Continuous Renal Replacement Therapy for Sepsis Treatment

1. Continuous Renal Replacement Therapy for Sepsis Treatment Patrick D Brophy MD Pediatric Nephrology, Dialysis & Transplantation University of Michigan

2. From Gina

3. Approach • Why do we care? • Definition & Background • Briefly- pathophysiology • Theories • CRRT- why, how, evidence & human correlates • Other alternatives and conclusions

4. SEPSIS: BACKGROUND • Severe Sepsis and Septic Shock are the primary causes of Multiple Organ Dysfunction Syndrome (MODS) [of which Acute Renal Failure-is part of] • One of the most common cause of mortality in the ICU setting

5. SEPSIS: BACKGROUND • Variety of Water soluble mediators with Pro & Anti- Inflammatory Activities play a strategic role in Septic Syndrome including (but not limited to): TNF, IL-6,IL-8 and IL-10, Kinins, Thrombins, heat shock proteins

6. SEPSIS: BACKGROUND • Infectious Sepsis (gram +/-, viral, fungal) & Noninfectious --Systemic Inflammatory Response Syndrome (SIRS) encompass a complex mosaic of interconnected events • Molecular triggers (ie. LPS) activate the principal sensors of the innate immune system (Toll-like receptors and related molecules)

7. SEPSIS: BACKGROUND • Stimulus –Receptor coupling sets off the signal transduction cascade resulting in exacerbated generation of; Platelet activating factor, cytokines, leukotrienes, Arachidonic acid derivatives etc.) and activation of the complement cascade and coagulation pathways.

8. SEPSIS: Pathophysiology • Dysfunctional homeostatic balance results in increased biological activity of sepsis associated mediators and loss of control over these by specific inhibitors-cell hypo-responsiveness • This excessive anti-inflammatory counterpart to SIRS has been coined “CARS- Compensated Anti-inflammatory Response Syndrome” • Bone et al. Chest 112:235-43, 1997

9. Goals of Treatment are hemodynamic and relate to outcome • Early Goal-Directed Therapy in the treatment of Severe Sepsis and Septic Shock. Rivers E, N Engl J Med 2001;345:1368-1377. • RCT 130 adults randomized to aggressive care In First few hours • Results: In Hospital Mortality 30.5% vs 46.5% in Controls • Early goal directed therapy improves shock outcome(Han Y. 2000 Pediat Res 47:108a. Ceneviva G. Pediatrics 1998;102:e19.)

10. CRRT for SEPSIS • Since the data support early intervention for sepsis treatment?- why not introduce CRRT early in the course • Criticisms: Lack of specificity of removal of mediators & INHIBITORS of sepsis--This may actually be a strength of the therapy! • Others have shown +clinical effects with no change in cytokine levels (depends what you measure) • CRRT may not only be supportive but rather therapeutic

11. CRRT & SEPSIS • Which cytokines/mediators do we measure? Absolute mediator value measurements are less likely helpful than more local/tissue levels- they need each other to work in concert-controversial! • Problem: With Conventional CRRT (conventional filters & Flow rates) clinical benefits in sepsis have been less than optimal (De Vriese et al, Intensive Care Medicine, 25; 903-10, 1999)

12. SEPSIS: Theoretical Models Inflammation SIRS Normal Range of Immunohomeostasis Serial CARS Hyporesponsiveness STIMULUS SIRS Pro-Inflammatory mediators Inflammation Parallel Normal Range of Immunohomeostasis CARS Hyporesponsiveness Anti-Inflammatory mediators (Inhibitors) Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003

13. SEPSIS: Theoretical Models Pro-Inflammatory Mediators Anti-Inflammatory Mediators (Inhibitors) IL10 TNF IL1 IL6 PAF Mediator Levels Serial Time Pro/Anti-Inflammatory Mediators Activation Depression Mediator Levels Parallel Time Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003

14. Continuous Renal Replacement Therapy and Sepsis • Allows extracorporeal treatment in critically ill patients with hypercatabolism and fluid overload • Three mechanisms thought to be at work • Convection • Diffusion • Adsorption (to Membrane) • These presumably allow blood purification of septic mediators (GOOD and BAD)

15. CRRT & SEPSIS • Multiple studies (human & animal) have demonstrated that synthetic filters can remove almost all sepsis mediators to some degree (DeVriese etal, Intensive Care Med 25: 903-10,1999)

16. SEPSIS & CRRT • The “Peak Concentration Hypothesis” • “The nonselective control of the peaks of inflammation and immunoparalysis may contribute to bring the patient to a lesser degree of imbalance and close to the self-defenses induced by a nearly normal immunohomeostasis” • Ronco et al. Artificial Organs 27(9) 792-801, 2003

17. Pro-inflammatory Mediators Anti-inflammatory Mediators High Dose Steroids Antimicrobial Agents Immunohomeostasis IL-10 CRRT TNF PAF SIRS CARS IL-1 SIRS CARS Time Pro/Anti-inflammatory Mediators Pharmacotherapy? Immunohomeostasis CRRT SIRS/CARS Time Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003

18. CRRT: New Approaches • Improving removal of soluble sepsis mediators by improving the efficacy of plasma water exchange- ie increasing ultrafiltration rates. • SUPPORT: Grootendorst et al, J Crit Care; 7: 67-75, 1999 • Porcine model of (endotoxin infusion) septic shock • Decreased CO, hypotension, stroke volume

19. Grootendorst et al; J Crit Care: 67-75, 7, 1992 • Initiation of High Volume Hemofiltration (HVHF) 6L/hr- all parameters were improved compared to the Sham group • Further: administration of UF from LPS infused animals to healthy animals was able to induce sepsis like hemodynamic parameters • Early initiation of HVHF (prior to inducing the model) in a bowel ischemia model from the same group prevented hemodynamic instability

20. Clinical Correlation ie Survival • Several studies have shown correlation of survival and increased UF rates • Improved Cardiac Function, Systemic and Pulmonary vascular resistance. • Lee et al., Crit Care Med 21: 914-24, 1993 • Rogiers et al., Crit Care Med 27: 1848-55, 1999 • Yekebas et al., Crit Care Med 29: 1423-30, 2001

21. Yekebas et al., Crit Care Med 29: 1423-30, 2001 • Low Volume CVVH vs HVHF (100ml/kg/hr)- porcine model- sepsis induced by pancreatitis- Also evaluated impact of frequent filter changes • Late initiation (Hemodynamic instability-to mimic real circumstances) • All parameters: cardiac function, systemic and pulmonary resistance, and hepatic perfusion improved in the HVHF group (filter changes had little impact)

22. What About Human Correlates?Ronco et al., Lancet 356: 26-30, 2001

23. What About Human Correlates? • Ronco et al- landmark study reviewed a variety of UF rates and looked at outcomes based on survival • 11-14% of each treatment group had sepsis • Subgroup analysis of these septic patients demonstrated a direct correlation between treatment dose and survival even above 35ml/kg/hr in contrast to the whole group where a survival plateau was reached

24. Ronco et al. Lancet 2000; 351: 26-30 • Conclusions: • Minimum UF rates should reach at least 35 ml/kg/hr (higher in septic patients) • Survivors in all their groups had lower BUNs than non-survivors prior to commencement of hemofiltration

25. Cole et al. Intensive Care Medicine; 27: 978-86, 2001 • 11 patients with shock and MODS - randomized crossover trial design • 6L/hr vs 1L/hr • HVHF group- greater reduction in vasopressor requirements and greater reduction in C3a and C5a plasma levels

26. Other Approaches • Increasing Filter pore size to enhance middle molecule removal • Addition of plasma filtration coupled with adsorption, followed by dialysis or filtration (CPFA) • Polymyxin impregnated fibers (animal and adult data) • Early evidence (Ronco et al. Crit Care Med; 30: 903-10, 2002) is promising

27. Conclusions • Early intervention is key • CRRT adds a new dimension to this therapy and should be used! • HVHF for sepsis therapy- need controlled trials • CPFA also is promising

28. Conclusions • Early evidence suggests utilizing at least 35 ml/kg/hr UF (likely higher rates are better) • Little detrimental effect to patients with these volumes (cooling?) • We need to be adaptive and embrace new techniques and work together to improve survival in pediatric and adult patients with sepsis

29. ACKNOWLEDGEMENTS Theresa Mottes Tim Kudelka Betsy Adams Tammy Kelly Robin Nievaard