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Management of cardiac arrests due to oleander or pharmaceutical poisoning. Andrew Dawson Program Director Management of cardiac arrests due to oleander or pharmaceutical poisoning. Andrew Dawson Program Director Sri Lanka www. sactrc. org Management of cardiac arrests due to oleander or pharmaceutical poisoning. Wellcome Trust & Australian National Health and Medical Research Council International Collaborative Capacity Building Research Grant (GR 071669 MA ) South Asian Clinical Toxicology Research Collaboration

Toxic Cardiac Arrest Advanced Cardiac Life Support (ACLS) = Don’t Stop N Albertson TE, Toxic Cardiac Arrest Advanced Cardiac Life Support (ACLS) = Don’t Stop N Albertson TE, Dawson A, de Latorre F, et al TOX-ACLS: toxicologic-oriented advanced cardiac life support. Ann Emerg Med 2001 Apr; 37(4 Suppl): S 78 -90 – www. sactrc. org South Asian Clinical Toxicology Research Collaboration

Why did ACLS forget cardiac glycosides? South Asian Clinical Toxicology Research Collaboration Why did ACLS forget cardiac glycosides? South Asian Clinical Toxicology Research Collaboration

The Toxic CVS mnemonic Atropine Bicarbonate Cations Calcium Mg Diazepam Epinephrine Fab Digoxin Antibodies The Toxic CVS mnemonic Atropine Bicarbonate Cations Calcium Mg Diazepam Epinephrine Fab Digoxin Antibodies Glucagon Human Insulin Euglycaemia South Asian Clinical Toxicology Research Collaboration

 DRUG INDICATION DOSE A Atropine Vagal 0. 6 - 1. 2 mgs Organophosphates DRUG INDICATION DOSE A Atropine Vagal 0. 6 - 1. 2 mgs Organophosphates 50 -100 mgs B Bicarbonate Alkalinsation Tricyclic, Antipsychotics, Cocaine, Verapamil 1 -2 meq/kg in repeated bolus doses. Target p. H 7. 5 -7. 55 C Calcium Chloride/ Gluconate Calcium Channel Blockers 1 gram bolus repeated every 3 minutes. Target calcium double normal level D Diazepam Chloroquine Cocaine & Amphetamine Up to 3 mgs/kg in chloroquine, unitl sedated in cocaine E Epinephrine & Inotropics Chloroquine F Fab Antibodies Digoxin & Cardiac Glycosides Dose based on ingestion or concentration or titrated against effect G Glucagon Beta Blockers, Calcium Channel Blockers 5 -10 mgs IVI stat then infusion if response H I Human Insulin Euglycaemia Calcium Channel Blockers, Beta Blockers 0. 5 us/kg plus glucose see protocol South Asian Clinical Toxicology Research Collaboration

The Case N A 70 kg man presents on 1 -2 hours following a The Case N A 70 kg man presents on 1 -2 hours following a TCA overdose (3000 mg Amitryptilline) – Unconscious – Seizure – BP 60 Systolic South Asian Clinical Toxicology Research Collaboration

Antidepressants (& Antipsychotics) N N Rapidly absorbed Clinical Correlates – Asymptomatic at 3 hours Antidepressants (& Antipsychotics) N N Rapidly absorbed Clinical Correlates – Asymptomatic at 3 hours remain well ØLiebelt EL, et al Ann Emerg Med 1995; 26(2): 195 -201 – >15 mg/kg associated major toxicity TCA South Asian Clinical Toxicology Research Collaboration

Phospholipid Barrier N Passive diffusion depends – Ionization status – Lipid solubility – [Gradient] Phospholipid Barrier N Passive diffusion depends – Ionization status – Lipid solubility – [Gradient] South Asian Clinical Toxicology Research Collaboration

TCA: Amitryptilline N N Weak Base Highly bound – Albumin: high capacity low affinity TCA: Amitryptilline N N Weak Base Highly bound – Albumin: high capacity low affinity – alpha 1 glycoproteins: low capacity high affinity – Lipids N Sodium channel blocker South Asian Clinical Toxicology Research Collaboration

Altering Ionization HA N N N + +AH Equilibrium influenced by external p. H Altering Ionization HA N N N + +AH Equilibrium influenced by external p. H The balance of the equilibrium can be expressed by p. Ka The p. Ka is the p. H where [ionized] = [unionized] South Asian Clinical Toxicology Research Collaboration

Phospholipid Cell Wall & Na Channel N Non-ionized drug diffuses through the phospholipid membrane Phospholipid Cell Wall & Na Channel N Non-ionized drug diffuses through the phospholipid membrane – Ionization is p. H dependent N Bicarbonate transport via cell membrane exchanger – block exchanger you lose the bicarbonate effect Ø Wang R, Schuyler J, Raymond R J Toxicol Clin Toxicol. 1997; 35: 533. South Asian Clinical Toxicology Research Collaboration

Altering Ionization N N Drugs and Receptors can be considered to be weak acids Altering Ionization N N Drugs and Receptors can be considered to be weak acids or bases. Physiologically tolerated changes in p. H can have significant effect on ionization – Distribution – Target binding – Metabolism South Asian Clinical Toxicology Research Collaboration

Distribution N N Protein Binding Changing Compartments – intra v. s extra cellular – Distribution N N Protein Binding Changing Compartments – intra v. s extra cellular – Between compartments Excretion l Concentrations at the target l N “Toxic Compartment” – high concentrations in the distribution phase N Ionization Trapping South Asian Clinical Toxicology Research Collaboration

Receptor Effects N N Binding affinity is effected by the charge of both the Receptor Effects N N Binding affinity is effected by the charge of both the receptor and the drug Protein Binding – important > 90% N Enzyme Function – binding and catalytic sites N Efficacy – steep concentration response curve – physiologically tolerated change in p. H South Asian Clinical Toxicology Research Collaboration

p. H: Local anesthetics Sodium Channel Blocker N N Non-ionized form to diffuse Preferential p. H: Local anesthetics Sodium Channel Blocker N N Non-ionized form to diffuse Preferential binding of ionized form in the channel Ø N Narahashi T, Fraser DT. Site of action and active form of local anesthetics. Neurossci Res, 1971, 4, 65 -99 Demonstration p. H sensitivity – p. H 7. 2 to 9. 6 unblock the channel Ø Ritchie JM, Greengard P. On the mode of action of local anesthetics. Annu Rev Pharmacol. 1966, 6, 405 -430 South Asian Clinical Toxicology Research Collaboration

TCA: p. H = 7. 1 South Asian Clinical Toxicology Research Collaboration TCA: p. H = 7. 1 South Asian Clinical Toxicology Research Collaboration

TCA: p. H= 7. 3 N 200 meq bicarbonate South Asian Clinical Toxicology Research TCA: p. H= 7. 3 N 200 meq bicarbonate South Asian Clinical Toxicology Research Collaboration

TCA: p. H =7. 4 N 200 meq bicarbonate South Asian Clinical Toxicology Research TCA: p. H =7. 4 N 200 meq bicarbonate South Asian Clinical Toxicology Research Collaboration

Risk? N N Shift oxygen desaturation curve Cerebral blood flow & hypocapnoea – CBF Risk? N N Shift oxygen desaturation curve Cerebral blood flow & hypocapnoea – CBF varies linearly with Pa. CO 2 ( 20 - 80 mm. Hg) – CBF change is 4% per mm. Hg PCO 2 N Sodium loading and hypertonicity South Asian Clinical Toxicology Research Collaboration

Bicarbonate / Alkalinisation: p. H manipulation Indications N Should be trialled in any broad Bicarbonate / Alkalinisation: p. H manipulation Indications N Should be trialled in any broad complex rhythm associated with poisoning South Asian Clinical Toxicology Research Collaboration

Bicarbonate / Alkalinisation N Indications – Tricyclic antidepressants & Phenothiazines – Chloroquine – Antiarrythmics Bicarbonate / Alkalinisation N Indications – Tricyclic antidepressants & Phenothiazines – Chloroquine – Antiarrythmics – Cocaine – Calcium Channel Blockers – ? Organophosphates N Dose – 1 -2 meq/kg in repeated bolus doses – Titrated ECG – Target p. H 7. 5 -7. 55 South Asian Clinical Toxicology Research Collaboration

South Asian Clinical Toxicology Research Collaboration South Asian Clinical Toxicology Research Collaboration

Yellow oleander cardiotoxicity South Asian Clinical Toxicology Research Collaboration Yellow oleander cardiotoxicity South Asian Clinical Toxicology Research Collaboration

Oleander poisoning N Epidemiology N Standard treatment = pharmacokinetics N Mechanisms of toxicity N Oleander poisoning N Epidemiology N Standard treatment = pharmacokinetics N Mechanisms of toxicity N Possibilities for treatment that result from this knowledge N Future research? ? South Asian Clinical Toxicology Research Collaboration

Oleander: Multiple cardioglycosides N 22% of all poisonings N Mortality – N= 4111 – Oleander: Multiple cardioglycosides N 22% of all poisonings N Mortality – N= 4111 – 3. 9% ( 95% CI 3. 3 -4. 6) N Morbidity – Resources: transfer and monitoring South Asian Clinical Toxicology Research Collaboration

Symptoms of substantial oleander poisoning (n=66) Cardiac dysrhythmias Nausea Vomiting Weakness Fatigue Diarrhoea Dizziness Symptoms of substantial oleander poisoning (n=66) Cardiac dysrhythmias Nausea Vomiting Weakness Fatigue Diarrhoea Dizziness Abdominal Pain Visual Symptoms Headache Sweating Confusion Fever and/or Chills Anxiety Abnormal Dreams 100% 88% 86% 80% 67% 59% 36% 34% 20% 19% 5% 3% 3% South Asian Clinical Toxicology Research Collaboration

Time from hospital admission to death in RCT n= 1500 South Asian Clinical Toxicology Time from hospital admission to death in RCT n= 1500 South Asian Clinical Toxicology Research Collaboration

Capacity for clinical observation South Asian Clinical Toxicology Research Collaboration Capacity for clinical observation South Asian Clinical Toxicology Research Collaboration

Cardiac Glycosides: Multiple Mechanisms N Vagotonic effects – Sinus bradycardia, AV block – Slows Cardiac Glycosides: Multiple Mechanisms N Vagotonic effects – Sinus bradycardia, AV block – Slows ventricular rate in atrial fibrillation N Inhibits Na+-K+-ATPase pump – extracellular K+ N Myocardial Toxicity ? K+ (outside cell) ATP Na+ (inside cell) South Asian Clinical Toxicology Research Collaboration

Glycosides N N N Block Na+/K+-ATPase pump Increased intracellular Na+ reduces the driving force Glycosides N N N Block Na+/K+-ATPase pump Increased intracellular Na+ reduces the driving force for the Na+/Ca++ exchanger Ca++ accumulates inside of cell – Increased inotropic effect – Too much intracellular Ca++ can cause ventricular fibrillation, and possibly excessive actin-myosin contraction OUT K Na+ + AT P IN Na+ Ca+ + South Asian Clinical Toxicology Research Collaboration

Na+ channel Voltage dependent L-type Ca 2+ channel L-type Na+/K+ ATPase 2 K+ 3 Na+ channel Voltage dependent L-type Ca 2+ channel L-type Na+/K+ ATPase 2 K+ 3 Na+ K+ channel(s) Ca 2+ 3 Na+ β-adrenergic receptor Na+/Ca 2+ exchanger SR (Mitochondria) Heart muscle Ryanodine receptor Na+/K+ ATPase Na+/Ca 2+ Antiporter Representative Cardiac Cell South Asian Clinical Toxicology Research Collaboration

2 K+ Phase 2 3 Na+ 2+ Ca Ca 2+ 3 Na+ Ca 2+ 2 K+ Phase 2 3 Na+ 2+ Ca Ca 2+ 3 Na+ Ca 2+ SR (Mitochondria) Ca 2+ Cell Electrophysiology South Asian Clinical Toxicology Research Collaboration

Digoxin = Digoxin K+ 2 [K+] Phase 2 3 [Na+] 2+ Ca Ca 2+2+ Digoxin = Digoxin K+ 2 [K+] Phase 2 3 [Na+] 2+ Ca Ca 2+2+ Ca 2+ 2+ 2+ Ca Ca Ca 2+ 2+ Ca Ca 2+ Ca 2+2+ Ca Ca 2+ 2+ Ca Ca 2+ Na+ SR (Mitochondria) Ca Therapeutic & Toxic Mo. A South Asian Clinical Toxicology Research Collaboration

Consequences of cardiac glycoside binding 1 N Rises in intracellular Ca 2+ and Na+ Consequences of cardiac glycoside binding 1 N Rises in intracellular Ca 2+ and Na+ concentrations N Partial membrane depolarisation and increased automaticity (QTc interval shortening) N Generation of early after-depolarisations (u waves) that may trigger dysrhythmias N Variable Na+ channel block, altered sympathetic activity, & increased vascular tone. South Asian Clinical Toxicology Research Collaboration

Consequences of cardiac glycoside binding 2 N Decrease in conduction through the SA and Consequences of cardiac glycoside binding 2 N Decrease in conduction through the SA and AV nodes N Due to increase in vagal parasympathetic tone and by direct depression of this tissue N Seen as decrease in ventricular response to SV rhythms and PR interval prolongation N In very high dose poisoning, Ca 2+ load may overwhelm the sarcoplasmic reticulum’s capacity to sequester it, resulting in systolic arrest – ‘stone heart’ South Asian Clinical Toxicology Research Collaboration

“Hyperkalaemia” : potassium effects 1 N N N Is a feature of poisoning, due “Hyperkalaemia” : potassium effects 1 N N N Is a feature of poisoning, due to inhibition of the Na+/K+ ATPase. Causes hyperpolarisation of cardiac tissue, enhancing AV block. Study of 91 acutely digitoxin poisoned patients before use of anti-digoxin Fab (Bismuth, Paris): – All with [K+] >5. 5 mmol/L died – 50% of those with [K+] 5. 0 -5. 5 mmol/L died – None of those with [K+] <5. 0 mmol/L died However, Rx of hyperkalaemia ‘does not improve outcome’ South Asian Clinical Toxicology Research Collaboration

Pre-existing hypokalaemia: Potassium effects 2 N Inhibits the ATPase & enhances myocardial automaticity, increasing Pre-existing hypokalaemia: Potassium effects 2 N Inhibits the ATPase & enhances myocardial automaticity, increasing the risk of glycoside induced dysrhythmias N Effect of hypokalaemia may be in part due to reduced competition at the ATPase binding site N Hypokalaemia <2. 5 mmol/L slows the Na pump, exacerbating glycoside induced pump inhibition. South Asian Clinical Toxicology Research Collaboration

Evidence based treatment Only two interventions have been carefully studied N Anti-digoxin/digitoxin Fab – Evidence based treatment Only two interventions have been carefully studied N Anti-digoxin/digitoxin Fab – Alters distribution N Activated charcoal – Reducing absorption – Speeding elimination South Asian Clinical Toxicology Research Collaboration

Digoxin Fab antibodies N Smith TW et al. N Engl J Med 1976; 294: Digoxin Fab antibodies N Smith TW et al. N Engl J Med 1976; 294: 797 -800 – 22. 5 mg of digoxin – K+ initially 8. 7 mmol/l N Fab fragments of digoxin -specific ovine antibodies South Asian Clinical Toxicology Research Collaboration

Effect of Fab in oleander poisoning • Eddleston M et al Lancet 2000 South Effect of Fab in oleander poisoning • Eddleston M et al Lancet 2000 South Asian Clinical Toxicology Research Collaboration

Effect of anti-digoxin Fab on dysrhythmias South Asian Clinical Toxicology Research Collaboration Effect of anti-digoxin Fab on dysrhythmias South Asian Clinical Toxicology Research Collaboration

Effect of Fab on serum potassium South Asian Clinical Toxicology Research Collaboration Effect of Fab on serum potassium South Asian Clinical Toxicology Research Collaboration

Activated Charcoal: two published RCTs N de Silva (Lancet 2003) – MDAC 5/201 [2· Activated Charcoal: two published RCTs N de Silva (Lancet 2003) – MDAC 5/201 [2· 5%] vs SDAC 16/200 [8%] – RR 0. 31 (95% CI 0. 12 to 0. 83) N SACTRC (Lancet 2007) – MDAC 22/505 [4· 4%] vs SDAC 24/505 [4. 8%] – RR 0. 92 (95% CI 0. 52 to 1. 60) Why? Different regimen? Poor compliance? South Asian Clinical Toxicology Research Collaboration

What other treatment options are available? N Anti-arrhythmics – lidocaine & phenytoin N Atropine What other treatment options are available? N Anti-arrhythmics – lidocaine & phenytoin N Atropine & pacemakers N Correction of electrolyte abnormalities – Correction of hyperkalaemia N Glucose/Insulin N Fructose 1, 6 diphosphate Unfortunately, as yet, no RCTs to guide treatment South Asian Clinical Toxicology Research Collaboration

Classic treatments N Phenytoin/lidocaine – depress automaticity, while not depressing AV node conduction. Phenytoin Classic treatments N Phenytoin/lidocaine – depress automaticity, while not depressing AV node conduction. Phenytoin reported to terminate digoxin-induced SVTs. N Atropine – given for bradycardias. N Temporary pacemaker – to increase heart rate, but cannot prevent ‘stone heart’. Also insertion of pacemaker may trigger VF in sensitive heart. Now not recommended where Fab is available. South Asian Clinical Toxicology Research Collaboration

Atropine N Indications (Management of Poisoning: Fernando R) – < pulse less than 40 Atropine N Indications (Management of Poisoning: Fernando R) – < pulse less than 40 beats/minute – 20 Block or greater N N N Reality: – most patients receive it (and are atropine toxic) No evidence that it decreases mortality Routine use may: – Increase oleander absorption and blood levels – Decrease effectiveness of gastrointestinal decontamination – Mask clinical deterioration South Asian Clinical Toxicology Research Collaboration

Response of atropine-naïve oleander poisoned patients to 0. 6 mg of atropine South Asian Response of atropine-naïve oleander poisoned patients to 0. 6 mg of atropine South Asian Clinical Toxicology Research Collaboration

Correction of electrolyte disturbances N Hypokalaemia exacerbates cardiac glycoside toxicity – However, in acute Correction of electrolyte disturbances N Hypokalaemia exacerbates cardiac glycoside toxicity – However, in acute self-poisoning (not acute on chronic), hypokalaemia is uncommon. N Hypomagnesaemia. Serum [Mg 2+] is not related to severity in oleander poisoning. However, low [Mg 2+] will make replacing K+ difficult. – Theoretically, giving Mg 2+ will be beneficial but this was tried in Sri Lanka without clear benefit (but not RCT). South Asian Clinical Toxicology Research Collaboration

Serum potassium on admission South Asian Clinical Toxicology Research Collaboration Serum potassium on admission South Asian Clinical Toxicology Research Collaboration

Serum magnesium on admission South Asian Clinical Toxicology Research Collaboration Serum magnesium on admission South Asian Clinical Toxicology Research Collaboration

Human- Insulin Euglycaemia N Indications – Beta Blockers, Calcium Channel Blockers N Dose – Human- Insulin Euglycaemia N Indications – Beta Blockers, Calcium Channel Blockers N Dose – 0. 5 - 1. 0 units/kg bolus then infusion plus glucose Ø Yuan TH et al. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Tox Clin Tox 1999; 37(4): 463– 474 South Asian Clinical Toxicology Research Collaboration

Human- Insulin Euglycaemia N Mechanism – In shock cardiac metabolism switches from FFA to Human- Insulin Euglycaemia N Mechanism – In shock cardiac metabolism switches from FFA to carbohydrate – At the same time shock is associated with: inhibition of insulin release l insulin resistance l poor tissue perfusion l impaired glycolysis and carbohydrate delivery l – CCB and beta blockers l insulin lack or resistance South Asian Clinical Toxicology Research Collaboration

Insulin & Glucose: Dose N 0. 5 – 1 Unit/kg/hr regular insulin N give Insulin & Glucose: Dose N 0. 5 – 1 Unit/kg/hr regular insulin N give 0. 5 gm/kg/hr dextrose (glu > 100) N check glucose every 30 mins initially South Asian Clinical Toxicology Research Collaboration

Use of insulin/dextrose: Cardiac glycoside N Van Deusen 2003 – single case. No effect Use of insulin/dextrose: Cardiac glycoside N Van Deusen 2003 – single case. No effect – neither dangerous nor beneficial. N Reports from India of ‘successfully’ treating yellow oleander poisoning with insulin dextrose when no otherapies were available. N Oubaassine and colleagues 2006 – reported case of combined digoxin (17. 5 mg) & insulin (50 iu) poisoning with no substantial cardiac effects and no hyperkalaemia. Might lowering [K+] > 5. 5 mmol/L be beneficial? ? ? South Asian Clinical Toxicology Research Collaboration

Oubaassine 2006 – rat work N Rats were infused with 0. 625 mg/hr digoxin. Oubaassine 2006 – rat work N Rats were infused with 0. 625 mg/hr digoxin. N After 20 mins, half received high dose glucose and insulin to keep glucose between 5. 5 to 6. 6 mmol/L. N Time to death recorded N Thirty minutes after digoxin infusion, plasma [K+] had risen in control group compared to insulin glucose group: 6. 9 ± 0. 5 mmol/L vs 4. 9 ± 0. 3 mmol/L. N Effect on clinically important outcomes? South Asian Clinical Toxicology Research Collaboration

Effect of insulin dextrose on survival South Asian Clinical Toxicology Research Collaboration Effect of insulin dextrose on survival South Asian Clinical Toxicology Research Collaboration

Fructose 1 -6 diphosphate N Extensive human experience for a number of conditions N Fructose 1 -6 diphosphate N Extensive human experience for a number of conditions N ? Cardiac glycoside South Asian Clinical Toxicology Research Collaboration

Case N N N 19 yo Ms R took 3 seeds of oleander 11 Case N N N 19 yo Ms R took 3 seeds of oleander 11 am Consented to the FDP phase II study 18: 45 – Sinus Brady (HR 40) for over a minute – Then narrow complex tachycardia) for 30 sec – Intermittent 2 nd degree HB South Asian Clinical Toxicology Research Collaboration

N 20: 45 – – Sinus bradycardia & pulseless l Adrenaline and atropine given N 20: 45 – – Sinus bradycardia & pulseless l Adrenaline and atropine given – VT and VF l l l N a total of 5 DC shocks were given. Ongoing DC shocks for VF – occasionally reverting, but VF refractory At this stage Mg 2 g has been given, Na. HCO 3, atropine, and dobutamine infusion 21: 45 – 60 mg/kg of FDP was given as a bolus over 5 mins – return of spontanous circulation BP 110/70 N 22: 55 re arrested, 23: 20 hrs resuscitation ceased South Asian Clinical Toxicology Research Collaboration

South Asian Clinical Toxicology Research Collaboration South Asian Clinical Toxicology Research Collaboration

Fructose 1, 6 diphosphate (FDP) 1 N Intermediate of muscle metabolism – mechanism? ? Fructose 1, 6 diphosphate (FDP) 1 N Intermediate of muscle metabolism – mechanism? ? N Markov 1999, Vet Hum Toxicol. Effect of FDP in dog Nerium oleander poisoning. N 12 dogs infused with 40 mg/kg oleander extract over 5 min N Then half the dogs were infused with 50 mg/kg FDP by slow IV bolus, followed by constant infusions. South Asian Clinical Toxicology Research Collaboration

Response of dysrhythmias to FDP South Asian Clinical Toxicology Research Collaboration Response of dysrhythmias to FDP South Asian Clinical Toxicology Research Collaboration

Response of blood pressure to FDP South Asian Clinical Toxicology Research Collaboration Response of blood pressure to FDP South Asian Clinical Toxicology Research Collaboration

Response of plasma [K+] to FDP South Asian Clinical Toxicology Research Collaboration Response of plasma [K+] to FDP South Asian Clinical Toxicology Research Collaboration

Conclusions N N N Pharmaceuticals may require non-intuitive treatment Treatments should be based on Conclusions N N N Pharmaceuticals may require non-intuitive treatment Treatments should be based on our understanding the mechanism Cardiac glycoside toxicity – Anti-digoxin Fab are effective but expensive l Probably the reason for ACLS failure to create guideline – Requires clinical trials l l Insulin and Dextrose is available and logical FDP still appears promising South Asian Clinical Toxicology Research Collaboration

Acknowledgements • Michael Eddleston (Scottish Poison Centre) • Prof Kent Olson (San Francisco Poison Acknowledgements • Michael Eddleston (Scottish Poison Centre) • Prof Kent Olson (San Francisco Poison Centre) • Dapo Odujebe (New York Poison Centre) www. wikitox. org Open. Source Toxicology Teaching [email protected] org South Asian Clinical Toxicology Research Collaboration