PCCRT CONGRESS

LONDON , JULY 2015

Plasma Exchange for TAMOF

Joseph A Carcillo MDUniversity of Pittsburgh

WFPICCS GPSI AND ASFA RECOMMENDATIONS FOR PLASMAPHERESIS IN SEPSIS

1) GPSI recommends the use of plasma therapies in children to correct sepsis induced thrombotic disorders including progressive Disseminated Intravascular Coagulation, Secondary Thrombotic Microangiopathy, and Thrombotic Thrombocytopenic Purpura (Grade 2c)

2) ASFA recommends Plasma Exchange for Sepsis induced TAMOF Grade Level III C

‘May be used on an individual basis’

THROMBOCYTOPENIA ASSOCIATED MOF

ICU PATIENT

PERSISTENT THROMBOCYTOPENIA HAS HIGHER MORTALITY RATE

Mortality rate on Thr pts vs non-Thr pts day 4 = 33% vs 16% day 14 = 66% vs 16%

(Akca et al., CCM 2002)

Survivors

Non-survivors

2D Graph 1

Day

0 2 4 6 8 10 12 14 16

Pla

tele

t C

ou

nt

(x 1

,00

0)

0

50

100

150

200

250

300

Non-survivorsSurvivors

n = 39

n = 8

Platelet count rises in survivors

Platelet

vWF

ADAMTS 13 (vWF-CP)

tPA PGI

Endothelium

Platelet

ADAMTS 13(vWF-CP)

Platelet

vWF

vWF Platelet

Homeostasis

tPA

TFPI

Heparin ATIII

Prot C

APC

+

PGI

Thrombomodulin

PGI

TFPI

Homeostasis

tPA

Platelet

Platelet

Platelet

Platelet

Platelet

Platelet

Fibrin

vWF:Platelet Thrombus

PAI-1PAI-1tPA

Platelet

vWF

vWF

Platelet

vWF

Fibrin

PAI-1Platelet

Platelet

PlateletFibrin

PlateletvWF

Platelet

Platelet

Platelet

PlateletFibrin

PlateletvWF

Platelet

EndotheliumPAI-1 tPA

Fibrin Thrombus

vWF

Platelet

vWFShear stress

TTP

Endothelium

Platelet

Platelet

vWFX ADAMTS 13 (vWF-CP)

ADAMTS 13 (vWF-CP Ab)

TTP

Fibrin

Platelet

Platelet

Platelet

Platelet

Platelet

Platelet

PlateletvWF

Platelet

Platelet

Platelet

Platelet

Platelet

Platelet

Fibrin

vWFvWF

TTP

Endothelium

Endothelium PAI-1

vWF

TF

TF

vWF

vWFPAI-1

TF

PAI-1

VII

DIC

TF TF

vWF

PAI-1

PAI-1

TF

VII

vWFTF

Platelet

Platelet

Platelet

Platelet Platelet

Platelet

Platelet

DICConsumptivelow fibrinogen

Endothelium

Endothelium PAI-1 TF

PAI-1

PAI-1

PAI-1

PAI-1

vWF

vWF

TFPI

TMA

¯vWF CP¯ADAMTS 13

PlasminPlasminogen

PAI-1

X

PAI-1 PAI-1

PAI-1

TMA

vWF

Platelet

Platelet

¯ADAMTS 14¯vWF CP

TF

PAI-1

PAI-1

vWF

TFPI

Platelet

Platelet

Platelet

Platelet

vWF

Platelet

Platelet

Platelet

TMA

Nonconsumptivenormal fibrinogen

Brain: 40x with no clots

Brain: 40x with clots

Kidney: 100x with no clots

Kidney: 100x with clot

DIAGNOSTIC CRITERIA FOR TAMOF

Thrombocytopenia + AKI Increased LDH Normal PT/aPTT or elevated Multiple organ failure Remove underlying cause and

can respond to TTP like steroid/plasma exchange protocol.

PLASMA INFUSION OR EXCHANGE? Plasma Infusion

Restores clotting factors (VII, VIII, X etc)

Restores vWF cleaving protease

Restores prostacyclin

Restores protein C and antithrombin III

Restores tPA

Plasma Exchange

Removes Abs to vWF cleaving protease

Removes vWF Removes PAI-1 Removes Tissue

Factor

PLASMAEXCHANGE

MAN

MULTICENTER RCT: PLASMA EXCHANGE THERAPY IMPROVES OUTCOME IN THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)

RCT comparing plasma infusion to plasma exchange for TTP showed a significant beneficial treatment effect with plasma exchange therapy

Plasma exchange: 2/51 (4%) deaths 40/51 (80%) responded

Plasma infusion: 8/51 (16%) deaths 25/51 (50%) responded

(Rock et al., NEJM 1991)

Plasma Exchange

Standard Therapy

(Busund et al., Intensive Care Med 2002)

Plasma Exchange Improved Outcome in Adult Severe Sepsis

NINE DAYS OF PLASMA EXCHANGE REDUCED MORTALITY TO 0/22 COMPARED TO 7/15 (P<0.001) IN ADULTS WITH 2O TMA INCREASED PLASMA VOLUME AND REDUCED BODY WEIGHT (P <0.05)

DARMON ET AL CRIT CARE MED 2006 34:2127-2133

PLASMA EXCHANGE REDUCED ORGAN FAILURE

DARMON ET AL CRIT CARE MED 3006 34:2127-2133

PLASMA EXCHANGE OR INFUSION REDUCED LDH LEVELS AND RESTORED PLATELET COUNTS OVER TIMEDARMON ET AL CRIT CARE MED 2006 34:2127-2133

PLASMA EXCHANGE REPLENISHES ADAMTS13 ACTIVITY

ADAMTS13 Activity and PEx vs No PEx

Day

0 1 2 3 4 5 6 7 8

AD

AM

TS

13 A

ctiv

ity (

% r

elat

ive

to c

ontr

ols)

-20

0

20

40

60

80

100

day vs pe cp day vs nope cp

Plasma Exchangen = 4

No Plasma Exchangen = 4

2F ANOVA p<0.05

PELODPediatric Logistic Organ Dysfunction Score

DAY

0 5 10 15 20 25 30

PE

LOD

0

20

40

60

80

100

Plasma ExchangeNo Plasma Exchange

Figure 3. Pediatric Logistic Organ Dysfunction Score, Mean with standarderror for patients who received plasma exchange therapy (N = 5) and who did not receive plasma exchange therapy (N = 5) for each day x 28 days.

17

PELOD decreased from 25.0 2.0 to 0.8 0.6 with plasma exchangeat 28 d

PELOD increased from 25.4 2.3 to 73.6 18.4 without plasma exchange at 28 d

p < 0.001, power = 1.0, 2F-RM ANOVA

CONTINUOUS PLASMA FILTRATION WITH PARTIAL PLASMA EXCHANGE WAS NOT EFFECTIVE(REEVES ET AL CCM 1999 24(10):2096-2104)

8/14 adults/children survived with 72 h plasmafitration and partial FFP replacement compared to 8/16 without.

38%

40%

42%

44%

46%

48%

50%

PF No PF

Mortality

TURKISH COHORT STUDY

Use of Therapeutic Plasma Exchange in Children With Thrombocytopenia-Associated Multiple Organ Failure in the Turkish Thrombocytopenia-Associated Multiple Organ Failure Network.

Sevketoglu, Esra; Yildizdas, Dincer; Horoz, Ozden; Kihtir, Hasan; Kendirli, Tanil; Bayraktar, Suleyman; Carcillo, Joseph Pediatric Critical Care Medicine. 15(8):e354-e359, October 2014. DOI:10.1097/PCC.0000000000000227

2

Blood Purification and Mortality in Sepsis: A Meta-Analysis of Randomized Trials*.Zhou, Feihu; MD, PhD; Peng, Zhiyong; MD, PhD; Murugan, Raghavan; MD, MS; Kellum, John; MD, MCCM Critical Care Medicine. 41(9):2209-2220, September 2013.DOI: 10.1097/CCM.0b013e31828cf412

CRIT CARE. 2014 DEC 20;18(6):699. [EPUB AHEAD OF PRINT]THE EFFICACY AND SAFETY OF PLASMA EXCHANGE IN PATIENTS WITH SEPSIS AND SEPTIC SHOCK: A SYSTEMATIC REVIEW AND META-ANALYSIS.RIMMER E, HOUSTON BL, KUMAR A, ABOU-SETTA AM, FRIESEN C, MARSHALL JC, ROCK G, TURGEON AF, COOK DJ, HOUSTON DS, ZARYCHANSKI R.

ADVANCED TECHNOLOGIES IN PEDIATRIC SEVERE SEPSIS: FINDINGS FROM THE PEDIATRIC HEALTHCARE INFORMATION SYSTEM

RUTH A, MCCRACKEN C, HALL M, FORTENBERRY J, HEBBAR K, EMORY UNIVERSITY CHILDREN’S HEALTHCARE OF ATLANTA

From 2004-2012 10.8% of Pediatric Severe Sepsis kids received ECMO(4.2%), CRRT (5.3%), and/ or PLEX (4.2%)

1, 162 received PLEX including 196 (11.9% of all ECMO); and 30 on CRRT + ECMO(1.8% of all ECMO).

PLEX and/or ECMO was more commonly used in infants and CRRT in adolescents

2004-2012 Hospital Mortality: PLEX = 20.9%; CRRT = 45%; ECMO = 49.5%

IS THERE A ROLE FOR PLASMA EXCHANGE?

Australian study – 40 + children with severe sepsis randomized to plasmafiltration showed no difference

US TAMOF cohort 81 patients showed sicker patients received plasma exchange with same survival

Turkey TAMOF cohort 46 patients showed improved survival with plasma exchange

My unofficial combination of the USA and Turkey TAMOF cohort studies (n =127) shows reduced mortality with plasma exchange. Mortality decreased from 56% to 30% (p < 0.05) NNT = 4.

Randomized controlled international trial is warranted for TAMOF (NOT severe sepsis without TAMOF) in children and adults.