marseille 23-24 avril 2008
TRANSCRIPT
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“Epuration extra-renale et sepsis…”
5th Journées Réanimation et Urgences Respiratoires
Didier Payen, MD, Ph DDept d’ Anesthésiologie & Réa & SAMU
Hopital Lariboisière- APHP Paris
Université Paris 7 Denis Diderot
Mail: [email protected]
Marseille 23-24 Avril 2008
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Content
• The concept
• The mediator removal in sepsis
• High volume HF
• Experimental studies
• Clinical studies
• Conclusion
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Introduction
• Sepsis or septic shock: “tsunami”changing rapidly with a predominantanti-inflammatory phenotype
• Sepsis cell dysfunctions immunecells – LPS tolerance; immunoparalysis; bio-energetic failure…
• The plasma: source of the celldysfunction– Immune cells oxymetry: an example
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PBMC ex vivo O2 consumption
O2 c
on
su
mp
tio
n r
ate
, n
gato
ms O
2/m
in/1
07 c
ell
sStimulation by ADP
0
4
8
12
16
20
p=0.002
p=0.001
Vo VstimVo Vstim
J Belikova & D Payen
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HCells + Septic plasmaO
2 c
on
su
mp
tio
n r
ate
, n
gato
ms O
2/m
in/1
07 c
ells Stimulation by ADP
Vo VstimVo Vstim0
4
8
12
16
20p<0.0001
p<0.0001
Plasma induces immune cells bioenergy
J Belikova & D Payen
O2 c
on
su
mp
tio
n
rate
, n
gato
ms
O2/m
in/1
07 c
ells
Stimulation by ADP
0
4
8
12
16
20
p=0.002
p=0.001
Vo VstimVo Vstim
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• Septic plasma contains “bad humors”– Types? Bacterial products; Mediators…
• Plasma environment changes cellularfunctions
•QS could be:– Should we purified the plasma?
• When? TIME IS CRUCIAL
• What type of molecules has to be removed?
– what is(are) the good technique(s)?
• HVolume?• High permeability?
• Others: apheresis; cartridges…
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Content
• The concept
• The mediator removal in sepsis
• High volume HF
• Experimental studies
• Clinical studies
• Conclusion
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Removing mediators:
• The goals:
– Elimination >> to the production
– Elimination enough to tissue level
– Elimination has to be selective for “toxic”
but not for “protective: mediators!!!
• Last point is lacking remove all?
– To “reset” the system ”reboot” the cells
• HVHF; plasmapheresis; cartridges…
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• HF removes plasma molecules having adequate
electrical charge and size limitations comefrom mbne characteristics
• The “tip of the iceberg”: a low plasma level maycorrespond to a high tissue level of mediators
• Do we know the tissue production ? fixingthe mediators elimination rate
• Knowing time evolution of mediators release best time to perform HVHF– Along time, phenotype moves from pro to anti-
inflammatory balance
Removing mediators:
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PRODUCERCELLS
TARGETCELLS
EXCESS(Biological
fluids)
REST ACTIVATION OF IMMUNE
SYSTEM
OVER-PRODUCTION
Detection ofcytokines
The “tip of the iceberg” from JM Cavaillon
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Content
• The concept
• The mediator removal in sepsis
• High volume HF
• Experimental studies
• Clinical studies
• Conclusion
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HVHF
• Definition:– Unclear: HV <-> higher V than 1 or 2 L/Hr
– Dose: is defined for RRT (35ml/kg/hr)
• HVHF from 4 l/hr to 11l/hr
• Middle term: 0.15L/kg/hr <->11l/hr for 70 kg– very specific device + trained team
• RCT is warranted
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Content
• The concept
• The mediator removal in sepsis
• High volume HF
• Experimental studies
• Clinical studies
• Conclusion
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The landmark paper:Grootendorst et al ICM 1992
• Pig LPS model
• After 4hrs of sepsis HD unstability +
signs of OF
• application of zero balance HVHF
(6l/hr; 200 ml/kg/hr)
– Better RVFunction
– Better CO and BP
– Outcome effect: uncertain…
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From Mateo et al AJRCCM 1996From Mateo et al AJRCCM 1996
1801501209060300
50
60
70
80
90
100
110
LPS
HAD + LPS
Aortic Blood Flow Velocity (%)
TIME (min)
* *
* * *
*
1801501209060300
50
60
70
80
90
100
110
LPS
HAD + LPS
Mean Arterial Pressure (%)
TIME (min)
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From Mateo et al AJRCCM 1996From Mateo et al AJRCCM 1996
0 30 60 120 180
0
1000
2000
3000
4000
5000
6000
LPS + HAD
LPS
TIME (min)
TNF- levels
*
*
*
*
* p < 0,05
( U.I / ML)
6000
8000
10000
LPSLPS + HAD
(E.U / ML)
0 10 60 120 1800
2000
4000
TIME (min)
* *
3000
1000
EDTX levels
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From Mateo et al AJ R&CCM 1996From Mateo et al AJ R&CCM 1996
0
20
40
60
80
100
120
140
160
180
1
Control
EDTX
EDTX + HAD
10-9 M 10-8 M 10-7 M 10-6 M 10-5 M
%
of
KCl
*
*
*
NE
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Minipigs pancreatogenic sepsismodel Yekebas et al CCM 2001
• After 12 hrs, during 60 hrs; 4 gps
– G1 control
– G2 + G 3 regular CVVH (20ml/kg) ± change the mbne
• The G4 (HV: 100ml/kg)
– higher survival rate (67% vs 33% in Gpe 3)
– best MAP & nl body temp
– The MHC class II +CD14 were preserved in G 4
improved innate immunity.
• The highest dose of HF was the most efficient
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Discussion/conclusion
• Difficult to transpose exp data toclinical field, because:– Delay for HVHF is always shorter than in
clinic
– The dose used is always > than used inhuman studies
• But, filtrated fluid from septic animals ex vivo induces sickness
• Direct proof for a benefit to remove“toxic compounds” is controversial for
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Content
• The concept
• The mediator removal in sepsis
• High volume HF
• Experimental studies
• Clinical studies
• Conclusion
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Literature…
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Literature…
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Clinical studies
• Review only data with zero fluid balance
• Most of the studies are uncontrolled studies
with small number of patients
• Heterogeneous trial for:
– Patients enrolled
– Technique used (mbne; surface; sieving coeff…)
– Time for application
D ti
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Hemodynamic OutcomeTimingInclusion
Criteria
Pats
no
Study
Ttmt
End-
points
Type of
Study
Author &
Publication
Higher dose increased (p<0.001)
PaO2/FiO2 ratio
12 hrHyperHD
sepsis with
ARF and ALI
80
1) 40
2) 40
1)20
ml/kg/hr
2)45
ml/kg/hr,
for 6 hrs)
PaO2/FiO2
ratio 48 h
after
Retrospecti
ve studyPiccinni P et alIntensive CareMed 2006
Reduced post op alveolar-
arterial oxygen gradient at 3 hrs
During re-
warming
CPB20 children5 mL/m2Resp &
mediator
response
R,B,CStudyJournois D. et al.Anesthesiology.1996
Responders.11/20
Hemodynamic improvement; 28-d
mortality: 82%; no difference at 60 and
90 d.
1)4 hrs
2)4 days
Early “fresh”
S shock +;
BUN < 15
mmol/L
20 Pts
circulatory
failure
1) 35 L
effluent; 0
FB.
2) CVVH
for 4 D.
HD & metab
& outcome
28 D
Prospective
interventionrefractory S
shock
Honoré P et alCCM 2000
Hemodynamic response (reduced
norepinephrine dose), but no difference
in mortality
Late (mean 71
hrs) after onset of
septic shock
Septic shock11 patients S
shock &
MOF.
1)6 L
2)2 L/hr
(iso Vol)
HD,
cytokines +
complement
Randomized,
crossoverCole L et alCCM 2001
Mortality 46% vs a predicted 70%;
p> 0.05 for SAP, CI, SVRI (from 36 to
96 hrs)
From 6 hrs to 4
days after onset of
sepsis
Post-abdo surg
Sepsis + 2 OF
2440 to 60
ml/kg/hr
28D
mortality +
HD
Prospective
Case seriesJoannes-Boyau Oet alASAIO J 2004
11/20 patients NE & lactate
(responders).
9 patients non responders.
ImmediateHyperHD
KTchol-
resistant S
shock
20Pulse
HVHF at
100
ml/kg/h for
12 hrs
Reversal
hypoTA &
hypoperf
severe S
shock
Goal
Directed
Earlier Use
of Pulse
HVHF
Cornejo L et alIntensive CareMed, 2006.
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A positive fluid balance is associated with a worseoutcome in patients with acute renal failure
Didier Payen MD, Ph DDept of Anesthesiology and Intensive Care, CHU Lariboisiere, Paris, France
Anne-Cornélie de Pont MD PhDAdult Intensive Care Unit, Academic Medical Center, University of Amsterdam, The
Netherlands
Yasser Sakr MB BChDept of Anesthesiology and Intensive Care, Friedrich-Schiller-University Jena, Germany
Claudia Spies MDDepartment of Anaesthesiology and Intensive Care, Charite-Universitatsmedizin Berlin,
Germany
Konrad Reinhart MD PhDDept of Anesthesiology and Intensive Care, Friedrich-Schiller-University Jena, Germany
Jean-Louis Vincent MD PhD FCCMDepartment of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium
on behalf of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Investigators
2nd submission to Crit Care 2008
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? Late ARF
? Early ARF
? No ARF
*†
*†
*†*
*
*
*†* *
**
*
†
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Outcome among patients with acute renal failure,stratified by time of initiation of renal
replacement therapy (RRT).
0.10527.0 (17.0
- 45.0)
25.0 (8.0 -
46.0)
Hospital stay
<0.00744 (67.7)102 (48.6)Hospital
mortality
< 0.00112.2 (8.0
– 26.5)
6.1 (2.5 -
14.8)
ICU stay
0.00240 (61.5)84 (39.4)ICU mortality
p valueLateRRT
n=65
Early RRTn=213
Characteristic
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Impact of continuous venovenous hemofiltration onorgan failure during the early phase of severe
sepsis. A Randomized Controlled Trial.Didier Payen, MD, PhD Joaquim Mateo,MD
Jean Marc Cavaillon, PhDFrançois Fraisse, MDChristian Floriot,MD Eric Vicaut, MD, PhD
for the Hemofiltration & Sepsis Group of the Collège National de Réanimation et de Médecine d’Urgence des Hôpitaux extra-Universitaires*.
4th submission to CCM
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Trial design (4th Submission to CCM)
• comparison conventional therapy vs conventionaltherapy + CVVH
Inclusion within 24 hours after meeting theinclusion criteria
• Conventional treatment: treatment decided by the
physician in charge
• HF treatment: conventional treatment + CVVH started
within 24 hrs for at least 96 hrs
• Primary end point: the reduction of numberand duration of sepsis-induced organ failure atday 14
• Secondary end point: mortality at day 14; withdrawal
of catecholamines infusion and length of mechanical
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Primary end point
Figure 1: evolution of SOFA score in the 2 groups:
SOFA was compared to Day 0. A positive value indicates a maintenance
or a deterioration
Log Rank test: Chi2: 8.73; p<0.003HF group
CT group
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Time, days
Fre
edom
ofev
ent
HF groupCT group
Figure 2 Time to multiple organ worsening SOFA(worsening corresponded to at least one point of SOFA score).
Log Rank test: Chi2 : 8.73; p<0.003
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Short Term HVHF
* 35 liters in 4 hours* Neutral balance
* Polysulfone membranes (1.6 m2)
* Post-dilution technique
* Bicarbonate as buffer (40 mMoles/l)
LVHF
* 1 L/hr (24 liters per day)* Polyacrylonitrile membranes (1 m2)
* Pre-dilution technique
* Bicarbonate as buffer (40 mMoles/l)
« The St Pierre Hemodynamical Study »
Honoré PM et al. Crit Care Med 2000;29:3581-87
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« The St Pierre Hemodynamical Study »
Hemodynamic
11 responders to the 4 therapeutic goals.
* after 2 hours : - > 50 % increase CI - > 25 % in SVO2
* after 4 hours: - pHa > 7.3 - 50 % I+ & pressors
Outcomeamong the 11 responders, 9 survived…From Honore et al, CCM 2000
• But, it is an uncontrolled study
• It concerned a limited number
of patients
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TheThe «« Amsterdam IIAmsterdam II »» StudyStudy..
Bouman C et al. CCM 2002;30:2205-2211
Randomized controlled « Two Centers » Study
106 ventilated, oliguric, inotropes
Inclusion
Group I Group II Group III
Early HVHF Early LVHF Late LVHF
(72-96 l/24Hr) (24-36 l/24Hr (24-36 l/24Hr
(~ 7 hrs)(45 ml) (~ 7 hrs)(20 ml) (~ 42 hrs)(20 ml)
Survival at 28 days
74.3 % 68.8 % 75 %
Discussion:- But what about septic population ?- Great proportion of « cardio-surgical ptns ».- « to high » Survival rate to detect a signal?
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24 Septic Shock > 2 Organ Failures
Post-op abdominal surgery
60 ml/kg/hr for 96 hrs of HVHF
Predicted mortality at 28 days: 70 %
Observed mortality at 28 days 46% (P<0,075)
RCT is still warranted !!!
The « Bordeaux study » (Sepsis & MOF):
The design
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APACHE II Similar Similar P > 0.05
NE Dose 0.20 ± 2 0.02 ± 0.2 P < 0.05
cgr/kg/min cgr/kg/min
Ventilator weaning 37 % 70 % P < 0.01
28 days survival 27.5 % 55 % P < 0.05
Lenght of stay 16 ± 4 days 9 ± 5 days P < 0.002
Piccinni P et al. Intensive Care Med;2006:32:80-96.
114 CRF
Creat > 2 mg/dl
40 H controls 40 EIHF Treated
± 20 ml/kg/h
C Haemofilt
45 ml/kg/h
CVVH
Retrospective Study
80 pts SShock
with oliguria
Controls ELVHF
Duration
= 6 H
« TheThe « « VicenzaVicenza - Piccinni - Piccinni StudyStudy » »
It is a retrospective Study!
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Little as changed from this 2002 Pro/Con viewpoint, but it will do….
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Content
• The concept
• The mediator removal in sepsis
• High volume HF
• Experimental studies
• Clinical studies
• Other EC techniques
• Conclusion
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C.Tetta et al. Continuous plasma filtration coupled with sorbents.
Critical Care Nephrology 1998; 66(sup): S186-S189
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6 Academic centers; 36 pts
Severe sepsis or SShock from
abdominal infection; PMX ttmt 2 hrs;
RESULTS:
-No diff in LPS level; in IL-6; SOFA
-Significant increase in LVSWI and
DO2
-Significant reduction in CRRT need
in PMX treated group
RCTrial to prove the benefit of the technique; what type of patients?
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The Japanese clinical experience
2 trials
first multicenter clinical study:,
• blood LPS detected in 37 out of 42 pts
• endotoxin level reduced significantly
(83± 26 pg/mL to 56 ± 27 pg/mL after 2 h
hemoperfusion.
• 20 patients survived more than 14 days
17 patients died.
Retrospective study;
• 37 patients treated with Toraymyxin
compared with 33 pts treated with
conventional therapy.
• severity scores and OF > in PMX group
•RESULTS: survival rate after 14 days > significantly
higher in theToraymyxin group than in the
control group
2nd multicenter clinical study,
88 patients; positive effect on HD
A major role of LPS in sepsis induced OFand poor outcome
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Foot print at day 0 of sepsis for ARF
occurrence
transcription factor 7-like 2 (T-cell specific, HMG-
box)TCF7L2
DEAD (Asp-Glu-Ala-Asp) box polypeptide 58DDX58
cathepsin LCTSL
churchill domain containing 1CHURC1
SLAM family member 8SLAMF8
elastase 2, neutrophilELA2
azurocidin 1 (cationic antimicrobial protein 37)AZU1
myeloperoxidaseMPO
carcinoembryonic antigen-related cell adhesion
molecule 6CEACAM6
cathepsin GCTSG
10 genes were potential predictor for 82.3 %
Using the “Leave One Out” technique
SOFA = 0 SOFA = 2 SOFA = 3-4SOFA 3-4 vs SOFA 0
P<0,01
FC>3
24 probesets
Hyper-expression
Under-expression
Genes of interest arerelated to the ROS
metabolism
-Both for synthesis and
detoxification
-And for maintenance of cell
structure
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Conclusion
• The good technique for the good goal!
• How to define the good goal?– What molecules to target?
– The cell function; the organ function
– Should the plasma be “normalized” ?
• What would be the consequences of ahuge fluid replacement by an artificialfluid on long term follow up
• What are the consequences of ECC oni fl mm ti ?
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Conclusion
• Is HVHF preferable to apheresis or
specific cartridges?
• Should we remove LPS? Cytokines?
Others? All?
• When? Early use or later?
• Different RCTrials have to be
performed on AKI:
– in a context with systemic inflammation
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ARF Epidemiology SOAP
Study Results
• ICU Mortality rate in Renal failure: 30.2% vs
12.1%; p<0.05
• Higher (33.2) in late than in early (29.2) RF
– Older pts 62.8 vs 59.3; p<0.05
– Higher rate of heart failure: 12% vs 8.6; p<0.05
– Lower BP: 68.9 vs 72.4; p<0.05
– Higher incidence of Severe Sepsis: 42.5 vs 22.4%;
p< 0.05, or septic shock 22.8 vs 10.2%; p<0.052nd Submitted to CCM
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Mean fluid balance and outcome among
survivors and non-survivors with acute renal
failure (ARF), stratified by time of onset
<0.010.71 (-0.13 - 1.34)0.13 (-0.52 - 0.62)Late ARF
<0.011.11 (0.40 - 2.21)0.18 (-0.41 - 0.73)Early ARF
<0.010.95 (0.31 - 1.97)0.17 (-0.44 - 0.70)ARF
p valueN-SurvSurvivors fluid balance
L/24 h
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Mean and cumulative fluid balances and outcomeamong patients with acute renal failure (ARF),
stratified by urine output and treatment.
<0.0116 (6.8-34.9)
10.8 (3.8-
24.1)<0.0110.3 (2.3-22.2)12.7 (5.5-21.0)Hospital stay
<0.018.4 (3.0-19.4)2.9 (1.6-6.9)<0.013 (1.4-8.6)4.5 (2.0-11.1)ICU stay
<0.01146 (52.2)267 (32.2)0.01223 (40.7)190 (33.2)Hosp mortality
<0.01124 (44.6)214 (25.4)0.04181 (33.0)157 (27.4)ICU mortality
<0.0013.90 (-1.91-
11.82)
0.27 (-1.58 -
2.00)0.021.75 (-0.21 -
6.00)
1.13 (-2.18 -
5.58)
Cumulative fluid
balance, L
0.0060.58 (-0.27 -
1.29)
0.27 (-0.28 -
0.97)<0.0010.5 1(-0.06 -
1.19)
0.28 (-0.43 -
0.92)
fluid balance
L/24h
p valueRRT
n=278
No RRT
n=842
p valueOliguricn=548
Non-oliguricn=572
Characteristic
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Baseline characteristics of patients with acuterenal failure (ARF), stratified by time of initiation
of renal replacement therapy (RRT).
<0.0016.34 (2.36 - 13.03)1.15 (-0.08 - 4.03)Cumulative fluid
balance, L
0.0583.29 (2.10 - 5.00)3.99 (2.57 - 6.17)Creatinine, mg/dL
<0.0010.47 (0.09 – 1.74)0.18 (0.03 – 0.50)Urine output, L
0.01327 (41.5)126 (59.2) surgical
0.01238 (58.5)87 (40.8) medical
Type of admission
0.00461 (93.8)166 (77.9)Mechanical
ventilation
0.0418.2 ± 3.59.2 ± 4.1SOFA score
0.03545.3 ± 18.049.7 ± 17.5SAPS II
0.17944 (68.8)126 (59.4)Male gender
0.30364.6 ± 15.062.3 ± 15.5Age
p valueLate RRTn=65
Early RRTn=213
Characteristic
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• Removal by convection:
– Molecular size has to fit with mbne
permeability
– Transmbne forces
– HPerm Mbne were used + Adsorption
– Blood flow and Mbne S have to be
sufficient to maintain good convection
• There are still a lot of unclear
aspects hazardous therapy…
Removing mediators:
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0
1
2
3
4
5
6
0 30 60 90 120 150 180 210 240
Time (min)
CI
(l/m
in/m
_)
7
7,05
7,1
7,15
7,2
7,25
7,3
7,35
7,4 pH
Evolution of pHa and the CI during HVHF
CI responders
CI non-responders
pH responders
pH non-responders
« The St Pierre Hemodynamical Study »
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HV-CRRT in HV-CRRT in SepticSeptic AKI AKI The « IVOIRE Study »
« IVOIRE study »
hIgh VOlume in Intensive caRE
Prospective randomized multinational single blind
study evaluating the adequate dose of CHVHF in
the early treatment of Septic Shock patients with
Acute Kidney Injury.
defined the adequate « Septic Dose » of
CRRT during Septic induced Acute Kidney Injury in ICU.
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480 patients with Septic Shock and Acute Renal Injury
Randomization
within 24 hours
after SShock onset
96 hours at 96 hours at
35 ml/kg/hr 70 ml/kg/hr
Mortality rate at 28 days
60 days
vasopressors(Noradrenaline)
or Dopamine >
5 g/kg/min
- creatinine x 2
basal value
- Oliguria<0.5 ml/kg/h
(13) Joannes-Boyau O, Honoré PM et al,
Submitted Crit Care 2007
RIFLE « injury
Level »
The « IVOIRE Study »: The design
it is a controlled study,
for efficacy…
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HEMOFILTRATION :In vivo experimental studies on
myocardial depression
HEMOFILTRATION :In vivo experimental studies on
myocardial depression
• Gomez et al, Anesthesiology, 1990
– dog model, alive E coli ; in vitro study
– Hfc with cuprophane membrane
–HFC reverses myocardialdepression
– septic sera depress ex vivo rat myocardial
contraction, an effect prevented by HFC
removing cardio-depressive