plasma exchange for tamof joseph a carcillo md university of pittsburgh
TRANSCRIPT
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.