Is There a Rationale To Use CRRT For Treating Sepsis?

James D. Fortenberry MD, FCCM, FAAPPediatrician in Chief

Children’s Healthcare of AtlantaProfessor of Pediatric Critical Care

Emory University School of Medicine

2

The Problem of Sepsis in Children

42,000 pediatric sepsis cases/year Annual cost > $2 billion Increased mortality 5.49.5/100,000 Pediatric sepsis mortality rate in US: 10.3%

- Watson RS, Carcillo JA, AJRCCM 2003

3

World Sepsis Day

Thursday, September 13, 2012

3

Sepsis: A Global Problem With Much To Be Done

Join.www.world-sepsis-day.org

5

Pediatric Sepsis Mortality

Overall pediatric mortality lower than adults (~10% vs. 20-60%)

Single organ failure rarely leads to mortality

Hematologic Failure < 5 %

Immunologic Failure < 5 %

CV Failure < 5 %Respiratory Failure < 5 %

Renal Failure < 5 %

6

Respiratory Failure

Cardiovascular Failure

Renal FailureHematologic Failure

Immunologic Failure

The MODS/Sepsis Patient

HIGH MORTALITY

50-90%

-Courtesy of Matt Paden

7

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)

8

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

9

Blood

Black BileYellow Bile

Phlegm

Direct Effect?: Removing The Evil Humours

10

CRRT/Plasma Exchange

CRRT/Plasma Exchange

Time

Time

SIRS/CARS

SIRS CARS SIRS CARS

I mmunohomeostasis

I mmunohomeostasis

Pro-inflammatoryMediators

Anti-inflammatoryMediators

IL-1TNF PAF

IL-10

Adapted f rom Ronco et al. Artificial Organs 27(9) 792-801, 2003

Peak Concentration Model of Sepsis

11

Experimental Support for CRRT in Sepsis

Multiple animal studies suggest physiologic and survival benefit

-McMaster et al. Ped CCM, 2003

12

CVVH – Restoration of Immune Homeostasis

Pre

-CV

VH

12 H

ou

rs

24 H

ou

rs

48 H

ou

rs

En

d o

f C

VV

H

24 H

ou

rs o

ff

CV

VH

Reduction of cytokines, chemokines, modulators of apoptosis• Convective removal• Membrane

adsorption

-Paden ML, et al. Ped Neph 2006

13

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

14

Solute Molecular Weight and Clearance

Solute (MW) Convective Coefficient Diffusion Coefficient

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

Cytokines (large) adsorbed minimal clearance

15

Impact of Early High Dose CRRT on Cytokines in Adult Sepsis: RCT Results

IL-6IL-8

TNF-aIL-10

-Cole et al., Crit Care Med 2002

16

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

17

Indirect Benefit?: Fluid Balance in Sepsis

18

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 -Boyd et al., Crit Care Med, 2011

*

*

19

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-Vincent et al., Crit Care Med 2006

20

Effect of Fluid Overload on Outcome in CRRT

N=113 *p=0.02; **p=0.01

- Foland, Fortenberry et al., CCM 2004

21

Theory: The Fluid/Outcome Balance

21

Time

Mortality,Vent LOS

Fluid Balance

SIRS

CARS

Stimulus

Immunohomeostasis

Does therapy change the late phase outcome in sepsis?

22

Is There a Rationale for CRRT?

Aggressive management of fluids does make a difference in ALI (FACTT trial)

Not proven in sepsisCould higher dose of CRRT impact the

sepsis outcome?

23

Effect of Filtration Rate on Outcome in Septic Adults with CVVH: Is More

Better?

- Ronco et al. Lancet 2000; 351: 26-30

425 patientsEndpoint = survival 15 days after D/C HF

146 UF rate 20ml/kg/hr41 % survival

139 UF rate 35ml/kg/hr57 % survival

p=0.0007

140 UF rate 45ml/kg/hr58 % survival

p=0.0013

At last, an answer!

24

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

-N Engl J Med. 2009

25

Meta-Analysis: No Benefit of High Dose CRRT in Adult Sepsis

26

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)

-Payen et al., Crit Care Med, 2009

27

Early CRRT in Sepsis: RCT

-Payen et al., Crit Care Med, 2009

28

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

-Boussekey et al. Intensive Care Med. 2008

29

Focusing on the most important outcomes

29

30

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

31

CRRT Use and Diagnosis: ppCRRT Registry

-Symons et al. Clin J Am Soc Nephrol 2007

32

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

-Goldstein et al., Kidney International, 2005

33

Can Combination Therapies Help in Sepsis?

Addition of plasma filtration coupled with adsorption, followed by dialysis or filtration (CPFA)

Polymyxin impregnated fibers

34

Hemoperfusion: Endotoxin Adsorption

Polymyxin B: high affinity for endotoxin

Charcoal hemoperfusion device: adsorption column

Significant experience in Japan, Europe

35

EUPHAS Trial: Survival

-Cruz et al., JAMA, 2009

14/30 (47%)

23/34 (68%)

Hazard Ratio 0.43 (0.21-0.90)

36

Is it all in how we measure?

37

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

38

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….”

39

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

40

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

41

Everything will be all right in the end. So if it is not all right, then it is not yet the end.