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

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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

Introduction


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

(1987) Hum Toxicol 6: 91-93


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

Urine PQ tests within the first 24 hours of

intoxication are good predictors of outcome.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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 ANDTHE EFFECTS OF HEMOPERFUSION IN THE DOG

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


In animal study

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.


In human

In human:

However, no previous investigation confirmed this finding.


In human1

In human:

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Method

Method


Patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Exclusion criteria

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Treatment protocols

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.


After hp therapy

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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


After hp therapy1

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


Outcome measurement

Outcome Measurement

  • the mortality of patients

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


Definitions

Definitions

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

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


Definitions1

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.


Statistical analysis

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


Statistical analysis1

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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Results

Results


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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

136/194 (70.1%) in late HP group


Kaplan meier survival analysis

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)


Univariate cox regression analysis

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)


Multivariate cox regression analysis

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)


Multivariate cox regression analysis1

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)


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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

  • 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.


Early hemoperfusion may improve survival of severe paraquat 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

  • 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

  • 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

  • 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

  • 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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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

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

  • 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

  • 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

  • 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

  • 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

  • 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)


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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).


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 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

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

When 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

  • 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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

Shortening the elapsed time from ER to HP may be important to save the life of severe PQ-poisoned patients with repeated pulse therapy.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • 46.3% (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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

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


Early hemoperfusion may improve survival of severe paraquat poisoned patients

  • Compared to the high dose therapy, the 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:

  • 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

  • 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

  • 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.


Early hemoperfusion may improve survival of severe paraquat poisoned patients

(1987) Hum Toxicol 6: 91-93


Conclusion

Conclusion

  • 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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