1. Prehospital use of antidotes in acute poisoning Vincent Danel SAMU - Centre 15 and Toxicovigilance Centre, University Hospital, Grenoble, France Philippe Lheureux Department of Emergency Medicine Erasme University Hospital, Brussels, Belgium EAPCCT XXVIII international congress 6-9 May 2008, Seville, Spain

2. Background ‘Fewer than 1% of people who present with self poisoning develop severe clinical effects. One of the main challenges in managing poisoned patients is to identify this group as early as possible so that appropriate supportive, and if necessary, specific management steps can be instituted to prevent serious complications.’ A L Jones, P I Dargan. Advances, challenges, and controversies in poisoning. Emerg Med J 2002;19:190–191

3. Acute poisoning, a dynamic process possible sequelae possible death Time t 0 recovery free interval 24 to 72 h exposure Worsening

4. Prehospital emergency care Decreasing the ‘free medical interval’ Diagnosis or approximation of diagnosis Evaluation of severity, recognition of risk factors Supportive treatment Specific treatment? antidotes? Prevention of early complications Orientation (Hospital, ICU) As early as possible

5. When to send a Medical Emergency Care Unit ? Severity assessment Toxicant(s), associations Ingested dose / toxic dose Formulation (slow release or not) Patient (age, co morbidity) Time from exposure, initial management? Early complications The French ETC score: Epidemiological Toxicological Clinical features The French ETC score: Epidemiological Toxicological Clinical features

6. Early stabilisation Cardio-pulmonary resuscitation Airway permeability, oxygen, respiratory support Fluids, vasoactive agents Control of arrhythmias Correction of hypoglycemia Control of convulsions Control of hypothermia / hyperthermia Specific treatment, antidotes?

7. Prehospital use of antidotes? Guidelines for hospital/ED antidotes availability International Program on Chemical Safety (OMS – 1997) US experts panel (2000) UK experts panel (2006) French and Belgian experts (2006, 2007) No specific guidelines for prehospital use of antidotes apart from some French guidelines (1997, 2000) and studies (1993 – 2006) likely to be a subset of antidotes needed in the ED

8. Availability? IPCS (OMS) 1997 1. effectiveness well documented 2. widely used, but … 3. questionable usefulness 1. effectiveness well documented 2. widely used, but … 3. questionable usefulness Availability of antidotes: A. within 30 minutes B. within 2 hours C. within 6 hours Availability of antidotes: A. within 30 minutes B. within 2 hours C. within 6 hours

9. Availability? IPCS (OMS) 1997 Methylene blue Naloxone Oxygen Phentolamine Physostigmine Prenalterol Protamin sulphate Sodium nitrite Sodium nitroprusside Sodium thiosulfate Methylene blue Naloxone Oxygen Phentolamine Physostigmine Prenalterol Protamin sulphate Sodium nitrite Sodium nitroprusside Sodium thiosulfate Atropine Beta-blockers Calcium gluconate Dicobalt edetate Digoxin antibodies Ethanol Glucagon Glucose Hydroxocobalamin Isoprenaline 4-methylpyrazole Atropine Beta-blockers Calcium gluconate Dicobalt edetate Digoxin antibodies Ethanol Glucagon Glucose Hydroxocobalamin Isoprenaline 4-methylpyrazole Availability < 30 min Well documented effectiveness Availability < 30 min Well documented effectiveness 21 ‘antidotes’

10. Availability? USA, 2000 Evaluation of 20 antidotes 1.Is the antidote effective? 2.Is the antidote needed within one hour? 3.How many patients should a facility prepare for …? 4.What amount of the antidote is needed to treat a 70-Kg patient? 1.Is the antidote effective? 2.Is the antidote needed within one hour? 3.How many patients should a facility prepare for …? 4.What amount of the antidote is needed to treat a 70-Kg patient?

11. Availability? USA, 2000 16 recommended ‘antidotes’: Acetylcysteine Atropine Crotalid snake anvenim Calcium salts Cyanide antidote kit Deferoxamine Digoxin antibodies Dimercaprol Ethanol Fomepizole Glucagon Methylene blue Naloxone Pralidoxime Pyridoxine Sodium bicarbonate 16 recommended ‘antidotes’: Acetylcysteine Atropine Crotalid snake anvenim Calcium salts Cyanide antidote kit Deferoxamine Digoxin antibodies Dimercaprol Ethanol Fomepizole Glucagon Methylene blue Naloxone Pralidoxime Pyridoxine Sodium bicarbonate 2 not recommended:. Black widow antivenin. CaNa 2 EDTA 2 not recommended:. Black widow antivenin. CaNa 2 EDTA No consensus:. Flumazenil. Physostigmine No consensus:. Flumazenil. Physostigmine

12. Availability? UK, 2006 Those that should be immediately available within A&E Those that should be available for use within one hour or four hours Those that are either not critically time dependent or are used rarely and could be held supra-regionally Those that should be immediately available within A&E Those that should be available for use within one hour or four hours Those that are either not critically time dependent or are used rarely and could be held supra-regionally

13. Availability? UK, 2006 Acetylcysteine Activated charcoal Atropine Benzatropine Calcium salts Hydroxocobalamin Diazepam Dicobalt edetate Ethanol Acetylcysteine Activated charcoal Atropine Benzatropine Calcium salts Hydroxocobalamin Diazepam Dicobalt edetate Ethanol Flumazenil Glucagon Glyceryl trinitrate Methylene blue Naloxone Procyclidine injection Sodium bicarbonate Sodium nitrite Sodium thiosulfate Flumazenil Glucagon Glyceryl trinitrate Methylene blue Naloxone Procyclidine injection Sodium bicarbonate Sodium nitrite Sodium thiosulfate Those that should be immediately available within A&E: 18 ‘antidotes’

14. Belgian and French authors Antidotes. EMC (Elsevier Masson SAS, Paris), Médecine d’urgence, 25-030-A-30, 2007. Acetylcysteine Atropine Calcium salts Diazepam Flumazenil Hydroxocobalamin Naloxone Phytomenadione Pralidoxime Sodium bicarbonate Tropatepine Acetylcysteine Atropine Calcium salts Diazepam Flumazenil Hydroxocobalamin Naloxone Phytomenadione Pralidoxime Sodium bicarbonate Tropatepine

15. Prehospital availability? French data Activated charcoal Adrenaline Atropine Calcium salts Dobutamine Flumazenil Hydroxocobalamin Hypertonic glucose Isoprenaline Naloxone Propranolol Thiosulfate Activated charcoal Adrenaline Atropine Calcium salts Dobutamine Flumazenil Hydroxocobalamin Hypertonic glucose Isoprenaline Naloxone Propranolol Thiosulfate ‘Antidotes’ needed in a Medical Emergency Care Unit (France, 1997)

16. Prehospital availability?

17. Which antidotes are actually used? French data: Acute poisoning = 3  10 % MECU interventions Dherbecourt V. Indication d’administration des antidotes sur les lieux d’intervention ou pendant les transferts par le SAMU. Thèse Université de Lille, 1993 Lardeur et al. Régulation et prise en charge des intoxications volontaires par un SAMU. Presse Medicale 2001; 30: 626-630. Labourel et al. Analyse épidemiologique des intoxications médicamenteuses volontaires aiguës: prise en charge par un SMUR. Rev Med Liège 2006:61: 3: 185-189.

18. Which antidotes? Most used: Flumazenil Hydroxocobalamin Hypertonic glucose Naloxone Sodium bicarbonate/lactate Rarely used: acetylcysteine, adrenaline, atropine, diazepam, digoxin antibodies, ethanol, fomepizole, glucagon

19. Prehospital use of antidotes Quality of the first call medical assessment Early lifesaving value, with little or no alternative measure Distance and time interval to the hospital Clinical situation: great value of toxidromes! Probability of use, depending on local epidemiology and industrial activities Particular risk of mass casualties (strategic storage) (hydroxocobalamin, atropine, pralidoxime, …)

20. Prehospital use of antidotes Ease and safety of use, possible adverse effects Storage conditions, shelf life (glucagon, fomepizole, hydroxocobalamine, …) Cost, including waste of unused or outdated products (hydroxocobalamin, digoxin antibodies, viper antivenom,..) Qualification and skill level of the prehospital emergency team (good knowledge of toxidromes)

21. Naloxone and opiate toxidrome Narcotic ‘simple’ overdose: miosis, bradypnea, bradycardia, CNS depression, needle tracks… Goal of prehospital naloxone therapy is to simply reverse respiratory depression No indication in the severe complicated overdose Should only be administered in small, diluted and titrated doses Short duration of a ‘toxicodynamic’ action: we ‘treat’ the patient not the ‘overdose’

22. Flumazenil and BZD toxidrome CNS depression, hypotonia, no focal sign, Normal ECG and blood pressure, no cyanosis Many people are benzodiazepine-dependent benzodiazepine withdrawal  tremors, high levels of anxiety, muscle jerks, seizures Many people co-ingest other drugs  convulsions, arrythmias,… Should only be administered in small, diluted and titrated doses Short duration of a ‘toxicodynamic’ action: we ‘treat’ the patient not the ‘overdose’

23. Na salts (bicarbonate / lactate) Na channel blockade: ‘membrane stabilizing effect’ Indications: widening of QRS complex arrhythmias hypotension Small volumes (heavy load of alcaline and sodium salts) With added K+

24. Cyanide antidotes Hydroxocobalamine +/- thiosulfate Expensive Very safe First choice if uncertain CN poisoning or smoke exposure: any sign of tissue hypoxia Dicobalt Edetate (Kelocyanor®) Relatively cheap Cardiovascular side-effects Mass CN poisoning (industrial, terrorism) ?

25. Conclusion In most acute poisoning conditions, primary care of the patient is mainly supportive Early medical intervention (MECU) gives the opportunity to start specific treatments Antidotes used in the prehospital settings are a subset of those used in ED Main conditions are: good phone call assessment of the situation well trained medical teams a clear history and a well defined toxidrome Risk of mass casualties must be anticipated

27. The French ETC score Leveau P. Normand R.- Les appels pour tentative de suicide par intoxication médicamenteuse aiguë. Revue des SAMU 1992; 20:159-66.