Transcript Metabolic Acidosis

Toxicity mediated by interference with
membrane pumps
- underlying mechanisms of
cardiac glycoside toxicity
Michael Eddleston
Scottish Poisons Information Bureau
Royal Infirmary of Edinburgh, UK
Cardiac glycoside poisoning
• Epidemiology of cardiac glycoside poisoning
• Standard treatment = pharmacokinetics
• Mechanisms of toxicity
• Possibilities for treatment that result from this
knowledge
• Future research??
Cardiac glycoside medication poisoning
Deaths uncommon in industrialised countries
• Schaper et al Eur J Intern Med 2006;17:474.
GIZ-Nord Poison Center consulted in 168,000 cases.
142 deaths (0.08% of cases)
None due to cardiac glycosides
• AAPCC data from USA 2005 Clin Tox 2006;44:803.
61 poison centres consulted in 2,424,180 cases
1261 deaths (0.05% of cases)
20 (1.6%) primarily due to cardiac glycosides
(10 due to therapeutic error, 3 ADR, only 3 intentional)
Self-poisoning in north central Sri Lanka
Prospective cohort of acutely poisoned patients started
in March 2002 in 2 district hospitals. Now contains over
13,000 patients.
Up to mid-2005:
8383 cases
98% due to self-harm
Pesticides:
3848 (45.9% of total)
Oleander seeds:
2423 (28.9% of total)
Other common poisons: medicines & hydrocarbons
All treated using a standard protocol
Case fatality for different classes of poison
all poisons
pesticides
oleander seeds
kerosene
0.0
2.5
5.0
7.5
10.0
12.5
Case fatality ratio (95% CI)
15.0
Case series of oleander poisoning
• Jaffna, Sri Lanka, 1980 - 170 patients over 3 years,
with 7 deaths (CFR 4.1%).
• Bankura, W Bengal, 1985 – 300 patients over 5
years, with 14 deaths (CFR 4.7%).
• Anuradhapura, Sri Lanka, 1995 – 79 patients over 4
months, with 6 deaths (CFR 7.6%)
• North Central Province, Sri Lanka 2005 – 2423
patients over 3 years, with 109 deaths (CFR 4.5%)
Symptoms of substantial
oleander poisoning (n=66)
Cardiac dysrhythmias
100%
Nausea
Vomiting
Weakness
Fatigue
Diarrhoea
Dizziness
Abdominal Pain
Visual Symptoms
Headache
Sweating
Confusion
Fever and/or Chills
Anxiety
Abnormal Dreams
100%
100%
88%
86%
80%
67%
59%
36%
34%
20%
19%
5%
3%
3%
Standard treatment
Only two interventions have been carefully studied
• Anti-digoxin/digitoxin Fab
• Activated charcoal
Both these treatments work by affecting the
pharmacokinetics of the cardiac glycoside, by:
o speeding elimination and/or
o reducing absorption
Standard treatment
Only two interventions have been carefully studied
• Anti-digoxin/digitoxin Fab
• Activated charcoal
Both these treatments work by affecting the
pharmacokinetics of the cardiac glycoside, by:
o speeding elimination and/or
o reducing absorption
The introduction of Fab fragments
for digoxin poisoning
• first reported in humans in April 1976
• reversal of advanced digoxin intoxication with Fab
fragments of digoxin-specific ovine antibodies
• Ingested dose = 22.5 mg of digoxin
• serum potassium initially 8.7 mmol/l
Time course of :
total serum digoxin (
)
Free serum digoxin (
)
Fab fragments (
)
serum potassium (
)
after iv administration of DA
in a 39-year-old man
with severe digoxin poisoning.
Smith TW et al. Reversal of
advanced digoxin intoxication
with Fab fragments of digoxinspecific antibodies. N Engl J
Med 1976;294:797-800.
Effect of Fab in oleander poisoning
Effect of anti-digoxin Fab on dysrhythmias
Effect of Fab on serum potassium
Standard treatment
Only two interventions have been carefully studied
• Anti-digoxin/digitoxin Fab
• Activated charcoal
Both these treatments work by affecting the
pharmacokinetics of the cardiac glycoside, by:
o speeding elimination and/or
o reducing absorption
Treated with Activated Charcoal vs Not Treated with Activated Charcoal
Odds ratio
(95% CI)
No. of events/ No. of participants
Treated AC Untreated AC
Poison
Test of
Interaction
P=0.7
Organophosphate
0.85 ( 0.57, 1.27)
74/624
45/330
Oleander
1.00 ( 0.60, 1.67)
46/1010
23/505
Other or NK Pesticide/Paraquat
1.10 ( 0.63, 1.89)
44/640
20/317
Other substances
1.50 ( 0.63, 3.56)
22/537
7/253
Severity
P=0.4
Asymptomatic
1.24 ( 0.66, 2.32)
35/1325
14/654
Symptomatic GCS 14/15
1.10 ( 0.71, 1.71)
67/1157
31/586
Symptomatic GCS <14
0.79 ( 0.52, 1.19)
84/329
50/165
Time since ingestion
P=0.6
<= 2 hours
0.79 ( 0.49, 1.29)
46/615
29/313
3-4 hours
1.10 ( 0.69, 1.74)
61/887
28/444
5-7 hours
1.04 ( 0.58, 1.86)
37/636
18/321
>=8 hours
Missing
1.15 ( 0.64, 2.06)
0.29 ( 0.04, 2.01)
40/646
2/27
17/313
3/14
Overall
0.98 ( 0.75, 1.28)
.1
.5
1
1.5 2 2.5
4
Odds Ratio
Favours Treated with AC
Favours Not treated with AC
186/2811
95/1405
Comparison of two published RCTs
de Silva
MDAC 5/201 [2·5%] vs SDAC 16/200 [8%]
RR 0.31 (95% CI 0.12 to 0.83)
SACTRC
MDAC 22/505 [4·4%] vs SDAC 24/505 [4.8%]
RR 0.92 (95% CI 0.52 to 1.60)
Fixed effects model, test of heterogeneity P=0.06
Why? Different regimen? Poor compliance?
Time from hospital admission to death in
RCT
No AC
SDAC
MDAC
0
12
24
36
48
60
72
84
96
Time from admission to death (hrs)
108 120
Standard treatment
Only two interventions have been carefully studied
• Anti-digoxin/digitoxin Fab
• Activated charcoal
Current situation:
Anti-digoxin Fab are too expensive for widespread use
The evidence for activated charcoal is ? negative
Are there other options?
Here we need to understand the mechanism of toxicity
Ion channels of cardiac muscle
Function of Na+/K+ ATPase
Effect of cardiac glycosides
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.
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 reticulum’s capacity to
sequester it, resulting in systolic arrest – ‘stone heart’
Yellow oleander
cardiotoxicity
Potassium effects 1
• Hyperkalaemia 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’
Potassium effects 2
• Pre-existing hypokalaemia also 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.
What other treatment options are available?
• Anti-arrhythmics – lidocaine & phenytoin
• Atropine & pacemakers
• Correction of electrolyte abnormalities
• Correction of hyperkalaemia
• Fructose 1,6 diphosphate
Unfortunately, as yet, no RCTs to guide treatment
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.
Rate at 5 min
Response of atropine-naïve oleander poisoned
patients to 0.6mg of atropine
140
130
120
110
100
90
80
70
60
50
40
50
60
70
80
baseline rate
90
100
Response of atropine-naïve oleander poisoned
patients to 0.6mg of atropine
140
Rate at 15 min
130
120
110
100
90
80
70
60
40
50
60
70
80
baseline rate
90
100
Importance of the nervous system
• In animals, spinal cord transection reduces the
toxicity of cardiac glycosides
• Administration of the a2-adrenoceptor agonist
clonidine increases the dose of cardiac glycoside
required to induce dysrhythmias and death. Inhibited
by administration of yohimbine.
• Can this information be confirmed in humans? Is this
partly how atropine is working?
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.
Correction of electrolyte disturbances
• Hypokalaemia exacerbates cardiac glycoside toxicity
therefore ? reasonable to replace K+.
• 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 admission
serum potassium mmol/L
8
7
6
5
4
mild or no cardiotoxicity
3
severe cardiotoxicity
2
0
1
2
3
4
[cardiac glycoside] (nmol/L)
5
Correction of electrolyte disturbances
• Hypokalaemia exacerbates cardiac glycoside toxicity
therefore ? reasonable to replace K+.
• 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 magnesium on admission
serum magnesium mmol/L
1.15
0.90
0.65
mild or no cardiotoxicity
severe cardiotoxicity
0.40
0
1
2
3
4
[cardiac glycoside] (nmol/L)
5
Correction of electrolyte disturbances
• Hypokalaemia exacerbates cardiac glycoside toxicity
therefore ? reasonable to replace K+.
• 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).
Correction of
hyperkalaemia
dangerous or
beneficial?
Cerbera manghas poisoning
(pink-eyed cerbera, odallam, kaduru, or sea mango)
Use of insulin/dextrose for hyperkalemia
• 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 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 survival
digoxin starts
10
Control
Insulin glucose
Survival
8
insulin
glucose/
saline
starts
6
4
2
0
0
30
60
90
Time
120
150
180
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.
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.
Response of dysrhythmias to FDP
Number of dogs with
dysrhythmia
6
5
4
3
Control
2
FDP
1
0
0
30
60
90
120 150 180 210 240
Time (mins post oleander)
Response of blood pressure to FDP
Response of plasma [K+] to FDP
Conclusions
• Cardiac glycoside toxicity is a common global problem
• Anti-digoxin Fab are an effective PK Rx but expensive
• Treatments based on a mechanistic understanding
may also be effective but none have been trialed,
perhaps due to the effectiveness of Fab
• FDP – if found to be effective, its safety and price make
it a very attractive future therapy. Unfortunately, we do
not yet know how FDP works!