Cytokine and Soluble Fas Ligand Response in Children with Septic

Acute Renal Failure (ARF) on CVVH Paden ML, Fortenberry JD, Rigby MR, Trexler AM,

Heard ML, Rogers K Children’s Healthcare of Atlanta at EglestonDivision of Pediatric Critical Care Medicine

Emory University School of Medicine, Atlanta, GA USA

2

Sepsis and CRRT

In septic adults, CRRT• Improves hemodynamics (Kamijo Y. Intensive Care Med

2000;26(9):1355-9)

• Allows control of fluid balance• Maximizes nutrition• Improves survival with high flow ultrafiltration rate

(Ronco C, Lancet 2000;356:26-30)

Cytokine removal postulated as the basis for these effects (Bellomo R, Contrib Nephrol 2001;132:367-74)

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Sepsis and CRRT:Peak Concentration Hypothesis

Adapted from Ronco C, et al, Artif Organs 2003

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Controversy in Sepsis and CRRT

Previous adult studies question the ability for CRRT to lower cytokine levels• Concentration ≠ activity

Cytokine clearance in children has not been adequately studied

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Fas/Soluble Fas Ligand (sFasL) System

Apoptotic pathway in multiple tissues Fas in HUS induced renal failure (Masri C, et al. Am J

Kidney Dis 2000;36(4):859-62.)

• Levels correlate with: Development of oligoanuria Need for acute dialysis Decreased GFR at 1 year after injury

sFasL in ARDS (Imay Y, et al. JAMA 2003;289(16):2104-12.)

• Significant correlation between changes in sFasL and changes in creatinine.

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Hypothesis

Convective clearance of IL-6, IL-8, IL-10, and sFasL occurs in pediatric patients with acute renal failure (ARF) treated with CVVH.

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Study Design

Enrollment of all patients on CVVH:• Acute renal failure• Greater than 5 kg• < 18 years old

Technique• CVVH via Braun Diapact• Citrate anticoagulation• Ultrafiltration rate 35-45 cc/kg/hour• Cytokines measured by cytometric bead array from BD

Pharmagen Serial measurements of cytokines

• Pre-CVVH• 12, 24, 48 hours on CVVH• End of CVVH and 24 hours after

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Study Design

Bacterial septic shock defined as• Vasopressor dependent• Positive blood culture

Compared values in children with bacterial septic shock/ARF to non-septic ARF patients

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Results

• Septic Shock Patients

Age Disease Organism

14 mo HUS S. pneumoniae

15 yo Septic shock MRSA

14 yo BMT for AML S. hominis

16 yo T-cell ALL S. viridans

7 yo Ruptured appendix Multiple

17 yo Toxic Shock MSSA

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Results

Non-septic ARF Patients

Age Disease

16 yo Pulmonary edema

15 yo ALL, pancreatitis

14 yo Severe dehydration

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Results

Septic ARF Patient #5

0

200

400

600

800

1000

1200

1400

1600

1800

2000C

on

cen

trat

ion

(p

g/m

l)

Human IL-10

Human IL-6

Human IL-8

Pre

-CV

VH

12 H

ours

24 H

ours

48 H

ours

En

d o

f C

VV

H

24 H

ours

off

C

VV

H

12

Results

Non-septic ARF Patient #3

0

10

20

30

40

50

60

70

80

90

Co

nc

en

tra

tio

n (

pg

/ml)

Human IL-10

Human IL-6

Human IL-8

Pre

-CV

VH

12 H

ours

24 H

ours

48 H

ours

En

d o

f C

VV

H

24 H

ours

off

C

VV

H

13

Absolute cytokine changes in septic shock/ARF patients

1

10

100

1000

10000

100000

IL-6 IL-10

Pre-CVVHEnd ofCVVH

Lo

g C

on

cen

trat

ion

(p

g/m

l)

p<0.02* p=0.04*

14

Absolute cytokine changes in septic shock/ARF patients

1

10

100

1000

10000

IL-8 sFasL

Pre-CVVHEnd ofCVVH

Lo

g C

on

cen

trat

ion

(p

g/m

l) p=0.132

p=0.818

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IL-8 Percent Changes From Pre-CVVH Baseline

-150

-100

-50

0

50

100

150

200

25012 Hours

24 Hours

48 Hours

End of CVVH

24 Hours offCVVH

Septic ARF Patients Non-septic ARF Patients

*p<0.03*** *

*

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Mean Percent Decrease in Septic Shock/ARF Patients

Cytokine Levels at the End of CVVH

-100

-80

-60

-40

-20

0

20

% D

ecre

ase

From

Bas

elin

e

IL-6

IL-8

IL-10

Septic ARF Patients Non-septic ARF Patients

*p<0.05

* *

17

Mean Percent Decrease in Septic Shock/ARF Patients

Cytokine Levels 24 hours after CVVH

-100

-80

-60

-40

-20

0

20

40

60

% D

ecre

ase

Fro

m B

asel

ine

IL-6

IL-8

IL-10

Septic ARF Patients Non-septic ARF Patients

*p<0.05

* *

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Ultrafiltrate Cytokine Levels

IL-6 Ultrafiltrate Concentrations

1

10

100

1000

10000

100000

Co

nce

ntr

atio

n (

pg

/ml)

12 Hour

End of CVVH

Septic ARF Patients Non-septic ARF Patients

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Ultrafiltrate Cytokine Levels

IL-8 Ultrafiltrate Concentrations

1

10

100

1000

10000

100000

1000000

Co

nc

en

tra

tio

n (

pg

/ml)

12 Hour

End of CVVH

Septic ARF Patients Non-septic ARF Patients

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sFasL Analysis

sFasL Response

0

50

100

150

200

250

300

350

Co

nce

ntr

atio

n (p

g/m

l)

Septic ARF

Non-Septic ARF

12 h 24 h 48 h End of CVVH

24 h off CVVH

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sFasL Response

sFasL concentration pre-CVVH was similar in Septic Shock/ARF and non-septic ARF patients• Median 130 pg/ml (24-439)

Levels did not significantly decrease with CVVH (p=0.818)

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Conclusions

CVVH significantly removes both pro-inflammatory (IL-6, IL-8) and anti-inflammatory (IL-10) cytokines in pediatric septic shock/ARF vs. non-septic patients• Absolute decrease• Greater relative decrease in septic patients

compared to non-septic ARF patients• Convective clearance is likely mechanism

sFasL concentration is not changed by CVVH

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Implications

Effects of decreasing cytokines remain uncertain Future studies to evaluate cytokine clearance

• “Regular” CVVH• High Volume Hemofiltration• Different filters• Clinical outcome studies