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Early Hemoperfusion May Improve Survival of Severe Paraquat-Poisoned Patients

Early Hemoperfusion May Improve Survival of Severe Paraquat-Poisoned Patients. 許景瑋 / 林杰樑醫師 2012/06/20. Introduction. Paraquat (PQ) one of the most widely used herbicides in the world.

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Early Hemoperfusion May Improve Survival of Severe Paraquat-Poisoned Patients

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  1. Early Hemoperfusion May Improve Survival of Severe Paraquat-Poisoned Patients 許景瑋/林杰樑醫師 2012/06/20

  2. Introduction

  3. Paraquat (PQ) • one of the most widely used herbicides in the world. • In humans, whether intentional or accidental, ingestion of PQ is frequently fatal, causing significant lung injury. Smith LL (1987) Hum Toxicol 6: 31-36.

  4. Thousands of PQ-poisoned patients died in the developing countries till now because of no effective treatments.

  5. The mortality rate of acute PQ poisoning is strongly affected by plasma PQ levels and urine PQ levels. • Hart TB, Nevitt A, Whitehead A (1984) Lancet 2: 1222-1223. • 2) Scherrmann JM, Houze P, bismuth C, Bourdon R (1987) Hum Toxicol 6: 91-93.

  6. (1987) Hum Toxicol 6: 91-93

  7. Koo JR, Kim JC, Yoon JW, Kim GH, Jeon RW, et al. (2002) Am J Kidney Dis 39: 55-59.

  8. The urine test for PQ intoxication (sodium dithionite test): A strong navy blue(≧25 ppm and <50 ppm) or dark blue (≧50 ppm) within 24 hours after PQ ingestion  indicates significant PQ poisoning and poor outcome as well as high mortality 1) Scherrmann JM, Houze P, bismuth C, Bourdon R (1987) Hum Toxicol 6: 91-93. 2) Lin JL, Leu ML, Liu YC, Chen GH (1999) Am J Respir Crit Care Med 159: 357-360. 3) Koo JR, Kim JC, Yoon JW, Kim GH, Jeon RW, et al. (2002) Am J Kidney Dis 39: 55-59.

  9. Urine PQ tests within the first 24 hours of intoxication are good predictors of outcome.

  10. Hemodialysis (HD) or hemoperfusion (HP) is a comprehensive therapy in the initial stages of intoxication. • PQ clearance is more effective with HP than with HD . Hong SY, Yang JO, Lee EY, Kim SH (2003) Toxicol Ind Health 19: 17-23.

  11. However, the efficiency of HP in severe PQ poisoning has been disappointing. 1) Mascie-Taylor BH (1983) Lancet 1: 1376-1377. 2) Van de Vyver FL (1985) J Toxicol Clin Toxicol 23: 117-131. 3) Pond SM (1987) J Toxicol Clin Toxicol 25: 305-316.

  12. KINETICS OF TOXIC DOSES OF PARAQUAT ANDTHE EFFECTS OF HEMOPERFUSION IN THE DOG Pond SM (1993) J Toxicol Clin Toxicol 31: 229-246.

  13. In animal study: Charcoal HP is effective to be begun and continued for 6 to 8 hours only if it can be initiated within 2 hours of PQ injection or within 4 hours of PQ ingestion. 1) Pond SM (1993) J Toxicol Clin Toxicol 31: 229-246. 2) Hampson EC (1990) J Pharmacol Exp Ther 254(2): 732-740. 3) Tominack RL (2002) Goldfrank’s toxicologic emergencies. 7th ed. New York: McGraw-Hill, pp 1393-1410.

  14. In human: However, no previous investigation confirmed this finding.

  15. In human: Whether early performance of HP improves the survival rate of severe PQ-poisoned patients ?

  16. We performed a 10-year retrospective study to analyze these patients admitted to Lin-Kou and Keelung CGMH.

  17. Method

  18. Patients • reviewed the medical charts of all patients with acute PQ poisoning admitted between Jan-1, 2000 to Dec-31, 2009. • The selection of cases was based on the patients’ diagnosis on discharge

  19. Patients who arrived ER within 24 hours after ingestion with a dark blue color showed by urine PQ tests were enrolled in this study.

  20. Exclusion criteria: • <18 year-old • arrived at ER < 24 hours after ingestion but had a colorless, or light blue color in urine tests • arrived at the ER > 24 hours after ingestion • without urine PQ tests < 24 hours after ingestion • not have oral ingestion of PQ • joined the previous prospective study • not require admission to the wards and were discharged from the ER

  21. Two physicians who did not know the aim of this study participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet. • The both abstractors reviewed the entire set of randomly selected medical charts.

  22. Treatment protocols • At ER: activated charcoal 1 g/kg added to 250 mL of Mg citrate through NG tubes after gastric lavage with normal saline. • All patients also received two courses of 8 hours HP therapy with a 4 hours interval in the HD center or ICU.

  23. After HP therapy • admitted from: • Jan-1, 2000 to Dec-31, 2001 in Lin-Kou CGMH • Jan-1, 2000 to Dec-31, 2003 in Keelung CGMH received high dose therapy: oral cyclophosphamide (CP) 100mg/day and dexamethasone (DX) intravenously 15 mg/day for 2 weeks.

  24. Crit Care Med 30: 2584-2587. (2002)

  25. J Toxicol Clin Toxicol 41: 877-881. (2003)

  26. After HP therapy • admitted from • Jan-1, 2002 to Dec-31, 2009 in Lin-Kou CGMH • Jan-1, 2004 to Dec-31, 2009 in Keelung CGMH received repeated pulse therapy : 1) methylprednisolone (MP) (1 g/day for 3 days) and CP (15 mg/kg/day for 2 days) initially 2) followed by DX 20 mg/day until PaO2 was >80 mmHg and repeated MP (1 g/day for 3 days) and/or CP (15 mg/kg/day for 1 day) therapy if PaO2 was <60 mmHg

  27. Outcome Measurement • the mortality of patients • Every patient who survived was F/U for at least 60 days at wards or OPD.

  28. Definitions • Early HP: initial HP therapy <4 hours after PQ ingestion • Late HP: initial HP ≧4 hours after PQ ingestion

  29. Definitions • Acute kidney injury was diagnosed according to the RIFLE classification. • Acute hepatitis was diagnosed when serum ALT values exceeded 70 in patients who had normal LFT previously. • Acute hypoxemia was diagnosed if a patient had PaO2 70 mmHg by ABG analysis.

  30. Statistical Analysis • The differences between the two study groups were compared by t-tests for continuous variables or the Chi-square test with Fisher’s exact test for categorical variables. • Kaplan-Meier survival curves

  31. Statistical Analysis • univariate Cox proportional hazard model to measure all basal variables and to determine the potential variables (P <0.1) for predicting mortality. • the potential variables were assessed by multivariate Cox proportional hazard model to evaluate the significant variables associated with HR for mortality.

  32. All study patients were also stratified into the repeated pulse group and high-dose group  clarify whether different treatment methods influenced the outcome of early HP and late HP.

  33. Results

  34. Of 342 patients with PQ poisoning during the 10-year period, a total of 207 patients met the criteria and were included in this investigation.

  35. All were suicidal cases and had ingested a 24% liquid PQ concentrate. • mean age: 39.3 ± 16.1 years • time elapsed from ingestion to ER • 3 (1.4%) <1 hour • 34 (16.4%) <2 hours • 72 (34.8%) <3 hours • 107 (51.7%) <4 hours • 133 (64.3%) <5 hours

  36. All patients received gastric lavage and active charcoal >1 hour after ingestion of PQ. • Only 2 patients received within 2 hours, and 23 patients received within 3 hours.

  37. Of the 207 patients, 142 (68.6%) died within 60 days after intoxication.

  38. 91 (44.0%) patients died of multiple organ failure, including 52 (25.1%) died within 24 hours after ingestion. • 51(24.6%) patients died of lung fibrosis related severe hypoxemia.

  39. Six of 13 (46.2%) patients receiving HP <4 hours after intoxication died. • 26 of 42 (61.9%) patients receiving HP <5 hours after intoxication died.

  40. mortality rate : 6/13 (46.2%) in early HP group 136/194 (70.1%) in late HP group

  41. Kaplan-Meier survival analysis severe paraquat-poisoned patients with early hemoperfusion (n=13, 7/13=53.8%) and those with late hemoperfusion (n=194; 65/194=29.9%). (Log rank tests, Chi-square=4.17; P=0.041)

  42. Univariate Cox regression analysis • potential predictors of all-cause mortality: • age • navy blue color in urine PQ tests • initial AKI • repeated pulse therapy • time elapsed for HP <4.0 hours after PQ ingestion (HR = 0.46, 95% CI: 0.20–1.03; P = 0.060)

  43. Multivariate Cox regression analysis • independent predictors of mortality: • age • navy blue color in urine PQ tests • initial AKI • time elapsed for HP <4.0 hours after PQ ingestion (HR = 0.38, 95% CI: 0.16–0.86; P = 0.020) • repeated pulse therapy (HR = 0.63, 95% CI: 0.44–0.90; P = 0.011)

  44. Multivariate Cox regression analysis • significant predictors of mortality: • age • navy blue color in urine PQ tests • initial AKI • repeated pulse therapy • the time elapsed to HP <5 hours (HR =0.60, 95% CI: 0.39-0.92; P = 0.018)

  45. Table 3. Multivariate Cox regression analysis for hazard ratios of all-cause mortality in severe PQ-poisoned patients, according to baseline variables (n=207).

  46. Table 4. Forward stepwise of multivariate Cox regression analysis for hazard ratios of all-cause mortality in severe PQ-poisoned patients, according to baseline variables and HP <4 hours (n=207).

  47. in forward stepwise multivariate Cox analysis • the time elapsed to HP <5 hours (HR = 0.59, 95% CI: 0.39–0.92; P = 0.018) was also a significant protector to reduce mortality. • Neither time elapsed to HP <6 hours nor <7 hours was the significant factor in determining the mortality of severe PQ-poisoned patients.

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