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Cardiac glycoside poisoning

Toxicity mediated by interference with membrane pumps - underlying mechanisms of cardiac glycoside toxicity Michael Eddleston Scottish Poisons Information Bureau Royal Infirmary of Edinburgh, UK. Cardiac glycoside poisoning. Epidemiology of cardiac glycoside poisoning

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Cardiac glycoside poisoning

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  1. Toxicity mediated by interference with membrane pumps- underlying mechanisms of cardiac glycoside toxicityMichael EddlestonScottish Poisons Information BureauRoyal Infirmary of Edinburgh, UK

  2. Cardiac glycoside poisoning • Epidemiology of cardiac glycoside poisoning • Standard treatment = pharmacokinetics • Mechanisms of toxicity • Possibilities for treatment that result from this knowledge • Future research??

  3. Cardiac glycoside medication poisoning Deaths uncommon in industrialised countries • Schaper et alEur J Intern Med 2006;17:474. GIZ-Nord Poison Center consulted in 168,000 cases. 142 deaths (0.08% of cases) None due to cardiac glycosides • AAPCC data from USA 2005 Clin Tox 2006;44:803. 61 poison centres consulted in 2,424,180 cases 1261 deaths (0.05% of cases) 20 (1.6%) primarily due to cardiac glycosides (10 due to therapeutic error, 3 ADR, only 3 intentional)

  4. Self-poisoning in north central Sri Lanka Prospective cohort of acutely poisoned patients started in March 2002 in 2 district hospitals. Now contains over 13,000 patients. Up to mid-2005: 8383 cases 98% due to self-harm Pesticides: 3848 (45.9% of total) Oleander seeds: 2423 (28.9% of total) Other common poisons: medicines & hydrocarbons All treated using a standard protocol

  5. Case fatality for different classes of poison

  6. Case series of oleander poisoning • Jaffna, Sri Lanka, 1980 - 170 patients over 3 years, with 7 deaths (CFR 4.1%). • Bankura, W Bengal, 1985 – 300 patients over 5 years, with 14 deaths (CFR 4.7%). • Anuradhapura, Sri Lanka, 1995 – 79 patients over 4 months, with 6 deaths (CFR 7.6%) • North Central Province, Sri Lanka 2005 – 2423 patients over 3 years, with 109 deaths (CFR 4.5%)

  7. 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%

  8. Standard treatment Only two interventions have been carefully studied • Anti-digoxin/digitoxin Fab • Activated charcoal Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by: • speeding elimination and/or • reducing absorption

  9. Standard treatment Only two interventions have been carefully studied • Anti-digoxin/digitoxin Fab • Activated charcoal Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by: • speeding elimination and/or • reducing absorption

  10. The introduction of Fab fragments for digoxin poisoning • first reported in humans in April 1976 • reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific ovine antibodies • Ingested dose = 22.5 mg of digoxin • serum potassium initially 8.7 mmol/l

  11. Time course of : total serum digoxin ( ) Free serum digoxin ( ) Fab fragments ( ) serum potassium ( ) after iv administration of DA in a 39-year-old man with severe digoxin poisoning. Smith TW et al. Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294:797-800.

  12. Effect of Fab in oleander poisoning

  13. Effect of anti-digoxin Fab on dysrhythmias

  14. Effect of Fab on serum potassium

  15. Standard treatment Only two interventions have been carefully studied • Anti-digoxin/digitoxin Fab • Activated charcoal Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by: • speeding elimination and/or • reducing absorption

  16. No. of events/ No. of participants Odds ratio Test of Interaction (95% CI) Treated AC Untreated AC Overall 0.98 ( 0.75, 1.28) 186/2811 95/1405 Poison P=0.7 Organophosphate 0.85 ( 0.57, 1.27) 74/624 45/330 Oleander 1.00 ( 0.60, 1.67) 46/1010 23/505 Other or NK Pesticide/Paraquat 1.10 ( 0.63, 1.89) 44/640 20/317 Other substances 1.50 ( 0.63, 3.56) 22/537 7/253 Severity P=0.4 Asymptomatic 1.24 ( 0.66, 2.32) 35/1325 14/654 Symptomatic GCS 14/15 1.10 ( 0.71, 1.71) 67/1157 31/586 Symptomatic GCS <14 0.79 ( 0.52, 1.19) 84/329 50/165 Time since ingestion P=0.6 <= 2 hours 0.79 ( 0.49, 1.29) 46/615 29/313 3-4 hours 1.10 ( 0.69, 1.74) 61/887 28/444 Missing 0.29 ( 0.04, 2.01) 2/27 3/14 5-7 hours 1.04 ( 0.58, 1.86) 37/636 18/321 >=8 hours 1.15 ( 0.64, 2.06) 40/646 17/313 .1 .5 1 1.5 2 2.5 4 Odds Ratio Favours Treated with AC Favours Not treated with AC Treated with Activated Charcoal vs Not Treated with Activated Charcoal

  17. Comparison of two published RCTs de Silva MDAC 5/201 [2·5%] vs SDAC 16/200 [8%] RR 0.31 (95% CI 0.12 to 0.83) SACTRC MDAC 22/505 [4·4%] vs SDAC 24/505 [4.8%] RR 0.92 (95% CI 0.52 to 1.60) Fixed effects model, test of heterogeneity P=0.06 Why? Different regimen? Poor compliance?

  18. Time from hospital admission to death in RCT

  19. Standard treatment Only two interventions have been carefully studied • Anti-digoxin/digitoxin Fab • Activated charcoal Current situation: Anti-digoxin Fab are too expensive for widespread use The evidence for activated charcoal is ? negative Are there other options? Here we need to understand the mechanism of toxicity

  20. Ion channels of cardiac muscle

  21. Function of Na+/K+ ATPase

  22. Effect of cardiac glycosides

  23. 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.

  24. 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’

  25. Yellow oleander cardiotoxicity

  26. Potassium effects 1 • Hyperkalaemia 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’

  27. Potassium effects 2 • Pre-existing hypokalaemia also 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.

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

  29. 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.

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

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

  32. Importance of the nervous system • In animals, spinal cord transection reduces the toxicity of cardiac glycosides • Administration of the a2-adrenoceptor agonist clonidine increases the dose of cardiac glycoside required to induce dysrhythmias and death. Inhibited by administration of yohimbine. • Can this information be confirmed in humans? Is this partly how atropine is working?

  33. 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.

  34. Correction of electrolyte disturbances • Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K+. • 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).

  35. Serum potassium on admission

  36. Correction of electrolyte disturbances • Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K+. • 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).

  37. Serum magnesium on admission

  38. Correction of electrolyte disturbances • Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K+. • 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).

  39. Correction of hyperkalaemia - dangerous or beneficial?

  40. Cerbera manghas poisoning(pink-eyed cerbera, odallam, kaduru, or sea mango)

  41. Use of insulin/dextrose for hyperkalemia • Van Deusen 2003 – single case. No effect – neither dangerous nor beneficial. • Reports from India of ‘successfully’ treating yellow oleander poisoning with insulin dextrose when no other therapies were available. • 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???

  42. Oubaassine 2006 – rat work • Rats were infused with 0.625 mg/hr digoxin. • After 20 mins, half received high dose glucose and insulin to keep glucose between 5.5 to 6.6 mmol/L. • Time to death recorded • 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. • Effect on clinically important outcomes?

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