PATIENT DATA Age : 32 Gender : male Marriage : single No past
medical history Education : university Allergy : denied Smoking : 1
PPD for 5 years Alcohol : denied Drug abuser history : denied
Slide 3
Suicide by drinking diluted Paraquat about 150~200ml at 2/12
01:00 CHIEF COMPLAINT
Slide 4
PRESENT ILLNESS Nausea, vomiting was noted after paraquat
drinking Sent to Gastric lavage Urine Paraquat test (+) Transfer to
NTUH ER for hemoperfusion At ER, TPR : 35.9/85/20 BP:142/99mmHg,
SpO2 92% room air 1:00 2:00 4: 27
Slide 5
PHYSICAL EXAMINATION Consciousness : clear, E3V5M6 General
appearance : acute ill-looking Vital signs : TPR : 36.2/101/19
BP:136/92mmHg Height : 172cm Weigh : 71.8kg BMI : 22.91 Skin : skin
rash (-) fair skin turgor HEENT : isocoric, 2.5mm/2.5mm,
conjunctiva : not pale, sclera : anicteric, corrosive injury over
oral mucosa Neck : supple, LAP(-), JVE(-), goiter(-), carotid bruit
(-) Chest : symmetric expansion, breath sound : clear, no accessory
muscle use Heart : RHB, no murmur, no S3 or S4 Abdomen : soft and
flat, no operation scar, normo-active bowel sound, no bruit, no
hepatosplenomegaly, no shifting dullness, no tenderness, no
rebounding pain Back : no knocking tenderness Extremities : freely
movable, pitting edema(-), cyanosis(-), peripheral pulsation :
intact
PRESENT ILLNESS Nausea, vomiting was noted after paraquat
drinking Sent to Gastric lavage Urine Paraquat test (+) Transfer to
our NTUH ER for hemoperfusion At ER, TPR : 35.9/85/20
BP:142/99mmHg, SpO2 92% room air Admitted to IAI 1:00 2:00 4: 27
5:45
Slide 9
Slide 10
2/12
Slide 11
TREATMENT COURSE (2/12) Admitted to IAI Vital signs :
36.2/85/15 BP: 136/92mmHg APACHE II Score : 29 Plasma level of
Paraquat 12.5ug/ml ( 5hrs after ingestion ) Hemoperfusion
Cyclophosphamide (1g/day) x 2 days and Methylprednisolone pulse
therapy (1g/day) x 3 days 5:45 7:40~13:40
Slide 12
TREATMENT COURSE (2/13) Plasma level of Paraquat 1.4 ug/ml
Hemoperfusion + Hemodialysis Respiratory distress and intubation at
13:00 10:45~18:00 BUN mg/dl Cr mg/dl Urine output ml
2012/02/12120.9490 2012/02/13394.72590 2012/02/14335.86190
2010/02/15397.4340
Slide 13
2/122/13
Slide 14
TREATMENT COURSE (2/14) Plasma level of Paraquat 1.4 ug/ml
Hemodialysis FiO2 0.55 PEEP 12 BUN mg/dl Cr mg/dl Urine output ml
2012/02/12120.9490 2012/02/13394.72590 2012/02/14335.86190
2010/02/15397.4340
Slide 15
TREATMENT COURSE (2/15) Plasma level of Paraquat 0.2 ug/ml
Profound shock, add Dopamine and Levophed Repeated Cyclophosphamide
and Solu-medrol FiO2 0.35 PEEP 12 BUN mg/dl Cr mg/dl Urine output
ml 2012/02/12120.9490 2012/02/13394.72590 2012/02/14335.86190
2010/02/15397.4340
Slide 16
TREATMENT COURSE Tazocin Cyclophosphamide 1gm QD
Methylprednisolone 1 gm QD Levophed Dopamin HP HP+HD HD Intubation
BP drop Expired
Slide 17
FINAL DIAGNOSIS Paraquat intoxication, status post
hemoperfusion (2/12~2/13) and cyclophosphamide, methylprednisolone
pulse therapy with acute respiratory distress syndrome and acute
kidney injury Acute respiratory distress syndrome, status post
intubation and mechanical ventilator support Acute kidney injury,
RIFLE F, status post hemodialysis (2/13~2/14) Urinary tract
infection
Slide 18
PARAQUAT INTOXICATION DISCUSSION
Slide 19
PARAQUAT 1,1-dimethyl-4,4-bipyridylium chloride Widely used as
herbicide since 1962 Concentration : 20%~40% Volume distribution :
1.0~1.5L/kg body weight Less than 10% of ingested dose is absorbed
over 1~6 hours Serum peak level about 60~90 mins after ingestion
Paraquat can be detected in the urine as early as 1 hour after
ingestion Mortality rate : 50~90%
Slide 20
TOXICOKINETICS Human Toxicology. (1987), 6, 37-40
Slide 21
CLINICAL EXPOSURE Skin absorption 0.4% for unoccluded site 1.4%
for occluded site 3.6% for occluded and damaged dermal site Lung:
poor due to large droplet and low vapor pressure GI tract:
significant systemic toxicity observed J toxico Enviro Health.
(1984), 14, 759
Slide 22
THREE-COMPARTMENT MODEL Plasma compartment Compartment with
rapid uptake and removal such as kidney Slow uptake compartment
such as lungs, reaching a maximum concentration about 4~5 hrs after
ingestion
Slide 23
Slide 24
MECHANISM OF TOXICITY 1)The generation of superoxide anion
which can lead to the formation of more toxic reactive oxygen
species 2)The oxidation of the cellular NADPH which result in the
disruption of important NADPH-requiring biochemical processes
3)Lipid peroxidation which results in the oxidative degeneration of
cellular polyunsaturated fatty acids Toxicology 180(2002)
65-77
Slide 25
TOXICITY Mild toxicity : < 20 mg/kg of paraquat ion Minor GI
symptoms Severe toxicity : 20~40 mg/kg of paraquat ion Acute renal
failure, acute lung injury, progressive pulmonary fibrosis Most
died, but delayed for 2~3 weeks Fulminant : > 40 mg/kg of
paraquat ion Multiple organ failure within hours to days Mortality
rate 100%
Slide 26
SYMPTOMS Gastrointestinal : nausea, vomiting, corrosive injury
or perforation Cardiovascular : hypotension due to massive fluid
loss and cardiac dysrhythmias Renal : acute tubular necrosis
Hepatic : centrilobular necrosis within 24~48hrs Neurologic : CNS
depression and seizures Pulmonary : acute lung injury, pulmonary
fibrosis, hypoxia
Slide 27
LUNG Maximum concentration about 4~5 hrs after ingestion
Paraquat concentration in lung is 10~20 times greater than plasma
because of active, energy-dependent uptake of paraquat Concentrated
in type I and type II pneumocytes and leads to the generation of
oxygen free radicals and subsequent pulmonary fibrosis Human
Toxicology. (1987), 6, 37-40
Slide 28
Paraquat is toxic to renal proximal tubule cells through the
generation of ROS, which cause lipid peroxidation of the cell
membrane, leading to loss of membrane integrity and cell death. The
average peak serum Cr level was achieved on the fifth day after
ingestion and the Cr level normalized within 3 weeks. Initial serum
Cr level was a very important prognostic factor for mortality [ OR
9, 95% CI (4.747- 17.061), p 1.2mg/dl
Slide 29
DIAGNOSIS Qualitative dithionite urine test with alkaline
sodium dithionite Can detect concentrations of 1 mg/ml or above
(1ppm) Negative within 4 hrs no need for quantitative assay
Positive measurement serum paraquat concentration Gas
chromatography and high pressure liquid chromatography Can detect
concentrations of 1-2 mg/ml Radioimmunoassay Can detect and measure
levels < 0.1 mg/ml
TREATMENT Cyclophosphamide (15mg/kg) ivd for 2 days
Glucocorticoids (dexamethasone) 5mg iv every 6 hours until PaO2
> 80mmHg 3 RCT with total 164 participants who had moderate to
severe paraquat poisoning Patients who received glucocorticoid with
cyclophosphamide had a lower risk of death [RR 0.72 (95% CI 0.59 to
0.89)] Other medication : superoxide dismutase, propranolol,
vitamin E, ascorbic acid, riboflavin, niacin, deferoxamine,
clofibrate, acetylcysteine
Slide 32
IMMUNOSUPPRESSIVE THERAPY Singapore Med J 2007;
48(11):1002
Slide 33
Slide 34
IMMUNOSUPPRESSIVE THERAPY Singapore Med J 2007;
48(11):1002
Slide 35
111 patients with severe paraquat poisoning Control group (52
patients) : High dose of cyclophosphamide 2mg/kg/day and
Dexamethasone 5mg q6h x 14 days Study group (59 patients):
Methylprednisolone 1gm x 3 days and Cyclophosphamide 15mg/kg/day x
2 days, followed by Dexamethasone 5mg q6h until PaO2>80mmHg If
PaO2 5000 and duration > 2wks) IMPROVED SURVIVAL IN SEVERE
PARAQUAT POISONING WITH REPEATED PULSE THERAPY OF CYCLOPHOSPHAMIDE
AND STEROID Intensive Care Med (2011) 37: 1006-1013 52 patients
received high-dose therapy 59 patients received repeated pulse
therapy 48 (92.3%) died after 60 days 39 (66.1%) died after 60
days
Slide 36
IMPROVED SURVIVAL IN SEVERE PARAQUAT POISONING WITH REPEATED
PULSE THERAPY OF CYCLOPHOSPHAMIDE AND STEROID Intensive Care Med
(2011) 37: 1006-1013 Repeated pulse therapy was correlated with
decreased hazard ratios (HR=0.5, 95% CI 0.31-0.8, P= 0.004) for
all-cause mortality and death from lung-fibrosis-related hypoxemia
(HR=0.1, 95% CI 0.04-0.25, P< 0.001) in severely paraquat
intoxicated patients
Slide 37
ELIMINATION ENHANCEMENT Peritoneal dialysis Poor removing
paraquat Hemodialysis Good when plasma concentration of paraquat
are high (>10mg/l) Poor when the concentration is less than
1mg/l Hemoperfusion The most effective means of extracoporeal
elimination of paraquat Human toxicology(1987), 6, 69-74
Slide 38
HEMOPERFUSION VS HEMODIALYSIS J. Toxicol Clin Toxico, 19(8),
807-819(1982-83)
Slide 39
INCREASE PARAQUAT ELIMINATION Normal renal function : Renal
clearance of paraquat exceeds the glomerular filtration rate
because of an active transport process Okonek and associates have
proposed that hemoperfusion be performed for several days ( 8 hours
per day for 2-3 weeks ) Daily four to six hours hemoperfusion,
until paraquat is no longer detectable in the blood J Toxicol Clin
Toxicol 1982; 19:807
Slide 40
HEMOPERFUSION VS HEMOPERFUSION+CVVH Ja-Ryong Koo, MD et al
Hemoperfusion(44) VS Hemoperfusion 6 hours followed by CVVH(36)
Conclusion: Prophylactic CVVH after HP prevented early death caused
by circulatory collapse and prolonged survival time However, it
could not prevent late death caused by respiratory failure and did
not provide a survival benefit in acute poisoning AJKD, Vol 39, No
1(Jan), 2002: pp 55-59
Slide 41
The elimination of paraquat was higher with hemoperfusion when
the paraquat level in the plasma was higher then 1ug/ml COMPARISON
BETWEEN HEMOPERFUSION AND KIDNEY FOR PARAQUAT ELIMINATION J Korean
Med Sci 2009; 24 (suppl 1):S156-600
Slide 42
As creatinine clearance decreases, the paraquat elimination by
hemoperfusion was more effective than the renal elimination Early
hemoperfusion must be provided for life saving treatment in
patients with acute paraquat intoxication COMPARISON BETWEEN
HEMOPERFUSION AND KIDNEY FOR PARAQUAT ELIMINATION J Korean Med Sci
2009; 24 (suppl 1):S156-600
Slide 43
PROGNOSTIC FACTOR Serum paraquat concentrations and hours after
ingestion Lactate acid Serum uric acid level
Slide 44
Hart et al created a nomogram with 6 concentration-time curves
of about 10~90% survival probability PROGNOSTIC FACTOR : SERUM
PARAQUAT CONCENTRATION Lancet 1979; 2:330-332
PROGNOSTIC FACTOR : URIC ACID UnadjustedAdjusted for age,
gender and amount of PQ ingestion OR for
death3.49(1.67-7.31)3.67(1.35-9.98) NDT (2011) 26: 1846-1852
Slide 47
TAKE HOME MESSAGE Early hemoperfusion is indicated for patients
with acute paraquat intoxication Repeated pulses of
cyclophosphamide and steroids, rather than high doses of
cyclophosphamide and dexamethasone, may result in a lower mortality
rate in patients with severe paraquat poisoning
Slide 48
THANKS FOR YOUR ATTENTION
Slide 49
NDT (2009) 24: 1226-1232
Slide 50
Lipid peroxidation may be enhanced by iron radicals, since
removal of iron by the chelating agent deferoxamine reduces
toxicity in bacterial preparations or in normal mice, as well as in
vitamin E deficient rats Vitamin E, a potent antioxidant, may
prevent cytotoxicity in cultured cells Exogenous glutathione and
n-acetylcysteine, a donor of glutathione, may protect against
injury Sulfite or thiosulfate may be protective by reversing
oxidized glutathione, which competes with glutathione for peroxide,
hydroxyl and superoxide radicals Animal studies suggest that
salicylates help prevent paraquat induced lung, kidney and liver
injury. The mechanisms may involve interruption of pro-
inflammatory factors, scavenging of reactive oxygen species, and
inhibition of both myeloperoxidase pathways and platelet
aggregation. There is also some evidence that salicylates can
chelate bipyridyls.
Slide 51
IMMUNOSUPPRESSIVE THERAPY Singapore Med J 2007;
48(11):1002
Slide 52
IMMUNOSUPPRESSIVE THERAPY Singapore Med J 2007;
48(11):1002
Slide 53
MODE OF ACTION Interfere with the intracellular electron
transfer system in plant Inhibit reduction of NDP to NADPH during
photosynthesis Lead to the formation of superoxide These superoxide
interact with the unsaturated lipid of membranes Destruction of
organelle and cell death Toxicology 180(2002) 65-77
Slide 54
RenalHemoperfusion Clearance (ml/min)79.8 56111 11 Actual
amount of PQ elimination ( mg )75.4 73.6251.4 506.3 As creatinine
clearance decreases, the paraquat elimination by HP was more
effective than the renal elimination Early hemoperfusion must be
provided for life saving treatment in patients with acute paraquat
intoxication COMPARISON BETWEEN HEMOPERFUSION AND KIDNEY FOR
PARAQUAT ELIMINATION J Korean Med Sci 2009; 24 (suppl
1):S156-600