ICU Combined Conference

1. ICU Combined Conference R4 梁家欣 / VS 姜至剛

2. 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

3. Chief Complaint • Suicide by drinking diluted Paraquat about 150~200ml at 2/12 01:00

4. Present illness • Nausea, vomiting was noted after paraquat drinking • Sent to 國立陽明大學附設醫院 • 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

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

6. Laboratory data

7. Laboratory data

8. Present illness • Nausea, vomiting was noted after paraquat drinking • Sent to 國立陽明大學附設醫院 • 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

10. 2/12

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

12. Treatment course (2/13) • Plasma level of Paraquat1.4 ug/ml • Hemoperfusion + Hemodialysis • Respiratory distress and intubation at 13:00 10:45~18:00

13. 2/12 2/13

14. Treatment course (2/14) • Plasma level of Paraquat1.4 ug/ml • Hemodialysis • FiO2 0.55 PEEP 12

15. Treatment course (2/15) • Plasma level of Paraquat0.2 ug/ml • Profound shock, add Dopamine and Levophed • Repeated Cyclophosphamide and Solu-medrol • FiO2 0.35 PEEP 12

16. Treatment course HP+HD HD HP BP drop Intubation Expired Tazocin Cyclophosphamide 1gm QD Cyclophosphamide 1gm QD Methylprednisolone 1 gm QD Levophed Dopamin

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

18. Discussion PARAQUAT INTOXICATION

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%

20. Toxicokinetics Human Toxicology. (1987), 6, 37-40

21. Clinical exposure • Skin absorption • 0.4% for unoccludedsite • 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

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

24. Mechanism of toxicity • The generation of superoxide anion which can lead to the formation of more toxic reactive oxygen species • The oxidation of the cellular NADPH which result in the disruption of important NADPH-requiring biochemical processes • Lipid peroxidation which results in the oxidative degeneration of cellular polyunsaturated fatty acids Toxicology 180(2002) 65-77

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%

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

27. Lung • Maximum concentration about 4~5hrsafter 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

28. Acute kidney injury • 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 <0.01] Cr≤1.2mg/dl Cr >1.2mg/dl NDT (2009) 24: 1226-1232

29. Diagnosis • Qualitative dithionite urine test with alkalinesodium 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

30. 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

31. 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

32. Immunosuppressive therapy Singapore Med J 2007; 48(11):1002

33. Singapore Med J 2007; 48(11):1002

34. Immunosuppressive therapy Singapore Med J 2007; 48(11):1002

35. Improved survival in severe paraquat poisoning with repeated pulse therapy of cyclophosphamide and steroid • 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 < 60 mmHg → repeated 1gm Methylprednisolone x 3 days and 1gm Cyclophosphamide x 1 day (WBC>5000 and duration > 2wks) 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 Intensive Care Med (2011) 37: 1006-1013

36. Improved survival in severe paraquat poisoning with repeated pulse therapy of cyclophosphamide and steroid • 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 Intensive Care Med (2011) 37: 1006-1013

37. Elimination enhancement • Peritoneal dialysis • Poor removing paraquat • Hemodialysis • Good when plasma concentration of paraquatare 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

38. Hemoperfusionvs hemodialysis J. Toxicol Clin Toxico, 19(8), 807-819(1982-83)

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 ToxicolClinToxicol 1982; 19:807

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

41. Comparison between Hemoperfusion and kidney for paraquat elimination • The elimination of paraquat was higher with hemoperfusion when the paraquat level in the plasma was higher then 1ug/ml J Korean Med Sci 2009; 24 (suppl 1):S156-600

42. Comparison between Hemoperfusion and kidney for paraquat elimination • 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 J Korean Med Sci 2009; 24 (suppl 1):S156-600

43. Prognostic factor • Serum paraquat concentrations and hours after ingestion • Lactate acid • Serum uric acid level

44. Prognostic factor : Serum paraquat concentration • Hart et al created a nomogram with 6 concentration-time curves of about 10~90% survival probability Lancet 1979; 2:330-332

45. Prognostic factor : lactate Lactate ≤ 4.4 Lactate > 4.4 Clinical Toxicology (2012) 50: 52-56

46. Prognostic factor : uric acid NDT (2011) 26: 1846-1852

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

48. Thanks for your attention

49. NDT (2009) 24: 1226-1232

50. Lipid peroxidation may be enhanced by iron radicals, since removal of iron by the chelating agent deferoxaminereduces 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.