south asian clinical toxicology research collaboration management of cardiac arrests due to oleander...

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.


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


Why did ACLS forget cardiac Why did ACLS forget cardiac glycosides?glycosides?


The Toxic CVS mnemonicThe Toxic CVS mnemonicAtropine

Bicarbonate

Cations Calcium Mg

Diazepam

Epinephrine

Fab Digoxin Antibodies

Glucagon

Human Insulin Euglycaemia


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


The CaseThe Case A 70 kg man presents on 1-2 hours following a

TCA overdose (3000 mg Amitryptilline)– Unconscious – Seizure– BP 60 Systolic


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)


Phospholipid BarrierPhospholipid Barrier

Passive diffusion depends– Ionization

status– Lipid solubility– [Gradient]


TCA: AmitryptillineTCA: Amitryptilline Weak Base Highly bound

– Albumin: high capacity low affinity

– alpha 1 glycoproteins: low capacity high affinity

– Lipids Sodium channel blocker


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


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


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


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


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


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


TCA: pH = 7.1TCA: pH = 7.1


TCA: pH= 7.3TCA: pH= 7.3

200 meq bicarbonate


TCA: pH =7.4TCA: pH =7.4

200 meq bicarbonate


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


Bicarbonate / Alkalinisation: Bicarbonate / Alkalinisation: pH manipulationpH manipulation

IndicationsIndications

Should be trialled in any broad complex rhythm associated with poisoning


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


Yellow oleander Yellow oleander cardiotoxicitycardiotoxicity


Oleander poisoningOleander poisoning

Epidemiology

Standard treatment = pharmacokinetics

Mechanisms of toxicity

Possibilities for treatment that result from this knowledge

Future research??


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


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%


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)


Capacity for clinical observation


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)


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


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


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+


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+


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.


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’


““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’


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.


Evidence based treatmentEvidence based treatment

Only two interventions have been carefully studied

Anti-digoxin/digitoxin Fab– Alters distribution

Activated charcoal– Reducing absorption– Speeding elimination


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


Effect of Fab in oleander poisoning

•Eddleston M et al Lancet 2000


Effect of anti-digoxin Fab on dysrhythmiasEffect of anti-digoxin Fab on dysrhythmias


Effect of Fab on serum potassiumEffect of Fab on serum potassium


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


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


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.


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


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


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).


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


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


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


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


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


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???


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?


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


Fructose 1-6 diphosphateFructose 1-6 diphosphate

Extensive human experience for a number of conditions

? Cardiac glycoside


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


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


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.


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


Response of blood pressure to FDPResponse of blood pressure to FDP


Response of plasma [KResponse of plasma [K++] to FDP] to FDP


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


AcknowledgementsAcknowledgements• Michael Eddleston (Scottish Poison Centre)

• Prof Kent Olson (San Francisco Poison Centre)

• Dapo Odujebe (New York Poison Centre)

www.wikitox.orgOpenSource Toxicology Teaching

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