Title: Management of cardiac arrests due to oleander or pharmaceutical poisoning'
1Management 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 )
2Toxic 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
3Why did ACLS forget cardiac glycosides?
4The Toxic CVS mnemonic
- Atropine
- Bicarbonate
- Cations Calcium Mg
- Diazepam
- Epinephrine
- Fab Digoxin Antibodies
- Glucagon
- Human Insulin Euglycaemia
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6The Case
- A 70 kg man presents on 1-2 hours following a TCA
overdose (3000 mg Amitryptilline) - Unconscious
- Seizure
- BP 60 Systolic
7Antidepressants ( 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
8Phospholipid Barrier
- Passive diffusion depends
- Ionization status
- Lipid solubility
- Gradient
9TCA Amitryptilline
- Weak Base
- Highly bound
- Albumin high capacity low affinity
- alpha 1 glycoproteins low capacity high affinity
- Lipids
- Sodium channel blocker
10Altering Ionization
- Equilibrium influenced by external pH
- The balance of the equilibrium can be expressed
by pKa - The pKa is the pH where ionized unionized
11Phospholipid 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.
12Altering 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
13Distribution
- 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
14Receptor 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
15pH 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
16TCA pH 7.1
17TCA pH 7.3
18TCA pH 7.4
19Risk?
- 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
20Bicarbonate / Alkalinisation pH
manipulationIndications
- Should be trialled in any broad complex rhythm
associated with poisoning
21Bicarbonate / 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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23Yellow oleander cardiotoxicity
24Oleander poisoning
- Epidemiology
- Standard treatment pharmacokinetics
- Mechanisms of toxicity
- Possibilities for treatment that result from this
knowledge - Future research??
25Oleander Multiple cardioglycosides
- 22 of all poisonings
- Mortality
- N 4111
- 3.9 ( 95 CI 3.3-4.6)
- Morbidity
- Resources transfer and monitoring
26Symptoms 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
27Time from hospital admission to death in RCT n
1500
28Capacity for clinical observation
29Cardiac Glycosides Multiple Mechanisms
- Vagotonic effects
- Sinus bradycardia, AV block
- Slows ventricular rate in atrial fibrillation
- Inhibits Na-K-ATPase pump
- ? extracellular K
- Myocardial Toxicity ?
30Glycosides
- 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
31Voltage 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
32Phase 2
Ca2
Ca2
3 Na
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Ca2
Cell Electrophysiology
33K
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
34Consequences 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.
35Consequences 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
36Hyperkalaemia 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
37Pre-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.
38Evidence based treatment
- Only two interventions have been carefully
studied - Anti-digoxin/digitoxin Fab
- Alters distribution
- Activated charcoal
- Reducing absorption
- Speeding elimination
-
-
39Digoxin 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
40Effect of Fab in oleander poisoning
- Eddleston M et al Lancet 2000
41Effect of anti-digoxin Fab on dysrhythmias
42Effect of Fab on serum potassium
43Activated 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?
44What 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
45Classic 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.
46Atropine
- 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
47Response of atropine-naïve oleander poisoned
patients to 0.6mg of atropine
48Correction 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).
49Serum potassium on admission
50Serum magnesium on admission
51Human- 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
52Human- 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
53Insulin 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
54Use 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???
55Oubaassine 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?
56Effect of insulin dextrose on survival
57Fructose 1-6 diphosphate
- Extensive human experience for a number of
conditions - ? Cardiac glycoside
58Case
- 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
59- 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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61Fructose 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.
62Response of dysrhythmias to FDP
63Response of blood pressure to FDP
64Response of plasma K to FDP
65Conclusions
- 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
66Acknowledgements
- 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