Transcript Continuous Renal Replacement Therapies for Sepsis Therapy

Continuous Renal
Replacement Therapy for
Sepsis Treatment
Patrick D Brophy MD
Pediatric Nephrology, Dialysis &
Transplantation
University of Michigan
From Gina
Approach
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Why do we care?
Definition & Background
Briefly- pathophysiology
Theories
CRRT- why, how, evidence & human correlates
Other alternatives and conclusions
SEPSIS:
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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
SEPSIS:
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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
SEPSIS:
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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)
SEPSIS:
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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.
SEPSIS: Pathophysiology
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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 Antiinflammatory Response Syndrome”
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Bone et al. Chest 112:235-43, 1997
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
Results:
130 adults randomized to aggressive care In First few hours
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.)
CRRT for SEPSIS
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Since the data support early intervention for sepsis
treatment?- why not introduce CRRT early in the
course
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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
CRRT & SEPSIS
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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)
SEPSIS: Theoretical Models
Inflammation
SIRS
Normal Range of Immunohomeostasis
CARS
Serial
Hyporesponsiveness
STIMULUS
Inflammation
Parallel
SIRS
Pro-Inflammatory
mediators
Normal Range of Immunohomeostasis
Hyporesponsiveness
CARS
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
Anti-Inflammatory
mediators
(Inhibitors)
Serial
Mediator Levels
SEPSIS: Theoretical Models
Pro-Inflammatory
Anti-Inflammatory
Mediators
Mediators (Inhibitors)
IL10
TNF
IL1
IL6
PAF
Parallel
Mediator Levels
Time
Pro/Anti-Inflammatory
Mediators
Activation
Depression
Time
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
Continuous Renal Replacement
Therapy and Sepsis
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Allows extracorporeal treatment in critically ill
patients with hypercatabolism and fluid overload
Three mechanisms thought to be at work
Convection
 Diffusion
 Adsorption (to Membrane)
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These presumably allow blood purification of septic
mediators (GOOD and BAD)
CRRT & SEPSIS
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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)
SEPSIS & CRRT
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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”
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Ronco et al. Artificial Organs 27(9) 792-801, 2003
Pro-inflammatory Anti-inflammatory High Dose Antimicrobial
Mediators
Mediators
Steroids
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) 792-801, 2003
CRRT: New Approaches
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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
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Porcine model of (endotoxin infusion) septic shock
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Decreased CO, hypotension, stroke volume
Grootendorst et al; J Crit Care:
67-75, 7, 1992
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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
Clinical Correlation ie Survival
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Several studies have shown correlation of
survival and increased UF rates
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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
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Low Volume CVVH vs HVHF (100ml/kg/hr)- porcine
model- sepsis induced by pancreatitis- Also evaluated
impact of frequent filter changes
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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)
What About Human Correlates?
Ronco et al., Lancet 356: 26-30, 2001
425 patients
Endpoint = survival 15 days after D/C HF
146 UF rate 20ml/kg/hr
survival significantly lower
in this group compared
to the others
139 UF rate 35ml/kg/hr
p=0.0007
140 UF rate 45ml/kg/hr
p=0.0013
What About Human Correlates?
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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
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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
Ronco et al. Lancet 2000; 351: 26-30
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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
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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
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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
Conclusions
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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
Conclusions
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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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