TR 121 – Efficacy and safety of antidotes for acute poisoning by cyanides

TR 121 : Efficacy and safety of antidotes for acute poisoning by cyanides | 19 November 2013

SCIENCE NEWS FLASH: New ECETOC report offers guidance on

the efficacy and safety of antidotes for acute poisoning by cyanides

Brussels, November 2013

When it happens, cyanide poisoning can have very serious neurological consequences that may result in severe disability and death. Cyanide poisoning may occur after swallowing of, inhalation of, or skin contact with hydrocyanic acid, cyanide salts, or cyanide forming compounds (cyanogens, e.g. nitriles or amygdalin), or from smoke inhalation. So far, there has been no recognised consensus on when to apply the various antidotes being used across the world.

This report, therefore, reviews the efficacy, efficiency, safety, and practicality of the various antidote regimes used under different poisoning circumstances. The review was based on an extensive literature survey and analysis and statistical evaluation of more than 400 published and unpublished cases of poisoning by cyanides. The report concludes that certain antidotes (sodium thiosulphate, amyl nitrite and hydroxocobalamin), when administered alone, counteract moderate to severe poisoning. The combination of sodium nitrite and sodium thiosulphate, with or without amyl nitrite, also was effective in severe poisonings. Dimethylaminophenol and sodium thiosulphate are at least peffective in moderate poisonings, probably (few actual cases) also in severe cases. Because of significant side effects di-cobalt-EDTA is not recommended. Oxygen is not regarded as an antidote, but is an important supportive treatment. The final choice of antidote additionally depends on thepracticality, e.g. cold storage requirement in a tropical country, or high price in developingcountries. Recommendations are also given for the treatment of poisoned children, or mass poisonings and for use by first aiders, e.g. in industry.

Summary and conclusions

Cyanide poisoning is a very serious, albeit rare, event with possible neurological sequelae that may result in severe disability, and death. It can occur after exposure by ingestion, inhalation and dermal absorption of hydrocyanic acid, cyanide salts, or cyanogenic compounds such as acetone cyanohydrin, nitriles, biological substances like cassava or amygdalin (Vitamin B17), or sodium nitroprusside (SNP) (used as a medication for hypertension). Fire smoke inhalation may also cause cyanide poisoning under certain conditions of combustion.

Despite the 1993 overview on 'Antidotes of Poisoning by Cyanide' (IPCS/CEC Evaluation of Antidotes Series) and the review of commonly used cyanide antidotes in the 2007 ECETOC Report in the JACC (Joint Assessment of Commodity Chemicals) series 'Cyanides of Hydrogen, Sodium and Potassium, and Acetone Cyanohydrin' there has been no recognised consensus on the relative efficacy, efficiency, safety, and practicality of the various antidote treatments being used across the world. This situation although undesirable was sustained by the absence of any comprehensive review which was in turn due to the complexity of the clinical picture, since cyanide antidotes are employed in different circumstances of poisoning. In order to address this situation ECETOC established a new Task Force to review the available evidence on the efficacy, efficiency, safety, and practicality of antidote regimes under the different poisoning circumstances in which they were used. The four circumstances considered were direct poisonings with hydrocyanic acid or its salts, poisoning with cyanogenic compounds (above), fire smoke inhalation, and poisoning with initially unknown substances.

The Task Force reviewed the available literature until mid-2010 and collected further cases with a questionnaire from industry and Poison Control Centres. The Poisoning Severity Score (PSS), a well-est ablished score system addressing all organ systems for grading of poisoning severity, was adjusted slightly to meet the specifics of cyanide poisoning (PSSa - 'a' denotes adapted).

The reported cases were then evaluated for antidote use. In the majority of cases single antidotes were given although in some combinations of antidotes were used. Cases were split into treatment groups based on the sequence in which different antidotes were administered, if more than one antidote was given. For each such sequence the efficacy based on the PSSa and the safety of the respective antidote or antidote combinations were described. This sequential view allowed in many cases for a statistical analysis of efficacy which was included in the single antidote assessments together with pharmaceutical data, pharmacokinetic data, safety/side effects, practicality, an overview of reported cases and case series. Single casuistic case reports shortly described in tables were collected in an appendix as summaries to make the antidote chapters more readable. An overall assessment was made for each antidote.

Pre-clinical antidotes were addressed based on data from animal experiments. In particular alpha-ketoglutarate and cobinamide, and to a lesser extent, dihydroxyacetone and pyruvate (pro-drugs) seem to have promising potential as cyanide antidotes.

It was apparent that although all direct acting antidotes (excluding sodium thiosulphate) may reverse cardiac arrest or at least facilitate resuscitation, they cannot prevent neurological sequelae due to hypoxia in all cases.

Sodium thiosulphate appears to act more rapidly than previously thought, but is effective, when administered alone, only in moderate poisoning (PSSa 2). Amyl nitrite, when administered alone, was found to be effective in moderate to severe poisonings (PSSa 2.5). Hydroxocobalamin, when administered alone, was found to be effective in severe poisonings (PSSa 3). The combinations of sodium nitrite and sodium thiosulphate, with or without amyl nitrite (PSSa 3), and of dimethylaminophenol and sodium thiosulphate (PSSa 2) were also found to be at least partially effective. These methaemoglobin forming agents all require combination with sodium thiosulphate to capture cyanide released during physiological methaemoglobin reduction. Dicobalt edetate has rarely been given, so that no comprehensive evaluation was possible. In any case, the intrinsic toxicity of dicobalt edetate significantly reduces its applicability. In regard of its effectiveness and low toxicity sodium thiosulphate can be given after all direct acting antidotes in situations when a delayed formation of cyanides cannot be excluded.

Oxygen, in contrast to the other antidotes discussed, has no effect on cyanide toxicokinetics, and is therefore not regarded as an antidote in its own right. Oxygen was only partially effective in severe poisonings (PSSa 3), and other antidotes were fully effective without oxygen. The administration of normobaric oxygen in combination with other antidotes to cyanide is very effective and possibly at least additive. It is however recommended that in conditions where oxygen is not available, treatment with antidotes to cyanide should not be delayed.

For the different circumstances of cyanide poisoning mechanism of cyanide formation, course,case series, case tables and an overview of antidote uses in the respective conditions wereaddressed, before recommending (a) specific antidote(s) for the condition. These recommendations could not only deal with efficacy and safety, but had also to account forpracticility, e.g. cold storage requirement in a tropical country, or high price in developingcountries. These combined aspects prompted recommendations for different situations/circumstances and severities shown in the following table.

Table 1: Antidotes ^a recommended for acute poisoning by cyanides

^a STS, sodium thiosulphate; HOCO, hydroxocobalamin; AN, amyl nitrite; SN, sodium nitrite; DMAP, dimethylaminophenol; i.m., intramuscular (injection).

^b HCN, hydrogen cyanide; SNP, sodium nitroprusside; CO, carbon monoxide.