Transcript CRRT Sepsis Talk - Pediatric Continuous Renal Replacement

Is There a Rationale To Use CRRT
For Treating Sepsis?
James D. Fortenberry MD, FCCM, FAAP
Pediatrician in Chief
Children’s Healthcare of Atlanta
Professor of Pediatric Critical Care
Emory University School of Medicine
The Problem of Sepsis
in Children
 42,000 pediatric sepsis cases/year
 Annual cost > $2 billion
 Increased mortality 5.49.5/100,000
 Pediatric sepsis mortality rate in US: 10.3%
- Watson RS, Carcillo JA, AJRCCM 2003
2
World Sepsis Day
 Thursday, September 13, 2012
3
3
Sepsis: A Global Problem With Much To Be
Done
Join.
www.world-sepsis-day.org
Pediatric Sepsis Mortality
 Overall pediatric
mortality lower than
adults (~10% vs. 2060%)
Respiratory Failure < 5 %
 Single organ failure
rarely leads to
mortality
CV Failure < 5 %
Immunologic Failure < 5 %
Hematologic Failure < 5 % Renal Failure < 5 %
5
The MODS/Sepsis Patient
Respiratory Failure
Immunologic Failure
Cardiovascular Failure
HIGH MORTALITY
50-90%
Hematologic Failure
6
Renal Failure
-Courtesy of Matt Paden
Is There a Rationale
For Extracorporeal Therapies in
Sepsis?
 Potential benefits in severe sepsis: MOSF
• Management of fluid overload (CRRT)
• Immunohomeostasis: pro/anti-inflammatory
mediators (CRRT/plasma)
• Mechanical support of organ perfusion during
acute episode (ECMO)
• Improved coagulation response with decreased
organ microthrombosis (plasma exchange)
• Clearance of circulating endotoxin
(hemoperfusion)
7
Possible Benefits of CRRT in
Sepsis
 Direct
• Clearance of immune mediators
• Adsorption of mediators to membrane
• Clearance of organic acids
 Indirect
• Improvement of fluid balance
• “Kinder, gentler” effect on
hemodynamics in shock
• Opportunity for enhanced nutrition
8
Direct Effect?: Removing The
Evil Humours
9
Blood
Phlegm
Yellow
Bile
Black Bile
Peak Concentration
Model of Sepsis
Pro-inflammatory
Mediators
Anti-inflammatory
Mediators
Immunohomeostasis
IL-10
CRRT/Plasma Exchange
TNF
PAF
IL-1
SIRS
CARS
SIRS
CARS
Time
Immunohomeostasis
CRRT/Plasma Exchange
SIRS/CARS
Time
10
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
Experimental Support for
CRRT in Sepsis
 Multiple animal studies suggest physiologic and
survival benefit
11
-McMaster et al. Ped CCM, 2003
CVVH – Restoration of Immune
Homeostasis
12
-Paden ML, et al. Ped Neph 2006
24 Hours off
CVVH
End of CVVH
48 Hours
24 Hours
12 Hours
Pre-CVVH
 Reduction of cytokines,
chemokines,
modulators of apoptosis
• Convective removal
• Membrane
adsorption
Is There A “Best” Method of
CRRT In Sepsis?
 No prospective data available assessing
patient outcomes using diffusive (CVVHD)
and convective (CVVH) therapies
• Retrospective data suggested benefit of
CVVH in sepsis
• No convincing prospective data
13
Solute Molecular Weight and
Clearance
Solute (MW)
Urea (60)
1.01 ± 0.05
1.01 ± 0.07
Creatinine (113)
1.00 ± 0.09
1.01 ± 0.06
Uric Acid (168)
1.01 ± 0.04
0.97 ± 0.04
Vancomycin (1448)
0.84 ± 0.10
0.74 ± 0.04
Cytokines (medium)
cleared
minimal clearance
adsorbed
minimal clearance
Cytokines (large)
14
Convective Coefficient Diffusion Coefficient
Impact of Early High Dose CRRT on
Cytokines in Adult Sepsis: RCT Results
IL-6
IL-10
15
IL-8
TNF-a
-Cole et al., Crit Care Med 2002
Unknowns of Hemofiltration
for Sepsis
 Interaction of immune system with foreign surface
of the circuit? Good or bad?
• Complement activation
• Bradykinin generation
• Leukocyte adhesion
 Clearance of anti-inflammatory mediators?
 Clearance of unknown good mediators?
 What do plasma levels of mediators really mean?
• Honore concept: tissue levels
16
Indirect Benefit?: Fluid
Balance in Sepsis
17
Fluid Balance in Septic Shock
 Vasopressin in Septic
Shock Trial (VASST)
study: 778 adults
 More positive fluid
balance at 12 hours
and at day 4 (quartiles)
correlated with
increased mortality
*
*
18
18
-Boyd et al., Crit Care Med, 2011
Fluid Balance in Septic
Shock
 Sepsis Occurrence in Acutely Ill Patients (SOAP):
multicenter prospective observational European
trial
 1177 septic adults
 Multivariate analysis predictors of mortality:
• Cumulative fluid balance in first 72 hours (per
liter increase: OR 1.1 (1.0-1.1; p = 0.001)
19
19
-Vincent et al., Crit Care Med 2006
Effect of Fluid Overload on
Outcome in CRRT
N=113
20
*p=0.02; **p=0.01
- Foland, Fortenberry et al., CCM 2004
Theory: The Fluid/Outcome
Balance
Fluid Balance
SIRS
Mortality,
Vent LOS
Immunohomeostasis
CARS
Stimulus
21
21
Time
Does therapy change the late
phase outcome in sepsis?
Is There a Rationale for
CRRT?
 Aggressive management of fluids does
make a difference in ALI (FACTT trial)
 Not proven in sepsis
 Could higher dose of CRRT impact the
sepsis outcome?
22
Effect of Filtration Rate on Outcome in
Septic Adults with CVVH: Is More
Better?
425 patients
Endpoint = survival 15 days after D/C HF
146 UF rate 20ml/kg/hr
41 % survival
139 UF rate 35ml/kg/hr
57 % survival
p=0.0007
140 UF rate 45ml/kg/hr
58 % survival
p=0.0013
At last, an answer!
23
- Ronco et al. Lancet 2000; 351: 26-30
On Further Review:
Does Dose Matter?
 The RENAL Replacement
Therapy Study
 RCT: 1508 critically ill adults
 CRRT of high (40) vs. low
intensity (25 ml/kg/hr)
 No difference in 90 day
mortality or RRT
independence
24
-N Engl J Med. 2009
Meta-Analysis: No Benefit of
High Dose CRRT in Adult Sepsis
25
Early Initiation of CVVH in
Adult Sepsis: RCT
 80 adults
 Randomized:
• UF 25 ml/kg/hr for 96
hours
• Conventional
treatment
 All met SIRS/Sepsis
criteria
 Number and severity of
organ dysfunction
higher in CVVH
(p=0.05)
26
-Payen et al., Crit Care Med, 2009
Early CRRT in Sepsis: RCT
27
-Payen et al., Crit Care Med, 2009
RRT in Sepsis/MODS: High
Volume Hemofiltration
 Pilot RCT of 20 adults with septic shock and ARF to
high volume hemofiltration [HVHF 65 ml/(kg h)] vs
low volume hemofiltration [LVHF 35 ml/(kg h).
 HVHF:
• decreased vasopressor requirement
• trend towards increased urine output
• no effect on survival, LOS, RRT, mechanical
ventilation
28
-Boussekey et al. Intensive Care Med. 2008
Focusing on the most
important outcomes
29
29
CRRT and Outcome in
Pediatric MODS
 Single center: 113 patients
 103 patients with MODS
 Diagnosis of sepsis not well delineated
 70% on vasopressors
 Overall survival 61%/59% in MODS
 >3 organ MODS patient survival independently
associated with fluid overload
 Outcomes better than predicted
-Foland et al., Crit Care Med 2004
30
CRRT Use and Diagnosis:
ppCRRT Registry
31
-Symons et al. Clin J Am Soc Nephrol 2007
MODS/Sepsis and CRRT:
The PPCRRT Registry
 116 patients
 47 with sepsis
 51.7% overall survival
 Fluid overload specific risk factor independent of
PRISM 2
32
-Goldstein et al., Kidney International, 2005
Can Combination Therapies
Help in Sepsis?
 Addition of plasma filtration coupled with
adsorption, followed by dialysis or filtration
(CPFA)
 Polymyxin impregnated fibers
33
Hemoperfusion: Endotoxin
Adsorption
 Polymyxin B: high
affinity for endotoxin
 Charcoal
hemoperfusion
device: adsorption
column
 Significant
experience in
Japan, Europe
34
EUPHAS Trial: Survival
23/34 (68%)
14/30 (47%)
Hazard Ratio 0.43 (0.21-0.90)
35
-Cruz et al., JAMA, 2009
Is it all in how we measure?
36
Problems with CRRT Sepsis
Studies
 No consistent definitions of AKI
 Stratification of severity of AKI missing
• Fluid overload
• Biomarkers absent
 Many studies-intervention late
 No pediatric trials
37
CRRT Recommended for
Use in Pediatric Sepsis
 2007 ACCM guidelines
(SCCM 2009)
 “…after shock
resusucitation…CRRT
can be used to remove
fluid in patients who are
10% overloaded”
 “high flux CRRT (> 35
ml/kg/hr should be
considered….”
38
Conclusions
 There is a rationale for CRRT in sepsis
 So far, data hasn’t demonstrated earlier CVVH or
more intense RRT dosing improves outcome in
adults
 Insufficient evidence to support a role for RRT as
adjuvant therapy for septic shock in adults unless
severe AKI
39
What Do We Need?
 Pediatric studies! We don’t really know in children
yet
 Use of PRIFLE/AKIN for classification/study entry
 Correlation with/correction for
FO
 Biomarkers to identify injury earlier
 Mortality is not the only outcome
 In absence of RCT, continue assertive use of fluid
management and CRRT to address FO and sepsis
in children
40
Everything will be all right in the
end. So if it is not all right, then
it is not yet the end.
41