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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

slide4
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.

slide5
Thousands of PQ-poisoned patients died in the developing countries till now because of no effective treatments.
slide6
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.
slide9
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.

slide10
Urine PQ tests within the first 24 hours of

intoxication are good predictors of outcome.

slide11
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.

slide12
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 ?

slide17
We performed a 10-year retrospective study to analyze these patients admitted to Lin-Kou and Keelung CGMH.
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
slide20
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
slide22
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.

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.
slide33
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.

slide35
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.
slide37
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
slide38
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.
slide40
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.
slide41
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.
slide43

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)
slide48

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

slide49

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.
slide51
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
slide56

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

slide57

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)
slide64

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).

slide65

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).

slide67
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.

slide69
This finding in humans first confirms the previous results in animal studies indicating HP within 4 hours after ingestion effectively reduced mortality of animals.
slide72
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

slide74
Shortening the elapsed time from ER to HP may be important to save the life of severe PQ-poisoned patients with repeated pulse therapy.
slide75
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

slide76
The aggressive attitude of medical staff is important to shorten the elapsed time from ER to HP.
slide77
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.
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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