Antidotes in the management of poisoned patients: What have we gained over the last decade?

Abstract

Poisoning remains an extremely common medical issue worldwide, with just over 71 000 poisoning-related admissions to hospitals in England in the 2023/24 financial year¹ and a global age-standardized death rate from poisoning of 0.7 per 100 000 people in 2021.² The management of poisoning frequently involves decontamination (to reduce absorption/exposure to the poison), close observation to identify clinical deterioration and, where appropriate, consideration of antidote therapy to attenuate the effects of the poison. As a result, antidotes remain commonly used in the emergency management of the poisoned patient. The Toxicology Investigators Consortium (ToxIC) reported that 41% of 7392 poisoned patients who had a bedside consult by a medical toxicologist in the United States in 2023 were treated with one or more antidotes; the most commonly used antidotes (defined as being administered to more than 10% of patients) were thiamine, folate, acetylcysteine and naloxone.³

In 2016, the British Journal of Clinical Pharmacology published a themed issue reviewing the evidence for the use of various antidotes in gut decontamination, the management of specific poison-related clinical complications (e.g., ECG QT prolongation, seizures), the use of specific antidotes (e.g., flumazenil, naloxone, acetylcysteine) and the management of specific drug-related poisonings (such as poisonings involving calcium channel blockers, beta-blockers, organophosphates, digoxin, insulin, sulfonylureas and toxic alcohols). The themed issue included two accompanying editorials discussing the challenges around the use of antidotes and the limited evidence for their effectiveness and safety.^{4, 5} It was noted that ‘there are dozens of antidotes used for hundreds of potential toxins, but only a few are used regularly’, and also that the most commonly-used antidotes included ‘activated charcoal, acetylcysteine, naloxone, sodium bicarbonate, atropine, flumazenil, therapeutic antibodies and various vitamins’.⁴ Based on the challenges and lack of evidence, clinicians should seek input of specialized toxicological advice from poisons centres and information services when using antidotes, particularly those that are rarely used or that the clinician is unfamiliar with.⁴

Since the 2016 British Journal of Clinical Pharmacology antidote-themed issue, there have been changes, as summarized in the review by Gosselin et al., in how toxicologists view the role of gut decontamination in the management of poisoned patients.⁶ Additionally, several new drugs and drug classes have been developed and licensed for therapeutic use. As these become more widely used, there is an increased risk of accidental or intentional poisoning from them. In some instances, novel antidotes have been developed to manage the unwanted clinical effects from both therapeutic use and overdose of these drugs. Examples include idarucizumab for dabigatran toxicity in 2015 and andexanet-alpha for apixaban and rivaroxaban toxicity in 2018. The review by Bekka and Liakoni in this themed issue highlights the lack of robust evidence that these novel antidotes are superior to standard treatments for managing anticoagulant toxicity and that their high cost as novel drugs may limit their widespread use.⁷ There have also been additional novel antidotes that have been approved for long-standing medicinal drugs where antidotes have not been available, such as the approval of uridine triacetate for 5-fluorouracil toxicity overdose and severe toxicity in 2015 and glucarpidase for methotrexate toxicity in 2022. Whilst there is evidence that uridine triacetate improves survival in those with fluoropyrimidine and capecitabine severe toxicity and overdose, there is no evidence that it is beneficial in poisoning involving tegafur, an oral 5-FU prodrug.⁸ The review by Chan et al. reports that glucarpidase rapidly metabolizes methotrexate and therefore methotrexate intrathecal and blood concentrations rapidly fall.⁹ However, the usefulness of glucarpidase as an antidote in the more commonly seen high-dose therapeutic methotrexate toxicity remains unclear. The repurposing of existing drugs as antidotes on the basis of mechanistic rationale, for example, the use of L-carnitine and carbapenem antibiotics for valproic acid toxicity, is also discussed.^{10, 11} Finally, since the last themed issue, there have been more published data on the use of antidotes that have been available for longer, including 5-HT_2A antagonists such as cyproheptadine, chlorpromazine and olanzapine for serotonin toxicity and fomepizole for toxic alcohol ingestion, which have been reviewed in this themed issue.^{12, 13}

There remains an increasing interest in the use of antidotes in the management of poisoned patients. Some countries have developed guidance on what antidotes should be stocked and how rapidly they should be available to clinicians managing a poisoned patient.¹⁴ However, there are ongoing controversies regarding the appropriate dose and route of administration of some antidotes. Additionally, whilst an antidote may have a plausible mechanism of action in relation to a specific poison or toxin, for most antidotes it remains unclear whether they favourably influence clinical outcomes. There is a clear unmet need for well-designed clinical studies that address the evidence gap in antidote utility. Finally, cost may be a limiting factor for some antidotes, particularly newer ones, and this is particularly pertinent in resource-poor areas of the world. Therefore, as Chiew and colleagues conclude in their review in this themed issue, ‘the cornerstone of treating severe cases does not lie in ‘antidote’ administration or even diagnosis but in effective early resuscitative and supportive care’.¹² Perhaps, a decade hence, further evidence generated by clinical toxicologists, emergency physicians, intensivists and others managing poisoned patients will enable us to provide more robust evidence on the appropriate use of antidotes.