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Epuration extra-rénale en cas d’insuffisance rénale aiguë en réanimation
QUAND et COMMENT ?
Stéphane Gaudry
M.D., Ph.D. Médecine Intensive et Réanimation
Hôpital Avicenne, Bobigny UMRS 1155
Groupe de Recherche en Réanimation Rénale et Métabolique (G3RM)
Conflict of interest
No conflict of interest regarding RRT
AKIKI study funded by a grant from French Ministry of Health
Educational grants from Xenios France (ECCO2R machines)
KDIGO 2012 Classification de l’IRA
STADE Créatinine Diurèse
1 > 1,5 Créat de base
ou > 26,5 micromol/l
< 0,5 ml/kg/h en 6 h
2 2 Créat de base < 0,5 ml/kg/h en 12 h
3
> 3 Créat de base ou
> 354 micromol/l
< 0,3ml/kg/h en 12 h Ou
Anurie > 12h
57% d’IRA en réanimation
OR Mortality
Invention of the artificial kidney
• The father of artificial organs
– Hemodialysis, first life saving (1945) – Membrane oxygenators (1948) – Artificial heart (with Jarvik) (1957)
• He immigrated to USA (1950)
• Albert Lasker award (2002)
• He was recognized Righteous Among the Nations by Yad Vashem Jerusalem center (2012) for hiding jews during WW2 Willem Johan "Pim" Kolff
February 14, 1911, Leiden February 11, 2009
Kolff WJ First clinical experience with artificial kidney
Ann Intern Med 62: 608-619; 1965
Jean Hamburger 1909-1992
• Néphrologue • Inventeur de la réanimation moderne • Hôpital Necker • 1952: première transplantation rénale
Président de l’académie des sciences • Membre de l’académie française
• WHEN ?: RRT Initiation strategies • HOW ?
– Catheters – Continuous/Intermittent – Dose – Anticoagulation
• WHEN ?: RRT Initiation strategies • HOW ?
– Catheters – Continuous/Intermittent – Dose – Anticoagulation
Early RRT initiation • Pros:
– Fluid balance control – Improve acid-base status – Corrects electrolytes abnormalities – Removal of toxins or cytokines in sepsis ??
• Cons: – Potential harm (catheter, hypotension, metabolic) – Costs
Early RRT initiation • Pros:
– Fluid balance control – Improve acid-base status – Corrects electrolytes abnormalities – Removal of toxins or cytokines in sepsis ??
• Cons: – Potential harm (catheter, hypotension, metabolic) – Costs
10kDA 30kDa 60kDa
Bradykinin 1 KDa
C3a/C5a 11 kDa
IL 8 8 kDa
RANTES 8kDa
Autacoids <1 kDa
Endothelin I <1kDa
LPS 100 kDa
TNF-α polymer 54 kDa
Albumine 69 kDa
LPS fragments 1-20kDa
TNF-α 17 kDa
IL-1 17kDa
IL-1ra 24 kDa
IL-6 22kDa
IL 10 18kDa
1
0.5
FIL
TR
AT
ION
RA
TE
Rimmelé et Kellum, Critical Care 2011, 15:205
cut-offs standard membranes
high-cutoff membranes
Days
Pro
po
rtio
n o
f p
atie
nts
fre
e o
f o
rgan
fai
lure
RRT
No RRT
HEMOFILTRATION
P<0.01
Absolute indications to start RRT Life-threatening complications
• Refractory severe hyperkalemia
• Refractory severe metabolic acidosis (pH<7.15)
• Pulmonary edema resistant to diuretics
What is the question ?
In critically ill patients with severe AKI who have no life-threatening complication, should we delay RRT ?
Facteurs qui font débuter l’EER chez les réanimateurs européens
Urée/Créatinine
Diurèse
ICM 2013
Observational studies
Randomized controlled trials
Available data on the timing
Co
ho
rt s
tud
ies
RC
Ts
1961
1963
1963
1966
1965
1970
1971
1972
N=270
N=2118
Early RRT Delayed RRT
Patients with AKI
No RRT
Patients managed with RRT
Early RRT initiation
Late RRT initiation
Paul M. Palevsky Crit Care Med 2008
Patients with AKI
No RRT
Patients managed with RRT
Early RRT initiation
Late RRT initiation
Paul M. Palevsky Crit Care Med 2008
Observational studies
Patients with AKI
Early RRT strategy Late RRT strategy
Receive RRT Receive RRT No RRT
study design to adequately answer clinical question of timing of RRT in AKI
Paul M. Palevsky Crit Care Med 2008
AKIKI IDEAL-ICU STARRT-AKI
3 large multicenter RCTs have been launched
Recruitment in progress
2016 2018
AKIKI IDEAL-ICU STARRT-AKI
3 large multicenter RCTs have been launched
Recruitment in progress
2016 2018
Opposite hypotheses
July 2016
Inclusion Criteria
• Adults
• Invasive MV and/or catecholamine infusion
• AKI Stage 3 of KDIGO classification – Serum creatinine 3.0 times baseline or > 354 µmol/l (4.0 mg/dl) – or Urine output <0.3 ml/kg/h for 24 hours – or Anuric for >12 hours
Study Interventions
Early Strategy Group Delayed Strategy Group
RRT as soon as possible RRT only if pre-specified criteria present Within 6 hours after
inclusion criteria
Delayed Strategy Group
Pre-specified criteria
• Severe hyperkalemia potassium > 6 mmol/l, or > 5.5 mmol/l Despite medical treatment
• Severe acidosis (pH <7.15)
• Acute pulmonary edema due to fluid overload Responsible for severe hypoxemia
• Oliguria/Anuria >72 hours
• Serum urea concentration > 40mmol/l Gaudry et al NEJM 2016
5528 Had AKI and received vasoactive
agent and/or invasive MV
3430 Had AKI stage 3
of KDIGO classification
620 Underwent randomization
Early RRT Strategy
n=312
Delayed RRT Strategy
n=308
619 Were included in the analysis
1 patient refused the use of data
Life threatening conditions
Table 1. Baseline Patient Characteristics
Characteristic Early RRT strategy (N=311)
Delayed RRT strategy (N=308)
Age – yr 64.8±14.2 67.4±13.4
SAPS III 72.6±14.4 73.7±14.2
Nephrotoxic agent in past 2 days – no. (%)
Intravenous contrast
Aminoglycoside
Vancomycin
194 (63)
66
106
26
195 (65)
71
106
29
Physiological support – no. (%)
Invasive MV
Vasopressor support
266 (86)
265 (85)
267 (87)
263 (86)
Sepsis status – no. (%)
Sepsis
Severe sepsis
Septic shock
25 (8)
16 (5)
209 (67)
21 (7)
19 (6)
204 (66)
Biological characteristics
Serum creatinine – micromoles/L
Serum urea– mmol/L
Serum potassium – mmol/L
Serum bicarbonate – mmol/L
287±124
19±9
4.4±0.7
18.7±5.1
283±117
19±9
4.4±0.7
18.8±5.5
0 7 14 21 28 35 42 49 56 60
0
0.2
0.4
0.6
0.8
1
Days
Pro
port
ion
of s
urvi
vors
Early RRT strategy
Delayed RRT strategy
A
p−value: 0.79
311 241 207 194 179 172 167 161 158 157
308 239 204 191 178 165 161 156 156 155
0 1 2 3 4 5 6 7 8 12 16 20 24 28
0
0.2
0.4
0.6
0.8
1
Days
Pro
port
ion
of p
atie
nts
free
of R
RT
311 7 4 4 4 4 3 3 3 1 1 0 0 0
308 268 229 192 153 135 118 105 92 61 39 28 21 13
Early RRT strategy
Delayed RRT strategy
B
p−value: <0.001
Patients free of RRT
Gaudry et al NEJM 2016
0 7 14 21 28 35 42 49 56 60
0
0.2
0.4
0.6
0.8
1
Days
Pro
port
ion
of s
urvi
vors
Early RRT strategy
Delayed RRT strategy
A
p−value: 0.79
311 241 207 194 179 172 167 161 158 157
308 239 204 191 178 165 161 156 156 155
0 1 2 3 4 5 6 7 8 12 16 20 24 28
0
0.2
0.4
0.6
0.8
1
Days
Pro
port
ion
of p
atie
nts
free
of R
RT
311 7 4 4 4 4 3 3 3 1 1 0 0 0
308 268 229 192 153 135 118 105 92 61 39 28 21 13
Early RRT strategy
Delayed RRT strategy
B
p−value: <0.001
Survival
Gaudry et al NEJM 2016
Time to renal function recovery ?
Gaudry et al NEJM 2016
0 7 14 21 28
0
0.2
0.4
0.6
0.8
1
Days
Pro
babi
lity
of a
dequ
ate
diur
esis
with
no
need
for r
enal
repl
acem
ent t
hera
py
Early RRT strategy
Delayed RRT strategyp−value: <0.001
311 99 42 27 10
308 68 29 14 7
Adequate urine output with no need for RRT
Gaudry et al NEJM 2016
0 7 14 21 28
0
0.2
0.4
0.6
0.8
1
Days
Pro
babi
lity
of s
pont
aneo
us c
reat
inin
e de
crea
se
No. at Risk
311
308
136
105
60
51
32
26
14
16
Early RRT strategy
Delayed RRT strategyp−value: 0.01
Spontaneous creatinine decrease
Gaudry et al NEJM 2016
How explain delayed renal function recovery
in the early strategy ?
During recovery from AKI, the kidneys are more susceptible to further injury
Early RRT ?
During recovery from AKI, the kidneys are more susceptible to further injury
Early RRT
Delayed RRT
Urine output D1-D2
Urine output D1-D2
URINE OUTPUT First 2 (D1-D2)
Multivariate analysis Urine output D1-D2 is independently associated
with renal function recovery
1881 ml
994 ml
p<0.0001
Early RRT
Delayed RRT
UF
D1-D2
UF D1-D2
ULTRAFILTRATION First 2 days (D1-D2)
208 ml
795 ml
p<0.0001
Early RRT
Delayed RRT
Urine output D1-D2
UF D1-D2
Urine output D1-D2
UF D1-D2
ns
Risk of early RRT ?
Emergence of a new concept
Artificial Kidney-Induced Kidney Injury (AKIKI) and
Permissive hyper-uremia
Fluid balance
ARDS: n=207
Early RRT (N=104) Delayed RRT (N=103)
ARDS: n=207
SURVIVAL
Log-rank p-value: 0.43 Time to successful extubation
Risk of delayed RRT ?
Maybe if RRT is delayed in the context of pulmonary edema due to fluid
overload ?………
Funded by Fresenius
Single-center N=231
ELAIN
Funded by Fresenius
Surgery (cardiac surgery++)
ELAIN
Early RRT: KDIGO 2 Delayed RRT: KDIGO 3
Funded by Fresenius
difference in the timing of initiation of RRT < 24 hours
Only 9% in the “delayed RRT” group did not receive
RRT
Early RRT: KDIGO 2 Delayed RRT: KDIGO 3
Funded by Fresenius
ns ns p 0.03
Fragility index: 3
Funded by Fresenius ELAIN
Early Delayed p
Duration of RRT (d) 9 25 .04
Hospital stay (d) 51 82 <.001
Funded by Fresenius
N. LAMEIRE Professor of Medicine University Hospital of
Ghent
“ELAIN investigated the effect of delaying dialysis in patients
who really needed it: severe pulmonary edema is universally
recognized as an absolute indication for emergent RRT.
The fact that over 90% of patients in the delayed group eventually received
dialysis underscores this. It is thus not surprising that ELAIN concluded that
early start improved patient outcome”
About ELAIN
Am J Respir Crit Care Med. 2018 Feb 2 [Epub ahead of print]
AKIKI IDEAL-ICU STARRT-AKI
3 large multicenter RCTs have been launched
Recruitment in progress
2016 2018
11 OCT 2018
IDEAL-ICU
Patients • Early-stage septic shock • Severe AKI (Failure stage of RIFLE) • Without life-threatening complication
EARLY: within 12 hours DELAYED: > 48hours
IDEAL-ICU
11 OCT 2018
488 patients
In the delayed-strategy group, 38% (93 patients)
did not receive RRT
IDEAL-ICU
Accumulation of evidence from large RCTs
AKIKI IDEAL-ICU STARRT-AKI
Recruitment in progress 0 7 14 21 28 35 42 49 56 60
0
0.2
0.4
0.6
0.8
1
Days
Pro
port
ion
of s
urvi
vors
Early RRT strategy
Delayed RRT strategy
A
p−value: 0.79
311 241 207 194 179 172 167 161 158 157
308 239 204 191 178 165 161 156 156 155
0 1 2 3 4 5 6 7 8 12 16 20 24 28
0
0.2
0.4
0.6
0.8
1
Days
Pro
port
ion
of p
atie
nts
free
of R
RT
311 7 4 4 4 4 3 3 3 1 1 0 0 0
308 268 229 192 153 135 118 105 92 61 39 28 21 13
Early RRT strategy
Delayed RRT strategy
B
p−value: <0.001
Almost 1100 patients Planned enrollement
2866 patients
Acute kidney injury (AKI) in ICU (context of multiple organ failure)
Severity of AKI > KDIGO 2 stage
Potential severe complication
YES NO
Acute kidney injury (AKI) in ICU (context of multiple organ failure)
Severity of AKI > KDIGO 2 stage
Potential severe complication
AKIKI IDEAL-ICU
YES NO
No RRT indication
Acute kidney injury (AKI) in ICU (context of multiple organ failure)
Severity of AKI > KDIGO 2 stage
Potential severe complication
Hyperkalemia
Severe metabolic acidosis (pH<7.20)
Sodium Bicarbonate No RRT indication if
efficient
Urgent indication for RRT initiation
Refractory severe metabolic acidosis
Severe pulmonary edema
(fluid overload)
Diuretic therapy No RRT indication if
efficient
Refractory severe pulmonary edema
AKIKI IDEAL-ICU
ELAIN
BICAR-ICU
YES NO
No RRT indication
Medical treatment No RRT indication if
efficient
STARRT-AKI
Life-threatening Hyperkalemia
Acute kidney injury (AKI) in ICU (context of multiple organ failure)
Severity of AKI > KDIGO 2 stage
Potential severe complication
Hyperkalemia
Severe metabolic acidosis (pH<7.20)
Sodium Bicarbonate No RRT indication if
efficient
Urgent indication for RRT initiation
Refractory severe metabolic acidosis
Severe pulmonary edema
(fluid overload)
Diuretic therapy No RRT indication if
efficient
Refractory severe pulmonary edema
Hyper-uremia
No RRT indication based on level of BUN
AKIKI IDEAL-ICU
ELAIN
BICAR-ICU
Neurological symptoms suggesting uremic encephalopathy
YES NO
No RRT indication
Medical treatment No RRT indication if
efficient
STARRT-AKI
Life-threatening Hyperkalemia
• WHEN ?: RRT Initiation strategies • HOW ?
– Catheters – Continuous/Intermittent – Dose – Anticoagulation
• WHEN ?: RRT Initiation strategies • HOW ?
– Catheters – Continuous/Intermittent – Dose – Anticoagulation
Vascular access
Subclavian Site
Jugular Site
Femoral Site
Vascular access
• Nosocomial events ?
• Catheter dysfunction ?
Nosocomial events
Catheter dysfunction
Catheter dysfunction
2011
Femoral = Right jugular • Nosocomial events • Catheter dysfunction
Except BMI > 28 kg/m2
• WHEN ?: RRT Initiation strategies • HOW ?
– Catheters – Continuous/Intermittent – Dose – Anticoagulation
• Hemodynamic ? • Mortality ? • Renal function recovery ?
Shortgen et al. Am J Respir Crit Care Med 2000
hypotension
Mortality
Mortality
Renal function recovery
Meta-analysis (schneider ag & al, Intensive Care Med 2013)
Long term RRT dependence IRRT < CRRT: RR 1,99 (IC 1,53-2,59)
But CRRT patients were more severe=increase mortality=less RRT dependence
Cox structural marginal model
OR 90j = 1.19 (IC 95%, 0.91-1.55) ; OR 365j = 0.93 ; (IC95%, 0.72-1.2) LIANG k.v. & al, Clin J Am Soc Nephrol CJASN 2016
Composite endpoint (mortality and dependence) :
RR 1,00 (IC95 % 0,77-1,29]) (TRUCHE A.S.& al, Intensive Care Med 2016)
• WHEN ?: RRT Initiation strategies • HOW ?
– Catheters – Continuous/Intermittent – Dose – Anticoagulation
Dose de dialyse
• Clairance plasmatique d’une molécule (urée) par la membrane de dialyse
– Taux de réduction de l’urée
– KT/V
Kt/V
t= RRT duration (simple)
K=clairance de l’urée propre à la membrane (coefficient de filtration) V= volume de distribution de l’urée ?? In ICU ??
• WHEN ?: RRT Initiation strategies • HOW ?
– Catheters – Continuous/Intermittent – Dose – Anticoagulation
Circuit loss Citrate > Heparin Bleeding Citrate > Heparin Mortality Citrate = Heparin
ONLY CRRT
RRT initiation strategies • 2018:
A conservative strategy might be considered as the standard
• Benefits of the conservative strategy Obviated the need for RRT in almost 50% of cases
Mortality did not differ significantly
Renal function recovery was more rapid
RRT modalities • Vascular access: Femoral = Jugular (right)
• CRRT ≈ IRRT (severe hemodynamic instability: CRRT ?)
• Dose • IRRT: 3X4-6h/week (blood flow 200ml/min, Dialysate flow 500 ml/min)
• CRRT: 24/24h (25 ml/kg/h)
Take home message
More information ?