45 paden pcrrt and cytokine
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45 paden pcrrt and cytokine

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  • Failure of Anti TNF-alpha , IL-1, and Interferon Gamma monoclonal antibodies. Improve hemodynamics/nutrition/volume overload, Controversy on cardiac output and oxygenation
  • SIRS = pro-inflammatory response mediated by IL-1, 6, 8, TNF alpha CARS = coined by Dr. Bone to reflect anti-inflammatory response mediated by IL-10, PGE2 It is the overall overproduction of both pro and anti inflammatory cytokines that is the problem in sepsis. CRRT’s clearance of everything is its greatest benefit. Restore cytokine levels to a more homeostatic and physiologic level.
  • Found to play a role in decreased creatinine clearance in CRF. Uremic serum upregulates this pathway.
  • Mention IRB approval. Part of a larger study examining the response of urine output to initiation of CVVH. Excluded chronic renal failure. Cytokines measured by cytometric bead array - flow cytometry
  • Point 1 is pre-CVVH, point 5 is discontinuation of CVVH. Generally, you see a decrease overtime with institution of CRRT. Is this because the patient is getting CRRT or just because the patient is getting better? Note what happens in septic patients 24 hours after off CVVH (time point 6). Argues that CVVH is at least having some response in clearing these and not just patient improving. Also note scale – levels at d/c of CVVH in septic patients are more than the highest levels in non-septic patients.
  • Still see the same overall pattern, the scale is just smaller. Lack a rebound after coming off of CVVH.
  • IL-6 12704 to 183 IL-10 706 to 45
  • Note scale change. While trend was the same, it was not statistically signifant in this small sample. IL-8 4166 to 384 sFasL 130.5 to 41.1 No signifcant absolute change was seen for any cytokine in non-septic patients.
  • Because of such large differences in starting cytokine concentrations, we compared values at the end of CVVH and 24 hours afterwards to baseline (Pre-CVVH) values in both septic and control patients. We found that IL-8,10 concentrations had signficant decreases in septic patients. This same decrease was not seen in the control population.
  • FAKE DATA HERE – REPLACE BEFORE CONFERENCE
  • Both absolute decrease and greater relative decrease compared to non-septic ARF patients.
  • Thank Dr. Pearson and the Emory Transplant Center.

45 paden pcrrt and cytokine 45 paden pcrrt and cytokine Presentation Transcript

  • 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
  • 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)
  • Sepsis and CRRT: Peak Concentration Hypothesis Adapted from Ronco C, et al, Artif Organs 2003
  • 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
  • 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.
  • Hypothesis
    • Convective clearance of IL-6, IL-8, IL-10, and sFasL occurs in pediatric patients with acute renal failure (ARF) treated with CVVH.
  • 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
  • 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
  • Results
    • Septic Shock Patients
    MSSA Toxic Shock 17 yo Multiple Ruptured appendix 7 yo S. viridans T-cell ALL 16 yo S. hominis BMT for AML 14 yo MRSA Septic shock 15 yo S. pneumoniae HUS 14 mo Organism Disease Age
  • Results
    • Non-septic ARF Patients
    Severe dehydration 14 yo ALL, pancreatitis 15 yo Pulmonary edema 16 yo Disease Age
  • Results Pre-CVVH 12 Hours 24 Hours 48 Hours End of CVVH 24 Hours off CVVH
  • Results Pre-CVVH 12 Hours 24 Hours 48 Hours End of CVVH 24 Hours off CVVH
  • Absolute cytokine changes in septic shock/ARF patients Log Concentration (pg/ml) p<0.02 * p=0.04 *
  • Absolute cytokine changes in septic shock/ARF patients Log Concentration (pg/ml) p=0.132 p=0.818
  • IL-8 Percent Changes From Pre-CVVH Baseline Septic ARF Patients Non-septic ARF Patients * p<0.03 * * * * *
  • Mean Percent Decrease in Septic Shock/ARF Patients Septic ARF Patients Non-septic ARF Patients * p<0.05 * *
  • Mean Percent Decrease in Septic Shock/ARF Patients Septic ARF Patients Non-septic ARF Patients * p<0.05 * *
  • Ultrafiltrate Cytokine Levels Septic ARF Patients Non-septic ARF Patients
  • Ultrafiltrate Cytokine Levels Septic ARF Patients Non-septic ARF Patients
  • sFasL Analysis 12 h 24 h 48 h End of CVVH 24 h off CVVH
  • 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)
  • 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
  • Implications
    • Effects of decreasing cytokines remain uncertain
    • Future studies to evaluate cytokine clearance
      • “Regular” CVVH
      • High Volume Hemofiltration
      • Different filters
      • Clinical outcome studies