Continuous Renal Replacement Therapy for Sepsis Treatment

1. Continuous Renal Replacement Therapy for Sepsis Treatment

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

3. 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

4. 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

5. 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)

6. 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.

7. 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

8. 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.)

9. 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

10. 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)

11. 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

12. 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

13. 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)

14. 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)

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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)

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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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