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 Egleston Division 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): ) 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): ) 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 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 AgeDiseaseOrganism 14 moHUSS. pneumoniae 15 yoSeptic shockMRSA 14 yoBMT for AMLS. hominis 16 yoT-cell ALLS. viridans 7 yoRuptured appendixMultiple 17 yoToxic ShockMSSA

10 Results  Non-septic ARF Patients AgeDisease 16 yoPulmonary edema 15 yoALL, pancreatitis 14 yoSevere dehydration

11 Results Pre-CVVH 12 Hours 24 Hours 48 Hours End of CVVH 24 Hours off CVVH

12 Results Pre-CVVH 12 Hours 24 Hours 48 Hours End of CVVH24 Hours off CVVH

13 Absolute cytokine changes in septic shock/ARF patients Log Concentration (pg/ml) p<0.02 * p=0.04 *

14 Absolute cytokine changes in septic shock/ARF patients Log Concentration (pg/ml) p=0.132 p=0.818

15 IL-8 Percent Changes From Pre-CVVH Baseline Septic ARF Patients Non-septic ARF Patients * p<0.03 * * * * *

16 Mean Percent Decrease in Septic Shock/ARF Patients Septic ARF Patients Non-septic ARF Patients * p<0.05 * *

17 Mean Percent Decrease in Septic Shock/ARF Patients Septic ARF Patients Non-septic ARF Patients * p<0.05 * *

18 Ultrafiltrate Cytokine Levels Septic ARF Patients Non-septic ARF Patients

19 Ultrafiltrate Cytokine Levels Septic ARF Patients Non-septic ARF Patients

20 sFasL Analysis 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