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Continuous Renal Replacement Therapy for Sepsis Treatment PowerPoint PPT Presentation


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Continuous Renal Replacement Therapy for Sepsis Treatment. Patrick D Brophy MD Pediatric Nephrology, Dialysis & Transplantation University of Michigan. From Gina. Approach. Why do we care? Definition & Background Briefly- pathophysiology Theories

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Continuous renal replacement therapy for sepsis treatment l.jpg

Continuous Renal Replacement Therapy for Sepsis Treatment

Patrick D Brophy MD

Pediatric Nephrology, Dialysis & Transplantation

University of Michigan


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From Gina


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Approach

  • Why do we care?

  • Definition & Background

  • Briefly- pathophysiology

  • Theories

  • CRRT- why, how, evidence & human correlates

  • Other alternatives and conclusions


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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


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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


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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)


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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.


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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


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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.)


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    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


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    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)


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    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


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    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


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    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)


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    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)


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    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


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    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


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    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


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    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


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    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


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    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)


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


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    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


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    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


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    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


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    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


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    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


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    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


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    ACKNOWLEDGEMENTS

    Theresa Mottes

    Tim Kudelka

    Betsy Adams

    Tammy Kelly

    Robin Nievaard


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