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Therapeutics in clinical toxicology: in the absence of strong evidence how do we choose between antidotes, supportive care and masterful inactivity

2016; Wiley; Volume: 81; Issue: 3 Linguagem: Inglês

10.1111/bcp.12819

1365-2125

Geoffrey K. Isbister, Nicholas A. Buckley,

Healthcare Decision-Making and Restraints

British Journal of Clinical PharmacologyVolume 81, Issue 3 p. 408-411 Editors' ViewFree Access Therapeutics in clinical toxicology: in the absence of strong evidence how do we choose between antidotes, supportive care and masterful inactivity Geoffrey K. Isbister, Corresponding Author Geoffrey K. Isbister Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales NSW Poisons Information Centre, The Childrens Hospital Westmead, Sydney, New South Wales CorrespondenceProfessor Geoffrey K. Isbister, School of Medicine and Public Health, University of Newcastle, c/o Calvary Mater Newcastle, Edith Street, Waratah NSW 2298, Australia.Tel.: +61 (2) 4921 1211Fax: +61 (2) 4014 4933 E-mail: geoff.isbister@gmail.comSearch for more papers by this authorNicholas A. Buckley, Nicholas A. Buckley NSW Poisons Information Centre, The Childrens Hospital Westmead, Sydney, New South Wales Sydney Medical School, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this author Geoffrey K. Isbister, Corresponding Author Geoffrey K. Isbister Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales NSW Poisons Information Centre, The Childrens Hospital Westmead, Sydney, New South Wales CorrespondenceProfessor Geoffrey K. Isbister, School of Medicine and Public Health, University of Newcastle, c/o Calvary Mater Newcastle, Edith Street, Waratah NSW 2298, Australia.Tel.: +61 (2) 4921 1211Fax: +61 (2) 4014 4933 E-mail: geoff.isbister@gmail.comSearch for more papers by this authorNicholas A. Buckley, Nicholas A. Buckley NSW Poisons Information Centre, The Childrens Hospital Westmead, Sydney, New South Wales Sydney Medical School, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this author First published: 23 February 2016 https://doi.org/10.1111/bcp.12819Citations: 3AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat "The art of medicine consists in amusing the patient while nature cures the disease" Voltaire It is often taught that the key to treatment in clinical toxicology is supportive care, and we merely support the patient while their body eliminates the toxin(s) and they recover. In many cases this does seem to be all that is required, particularly with changes in drug and poison regulation that have reduced in-hospital mortality from poisoning to as low as 0.2% in Western countries 1. However, in a small but important proportion of cases of poisoning there is a role for specific treatment – antidotes. This special issue aims to cover the evidence and practical use of the most common treatments in clinical toxicology, including antidotes and adjunct treatments. Across the reviews in this series it is apparent that there is currently a lack of high quality evidence for most antidotes. Further, large randomized clinical trials evaluating most antidotes might never be done for ethical and practical reasons. In the absence of randomized controlled trial evidence, treatment advice has thus often been based on a combination of clinical anecdotes and expert opinion. However, we believe the reviews in this issue frequently demonstrate that there is a third alternative, which borrows heavily from 'clinical pharmacology'. Evidence of efficacy can be found in well-constructed animal models, followed by human studies that generate 'causal evidence' – i.e. evidence that the antidote is achieving the endpoints expected in the time course expected and measures when the optimal dose is being achieved. These combined with knowledge of the expected pharmacokinetic and pharmacodynamic time course of the poisoning, can guide the time frame and indications for interventions. Well-constructed cohort studies can also indicate if there are situations where serious adverse effects are occurring. Finally a risk/benefit and cost–effectiveness framework can be applied to generate a judicious approach to interpreting this lower quality evidence. If this seems to be obvious, it is worth considering that for many years questioning the benefit of some antidotes bordered on heresy. The expert opinion in textbooks often simply referenced previous expert opinion with often no accurately cited supporting original scientific material 2. Antivenom has a long history of being recommended by experts without any evidence of benefit and indeed more recently some antivenoms continue to be recommended despite good evidence that there is no benefit 3. Widow spider antivenom, and in particular red-back spider antivenom in Australia, has been shown to be no better than standard analgesia in two placebo randomized controlled trials 4, 5 and two comparative trials 6, 7. Widow spider-bites are not generally life-threatening, there is a risk of immediate hypersensitivity reactions and antivenom is expensive. Yet so strong are beliefs in the power of antivenoms that for some people the onus of proof is reversed, the antidote must apparently be proven to be useless in all people, in all situations 3. Evidence is now also being created for snake antivenom. Adverse reactions are clearly a major problem for which there are preventive measures that can be taken 8. However, there is little causal evidence so far that they reverse any toxicity 9. This contrasts with an inexplicable reticence to use some newer low-risk antidotes, often only justified by the lack of a registered indication, a consequence of the lack of large placebo randomized controlled trials to support effectiveness. There are some very safe drugs with a strong pharmacological rationale, and animal, volunteer and cohort studies supporting their use. Octreotide is often reserved as a second line therapy for sulfonylurea overdose. However, it makes more pharmacological sense to block insulin secretion with octreotide, than to stimulate repeatedly further insulin secretion with boluses of glucose. It has an excellent safety record when used for this and other indications, and volunteer studies and uncontrolled case series demonstrate its effectiveness 10. Short term corticosteroids consistently reduce late stricture formation after caustic injuries in animal models. They are inexpensive, widely used for many indications and have a well described safety profile. Yet for decades some texts have argued against this treatment because there was a lack of evidence from randomized controlled trials. The recent trial finally providing clinical evidence that high dose methylprednisone reduces the frequency of oesophageal strictures 11 may finally lead to consistent advice. The challenge we set our contributors in this issue on therapeutics in clinical toxicology was thus to discover the evidence that exists (often ignored), combine this with expert opinion and clinical practicalities, and arrive at a reasoned approach to therapeutics. Although activated charcoal is regarded as the universal antidote by some, over the last few decades it has gone in and out of favour, and currently is uncommonly used because of the perceived lack of evidence. Juurlink reviews the problems with the evidence for activated charcoal and makes the important point that no randomized controlled trial of charcoal has evaluated, or is ever likely to evaluate, its early use in the most serious poisonings, where it is most likely to be beneficial 12. However, this does not mean that evidence cannot be used from other study designs and he suggests that recent population pharmacokinetic and pharmacodynamic studies have provided evidence of benefit for activated charcoal in poisoning by individual agents 13. With a trend in some countries to not using charcoal at all, because no randomized controlled trial evidence exists in its favour, it is essential that guidelines are based on a sensible assessment of the available studies, animal, human volunteer and pharmacokinetic studies, rather than therapeutic nihilism. There has been increasing attention on drug-induced QT prolongation in the last two decades. Although an occasional concern for prescribers of drugs that affect the QT interval, drug-induced QT prolongation is a common issue in overdose patients, and the risk of a long QT, torsades de pointes and lethal arrhythmias are much higher. There is an increasing focus on assessing the risk of QT prolongation and arrhythmias in clinical toxicology 14, 15, but ongoing controversy regarding potential therapeutics. It is inconceivable that a randomized controlled trial of treatments for torsades de pointes, such as magnesium or isoproterenol could ever be conducted. However, as Thomas & Behr discuss, small open label trials of magnesium are all that is needed to show that it can be rapidly effective in resolving torsades de pointes 16. However, this does not indicate whether the risk : benefit ratio is favourable for magnesium in patients with drug-induced prolonged QT without torsades. Similarly, in other cardiotoxic drug poisonings we often have a much better guide to what treatments are warranted in cardiac arrest and life-threatening situations, but have conflicting evidence or a lack of evidence on how to proceed up this point 17. McMartin et al. take on the controversial topic of which antidote is best for toxic alcohol poisoning. Is it the more efficacious, potentially safer, but very expensive fomepizole, or ethanol which is inexpensive, but harder to use and associated with more adverse events 18. There is no simple answer and the decision will be based on geographical region and the resources available in the country. North America and parts of Europe have sufficient cases and wealth to almost exclusively use fomepizole (and haemodialysis). However, in resource poor countries, and even some developed countries such as Australia where toxic alcohol poisoning is rare, the high cost will mean fomepizole is not readily available or used. Seizures are an important complication of drug overdose and occur with a range of medications. Most seizures are short-lived and uncomplicated, and require no treatment. Rarely do drug induced seizures require treatment. Unlike other causes, treatment of drug-induced seizures focuses on supportive care, benzodiazepines and avoids traditional anticonvulsants such as phenytoin 19. Pesticide poisoning remains a major cause of mortality in the developing world, particularly in Asia with millions of cases annually. However, the treatment of organophosphate poisoning has changed little over decades, with atropine remaining as the only proven beneficial treatment, and increasing evidence that oximes may cause more harm than good. Even with good supportive care deaths still occur with organophosphate poisoning so improved antidotes and specific therapies are desperately needed. Eddleston & Chowdhury discuss some of the potential new agents, such as nicotinic antagonists and β-adrenoceptor agonists 20. In contrast to pesticides, paracetamol poisoning is the most important common poisoning in the developed world and rapidly becoming a problem in resource poor countries. Acetylcysteine has been available for decades as an effective antidote, but is associated with adverse effects thought to be related to the large loading dose that is given. Recent studies have explored different treatment regimens which Chiew et al. discuss and provides some insight into the pharmacokinetic profile of different regimens and the reasons for high reaction rates with some 21. There are clearly a number of ways the conventional acetylcysteine treatment can be improved and a number of modified protocols have been introduced around the world 21-23. Sivilotti discusses how the use of the 'coma cocktail' in unconscious patients potentially taking mixed overdoses is problematic because of precipitating withdrawal and seizures 24. Taking a protocolized approach to coma is fraught with problems and adverse effects. The same holds true for other areas of toxicology where following a standard dosing protocol may not be the most safe or efficient approach. Fixed high doses of anticholinesterases such as physostigmine in anticholinergic poisoning may be leading to unnecessary morbidity 25. Instead, antidotes and supportive care should be targeted to correct immediate life-threatening effects of drug toxicity, and often simple measures of basic life support are far more effective. The word pharmacology comes from the Greek word for poison. It is fitting that the practice of clinical toxicology (perhaps more than any other medical specialty) needs to be justified through clinical pharmacological principles. There are no positive large hypothesis testing trials to guide us. This brief overview has covered some of the key conclusions that we can draw from the often limited evidence that clinical toxicologists have to grapple with. However, we hope this is just an introduction to a deeper journey into the world of clinical toxicology therapeutics. Drink deeply, but beware it is a highly addictive subject. Competing Interests Neither author has any competing interests. References 1Buckley NA, Whyte IM, Dawson AH, Isbister GK. A prospective cohort study of trends in self-poisoning, Newcastle, Australia, 1987–2012: plus ca change, plus c'Est la meme chose. Med J Aust 2015; 202: 438– 42. 2Eddleston M, Juszczak E, Buckley N. Does gastric lavage really push poisons beyond the pylorus? A systematic review of the evidence. Ann Emerg Med 2003; 42: 359– 64. 3Isbister GK, Page CB, Isbister GK, Buckley NA, Fatovich DM, Brown SG. In reply. Ann Emerg Med 2015; 65: 124– 5. 4Isbister GK, Page CB, Buckley NA, Fatovich DM, Pascu O, MacDonald SP, Calver LA, Brown SG. Randomized controlled trial of intravenous antivenom versus placebo for latrodectism: the Second Redback Antivenom Evaluation (RAVE-II) Study. Ann Emerg Med 2014; 64: 620– 8.e2. doi:10.1016/j.annemergmed.2014. 5Dart RC, Bogdan G, Heard K, Bucher Bartelson B, Garcia-Ubbelohde W, Bush S, Arnold T, Clark RC, Hendey GW, Holstege C, Spradley EA. A randomized, double-blind, placebo-controlled trial of a highly purified equine F(ab)2 antibody black widow spider antivenom. Ann Emerg Med 2013; 61: 458– 67. 6Isbister GK, Brown SG, Miller M, Tankel A, MacDonald E, Stokes B, Ellis R, Nagree Y, Wilkes GJ, James R, Short A, Holdgate A. A randomised controlled trial of intramuscular vs. intravenous antivenom for latrodectism–the RAVE study. QJM 2008; 101: 557– 65. 7Ellis R, Jelinek G, Sprivulis P, Banham N, Siegmund A, Wilkes G, Wood S, Marillier E, Roberts B. Comparison Of Routes Of Injection For The Treatment Of Envenomation By Redback Spider: Critter Trial 2003; Perth, Australia: ACEM. p. 49. 8de Silva HA, Ryan NM, de Silva HJ. Adverse reactions to snake antivenom, and their prevention and treatment. Br J Clin Pharmacol 2016; 81: 446– 52. 9Maduwage K, Buckley NA, de Silva HJ, Lalloo DG, Isbister GK. Snake antivenom for snake venom induced consumption coagulopathy. 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Pharmacological treatment of acquired QT prolongation and torsades de pointes. Br J Clin Pharmacol 2016; 81: 420– 27. 17Graudins A, Lee HM, Druda D. Calcium channel and beta-blocker antagonist antidotes and adjunct therapies. Br J Clin Pharmacol 2016; 81: 453– 61. 18McMartin K, Jacobsen D, Hovda KE. Antidotes for poisoning by alcohols that form toxic metabolites. Br J Clin Pharmacol 2016; 81: 505– 15. 19Chen HY, Albertson TE, Olson KR. Treatment of drug-induced seizures. Br J Clin Pharmacol 2016; 81: 412– 19. 20Eddleston M, Chowdhury FR. Pharmacological treatment of organophosphorus insecticide poisoning: the old and the (possible) new. Br J Clin Pharmacol 2016; 81: 462– 70. 21Chiew AL, Isbister GK, Duffull SB, Buckley NA. Evidence for the changing regimens of acetylcysteine. Br J Clin Pharmacol 2016; 81: 471– 81. 22Bateman DN, Dear JW, Thanacoody HK, Thomas SH, Eddleston M, Sandilands EA, Coyle J, Cooper JG, Rodriguez A, Butcher I, Lewis SC, Vliegenthart AD, Veiraiah A, Webb DJ, Gray A. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet 2014; 383: 697– 704. 23Isbister GK, Downes MA, Mcnamara K, Berling I, Whyte IM, Page CB. A prospective observational study of a novel 2-phase infusion protocol for the administration of acetylcysteine in paracetamol poisoning. Clin Toxicol (Phila) 2015; 22: 1– 7. 24Sivilotti ML. Flumazenil, naloxone and the 'coma cocktail'. Br J Clin Pharmacol 2016; 81: 428– 36. 25Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium-theory, evidence and practice. Br J Clin Pharmacol 2016; 81: 516– 24. Citing Literature Volume81, Issue3Special Issue: Antidotes in Clinical ToxicologyMarch 2016Pages 408-411 ReferencesRelatedInformation