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South Asian Clinical Toxicology Research Collaboration
Management of cardiac arrests due Management of cardiac arrests due to oleander or pharmaceutical to oleander or pharmaceutical
poisoning.poisoning.
Andrew Dawson
Program Director
Sri Lanka
www.sactrc.org
Wellcome Trust & Australian National Health and Medical Research Council International Collaborative Capacity Building Research Grant (GR071669MA )
Management of cardiac arrests due to oleander or pharmaceutical poisoning.
South Asian Clinical Toxicology Research Collaboration
Toxic Cardiac ArrestToxic Cardiac ArrestAdvanced Cardiac Life Support Advanced Cardiac Life Support
(ACLS)(ACLS)= Don’t Stop= 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
South Asian Clinical Toxicology Research Collaboration
Why did ACLS forget cardiac Why did ACLS forget cardiac glycosides?glycosides?
South Asian Clinical Toxicology Research Collaboration
The Toxic CVS mnemonicThe Toxic CVS mnemonicAtropine
Bicarbonate
Cations Calcium Mg
Diazepam
Epinephrine
Fab Digoxin Antibodies
Glucagon
Human Insulin Euglycaemia
South Asian Clinical Toxicology Research Collaboration
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
South Asian Clinical Toxicology Research Collaboration
The CaseThe Case A 70 kg man presents on 1-2 hours following a
TCA overdose (3000 mg Amitryptilline)– Unconscious – Seizure– BP 60 Systolic
South Asian Clinical Toxicology Research Collaboration
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
Antidepressants Antidepressants (& Antipsychotics)(& Antipsychotics)
South Asian Clinical Toxicology Research Collaboration
Phospholipid BarrierPhospholipid Barrier
Passive diffusion depends– Ionization
status– Lipid solubility– [Gradient]
South Asian Clinical Toxicology Research Collaboration
TCA: AmitryptillineTCA: Amitryptilline Weak Base Highly bound
– Albumin: high capacity low affinity
– alpha 1 glycoproteins: low capacity high affinity
– Lipids Sodium channel blocker
South Asian Clinical Toxicology Research Collaboration
HAHA HH++ +A +A--
Altering Altering IonizationIonization
Equilibrium influenced by external pH The balance of the equilibrium can be
expressed by pKa The pKa is the pH where [ionized] =
[unionized]
pKa 8.5
pH 6.9 7 7.1 7.2 7.3 7.4 7.5
ratio I/U 39.8 31.6 25.1 20.0 15.8 12.6 10.0
South Asian Clinical Toxicology Research Collaboration
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.
Phospholipid Cell Wall &Phospholipid Cell Wall &Na ChannelNa Channel
South Asian Clinical Toxicology Research Collaboration
Altering IonizationAltering 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
pKa 8.5
pH 6.9 7 7.1 7.2 7.3 7.4 7.5
ratio I/U 39.8 31.6 25.1 20.0 15.8 12.6 10.0
South Asian Clinical Toxicology Research Collaboration
DistributionDistribution 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
South Asian Clinical Toxicology Research Collaboration
Receptor EffectsReceptor 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
South Asian Clinical Toxicology Research Collaboration
pH: Local anesthetics Sodium pH: Local anesthetics Sodium Channel BlockerChannel 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
South Asian Clinical Toxicology Research Collaboration
TCA: pH = 7.1TCA: pH = 7.1
South Asian Clinical Toxicology Research Collaboration
TCA: pH= 7.3TCA: pH= 7.3
200 meq bicarbonate
South Asian Clinical Toxicology Research Collaboration
TCA: pH =7.4TCA: pH =7.4
200 meq bicarbonate
South Asian Clinical Toxicology Research Collaboration
Risk?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
South Asian Clinical Toxicology Research Collaboration
Bicarbonate / Alkalinisation: Bicarbonate / Alkalinisation: pH manipulationpH manipulation
IndicationsIndications
Should be trialled in any broad complex rhythm associated with poisoning
South Asian Clinical Toxicology Research Collaboration
Bicarbonate / AlkalinisationBicarbonate / 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
South Asian Clinical Toxicology Research Collaboration
South Asian Clinical Toxicology Research Collaboration
Yellow oleander Yellow oleander cardiotoxicitycardiotoxicity
South Asian Clinical Toxicology Research Collaboration
Oleander poisoningOleander poisoning
Epidemiology
Standard treatment = pharmacokinetics
Mechanisms of toxicity
Possibilities for treatment that result from this knowledge
Future research??
South Asian Clinical Toxicology Research Collaboration
Oleander: Oleander: Multiple cardioglycosidesMultiple cardioglycosides
22% of all poisonings
Mortality– N= 4111– 3.9% ( 95% CI 3.3-4.6)
Morbidity– Resources: transfer and monitoring
South Asian Clinical Toxicology Research Collaboration
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%
South Asian Clinical Toxicology Research Collaboration
Time from hospital admission to death in Time from hospital admission to death in RCT n= 1500RCT n= 1500
0 12 24 36 48 60 72 84 96 108 120
MDAC
SDAC
No AC
Time from admission to death (hrs)
South Asian Clinical Toxicology Research Collaboration
Capacity for clinical observation
South Asian Clinical Toxicology Research Collaboration
Cardiac Glycosides: Cardiac Glycosides: Multiple MechanismsMultiple 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)
South Asian Clinical Toxicology Research Collaboration
GlycosidesGlycosides
IN
OUT
NaNa++
ATP
NaNa++
KK++
CaCa++++
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
South Asian Clinical Toxicology Research Collaboration
Na+/K+ ATPase
3 Na3 Na++
2 K2 K++
Representative Cardiac CellRepresentative Cardiac Cell
NaNa++ channel channelNaNa++ channel channelVoltage dependentVoltage dependentL-typeL-type CaCa2+2+ channel channelVoltage dependentVoltage dependentL-typeL-type CaCa2+2+ channel channel NaNa++/K/K++ ATPase ATPaseNaNa++/K/K++ ATPase ATPase
NaNa++/Ca/Ca2+2+ exchangerexchangerNaNa++/Ca/Ca2+2+
exchangerexchangerSR (Mitochondria)SR (Mitochondria)SR (Mitochondria)SR (Mitochondria)
Heart muscleHeart muscleHeart muscleHeart muscle
KK++ channel(s) channel(s)KK++ channel(s) channel(s)
Na+/Ca2+ Antiporter
Ryanodine receptorRyanodine receptorRyanodine receptorRyanodine receptor
3 Na3 Na++
CaCa2+2+
ββ-adrenergic receptor-adrenergic receptorββ-adrenergic receptor-adrenergic receptor
South Asian Clinical Toxicology Research Collaboration
3 Na3 Na++
2 K2 K++
Cell ElectrophysiologyCell Electrophysiology
SR (Mitochondria)SR (Mitochondria)SR (Mitochondria)SR (Mitochondria)
CaCa2+2+
Phase 2Phase 2
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
3 Na3 Na++
CaCa2+2+
South Asian Clinical Toxicology Research Collaboration
3 [Na3 [Na++]]
2 [K2 [K++]]
Therapeutic & Toxic MoATherapeutic & Toxic MoA
SR (Mitochondria)SR (Mitochondria)SR (Mitochondria)SR (Mitochondria)
CaCa2+2+
Phase 2Phase 2
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
= Digoxin= Digoxin
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
CaCa2+2+
Digoxin
NaNa++
K+K+
South Asian Clinical Toxicology Research Collaboration
Consequences of cardiac glycoside Consequences of cardiac glycoside binding 1binding 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.
South Asian Clinical Toxicology Research Collaboration
Consequences of cardiac glycoside Consequences of cardiac glycoside binding 2binding 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’
South Asian Clinical Toxicology Research Collaboration
““HyperHyperkalaemia” :potassium effects 1kalaemia” :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’
South Asian Clinical Toxicology Research Collaboration
Pre-existing Pre-existing hypohypokalaemia: kalaemia: Potassium Potassium effects 2effects 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.
South Asian Clinical Toxicology Research Collaboration
Evidence based treatmentEvidence based treatment
Only two interventions have been carefully studied
Anti-digoxin/digitoxin Fab– Alters distribution
Activated charcoal– Reducing absorption– Speeding elimination
South Asian Clinical Toxicology Research Collaboration
Digoxin Fab antibodiesDigoxin Fab 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
South Asian Clinical Toxicology Research Collaboration
Effect of Fab in oleander poisoning
•Eddleston M et al Lancet 2000
South Asian Clinical Toxicology Research Collaboration
Effect of anti-digoxin Fab on dysrhythmiasEffect of anti-digoxin Fab on dysrhythmias
South Asian Clinical Toxicology Research Collaboration
Effect of Fab on serum potassiumEffect of Fab on serum potassium
South Asian Clinical Toxicology Research Collaboration
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?
Activated Charcoal:Activated Charcoal: two published RCTs two published RCTs
South Asian Clinical Toxicology Research Collaboration
What other treatment options are What other treatment options are available?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
South Asian Clinical Toxicology Research Collaboration
Classic treatmentsClassic 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.
South Asian Clinical Toxicology Research Collaboration
AtropineAtropine Indications (Management of Poisoning: Fernando R)
– < 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
South Asian Clinical Toxicology Research Collaboration
Response of atropine-naïve oleander poisoned patients to 0.6mg of atropine
40 50 60 70 80 90 10050556065707580859095
100105110115120125130135
rate at 15minrate at 5min
baseline rate
Rat
e
South Asian Clinical Toxicology Research Collaboration
Correction of electrolyte disturbancesCorrection 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).
South Asian Clinical Toxicology Research Collaboration
Serum potassium on admissionSerum potassium on admission
0 1 2 3 4 52
3
4
5
6
7
8
mild or no cardiotoxicity
severe cardiotoxicity
[cardiac glycoside] (nmol/L)
seru
m p
ota
ssiu
m m
mo
l/L
South Asian Clinical Toxicology Research Collaboration
Serum magnesium on admissionSerum magnesium on admission
0 1 2 3 4 50.40
0.65
0.90
1.15
mild or no cardiotoxicity
severe cardiotoxicity
[cardiac glycoside] (nmol/L)
seru
m m
agn
esiu
m m
mo
l/L
South Asian Clinical Toxicology Research Collaboration
Human- Insulin EuglycaemiaHuman- 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): 463–474
South Asian Clinical Toxicology Research Collaboration
Human- Insulin EuglycaemiaHuman- 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
South Asian Clinical Toxicology Research Collaboration
0.5 – 1 Unit/kg/hr regular insulin
give 0.5 gm/kg/hr dextrose (glu > 100)
check glucose every 30 mins initially
Insulin & Glucose: DoseInsulin & Glucose: Dose
South Asian Clinical Toxicology Research Collaboration
Use of insulin/dextrose: Cardiac Use of insulin/dextrose: Cardiac glycosideglycoside
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???
South Asian Clinical Toxicology Research Collaboration
Oubaassine 2006 – rat workOubaassine 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?
South Asian Clinical Toxicology Research Collaboration
Effect of insulin dextrose on survivalEffect of insulin dextrose on survival
0 30 60 90 120 150 180
0
2
4
6
8
10 Control
Insulin glucose
insulinglucose/salinestarts
digoxin starts
Time
Su
rviv
al
South Asian Clinical Toxicology Research Collaboration
Fructose 1-6 diphosphateFructose 1-6 diphosphate
Extensive human experience for a number of conditions
? Cardiac glycoside
South Asian Clinical Toxicology Research Collaboration
CaseCase 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
South Asian Clinical Toxicology Research Collaboration
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
South Asian Clinical Toxicology Research Collaboration
South Asian Clinical Toxicology Research Collaboration
Fructose 1,6 diphosphate (FDP) 1Fructose 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.
South Asian Clinical Toxicology Research Collaboration
Response of dysrhythmias to FDPResponse of dysrhythmias to FDP
0 30 60 90 120 150 180 210 240
0
1
2
3
4
5
6
Control
FDP
Time (mins post oleander)
Nu
mb
er o
f d
og
s w
ith
dys
rhyt
hm
ia
South Asian Clinical Toxicology Research Collaboration
Response of blood pressure to FDPResponse of blood pressure to FDP
South Asian Clinical Toxicology Research Collaboration
Response of plasma [KResponse of plasma [K++] to FDP] to FDP
South Asian Clinical Toxicology Research Collaboration
ConclusionsConclusions 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
South Asian Clinical Toxicology Research Collaboration
AcknowledgementsAcknowledgements• Michael Eddleston (Scottish Poison Centre)
• Prof Kent Olson (San Francisco Poison Centre)
• Dapo Odujebe (New York Poison Centre)
www.wikitox.orgOpenSource Toxicology Teaching