Intensive Care Unit Renal Support:
In Search of New Directions
Balazs Szamosfalvi, MD
Monday, 08/30/2010 09:45-10:30
Presenter Disclosure Information
I will discuss off label (US/FDA) use and/or investigational use of
citrate solutions for regional anticoagulation during renal
replacement therapy in my presentation.
I have financial relationships to disclose:
Employee of: Henry Ford Health System, Detroit, MI
Consultant for: Baxter, Inc
Stockholder in:
Research support from: Fresenius-NA, Cytopherx, Inc (formerly
Nephrion)
Honoraria from:
Patent: Automated RCA Systems
Objectives
1.
Introduce ICU renal support equipment and
terminology
2.
Summarize current recommendations and future
directions after the ATN and RENAL trials
3.
Present our novel CRRT program integrating regional
citrate anticoagulation (RCA) and 24-hour sustained
low efficiency dialysis (SLED) with computerized
prescription generation and internet-based telemetry
Select CRRT Machines in the USA
Scale-based
effluent balancing
Scale-based
effluent balancing
Sterile effluent
balancing chamber
Additional pumps
added here for
regional citrate
anticoagulation in
Europe
Figure 1 Gambro Prismaflex
Machine
Figure 2 Edwards Aquarius
Machine
Figure 3 NxStage System One
Machine
CRRT Device in Europe
©Fresenius
©Fresenius
Fresenius Multifiltrate™ CRRT System —
Integrated Citrate & Calcium Pumps
CRRT Machine: Basic Layout
Pressure Pod
Blood
Pump
Filter
Effluent
Pump
Replacement
Fluid Warmer
Replacement
and/or Dialysis
Fluid Pumps
Heparin
Syringe Pump
Scales x 2
Continuous Renal Replacement Therapy
(CRRT): Modalities
1. Continuous Arterio-Venous Hemofiltration: CAVH
The earliest form of CRRT, it used arterial blood pressure to
drive blood flow and ultrafiltration in the circuit
2. Continuous Veno-Venous Hemofiltration: CVVH
It replaced CAVH with a blood pump added to the circuit;
Pre-dilution CVVH: Replacement fluid infused pre-filter
Post-dilution CVVH: Replacement fluid infused post-filter
3. Continuous Veno-Venous Hemodialysis: CVVHD
Uses counter-current dialysis for solute removal; it is being
replaced by less expensive sustained low efficiency dialysis
(SLED) using online generated dialysis fluid
4. Continuous Veno-Venous Hemodiafiltration: CVVHDF
The combination of CVVH and CVVHD on a single filter
RCA for 24-hour
Post-Dilution CVVHDF
Data
Screen
Ca2+
Infusion
1 L/24h
PostDilution
Pump
Anticoagulation
Reversed Here
Hematocrit
Sensor
Blood is Anticoagulated
at this Point
Hemofilter
Dialysis fluid
Pump
Ultrafiltration
Pump
78+ L/24h
Vein
Access
Catheter
Bicarbonate Post-Dilution
and Dialysis Fluid
72 L/24h
Blood
Pump
Citrate
Infusion
5 L/24h
RCA for Simultaneous Pre-and Post-Dilution
High Volume Hemofiltration for SIRS
Data
Screen
Ca2+
Infusion
1 L/10 h
PostDilution
Pump
Anticoagulation
Reversed Here
Hematocrit
Sensor
Blood is Anticoagulated
at this Point
Hemofilter
Pre-Dilution
Pump
Ultrafiltration
Pump
85+ L/10h
Vein
Access
Catheter
Bicarbonate Pre-Dilution
and Post-Dilution Fluid
80 L/10h
Blood
Pump
Citrate
Infusion
4 L/10h
Commercial Bicarbonate Fluids
Na+
(130) 140
mM
Na+
2
mM
K+
(25) 35
mM
HCO3-
0.75
mM
Mg2+
108.5
mM
Cl-
0
mM
Ca2+
Dextrose (0) 5.5
mM
K+
HCO3Mg2+
Cl–
Ca2+
(130) 140
mM
4
mM
(25) 35
mM
0.75
mM
110.5
mM
0
mM
Dextrose (0) 5.5
mM
• High Mg2+; little Mg2+ supplementation needed
• Ca2+ infusion is required
• Sodium-phosphate supplementation required
The ATN Study (2008)
1.
Significance
•
•
•
2.
Large, randomized clinical outcomes study for intensity of
CRTT and intermittent HD in acute renal failure
Compared CRRT with 20 ml/kg/h versus 35 ml/kg/h filter
effluent flow rate
Compared intermittent HD 1.2-1.4 single-pool urea Kt/V
per session 3x/week versus 6x/week
Conclusions1
•
“Intensive renal support in critically ill patients with acute
kidney injury did not decrease mortality, improve recovery
of kidney function, or reduce the rate of non-renal organ
failure as compared with less-intensive therapy involving
a defined dose of intermittent hemodialysis three times
per week and continuous renal-replacement therapy at 20
ml per kilogram per hour.”
1. Palevsky P et al: Intensity of Renal Support in Critically Ill Patients with Acute Kidney
Injury; N Engl J Med 2008;359:7-20.
The RENAL Study (2009)
1. Significance
• Large, multicenter, randomized clinical study of
the intensity of CRTT in acute kidney injury for
90-day mortality endpoint
• Compared CRRT with 25 ml/kg/hour versus 40
ml/kg/hour filter effluent flow rate
2. Conclusions1
• “In critically ill patients with acute kidney injury,
treatment with higher-intensity continuous renalreplacement therapy did not reduce mortality at
90 days.”
1. Bellomo R et al: Intensity of Continuous Renal-Replacement Therapy in Critically Ill
Patients; N Engl J Med 2009;361:1627-38.
ICU Renal Support 2010
•
•
•
•
Prescribe 25-30 ml/kg/h filter effluent rate
24-hour continuous therapy with early start
Regional citrate anticoagulation1,2
(?) Plasma adsorption: protein-bound toxin,
cytokine and endotoxin removal; liver support3
• (?) Selective cytopheretic device: ameliorate
severe inflammatory response syndrome4
• (?)Online measured small solute clearance: for
dosing of dialysis and medications
1.
2.
3.
4.
Davenport A et al, Citrate anticoagulation…; NDT Plus (2009) 2: 439–447
Oudemans-van Straaten HM, Citrate Anticoagulation…; Blood Purif 2010;29:191-196
Cruz DN et al, Early Use of Polymyxin B Hemoperfusion…; JAMA. 2009;301(23):2445-2452
Humes HD et al, A Selective Cytopheretic Inhibitory Device… Blood Purif 2010;29:183-190
What is the biggest disadvantage of
traditional CRRT?
Problems with traditional CRRT
1. Cumbersome despite improved machines:
•
•
•
Scale-based balancing of > 50 liters effluent
Frequent clotting complications
Cannot use fistula or graft access
2. Very expensive compared to dialysis:
•
•
•
Custom blood circuits and filters
Pre-packaged replacement fluid
Nurse time if 1:1 nurse: patient ratio is needed
3. Lack of consensus on best approach:
•
•
•
CVVH versus CVVHDF versus CVVHD
Optimal replacement fluid compositions
Optimal anticoagulation strategy
SLED or Standard Hemodialysis with RCA
Calcium
0.5-Liter bag
Citrate
1-Liter bag
Hematocrit
Monitor
Flow Rate
Ca
Optical
Hematocrit and
O2 Saturation
Sensor
Flow Rate
Citrate
Patient Access
Catheter
Citrate
Anticoagulation
Dialysis
Machine
ICU Extracorporeal Support 2010 → Future
NO clotting and reduced WBC,
PLT and complement activation:
Automated RCA
Computer-aided RRT design and
monitoring (Online clearance)
Safer ultrafiltration: Blood
volume and central venous O2
saturation monitoring
Antibiotic dosing: According to
measured online clearance
Better biocompatibility: smaller
catheters, lower blood flows,
ultrapure dialysate without GDP
Cytokine removal: internal
filtration on superflux filter with
very high membrane surface
area to blood flow ratio
Columns for endotoxin, virus,
inflammatory cell and proteinbound toxin removal
FOCUS ON EARLY START, EASE
OF USE AND RESOURCE
ALLOCATION IN ER, OR & ICU
IMPROVED SURVIVAL & RENAL RECOVERY
OR (at least equal outcomes plus):
REDUCED COMPLICATIONS & COST
Citric Acid / Citrate
Fundamental Properties
ƒ Only citrate3- in plasma
pK’’’a
pK’a
ƒ Molecular weights:
pK’’a
• Citrate3- 189 Da
• Ca-Citrate- 229 Da
ƒ No RBC entry
ƒ Metabolized to HCO3–
ƒ Anti-inflammatory: blocks
©David B. Fankhauser, Ph.D.
WBC, PLT and complement
activation
Walser M, J Clin Invest. 1961 April; 40(4): 723–730
Whitfield LR et al, Thrombosis Research 1981; 21: 681-684
Crismon et al, J Appl Physiol 1961; 16(6):1103-1108
Janssen et al, Blood Purif 1994; 12:308-316
Citrate Effects on Plasma
Calcium
Citrate
Albumin
• 90–95 % of Ca
dialyzable
Magnesium
• KCa = 0.95 × KCitrate
Citrate
• KCa ≈ DMg
Regional Citrate Anticoagulation
Ready for Automated Delivery
Calcium
Infusion
~ 90% Removal of
Calcium and Citrate
Dialyzer
End RCA
Calcium
Fresh
Dialysate
Citrate
Drain
Circuit
Citrate
Infusion
Start RCA
Szamosfalvi B et al: Automated Regional Citrate Anticoagulation…; Blood Purif 2010;29:204-209
Commercial Citrate Solutions
ACD-A Solution
Na+
225 mM
Citrate375 mM
Citric acid
38 mM
Dextrose
124 mM
4%-TSC Solution
Na+
408 mM
Citrate3136 mM
Citric acid
0 mM
Dextrose
0 mM
ACD-A — Acid
4%-TSC — Basic
• Used most often
• Used rarely, briefly
• Provides acidic circuit pH
• Acidemic patients
(pH <7.1 or HCO3- <10)
• Plasma ∆Na+ ≈ +3 mEq
• Plasma ∆HCO3- ≈ -3 mEq
• Plasma ∆Na+ ≈ +9 mEq
• Plasma ∆HCO3- ≈ 0 mEq
Qcit (ml/h) = 2 x QB (ml/min) for 4%-TSC
Qcit (ml/h) = 2.5 x QB (ml/min) for ACD-A
(Ex: QB 100 ml/min → Qcit 200 ml/h if 4%-TSC is used)
Online-Generated Dialysate
Na+
140 (130-150)
mM
1, 2, 3 or 4
mM
32 (20-40)
mM
Mg2+
0.5
mM
Cl–
108
mM
Phosphate
1.0
mM
4
mM
5.5
mM
K+
HCO3–
Acetate
Dextrose
• High Mg2+; IV Mg2+ supplementation not required
• Contains P; IV phosphate supplementation not required
136 mM Calcium Solution
For ACD-A or 4%-TSC
Ca2+
136 mM
Mg2+
20 mM
Na+
140 mM
Cl452 mM
•
Ca2+ infusion restores Ca2+ mass balance
•
Na+ mass balance is restored by the dialysis fluid
•
Dextrose mass balance set by dialysis fluid dextrose
•
At QB of 200 ml/min, QCa = 100–140 (120) ml/hour
SLED-RCA in vitro Testing
Calcium
Infusion
Citrate Infusion
Venous Pre
Calcium
Venous Post
Calcium
Blood Container
0.5 Liter
Arterial Pre
Citrate
Arterial Post
Citrate
Szamosfalvi B et al: Automated Regional Citrate Anticoagulation…; Blood Purif 2010;29:204-209
RCA Circuit Chemistry Data [n=6]
Anhepatic Sham Dialysis
Total Ca
2.5
Citrate
Ionized Ca
7
6.87
2
2.20
6
2.10
1.95
Calcium
(mM)
5
1.5
4
1
3
1.08
1.01
2
0.5
1.45
0.23
0
Arterial Pre Citrate
Infusion
1.44
0.48
Arterial Post
Citrate Infusion
Pre Dialyzer
1.35
0.21
1
0
Venous Pre
Calcium Infusion
Venous Post
Calcium Infusion
Post Dialyzer
Hct 30% (repeated at Hct = 21-45%)
Szamosfalvi B et al: Automated Regional Citrate Anticoagulation…; Blood Purif 2010;29:204-209
Citrate
(mM)
Hematocrit and Blood Calcium Content
More red cells ⇒ Less plasma ⇒ Less Ca Needed
Albumin and Plasma Total Calcium Goal
More Albumin ⇒ More Bound Ca ⇒ More Ca Needed
Optical Hemoglobin Monitor
• Probe clips on blood circuit
• No-contact technology
ƒ Light absorption based
• Measures hematocrit
• Measures O2 saturation
©Fresenius
©Fresenius
Hemametrics Crit-Line III TQA™—
Online Hematocrit and O2 saturation Sensor
Ca (136 mM) Infusion Rate for 10-h SLED
Hgb g/dL
ALB g/dL
6-6.9 7-7.9 8-8.9 9-9.9 10-10.9
11-11.9
12-12.9
13-13.9
14-14.9
15-15.9
0.0-0.7
110
105
100
95
95
90
85
80
75
75
0.8-1.2
115
110
105
100
100
95
90
85
80
75
1.3-1.7
120
115
110
110
105
100
95
90
85
80
1.8-2.2
125
125
120
115
110
105
100
95
90
85
2.3-2.7
135
130
125
120
115
110
105
100
95
90
2.8-3.2
140
135
130
125
120
115
110
105
100
95
3.3-3.7
145
140
135
130
125
120
115
110
100
95
3.8-4.2
150
145
140
135
130
125
120
110
105
100
4.3-4.7
160
150
145
140
135
130
120
115
110
105
4.8-5.2
165
160
150
145
140
135
125
120
115
110
125 115
Safe SLED-RCA Operation
Obtain Patient labs
Start RCA
Disease process: less impact
with large Kt/V
SLED only
normalizes labs
Citrate
metabolism
irrelevant
Check Ca2+, Na+, HCO3- (ABG)
Stable patient chemistry
Modify treatment if needed
24-h SLED-RCA: The Future of CRRT?
1. 24-h sustained low efficiency dialysis: SLED
ƒ
ƒ
ƒ
ƒ
Easy to perform with commercial equipment
Regional citrate anticoagulation (RCA) is simple + safe
Modality costs are very low: allows increased utilization with
early start strategies
Commercial module for online small solute clearance
measurement is standard
2. Additional features of novel 24-h SLED-RCA
ƒ
ƒ
ƒ
ƒ
Diagnostic use of CRRT: online optical hemoglobin level and
O2 saturation sensing
Small (8 F) dialysis catheter may be used with blood flow =
50-60 ml/min
Commercial software for telemetry available
Computerized order generation and database archival
developed at Henry Ford Hospital
Uniform 24-hour SLED-RCA Prescription
1. SLED Prescription w Rexeed 15S filter
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
QB = 60 ml/min fixed rate
QD = 400 ml/min (Ca-free) fixed rate
QCit = 120 ml/h (4%-TSC) fixed rate
QCa = 48 ml/h (from table)
QNetUF = 0-500 ml/h
24-hour duration (continuous)
2. Other Features w IHD mode 9h59m
ƒ
ƒ
ƒ
Continuous online display of the hematocrit
Online measured delivered dose of dialysis
Gradual correction of uremia, hyponatremia,
and metabolic acidosis
HD access catheter: 12 F versus 8 F size
Blood Flow = 60 ml/min
S
L
E
D
24
hr.
Rexeed 15S Dialyzer
Hematocrit Chamber
on Arterial Blood Line
Lab Values of a Severe Liver Failure Patient
Treated with 24-hour SLED-Citrate
Ionized Ca
Dialysis end
Dialysis start
Flexible Dialysate Na+/HCO3- Selection
Hematocrit Monitor Screen
Online optical
hemoglobin level
Vena cava O2
saturation
Online Ionic Dialysance Kinetic Modeling
(at 15 hrs)
At 24 hrs Kt/V =1.2
Online Dialyzer Clearance
Dialyzer
after
43 hours
Dialyzer
New
Summary 24-hour SLED-RCA
1. RCA is 100% efficient in preventing clotting when a
high, fixed citrate infusion to blood flow rate is used
2. Systemic citrate accumulation can be prevented even
in patients with severe liver failure if the single pass
citrate extraction on the dialyzer is >90%
3. Predictive dosing of the Ca-infusion based on the
patient’s albumin level and online measured
hemoglobin can maintain a normal systemic ionized Ca
level
4. Routine chemistry monitoring during therapy is not
necessary
5. Online clearance monitoring and telemetry is feasible
during SLED-RCA
Szamosfalvi B et al: 24-hour SLED-RCA… ASN Renal Week 2010; Abstract submitted
ICU Dialysis: The Logistics
1. Increased F2008K use in the ICU
ƒ
ƒ
ƒ
ƒ
ƒ
0-15 intermittent HD treatments per day
0-10 SLED treatments per day
160 ICU beds now in multiple areas
Some therapies are 24-hour (SLED-citrate)
SLED is delivered by the ICU nurse
2. Logistics Challenges
ƒ
ƒ
ƒ
ƒ
Communicate safely >20 ICU dialysis orders
Monitor treatments administered by technicians
Generate flow sheets, monitor data for QA&QI
Collect data on resource utilization and for billing
SLED with RCA at HFH
Nephrology orders SLED with RCA in CarePlus NG (EHR)
CRRT Team sets up
system
ICU Team notified of
SLED order and progress
Pharmacy notified of
SLED order and progress
SLED is performed by ICU RN per protocol
with CRRT Team support
Telemetry by CRRT
Team (FMiS)
Automatic
charting in
MetaVision (EHR)
Clinical
Monitoring
Nephrology modifies SLED with RCA as needed
Inpatient Rounding List
Click Here
to Order a
Dialysis Treatment
NEW
Inpatient Dialysis Orders
z
Calcium Magnesium in
0.9%saline (10 gm CaCl2 +
2 gm MgCl2 / 500 mL)
z
2.5
Hep. B
z
17
8.7
Citrate Dextrose (ACD-A) at 425 ml/hr
110
170
70
72
38
150
150
6850
5/5/2010
Hemoglobin
9 (g/dL)
Albumin
3 (g/dL)
Calcium
Infusion
Rate
39 (ml/hour)
Net Fluid
Removal
Rate
150 (ml/hour)
ICU Dialysis Telemetry
1. Features of dialysis telemetry
ƒ
ƒ
ƒ
ƒ
ƒ
Commercial equipment and software (Fresenius)
Portable computer attached to F2008K
Securely communicates to server over internet
Client PC and software connects to server
Ability to interface with medical records, billing, lab
2. Quality improvements
ƒ
Real-time monitoring of treatments by HD charge nurse
o
o
o
ƒ
Online alarm condition reporting
Online tracking of resource utilization
Online tracking of operator ICU nurse performance
Post-hoc treatment flow sheet review (QA + QI)
Computer
Telemetry
Data Server
Dialysis Unit
Nurse Station
ICU Bedside
Dialysis Machine +
Computer
Computer
Acute Dialysis Unit
Machine +
Computer
Physician
Office
Hospital Electronic
Health Record
HFH “Citrate Group”
ƒ Balazs Szamosfalvi, MD
ƒ Stanley Frinak, MSEE
ƒ Jerry Yee, MD
ƒ Tom Lubkowski
ƒ Gary Zasuwa
ƒ CRRT Technician Team
ƒ ICU Teams
ƒ Greenfield Health
System