The emergency and intensive care management of OP poisoning

Dr Bishan Rajapakse - Management of OP Poisoning (TWH ICU 2014)

Dr Bishan Rajapakse PhD Candidate Australia National University,

Advanced Trainee, Emergency Medicine, Wollongong Hospital South Asian Clinical Toxicology Research Collaboration

(SACTRC)

ICU Registrar Teaching – Thu 11th December 2014


•  Background of topic (5 mins) – References/source

•  OP Poisoning (25 mins) – Epidemiology/Pathophysiology

– Clinical Cases/Management

– Controversies of therapy

•  Knowledge translation (5 mins) with surprise ending?

•  Discussion (15mins)


•  OPP High case fatality and global mortality

•  ALS for OPP: concurrent atropine – High (doubling) doses

•  Pralidoxime controversial

•  Nosocomial poisoning (minimal risk to health workers)

•  New research is constantly unfolding in OP management!


•  Started as a bright spark 1st Year Advanced Trainee EM taking a year out… (and the rest is history)

•  MPhil (in Tox) ! to PhD in medical education & knowledge translation –  Measurement of AChE in acute

OP poisoning management –  Rural doctor resuscitation training

•  Worked with the “South Asian Clinical Toxicology Research Collaboration” (SACTRC) –  5 Hospitals in Sri Lanka


•  PhD thesis related reading/research –  Primary published research –  Discussion with toxicologist supervisors/colleagues –  Original research –  Clinical experience Thesis contents

Ch1 – Management of OP poisoning (text book chapter: Lippincott, Williams and Wilkins)

Ch2 – Review : recommendations for use of AChE in OP Mx

Ch 3 – Review : ALS for OP poisoning

Ch 4 – POC testing for AChE (Annals of EM 2011)

Ch 5 – Knowledge attitudes and practice (BMC-HSR 2014)

Ch 6 - Rurual ALS training (Plos One 2013)

Ch 7 – Knowledge translation in OP Mx


“The only thing I know is that I don’t know anything”

'The more you know, the more you know you don't know.'

'The more I learn, the more I realize how much I don't know.'

- Socrates

- Aristotle

- Albert Einstein


“Sharing something is better than sharing nothing”


A global health problem of massive proportion….


•  Prevalent in developing world –  300,000 deaths /year –  Self–poisoning

predominates

•  15-30% mortality –  (0.3% for all poisoning in

the west)

•  Also affects developed world nations –  Occupational exposure &

HAZMAT incidents –  Nerve gas attacks

Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning. Lancet. Feb 16 2008;371(9612):597-607.

Vale A. What lessons can we learn from the Japanese sarin attacks? Przegl Lek. 2005;62(6):528-532.


0

200

400

600

800

1000

1200

1400

1600

Death Cases


Men

Women

68%

Konradsen et al, 2004

Use of alcohol during self-harm in Uda Walawe

?


•  High toxicity of agents

•  Lack of 100% effective antidote

•  Accessibility to healthcare – emergency and intensive care resource

limitations in rural setting

Dr Bishan Rajapakse - Management of OP Poisoning (TWH ICU 2014) Image accessed from CNSForum.com

Dr Bishan Rajapakse - Management of OP Poisoning (TWH ICU 2014) Figure from Chapter: “Organophosphorus and Carbamate Agents (Anti-cholinesterase pesticide poisoning)” – B.Rajapakse, N. Buckley - “Emergency Medicine Textbook” Ed S David, WoltersKluwer


Cholinergic Effects on

Central (CNS)

Peripheral (PNS)

Somatic

Autonomic P

S

Life threatening features

+ Death

Neuro: -  " GCS -  Seizure

Resp:

CVS:

-  # Lung Secretions

-  " HR -  " BP

- Respiratory muscle weakness


•  Acute cholinergic syndrome –  Immediate onset

•  Intermediate Syndrome – Delayed respiratory failure (24-96hrs)

– Nerve conduction can predict weakness

•  OP induced delayed peripheral neuropathy

Jayawardane P, Dawson AH, Weerasinghe V, Karalliedde L, Buckley NA, Senanayake N. The spectrum of intermediate syndrome following acute organophosphate poisoning: a prospective cohort study from Sri Lanka. PLoS Med. Jul 15 2008;5(7):e147.


CASE

36 yo female Ingestion of Dimethoate

(Severely Toxic OP)

Village

•  Drunk 100mls after dispute

•  Found by family vomiting

•  Taken to nearest peripheral hospital (1 doctor, 2 nurses)

•  Sent by Ambulance (no paramedics) to nearest General hospital

0930 hrs

1000 hrs

0900 hrs (village)

1115 hrs


Hazmat incident involving OP – ICU called to help down in the ED…

Things are steaming in unit but still the pager rings….


•  27 yo female – A: Audible crackles, excessive salivation and

frothing at mouth

– B: Crackles through both lung fields, RR 40, O2 sats 86% on 15L/min

– C: P40, sBP 70-80, paradoxical breathing

– D: GCS 11/14, fasiculations, clonus


•  x2 large bore cannula

•  1.5L crystalloid

•  IV atropine by ED, total dose 30mg given in increments. – Last dose 16mg, given 5 mins ago

– Minimal improvement in Resp and CVS systems


a) atropine 5mg; + further 5mg every 5mins

b) atropine 32mg; doubling dose of atropine every 5 mins

c) Pralidoxime 2g IV

d) Pralidoxime 0.5g IV

e) Intubation is more immediately important than antidote therapy at this point


•  Resuscitation! –  A, B, C, D –  Consider early intubation

•  IV Atropine –  Stops lung secretions –  Increases blood pressure

Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning. Lancet. Feb 16 2008;371(9612):597-607.


A B C D

•  Acute Cholinergic Syndrome:

•  Neuro: Low GCS, Coma, Seizure

•  Resp: Lung Secretions

Respiratory Muscle Weakness

•  CVS: Bradycardia and Hypotension

ATROPINE

DIAZEPAM

Roberts DM, Aaron CK. Management of acute organophosphorus pesticide poisoning. Bmj. Mar 24 2007;334(7594):629-634.


•  Large doses of Atropine are required –  Mean dose in severe OP poisoning 23.4mg (range

1-75mg)

•  Text book recommendations vary –  Upto 1,380 minutes to administer 23.4mg

•  Doubling IV bolus doses most effective –  Eg. 2mg, then 4mg, then 8mg etc every 5 minutes

until “clinical response” –  Continue with 10-20% of loading dose/hour

Eddleston et al. Speed of initial atropinisation in significant organophosphorus pesticide poisoning--a systematic comparison of recommended regimens. J.Toxicol.Clin.Toxicol 2004;42(6):

865-75.

Connors et al. J Med Toxicol. 2013 Jul 31


Lung Secretions

Hypotension

Bradycardia

Sweating

(Miosis)

Clear Chest

sBP > 80mmHg

HR > 80/min

Dry Axillae

(Pupils no longer pinpoint)

ATROPINE


•  Oximes reverse the inhibition of AChE

–  " mucarinic & nicotinic symptoms

– Potential to prevent delayed respiratory failure.. if given early enough?

•  Neuro: Low GCS, Coma, Seizure

•  Resp: Lung Secretions

Respiratory Muscle Weakness

•  CVS: Bradycardia and Hypotension


•  2 important factors – kinetics of ageing

– achieving therapeutic dose


•  t 1/2 inhibition –  Milliseconds for both

diMethyl and diEthyl OPs

Eddleston M, Eyer P, Worek F, Mohamed F, et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9

•  t1/2 Spontaneous reactivation –  0.7 hr for diMethyl –  31 hrs for diEthyl

•  t1/2 of Ageing – 3.7 hrs for diMethyl – 33 hrs for diEthyl


Rate of “Ageing”

t ½ 3.7 hrs

t ½ 33 hrs

0 1 0 2 0 3 0 4 0

chlorpyrifos

fenthion

dimethoate

C a s e f a t a l i t y r a t i o ( 9 5 % C I )

Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005

Die

thyl

D

imet

hyl

Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. Qjm. May 2002;95(5):275-283.


Reproduced from - Eyer P, Buckley NA “Pralidoxime for organophosphate poisoning”.Comment in the Lancet 2006: 368:2110-2111


•  Double blind RCT, n= 235

•  No significant difference between mortality in treatment arm and control (saline)

• #Biomarkers but not clinical improvement

Eddleston M, Eyer P, Worek F, et al. Pralidoxime in acute organophosphorus insecticide poisoning--a randomised controlled trial. PLoS Med. Jun 30 2009;6(6):e1000104.


Improvement in Biomarkers

•  D

Non significant worsening of mortality

24.8%

15.8%


[HR] 1.69 (95% CI 0.88–3.26), p = 0.12

Dimethyl OP Diethyl OP


•  No consistent clinical trial evidence of benefit

•  Cochrane (Buckley et al 2011) –  insufficient evidence to suggest if harmful

or beneficial


“The only thing I know is that I don’t know anything”


Three factors:

– The Evidence

– Clinical Expertise

– The Patient


What would I do – symptomatic OP pt?

•  Patient responding to atropine - would use this alone and not use pralidoxime.

•  If they are not getting better or decompensating with atropine, then treat with pralidoxime


•  2 commonly monitored “Biomarkers of Exposure” –  Plasmacholinesterase (PChE)

•  Large variation in normal population

–  Red cell acetylcholinestersase (RBC-AChE) •  Correlates better with neuronal AChE and clinical picture •  Reactivation by oximes


•  Potential Uses of RBC-AChE – Confirmation of diagnosis – Guidance of Oxime therapy – Early discharge of low acuity patients

•  Biomarkers do not replace clinical judgment

Eddleston M et al. Management of acute organophosphorus pesticide poisoning. Lancet. Feb 16 2008;371(9612):597-607.

Eyer P, Worek F, Thiermann H, Eddleston M. Paradox findings may challenge orthodox reasoning in acute organophosphate poisoning. Chem Biol Interact. Oct 31 2009.

Dr Bishan Rajapakse - Management of OP Poisoning (TWH ICU 2014) Rajapakse BN, Thiermann H, Eyer P, Worek F, Bowe SJ, et al. (2011) Evaluation of the Test-mate ChE (cholinesterase) field kit in acute organophosphorus poisoning. Ann Emerg Med 58: 559-564 e556.


35 yo male – ingested 200mls chlorpyrifos, 2hrs prior to presentation Rx – ABCDE, Atropine 16mg, Pralidoxime1g 6hrly

10%


Improvement in Biomarkers

•  D

Non significant worsening of mortality

24.8%

15.8%


[HR] 1.69 (95% CI 0.88–3.26), p = 0.12

Dimethyl OP Diethyl OP


•  May have a role in predicting delayed respiratory failure – Proximal muscle weakness

– Nicotinic, motor endplate

– 24-96 after initial cholinergic crisis

Jayawardane P, Dawson AH, Weerasinghe V, Karalliedde L, Buckley NA, Senanayake N. The spectrum of intermediate syndrome following acute organophosphate poisoning: a prospective cohort study from Sri Lanka. PLoS Med. 2008 Jul 15;5(7):e147


•  Prospective cohort study (n=78) – 10 diagnosed with IMS

– Characteristic changes observed in RNS

– Decrement- increment at lower frequencies



ALS in OP poisoning


•  27 texts reviewed – 15 book chapters (Tox and EM)

– 6 monographs (online – eg Upto date, emedicine)

– 6 Review articles


0 10 20

BuChE scavengersHaemodialysis

NaHCO3Alpha 2 blockers (clonidine)

Magenesium sulphatelower priority than standard treatment

Titrate to RBC-AChE endpoints?Titrate to provided clincal endpoint?

Alternative dose PAMWHO dose PAM (2g bolus, 0.5-1g/h infusion)

Specifies obidoximeSpecifies pralidoxime (PAM)

Indication clearly providedControversy of efficacy discussed

Linked to resuscitationOxime therapy mentioned

Describe management of toxicityDescribe symptoms of toxicity

No need for oxygen before atropineAtropoine endpoints (>2/4) mentioned

Review frequently (every 5 mins)Doubling dose recommendedIdentified as core treatment

Linked to resuscitationAtropine therapy mentioned

Number of texts covering topic

General recommendations for antidote therapy in OP poisoning

evidence citedNo citation

Atropine

Oximes

Other Treatments


For acute severe OP poisoning


•  Remove contaminated clothes

•  Soap and water •  Limited evidence for

GI decontamination –  No gastric lavage

unless airway is protected

•  Aspiration

•  Trauma –  Oesphageal Injury

–  Nasopharyngeal injury 1. Eddleston et al. The hazards of gastric lavage for intentional self-poisoning in a resource poor location. Clin Toxicol (Phila) 2007;45(2):136-43.


0 10 20

Recommends specific ionotropes

Inotropic support indication

Arrhythmia management

Rate specfied to target physiologic endpoint

IV fluids

x2 IV cannulae

IV access

Avoid suxamethonium

Indication to intubation provided

Monitor ventilation volume

Monitor neck flexors

Left lateral position, neck extended

Open airway

Oxygen

Respiratory support is management priority

Number of texts covering topic

Airway, Breathing and Circulation ALS recommendations in OP resuscitation

evidence citedNo citation

Airway/ Breathing

Circulation & IV therapy

Dr Bishan Rajapakse - Management of OP Poisoning (TWH ICU 2014) Eddleston et al. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 2006;99(8):513-22.

Fenthion

<2hours

All OP’s

2-24hours

>24hours


•  Open label RCT, n=4629 – 2338 ingested pesticides

– 1310 ingested OP or carbamates

•  Limited evidence for routine use of multiple dose activated charcoal

Eddleston et al. Lancet. 2008 Feb 16;371(9612):579-87


•  Consensus Statement – Little evidence of secondary poisoning in

staff caring for OP poisoned patients

– Hydrocarbon vapours •  Mild self limiting symptoms

•  Well ventilated areas recommended

– Recommend universal precautions to avoid dermal exposure to OP agents

Little et al. Emerg Med Australas. 2004 Oct-Dec;16(5-6):456-8




•  Pralidoxime controversial –  On expert advice of if non responsive to

atropine

•  Nosocomial poisoning (minimal risk to health workers) – Universal precautions enough (eye/mask/gown/gloves)

•  New research is constantly unfolding!


amongst friends and colleagues..

Discussion time


SACTRC I would like to acknowledge all the staff at the South Asian clinical toxicology research collaboration, and in particular:-

Professor Nick Buckley, Professor Andrew Dawson, Dr Indika Gawarmanna, Dr Michael Eddleston, Dr Darren Roberts & Mr Lalith Senarathna

Sri Lanka Hospital Staff I would like to thank and acknowledge the patients and the hospital staff of Sri Lankan hospitals for their support in my research

Funders & University Welcome Trust (GR071669) & Australia National University




•  Pralidoxime controversial –  On expert advice of if non responsive to

atropine

•  Nosocomial poisoning (minimal risk to health workers) – Universal precautions enough (eye/mask/gown/gloves)

•  New research is constantly unfolding!

Dr Bishan Rajapakse - Management of OP Poisoning (TWH ICU 2014) Buckley N, Kenyon R, Robertson A – “A review of emergency first-aid treatment of anticholinesterase pesticide poisoning in Australia” – Australian Government – Department of Health and Ageing. Office of Chemical Safety

Figure 1. Trends in the reporting of OP and carbamate exposure made to the NSW and Victorian Poisons Information Centres.

Figure 4.1.a Figure 4.1.b

0

100

200

300

400

500

600

Number of incidents

reported to the NSW Poisons Information

Centre

NSW: OP exposure 596 475 469 408

NSW carbamateexposure

119 113 70 63

2003 2004 2005 2006

0

20

40

60

80

100

120

140

160

Number of incidents

reported to the Victorian Poisons

Information Centre

VIC: OP exposure 152 85 89

VIC: carbamateexposure

61 15 8

2004 2006 2007

The above figures have been generated by the OCS. Data is incorporated from Tables 2a and 2b, which contain the number of calls regarding OP and Carbamate exposure recorded at both PIC’s. The figures demonstrate a downwards trend in reported OP and carbamate exposure from 2003 to 2007. Tables 2a and 2b indicate that the drop in reports of OP and carbamate exposure is not associated with a reduced number in the total number of calls made to either Centre.

Table 2a. OP and Carbamate exposure reports made to the NSW Poisons Information Centre Annual Report year No of Carbamate exposure

reported No of OP exposure

reported Total number of calls

to NSW 2003 119 596 108,727 2004 113 475 108,708 2005 70 469 110,874 2006 63 408 113,982

Data acquired from the NSW PIC annual reports

Table 2b. OP and Carbamate exposure reports made to the Victorian Poisons Information Centre Annual Report year No of Carbamate exposure



to Victoria 2004 61 152 40,303 2006 15 85 37,668 2007 8 89 40,050

Data acquired from the Victorian PIC annual reports

9

Figure 1. Trends in the reporting of OP and carbamate exposure made to the NSW and Victorian Poisons Information Centres.

Figure 4.1.a Figure 4.1.b

0

100

200

300

400

500

600

Number of incidents

reported to the NSW Poisons Information

Centre

NSW: OP exposure 596 475 469 408

NSW carbamateexposure

119 113 70 63

2003 2004 2005 2006

0

20

40

60

80

100

120

140

160

Number of incidents

reported to the Victorian Poisons

Information Centre

VIC: OP exposure 152 85 89

VIC: carbamateexposure

61 15 8

2004 2006 2007

The above figures have been generated by the OCS. Data is incorporated from Tables 2a and 2b, which contain the number of calls regarding OP and Carbamate exposure recorded at both PIC’s. The figures demonstrate a downwards trend in reported OP and carbamate exposure from 2003 to 2007. Tables 2a and 2b indicate that the drop in reports of OP and carbamate exposure is not associated with a reduced number in the total number of calls made to either Centre.

Table 2a. OP and Carbamate exposure reports made to the NSW Poisons Information Centre Annual Report year No of Carbamate exposure



to NSW 2003 119 596 108,727 2004 113 475 108,708 2005 70 469 110,874 2006 63 408 113,982

Data acquired from the NSW PIC annual reports

Table 2b. OP and Carbamate exposure reports made to the Victorian Poisons Information Centre Annual Report year No of Carbamate exposure



to Victoria 2004 61 152 40,303 2006 15 85 37,668 2007 8 89 40,050

Data acquired from the Victorian PIC annual reports

9


Evidence delivery systems

Systematic reviews and syntheses

Studies

2. Bedside Evidence based medicine - validated instruments

3. Continuous quality improvement - monitoring adherence to initiatives

4. Decision aids / decision support

Education (lectures/workshops/ courses)

Evidence

Practice

Ch 2 Ch 3 Ch 4 Ch 5 Ch 6

1. Evidence

knowledge, attitudes and practice of treating physicians on AChE

Validation of AChE POC test

AChE

Resuscitation

Study description

workshop based resuscitation education

Systematic review of ALS guidelines

Systematic review of AChE recommendations


•  Retrospective study 1990-2003 – Royal Brisbane hospital

•  40 presentations – 8 (20%) severe poisoning; tachycardia,

fasciculations, weaknesss, and metabolic acidosis

– AChE measured in 49%

– 1 death (2.4%, or 12.5% of severe poisonings)

D. M. ROBERTS*, J. F. FRASER†, N. A. BUCKLEY, B. VENKATESH Experiences of Anticholinesterase Pesticide Poisonings in an Australian Tertiary Hospital, Anaesth Intensive Care 2005; 33: 469-476

The emergency and intensive care management of OP poisoning

Education

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