support of sepsis/mosf: ecmo and plasma exchange€¢fluid-management... · ecmo in neonatal...
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Support of Sepsis/MOSF: ECMO and Plasma Exchange
James D. Fortenberry MD, FCCM, FAAPDirector, Critical Care Medicine and Pediatric ECMO/Advanced
TechnologiesEmory University School of Medicine
Children’s Healthcare of Atlanta at EglestonAtlanta, Georgia, USA
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Overwhelming Sepsis: Desperate Times…
-Claudius, King of DenmarkIn Hamlet Act IV Scene 3W. Shakespeare
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Potential Extracorporeal Devices for Sepsis
CRRTExtracorporeal Membrane Oxygenation (ECMO)• Potential benefits• Experience• Expert recommendations
Plasma Exchange/Plasmapheresis• Use in TAMOF• Development of study network• Early results
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ECMO in Sepsis-Why Use It?
Temporary cardiovascular supportTemporary lung supportTemporary renal supportDilution of cytokines“Platform” for other therapies
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ECMO in Sepsis
Earlier view:• Sepsis a CONTRAINDICATION for use of
ECMO in neonates and children• Concerns:
Cannula might perpetuate bacteremiaForeign membranes might aggravate inflammatory responseSepsis: pre-existing coagulopathy might increase bleeding complications
- Arensman, Extracorporeal Life Support, 1993 (1st ed.)
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ECMO in Neonatal Sepsis: Clinical Experience
Neonates: persistent pulmonary hypertension with Group B streptococcal sepsisECMO used in this setting with good resultsCase series experience: 70-100% survival (McCune, J Ped Surg 1990; Hocker Peds 1992)
ELSO registry review 1995: 1060 with sepsis (74% GBS): survival similar to nonsepticpatients (Meyer, J Thorac Cardiovasc Surg, 1995)
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ECMO in Neonatal Sepsis: Not A Contraindication
“ECMO should not be withheld from neonates solely on the basis of sepsis”
-Meyer, J Thorac Cardiovasc Surg, 1995
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ECMO in Neonatal Sepsis: Does It Improve Outcome?
1997 ECMO center survey107 septic neonates on ECMOGram positive infections (83%): 77% survivalGram negative infections (13%): 60% survival
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ECMO in Neonatal Sepsis: Does It Improve Outcome?
Neonates: ELSO Registry 2428 “sepsis”patients to presentMean run time: 138 hours 75% survivalDifficult to know “how septic” from RegistryPrevious review: higher predicted risk of mortality than observed riskSimilar to overall ECMO survival
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ECMO in Neonatal Sepsis: Clinical Experience
Septic neonates:• Higher incidence of intracranial hemorrhage• Higher incidence of VA support (89%)• Increasing use of VV ECMO could impact
these outcomes
-Meyer, J Thorac Cardiovasc Surg, 1995
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ECMO in Pediatric Sepsis: Clinical Experience
More difficult to assessSepsis not listed as a primary indication for ECMO in ELSO registry for pediatricsCoexisting sepsis in at least 12 % of pediatric ARF ECMO
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ECMO in Pediatric Sepsis: Clinical Experience
1997 ELSO registry pediatric reviewECMO patients (univariate analysis)• With sepsis: 37% survival• Nonseptic 52% survival
But multivariate Sepsis NOT an independent predictor of ECMO survivalDon’t exclude from ECMO for sepsis
-Meyer et al., Ann Thorac Surg 1997
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ECMO in Pediatric Sepsis: Clinical Experience
Increased likelihood of seizures, CNS complications with sepsisSepsis survival decreased with advancing age83% of patients on VA ECMO (? impact of increasing VV use)
-Meyer et al., Ann Thorac Surg 1997
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ECMO in Pediatric Sepsis: Clinical Experience
Our center:• Occasional use for refractory septic shock
alone12 patients with primary or contributing indication (50% survival)
• Sepsis a frequent coexisting diagnosis (40%)
- Pettignano, Fortenberry et al.,Pediatr Crit Care Med 2003
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ECMO in Pediatric Sepsis: Clinical Experience
• 35% of VV respiratory failure (36% of VA) patients on significant pressors prior to cannulation
• Able to wean rapidly off pressors even on VV ECMO
- Pettignano, Fortenberry et al.,Pediatr Crit Care Med 2003;4:291
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ECMO in Pediatric Sepsis: Vasopressors in VV vs. VV ECMO
- Pettignano, Fortenberry et al.,Pediatr Crit Care Med 2003;4:291
0
10
20
30
40
50
60
0 24 48 72 96 120 144 168Hours on ECMO
VV pressorsVV inotropesVA pressorsVA inotropes
Perc
ent
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ELS For Intractable Cardiorespiratory Failure Due to Meningococcal Disease: Good News
ECMO in 12 children with meningococcemia7 for intractable shock within 36 hours (5 ARDS)6/12 required CPR pre-ECMO8/12 survived• 4/7 with shock• 4/5 with ARDS
6 functionally normal
- Goldman et al., Lancet 1997;349:466
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ECMO for Meningococcal Sepsis: Not-So-Good News
11 children (prognostic scores 90% mortality) treated with ECMOOverall survival 55 percent• 5 with ARDS (4/5 VV, time to initiation 946
hours): all survived• 6 with refractory shock and organ failure
(all VA, time to initiation 8.5 hours): only 1/6 survived (survivor cannulated at 74 hours)
- Luyt et al., Acta Pediatr 2004
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Methicillin-Resistant Staphylococcus Aureus (MRSA)
New scourge• Community acquired
vs. hospital acquired• Marked increase• Immunocompetent• Adolescents• Associated with skin,
soft tissue infections• Increased osteo,
empyema, DVT• Profound sepsis
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Methicillin-Resistant Staphylococcus Aureus (MRSA)
Panton Valentine Leukocidin (PVL) gene expression• Risk factor for severity?
Local tissue invasion, DVT, severe systemic infection
• 75% mortality in PVL+ patients presenting in septic shock
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ECMO for MRSA Sepsis: ELSO Experience
Review of ELSO experience 1986-2005123 S. aureus patients45 MRSA20 in 2004-2005 aloneMedian age 2.4 yearsOverall S. aureus survival 43% (vs. 57.3 overall peds)VA ECMO in 53% of patients
-Creech et al., Ped Crit Care Med, 2007
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ELSO Registry: Staph Aureus Runs
Prevalence of Staphylococcal infections
0
5
10
15
20
25
30
19951996
19971998
19992000
20012002
20032004
2005
Nu
mb
er o
f cas
es (
n)
Staph
MRSA
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ELSO Registry Data: S. Aureus Cases Are Increasing
41
146
30
96
11
50
0
20
40
60
80
100
120
140
160
1995-1999 2000-2005
Cas
es (
n)
Total Staph
Staph
MRSA
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MRSA and ECMO: Age and Mortality
0
10
20
30
40
50
60
70
80
< 1 1-4 year 5-9 year 13-18 year
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ELSO Registry Data: S. AureusMortality is Increasing
0
10
20
30
40
50
60
1995-1999 2000-2005
Per
cen
t M
ort
alit
y
Total Staph
Staph
MRSA
*p < .02
*
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ECMO and Sepsis: Questions
Current data difficult to assessWhen is ECMO used for “overwhelming” sepsis with C-R failure vs. respiratory failure alone?Need for more directed data collection (ELSO Registry)
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ACCM Clinical Practice Parameters for Pediatric Septic Shock Support
Recommendations for use of ECMO:• Newborns: Use for “refractory shock”• Pediatric: “Consider ECMO”• Both Level II = Reasonably justifiable by
scientific evidence and strongly supported by expert critical care opinion
- Carcillo et al., CCM 2002; 30:1365
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ACCM Clinical Practice Parameters for Neonatal Septic Shock Support
… persistent catecholamine-resistant shock
Refractory shock
Use ECMO
- Carcillo et al., CCM 2002; 30:1365
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ACCM Clinical Practice Parameters for Pediatric Septic Shock Support
… persistent catecholamine-resistant shock
Place PA catheter and direct therapies toattain normal MAP-CVP and CI . 3.3 and < 6.0
L/min/m2
Refractory shock
Consider ECMO
- Carcillo et al., CCM 2002; 30:1365
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Benefits of ECMO in Sepsis:”Platform” for Immunomodulatory Therapies”?
• Allows for “easier” delivery of Continuous renal replacement therapies (CRRT)PlasmapheresisPlasma exchange
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Plasma Exchange on ECMO
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Pro-InflammatoryMediators
Anti- InflammatoryMediators (Inhibitors)
Pro/Anti-InflammatoryMediators
Activation Depression
Time
Time
Parallel
Serial
IL1TNF
PAF
IL10
IL6M
edia
tor
Leve
lsM
edia
tor
Leve
ls
Adapted from Ronco et al. Ar t if icial Or gans 27(9) 792-801, 2003
SI RS CARS
SIRS/CARS
Peak Concentration Model of Sepsis
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CRRT/Plasma Exchange
CRRT/Plasma Exchange
Time
Time
SIRS/CARS
SIRS CARS SIRS CARS
Immunohomeostasis
Immunohomeostasis
Pro-inflammatoryMediators
Anti-inflammatoryMediators
IL-1TNF PAF
IL-10
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
Peak Concentration Model of Sepsis
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Plasma Therapies
Plasmapheresis: plasma removed replaced with 5% albuminPlasma exchange: plasma removed replaced with donor plasma• centrifugation• filtration
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Plasmapheresis in Severe Sepsis and Septic Shock
PRCT, Russian adult ICU106 sepsis patients randomized to:• Standard therapy• Addition of
plasmapheresis (1/2 FFP, 1/2 albumin)
Decreased mortality with plasma exchange
- Busund et al., Intensive Care Medicine 2002
53.8
33.3
0
10
20
30
40
50
60
Standard Plasma
*
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Plasma Exchange in Septic Shock
Growing interest in use in children in sepsisTAMOF:particular subsetDeveloped from interest in experience with TAMOF and plasma exchange at Children’s Hospital of Pittsburgh10 institution pediatric multicenter TAMOF study network- plasma exchange in 6 centersIncludes use in ECMO
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Thrombocytopenia-Associated Multiple Organ Failure (TAMOF)
TAMOF• MOF>2 organs• Platelet count < 100K
Variant of TTPPrimarily secondary to sepsisHigh mortality in childrenDeficient ADAMTS-13 (vWf cleaving protease), increased vWf-CP antibodies, increased ulvWfmultimersPotential therapy: plasma exchange
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Thrombotic Microangiopathy: TAMOF
IL- 8TNF-IL- 6+R
ADAMTS13 AbIL-6
X
ADAMTS13(vWF-CP)
Endothelium
Endothelium PAI-1
PAI-1
PAI-1
PAI-1
PAI-1 PAI-1
vWF
vWF
PAI-1
TFPI TFPI
PlasminPlasminogen
PAI-1
X
Platelet
Platelet
Platelet
Platelet
Platelet
Platelet
TF TF
Shear stress
Platelet
Platelet
Platelet
ADAMTS13 AbIL-6
ADAMTS13(vWF-CP)
xIL- 8
TNF-IL- 6+R
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CHP Pilot Data-Pediatric TAMOF
Pediatric 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.
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Children’s TAMOF Network
Active centers:• Children’s of Atlanta at Egleston: coordinating
center• Children’s of Atlanta at Scottish Rite• Children’s of Pittsburgh• Cook Children’s-Fort Worth• Vanderbilt Children’s• Cincinnati Children’s• Columbus Children’s• LSU-Shreveport• Arkansas Children’s• University of Michigan
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Children’s TAMOF Network Preliminary Data
34 TAMOF patients registered to date-21 data completeMedian age 12 yearsMedian OFI: 4Similar PRISM, PELOD at admission
21 TAMOF patients
15 plasma exchange 6 standard therapy
2 survived(33%)
4 died11 lived(73%)
4 died
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TAMOF Network Preliminary Data
PELOD Score
Dying with standard therapy
Surviving with plasma exchange
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Conclusions
Outcome evidence is suggestive of benefit of ECMO for sepsis in neonatesLess convincing results in children/adultsECMO is potential alternative of last resort in sepsis and a platform for adjuncts of CRRT and plasma exchangePlasma exchange in sepsis/TAMOF promising but needs study
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Alexis-A Success Story
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Plasma Therapies in Sepsis-Why Use Them?
General: exchange “transfer factors”Specific: control thrombotic microangiopathy(TMA)Slow progression of TMA-induced organ failureTreat coagulation abnormalities
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CRRT in Sepsis-Why Use It?
• Remove/modulate cytokines, pro- and anti-inflammatory factors
Over 30 studies demonstrate removal by clearance/absorption–Most known mediators are water soluble–500-60,000D “middle molecules”
• Manage septic ARF complications• Manage fluid overload• Multiple case reports, retrospective series:
hemodynamic improvement, resolution of sepsis
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Pediatric Patients Receiving CVVH Factors Associated with Mortality
All Patients
Effect
SE OR 95% CI p
PRISM III 0.107
0.049
1.24
1.02, 1.50 0.03
% FO 0.032
0.018
1.37
0.97, 1.94 0.07
- Foland, Fortenberry et al., CCM 2004
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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
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Good Humours
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Extracorporeal Support in Sepsis
There would seem to be a consensus in the movements of fluids and vapours. Thus the stronger draws and the weaker is evacuated.
- Claudius Galen, ca. 170 AD
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Back to “Bad Humours”
Lots of interest in specific cytokine/factor controlAnimal experiments have not translated into human successRenewed interest in generalized control of immunologic stability-balancing inhibition of excessive inflammation with enhancement of anti-inflammatory and anti-thromboticactivity
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Trends in Immune/Inflammatory Modulation Therapies for Sepsis
Specific: removal/blunting of proinflammatoryfactor
General: restoring immunologic stability reduce both
pro- and anti-inflammatory factors
-Kellum, Bellomo, Crit Care 2000
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Blood
Black BileYellow Bile
Phlegm
The Humours