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

From GinaFrom Gina

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