r4 梁家欣 / vs 姜至剛 icu combined conference. patient data age : 32 gender : male marriage :...

R4 / VS ICU COMBINED CONFERENCE

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

Suicide by drinking diluted Paraquat about 150~200ml at 2/12 01:00 CHIEF COMPLAINT

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

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

LABORATORY DATA Hemogram ( 2012/02/12) WBCSegEosBasoMonoLymHbHctPlt /uL%%%g/dl%K/uL 2283085.10.1 4.610.116.948.8265 Biochemistry ( 2012/02/12) BUNCrNaKCaT.BilASTLipaseLactate mg/dl mmol/L mg/dlU/L mmol/L 120.91443.42.330.9526646.0 Biochemistry ( 2012/02/12) CKCK-MBTro-IPTINRaPTT U/L ng/mlsecSec 18118

LABORATORY DATA Blood Gas( 2012/02/12) pHpCO2pO2HCO3-BE mmHg mmol/L 7.37631.459.218.5-4.9 Urine analysis (2012/02/12) Sp. GrpHProteinGluKetoneRBCWBCEpiCastBac **mg/dl /HPF /LPF* 1.0087.5100(2+)300(3+)->100 0-2-4+

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

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

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

2/122/13

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

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

TREATMENT COURSE Tazocin Cyclophosphamide 1gm QD Methylprednisolone 1 gm QD Levophed Dopamin HP HP+HD HD Intubation BP drop Expired

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

PARAQUAT INTOXICATION DISCUSSION

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%

TOXICOKINETICS Human Toxicology. (1987), 6, 37-40

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

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

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

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%

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

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

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

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 Decontamination : Nasogastric suction Adsorbent agent ( activated charcoal 50~100g ) Gastric lavage : not suggest Aggressive fluid resuscitation : Replace fluid loss Maintain renal blood flow Oxygen : withheld until PaO2 < 50mmHg Stress ulcer prophylaxis

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

IMMUNOSUPPRESSIVE THERAPY Singapore Med J 2007; 48(11):1002

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

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

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

HEMOPERFUSION VS HEMODIALYSIS J. Toxicol Clin Toxico, 19(8), 807-819(1982-83)

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

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

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

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

PROGNOSTIC FACTOR Serum paraquat concentrations and hours after ingestion Lactate acid Serum uric acid level

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 : LACTATE Cut-off pointSensitivitySpecificityAURCPPVNPV Lactate4.482880.8869753 APACHE II975840.8599543 Clinical Toxicology (2012) 50: 52-56 Lactate 4.4 Lactate > 4.4

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

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

THANKS FOR YOUR ATTENTION

NDT (2009) 24: 1226-1232

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.

IMMUNOSUPPRESSIVE THERAPY Singapore Med J 2007; 48(11):1002

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

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

r4 梁家欣 / vs 姜至剛 icu combined conference. patient data age : 32 gender : male marriage :...

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