45 paden pcrrt and cytokine

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)

3

Sepsis and CRRT:Peak Concentration Hypothesis

Adapted from Ronco C, et al, Artif Organs 2003

4

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

5

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.

6

Hypothesis

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

7

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

8

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

9

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

10

Results

Non-septic ARF Patients

Age Disease

16 yo Pulmonary edema

15 yo ALL, pancreatitis

14 yo Severe dehydration

11

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

15

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*** *

*

16

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

* *

18

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

19

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

20

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

21

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)

22

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

23

Implications

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

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