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
South Asian Clinical Toxicology Research Collaboration
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


South Asian Clinical Toxicology Research Collaboration
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
South Asian Clinical Toxicology Research Collaboration
Paraquat
proportion of death
Carbamates, 6%
Other
OP, 6%
Fenthion,
5%
Chlorpyrifos,
14%
Carbamates
Other Herbicides
Other Herbicides,
14%
Paraquat
Dimethoate
Fenthion
Chlorpyrifos
Dimethoate, 20%
Paraquat, 35%
Other OP
SoSouth Asian Clinical Toxicology Research Collaboration
Generates free radicals
Activation of NFkB
NFkB is translocated into the nucleus,
binds to promoter regions
induces target genes involved in inflammation
South Asian Clinical Toxicology Research Collaboration
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
+
+
+
N CH3
H3C N
H3C N
C
N CH3
alkali
PARAQUAT
PARAQUAT
RADICAL ION
(BLUE)
South Asian Clinical Toxicology Research Collaboration
Paraquat level (ug/mL)
Plasma paraquat
concentration
Jones (.5)
Proudfoot
Schermann's extension of Proudfoot line
SIPP=10
5.0
2.0
1.0
0.5
0.2
0.1
0
6
12
18
24
30
36
42
48
Hours after ingestion
South Asian Clinical Toxicology Research Collaboration
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
South Asian Clinical Toxicology Research Collaboration
“Paraquat Tongue”
South Asian Clinical Toxicology Research Collaboration
Peripheral burning sensation
100
case fatality (%)
80
60
40
20
0
burning sensation
73%- median time to death
36 hrs
no burning sensation
25%- median time to death
50hrs
South Asian Clinical Toxicology Research Collaboration
Proportion of deaths- volume of
ingestion
Proportion deceased
1.0
0.5
5-15 mls
15-50mls
>50mls
0.0
0
5
10
15
20
25
30
time since ingestion (days)

Log Rank (Chi square 79.69, p<0.0001)
South Asian Clinical Toxicology Research Collaboration

Case fatality
– 73.9% (95% CI 69-78).

Median time to death
– 1.53 days (IQR 0.5-3.7).
South Asian Clinical Toxicology Research Collaboration
Clinical course


Severe toxicity = rapid death from MOF
Others= slow death over days due to hypoxia
South Asian Clinical Toxicology Research Collaboration
Respiratory rate
survivors
South Asian Clinical Toxicology Research Collaboration
Biochemical evolution
Admission creatinine
0.9mg/dL
(IQR 0.7-1.3)
creatinine (mg/dL)
5
4
2.05 mg/dL
(IQR 1.3-3.1)
3
2
1
0
rs
o
v
vi
r
su
ed
s
ea
c
de
South Asian Clinical Toxicology Research Collaboration
Evolution
Survivors
10
mean
creatinine (mg/dL)
8
6
4
2
Normal
range
0
0
1
2
3
4
5
days since ingestion
Deaths
10
mean
creatinine (mg/dL)
8
6
4
2
Normal
range
0
0
1
2
3
4
5
days since ingestion
South Asian Clinical Toxicology Research Collaboration
Admission WBC
20000
10000
de
ce
as
ed
0
su
rv
iv
or
s
white cell count/cmm
30000
South Asian Clinical Toxicology Research Collaboration
case fatality (%)
100
80
60
40
20
0
>19550
<19550
OR 81, 95% CI 67-84
South Asian Clinical Toxicology Research Collaboration
Evolution
Survivors
mean (SD)
WBC
30000
20000
10000
Normal range
0
1
2
3
4
5
days since ingestion
Deaths
mean (SD)
WBC
30000
20000
10000
Normal range
0
0
1
2
3
4
5
days since ingestion
South Asian Clinical Toxicology Research Collaboration
Admission ALT
ALT (u/L)
1000
100
normal range
ed
de
ce
as
su
rv
iv
or
s
10
South Asian Clinical Toxicology Research Collaboration
Evolution
Survivors
mean (SD)
AST (U/L)
1000
500
Normal
range0
0
1
2
3
4
5
days since ingestion
Deaths
mean (SD)
AST (U/L)
1000
500
Normal
range0
0
1
2
3
4
5
days since ingestion
South Asian Clinical Toxicology Research Collaboration
Treatment



Supportive care
N acetylcysteine, DFO, Vitamin E
Immunosuppression
South Asian Clinical Toxicology Research Collaboration
haemodialysis and haemoperfusion
plasma
lung
tissue
South Asian Clinical Toxicology Research Collaboration
Immunosuppression
popular

Inconclusive evidence
(Eddleston M et al QJM. 2003 and Agarwal et al Singapore Med J. 2007)
South Asian Clinical
South Asian Clinical Toxicology Research Collaboration
RCT in Sri Lanka
Fraction survival
1.0
Immunosuppression group
Placebo group
0.5
0.0
0
10
20
30
40
50
60
70
80
90
Days post-ingestion
Chi squared 0.74, p=0.34
South Asian Clinical Toxicology Research Collaboration
ROC curves
Area under the curve
1= perfect test
South Asian Clinical Toxicology Research Collaboration
Assessment of prognosis
Admission plasma paraquat concentration
SIPP score
Plasma paraquat
100
100
80
Sensitivity (%)
Sensitivity (%)
80
60
40
AUC= 0.96
20
60
40
AUC=0.95
20
0
0
0
20
40
60
100% - Specificity%
80
100
0
20
40
60
100% - Specificity%
80
100
Semi-quantitative
Urine dithionite test
Number
Number and %
deaths
Positive test
418
251 (60%)
Negative test
149
7 (4.7%)
South Asian Clinical Toxicology Research Collaboration
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
South Asian Clinical Toxicology Research Collaboration
Admission creatinine
>1.26mg/dL
Sensitivity of 78% (95% CI: 69-85), specificity of 73%
(95% CI: 59-84) [positive likelihood ratio 2.91]
100
80
sensitivity

60
40
AUC=0.82
20
0
0
20
40
60
80
100
100% - Specificity%
South Asian Clinical Toxicology Research Collaboration
Creatinine >2.64mg/dL
100
case fatality (%)
80
60
40
20
0
>2.635mg/dL


<2.635mg/dL
(OR 16.7, 95% CI: 3.8-72, specificity: 0.96 (95% CI 0.870.99),
PPV 0.95 (95% CI 0.85-0.99, p<0.001).
South Asian Clinical Toxicology Research Collaboration
Median rise of serum creatinine within 24 hours
100
5
80
Sensitivity (%)
mg/dL
4
3
2


40
AUC=0.88
20
0
0
de
ce
as
ed
1
su
rv
iv
or
s

60
0
20
40
60
80
100
100% - Specificity%
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)
South Asian Clinical Toxicology Research Collaboration
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
100
80
Sensitivity (%)

60
40
AUC=0.88
20
0
0
20
40
60
80
100
100% - Specificity%
South Asian Clinical Toxicology
Research Collaboration
summary



Survivors and non
survivors can be
identified early
Immunosuppression
does not work
Prevent access to
paraquat as outcome is
poor
South Asian Clinical Toxicology Research Collaboration
Poisoning Deaths Transition
2006-2013
6.00%
5.00%
4.00%
Non Ag deaths
Other Pesitcides
Paraquat
3.00%
Glyphosate
Carbamates
2.00%
Chlorpyrifos
Dimethoate
1.00%
0.00%
2006
Fenthione
2007
2008
2009
2010
2011
2012
2013
Pesticide bans (3 years)
South Asian Clinical Toxicology Research Collaboration
Acknowledgements
Andrew Dawson, Nick Buckley,
Michael Eddleston,
Michael Eddleston1,2,3*, Peter Eyer4, Franz Worek5, Edmund Juszczak6, Nicola Alder6, Fahim
Mohamed2,3, Lalith Senarathna2,3, Ariyasena Hittarage7, Shifa Azher8, K. Jeganathan7,
Shaluka
Jayamanne8, 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; the
IDMC and Professor Doug Altman for advice; Renate Heilmair, Bodo
Pfeiffer, and Elisabeth Topoll for technical assistance; J. V. Peter for
information on the Vellore RCTs; and Allister Vale and Nick Bateman for
critical review.
Ox-Col Poisoning Study Collaborators: Darren Roberts, Damithe
Pitahawatte, 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, Nilumdima
Wijekoon, 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, Paramananthan
Sajeevan, Vethanathan Bavanthan, Janitha Kumari Illangakoon,
Chamantha Dilmini Karunarathne, Kuleesha Kodisinghe, Buddika
Jeevantha Wimalarathne, Asela Udagedara, Ashoka Subasinghe, Kiloshini
Samanthi Hendawitharana, Dammika Prabath Nungamugedara, Aruna
Wijayanayaka, Sanjeewa Amarasinghe, Sakunthala Nilmini Liyanage,
Indika de Alwis, Thushara Priyawansha, Chathura Pallangasinghe, Shukry
Zawahir, Mohamed Ashrafdeen Isnan, and Syed Shahmy
Independent Data Monitoring Committee (IDMC): Professor
Mike Clarke (Director, UK Cochrane Centre, Oxford; Chair); Professor
Keith Hawton (Department of Psychiatry, Oxford); Dr. Julian Higgins
(MRC Biostatistics Unit, Cambridge University; statistician); Professor
Saroj 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, medical
and 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, LyMee Yu and Nicola Alder for statistical support, Shukry Zawahir, and
Chathura 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 a
Wellcome 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 Council
International Collaborative Research Grant 071669.
Ox-Col poisoning study collaborators
Darren 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 (MRC
Biostatistics Unit, Cambridge University; Statistician); Saroj Jayasinghe
(Department of Clinical Medicine, Colombo); Nimal Senanayake
(Department of Clinical Medicine, Peradeniya); Kris Weerasuriya
(WHO/SEARO, New Delhi).
SACTRC collaborators, research
team and hospital staff
University of Peradeniya
Wellcome Trust & NHMRC
Syngenta
South Asian Clinical Toxicology Research Collaboration
Other markers of prognosis
100
admission bilirubin
admission paraquat
admission creatinine
admission ALT
admission WBC
SIPP score
rise of creatinine
Sensitivity (%)
80
60
40
20
0
0
20
40
60
80
100
100% - Specificity%
South Asian Clinical Toxicology Research Collaboration
No rise CFR 52.5%
South Asian Clinical Toxicology Research Collaboration
South Asian Clinical Toxicology Research Collaboration