Management of cardiac arrests due to oleander or pharmaceutical poisoning.

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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 )
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Toxic Cardiac ArrestAdvanced Cardiac Life
Support (ACLS) Dont Stop

• Albertson TE, Dawson A, de Latorre F, et al
  TOX-ACLS toxicologic-oriented advanced cardiac
  life support. Ann Emerg Med 2001 Apr37(4
  Suppl)S78-90
• www.sactrc.org

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Why did ACLS forget cardiac glycosides?
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The Toxic CVS mnemonic

• Atropine
• Bicarbonate
• Cations Calcium Mg
• Diazepam
• Epinephrine
• Fab Digoxin Antibodies
• Glucagon
• Human Insulin Euglycaemia

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DRUG INDICATION DOSE
A 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 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
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The Case

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

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Antidepressants ( Antipsychotics)

• Rapidly absorbed
• Clinical Correlates
• Asymptomatic at 3 hours remain well
• Liebelt EL, et al Ann Emerg Med 1995
  26(2)195-201
• gt15 mg/kg associated major toxicity TCA

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Phospholipid Barrier

• Passive diffusion depends
• Ionization status
• Lipid solubility
• Gradient

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TCA Amitryptilline

• Weak Base
• Highly bound
• Albumin high capacity low affinity
• alpha 1 glycoproteins low capacity high affinity
• Lipids
• Sodium channel blocker

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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

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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 . 199735533.

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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

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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

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Receptor Effects

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

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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

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TCA pH 7.1
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TCA pH 7.3

• 200 meq bicarbonate

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TCA pH 7.4

• 200 meq bicarbonate

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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

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Bicarbonate / Alkalinisation pH
manipulationIndications

• Should be trialled in any broad complex rhythm
  associated with poisoning

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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

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Yellow oleander cardiotoxicity
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Oleander poisoning

• Epidemiology
• Standard treatment pharmacokinetics
• Mechanisms of toxicity
• Possibilities for treatment that result from this
  knowledge
• Future research??

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Oleander Multiple cardioglycosides

• 22 of all poisonings
• Mortality
• N 4111
• 3.9 ( 95 CI 3.3-4.6)
• Morbidity
• Resources transfer and monitoring

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Symptoms of substantial oleander poisoning
(n66) Cardiac dysrhythmias 100 Nausea 10
0 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
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Time from hospital admission to death in RCT n
1500
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Capacity for clinical observation
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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 ?

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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

Na
?K
OUT
ATP
IN
?Na
?Ca
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Voltage dependent L-type Ca2 channel
Na channel
Na/K ATPase

K channel(s)
Ca2
3 Na
ß-adrenergic receptor
Na/Ca2 exchanger
Heart muscle
Representative Cardiac Cell
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Phase 2

Ca2
Ca2
3 Na
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Cell Electrophysiology
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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
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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.

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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 reticulums capacity
  to sequester it, resulting in systolic arrest
  stone heart

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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 gt5.5 mmol/L died
• 50 of those with K 5.0-5.5 mmol/L died
• None of those with K lt5.0 mmol/L died
• However, Rx of hyperkalaemia does not improve
  outcome

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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 lt2.5 mmol/L slows the Na pump,
  exacerbating glycoside induced pump inhibition.

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Evidence based treatment

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

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Digoxin Fab antibodies

• Smith TW et al. N Engl J Med 1976294797-800
• 22.5 mg of digoxin
• K initially 8.7 mmol/l
• Fab fragments of digoxin-specific ovine
  antibodies

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Effect of Fab in oleander poisoning

• Eddleston M et al Lancet 2000

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Effect of anti-digoxin Fab on dysrhythmias
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Effect of Fab on serum potassium
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Activated Charcoal two published RCTs

• de Silva (Lancet 2003)
• MDAC 5/201 25 vs SDAC 16/200 8
• RR 0.31 (95 CI 0.12 to 0.83)
• SACTRC (Lancet 2007)
• MDAC 22/505 44 vs SDAC 24/505 4.8
• RR 0.92 (95 CI 0.52 to 1.60)
• Why? Different regimen? Poor compliance?

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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

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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.

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Atropine

• Indications (Management of Poisoning Fernando R)
• lt 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

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

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Serum potassium on admission
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Serum magnesium on admission
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Human- Insulin Euglycaemia

• Indications
• Beta Blockers, Calcium Channel Blockers
• Dose
• 0.5- 1.0 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) 463474

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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

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Insulin Glucose Dose

• 0.5 1 Unit/kg/hr regular insulin
• give 0.5 gm/kg/hr dextrose (glu gt 100)
• check glucose every 30 mins initially

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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 gt 5.5 mmol/L be beneficial???

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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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Effect of insulin dextrose on survival
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Fructose 1-6 diphosphate

• Extensive human experience for a number of
  conditions
• ? Cardiac glycoside

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Case

• 19 yo Ms R took 3 seeds of oleander 11 am
• Consented to the FDP phase II study
• 1845
• Sinus Brady (HR 40) for over a minute
• Then narrow complex tachycardia) for 30sec
• Intermittent 2nd degree HB

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• 2045
• 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
• 2145
• 60mg/kg of FDP was given as a bolus over 5mins
• return of spontanous circulation BP 110/70
• 2255 re arrested, 2320hrs resuscitation ceased

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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.

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Response of dysrhythmias to FDP
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Response of blood pressure to FDP
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Response of plasma K to FDP
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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

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Acknowledgements

• Michael Eddleston (Scottish Poison Centre)
• Prof Kent Olson (San Francisco Poison Centre)
• Dapo Odujebe (New York Poison Centre)

www.wikitox.org OpenSource Toxicology Teaching
adawson_at_sactrc.org