South Asian Clinical Toxicology Research Collaboration Paraquat Poisoning Lessons from a Large...

South Asian Clinical Toxicology Research Collaboration

Paraquat PoisoningLessons from a Large

Cohort

Indika Gawarammana(MD, FRCPE, PhD)

Department of Medicine and South Asian Clinical Toxicology Research Collaboration

Faculty of Medicine- University of Peradeniya

Sri Lanka


Paraquat- history First described in 1882 Electron donation to PQ forms a stable PQ.+

Used as an oxidation-reduction indicator Introduced as a herbicide in 1962


Paraquat in agriculture

Non-systemic, fast acting Rain-fast, quickly

deactivated in soil No tillage preserves soil

structure

No damage to surrounding crops

Broad spectrum, no weed resistance

Key crops in Sri Lanka are tea and rice


Paraquatproportion of death

So

Carbamates6%

Other Her-bicides

14%

Paraquat35%

Dimethoate20%

Fenthion4%

Chlorpyrifos14%

Other OP6% Carbamates

Other Herbicides

Paraquat

Dimethoate

Fenthion

Chlorpyrifos

Other OP


Generates free radicalsActivation of NFkB

NFkB is translocated into the nucleus, binds to promoter regionsinduces target genes involved in inflammation


N+

N+

CH3CH3 C NN+

CH3CH3

Diagnosis

DITHIONITE REDUCTION OF PARAQUAT

Sodium

dithionite

alkali

PARAQUAT PARAQUAT RADICAL ION

(BLUE)

Paraquat is converted to a blue colour by sodium dithionite

Limit of detection of plasma and urine: 2-3 µg/mL


Plasma paraquat concentration

0.10.2

0.51.02.0

5.0

0 6 12 18 24 30 36 42 48

0.10.2

0.51.02.0

5.0

ProudfootSchermann's extension of Proudfoot line

Jones (.5)

SIPP=10

Hours after ingestion

Par

aqua

t le

vel (

ug/m

L)


symptoms Nausea and vomiting in 81.6% Burning oral pain in 62.5% Odynophagia 30% Abdominal pain in 57.5% Low GCS is uncommon (8%)- but all recover

within hours


“Paraquat Tongue”


Peripheral burning sensation

burning sensation no burning sensation0

20

40

60

80

100

case

fat

alit

y (%

)

73%- median time to death36 hrs

25%- median time to death50hrs


Proportion of deaths- volume of ingestion

Log Rank (Chi square 79.69, p<0.0001)

0 5 10 15 20 25 300.0

0.5

1.0

5-15 mls

15-50mls

>50mls

time since ingestion (days)

Pro

po

rtio

n d

ecea

sed


Case fatality– 73.9% (95% CI 69-78).

Median time to death– 1.53 days (IQR 0.5-3.7).


Clinical course Severe toxicity = rapid death from MOF Others= slow death over days due to hypoxia


Respiratory rate

survivors


Biochemical evolutionAdmission creatinine

surv

ivors

decea

sed

0

1

2

3

4

5

crea

tin

ine

(mg

/dL

)

2.05 mg/dL (IQR 1.3-3.1)

0.9mg/dL (IQR 0.7-1.3)


EvolutionSurvivors

0 1 2 3 4 50

2

4

6

8

10

Normal range

mean

days since ingestion

creatin

ine (m

g/d

L)

Deaths

0 1 2 3 4 50

2

4

6

8

10

Normal range

mean


creatin

ine (m

g/d

L)


Admission WBC

0

10000

20000

30000

wh

ite

cell

cou

nt/

cmm


>19550 <195500

20

40

60

80

100

case

fat

alit

y (%

)

OR 81, 95% CI 67-84


EvolutionSurvivors

0 1 2 3 4 5

10000

20000

30000

Normal range

mean (SD)


WB

C

Deaths

0 1 2 3 4 50

10000

20000

30000

Normal range

mean (SD)


WB

C


Admission ALT

10

100

1000

normal range

AL

T (

u/L

)


EvolutionSurvivors

0 1 2 3 4 50

500

1000

Normal range

mean (SD)


AS

T (U

/L

)

Deaths

0 1 2 3 4 50

500

1000

Normal range

mean (SD)


AS

T (U

/L

)


Treatment Supportive care N acetylcysteine, DFO, Vitamin E Immunosuppression


haemodialysis and haemoperfusion

lung

plasma

tissue


Immunosuppressionpopular

Inconclusive evidence

(Eddleston M et al QJM. 2003 and Agarwal et al Singapore Med J. 2007)

South Asian Clinical Toxicology Research Collaboration Faculty of Medicine, University of Peradeniya


RCT in Sri Lanka

Chi squared 0.74, p=0.34

0 10 20 30 40 50 60 70 80 900.0

0.5

1.0

Immunosuppression groupPlacebo group

Days post-ingestion

Fra

ctio

n s

urv

ival


ROC curves

Area under the curve

1= perfect test

Assessment of prognosisAdmission plasma paraquat concentration

0 20 40 60 80 1000

20

40

60

80

100

AUC=0.95

100% - Specificity%

Sen

siti

vity

(%

)

0 20 40 60 80 1000

20

40

60

80

100

AUC= 0.96

100% - Specificity%

Sen

siti

vity

(%

)

Plasma paraquat SIPP score


Number Number and % deaths

Positive test 418 251 (60%)

Negative test 149 7 (4.7%)

Semi-quantitativeUrine dithionite test


Negative test= survival Sensitivity of 0.97 (95% CI 0.94-.98) Specificity of 0.45 (95% CI 0.4-0.5) Negative predictive value of 0.95 (95% CI

0.90-0.98)

Easy to perform, cheap Negative tests= survival Positive tests: need further evaluation


Admission creatinine>1.26mg/dL

Sensitivity of 78% (95% CI: 69-85), specificity of 73% (95% CI: 59-84) [positive likelihood ratio 2.91]

0 20 40 60 80 1000

20

40

60

80

100

AUC=0.82

100% - Specificity%

sen

siti

vity


Creatinine >2.64mg/dL

(OR 16.7, 95% CI: 3.8-72, specificity: 0.96 (95% CI 0.87-0.99),

PPV 0.95 (95% CI 0.85-0.99, p<0.001).

>2.635mg/dL <2.635mg/dL0

20

40

60

80

100

case

fat

alit

y (%

)


Median rise of serum creatinine within 24 hours

Survivors (0.2mg/dL, IQR 0-0.6) Deceased (2mg/dL, IQR 1-3) ( p<0.0001). Cut off rise of 0.88mg/dL (95% CI 0.82-0.94, p<0.0001)

0

1

2

3

4

5

mg

/dL

0 20 40 60 80 1000

20

40

60

80

100

AUC=0.88

100% - Specificity%

Se

ns

itiv

ity

(%

)


Rise of creatinine

Cut off rise of 0.88mg/dL (95% CI 0.82-0.94, p<0.0001)

Sensitivity, 81.8% (95% CI 70-90); specificity 83% (95% CI 67-93)

likelihood ratio of 4.64

0 20 40 60 80 1000

20

40

60

80

100

AUC=0.88

100% - Specificity%

Se

ns

itiv

ity

(%

)


summary Survivors and non

survivors can be identified early

Immunosuppression does not work

Prevent access to paraquat as outcome is poor


Poisoning Deaths Transition 2006-2013

20062007

20082009

20102011

20122013

0.00%

1.00%

2.00%

3.00%

4.00%

5.00%

6.00%

Non Ag deathsOther PesitcidesParaquatGlyphosateCarbamatesChlorpyrifosDimethoateFenthione

Pesticide bans (3 years)


AcknowledgementsAndrew Dawson, Nick Buckley,

Michael Eddleston,

SACTRC collaborators, research team and hospital staff

University of PeradeniyaWellcome Trust & NHMRC

Syngenta

Michael Eddleston1,2,3*, Peter Eyer4, Franz Worek5, Edmund Juszczak6, Nicola Alder6, FahimMohamed2,3, Lalith Senarathna2,3, Ariyasena Hittarage7, Shifa Azher8, K. Jeganathan7,

ShalukaJayamanne8, Ludwig von Meyer9, Andrew H. Dawson3,10, Mohamed Hussain Rezvi Sheriff2,3,

Nick A.Buckley3, We thank the Directors and the medical and nursing staff of the study

hospitals for their help and support; Stuart Allen for programming; theIDMC and Professor Doug Altman for advice; Renate Heilmair, BodoPfeiffer, and Elisabeth Topoll for technical assistance; J. V. Peter for

information on the Vellore RCTs; and Allister Vale and Nick Bateman forcritical review.

Ox-Col Poisoning Study Collaborators: Darren Roberts, DamithePitahawatte, Asanga Dissanayaka, Nalinda Deshapriya, Ruwan Seneviratne,

Sandima Gunatilake, Indika Weerasinghe, Thushara Diunugala,Sriyantha Adikari, Suwini Karunaratne, Prabath Piyasena, Senarath

Angammana, Deepal Inguruwatte, Samithe Egodage, Mathisha Dissanayake,Waruna Wijeyasiri-wardene, Shammi Rajapakshe, Sidath Yawasinghe,

Bandara, Sumith Kumara, Thushita Kumara, NilumdimaWijekoon, Kusal Wijeweera, Himali Sepalika Sudusinghe, Hasantha

Ranganath, Mahi Wickramagamage, R. U. Wijesinghe, S. M. I.Senavirathne, Chinthaka De Silva, Chaminda Manamperi, T. Suhitharan,Sevana-yagam David, D. Y. Mohamed Mahir, Lakshmi Sriskandarajah,

Sellakkuddy Selva-ganesh, Chamila Bandara Herath, Kanchana Liyanage,Chinthaka Semasinghe, Pandula Illangasinghe, Gayan Wickramasinghe,Sudesh Rathnayake, Vindhya Jayasinghe, Iranga Jayasundara, Mahesh

Dahanayake, Prasanna Weerakoon, Praba W. Nanayakkara, ParamananthanSajeevan, Vethanathan Bavanthan, Janitha Kumari Illangakoon,

Chamantha Dilmini Karunarathne, Kuleesha Kodisinghe, BuddikaJeevantha Wimalarathne, Asela Udagedara, Ashoka Subasinghe, Kiloshini

Samanthi Hendawitharana, Dammika Prabath Nungamugedara, ArunaWijayanayaka, Sanjeewa Amarasinghe, Sakunthala Nilmini Liyanage,

Indika de Alwis, Thushara Priyawansha, Chathura Pallangasinghe, ShukryZawahir, Mohamed Ashrafdeen Isnan, and Syed Shahmy

Independent Data Monitoring Committee (IDMC): ProfessorMike Clarke (Director, UK Cochrane Centre, Oxford; Chair); ProfessorKeith Hawton (Department of Psychiatry, Oxford); Dr. Julian Higgins

(MRC Biostatistics Unit, Cambridge University; statistician); ProfessorSaroj Jayasinghe (Department of Clinical Medicine, Colombo, Sri Lanka);

Professor Nimal Senanayake (Department of Clinical Medicine, Peradeniya,Sri Lanka); Professor Kris Weerasuriya (WHO/SEARO, New Delhi).- Michael Eddleston, Edmund

Juszczak, Nick A Buckley, Lalith Senarathna, Fahim Mohamed, Wasantha Dissanayake, Ariyasena Hittarage,

Shifa Azher, K Jeganathan, Shaluka Jayamanne, M H Rezvi Sheriff , David A Warrell, We thank Palitha Abeykoon and Kan Tun (WHO), Lakshman Karalliedde,

D G S Alahakoon, and W M T B Wijekoon, and the Directors, medicaland nursing staff of the study hospitals for their help and support, the

IDMEC, Robin Ferner, and Doug Altman for advice, Geoff Isbister,Simon Thomas, Lewis Nelson, and Nick Bateman for critical review, Ly-

Mee Yu and Nicola Alder for statistical support, Shukry Zawahir, andChathura Palagasinghe for help with the fi nal patient audit; and the

Ox-Col study doctors for their work in the face of many pressures. ME is aWellcome Trust Career Development Fellow; this work was funded by

grant 063560 from the Wellcome Trust’s Tropical Interest Group to ME.The South Asian Clinical Toxicology Research Collaboration is funded by

a Wellcome Trust/National Health and Medical Research CouncilInternational Collaborative Research Grant 071669.

Ox-Col poisoning study collaboratorsDarren Roberts, Asanka Perera, Manjula Rajapakshe, K Reginald,

Sapumal Haggalla, Samantha Wijesundara, Jaya Ratnayake,S M T Bandara, Subashini Kumarasinghe, Manjula Weerakoon,

Ayanthi Karunaratne, Manonath Marasinghe, Ruwan Kumara,Sumedha Kumara, Nilan Suranga, Jamal Dean, Dharshana Fernando,

Sagara Kumara, Koshitha Gunarathne, R M Senanayake, Najeeb Khan,Kalum Dhammika, Anuradhi Weerasinghe, M S F Zanoona,

Samanmali Edirisinghe, Medhangi Karunaratne, Sampath Attapattu,Upul Hendalage, Indika Wanasinghe, Lal Bogahawattage,

SyngentaR D S M Peiris, S M Dayarathne, Gayan Costa, Chandana de Silva,Prabath Abeyrathna, Bandula Senadeera, Gayan Gunarathne,

Kusal Wijayaweera, M Senthilkumaran, Y Ruthra, K Sutharshan,Dimuth de Silva, Anjana Amarasinghe, Janaka Balasooriya,

Damithe Pitahawatte, Asangha Dissanayaka, Aravinda Perera,Nalinda Deshapriya, Suranga Gurusinghe, Ruwan Seneviratne,Saman Chandana; Mubashi Mohamed, Koshala Abeysundera,

Nasmiyar Mubarak, Lumbini de Silva, Daniel, Sandima Gunatilake,Indika Weerasinghe, Thushara Diunugala, Sriyantha Adikari,

Suwini Karunaratne, Prabath Piyasena, Senarath Angammana,Deepal Inguruwatte, Samithe Egodage, Mathisha Dissanayake,

Waruna Wijeyasiriwardene, Shammi Rajapakshe, Sidath Yawasinghe,Samanthi Bandara, Sumith Kumara, Thushita Kumara,

Nilumdima Wijekoon.Independent data monitoring and ethics committee

Mike Clarke (Director, UK Cochrane Centre, Oxford; Chair);Keith Hawton (Department of Psychiatry, Oxford); Julian Higgins (MRCBiostatistics Unit, Cambridge University; Statistician); Saroj Jayasinghe

(Department of Clinical Medicine, Colombo); Nimal Senanayake(Department of Clinical Medicine, Peradeniya); Kris Weerasuriya

(WHO/SEARO, New Delhi).


Other markers of prognosis

0 20 40 60 80 1000

20

40

60

80

100

admission paraquatadmission creatinineadmission ALTadmission WBCSIPP scorerise of creatinine

admission bilirubin

100% - Specificity%

Sen

siti

vity

(%

)


No rise CFR 52.5%

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