1. Andrew Dawson Program Director Sri Lanka
Management of cardiac arrests due to oleander or pharmaceutical poisoning.
Andrew Dawson
Program Director
Sri Lanka
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 Arrest Advanced 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

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. A B C D E F G H I DRUG INDICATION DOSE Atropine Vagal 0.6 - 1.2mgs
Organophosphates
50-100mgs B
Bicarbonate Alkalinsation
Tricyclic, Antipsychotics, Cocaine, Verapamil
1-2 meq/kg in repeated bolus doses. Target pH 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

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

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

8. Phospholipid Barrier Passive diffusion depends Ionization status
Lipid solubility
[Gradient]
Phospholipid Barrier
Charged phospholipid barriers
Passive diffusion of drugs across the of cell walls is dependent
lipid solubility
concentration gradient
Ionization status of the drug

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

10. 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]
Altering Ionization
Importance of Pka
Chemicals exist in an equilibrium which includes ionized & non-ionized forms
The balance between these forms is influenced by external pH (amount of hydrogen ions)
The balance of the equilibrium can be expressed by pKa
The pKa is the pH at which the [ionized] = [unionized]

11. 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 ;35:533.

12. 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
Basic Physiology
Most drugs and receptors can be considered to be weak acids or bases.
Drugs have to pass through a number of phopho-lipid membranes
For some compounds physiologically tolerated changes in pH can have significant effect on ionization

13. Distribution Protein Binding Changing Compartments “Toxic Compartment”
intra v.s extra cellular
Between compartments
Excretion
Concentrations at the target
“Toxic Compartment”
high concentrations in the distribution phase
Ionization Trapping
Distribution
Between Compartments and therefore excretion
At a cellular level
Ionisation Trapping

14. 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

15. 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,

16. TCA: pH = 7.1

17. TCA: pH= 7.3
200 meq bicarbonate

18. TCA: pH =7.4
200 meq bicarbonate

19. Risk? Shift oxygen desaturation curve
Cerebral blood flow & hypocapnoea
CBF varies linearly with PaCO2 ( mmHg)
CBF change is 4% per mmHg PCO2
Sodium loading and hypertonicity
Variation in response
pons and putamen, temporal, temporo-occipital, and
occipital cortices a significant relative hypoperfusion during hypocapnia,
Ito H. et al Regional differences in cerebral vascular response to PaCO2 changes in humans measured by positron emission tomography.
Journal of Cerebral Blood Flow & Metabolism. 20(8): , 2000 Aug
cerebral blood flow (CBF) 30% reduction at PCO 25
Serrador JM et al MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis.
Stroke. 31(7):1672-8, 2000 Jul

20. Bicarbonate / Alkalinisation: pH manipulation Indications
Should be trialled in any broad complex rhythm associated with poisoning
Introduction: pH manipulation
Established roles in toxicology
possibly unrealised potential.
Relevance to areas of medicine
not to be confused with the correction of acidosis per sec
Effects either Kinetic, Dynamic or both

21. 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

23. Yellow oleander cardiotoxicity

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

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

26. Symptoms of substantial oleander poisoning (n=66)
Cardiac dysrhythmias 100%
Nausea %
Vomiting %
Weakness 88%
Fatigue %
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%

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

28. Capacity for clinical observation

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

30. Glycosides Na+ Ca++ K+ 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++

31. Representative Cardiac Cell
Voltage dependent
L-type Ca2+ channel
Na+ channel
Na+/K+ ATPase
2 K+
3 Na+
K+ channel(s)
Ca2+
3 Na+
β-adrenergic receptor
Na+/Ca2+ exchanger
SR (Mitochondria)
Therapeutic:
Digoxin inhibits Na+/K+ ATPase (exchange pump)
Increased intracellular [Na+], and increased extracellular [K+]
Leads to decreased Na+/Ca++ exchange
Which leads to increased intracellular [Ca++]
Leading to increased contractility
Toxicologic
Excessive intracellular [Ca++]
Less negative membrane potential (closer to threshold = depolarization)
Increased automaticity
Tachydysrhythmias
Ryanodine receptor
Heart muscle
Na+/K+ ATPase
Na+/Ca2+ Antiporter
Representative Cardiac Cell

32. Cell Electrophysiology
2 K+
Phase 2
3 Na+
Ca2+
Ca2+
3 Na+
Ca2+
Ca2+
SR (Mitochondria)
Ca2+
Therapeutic:
Digoxin inhibits Na+/K+ ATPase (exchange pump)
Increased intracellular [Na+], and increased extracellular [K+]
Leads to decreased Na+/Ca++ exchange
Which leads to increased intracellular [Ca++]
Leading to increased contractility
Toxicologic
Excessive intracellular [Ca++]
Less negative membrane potential (closer to threshold = depolarization)
Increased automaticity
Tachydysrhythmias
Ca2+
Ca2+
Ca2+
Ca2+
Cell Electrophysiology

33. Therapeutic & Toxic MoA
Digoxin K+
= Digoxin
2 [K+]
Phase 2
3 [Na+]
Na+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
SR (Mitochondria)
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Therapeutic:
Digoxin inhibits Na+/K+ ATPase (exchange pump)
Increased intracellular [Na+], and increased extracellular [K+]
Leads to decreased Na+/Ca++ exchange
Which leads to increased intracellular [Ca++]
Leading to increased contractility
Toxicologic
Excessive intracellular [Ca++]
Less negative membrane potential (closer to threshold = depolarization)
Increased automaticity
Tachydysrhythmias
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Therapeutic & Toxic MoA

34. 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.

35. 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’

36. “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+] mmol/L died
None of those with [K+] <5.0 mmol/L died
However, Rx of hyperkalaemia ‘does not improve outcome’

37. 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.

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

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

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

41. Effect of anti-digoxin Fab on dysrhythmias

42. Effect of Fab on serum potassium

43. 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?

44. 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

45. 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.

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

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

48. 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).

49. Serum potassium on admission

50. Serum magnesium on admission

51. Human- Insulin Euglycaemia
Indications
Beta Blockers, Calcium Channel Blockers
Dose
units/kg bolus then infusion plus glucose
Yuan TH et al. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Tox Clin Tox 1999; 37(4): 463–474

52. Human- Insulin Euglycaemia
Mechanism
In shock cardiac metabolism switches from FFA to carbohydrate
At the same time shock is associated with:
inhibition of insulin release
insulin resistance
poor tissue perfusion
impaired glycolysis and carbohydrate delivery
CCB and beta blockers
insulin lack or resistance

53. Insulin & Glucose: Dose
0.5 – 1 Unit/kg/hr regular insulin
give 0.5 gm/kg/hr dextrose (glu > 100)
check glucose every 30 mins initially
Vagal stimulation can induce arrythmias in patients with bradycardias

54. Use of insulin/dextrose: Cardiac glycoside
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???

55. 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?

56. Effect of insulin dextrose on survival

57. Fructose 1-6 diphosphate
Extensive human experience for a number of conditions
? Cardiac glycoside

58. Case 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 30sec
Intermittent 2nd degree HB

59. 22:55 re arrested, 23:20hrs resuscitation ceased
20:45 –
Sinus bradycardia & pulseless
Adrenaline and atropine given
VT and VF
a total of 5 DC shocks were given.
Ongoing DC shocks for VF – occasionally reverting, but VF refractory
At this stage Mg 2g has been given, NaHCO3, atropine, and dobutamine infusion
21:45
60mg/kg of FDP was given as a bolus over 5mins
return of spontanous circulation BP 110/70
22:55 re arrested, 23:20hrs resuscitation ceased

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

62. Response of dysrhythmias to FDP

63. Response of blood pressure to FDP

64. Response of plasma [K+] to FDP

65. Conclusions 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
Probably the reason for ACLS failure to create guideline
Requires clinical trials
Insulin and Dextrose is available and logical
FDP still appears promising

66. OpenSource Toxicology Teaching
Acknowledgements
Michael Eddleston (Scottish Poison Centre)
Prof Kent Olson (San Francisco Poison Centre)
Dapo Odujebe (New York Poison Centre)
OpenSource Toxicology Teaching