Use of CRRT in ECMO: Is It Valuable? James D. Fortenberry MD, FCCM, FAAP Associate Professor of Pediatrics Emory University School of Medicine Director,

Use of CRRT in ECMO: Is It Valuable?

James D. Fortenberry MD, FCCM, FAAPAssociate Professor of Pediatrics

Emory University School of MedicineDirector, Critical Care Medicine and

Pediatric ECMO/Advanced TechnologiesChildren’s Healthcare of Atlanta at Egleston

2

CRRT and ECMO

What are potential benefits? What is the experience? How do you do it? What are the risks? What more do we need to know?

3

CRRT on ECMO: Potential Benefits

Management of fluid balanceDecreasing fluid overloadRemoval of inflammatory mediatorsEnhanced nutritional supportControl of electrolyte abnormalitiesDecreased use of furosemide

4

Is Fluid Overload Bad?

Remember: fluid is good in resuscitation!

Early goal directed therapy outcome benefits

However, multiple studies (adults, pediatric) suggest survival benefit with decreased fluid overload in critical illness

5

Fluid Overload

Texas Children’s Hospital

21 pediatric ARF patients

Survival benefit remains even after adjusted for PRISM scores

0

5

10

15

20

25

30

35

Survivors Non-Survivors

Goldstein SL, et al: Pediatrics 107:1309-1312, 2001

Per

cen

t F

luid

Ove

rloa

d

*

6

Fluid Overload

Children’s Healthcare of Atlanta at Egleston

113 pediatric patients on CVVH

Multivariate analysis • Percent fluid overload

independently associated with survival in ≥ 3 organ MODS

0

2

4

6

8

10

12

14

16

Survivors Non-Survivors

-Foland JA, Fortenberry et al. Crit Care Med, 2004

*

Per

cen

t F

luid

Ove

rloa

d

7

Fluid Overload Decreased in 3 Organ MODS CRRT Survivors

-Foland JA et al. Crit Care Med, 2004

8

Fluid Overload and ECMO: Neonates

As weight gain decreases, ECMO flow decreases which comes first?

• As weight reduces, ECMO flow reduces

-Kelley RE, et al. J Pediatr Surg, 1991

111 cc/kg

97 cc/kg

73 cc/kg

30 cc/kg

9.1%

3.8%

2.0%

5.4%

0

20

40

60

80

100

120

25% 50% 75% 100%

Duration of ECMO

EC

MO

Flo

w (

cc

/kg

)

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

9.0%

10.0%

We

igh

t G

ain

(p

erc

en

t)

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Fluid Overload and Outcome

Seattle Children’s Hospital 77 pediatric patients

• If pre-CRRT percent fluid overload >10% 3.02 times greater risk of mortality (95% CI 1.5-6.1,

p=0.002)

Gillespie RS, et al. Pediatr Nephrol 19:1394-1399, 2004

10

Fluid Overload/Oliguria is Common on ECMO

Children's Healthcare of Atlanta 30 consecutive neonates meeting ECMO

criteria – • 18 VV ECMO, 12 conventional management• Patients who went onto ECMO had:

Greater fluid overload Lower UOP Higher BUN Higher creatinine

-Roy BJ, Pediatrics 1995

11

ECMO and Urine Output

-Roy BJ, Pediatrics 1995

12

Blood

Black BileYellow Bile

Phlegm

Requisite Bad Humour Slide

13

Good Humours

CRRT/Plasma Exchange

CRRT/Plasma Exchange

Time

Time

SI RS/CARS

SI RS CARS SI RS 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

15

Hemofiltration Cytokine Clearance

Children’s Healthcare of Atlanta at Egleston 6 pediatric patients with culture proven

bacterial septic shock and ARF• 2 on ECMO

Compared to 3 ARF patients without septic shock• 1 on ECMO

-Paden M et al., submitted 2008

16

Absolute cytokine changes in septic shock/ARF patients

1

10

100

1000

10000

100000

IL-6 IL-10

Pre-CVVHEnd ofCVVH

Lo

g C

on

cen

trat

ion

(p

g/m

l)

p<0.02* p=0.04*

-Paden et al., submitted 2008

17

CVVH Associated With Decreased Cytokines in Children with Septic Shock

Cytokine Levels at the End of CVVH

-100

-80

-60

-40

-20

0

20

% D

ecre

ase

From

Bas

elin

e

IL-6

IL-8

IL-10

Septic ARF Patients Non-septic ARF Patients

*p<0.05

* *

-Paden et al., submitted 2008

18

Cytokine Results: Sample CVVH Patient-Nonseptic

Non-septic ARF Patient #3

0

10

20

30

40

50

60

70

80

90

Co

nc

en

tra

tio

n (

pg

/ml)

Human IL-10

Human IL-6

Human IL-8

Pre

-CV

VH

12 H

ours

24 H

ours

48 H

ours

En

d o

f C

VV

H

24 H

ours

off

C

VV

H

Note Scale

19

Cytokine Results in Sample CVVH Patient: Septic

Septic ARF Patient #5

0

200

400

600

800

1000

1200

1400

1600

1800

2000C

on

cen

trat

ion

(p

g/m

l)

Human IL-10

Human IL-6

Human IL-8

Pre

-CV

VH

12 H

ours

24 H

ours

48 H

ours

En

d o

f C

VV

H

24 H

ours

off

C

VV

H

20

ECMO/CVVH Produces Cytokine Reduction

In vitro study –

• Increased cytokine levels overall due to ECMO membrane activation

• Adding a hemofiltration circuit significantly reduced : IL-1beta IL-1ra IL-6 IL-8

-Skogby M, et al. Scand Cardiovasc J. 2000

21 Skogby M, et al. Scand Cardiovasc J. 2000 Jun;34(3):315-20

IL – 8 Reduction with CRRT in ECMO

22

Is Avoiding Lasix Overuse Important?

Potential ototoxicity-particularly in neonates

Lasix use associated with worsened outcomes in adult renal failure

23

Diuretics and Critical Illness

4 University of California Hospitals 552 adults Use of diuretics increased risk of death or

renal non-recovery in adults with ARF• Overall 1.77 times greater risk

-Mehta RL, et al. JAMA 2002

24

CRRT and ECMO


25

CRRT on ECMO: Published Experience with Use

Michigan• PICU• Cardiac surgery

Vanderbilt Atlanta Chile

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CRRT/ECMO Experience: Michigan

U of M ECMO Database 35 neonatal and pediatric patients who

received ECMO + hemofiltration• 15 Survivors

Renal recovery in 14 of 15 (93%) survivors• One had Wegener’s as underlying cause of

renal failure-subsequently transplanted

-Meyer RJ, et al Pediatr Crit Care Med 2001

27

CRRT/ECMO Experience: Cardiac Surgery

University of Michigan 74 post-operative congenital heart disease

patients• Use of hemofiltration in 35%

5.01 times increased risk of death Use of hemofiltration indicative of longer

ECMO support time worse outcome was from duration, not hemofiltration

-Kolovos et al. Ann Thorac Surg 2003

28

CRRT/ECMO Experience: Cardiac Surgery

Vanderbilt University 84 post-operative congenital heart disease

patients• Temporary renal insufficiency in 41 patients

(48.9%)

CVVH NOT associated with :• Ability to wean off ECMO• Survival to discharge

-Shah SA et al. ASAIO J 2005

29

ECMO/CVVH Experience: Atlanta

Children’s at Egleston ECMO Database (11/97-12/05)

95 neonatal and pediatric patients who received ECMO + CVVH• 55 survivors• 14 came off ECMO on RRT (1 on prior to ECMO)• 1 needed RRT chronically• 1 with CRF but does not need RRT

Renal recovery in 53/55 (96%) survivors• Both CRF patients had primary vasculitis

-Paden et al., CCM 2007 (abstr)

30

Comparison of CVVH/ECMO vs. ECMO without CVVH

26/86 peds respiratory failure patients received CVVH for >24 hours

Case control comparison: 26 CVVH/ECMO pts. and 26 pts. receiving ECMO without CVVH

No difference in survival or vent days during or after ECMO

Significant differences in fluid balance Significant treatment differences

-Hoover et al., Intensive Care Medicine, in press 2008

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Fluid Balance With CVVH/ECMO vs. No CVVH/ECMO

Flu

id B

alan

ce (

cc/k

g/d

ay)

-50

0

50

100

150 ECMO/non-CVVHECMO/CVVH ECMO/CVVH -CVVH days only

All Patients Survivors

* **

#


32

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Lasixuse

Days todesiredcalories

CVVH/ECMO

ECMO alone

Comparison of CVVH/ECMO vs. ECMO without CVVH


** *

33

CRRT/ECMO Experience in Infants: Chile

6 of 12 infants on ECMO received CRRT Observed complication: excessive

ultrafiltration Survival to discharge in 5 of 6 (83%) All with normal renal function at discharge

-Cavagnaro et al., Int J Artif Organs 2007

34

CRRT and ECMO


35

CRRT on ECMO: How to Perform It

Options:• Parallel use of stand-alone CRRT devices

(Gambro, Braun) Pros Cons

• Use of inline hemofilter with syringe pumps Pros Cons

ECMO/CRRT Arrangement: The “Michigan Method”

37

Use of Standard CRRT Devices for Delivery on ECMO

38

CRRT and ECMO


39

CVVH/ECMO: Are There Risks?

Complexity of machineryErrors due to replacement fluidsUnderestimation of fluid removal

40

Sometimes it gets a little crowded

41

CRRT Error Rate Increases with Increasing Flow/Pressure

-Sucosky, Paden et al., JMD, in press 2008

42

Error Rate in CRRT/ECMO Circuits

Potential error rate noted in stand-alone CVVH Ex vivo ECMO circuit Compared measured versus actual fluid removal

rates with inline hemofilter arrangement and with Braun Diapact for CVVH

Significant excess fluid removal over “expected” both for inline device and commercial device

-Paden et al., ppCRRT Conference 2008 (abstr)

43

Potential Solutions

Collaboration with GeorgiaTech

Paden, Sucosky Development of

fluid management/CRRT device

High accuracy in delivery

Patent pending

44

What Further Work Needs to be done?

Improved control of fluid management Randomized trial to compare CVVH/ECMO

to ECMO without routine CVVH Potential use of biomarkers for initiation?

45

Conclusions

CRRT on ECMO can potentially provide a variety of benefits

CRRT can be provided• without worsening renal insufficiency• with improved fluid balance• with decreased furosemide exposure

Potential risks of excessive fluid removal Further work to improve accuracy of fluid balance

and to determine if use translates into outcome benefit

46

MODS & 3 Organ Involvement

Effect SE OR 95% CI p

PRISM III 0.049 0.058 1.10 0.88, 1.39 0.4

% FO 0.058 0.023 1.78 1.13, 2.82 0.01

Pediatric Patients Receiving CVVH

Factors Associated with Mortality

- Foland, Fortenberry et al., CCM 2004

Pro-I nflammatoryMediators

Anti-I nflammatoryMediators (I nhibitors)

Pro/ Anti-I nflammatoryMediators

Activation Depression

Time

Time

Parallel

Serial

IL1TNF

PAF

IL10

IL6

Med

iato

r Le

vels

Med

iato

r Le

vels

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

Documents

Use of CRRT in ECMO: Is It Valuable? James D. Fortenberry MD, FCCM, FAAP Associate Professor of Pediatrics Emory University School of Medicine Director,