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Management of cardiac arrests due to oleander or pharmaceutical poisoning.

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.

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Management of cardiac arrests due to oleander or pharmaceutical poisoning.

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  1. 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 (GR071669MA )

  2. Toxic Cardiac ArrestAdvanced Cardiac Life Support (ACLS)= Don’t Stop • 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):S78-90 • www.sactrc.org

  3. Why did ACLS forget cardiac glycosides?

  4. The Toxic CVS mnemonic Atropine Bicarbonate Cations Calcium Mg Diazepam Epinephrine Fab Digoxin Antibodies Glucagon Human Insulin Euglycaemia

  5. The Case • A 70 kg man presents on 1-2 hours following a TCA overdose (3000 mg Amitryptilline) • Unconscious • Seizure • BP 60 Systolic

  6. Antidepressants (& Antipsychotics) • Rapidly absorbed • Clinical Correlates • Asymptomatic at 3 hours remain well • Liebelt EL, et al Ann Emerg Med 1995; 26(2):195-201 • >15 mg/kg associated major toxicity TCA

  7. Phospholipid Barrier • Passive diffusion depends • Ionization status • Lipid solubility • [Gradient]

  8. TCA: Amitryptilline • Weak Base • Highly bound • Albumin: high capacity low affinity • alpha 1 glycoproteins: low capacity high affinity • Lipids • Sodium channel blocker

  9. HA H+ +A- Altering Ionization • Equilibrium influenced by external pH • The balance of the equilibrium can be expressed by pKa • The pKa is the pH where [ionized] = [unionized]

  10. Phospholipid Cell Wall &Na Channel • Non-ionized drug diffuses through the phospholipid membrane • Ionization is pH dependent • Bicarbonate transport via cell membrane exchanger • block exchanger you lose the bicarbonate effect • Wang R,Schuyler J,Raymond R J Toxicol Clin Toxicol. 1997;35:533.

  11. Altering Ionization • Drugs and Receptors can be considered to be weak acids or bases. • Physiologically tolerated changes in pH can have significant effect on ionization • Distribution • Target binding • Metabolism

  12. Distribution • Protein Binding • Changing Compartments • intra v.s extra cellular • Between compartments • Excretion • Concentrations at the target • “Toxic Compartment” • high concentrations in the distribution phase • Ionization Trapping

  13. Receptor Effects • Binding affinity is effected by the charge of both the receptor and the drug • Protein Binding • important > 90% • Enzyme Function • binding and catalytic sites • Efficacy • steep concentration response curve • physiologically tolerated change in pH

  14. pH: Local anesthetics Sodium Channel Blocker • Non-ionized form to diffuse • Preferential binding of ionized form in the channel • Narahashi T, Fraser DT. Site of action and active form of local anesthetics. Neurossci Res, 1971, 4, 65-99 • Demonstration pH sensitivity • pH 7.2 to 9.6 unblock the channel • Ritchie JM, Greengard P. On the mode of action of local anesthetics. Annu Rev Pharmacol. 1966, 6, 405-430

  15. TCA: pH = 7.1

  16. TCA: pH= 7.3 • 200 meq bicarbonate

  17. TCA: pH =7.4 • 200 meq bicarbonate

  18. Risk? • Shift oxygen desaturation curve • Cerebral blood flow & hypocapnoea • CBF varies linearly with PaCO2 ( 20 - 80 mmHg) • CBF change is 4% per mmHg PCO2 • Sodium loading and hypertonicity

  19. Bicarbonate / Alkalinisation: pH manipulationIndications • Should be trialled in any broad complex rhythm associated with poisoning

  20. Bicarbonate / Alkalinisation • Indications • Tricyclic antidepressants & Phenothiazines • Chloroquine • Antiarrythmics • Cocaine • Calcium Channel Blockers • ? Organophosphates • Dose • 1-2 meq/kg in repeated bolus doses • Titrated ECG • Target pH 7.5-7.55

  21. Yellow oleander cardiotoxicity

  22. Oleander poisoning • Epidemiology • Standard treatment = pharmacokinetics • Mechanisms of toxicity • Possibilities for treatment that result from this knowledge • Future research??

  23. Oleander: Multiple cardioglycosides • 22% of all poisonings • Mortality • N= 4111 • 3.9% ( 95% CI 3.3-4.6) • Morbidity • Resources: transfer and monitoring

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

  25. Time from hospital admission to death in RCT n= 1500

  26. Capacity for clinical observation

  27. Cardiac Glycosides: Multiple Mechanisms • Vagotonic effects • Sinus bradycardia, AV block • Slows ventricular rate in atrial fibrillation • Inhibits Na+-K+-ATPase pump •  extracellular K+ • MyocardialToxicity ? K+ (outside cell) ATP (inside cell) Na+

  28. Glycosides • 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 K+ Na+ OUT ATP IN Na+ Ca++

  29. 2 K+ 3 Na+ SR (Mitochondria) Ryanodine receptor Na+/K+ ATPase Na+/Ca2+ Antiporter Voltage dependent L-typeCa2+ channel Na+ channel Na+/K+ ATPase K+ channel(s) Ca2+ 3 Na+ β-adrenergic receptor Na+/Ca2+ exchanger Heart muscle Representative Cardiac Cell

  30. 2 K+ 3 Na+ SR (Mitochondria) Phase 2 Ca2+ Ca2+ 3 Na+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Cell Electrophysiology

  31. Digoxin = Digoxin SR (Mitochondria) K+ 2 [K+] Phase 2 3 [Na+] Na+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Therapeutic & Toxic MoA

  32. Consequences of cardiac glycoside binding 1 • Rises in intracellular Ca2+ and Na+ concentrations • Partial membrane depolarisation and increased automaticity (QTc interval shortening) • Generation of early after-depolarisations (u waves) that may trigger dysrhythmias • Variable Na+ channel block, altered sympathetic activity, & increased vascular tone.

  33. Consequences of cardiac glycoside binding 2 • Decrease in conduction through the SA and AV nodes • Due to increase in vagal parasympathetic tone and by direct depression of this tissue • Seen as decrease in ventricular response to SV rhythms and PR interval prolongation • In very high dose poisoning, Ca2+ load may overwhelm the sarcoplasmic reticulum’s capacity to sequester it, resulting in systolic arrest – ‘stone heart’

  34. “Hyperkalaemia” :potassium effects 1 • 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’

  35. Pre-existing hypokalaemia: Potassium effects 2 • Inhibits the ATPase & enhances myocardial automaticity, increasing the risk of glycoside induced dysrhythmias • Effect of hypokalaemia may be in part due to reduced competition at the ATPase binding site • Hypokalaemia <2.5 mmol/L slows the Na pump, exacerbating glycoside induced pump inhibition.

  36. Evidence based treatment Only two interventions have been carefully studied • Anti-digoxin/digitoxin Fab • Alters distribution • Activated charcoal • Reducing absorption • Speeding elimination

  37. DigoxinFab antibodies • Smith TW et al. N Engl J Med 1976;294:797-800 • 22.5 mg of digoxin • K+ initially 8.7 mmol/l • Fab fragments of digoxin-specific ovine antibodies

  38. Effect of Fab in oleander poisoning • Eddleston M et al Lancet 2000

  39. Effect of anti-digoxin Fab on dysrhythmias

  40. Effect of Fab on serum potassium

  41. Activated Charcoal: two published RCTs • de Silva (Lancet 2003) • MDAC 5/201 [2·5%] vs SDAC 16/200 [8%] • RR 0.31 (95% CI 0.12 to 0.83) • 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?

  42. What other treatment options are available? • Anti-arrhythmics – lidocaine & phenytoin • Atropine & pacemakers • Correction of electrolyte abnormalities • Correction of hyperkalaemia • Glucose/Insulin • Fructose 1,6 diphosphate Unfortunately, as yet, no RCTs to guide treatment

  43. Classic treatments • Phenytoin/lidocaine – depress automaticity, while not depressing AV node conduction. Phenytoin reported to terminate digoxin-induced SVTs. • Atropine – given for bradycardias. • 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.

  44. Atropine • Indications (Management of Poisoning: Fernando R) • < pulse less than 40 beats/minute • 20 Block or greater • Reality: • mostpatients 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

  45. Response of atropine-naïve oleander poisoned patients to 0.6mg of atropine

  46. Correction of electrolyte disturbances • Hypokalaemia exacerbates cardiac glycoside toxicity • However, in acute self-poisoning (not acute on chronic), hypokalaemia is uncommon. • Hypomagnesaemia. Serum [Mg2+] is not related to severity in oleander poisoning. However, low [Mg2+] will make replacing K+ difficult. • Theoretically, giving Mg2+ will be beneficial but this was tried in Sri Lanka without clear benefit (but not RCT).

  47. Serum potassium on admission

  48. Serum magnesium on admission

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