Transcript Thrombocytopenia Associated MOF - Pediatric Continuous Renal

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
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The MODS Patient
Respiratory Failure
Immunologic Failure
Cardiovascular Failure
HIGH MORTALITY
50-90%
Hematologic Failure
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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
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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
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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
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-Martin et al., Crit Care Med 2007
Adult Sepsis-Survival by
ADAMTS-13 Level
ADAMTS-13
above median
Below median
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-Martin et al., Crit Care Med 2007
ADAMTS-13 Deficiency in
Pediatric Sepsis
-Nguyen, Hematologica 2006
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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
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Rationale for Plasma
Exchange: TTP
 80-90% mortality
 Plasma Exchange 
10% mortality:
• Replenishes ADAMTS13
• Removes ADAMTS-13
inhibitors
• Removes
thrombogenic ULvWf
multimers
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-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
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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
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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
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- 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)
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-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.
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-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
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-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
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Children’s TAMOF Network
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 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.
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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
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Methods
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 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
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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
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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
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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
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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)
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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
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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
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Alexis- A Success Story
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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
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 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
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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 %
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Everything will be all right in the
end. So if it is not all right, then
it is not yet the end.
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Desperate but Reasonable?
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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