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:
RCT 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 Pediat Res 47:108a. Ceneviva G. Pediatrics ;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; , 1999)

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

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

17. Pro/Anti-inflammatory Mediators Pharmacotherapy?
Pro-inflammatory
Mediators
Anti-inflammatory
Mediators
High Dose
Steroids
Antimicrobial
Agents
Immunohomeostasis
IL-10
CRRT
TNF
PAF
IL-1
SIRS CARS
SIRS CARS
Time
Pro/Anti-inflammatory Mediators
Pharmacotherapy?
Immunohomeostasis
CRRT
SIRS/CARS
Time
Adapted from Ronco et al. Artificial Organs 27(9) , 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: , 1993
Rogiers et al., Crit Care Med 27: , 1999
Yekebas et al., Crit Care Med 29: , 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: , 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