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Continuous Renal Continuous Renal Replacement Therapy Replacement Therapy for Sepsis Treatmentfor Sepsis Treatment
Patrick D Brophy MDPatrick D Brophy MD
Pediatric Nephrology, Dialysis Pediatric Nephrology, Dialysis & Transplantation& Transplantation
University of MichiganUniversity of Michigan
ApproachApproach
Why do we care?Why do we care? Definition & BackgroundDefinition & Background Briefly- pathophysiologyBriefly- pathophysiology TheoriesTheories CRRT- why, how, evidence & human CRRT- why, how, evidence & human
correlatescorrelates Other alternatives and conclusionsOther alternatives and conclusions
SEPSIS: SEPSIS: BACKGROUNDBACKGROUND
Severe Sepsis and Septic Shock are Severe Sepsis and Septic Shock are the primary causes of Multiple the primary causes of Multiple Organ Dysfunction Syndrome Organ Dysfunction Syndrome (MODS) [of which Acute Renal (MODS) [of which Acute Renal Failure-is part of]Failure-is part of]
One of the most common cause of One of the most common cause of mortality in the ICU settingmortality in the ICU setting
SEPSIS: SEPSIS: BACKGROUNDBACKGROUND
Variety of Water soluble mediators Variety of Water soluble mediators with Pro & Anti- Inflammatory with Pro & Anti- Inflammatory Activities play a strategic role in Activities play a strategic role in Septic Syndrome including (but not Septic Syndrome including (but not limited to):limited to):
TNF, IL-6,IL-8 and IL-10, Kinins, TNF, IL-6,IL-8 and IL-10, Kinins, Thrombins, heat shock proteinsThrombins, heat shock proteins
SEPSIS: SEPSIS: BACKGROUNDBACKGROUND
Infectious Sepsis (gram +/-, viral, Infectious Sepsis (gram +/-, viral, fungal) & Noninfectious --Systemic fungal) & Noninfectious --Systemic Inflammatory Response Syndrome Inflammatory Response Syndrome (SIRS) encompass a complex mosaic (SIRS) encompass a complex mosaic of interconnected eventsof interconnected events
Molecular triggers (ie. LPS) activate Molecular triggers (ie. LPS) activate the principal sensors of the innate the principal sensors of the innate immune system (Toll-like receptors immune system (Toll-like receptors and related molecules)and related molecules)
SEPSIS: SEPSIS: BACKGROUNDBACKGROUND
Stimulus –Receptor coupling sets off Stimulus –Receptor coupling sets off the signal transduction cascade the signal transduction cascade resulting in exacerbated generation resulting in exacerbated generation of; Platelet activating factor, of; Platelet activating factor, cytokines, leukotrienes, Arachidonic cytokines, leukotrienes, Arachidonic acid derivatives etc.) and activation acid derivatives etc.) and activation of the complement cascade and of the complement cascade and coagulation pathways.coagulation pathways.
SEPSIS: PathophysiologySEPSIS: Pathophysiology
Dysfunctional homeostatic balance results Dysfunctional homeostatic balance results in increased biological activity of sepsis in increased biological activity of sepsis associated mediators and loss of control associated mediators and loss of control over these by specific inhibitors-cell hypo-over these by specific inhibitors-cell hypo-responsivenessresponsiveness
This excessive anti-inflammatory This excessive anti-inflammatory counterpart to SIRS has been coined counterpart to SIRS has been coined “CARS- Compensated Anti-inflammatory “CARS- Compensated Anti-inflammatory Response Syndrome” Response Syndrome” Bone et al. Chest 112:235-43, 1997Bone et al. Chest 112:235-43, 1997
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.)
Goals of Treatment are Goals of Treatment are hemodynamic and relate to hemodynamic and relate to
outcomeoutcome
CRRT for SEPSISCRRT for SEPSIS Since the data support early intervention Since the data support early intervention
for sepsis treatment?- why not introduce for sepsis treatment?- why not introduce CRRT early in the courseCRRT early in the course Criticisms: Lack of specificity of removal of Criticisms: Lack of specificity of removal of
mediators & INHIBITORS of sepsis--This may mediators & INHIBITORS of sepsis--This may actually be a strength of the therapy!actually be a strength of the therapy!
Others have shown +clinical effects with no Others have shown +clinical effects with no change in cytokine levels (depends what you change in cytokine levels (depends what you measure)measure)
CRRT may not only be supportive but rather CRRT may not only be supportive but rather therapeutictherapeutic
CRRT & SEPSISCRRT & SEPSIS
Which cytokines/mediators do we Which cytokines/mediators do we measure? Absolute mediator value measure? Absolute mediator value measurements are less likely helpful than measurements are less likely helpful than more local/tissue levels- they need each more local/tissue levels- they need each other to work in concert-controversial!other to work in concert-controversial!
Problem: With Conventional CRRT Problem: With Conventional CRRT (conventional filters & Flow rates) clinical (conventional filters & Flow rates) clinical benefits in sepsis have been less than benefits in sepsis have been less than optimal optimal (De Vriese et al, Intensive Care Medicine, 25; (De Vriese et al, Intensive Care Medicine, 25; 903-10, 1999)903-10, 1999)
Normal Range of Immunohomeostasis
Normal Range of Immunohomeostasis
CARSCARS
SIRSSIRS
SIRSSIRS
CARSCARS
STIMULUS
Inflammation
Inflammation
Hyporesponsiveness
Hyporesponsiveness
Pro-Inflammatory mediators
Anti-Inflammatory mediators (Inhibitors)
Serial
Parallel
SEPSIS: Theoretical SEPSIS: Theoretical ModelsModels
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
Pro-Inflammatory Mediators
Anti-Inflammatory Mediators (Inhibitors)
Pro/Anti-Inflammatory Mediators
Activation Depression
Time
Time
Parallel
Serial
IL1TNF
PAF
IL10
IL6
Med
iato
r L
evel
sM
edia
tor
Lev
els
SEPSIS: Theoretical ModelsSEPSIS: Theoretical Models
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
Continuous Renal Continuous Renal Replacement Therapy and Replacement Therapy and
SepsisSepsis Allows extracorporeal treatment in Allows extracorporeal treatment in
critically ill patients with critically ill patients with hypercatabolism and fluid overloadhypercatabolism and fluid overload
Three mechanisms thought to be at Three mechanisms thought to be at workwork ConvectionConvection DiffusionDiffusion Adsorption (to Membrane)Adsorption (to Membrane)
These presumably allow blood purification These presumably allow blood purification of septic mediators (GOOD and BAD)of septic mediators (GOOD and BAD)
CRRT & SEPSISCRRT & SEPSIS
Multiple studies (human & animal) Multiple studies (human & animal) have demonstrated that synthetic have demonstrated that synthetic filters can remove almost all sepsis filters can remove almost all sepsis mediators to some degree (mediators to some degree (DeVriese etal, DeVriese etal,
Intensive Care Med 25: 903-10,1999Intensive Care Med 25: 903-10,1999))
SEPSIS & CRRTSEPSIS & CRRT
The “Peak Concentration Hypothesis”The “Peak Concentration Hypothesis” ““The nonselective control of the peaks The nonselective control of the peaks
of inflammation and immunoparalysis of inflammation and immunoparalysis may contribute to bring the patient to may contribute to bring the patient to a lesser degree of imbalance and close a lesser degree of imbalance and close to the self-defenses induced by a to the self-defenses induced by a nearly normal immunohomeostasis”nearly normal immunohomeostasis” Ronco et al. Artificial Organs 27(9) 792-801, 2003Ronco et al. Artificial Organs 27(9) 792-801, 2003
CRRT
CRRT
Time
Time
SIRS/CARS
SIRS CARS SIRS CARS
Immunohomeostasis
Immunohomeostasis
Pro/Anti-inflammatory Mediators Pharmacotherapy?
Pro-inflammatory Mediators
Anti-inflammatory Mediators
High DoseSteroids
AntimicrobialAgents
IL-1TNF PAF
IL-10
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
CRRT: New ApproachesCRRT: New Approaches
Improving removal of soluble sepsis Improving removal of soluble sepsis mediators by improving the efficacy mediators by improving the efficacy of plasma water exchange- ie of plasma water exchange- ie increasing ultrafiltration rates.increasing ultrafiltration rates.
SUPPORT: SUPPORT: Grootendorst et al, J Crit Care; 7: Grootendorst et al, J Crit Care; 7: 67-75, 199967-75, 1999 Porcine model of (endotoxin infusion) Porcine model of (endotoxin infusion)
septic shockseptic shock Decreased CO, hypotension, stroke volumeDecreased CO, hypotension, stroke volume
Grootendorst et al; J Crit Grootendorst et al; J Crit Care: 67-75, 7, 1992Care: 67-75, 7, 1992
Initiation of High Volume Hemofiltration Initiation of High Volume Hemofiltration (HVHF) 6L/hr- all parameters were (HVHF) 6L/hr- all parameters were improved compared to the Sham groupimproved compared to the Sham group
Further: administration of UF from LPS Further: administration of UF from LPS infused animals to healthy animals was infused animals to healthy animals was able to induce sepsis like hemodynamic able to induce sepsis like hemodynamic parametersparameters
Early initiation of HVHF (prior to Early initiation of HVHF (prior to inducing the model) in a bowel ischemia inducing the model) in a bowel ischemia model from the same group prevented model from the same group prevented hemodynamic instabilityhemodynamic instability
Clinical Correlation ie Clinical Correlation ie SurvivalSurvival
Several studies have shown Several studies have shown correlation of survival and increased correlation of survival and increased UF ratesUF rates Improved Cardiac Function, Systemic Improved Cardiac Function, Systemic
and Pulmonary vascular resistance.and Pulmonary vascular resistance. Lee et al., Crit Care Med 21: 914-24, 1993Lee et al., Crit Care Med 21: 914-24, 1993 Rogiers et al., Crit Care Med 27: 1848-55, Rogiers et al., Crit Care Med 27: 1848-55,
19991999 Yekebas et al., Crit Care Med 29: 1423-30, Yekebas et al., Crit Care Med 29: 1423-30,
20012001
Yekebas et al., Crit Care Yekebas et al., Crit Care Med 29: 1423-30, 2001Med 29: 1423-30, 2001
Low Volume CVVH vs HVHF Low Volume CVVH vs HVHF (100ml/kg/hr)- porcine model- sepsis (100ml/kg/hr)- porcine model- sepsis induced by pancreatitis- Also evaluated induced by pancreatitis- Also evaluated impact of frequent filter changesimpact of frequent filter changes Late initiation (Hemodynamic instability-to Late initiation (Hemodynamic instability-to
mimic real circumstances)mimic real circumstances) All parameters: cardiac function, systemic and All parameters: cardiac function, systemic and
pulmonary resistance, and hepatic perfusion pulmonary resistance, and hepatic perfusion improved in the HVHF group (filter changes improved in the HVHF group (filter changes had little impact)had little impact)
What About Human What About Human Correlates?Correlates?
Ronco et al., Lancet 356: 26-Ronco et al., Lancet 356: 26-30, 200130, 2001
146 UF rate 20ml/kg/hrsurvival significantly lower
in this group comparedto the others
139 UF rate 35ml/kg/hrp=0.0007
140 UF rate 45ml/kg/hrp=0.0013
425 patientsEndpoint = survival 15 days after D/C HF
What About Human What About Human Correlates?Correlates?
Ronco et al- landmark study reviewed a Ronco et al- landmark study reviewed a variety of UF rates and looked at variety of UF rates and looked at outcomes based on survivaloutcomes based on survival
11-14% of each treatment group had 11-14% of each treatment group had sepsissepsis Subgroup analysis of these septic patients Subgroup analysis of these septic patients
demonstrated a direct correlation between demonstrated a direct correlation between treatment dose and survival even above treatment dose and survival even above 35ml/kg/hr in contrast to the whole group 35ml/kg/hr in contrast to the whole group where a survival plateau was reachedwhere a survival plateau was reached
Ronco et al. Lancet 2000; 351: 26-Ronco et al. Lancet 2000; 351: 26-3030
Conclusions:Conclusions: Minimum UF rates should reach at least Minimum UF rates should reach at least
35 ml/kg/hr (higher in septic patients)35 ml/kg/hr (higher in septic patients) Survivors in all their groups had lower Survivors in all their groups had lower
BUNs than non-survivors prior to BUNs than non-survivors prior to commencement of hemofiltrationcommencement of hemofiltration
Cole et al. Intensive Care Cole et al. Intensive Care Medicine; 27: 978-86, Medicine; 27: 978-86,
20012001 11 patients with shock and MODS - 11 patients with shock and MODS -
randomized crossover trial design randomized crossover trial design 6L/hr vs 1L/hr6L/hr vs 1L/hr HVHF group- greater reduction in HVHF group- greater reduction in
vasopressor requirements and greater vasopressor requirements and greater reduction in C3a and C5a plasma levelsreduction in C3a and C5a plasma levels
Other ApproachesOther Approaches
Increasing Filter pore size to Increasing Filter pore size to enhance middle molecule removalenhance middle molecule removal
Addition of plasma filtration coupled Addition of plasma filtration coupled with adsorption, followed by dialysis with adsorption, followed by dialysis or filtration (CPFA)or filtration (CPFA)
Polymyxin impregnated fibers Polymyxin impregnated fibers (animal and adult data)(animal and adult data)
Early evidence Early evidence (Ronco et al. Crit Care Med; (Ronco et al. Crit Care Med;
30: 903-10, 2002) 30: 903-10, 2002) is promisingis promising
ConclusionsConclusions
Early intervention is keyEarly intervention is key CRRT adds a new dimension to this CRRT adds a new dimension to this
therapy and should be used!therapy and should be used! HVHF for sepsis therapy- need HVHF for sepsis therapy- need
controlled trialscontrolled trials CPFA also is promisingCPFA also is promising
ConclusionsConclusions
Early evidence suggests utilizing at Early evidence suggests utilizing at least 35 ml/kg/hr UF (likely higher least 35 ml/kg/hr UF (likely higher rates are better)rates are better)
Little detrimental effect to patients Little detrimental effect to patients with these volumes (cooling?)with these volumes (cooling?)
We need to be adaptive and embrace We need to be adaptive and embrace new techniques and work together new techniques and work together to improve survival in pediatric and to improve survival in pediatric and adult patients with sepsisadult patients with sepsis
ACKNOWLEDGEMENTSACKNOWLEDGEMENTS Theresa MottesTheresa Mottes Tim KudelkaTim Kudelka Betsy AdamsBetsy Adams Tammy KellyTammy Kelly Robin NievaardRobin Nievaard