1. Paraquat Poisoning Lessons 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

2. Paraquat- history Introduced as a herbicide in 1962
First described in 1882
Electron donation to PQ forms a stable PQ.+
Used as an oxidation-reduction indicator
Introduced as a herbicide in 1962

3. 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

4. Paraquat proportion of deathSo

5. Generates free radicals Activation of NFkB
NFkB is translocated into the nucleus,
binds to promoter regions
induces target genes involved in inflammation

6. DITHIONITE REDUCTION OF PARAQUAT PARAQUAT RADICAL ION (BLUE)
Diagnosis
DITHIONITE REDUCTION OF PARAQUAT
Paraquat is converted to a blue colour by sodium dithionite
Limit of detection of plasma and urine: 2-3 µg/mL
Sodium
dithionite
alkali
PARAQUAT
PARAQUAT RADICAL ION (BLUE)

7. Plasma paraquat concentration

8. 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

9. “Paraquat Tongue”

10. Peripheral burning sensation
73%- median time to death
36 hrs
25%- median time to death
50hrs

11. Proportion of deaths- volume of ingestion
Log Rank (Chi square 79.69, p<0.0001)

12. Case fatality Median time to death 73.9% (95% CI 69-78).
1.53 days (IQR ).

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

14. Respiratory rate
survivors

15. Biochemical evolution Admission creatinine
2.05 mg/dL (IQR )
0.9mg/dL (IQR )

16. Evolution

17. Admission WBC

18. OR 81, 95% CI 67-84

19. Evolution

20. Admission ALT

21. Evolution

22. Treatment Supportive care N acetylcysteine, DFO, Vitamin E
Immunosuppression

23. haemodialysis and haemoperfusion
plasma
lung
tissue

24. Immunosuppression popular
Inconclusive evidence
(Eddleston M et al QJM and Agarwal et al Singapore Med J. 2007)
South Asian Clinical Toxicology Research Collaboration Faculty of Medicine, University of Peradeniya

25. RCT in Sri Lanka
Chi squared 0.74, p=0.34

26. ROC curves
Area under the curve 1= perfect test

27. Assessment of prognosis Admission plasma paraquat concentration
SIPP score
Plasma paraquat

28. Semi-quantitative Urine dithionite test Number Number and % deaths
Positive test
418
251 (60%)
Negative test
149
7 (4.7%)

29. Negative test= survival
Sensitivity of 0.97 (95% CI )
Specificity of 0.45 (95% CI )
Negative predictive value of 0.95 (95% CI )
Easy to perform, cheap
Negative tests= survival
Positive tests: need further evaluation

30. Admission creatinine >1.26mg/dL
Sensitivity of 78% (95% CI: 69-85), specificity of 73% (95% CI: 59-84) [positive likelihood ratio 2.91]

31. Creatinine >2.64mg/dL
(OR 16.7, 95% CI: , specificity: 0.96 (95% CI ),
PPV 0.95 (95% CI , p<0.001).

32. 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 , p<0.0001)

33. Rise of creatinine
Cut off rise of 0.88mg/dL (95% CI , p<0.0001)
Sensitivity, 81.8% (95% CI 70-90); specificity 83% (95% CI 67-93)
likelihood ratio of 4.64

34. summary Survivors and non survivors can be identified early
Immunosuppression does not work
Prevent access to paraquat as outcome is poor

35. Poisoning Deaths Transition 2006-2013
44000
Pesticide bans (3 years)

36. Andrew Dawson, Nick Buckley, Michael Eddleston,
Acknowledgements
Andrew Dawson, Nick Buckley, Michael Eddleston,
SACTRC collaborators, research team and hospital staff
University of Peradeniya
Wellcome Trust & NHMRC
Syngenta
Michael Eddleston1,2,3*, Peter Eyer4, Franz Worek5, Edmund Juszczak6, Nicola Alder6, Fahim
D G S Alahakoon, and W M T B Wijekoon, and the Directors, medical
Mohamed2,3, Lalith Senarathna2,3, Ariyasena Hittarage7, Shifa Azher8, K. Jeganathan7, Shaluka
and nursing staff of the study hospitals for their help and support, the
IDMEC, Robin Ferner, and Doug Altman for advice, Geoff Isbister,
Jayamanne8, Ludwig von Meyer9, Andrew H. Dawson3,10, Mohamed Hussain Rezvi Sheriff2,3, Nick A.
Simon Thomas, Lewis Nelson, and Nick Bateman for critical review, Ly-
Mee Yu and Nicola Alder for statistical support, Shukry Zawahir, and
Buckley3, We thank the Directors and the medical and nursing staff of the study
Chathura Palagasinghe for help with the fi nal patient audit; and the
hospitals for their help and support; Stuart Allen for programming; the
Ox-Col study doctors for their work in the face of many pressures. ME is a
IDMC and Professor Doug Altman for advice; Renate Heilmair, Bodo
Wellcome Trust Career Development Fellow; this work was funded by
Pfeiffer, and Elisabeth Topoll for technical assistance; J. V. Peter for
grant from the Wellcome Trust’s Tropical Interest Group to ME.
information on the Vellore RCTs; and Allister Vale and Nick Bateman for
The South Asian Clinical Toxicology Research Collaboration is funded by
critical review.
a Wellcome Trust/National Health and Medical Research Council
Ox-Col Poisoning Study Collaborators: Darren Roberts, Damithe
International Collaborative Research Grant
Pitahawatte, Asanga Dissanayaka, Nalinda Deshapriya, Ruwan Seneviratne,
Ox-Col poisoning study collaborators
Sandima Gunatilake, Indika Weerasinghe, Thushara Diunugala,
Darren Roberts, Asanka Perera, Manjula Rajapakshe, K Reginald,
Sriyantha Adikari, Suwini Karunaratne, Prabath Piyasena, Senarath
Sapumal Haggalla, Samantha Wijesundara, Jaya Ratnayake,
Angammana, Deepal Inguruwatte, Samithe Egodage, Mathisha Dissanayake,
S M T Bandara, Subashini Kumarasinghe, Manjula Weerakoon,
Waruna Wijeyasiri-wardene, Shammi Rajapakshe, Sidath Yawasinghe,
Ayanthi Karunaratne, Manonath Marasinghe, Ruwan Kumara,
Bandara, Sumith Kumara, Thushita Kumara, Nilumdima
Sumedha Kumara, Nilan Suranga, Jamal Dean, Dharshana Fernando,
Wijekoon, Kusal Wijeweera, Himali Sepalika Sudusinghe, Hasantha
Sagara Kumara, Koshitha Gunarathne, R M Senanayake, Najeeb Khan,
Ranganath, Mahi Wickramagamage, R. U. Wijesinghe, S. M. I.
Kalum Dhammika, Anuradhi Weerasinghe, M S F Zanoona,
Senavirathne, Chinthaka De Silva, Chaminda Manamperi, T. Suhitharan,
Samanmali Edirisinghe, Medhangi Karunaratne, Sampath Attapattu,
Sevana-yagam David, D. Y. Mohamed Mahir, Lakshmi Sriskandarajah,
Upul Hendalage, Indika Wanasinghe, Lal Bogahawattage,
Sellakkuddy Selva-ganesh, Chamila Bandara Herath, Kanchana Liyanage,
SyngentaR D S M Peiris, S M Dayarathne, Gayan Costa, Chandana de Silva,
Chinthaka Semasinghe, Pandula Illangasinghe, Gayan Wickramasinghe,
Prabath Abeyrathna, Bandula Senadeera, Gayan Gunarathne,
Sudesh Rathnayake, Vindhya Jayasinghe, Iranga Jayasundara, Mahesh
Kusal Wijayaweera, M Senthilkumaran, Y Ruthra, K Sutharshan,
Dahanayake, Prasanna Weerakoon, Praba W. Nanayakkara, Paramananthan
Dimuth de Silva, Anjana Amarasinghe, Janaka Balasooriya,
Sajeevan, Vethanathan Bavanthan, Janitha Kumari Illangakoon,
Damithe Pitahawatte, Asangha Dissanayaka, Aravinda Perera,
Chamantha Dilmini Karunarathne, Kuleesha Kodisinghe, Buddika
Nalinda Deshapriya, Suranga Gurusinghe, Ruwan Seneviratne,
Jeevantha Wimalarathne, Asela Udagedara, Ashoka Subasinghe, Kiloshini
Saman Chandana; Mubashi Mohamed, Koshala Abeysundera,
Samanthi Hendawitharana, Dammika Prabath Nungamugedara, Aruna
Nasmiyar Mubarak, Lumbini de Silva, Daniel, Sandima Gunatilake,
Wijayanayaka, Sanjeewa Amarasinghe, Sakunthala Nilmini Liyanage,
Indika Weerasinghe, Thushara Diunugala, Sriyantha Adikari,
Indika de Alwis, Thushara Priyawansha, Chathura Pallangasinghe, Shukry
Suwini Karunaratne, Prabath Piyasena, Senarath Angammana,
Zawahir, Mohamed Ashrafdeen Isnan, and Syed Shahmy
Deepal Inguruwatte, Samithe Egodage, Mathisha Dissanayake,
Independent Data Monitoring Committee (IDMC): Professor
Waruna Wijeyasiriwardene, Shammi Rajapakshe, Sidath Yawasinghe,
Mike Clarke (Director, UK Cochrane Centre, Oxford; Chair); Professor
Samanthi Bandara, Sumith Kumara, Thushita Kumara,
Keith Hawton (Department of Psychiatry, Oxford); Dr. Julian Higgins
Nilumdima Wijekoon.
(MRC Biostatistics Unit, Cambridge University; statistician); Professor
Independent data monitoring and ethics committee
Saroj Jayasinghe (Department of Clinical Medicine, Colombo, Sri Lanka);
Mike Clarke (Director, UK Cochrane Centre, Oxford; Chair);
Professor Nimal Senanayake (Department of Clinical Medicine, Peradeniya,
Keith Hawton (Department of Psychiatry, Oxford); Julian Higgins (MRC
Sri Lanka); Professor Kris Weerasuriya (WHO/SEARO, New Delhi).- Michael Eddleston, Edmund Juszczak, Nick A Buckley, Lalith Senarathna, Fahim Mohamed, Wasantha Dissanayake, Ariyasena Hittarage,
Biostatistics Unit, Cambridge University; Statistician); Saroj Jayasinghe
(Department of Clinical Medicine, Colombo); Nimal Senanayake
(Department of Clinical Medicine, Peradeniya); Kris Weerasuriya
Shifa Azher, K Jeganathan, Shaluka Jayamanne, M H Rezvi Sheriff , David A Warrell, We thank Palitha Abeykoon and Kan Tun (WHO), Lakshman Karalliedde,
(WHO/SEARO, New Delhi).

37. Other markers of prognosis

38. No rise CFR 52.5%