Continuous Renal Replacement Therapy for Sepsis Treatment

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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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• 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 112235-43, 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 20013451368-1377. 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 47108a. Ceneviva G. Pediatrics
1998102e19.)
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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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