Thrombocytopenia Associated MOF - Pediatric Continuous Renal

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Thrombocytopenia-Associated Multiple Organ
Failure and Pediatric Septic Shock: Is Plasma
Exchange a Promising Therapy?
James D Fortenberry MD, FCCM, FAAP
Pediatrician in Chief
Children’s Healthcare of Atlanta
Professor, Pediatric Critical Care
Emory University School of Medicine
Atlanta, Georgia
Disclosures
 No financial disclosures
 I am an intensivist
• Dumber than smartest nephrologist
• Able to intubate dumbest kidney
2
The MODS Patient
Respiratory Failure
Immunologic Failure
Cardiovascular Failure
HIGH MORTALITY
50-90%
Hematologic Failure
3
Renal Failure
-Courtesy of Matt Paden
Thrombotic Thrombocytopenic
Purpura (TTP)
 A thrombotic microangiopathy syndrome
 Critical defect: deficiency of ADAMTS-13
(< 10%):
A disintegrin and metalloprotease with
thrombospondin motifs-13 (formerly vWf cleaving
protease)
 Ultra-large vWf multimer-platelet thrombi
 Microthrombotic multi-organ vascular injury:
MOF and autopsy findings
4
Thrombotic Microangiopathy:
TTP/TAMOF
TF
PAI-1
Endothelium
PAI-1
TF
PAI-1
TFPI
TFPI
PAI-1
PAI-1
PAI-1
PAI-1
Platelet
PAI-1
Plasminogen
ADAMTS13
(vWF-CP)
x
IL- 8
IL8
TNF-
TNF-
IL- 6+R
IL- 6+R
Endothelium
5
vWF
Shear stress
Plasmin
X
Platelet
vWF
X
Platelet
Platelet
ADAMTS13
Platelet
Platelet
(vWF-CP)
ADAMTS13 Ab
IL-6
Platelet
ADAMTS13 Ab
IL-6
Platelet
Platelet
Thrombocytopenia-Associated
Multiple Organ Failure (TAMOF)
 A thrombotic microangiopathy described in children
(Nguyen, Carcillo 2001)
 Similarities to TTP
•
•
•
•
•
Deficient ADAMTS-13
Increased ADAMTS-13 inhibitors
Increased vWF antigen
Increased ULvWF multimers
Thrombocytopenia
 Primarily secondary to sepsis
 3 or greater organ failure
 High mortality in children
6
ADAMTS-13 Deficiency in
Adult Sepsis
7
-Martin et al., Crit Care Med 2007
Adult Sepsis-Survival by
ADAMTS-13 Level
ADAMTS-13
above median
Below median
8
-Martin et al., Crit Care Med 2007
ADAMTS-13 Deficiency in
Pediatric Sepsis
-Nguyen, Hematologica 2006
9
Refractory Sepsis/MOSF:
Desperate Times…
Diseases desperate grown
By desperate appliance are relieved,
Or not at all.
-Claudius, King of Denmark,
Hamlet Act IV Scene 3
W. Shakespeare
10
Rationale for Plasma
Exchange: TTP
 80-90% mortality
 Plasma Exchange 
10% mortality:
• Replenishes ADAMTS13
• Removes ADAMTS-13
inhibitors
• Removes
thrombogenic ULvWf
multimers
11
-Rock, NEJM 1991
Plasma Exchange: Rationale
In Sepsis
 Subset of patients who demonstrate thrombotic
microangiopathy similar to TTP
 Similar clinical and coagulation factor profile
• Deficiency of vWf cleaving protease (ADAMTS13)
• Platelet/vWf microthrombi
• Thrombocytopenia
12
13
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
14
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
Plasmapheresis in Severe
Sepsis and Septic Shock
 PRCT, Russian adult
ICU
 106 sepsis patients
randomized to:
• Standard therapy
• Addition of
plasmapheresis (1/2
FFP, 1/2 albumin)
 Decreased mortality
with plasmapheresis
60
53.8
50
*
33.3
40
30
20
10
0
Standard
Plasma
*P< .05
15
- Busund et al., Intensive Care Medicine 2002;28:1410
TAMOF/Plasma Exchange in
Children: CHP Trial
 28 children with TAMOF
• Decreased ADAMTS-13 vs. non-TAMOF
• Correlated with outcome
 Small RCT (10 patients)
 28-day survival
• No PEx: 1/5
• PEx: 5/5 (p < .05)
16
-Nguyen et al., CCM 2008
CHP Trial: PELOD
Improved with PEx
Pediatric Logistic Organ Dysfunction Score
100
PELOD
80
60
40
20
PEx
0
0
5
10
15
20
25
30
DAY
Plasma Exchange
No Plasma Exchange
Figure 3. Pediatric Logistic Organ Dysfunction Score, Mean with standard
error 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
-Nguyen 17et al., CCM 2008
Plasma Exchange
Replenishes ADAMTS-13
ADAMTS13 Activity and PEx vs No PEx
ADAMTS13 Activity (% relative to controls)
100
2F ANOVA p<0.05
80
Plasma Exchange
n=4
60
40
20
No Plasma Exchange
n=4
0
-20
0
1
2
3
4
5
6
7
8
Day
18
-Nguyen et al., CCM 2008
Children’s TAMOF
Network
 Broader group of Pediatric ICUs
 Goals:
• Create a study group to perform prospective,
observational studies
• Identify TAMOF and evaluate:
 Clinical and biochemical course
 Use of specific therapies
 Associated outcomes
• Inform development of future prospective trials
19
Children’s TAMOF Network
20
 Enrolling centers (site co-I):
• Children’s of Atlanta at Egleston: coordinating
center (Fortenberry)
• Children’s of Pittsburgh (Raj Aneja/Joe Carcillo)
• Cincinnati Children’s (Derek Wheeler)
• Nationwide Children’s-Columbus OH (Mark Hall)
• Phoenix Children’s Hospital (Sandra Buttram/Heidi
Dalton)
• Texas Childrens’ Hospital (Laura Loftis/Trung
Nguyen)
• Michigan-Mott Children’s (Yong Han)
• Minnesota (Rod Tarrago)
• Vanderbilt-Carrell Children’s (Rick Barr/Geoffrey
Fleming)
Hypotheses
 Children with TAMOF demonstrate decreased
ADAMTS-13 levels and increased vWf antigen
levels.
 Children with TAMOF receiving PEx demonstrate
associated improvement of organ dysfunction and
survival vs. those receiving standard therapy alone.
21
Methods
 Prospective, observational, nonrandomized cohort
study
 Enrolled patients 1 month-21 years of age meeting
TAMOF criteria:
• Sepsis, transplant, chemotherapy
• Platelet count < 100,000/mm3
• Organ failure index (OFI) > 2
 Data collected via web-based registry
22
Methods
23
 Blood obtained for:
• ADAMTS-13
• vWf antigen levels
• Studies performed at Baylor College of Medicine
(Trung Nguyen MD)
 Therapy, and use of PEx at attending/center
discretion
• Typical: centrifugation approach
• Suggested protocol:
 FFP: 1.5x plasma volume day 1
 1x plasma volume daily exchanges x 4 days
• Duration at MD discretion
Results: Demographics
- 81 patients enrolled and met criteria
Overall
No PEx (21)
PEx (60)
Mean age (yr)
8.6 + 6.2
6.7 + 6.3
9.2 + 6.4
Mean weight
(kg)
35.2 + 27.9
29.8 + 27.6
37.2 + 28.5
Race: White (%) 65.4
63.6
66.1
Race: A-A
19.8
22.7
18.6
DiagnosisSepsis
79/81
20/21
59/60
Ever on ECMO
30/81 (37%)
4/21 (13)
26/60 (43.3)
Ever on CRRT
46/81 (56.8%)
8/21 (41.1)
38/60 (63.3)
-No differences between groups
24
Results: Severity of Ilness
Overall
No PEx (21)
PEx (60)
P
value
20.2 + 12.1
15.8 + 10.1
21.9 + 12.4
.04
Baseline PRISM 18.2 + 6.8
16.9 + 5.5
18.7 + 7.2
0.28
Baseline OFI
4.5 + 1.2
4.2 + 1.0
4.6 + 1.2
0.21
Baseline
Platelet Count
(x 1000)
62.2 + 42.1
55.9 + 35
64.6 + 44.7
0.42
Baseline
ADAMTS-13
(%)
52.9 + 27.8
63.7 + 26
49.9 + 28
0.22
Baseline vWF
Ag (%)
161 + 66.3
217 + 73
146 + 56.4
0.005
Baseline
PELOD
25
Results: Therapies
 Treatment:
• No PEx: 21 patients
• PEx: 60 patients
 Use of CVVH: 46 patients (57%)
• No PEx 8 (41%)
• PEx 38 (63%) p = 0.07
 Use of ECMO: 30 patients (37%)
• No PEx: 4 (13%)
• PEx: 26 (44%) p = 0.07
26
TAMOF Network Results: 28
Day Survival
PEx: 68.3%
No PEx: 61.9%
P = 0.5
27
*
-PELOD scores decreased more rapidly in patients
receiving PEx (p < .05)
- PEx associated with increase in ADAMTS-13 in first 4 days
Multivariable Risk Factors for Death:
PELOD and Plasma Exchange
Variable
Descriptive
Statistics
No. (%) / Mean
(SD)
ECMO
30/81 (37.0%)
0.4676
0.6167
1.596 0.48-5.4
0.45
CVVH
45/81 (55.6%)
0.7484
0.6215
2.114 0.63-7.2
0.23
Baseline
PELOD
(per 5 pt
increase)
21.2 (11.4)
0.1100
0.0321
1.734 1.27-2.4
0.0006
0.8618
1.2200
2.367
0.5110.9
0.27
-1.3213
0.6801
0.267
0.071.01
0.05
MRSA Infection 12/81 (14.8%)
Plasma
Exchange
30
60/81 (74.1%)
Estimate
Standard
Error
Odds
Ratio
95% CI
P-value
Risk Factors
 For every 5 unit increase in PELOD score at
baseline (day 1 on study) mortality risk increases
1.73 times (p=0.0006)
 PEx reduced risk of death by 73.3% = odds of
survival 3.75 times higher with PEx (p = 0.05)
31
Conclusions
 TAMOF patients demonstrated:
• Decreased ADAMTS-13, increased vWf
antigen, consistent with TTP profile
 Use of PEx vs. standard therapy was
associated with:
 Greater improvement in organ dysfunction
 Better survival (adjusted for severity, risk
factors)
 Cannot conclude outcome benefit
32
Next Steps
 These results could inform a randomized trial to
determine contribution of PEx to TAMOF outcome
 Need to better define subgroups; use biomarkers
• ADAMTS-13 real-time
 Submitted a U34 Planning Grant: Rare Thrombotic
and Hemostatic Disorders
33
Alexis- A Success Story
34
Why Not Plasma Infusion
Alone?
 Plasma Infusion
• Restores procoagulant
factors
• Restores anticoagulant
factors (protein C, AT III,
TFP-I)
• Restores prostacyclin
• Restores tPA
• Restores ADAMTS-13
35
 Plasma Exchange
• Restores factor
homeostasis like plasma
infusion
In addition:
• Removes ADAMTS-13
inhibitors
• Removes ultra-large vWF
multimers
• Removes tissue factor
• Removes excess PAI-1
• Maintains fluid balance
during procedure vs.
infusion
Course of Organ Dysfunction and
TMA: Plasma Infusion vs. Plasma
Exchange
35
 36 adult TMA patients
 Decreased mortality
with plasma exchange
 Plasma infusion group
• received larger
volumes
• had larger weight
gain
36
31.8
30
25
20
15
*
10
5
0
0
Plasma
Plasma
Infusion
Exchange
- Darmon et al., Crit Care Med, 2006
Days of Plasma Exchange
Non-survivors
Survivors
(n = 19)
(n = 40)
No. / Total (%)
37
Total Days on PEx Therapy 1
6/19 (31.6%)
0/40 (0%)
2
4/19 (21.1%)
1/40 (2.5%)
3
1/19 (5.3%)
7/40 (17.5%)
4
1/19 (5.3%)
1/40 (2.5%)
5
2/19 (10.5%)
14/40 (35.0%)
6
1/19 (5.3%)
6/40 (15.0%)
7
1/19 (5.3%)
9/40 (22.5%)
8
2/19 (10.5%)
0/40 (0%)
10
0/19 (0%)
2/40 (5.0%)
14
1/19 (5.3%)
0/40 (0%)
Results: Site Enrollment
Non-Plasma Exchange Group
Plasma Exchange Group
(n = 21)
(n = 60)
Deaths by Site
CHOA-Egleston
0/1 (0%)
10/22 (45.5%)
Pittsburgh
-
0/6 (0%)
Columbus
3/5 (60.0%)
-
Cincinnati
0/2 (0%)
-
3/5 (60.0%)
1/2 (50.0%)
Minnesota
0/1 (0%)
3/13 (23.1%)
Vanderbilt
1/6 (16.7%)
2/4 (50.0%)
Michigan
-
1/9 (11.1%)
Phoenix
1/2 (50.0%)
2/3 (66.7%)
All sites
8/21 (36.4%)
19/60 (32.2%)
Texas Children’s
38
Results: TAMOF Patients
 Overall survival 54/81 (67%)
• No PEx: 13/21 (61.9%)
• PEx: 41/60 (68.3%) NS
 Survival: PELOD > 21 (47)
• No PEx 50 %
• PEx 56.4 %
 Survival: PELOD < 21 (34)
• No PEx 77.8 %
• PEx 90.5 %
39
Everything will be all right in the
end. So if it is not all right, then
it is not yet the end.
40
Desperate but Reasonable?
41
Plasma Therapies in SepsisWhy Use Them?
 General: exchange “transfer factors”
 Specific: control thrombotic microangiopathy
(TMA)
 Slow progression of TMA-induced organ
failure
 Treat coagulation abnormalities
42
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