rénale aiguë en réanimation QUAND et COMMENT

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 ?