Management of yellow oleander poisoning Michael Eddleston Clinical Pharmacology Unit, University of Edinburgh South Asian Clinical Toxicology Research Collaboration, Sri Lanka National Poisons Information Service - Edinburgh Royal Infirmary of

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Management of yellow oleander poisoning
Michael EddlestonClinical Pharmacology Unit,
University of EdinburghSouth Asian Clinical
Toxicology Research Collaboration,Sri
LankaNational Poisons Information Service -
EdinburghRoyal Infirmary of EdinburghFunded by
the
m.eddleston_at_ed.ac.uk
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Yellow oleander poisoning

• Common in Sri Lanka and India.
• In SACTRC cohort of self-poisoning patients
• 26 of admission are due to ingestion of oleander
  seeds
• Case fatality 4 (95 CI 3.3-4.6)
• Patients are ill! Abdominal pain, vomiting,
  diarrhoea
• Plant cardiac glycoside (thevetins A B,
  neriifolin)

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Ventricular Myocyte
Extracellular space
Na
K channel
Na
Ventricular Action Potential
K
Na channel
Ca2
Na
Na
Ca2
Junctin Triadin
Ca2
Ca2
Na/Ca exchanger
Ca2
Casq
Ca2
Casq
Ca2
CSQ
Ca2
CSQ
Ca2
Casq
Ca2
Sarcoplasmic reticulum
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
T-tubule
Ca2
Ca2
Ca2
PLB
Casq
Ca2
Ryanodine receptor
ATPase
Ca2 channel
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
ATPase
Cytoplasm
Ca2
K
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Na
Na pump
Contractile filaments (myosin, actin)
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Yellow oleander cardiotoxicity
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Treatment of self-poisoning

• OP pesticides Oleander
• 1. Resuscitate
• 2. Empty the stomach gastric lavage
• 3. Adsorb the poison activated
  charcoal
• 4. Give supportive care
• 5. Give antidotes atropine
  pralidoxime anti-digoxin Fab

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• A randomised controlled double-blind phase
  II/III study of anti-digoxin Fab in acute severe
  yellow oleander poisoning
• Patients all patients transferred to Colombo
  CCU with Hx
• and signs consistent with oleander
  self-poisoning
• (gt13yrs, not pregnant, not shocked)
• Outcome 1 resolution of cardiac dysrhythmia
  at 2 hrs
• 2 resolution of cardiac dysrhythmia at 8
  hrs,
• change in heart rate, control of hyperkalaemia
• Power to detect an increase in dysrhythmia
  resolution from
• 10 to 50, 40 patients must be recruited to
  each
• arm of the study (80 in total). 66 finally
  recruited.
• Interventions A) initial dose finding study
• B) saline placebo infusion, or
• 1200mg of anti-digoxin Fab infused in
  200ml saline over 20 min.

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Effect of Fab on heart rate
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Effect of Fab on serum electrolytes
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Effect of anti-digoxin Fab on dysrhythmias
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The RCT did not look at death. Did the antitoxin
make a clinical difference?
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Prospective data from Anuradhapura and
Polonnaruwaduring withdrawal of the antitoxin
from clinical practice in July 2002

• When antitoxin was available 194 patients
• 4 transferred
• 41 doses antitoxin (25)
• 6 deaths
• After antitoxin stocks ended 279 patients
• 54 transferred
• 26 deaths
• Case fatality 3.1 vs. 9.3
• Absolute risk reduction 6.2 (95 CI
  1.6-10.8)

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Costs and Benefits of the Antitoxin
   

• Number needed to treat 4.0
• Antitoxin bought 8000 vials (400 treatments)
• Lives saved with antitoxin 100
• Reduction in the suicide rate 3500 - 100 2.8

Cost of antitoxin 2650 100 400 per
course (USD) Cost per life saved 10,209
-73 1,137 Cost per life year 248
-1.8 28 saved
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Antidigoxin Fab

• Effective
• But expensive
• Therefore not used in Asia. Deaths continue to
  occur.
• ?Can Brasil make an affordable antitoxin for use
  in the developing world??

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Treatment of self-poisoning

• OP pesticides Oleander
• 1. Resuscitate
• 2. Empty the stomach gastric lavage
• 3. Adsorb the poison activated
  charcoal
• 4. Give supportive care
• 5. Give antidotes atropine
  pralidoxime anti-digoxin Fab

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An open RCT of SDAC vs MDAC vs no charcoal in
acute self-poisoning

• Patients All patients with a history of
  self-poisoning
• (gt13yrs, not pregnant, not
  hydrocarbon/corrosive)
• Outcome Death
• Power To detect a reduction in all-cause
  mortality from 10 to 7, 1400 patients must
  be recruited
• to each of the 3 arms of the study (4200 in
  total)
• Interventions - no charcoal.
• - 50g superactivated charcoal on admission
  only
• - 50g on admission, then q4h for 24hrs

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Baseline patient characteristics
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MDAC vs no charcoal
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SDAC vs no charcoal
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Other treatment options?

• Insulin dextrose to treat hyperkalaemia
• Magnesium
• FDP
• Flecainide

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FDP as an antidote

• Markov et al, Vet Hum Toxicol 1999, 419
• Study of Nerium oleander poisoning in dogs
• 12 dogs infused with oleander extract under
  anaesthesia
• Divided into two groups FDP (6) vs placebo (6)
• Intervention group given 50 mg/kg of FDP then
  infusion
• Measured K, observed cardiac rhythm

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Results

• Within 5 minutes of oleander infused, all
  developed dysrhythmias
• All control animals stayed in dysrhythmia until
  4hrs or death (1/4 - VF)
• All 6 intervention animals returned to sinus
  rhythm, median 1.5 hrs
• Mean arterial pressure fell in control animals
  but not FDB treated animals
• Hyperkalaemia occurred in control group but not
  intervention group

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Effect of FDP on mean arterial pressure
FDP
Control
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Results

• Within 5 minutes of oleander infused, all
  developed dysrhythmias
• All control animals stayed in dysrhythmia until
  4hrs or death (1/4 - VF)
• All 6 intervention animals returned to sinus
  rhythm, median 1.5 hrs
• Mean arterial pressure fell in control animals
  but not FDB treated animals
• Hyperkalaemia occurred in control group but not
  intervention group

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Effect of FDP on plasma K concentration
Control
FDP
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Fructose 1, 6 Diphosphate (FDP) as a Antidote in
oleander poisoning
IV
FDP increases ATP production
FDP stimulates Na-K-ATPase and inhibit K efflux
Chelates intracellular calcium
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FDP in humans

• It has a well established safety profile in
  humans, It is used in ischemic heart disease,
  heart failure and also is in TPN solutions
• Minimum effective dose is 25-50mg/kg. Doses up
  to 250mg/kg has been used safely.
• It is licensed in Italy.

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A dose escalation study of FDP in oleander
poisoning (Phase II)

• Prospective RCT (Apr 06 to Jul 07) by SACTRC
  ISRCTN64727867
• Open label randomization and computer generated
  allocation sequence
• Holter monitors for 72 hours. Frequent blood
  sampling for biochemical parameters.
• Endpoints
• Primary - Time to reverse to sinus rhythm (HRgt44)
• Secondary
• Number of patients in sinus rhythm ( HRgt 44) in 2
  hours.
• Potassium concentration
• Adverse events and likelihood of being caused by
  interventions.

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Sample size and dose levels
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Baseline characteristics
FDP Dose (mg/kg) Placebo (n8) Level 1 30 (n6) Level 2 60 (n6) Level 3 125 (n6) level 4 250 (n6)
Males 3(38) 4(67) 3(50) 1(17) 1(17)
Age in years 21(17,27) 31(22,45) 33(25,50) 22(18,37) 25(24,28)
Number of seeds ingested 3(2,5) 2(2,3) 4(2,5) 4(3,4) 5(1,6)
Alcohol ingestion 1(13) 2(33) 2(33) 0(0) 0(0)
Second-degree AV block 8 (100) 6(100) 4(67) 6(100) 6(100)
Apparent digitoxin (ug/L ) 26 (16,38) 22 (11,42) 15 (7,23) 20 (9,36) 29 (14,39)
Time from ingestion to start FDP (hrs) 18 (12,25) 15 (8,20) 6 (5,7) 13 (11,20) 11 (7,15)
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Results
14/32 holter reading uninterpretable
Total interpretable holter reading (18/32)
28/32 (88) transferred for cardiac pacing
(within 2 hours)
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Results
Efficacy Outcomes and Mortality Efficacy Outcomes and Mortality Efficacy Outcomes and Mortality Efficacy Outcomes and Mortality      
Placebo Level 1 Level 2 Level 3 level 4  
FDP Dose level (mg/kg) 30 60 125 250  
Reverted to Sinus rhythm at 30 minutes 3/5 (60) 1/2(50) 3/5(60) 3/5(60) 0/1(0)  
Death 0/8(0) 1/6(16) 0/6(0) 0/6(0) 1/6(16)  
Hypotension 0/8 (0) 1/6 (16) 1/6 (16) 0/6 (0) 0/6 (0)
Death occurred after transfer. Death occurred during treatment in hospital. Death occurred after transfer. Death occurred during treatment in hospital. Death occurred after transfer. Death occurred during treatment in hospital. Death occurred after transfer. Death occurred during treatment in hospital. Death occurred after transfer. Death occurred during treatment in hospital. Death occurred after transfer. Death occurred during treatment in hospital.  
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Electrolytes changes
Dose-related falls were seen in the serum calcium
and potassium within 30 minutes of the infusion
(p0.09 p0.03, ANOVA).
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ISRCTN71018309
Phase III Study
Fructose-1, 6-diphosphate (FDP) as a novel
antidote for yellow oleander-induced cardiac
toxicity A randomized controlled double blind
study
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Trial Intervention

• Active group
• 250mg/kg loading dose of FDP over 20 minutes
  followed by 6mg/kg/hr for 24 hours in addition to
  standard care
• Placebo group
• Equal volume (equal to the volume of FDP in the
  treatment arm) of 0.9 saline as a bolus and a 24
  hour infusion
• 120 patients in each arm

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Other treatment options?

• Insulin dextrose to treat hyperkalaemia
• Magnesium
• FDP
• Flecainide

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Ventricular Myocyte
Extracellular space
Na
K channel
Na
Ventricular Action Potential
K
Na channel
Ca2
Na
Na
Ca2
Junctin Triadin
Ca2
Ca2
Na/Ca exchanger
Ca2
Casq
Ca2
Casq
Ca2
CSQ
Ca2
CSQ
Ca2
Casq
Ca2
Sarcoplasmic reticulum
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
T-tubule
Ca2
Ca2
Ca2
PLB
Casq
Ca2
Ryanodine receptor
ATPase
Ca2 channel
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
ATPase
Cytoplasm
Ca2
K
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Na
Na pump
Contractile filaments (myosin, actin)
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