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

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Presentation on theme: "Continuous Renal Replacement Therapy for Sepsis Treatment Patrick D Brophy MD Pediatric Nephrology, Dialysis & Transplantation University of Michigan."— Presentation transcript:

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? Why do we care? Definition & Background Definition & Background Briefly- pathophysiology Briefly- pathophysiology Theories Theories CRRT- why, how, evidence & human correlates CRRT- why, how, evidence & human correlates Other alternatives and conclusions 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] 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 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): 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 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 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) 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. 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 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” This excessive anti-inflammatory counterpart to SIRS has been coined “CARS- Compensated Anti- inflammatory Response Syndrome” Bone et al. Chest 112:235-43, 1997 Bone et al. Chest 112:235-43, 1997

9 Early Goal-Directed Therapy in the treatment of Severe Sepsis and Septic Shock. Rivers E, N Engl J Med 2001;345: 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 Pediat Res 47:108a. Ceneviva G. Pediatrics 1998;102:e19.) Goals of Treatment are hemodynamic and relate to outcome

10 CRRT for SEPSIS Since the data support early intervention for sepsis treatment?- why not introduce CRRT early in the course 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! 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) Others have shown +clinical effects with no change in cytokine levels (depends what you measure) CRRT may not only be supportive but rather therapeutic 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! 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) 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 Normal Range of Immunohomeostasis CARS SIRS CARS STIMULUS Inflammation Hyporesponsiveness Pro-Inflammatory mediators Anti-Inflammatory mediators (Inhibitors) Serial Parallel SEPSIS: Theoretical Models Adapted from Ronco et al. Artificial Organs 27(9) , 2003

13 Pro-Inflammatory Mediators Anti-Inflammatory Mediators (Inhibitors) Pro/Anti-Inflammatory Mediators ActivationDepression Time Parallel Serial IL1 TNF PAF IL10 IL6 Mediator Levels SEPSIS: Theoretical Models 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 Allows extracorporeal treatment in critically ill patients with hypercatabolism and fluid overload Three mechanisms thought to be at work Three mechanisms thought to be at work Convection Convection Diffusion Diffusion Adsorption (to Membrane) Adsorption (to Membrane) These presumably allow blood purification of septic mediators (GOOD and BAD) 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 ) 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 “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” “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 Ronco et al. Artificial Organs 27(9) , 2003

17 CRRT Time SIRS/CARS SIRS CARS Immunohomeostasis Pro/Anti-inflammatory Mediators Pharmacotherapy? Pro-inflammatory Mediators Anti-inflammatory Mediators High Dose Steroids Antimicrobial Agents IL-1 TNFPAF IL-10 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. 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 SUPPORT: Grootendorst et al, J Crit Care; 7: 67-75, 1999 Porcine model of (endotoxin infusion) septic shock Porcine model of (endotoxin infusion) septic shock Decreased CO, hypotension, stroke volume Decreased CO, hypotension, stroke volume

19 Grootendorst et al; J Crit Care: , 7, 1992 Initiation of High Volume Hemofiltration (HVHF) 6L/hr- all parameters were improved compared to the Sham group 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 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 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 Several studies have shown correlation of survival and increased UF rates Improved Cardiac Function, Systemic and Pulmonary vascular resistance. Improved Cardiac Function, Systemic and Pulmonary vascular resistance. Lee et al., Crit Care Med 21: , 1993 Lee et al., Crit Care Med 21: , 1993 Rogiers et al., Crit Care Med 27: , 1999 Rogiers et al., Crit Care Med 27: , 1999 Yekebas et al., Crit Care Med 29: , 2001 Yekebas et al., Crit Care Med 29: , 2001

21 Yekebas et al., Crit Care Med 29: , 2001 Low Volume CVVH vs HVHF (100ml/kg/hr)- porcine model- sepsis induced by pancreatitis- Also evaluated impact of frequent filter changes 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) 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) 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 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 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 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: Conclusions: Conclusions: Minimum UF rates should reach at least 35 ml/kg/hr (higher in septic patients) 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 Survivors in all their groups had lower BUNs than non-survivors prior to commencement of hemofiltration

25 Cole et al. Intensive Care Medicine; 27: , patients with shock and MODS - randomized crossover trial design 11 patients with shock and MODS - randomized crossover trial design 6L/hr vs 1L/hr 6L/hr vs 1L/hr HVHF group- greater reduction in vasopressor requirements and greater reduction in C3a and C5a plasma levels 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 Increasing Filter pore size to enhance middle molecule removal Addition of plasma filtration coupled with adsorption, followed by dialysis or filtration (CPFA) Addition of plasma filtration coupled with adsorption, followed by dialysis or filtration (CPFA) Polymyxin impregnated fibers (animal and adult data) Polymyxin impregnated fibers (animal and adult data) Early evidence (Ronco et al. Crit Care Med; 30: , 2002) is promising Early evidence (Ronco et al. Crit Care Med; 30: , 2002) is promising

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

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

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

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