Advances in
Continuous Renal
Replacement Therapy
CSM 2011
Dr Anne Leung
17th May 2011
Overview
Timing of
initiation
Membrane
Fluid and
anticoagulation
To begin the “Dosing” story of CRRT….
20mL/Kg/hr 35mL/Kg/hr 45mL/Kg/hr
15-days
Survival
41%
57%
58%
Lancet 2000
Higher the dose the better
Piccinni ICM 2006
EIHF vs Conventional
45mL/Kg/hr for 6 hours then 20mL/Kg/hr vs 20mL/Kg/hr
28-day Survival: 55% vs 27.5%
CVVHDF: more may not be better
Tolwani et al JASN 2008
PRCT
Single Center
N=200
Pre-dilution
CVVHDF: 20mL/Kg/Hr
CVVDHF: 35mL/Kg/Hr
Intense
Conventional
Hemodynamic
stable
IHD /SLED
6x/week with
Kt/V of 1.2-1.4
IHD /SLED
3x/week with
Kt/V of 1.2-1.4
Hemodynamic
unstable
CVVHDF
35mL/Kg/Hr
CVVHDF
20mL/Kg/Hr
Intensive RRT = Equal
ATN trial
PRCT
N=1124
60 days mortality
Intensive: 53.6%
Less Intensive: 51.5%
What Dose ?
• Before the ATN trial
• CRRT: 35mL/Kg/Hr
• Daily iHD
• After the ATN trial
• SOFA 0-2: 3x/week iHD (Kt/V 1.2)
• SOFA 3-4: CRRT 20 mL/Kg/hr or SLED 3x/week
• But beware for the need for extra treatment!
Randomized
(Post-dilution CVVH)
1508
Low dose
(25ml/Kg/hr)
761
Lost to follow-up = 0
Consent withdrawn = 2
Consent not obtained = 16
Analyzed
743
High dose
(40ml/Kg/hr)
747
Lost to follow up = 1
Consent withdrawn = 2
Consent not obtained = 23
Analyzed
722
RENAL Study
High
Intensity
Low
Intensity
90-days mortality
44.7%
44.7%
28-days mortality
38.5%
36.5%
Conclusion
• Intensity of RRT DOES matter
• Beyond the threshold dose ( 25ml/kg/hr), increasing
intensity does not provide further clinical benefit
• Be-aware of the difference between prescribed and
delivered dose of RRT
• ATN study: 89% -95%
• RENAL study: 84-88%
• Minimize the interruption of the treatment time
IVOIRE (hIgh Volume in
Intensive Care)—French Study
• Inclusion criteria: Septic shock <24 hrs and RIFLE
criteria of injury or worse
• Intervention: High volume (70ml/kg/hr) vs Standard
(35ml/Kg/hr) for 96 hours
• Patient number: total of 460 patients
• Primary outcome: 28-day mortality
• Study period: 3 years and completed by Oct 2010
INITIATION OF THERAPY
RIFLE Criteria
Level of
injury
Outcome
measures
Currr Opin Crit Care 8: 509-514 (2002)
From RIFLE to AKIN
Serum Creatinine
Stage 1
Increase SCr
≥24.6mmol/L
Stage 2
2-3 folds
Stage 3
The Acute Kidney Injury
Network Classification ( AKIN)
Crti Care 11:R31 (2007)
Biomarkers of AKI
uNGAL
Serum Cystatin C
MEMBRANE OF FILTER
Super High-Flux or High Cut-ff
Membranes
Achieve greater clearance
of inflammatory cytokines
- Superior elimination of IL-6
- Decrease need of Noradrenaline over time
P. 20
SepteX—High Cut Off Membrane
Pilot Randomized Controlled Study Comparing the Effect
of High Cut-off Point Hemofiltration with Standard
Hemofiltration in Patient with Acute Renal Failure
• Study Population:
• Critically ill patient with AKI and shock that require Nor-adrenaline
• Intervention:
• Standard polyamide high flux membrane vs High cut-off polyamide
membrane (P2SH)
• CVVH: Qb: 200ml/min, UF of 25ml/Kg/hr
• Size of the study:
• 72 patients
• Primary measures
• NA-free time in first week after randomization
• Status:
• start in Jun 2009 and still recruiting
Early Use of Polymyxin B Hemoperfusion in Abdominal
Septic Shock--The EUPHAS Randomized controlled Trial JAMA 2009
P. 22
Early Use of Polymyxin B Hemoperfusion in
Abdominal sepsis
Decrease vasopressor requirement
Better BP and low SOFA score
Polymyxin B immobilized fiber
Direct Hemo-Perfusion
Mortality of 32 % vs 53%
FLUID & ANTICOAGULANT
Continuous renal replacement therapy:
B.E.S.T. Kidney (The Beginning and Ending Supportive Therapy for the kidney).
a worldwide practice survey. 23 Countries, 54 ICUs, 1006 patients with ARF on CRRT
Nafamostat
LMWH
6%
4%
Citrate
10%
Others
4%
UFH
43%
No anticoagulant
33%
Intensive Care Med. 2007;33(9):1563-70
Less clotting in Hollow Fibers
membrane Kid Int 1999
Commercial preparation of citrate
solution—Morgera S. et al .CCM 2009
Gp 1
(60Kg)
Gp 2 (6090Kg)
Gp 3
(>90Kg)
Patient No
19
97
45
Blood flow
(mL/min)
80
100
120
Dialysate
flow (mL/hr)
1500
2000
2500
Citrate
flow( mL/hr)
140
170
205
A safe citrate anticoagulation protocol with variable
treatment efficacy and excellent control of the acidbase status—CCM 2009
• Result
• Median filter time of 61.5
hrs
• 5% had filter clot
• Excellent control of acidbase and electrolyte
Use of citrate CVVH was safer and
reduced mortality Oudemans MH et al CCM
37:545-552 ( 2009)
Hospital mortality 41 vs 57% (p=0.03)
3-month Mortality 45 vs 62% (p=0.02)
Surgical
Sepsis
Higher SOFA
Younger than 73
CCM 37: 545 - 552 ( 2009)
Negative Fluid Balance Predicts Survival in
Patients with Septic Shock--Alsous F. et al Chest 2000
Net negative fluid
balance within first 3
days in ICU
100%
1
2
3
4
20%
5
6
7
The Importance of Fluid Management in Acute
Lung Injury Secondary to Septic Shock— Murphy CB
et al Chest 2009
20ml/Kg with CVP≥8
within 4 hrs after
vasopressors
Neutral or negative fluid for 2
consecutive days during first
7 days
Hospital
mortality of
18.3%
1
2
3
4
5
6
7
The Importance of Fluid Management in Acute
Lung Injury Secondary to Septic Shock— Murphy CB
et al Chest 2009
20ml/Kg with CVP≥8
within 4 hrs after
vasopressors
Neutral or negative fluid for 2
consecutive days during first
7 days
Hospital
mortality
of 77.1%
1
2
3
4
5
6
7
Survivor:
Fluid balance
non-positive by
D4
1
2
3
4
5
6
7
Sepsis in European Intensive Care Units: Results
of the SOFA study— JL Vincent et al 2006;344-353
Cumulative fluid
balance within 72 hrs
after onset of sepsis
was independent
predictor of mortality
10% increase
in mortality
with each 1L
increase in
cumulative
fluid balance
1
2
3
4
5
6
7
Conservative fluid mx
Comparison of Two Fluid-Management
-higher ventilator-free
Strategies in Acute Lung Injury— NEJMand
2006
ICU free days
-Less cardiovascular
failure
-Less on dialysis
Conservative group:
zero balance by D4
1
2
3
4
5
6
7
Fluid Accumulation, survival and recovery of
kidney function in critically ill patients with acute
kidney injury— (PICARD study)Bouchard J et al KI 2009id removal
Fluid overload patient tended to
be sicker patient
No Fluid
overload
Fluid
overload
APACHE III
score
79
90
SOFA score
6.7
8.7
No of organ
failure
2.6
3.2
Resp failure
55%
86%
On ventilator
32%
65%
Sepsis/Septic
shock
22%
39%
For each weight change class, fluid
overload is independent predictor of
mortality
? “Fluid” as the AKI biomarker
If I find 10,000 ways something won't work, I haven't
failed. I am not discouraged, because every wrong attempt
discarded is often a step forward....Thomas Edison
USE OF RCA IN QEH ICU
Citrate dose
Citric
Acid
mmol/L
Sodium
Citrate
mmol/L
Complementary solution
Therapy
BFR
mL/min
Citrate dose
(mmol/L blood)
Country
Apsner
5
10
-
CVVH
100
3.7
Austria
Dorval / Leblanc
5
15
Dia: 0.9% Saline (if needed)
CVVH(DF)
125
3.7
Canada
Niles
-
13.3
-
CVVH
180
2.0
USA
Gabutti
-
13.3
Dialysate same as citrate
CVVH(DF)
125
2.66
Switzerland
Tolwani
-
2%
0.9% Saline
CVVHD
150
2.0
USA
Sramek
-
2.2%
Na=120, Bicar=22
CVVHDF
100
3.6 - 6.3
Czech Republic
Bunchman
ACD-A
Dia: Normocarb
CVVHD(F)
150
2.8
USA
Chadha
ACD-A
Pre: Na=140, Bicar=20
CVVH
50 - 150
1.9 - 4.2
USA
Mitchell / Heemann
ACD-A
Calcium in dialysate
CVVHD
75
5.7 - 8.5
Germany
Gupta
ACD-A
Calcium in dialysate
CVVHDF
150
1.9
USA
Cointault
ACD-A
Calcium in dialysate & pre
CVVHDF
125
3.9
France
Kustogiannis / Gibney
-
3.9%
Dia: Na=110, Bicar=variable
CVVHDF
125
3.6
Canada
Mehta
-
4%
Dia: Na=117, Bicar=0
CVVHD(F)
100
3.7 - 5.9
USA
Hoffmann
-
4%
Pre: 0.9% Saline
CVVH
125
3.1
USA
Monchi
-
1000
Post: Na=120 , Bicar=0
CVVH
150
4.3
France
Evenepoel
-
1035
Calcium in dialysate
IHD
300
4.3
Belgium
Who can do that ?
PYNEH ICU (1995-2003)
AK 10 machine
Non-integrated
approach
Ci-Ca Dialysate solution
Solution for RCA--Gambro
PYNEH ICU ( 2004 …..
RCA CRRT—QEH Regime
RCA CRRT—QEH Regime
RCA CRRT—QEH Regime
CaCl2 infusion
Summary of the regime
• Machine: Prismaflex
• Pre-dilution with Primocitrate 10/2 at rate of 2500mL/hr
• Blood flow at 150ml/min
• Both UF and blood flow rate fixed
• Separate infusion of NaHCO3 ( initial 50ml/hr for 2 hr then
30ml/hr ) and Calcium chloride infusion via CVC at 6 ml/hr
• For fluid removal= desired fluid removal + flowrate of NaHCO3
• Measure Na, K, BE, ABG and ionized calcium Q4-6 hr
• Target ionized calcium 0.9 – 1.3 mmol/L
Implementation
• Theory Session
• For both nurses and doctors
• Practical Session
• By Gambro in early March
• Guideline as the reference
• Case selection
• Avoid those with liver dysfunction, after massive transfusion and severe
metabolic acidosis with pH<7.1
• Start with post-op case with mild to moderate acidosis and fluid
problems
• Start during the daytime
• Gambro technical support stand-by during the initial phase
• Trouble shooting
• Contact Dr Anne Leung
• Mechanism of action
• Exclusion criteria
• Set up of the citrate circuit
• Monitoring during RCA
• Titration of electrolyte and
acid-base
• Citrate toxicity
7th Jul 2010
Demographic data
Reasons for admission for CRRT
How long the circuit last?
Mean duration ( hr)
31.4±14.4
Maximum duration( hr)
62.3
Minimum duration ( hr)
5.2
Circuit
time
Number of
episode
Percentage
24 hrs
23
41%
>24%
33
59%
>48%
9
16%
Reasons for termination CRRT
Last from 22 to 49.5 hrs
30
-5 due to procedures
-3 due to nursing
manpower restrain
27
25
20
15
10
5
0
11
9
Series1
4
3
1
1
Electrolyte disturbance during
Citrate CVVH
Only 2 patients had citrate
accumulation
100%
Only 2 patients with
Total Ca/iCa >2.5 had
citrate accumulation
6
12
90%
80%
36
70%
45
60%
50%
40%
44
50
No Event
44
Event
30%
20%
10%
0%
20
11
12
Rate of correction of metabolic
acidosis
Median BE o f-4.5 and it took 20 hrs to reach the median BE of 0
Cases of citrate accumulation
Circuit
time(hr)
Anion
Gap
Base Excess changes over time
Baseline BE
4hrs
8 hrs
12 hrs
Case 1
9.6
-12
-6
-8
-10
Case 2
24
-3
-5
-3
-3
Case 3
9.8
-17
-15
-16
Case 4
25
-14
-11
-11
-13
16 hrs
-5
20 hrs
-4
Total
Bil(start)
Ca/iCa
24 hrs
-1.2
-15
29
4.1
27
27
2.87
61
32
2.4
54
36
2.46
5
Onset:10 to 25 hours after commencement of therapy
Lab data suggesting citrate accumulation: slow correction of metabolic
acidosis or worsening of control of metabolic acidosis
Confirmation:
Increased anion gap;
High Total Ca/iCa >2.5 and
Spontaneous correction of metabolic acidosis after stopping the
therapy
ICU and Hospital outcome
ICU mortality of 23%
Hospital mortality of 54.5%
45
40
10
24
35
30
Died
25
20
Survive
34
15
20
10
5
0
ICU outcome
Hospital outcome
"Genius is one per cent inspiration and ninety-nine per cent
perspiration. Accordingly, a 'genius' is often merely a talented
person who has done all of his or her homework."
--Thomas Edison