Early hemoperfusion may improve survival of severe paraquat poisoned patients
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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
Early Hemoperfusion May Improve Survival of Severe Paraquat-Poisoned Patients

許景瑋/林杰樑醫師 2012/06/20



  • 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.



  • 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.


(1987) Hum Toxicol 6: 91-93 affected by plasma PQ levels and urine PQ levels.



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.


Urine PQ tests within the first 24 hours of test):

intoxication are good predictors of outcome.


Hong SY, Yang JO, Lee EY, Kim SH (2003) Toxicol Ind Health 19: 17-23.


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.


Kinetics of toxic doses of paraquat and the effects of hemoperfusion in the dog
KINETICS OF TOXIC DOSES OF PARAQUAT AND been disappointing.THE EFFECTS OF HEMOPERFUSION IN THE DOG

Pond SM (1993) J Toxicol Clin Toxicol 31: 229-246.


In animal study
In animal study: been disappointing.

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.


In human
In human: been disappointing.

However, no previous investigation confirmed this finding.


In human1
In human: been disappointing.

Whether early performance of HP improves the survival rate of severe PQ-poisoned patients ?



Method
Method patients admitted to Lin-Kou and Keelung CGMH.


Patients
Patients patients admitted to Lin-Kou and Keelung CGMH.

  • 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



Exclusion criteria
Exclusion criteria: a dark blue color showed by urine PQ tests were enrolled in this study.

  • <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



Treatment protocols
Treatment protocols participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.

  • 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.


After hp therapy
After HP therapy participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.

  • 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.


Crit Care Med 30: 2584-2587. (2002) participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.


J Toxicol Clin Toxicol 41: 877-881. (2003) participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.


After hp therapy1
After HP therapy participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.

  • 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


Outcome measurement
Outcome Measurement participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.

  • the mortality of patients

  • Every patient who survived was F/U for at least 60 days at wards or OPD.


Definitions
Definitions participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.

  • Early HP: initial HP therapy <4 hours after PQ ingestion

  • Late HP: initial HP ≧4 hours after PQ ingestion


Definitions1
Definitions participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.

  • 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.


Statistical analysis
Statistical Analysis participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.

  • 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


Statistical analysis1
Statistical Analysis participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.

  • 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.


  • All study patients were also stratified into the participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet. repeated pulse group and high-dose group

     clarify whether different treatment methods influenced the outcome of early HP and late HP.


Results
Results participated in the study to abstract the charts using a standardized data collection form, in a Microsoft Excel spreadsheet.








mortality rate : 6/13 (46.2%) in early HP group intoxication died.

136/194 (70.1%) in late HP group


Kaplan meier survival analysis
Kaplan-Meier survival analysis intoxication died.

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)


Univariate cox regression analysis
Univariate Cox regression analysis intoxication died.

  • 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)


Multivariate cox regression analysis
Multivariate Cox regression analysis intoxication died.

  • 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)


Multivariate cox regression analysis1
Multivariate Cox regression analysis intoxication died.

  • 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)


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


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).


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

  • 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.


All patients were classified with the different treatment methods.

High dose therapy

vs

Repeated pulse therapy


High dose of cp and dx therapy
High dose of CP and DX therapy methods.

  • 71 patients

  • totally 57 (80.3%) patients died

  • Four of 5 (80%) patients receiving HP <4 hours after intoxication died

  • 17 of 21 (81%) patients receiving HP <5 hours after intoxication died


High dose therapy groups
High dose therapy groups methods.

  • in multivariate Cox or in forward stepwise Cox regression:

    • Neither time elapsed to HP <4 hours nor HP <5 hours was the significant variable for mortality in these patients.

      (4 hrs: HR = 0.99, 95% CI: 0.31–3.18; P = 0.992)

      (5 hrs: HR = 0.68, 95% CI: 0.33–1.37; P = 0.279)


Repeated pulse therapy group
Repeated pulse therapy group methods.

  • 136 patients

  • totally 85 (62.5%) patients died

  • time elapsed from ingestion of PQ to arrival at ER:

    • 0 patients (0 %) <1 hour

    • 13 (9.6 %) <2 hours

    • 41 (30.1%) <3 hours

    • 63 (46.3%) <4 hours

    • 84 (61.8%) <5 hours


Repeated pulse therapy group1
Repeated pulse therapy group methods.

  • Two of 8 (25%) patients with HP <4 hours after intoxication died

  • 9 of 21 (42.9%) patients with HP <5 hours after intoxication died


Table 5. Baseline characteristics of the survivors and non-survivors in severe PQ-poisoned patients with repeated pulse therapy (n=136).


Table 6. Baseline characteristics of severe PQ-poisoned patients with repeated pulse therapy, stratified with early and late HP. (n=136)


Kaplan meier survival analysis1
Kaplan-Meier survival analysis patients with repeated pulse therapy, stratified with early and late HP. (n=136)

severe paraquat-poisoned patients who received repeated pulse therapy with early hemoperfusion (n=21, 12/21=57.1%) and those with late hemoperfusion (n=115; 39/115=33.9%). (Log rank tests, Chi-square=4.47; P=0.035).


Univariate cox analysis
Univariate Cox analysis patients with repeated pulse therapy, stratified with early and late HP. (n=136)

  • potential predictors of mortality:

    • HP <4 hours (HR = 0.25, 95% CI: 0.06–1.04; P = 0.057) marginally significantly

    • Age

    • navy blue color in urine PQ tests

    • initial AKI


Multivariate cox regression analysis2
Multivariate Cox regression analysis patients with repeated pulse therapy, stratified with early and late HP. (n=136)

  • independent predictors of mortality:

    • Age

    • initial AKI

    • time elapsed for HP <4.0 hours after PQ ingestion (HR = 0.18, 95% CI: 0.04–0.74; P = 0.018)


Univariate cox analysis1
Univariate Cox analysis patients with repeated pulse therapy, stratified with early and late HP. (n=136)

  • potential predictors of mortality:

    • HP <5 hours (HR = 0.50, 95% CI: 0.25–1.00; P = 0.051) marginally significantly

    • Age

    • navy blue color in urine PQ tests

    • initial AKI


Multivariate cox regression analysis3
Multivariate Cox regression analysis patients with repeated pulse therapy, stratified with early and late HP. (n=136)

  • independent predictors of mortality:

    • Age

    • initial AKI

    • time elapsed for HP <5.0 hours after PQ ingestion (HR = 0.45, 95% CI: 0.22–0.90; P = 0.025)


Multivariate cox analysis
Multivariate Cox analysis patients with repeated pulse therapy, stratified with early and late HP. (n=136)

  • independent predictors of all-cause mortality:

    • Age

    • initial AKI

    • time elapsed for HP <4.0 hours after PQ ingestion (HR = 0.18, 95% CI: 0.04–0.78; P = 0.023)


Table 7. Forward stepwise of multivariate Cox regression analysis for hazard ratios of mortality in severe PQ-poisoned patients with repeated pulse therapy, according to baseline variables and HP <4 hours (n=136).


Table 8. Forward stepwise of multivariate Cox regression analysis for hazard ratios of mortality in severe PQ-poisoned patients with repeated pulse therapy, according to baseline variables and HP <5 hours (n=136).


Discussion
Discussion analysis for hazard ratios of mortality in severe PQ-poisoned patients with repeated pulse therapy, according to baseline variables and HP


  • The study results first showed, after the relating variables were adjusted, time elapsed from intoxication to HP <4 hours or <5 hours was associated with 62%, 41%, respectively, reduction of relative risk for mortality of all severe PQ-poisoned patients.

  • Early HP reduced the risk for mortality only in patients with repeated pulse therapy, not in patients with high dose therapy. Time elapsed from intoxication to HP <4.0 hours or <5.0 hours may significantly reduce the relative risk for mortality about 81%, 51%, respectively in these patients.


In multivariate cox analysis
In multivariate Cox analysis were adjusted, time elapsed from intoxication to HP

  • Time elapsed to administration of gastric lavage and active charcoal were not significant associated the HR of mortality.(HR = 1.06, 95% CI: 0.65–1.72; P = 0.802)

    • <3 hours (n=23) (HR = 1.15, 95% CI: 0.59–2.24; P = 0.691)

    • <4 hours (n=46) (HR = 1.25, 95% CI: 0.74–2.10; P = 0.404)

      Early HP is associated with the reduced risk for mortality of these patients.


This finding in humans first confirms the previous results in animal studies indicating HP within 4 hours after ingestion effectively reduced mortality of animals.


W results in animal studies indicating HP within 4 hours after ingestion effectively reduced mortality of animals. hen HP is initiated, potentially lethal concentrations of PQ have already been attained via active transport in the highly vascular tissues of the vital organs and in pneumocytes.


Peak time of pq intoxication
Peak time of PQ intoxication results in animal studies indicating HP within 4 hours after ingestion effectively reduced mortality of animals.

  • plasma :1-3 hours

  • lung cells : 4-5 hours

  • nearly 90% of PQ disappears 5-6 hours later in the plasma after ingestion

    Received HP therapy as early as possible

time is life


Shortening the elapsed time from ER to HP results in animal studies indicating HP within 4 hours after ingestion effectively reduced mortality of animals. may be important to save the life of severe PQ-poisoned patients with repeated pulse therapy.


  • 46.3% results in animal studies indicating HP within 4 hours after ingestion effectively reduced mortality of animals. (63/136) patients arrived at ER <4 hours after ingestion of PQ, only 5.9% (8/136) patients received HP <4 hours after intoxication.

  • 61.8 % (84/136) patients arrived at ER <5 hours after ingestion of PQ, only 15.4% (21/136) patients received HP <5 hours after intoxication.

The median time: 2.5 hours


The aggressive attitude of medical staff is important to shorten the elapsed time from ER to HP.


  • Compared to the high dose therapy, the shorten the elapsed time from ER to HP. repeated pulse therapy was associated with 37% reduction of relative risk for mortality of all severe PQ-poisoned patients.

  • The time elapsed for HP <4 hours and HP <5 hours were associated with 81% and 51%, respectively, reduction of relative risks for mortality in severe PQ-poisoned patients with repeated pulse therapy.


Possible reasons
Possible reasons: shorten the elapsed time from ER to HP.

  • the strongest anti-inflammatory effect of mega-dose of MP and CP-induced leucopenia and immunosuppressive effects.

  • the prolonged DX treatment may attenuate the inflammation changes of lung


Limitations of this study
limitations of this study shorten the elapsed time from ER to HP.

  • A retrospective investigation: observational bias is always possible when reviewing charts.

  • Early HP may effectively improve the survival, further prospective study with a large group of early HP patients is required.


Limitations of this study1
limitations of this study shorten the elapsed time from ER to HP.

  • Only some of study patients had serum PQ levels but all patients had urine PQ tests.

  • However, the plasma PQ levels drop rapidly after intoxication.


(1987) Hum Toxicol 6: 91-93 shorten the elapsed time from ER to HP.


Conclusion
Conclusion shorten the elapsed time from ER to HP.

  • The study first demonstrates that, similar to previous animal studies, early HP (<4 hours or <5 hours after ingestion of PQ) is associated with decrease of mortality in the severe PQ-poisoned patients after adjusting for significantly related variables.


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