Transcript Oximes, atropine and diazepam in organophosphate and carbamate poisoning
Oximes, atropine and diazepam in organophosphate and carbamate poisoning
Dr Martin Wilks, Syngenta Crop Protection AG, Basel, Switzerland
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Modes of action of the top-selling insecticides/acaricides and their world market share (Nauen, 2002) Mode of action Acetylcholinesterase
Voltage-gated Na channel Nicotinic receptor GABA-gated Cl channel Chitin biosynthesis Other
1987 (%) 71
17 1.5
5.0
2.1
0.5
1999 (%) 51
18 12 8.3
3.0
2.9
Change (%) -20
+1.4
+10 +3.3
+0.9
+2.4
The scale of the problem
● Asia: est. 300,000 deaths /year from pesticide poisoning ● Est. 200,000 involve ingestion of OPs (and carbamates) (Eddleston and Phillips, 2004, BMJ 328: 32 – 44) ● Sri Lanka - 17000 admissions - 35% ICU - 10% Die (20% of symptomatic) 3
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Outline
● Review the Mechanism ● Does the type of compound matter? ● Aspects of treatment - Do they need Atropine?
- Do they need Decontamination?
- Do they need Oximes?
● Magnesium, Diazepam, Bicarbonate ● Lessons learned
Organophosphate Carbamate
R 1 R 2 O(S) II P - O - X R 1,2 X = alkyl or aryl groups = wide range of branched or substituted groups R 1 O II - NH - C - O - R 2 R 1 = methyl, aromatic or benzimidazol group R 2 = aromatic or aliphatic group 5
Acetylcholinesterase and OP
Organophosphate 6
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Nicotinic, muscarinic and central syndrome
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Clinical Syndromes
● Acute Cholinergic:
- Central - Peripheral Muscarinic - Peripheral Nicotinic
● Intermediate Syndrome ● Delayed peripheral neuropathy ● Neurocognitive dysfunction
Respiratory failure
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Acute Cholinergic Syndrome Severity
Mild > 40% nausea, vomiting, diarrhoea, salivation, bronchorrhoea and -constriction, bradycardia Moderate 20 - 40% as above, + miosis, incontinence Severe
AChE (RBC)
< 20%
Muscarinic Nicotinic
fasciculations (fine muscles)
CNS
headache, dizziness as above, + dysarthria, ataxia as above, + fasciculations (diaphragm, resp. muscles) as above, + coma, convulsions
Moat common OP pesticides used in self-poisoning in Sri Lanka
10 Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9
Number of cases WHO Toxicity Formulation Chemistry Rat oral LD50 (mg/kg)
WHO OSHA Chlorpyrifos Dimethoate Fenthion 440 II 266 II 40% EC 40% EC Diethyl Dimethyl 100 II 50% EC Dimethyl 135 97 150 250
Not Given
215-245
Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9 11
Relative human toxicity of pesticides in self-poisoning X
symptomatic
X X X
12 Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9
Time to Death
● Early & late respiratory failure ● Hypotensive Shock (Dimethoate) ● Iatrogenic 13
Chlorpyrifos poisoning
700 600 500 400 300 200 100 ti -5,0 0 AChE in vivo AChE in vitro 24 48
Time [h]
72 96 3000 2500 2000 1500 1000 500 ti -5,0# 0 BChE 24 48
Time [h]
72 96 14
Fenthion poisoning
500 400 300 200 100 ti -3,7 0 24 48
Time [h]
AChE in vitro AChE in vivo 72 3000 2500 2000 1500 1000 500 96 ti -3,7 0 BChE 24 48
Time [h]
72 96 15
Dimethoate poisoning
500 400 300 200 100 ti -2,2 0 AChE in vivo AChE in vitro 24 48
Time [h]
72 96 3000 2500 2000 1500 1000 500 ti -2,2 0 BChE 24 48
Time [h]
72 96 16
OPs are different
● Differing Toxicity ● Different Kinetics ● Different Clinical Syndromes ● Different Response to Antidotes ● ? Need Different Treatment Responses
Complicates Assessment of the Evidence
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Sequence of Medical Management
1.
2.
3.
4.
5.
Basic Supportive Care Does the patient need Atropine ?
Poor air entry into the lungs due to bronchorrhoea and bronchospasm Bradycardia Excessive sweating Small pupils Hypotension.
Decontamination ?
Oximes?
Adjunctive Treatment ?
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Atropine – mechanism and endpoints
●
Mechanism
- Blocks the muscarinic effects due to excess acetylcholine - Competitive inhibitor - Control of symptoms determines the dose by titration ● Endpoint - Which cholinergic effect should be the endpoint?
- Pupil size?
- Secretions?
- Heart rate?
- Blood Pressure?
- Measurement of peripheral vascular resistance?
Atropine Dose in Organophosphates
● Sri Lankan ventilated OP patients who survived require - Mean initial dose of 23.4 mgs.
- Maximum initial dose of 75 mg ● 38 texts with 31 different recommendations Eddleston M et al .Speed of initial atropinisation in significant organophosphorus pesticide poisoning. J Tox Clin Tox 2004;42(6):865-75 20
Range of times it would take to give adequate doses of atropine (23mg and 75 mg) following the expert advice from each text
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Scheme of atropinization (endpoints to be reached) 2 4 8
40 30 20 10 0 0 5 10
min after first atropine dose
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16 Atropine requirement Poor air entry into lungs caused by bronchospasm and bronchorrhoea Excessive sweating (Hypotension) (Bradycardia) (Miosis) Atropinization Clear lungs Dry axillae Systol. BP > 80 mm Hg Heart rate > 80/min No miosis
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Atropine
●
Loading
- Doubling dose regime e.g. 2 4 8 16 mgs every 5 minutes ●
Maintenance
- Continuous infusion < 3mg/hr - 10-20% of loading dose/hour ●
Endpoints
- Clear chest on auscultation with no wheeze - Heart rate >80 beats/min ●
Withdrawal
- Atropine toxicity - Clinical Improvement 23
Decontamination
● Don’t confuse creating mess with efficacy ● Decisions based on risk/benefit analysis 24
Gastric emptying – what happens if you stop?
Case fatality Anuradhapura Hospital 1998-2002 30 20 10 0 1998 1999 2000 2001 2002
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The results of observational data on gastric emptying (GE) in pesticide self-poisoning Case fatality Anuradhapura Hospital in and not in RCT 75 No GE (in trial) GE (NIT) 50 25 0 GCS <14 GCS <10
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Eddleston M, et al (2008) Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet 371: 579 - 587
● 4632 patients recruited ● Overall death rate around 7%, pesticide death rate around 13% - No significant difference between no AC, SDAC and MDAC ● Mortality did not differ between groups. Odds ratios: - SDAC vs no AC 1.05 (95% CI: 0.79, 1.40) - MDAC vs no AC 0.93 (95% CI: 0.69, 1.25) - MDAC vs SDAC 0.89 (95% CI 0.66, 1.19) ● No difference in rates of ventilation for OP and Carb poisoned patients 27
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Therapy with Oximes: Basics
H 3 C RO X P O
+
EOH HON H 3 C P O O E RO X
+
H + R H 2 O O H 3 C RO P E O
+
X Inhibition
-
H 2 O EOH
+
H 3 C RO P O O N R Reactivatio n H O EOH
+
H 3 C RO P O H 3 C O E P O O
+
R +
+
H + Spontaneous reactivation Aging Worek et al. Biochem Pharmacol. 2004
AChE-Status in a Patient with Parathion Poisoning
obidoxime 800 600 reactivatability 400 200 RBC-AChE in vivo 0 0 25 50 hours 75
Patient
: A 45-year old, male 100 200 150 100 50 0 0 inhibitory activity 25 50 hours 75 100
Emergency situation
: Unconscious, severe signs and symptoms of cholinergic crisis. 1.5 mg of atropine, intubation and initiation of artificial ventilation.
Clinical course
: 2 bolus doses of obidoxime together with an atropine infusion at the local hospital. Transfer to the ICU of Technical University, Munich. The patient recovered uneventfully.
Eyer et al. Toxicol Rev. 2003 29
Oximes
● Effective protocols not established - Variation in use - Zero – 24 grams a day - Intermittent bolus vs continuous infusion ● Ineffective against some OPs ● Issues of availability/affordability - Pralidoxime - USA - India - Sri Lanka $600 / gram $9 / gram 55 cents / gram 30
... but do they work?
● Buckley et al (2005) Cochrane Database Syst Rev, CD005085 - Two published RCTs, one abstract RCT - Insufficient evidence whether oximes are harmful or beneficial ● Peter et al (2006) Crit Care Med 34: 502 – 510 - Two published RCTs, 5 controlled trials - Oximes either ineffective or harmful ● Rahimi et al (2006) Human Exp Toxicol 25: 157 – 162 - Six clinical trials - Oximes are not effective and can be dangerous 31
New antidotes, new therapies?
• • • • • • Protect AChE • Cholinesterase inhibitors Supply AChE Sacrifice • Synthetic and Natural (FFP) Reduce ACh Release • Magnesium, Clonidine Protect Receptor • Neuromuscular Blockers Reduce OP Load • Increase Hydrolase capacity Multiple Mechanisms • Altering Ph 32
Magnesium
● Reduces acetylcholine release - Blocks pre-synaptic calcium channels - Central and Peripheral Nervous System ● Decrease toxicity in animal models
Pajoumand A et al (2004) Hum Exp Toxicol 23(12):565-9
● ● 16 gram continuous infusion MgSO 4 for 24 hours Normal care (oximes and atropine) in both groups - 0/11 patients died with magnesium - 5/34 control patients - Methodological issues - pseudorandomisation 33
Diazepam
● Routinely used in OP poisoning for treatment of agitated delirium and seizures ● Diazepam reduces respiratory failure (rats) and cognitive deficit (primates) ● Postulate “uncoordinated stimulation of the respiratory centres decreases phrenic nerve output” ● Role for peripheral benzodiazepine receptor?
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Diazepam
● Synergistic response with anticholinergics - Dickson EW et al Diazepam inhibits organophosphate-induced central respiratory depression. Acad.Emerg.Med. 2003;10(12):1303 35
Organophosphates and pH
● Organophosphate Hydrolase is pH sensitive.
● Binding of pralidoxime is pH sensitive. ● Acetylcholinesterase ● Aging of OP-AChe complex and reactivation. 36
Comparative efficacy of i.v. pralidoxime vs. NaHCO 3 in rats lethally poisoned with OP insecticide (A Wong, Brazil)
● 5 Groups of 10 rats a) DDVP only (no treatment) b) Atropine (17 mg/kg) alone 0/10 3/10 c) Atropine + pralidoxime (1 g/kg) 4/10 d) Atropine +
NaHCO 3
(3 meq/kg) 9/10 e) Atropine + NaCl 0.9% (1.9 ml/kg) 5/10 37
Comparative efficacy of i.v. pralidoxime vs. NaHCO 3 in rats lethally poisoned with OP insecticide (A Wong, Brazil)
8000 7000 6000 5000 4000 3000 2000 1000 0 0
D.D.V.P.
p<0.001 D~B and D~C p<0.01 D~E 309.43
Atropine
462.17
Atrop. + Oxime
N = 10 rats in each group 7012.12
Atrop. + Bicarb.
2611.17
Atrop. + NaCl
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BalaliMood M. Effect of High Doses of Sodium Bicarbonate in Acute Organophosphorous Pesticide Poisoning. Clinical Toxicology, 43:571574, 2005
● RCT N=30 ● NaHCO 3 pH 7.45-7.55
- 5 mEq/Kg over 60 minutes - 5-6 mEq/Kg over 24 hours ● Length of hospital stay - Controls 5.59 ± 1.97
- Treatment 4.33 ± 1.99
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Some lessons from clinical research
● Influence of Initial Care on Mortality - Risk of decontamination ● Predictors of Mortality - Pesticide type & Clinical Status ● Use Atropine Aggressively but Titrate - The doubling protocol ● Reasons for Oxime Failure - Chemical and Kinetic - Implications for where, how and what treatment is delivered ● More Large-Scale Randomised Controlled Trials Are Needed, and They Will Be Coming from Sri Lanka
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