cyanokit was not included on the Australian Register of Therapeutic Goods, with the supply of this product requiring an application through the TGA Special Access Scheme. Ambulance services and hospital EDs might not stock cyanide antidotes. Therefore, even if a workplace has no personnel qualied to administer a cyanide antidote, a cyanide emergency kit containing an antidote is still recommended if the assessed risk of cyanide exposure is sufciently high. The cyanide emergency kit should accompany the patient for use when sufciently qualied personnel become available. The ARC recommends that it is reasonable to treat inhalational burn patients with neurological impairment or carboxyhaemoglobin >10% or plasma lactate >10 mmol/L with hydroxocobalamin, once other possible causes of metabolic acidosis have been addressed. Although there is no human evidence demonstrating harm, physiological 234

principles suggest that antidotes that produce methaemoglobin, such as the nitrites, are contraindicated in cyanide poisoning due to smoke inhalation because of the likely presence of signicant amounts of carboxyhaemoglobin. The ARC also recommends that sodium thiosulphate be considered as an adjunct to the treatment of severe cyanide toxicity, but that this treatment should generally be considered following failure to respond adequately to hydroxocobalamin. The exception to this recommendation is sodium nitroprusside toxicity, in which sodium thiosulphate has been successfully used as a sole agent. The approved adult dose is 12.5 g (50 mL of a 25% solution) administered intravenously at 1.25 g/min (5 mL/min), with the higher recommended paediatric dose of 412.5 mg/kg at 0.6251.25 g/ min to a maximum of 12.5 g.43 If signs of cyanide toxicity are still present 30 min to 2 h after administration, half the original dose may be repeated. Sodium thiosulphate is chemically incompatible with hydroxocobalamin, and so must be administered through a separate i.v. line. The ARC notes evidence of the efcacy of sodium nitrite and sodium thiosulphate in combination. In the absence of comparative studies, the known adverse effects of sodium nitrite suggest this might be an inferior approach to use of hydroxocobalamin; however, nancial cost-effectiveness may justify this approach. The approved adult dose of sodium nitrite (in combination with sodium thiosulphate) is 300 mg over 24 min, with half this dose repeated after 30 min if required. Recommended paediatric dosing is 4 mg/kg (although up to 10 mg/kg is listed as acceptable) at 75150 mg/min to a maximum of 300 mg, with half the initial dose repeated at 30 min if required. In anaemic children less than 25 kg, the dose of sodium nitrite must be reduced according to the table provided in the product information. In all cases, methaemoglobin must be monitored and kept below 40% by dose adjustment if required.88 The ARC recommends that prehospital emergency medical services and hospitals assess their likelihood of having to treat a victim of cyanide poisoning, and the possible availability of the recommended cyanide antidotes from external sources, when deciding on the selection and quantity of cyanide antidote they should stock. Our recommendations regarding choice of cyanide antidote accord with the conclusion of a similar recent systematic review.89 The ARC categorizes13 the treatment recommendations made above as Class B: accept-

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able. Class B treatment recommendations are given to those guidelines that might be benecial and are acceptable to be used if considered appropriate in the relevant setting. These recommendations are summarised in Appendix S1.

Competing interests
None declared. Accepted 6 January 2012

Conclusion
In the absence of comparative human trial data, treating clinicians and those that make occupational health risk assessments must combine animal studies, case reports and an understanding of pharmacology with clinical judgment. Although the published evidence favours the use of hydroxocobalamin sodium thiosulphate for cyanide poisoning, it is also true that no evidence demonstrates other strategies (including supportive care alone) might not be more effective in particular circumstances. A randomized controlled clinical trial might provide better guidance, but the low number of cyanide poisonings and the probable lack of equipoise make such a trial unlikely. One option is to make no recommendation for other than supportive care, as in the UK.47 The ARC, noting the reported frequency of enquiries into this topic9,47 and also the geographical remoteness from high-level intensive care of many Australian industries and Australian Defence Force establishments, has chosen instead to make recommendations based on the evidence available. In so doing, we trust these recommendations will be applied to the relevant circumstances by competent practitioners.

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Lieutenant Colonel Reade represents the Australian Defence Force on the ARC. The support of the Australian Defence Force and the contribution of Group Captain David Scott BMed FANZCA RAAF to the preparation of this guideline are gratefully acknowledged.

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Author contributions
MCR designed the research question, interpreted the results of the systematic review, and wrote and revised the manuscript. SRD performed the systematic review and summarized its conclusions. PTM, JD and ICJ chaired the ARC discussion of the systematic review and critically revised the manuscript.

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Supporting Information
Additional Supporting Information may be found in the online version of this article: Appendix S1. Management of a patient with suspected cyanide poisoning.

Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

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