use of oximes in the management of organophosphorus pesticide poisoning michael eddleston south...
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Use of oximes in the management of
organophosphorus pesticide poisoning
Michael Eddleston
South Asian Clinical Toxicology Research Collaboration,
Centre for Tropical Medicine,Nuffield Department of Medicine,
University of Oxford.
Dept of Clinical Medicine, University of Colombo,
Sri Lanka.
Funded by the
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Pralidoxime
Pyridine-2-aldoximeQuarternary ammonium salt discovered by Wilson 1955
Four salts: chloride (2-Pam, Mw 173), mesilate (Mw 232) metilsulfate (Mw 249), iodide (Mw 264),
Renal excretion (85% in urine 24hrs after bolus dose)
VD = 0.6 L/kgT ½ = 4.2 minsT ½ = 75 mins (Some papers suggest that PK is altered in patients)
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Wilson’s work in early 1950s [BBA 1955]
2 pyridine aldoxime
Nicotinohydroxamic acid methiodide
2 pyridine aldoxime methiodide
[2 pralidoxime methiodide, 2-PAM]
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Wilson’s work in early 1950s [BBA 1955]
LuH6
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Pralidoxime
Pyridine-2-aldoximeQuarternary ammonium salt discovered by Wilson 1955
Four salts: chloride (Mw 173), iodide (Mw 264), metilsulfate (Mw 249), mesilate (Mw
232)
Renal excretion (85% in urine 24hrs after bolus dose)
VD = 0.6 L/kgT ½ = 4.2 minsT ½ = 75 mins (Some papers suggest that PK is altered in patients)
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Effect of thiamine coadministration on pralidoxime PK
Josselson 1978
• Comparison of PAM chloride 5 mg/kg over 2 min alone vs
• PAM chloride + constant infusion of thiamine 100 mg/hr
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Oxime pharmacolog
y
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Pralidoxime
First used clinically by Namba in 1956
Most textbooks now recommend a regimen of:1g over 5-20 mins, repeated after 3-8 hrs. Commonly given for just 24 hrs.
However, many Asian clinicians doubt its effectiveness
The World Health Organization responds that pralidoxime should be given.
But what is the clinical trial evidence?
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What is the clinical evidence for oximes use? 1
1991 Senanayake, Peradeniya, SL.Found no difference in OP poisoning fatality rate during 6 months when pralidoxime was available compared to a 6 month period when it was not available (when each patient received 1g q6h for 1 day).
WHO response: “too low a dose”. But no trials to support this view.
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Plasma concentration of 2-PAMfollowing two different regimes
0 4 8 12 16 20 240
20
40
60
80
100A Single boluses 1 g qds
B Single bolus 1 g, followed by continuous infusion at 0.5 g/h
A
B
h
[PAM] 20 mg/L = 75 µMol
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What is the clinical evidence for oximes use? 2
1992 Samuel, Vellore, India.Compared 1g bolus pralidoxime with a 12g infusion over 4 days in 72 patients. Found non-significant increase in death and ventilation requirement in patients receiving the infusion.
1993 Cherian, Vellore, India.Compared 12g infusion over 3 days with placebo in 110 patients. Found significant increase in death, intermediate syndrome, and ventilation requirements in patients receiving pralidoxime
WHO: uncertain methodology, no loading dose
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1993 Cherian RCT
Compared 12g PAM given over 3 days (estimated 3.7mg/kg for a 45kg patient) with saline placebo in 110 patients
PAM increased mortality: AR 16/55 [29%] with PAM vs. 3/55 [5%] with placebo; Relative risk 5.3, 95% CI 1.7 to 17.3
PAM increased requirement for ventilation: AR 36/55 [67%] with PAM vs. 22/55 [40%] with placebo; Relative risk 1.7, 95% CI 1.1 to 2.4
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‘High dose’ PAM PK in RCT 2 from Vellore
(0.16g/hr infusion without bolus in 50kg person)
0 4 8 12 16 20 24 280
20
40
60
80
100
Hrs
Pla
sm
a P
AM
mg
/L
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Comparison of PAM and obidoxime
100 µMolEyer 2003, Toxicol Rev
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100 nMol paraoxon
Eyer 2003, Toxicol Rev
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There may also be differences between OPs in how they respond to oximes
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diEthyl vs. diMethyl OPs
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Oxime pharmacolog
y
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Half-life of reaction 1 - Inhibition
- Milliseconds for both diMethyl and diEthyl OPs
Half-life of reaction 2 - Spontaneous reactivation
- 1 hr for diMethyl
- 30hrs for diEthyl
Half-life of reaction 2 - Ageing
- 3hrs for diMethyl
- 33hrs for diEthyl
Summary
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Conclusions
• Inhibition is very fast, reactivation much slower.
• diMethyl OPs reactivate faster than diEthyl OPs.
• But oximes speed up reactivation for both.
• Ageing also occurs faster with diMethyl OPs – reactivation being no longer possible after 4 half-lives (12hrs) and severely limited after 1-2 half-lives (3-6hrs).
• Ageing takes longer with diEthyl OPs – oximes may therefore work for up to 130hrs (5 days), and be very effective after 1 half-life (> 1 day).
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Do we see any evidence of this variable response clinically?
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Organophosphorus pesticide poisoning
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Chlorpyrifos poisoning
0 24 48 72 96ti -5,0
100
200
300
400
500
600
700AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol
Hb
0 24 48 72 96ti -5,0#
500
1000
1500
2000
2500
3000
BChE
Time [h]m
U/m
l P
lasm
a
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Fenthion poisoning
0 24 48 72 96ti -3,7
100
200
300
400
500
AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol
Hb
0 24 48 72 96ti -3,7
500
1000
1500
2000
2500
3000
BChE
Time [h]
mU
/ml P
lasm
a
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Dimethoate poisoning
0 24 48 72 96ti -2,2
100
200
300
400
500AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol
Hb
0 24 48 72 96ti -2,2
500
1000
1500
2000
2500
3000
BChE
Time [h]m
U/m
l P
lasm
a
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Have we got the dose wrong for dimethoate?
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Plasma concentration of 2-PAMfollowing two different regimes
0 4 8 12 16 20 240
20
40
60
80
100A Single boluses 1 g qds
B Single bolus 1 g, followed by continuous infusion at 0.5 g/h
A
B
h
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Dimethoate poisoning in Munich
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Profenofos
Prothiofos
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Profenofos poisoning
0 24 48 72 96ti -3,5
100
200
300
400
500
AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol
Hb
0 24 48 72 96ti -3,5
500
1000
1500
2000
2500
3000
BChE
Time [h]m
U/m
l P
lasm
a
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Current view of OPs in relation to Rx
Diethyl OPs - toxic but responsive to PAM
Dimethyl OPs - less toxic but less responsive
S-linked OPs - less toxic but not responsive
Pralidoxime seems to work for some OPs, not for others
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An RCT of high-dose pralidoxime in acute symptomatic organophosphorus pesticide self-poisoning
Patients: all patients (>13yrs, not pregnant) with a history of OP self-poisoning and symptoms/signs consistent with Dx.
Outcome: vital status at discharge
Power: to detect a reduction in all-cause mortality from 25% to 19%, 750 patients must be recruited to each arm of the study (1500 in
total)
Rx: - saline placebo bolus and infusion.- bolus of 2g pralidoxime chloride followed by
an infusion of 500mg/hr for up to 7 days.
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2-PAM chloride regime2g bolus in 20 min;0.5g/h cont. infusion
fatal cases
0.0 0.1 0.2 0.3 0.4 0.50
100
200
300
400
500
1 2 3 4
1312 11
7 5 4 3
n=16
Time [d]
2-PAM chloride regime2g bolus in 20 min;0.5g/h cont. infusion
survived casesn=46
0.0 0.1 0.2 0.3 0.4 0.50
100
200
300
400
500
1 2 3 4
34
4039
35 21 11 8
Time [d]
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2-PAM chloride regime2g bolus in 20 min;0.5g/h cont. infusion
fatal cases
0.0 0.1 0.2 0.3 0.4 0.50
100
200
300
400
500
1 2 3 4
1312 11
7 5 4 3
n=16
Time [d]
2-PAM chloride regime2g bolus in 20 min;0.5g/h cont. infusion
survived casesn=46
0.0 0.1 0.2 0.3 0.4 0.50
100
200
300
400
500
1 2 3 4
34
4039
35 21 11 8
Time [d]
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0 1 2 3 4 5 6 70
100
200
300
400
500
Time [d]
in vitro
in vivo
AChE Activity in Chlorpyrifos Poisoning without 2-PAM
(means ± SEM, n=7)
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0 1 2 3 4 5 6 70
100
200
300
400
500
in vitro
in vivo
Influence of 2-PAM Treatment on AChE Activity in Chlorpyrifos Poisoning
(means ± SD; n= 11)
Time [days]
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Chlorpyrifos poisoning
0 24 48 72 96ti -5,0
100
200
300
400
500
600
700AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol
Hb
0 24 48 72 96ti -5,0#
500
1000
1500
2000
2500
3000
BChE
Time [h]m
U/m
l P
lasm
a
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Parathion reactivation
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Variation between OPs might be the reason why earlier trials did not find benefit from
pralidoxime
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• Another reason may be time to onset of poisoning
• If the patient becomes severely ill SOON after ingestion, they may well lose consciousness and aspirate the pesticide, or stop breathing and suffer hypoxic brain damage, before hospital admission.
• In this case, patients will die in hospital from aspiration pneumonia or hypoxic brain damage.
• Provision of antidotes including pralidoxime will then be irrelevant.
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Lancet 368: 2136
• A recent study carried out by S Pawar and colleagues in Baramati, Maharashtra, suggests that very high doses of pralidoxime iodide may benefit many patients with diEthyl and diMethyl OP poisoning who present early
• RCT of 200 patients
• All received 2g loading dose, then for 48hrseither 1g infused over 1 hr every 1 hror 1g infused over 1 hr every 4 hrs
followed by 1g every 4 hours until off ventilator
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Arm 2
0 12 24 36 48 60 72 84 960
20
40
60
80
100
TIME (h)
Pawar - usual dose arm
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Arm 1
0 12 24 36 48 60 72 84 960
20
40
60
80
100
Time (h)
Pawar - high dose arm
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Results
• Case fatality: 8% in control group1% in high dose group
• Ventilation: median time 10 hrs in control groupmedian time 3 hrs in high dose
group
• Interestingly, seemed to work for both dimethoate (diMethyl OP) and chlorpyrifos (diEthyl OP).
• The patients seem to have been moderately poisoned, with severely poisoned patients excluded.? Valid for severely poisoned patients?
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Different experiences of oxime use
• Baramati – good effect
– using PAM for all moderately ill cases
• CMC Vellore – no clinical benefit/adverse effect
– not using PAM anymore
– yet excellent CFR in ICU (~8%)
• Sri Lanka – little clinical benefit
– using bolus doses of PAM
– high CFR in ICU (~40%)
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Different experiences of oxime use
• Baramati – early presentation (median: 2hrs) – excellent supportive care – benefit for both diM and diE OPs
• CMC Vellore – late presentation (median: 10-12hrs) – excellent supportive care – most patients have taken diM OPs
• Sri Lanka – early presentation (median:3-4hrs) – very poor supportive care – biochemical effect only with diE OPs
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Conclusions
• The ideal regimen is likely to involve high doses and a bolus dose followed by an infusion
However • the evidence base for pralidoxime use is weak
• There is variable biochemical response to oximes by AChE inhibited by different OPs.
• Some OPs may not respond at all
• The time to presentation will affect whether pralidoxime is effective