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ASN Board Review:Acute Renal Replacement
Therapies
Ashita Tolwani, M.D., M.Sc.
University of Alabama at Birmingham
2013
Key issues in boards: RRT for AKI
•When should therapy be initiated?
•What are the critical elements of the RRT prescription?
•Type of technique
•Dose of RRT
•Anticoagulation
When to initiate RRT?
No Consensus Indications to start RRT Criteria to start RRT Appropriate time for initiation of RRT
Conventional Indications Volume overload Metabolic acidosis Hyperkalemia Uremia Azotemia without uremic manifestations Drug overdose
Early vs. Late RRT in AKI
Study Year Design N Early Late Early Late
Parsons et al 1961 Retro 33 120-150 >200 75 12
Fischer et al 1966 Retro 162 150 >200 43 26
Kleinknecht et al 1972 Retro 500 <93 >163 71 58
Conger 1975 Prosp 18 50 120 64 20
Gillum et al 1986 Prosp 34 60 100 41 53
Gettings et al 1999 Retro 100 <60 >60 39 20
Bouman et al 2002 Prosp 106 47 105 71 75
BUN pre-RRT (mg/dL) Survival (%)
Initiation of CVVH on Survival
Bouman CS, et al. Critical Care Med 2002; 30:2205-2211
Seabra et al AJKD 2008
RCT: RR 0.64 (95% CI, 0.40-1.05)
Cohort: RR 0.72 (95% CI, 0.64-0.82)
Early vs. Late RRT in AKI
Karvellas C et al. Crit Care 2011
Meta Analysis: All 15 studies
Karvellas C et al. Crit Care 2011
Timing of Intervention: Determinants
Level of renal function
Demand on renal capacity
Goals for clinical management
Prevention of organ dysfunction
Renal toxicity
Other organ toxicity
Indication and Timing of Dialysis for AKI Renal Replacement vs. Renal Support
Mehta: Blood Purification 2000Mehta. Blood Purif. 2001
AKI in ICU
Surgeon/Intensivist Nephrologist
Maintain tissue O2 delivery Fluid management
Increased cardiac output
Enhance ventilation
Maintain blood pressure Solute control
Prevent hypermetabolism
Provide adequate nutrition
Treat primary process Electrolyte balance
Acid -Base balance
Goals for treatment
Potential Indications for Dialysis in ICU Patients
Renal Replacement Life threatening
indications Hyperkalemia Acidemia Pulmonary Edema Uremic complications
Solute control Fluid removal Regulation of acid-base
and electrolyte status
Renal Support Nutrition Fluid removal in
congestive heart failure
Cytokine manipulation in sepsis
Cancer chemotherapy Treatment of
respiratory acidosis in ARDS
Fluid management in multi-organ failure
Fluid Overload is Associated with Poorer Outcomes in AKI
Bouchard J et al. KI 2009
• 396 patients with AKI requiring dialysis
• PICARD study
– Prospective cohort
– 5 teaching U.S. hospitals
– Between 1999 and 2001
RESULTS
• %FO >10% at dialysis initiation: 2 fold increase in mortality
• Duration and correction of fluid overload influences mortality rates-%FO >10% at dialysis cessation: 2.5 fold increase in mortality
%Fluid Overload ≤ 10%
% Fluid Overload > 10%
Sur
viva
l (fr
actio
n)
p = 0.007
After adjusting for APACHE III and dialysis modality, fluid overload at dialysis initiation remained associated with a 2.07 fold increase in the odds of death (95% CI 1.27-3.37)
SurvivorsNon‐survivors
P
Mean % FO at dialysis cessation
13.0% 22.1% 0.004
Effect of Fluid Balance on Mortality
Bouchard J et al. KI 2009
Effect of Dialysis Modality on Fluid Balance
Bouchard J et al. KI 2009
Fluid balance and patient outcomes in the RENAL trial
The RENAL Replacement Therapy Study Investigators. Crit Care Med.2012 Jun; 40(6):1753-60
KEY POINTS-Updates
Volume status and AKI Fluid therapy is integral to the acute resuscitation of
critically ill patients
A threshold may exist beyond which the perceived benefit of additional fluid therapy after resuscitation may contribute to harm
Volume overload may delay recognition of AKI and is associated with poorer outcomes in AKI
Prevention of fluid overload may be an important and under-appreciated determinant of survival and is evolving as a primary trigger for initiation of RRT
KEY POINTS-Board Review
RCT’s have not demonstrated any mortality benefit in starting RRT early vs late, but there is emerging evidence that starting therapy early may improve outcomes.
There is a need to develop and validate biomarkers that can predict the need for initiating and stopping dialysis.
Key issues in boards: RRT for AKI
•When should therapy be initiated?
•What are the critical elements of the RRT prescription?
•Type of technique
•Dose of RRT
•Anticoagulation
•Buffer Solutions
•Vascular Access
RRT MODALITIES
Intermittent Continuous
IHD SLED CRRT PD
SCUF
CVVH
CVVHD
CVVHDF
CRRT
Potential Advantages
Hemodynamic stability
Increased clearance
?Allows for more aggressive nutritional support
Can allow for more aggressive ultrafiltration over time
Fewer fluctuations in intracranial pressure
Potential Disadvantages
Labor intensive (nursing/pharmacy)
Requires ICU level care
Patient Immobility
Requires continuous anticoagulation
Azotemia Control ProfilesLiao et al, Artif Organs 2003
CRRT in management of ICP
Davenport, A. Sem Dialysis, 2009
Fal
l in
seru
m o
smol
ality
Intr
acra
nial
pre
ssur
e m
mH
g
Fluid Balance: CRRT vs IHDAugustine et al, AJKD 2004
IHD CVVHD
Hemodynamic Stability: CRRT vs IHDAugustine et al, AJKD 2004
Hemodynamic Stability During Hemofiltration
INTERMITTENT HEMODIALYSIS: Fluid removal rate 12.5 ml/min = 3 L fluid removal in 4 hs.
CONTINUOUS HEMOFILTRATION:
Fluid removal rate 2 ml/min = 3 L fluid removal in 24 hs
IF MORE FLUID MUST BE REMOVED:
To increase from 3 to 4 liters/day: IHD increases UFR 12.5 to 16.7 ml/min = 750 to 1002 ml/hr
CRRT increases UFR 2 to 2.7 ml/min = 120 to 162 ml/hr
RRT Modality in AKI: Evidence
Author Year Country Sites (No.) Design Primary Outcome
Simpson 1993 UK Single IHD vs. CVVHD Mortality
Kierdorf 1994 Germany Single IHD vs. CVVH Mortality
John 2001 Germany Single IHD vs. CVVH Hemodynamics, acid‐base status
Mehta 2001 USA Multicentre (4) IHD vs. CAV/VVHDF Mortality, renal recovery
Gasparovic 2003 Croatia Single IHD vs. CVVH Mortality
Augustine 2004 USA Single IHD vs. CVVHD Mortality, renal recovery
Uehlinger 2005 Switzerland Single IHD vs. CVVHDF Mortality
Vinsonneau 2006 France Multicentre (21) IHD vs. CVVHDF Mortality, renal recovery
Lins 2008 Belgium Multicentre (9) IHD vs. CVVH Mortality
Summary of Meta-analyses on Mortality (CRRT vs. IHD)
Study N RR Mortality CI
Tonelli 2002 >600 0.96 0.88-1.08
Kellum 2002 1400 0.93 0.79-1.09
Rabindranath2007
1550 1.06*
1.01**
0.90-1.26*
0.92-1.12**
Bagshaw 2008 1403 0.99 0.78-1.72
Pannu 2008 918 1.1 0.99-1.23
*ICU mortality
** Hospital mortality
SLED using a single pass batch system in AKI – a randomized interventional trial: the
RRT Study in ICU Patients
Schwenger et al. Critical Care 2012, 16:R140
SLED using a single pass batch system in AKI – a randomized interventional trial: the
RRT Study in ICU Patients
Schwenger et al. Critical Care 2012, 16:R140
SLED using a single pass batch system in AKI – a randomized interventional trial: the
RRT Study in ICU Patients
Schwenger et al. Critical Care 2012, 16:R140
KEY POINTS-Board Review CRRT vs. IHD
Despite the theoretical benefits apparent from the more physiologic nature of CRRT, no study has conclusively demonstrated a survival benefit of CRRT over IHD in AKI
Advantages Hemodynamic stability, correction of volume
overload, better solute removal
Therapy of choice for AKI patients with acute brain injury or other causes of increased intracranial pressure or generalized brain edema
Key issues in boards: RRT for AKI
•When should therapy be initiated?
•What are the critical elements of the RRT prescription?•Type of technique
•Dose of RRT
•Anticoagulation
Dose of Acute RRT
There are no well-established standard methods for assessing efficacy of RRT in AKI
Assessment of Dose in AKI limited to:
Urea kinetics in for IHD
BUN levels
Effluent volume in CRRT
Clinical Trials Evaluating Dialysis Dose in AKI
Bouchard et al. AJKD 2009
Access
Return
Effluent
SCUF CVVH CVVHD CVVHDF
CRRT Modalities
Replacement(pre or post dilution)
Access
Return
Effluent
Access
Return
Effluent
Dialysate
Replacemen(pre orpost dilution)I
Access
Return
Effluent
Dialysate
Calculating Solute Clearance
Generic Clearance = Mass removal rate / Blood concentration Effluent flow rate x Effluent concentration/Blood
concentration
K = QE x CE/CB
Using urea as solute QE << QB ( 17-50 ml/min vs. 150-200 ml/min) Equilibrium achieved (CE = CB)
CE/CB = = Sieving Coefficient
Sieving coefficients for small MW molecules such as urea = 1
Filtration Fraction
Filtration Fraction (FF) = QUF / QP
QUF = Ultrafiltration Rate
QP = Plasma Flow Rate
Filter clotting with FF > 30%
FF = 1500 / [6000 x (1-0.30)] = 0.36
Post-dilutional CVVH Parameters:Blood Flow Rate = 100 mL/min HCT 30%Ultrafiltration Rate = 1500 mL/hr
Pre-Dilution Replacement Fluid
Decreases filtration fraction
Diminishes solute clearance by diluting blood reaching dialyzer
Dilution Factor: QBW------------------------------------
QBW + QR
Pre-dilutional CVVH clearance
K = QE x [QBW / (QBW + QR)]
Diffusive ClearanceConvective Clearance
Convection vs. Diffusion
Brunet et al. AJKD 1999; 34: 486-492
Key points
•Clearance Effluent Rate for small molecular weight particles
•Increasing effluent rate increases solute clearance
•CVVH clearance = CVVHD clearance for same effluent rates for small molecular weight particles
Blood flow 150 mL/min Blood flow 150 mL/min
Hemofiltration compared to hemodialysis for AKI: systematic review and meta-analysis
Friedrich JO, Wald R, Bagshaw SM, Burns KE, Adhikari NK. Crit Care.2012 Aug 6; 16(4):R146
• 19 RCTs• 16 used CRRT
Hemofiltration compared to hemodialysis for AKI: systematic review and meta-analysis
Few RCTs comparing HF vs. HD for AKI
Pooled results do not suggest benefit of outcomes of HF vs. HD, but confidence intervals wide
HF may increase clearance of medium to larger molecules, but may also shorten the time to filter failure
Additional pilot trials are needed to evaluate the impact of HF vs. HD on outcomes
Friedrich JO, Wald R, Bagshaw SM, Burns KE, Adhikari NK. Crit Care.2012 Aug 6; 16(4):R146
Wald et al. CriticalCare 2012, 16:R205
Optimal Mode of clearance in critically ill patients with Acute Kidney Injury (OMAKI) - a pilot RCT of HF vs. HD: a Canadian Critical Care Trials Group project
Wald et al. Critical Care 2012, 16:R205
Optimal Mode of clearance in critically ill patients with Acute Kidney Injury (OMAKI) - a pilot RCT of HF vs. HD: a Canadian Critical Care Trials Group project
Wald et al. CriticalCare 2012, 16:R205
Optimal Mode of clearance in critically ill patients with Acute Kidney Injury (OMAKI) - a pilot RCT of HF vs. HD: a Canadian Critical Care Trials Group project
Overview of Study Design
Management Strategy
Intensive Less-Intensive
Hemodynamically Stable Patients
IHD* 6x/week 3x/week
Hemodynamically Unstable Patients
CVVHDF 35 mL/kg/hr 20 mL/kg/hr
SLED* 6x/week 3x/week
*target Kt/V: 1.2-1.4 per treatment
VA/NIH ATN study, Palevsky et al.
Management of IHDIntensive
Management Strategy(N=563)
Less-IntensiveManagement
Strategy(N=561)
Treatments per week (95% CI) 5.4 (5.2-5.6) 3.0 (2.8-3.1)
Interval between treatments (days, 95% CI) 1.1 (1.1-1.2) 2.1 (2.0-2.2)
Median treatment length (hours, IQR) 4.0 (3.3-4.5) 4.0 (3.5-4.5)
Blood flow rate (mL/min) 360±59 360±62
Dialysate flow rate (mL/min) 730±123 710±135
Net ultrafiltration (L) 1.7±1.2 2.1±1.4
BUNpre-dialysispost-dialysis
45±2516±12
70±3325±15
Kt/Vurea
First treatmentSubsequent treatments
1.13±0.311.32±0.37
1.13±0.321.31±0.33
.
Management of CVVHDF
Intensive Management
Strategy(N=563)
Less-IntensiveManagement
Strategy(N=561)
Median daily treatment duration (hours, IQR) 20.9 (13.0-23.7) 21.0 (13.0-24.0)
Blood flow rate (mL/min) 150±33 140±40
Dialysate flow rate (mL/hr) 1410±346 820±250
Replacement fluid flow rate (mL/hr) 1390±316 830±249
Net ultrafiltration (mL/hr) 130±135 130±189
24-hour effluent volume (L) 49.6±22.4 30.5±14.3
Effluent flow rate (mL/kg/hr)PrescribedDelivered
36.2±3.835.8±6.4
21.5±4.322.0±6.1
Mean daily BUN (mg/dL) 33±18 47±23
Percent of prescribed dose of therapy delivered 89±39 95±35
Results from the VA/NIH ATN study, Palevsky et al.
60-Day All Cause Mortality
Intensive – 53.6%
Less-Intensive – 51.5%
Odds Ratio: 1.0995% CI: 0.86-1.40P=0.47
KEY POINTS-Board Review Dose of RRT in AKI
Intensive renal support did not: Decrease mortality, Accelerate recovery of kidney function, or Alter the rate of non-renal organ failure
The intensive management strategy was associated with: A greater percentage of patients with
treatment associated hypotension More hypokalemia and hypophosphatemia
RENAL Trial
1508 patients35 sites3 years
IntensiveCRRT
(post-dilution CVVHDF at 40 ml/kg/hr
of effluent)(750 patients)
Randomization
ConventionalCRRT
(post-dilution CVVHDF at 25 ml/kg/hr
of effluent)(750 patients)
Low dose High dose p
Number of patients 743 722
Total number of study days 4190 4179
Mean Days of Study treatment/patient
5.9 (7.7) 6.3 ( 8.7) 0.35
Daily effluent (mls/hr)/patient 1772 (1257) 2698 (1154) <0.001
Dose delivered mls/kg/hr 22.0 (17.8) 33.4 (12.8) <0.001
% of prescribed 88 84 <0.001
Filters/day/patient 0.84 (0.81) 0.93 (0.86) <0.001
Patients treated with IHD in ICU 52 (7.0%) 55 (7.6%) 0.64
Process of Care in RENAL
Mortality Outcomes in RENAL
Renal vs. ATN
Renal vs. ATN
Solute clearance in CRRT: Prescribed vs. Actual Delivered Dose
Standard dose(20 mg/kg/h)
High dose(35 mg/kg/h)
P
Prescribed clearance (KP) 17.62 ± 0.96 28.10 ± 1.44 <0.0001
Estimated clearance (KE) 15.79 ± 2.47 25.10 ± 3.16 <0.0001
Urea clearance (KU) 15.55 ± 3.07 23.31 ± 5.30 <0.0001
Creatinine clearance (KC) 15.67 ± 3.88 21.62 ± 5.5 <0.0001
CVVHDF Clearance Comparisons
*
Group 20 ml/kg/hr Group 35 ml/kg/hr
*
*
*
* p < 0.001 Lyndon W. et al. 2011
Dose of Dialysis (Urea and Beyond)
Renal Replacement Therapy Dose
S u
r v
i v
a l
Practice-Dependent Region
Break Point(Staging dependent?)
Key Points: Board ReviewDosing of RRT in AKI
Intermittent hemodialysis
No need to provide treatments more than 3x/week so long as a target Kt/Vurea of 1.2-1.4 per treatment is achieved
Continuous renal replacement therapy
An effluent flow of at least 20 mL/kg/hr is sufficient, so long as there is careful attention to ensuring that the target dose of therapy is actually delivered
Delivered dose is less than prescribed dose
Clearances should be measured in routine care and used to optimize dose
Please indicate which ONE of these statements is true:
A. Recent randomized controlled trials demonstrate that early initiation of renal replacement therapy is associated with improved patient outcomes.
B. The recent ATN trial (VA/NIH Acute Renal Failure Trial Network, Dr. Palevsky et al) was a “modality” study, which demonstrated that there is no difference in survival between CRRT and IHD
C. Recent studies (the ATN and the RENAL trials) have shown that “high” or “low”, the dose of dialysis is unimportant and is not a determinant of patient survival.
D. Studies have shown that intermittent Hemodialysis is associated with fluid gains and increased hemodynamic instability, when compared with CRRT
E. Recent randomized controlled trials have conclusively demonstrated that renal functional recovery is superior among patients treated with CRRT, as compared with IHD.
Key issues in boards: RRT for AKI
•When should therapy be initiated
•What are the critical elements of the RRT prescription?
•Type of technique
•Dose of RRT
•Anticoagulation
Considerations for CRRT
Prescribed vs. Delivered Dose
Diffusion versus Convection
Filtration Fraction
Blood Flow
Anticoagulation
Membrane Material and Geometry
Delivered dose not prescribed!
Filtration Fraction (QUF/QP)
High UF Rate & low Blood Flow = CLOTTING
Case Example: 100 kg M placed on post-dilution CVVH, BFR 150 mL/min,
desired CVVH dose 25 mL/kg/hr; hct 30% (desired UF Rate = 2500 mL/hr)
FF = 2500/(0.7 X 150 X 60) = 40% !!!
Filtration Fraction (QUF/QP)
Which of the following options will decrease the effect of the filtration fraction in the previous case ?
A. Add Anticoagulation
B. Change to a diffusive therapy (CVVHD)
C. Increase Blood Flow Rate
D. Change to Pre-dilution Replacement Fluid
E. All of the above
Anticoagulation
• No anticoagulation
• Unfractionated heparin
• LMW Heparins
• Thrombin antagonists
• Citrate
• Prostaglandins - PGI2, PGE1
Why Citrate? Citrate and Bleeding
Zhang et al. Int Care Med. 2012
Why Citrate? Citrate and Circuit Patency
Zhang et al. Int Care Med. 2012
Largest Citrate RCT
•Post-dilutional CVVH
•Blood flow 220 ml/min
•Citrate 3 mmol/L blood flow
Oudemans-van Straaten et al. Crit Care Med 2009
Results
Patient Characteristics
Citrate Anticoagulation
Intrinsic pathway
Extrinsic pathway
XIIXIIa
XIXIa
IXIXa
VIIVIIa
VIII Ca++ Tissue factor
X XaCa++
V
Prothrombin Thrombin
FibrinogenFibrin
Cross linked fibrinXIIIa
Coagulant active phospholipid(e.g. platelet membrane)
Citrate Anticoagulation
Chelates free Ca+2 in extracorporeal circuit
Prevents activation of Ca+2-dependent procoagulants
Anticoagulant effect measured by iCa+2
Anticoagulation reversed by Ca+2 infusion
Citrate+iCa Calcium citrateBiologically inactivemeasurable as total Ca
Citrate Metabolism
Citric acid has plasma half life of 5 mins
Rapidly metabolized by liver, kidney and muscle cells
Na3Citrate + 3H2CO3
Citric Acid + 3NaHCO3
3H2CO3 + H2O + 3NaHCO3
4H2O + 6CO2
Flanagan MJ et al. AJKD 27: 519-24, 1996
Which of the following is indicative of adequate anticoagulation of citrate for
CRRT?A. CRRT circuit ionized calcium level of 0.3 mmol/L
B. CRRT circuit ionized calcium of 0.7 mmol/L
C. Systemic ionized calcium level of 0.7 mmol/L
D. Serum citrate level of 1 mmol/L
E. Total calcium level of 2.2 mmol/L
Citrate
Normal blood levels of citrate: 0.05 mmol/L
Bleeding time at citrate levels of 4 to 6 mmol/L (iCa2+ < 0.25 mmol/L)
Levels of 12 to 15 mmol/L required for stored blood products for transfusion therapy
Metabolic Consequences
Metabolic alkalosis Citrate overdose/toxicity
Metabolic acidosis Citrate toxicity in setting of severe liver
disease or hypoperfusion
Hypernatremia Hyperosmolar citrate solutions
Hypocalcemia and hypercalcemia Inappropriate calcium supplementation
Citrate Toxicity Risk Factors
Liver Disease
Nursing or pharmacy errors: overdose
Shock liver; severe hypoperfusion states
Detection Rising anion gap, worsening metabolic acidosis
Falling systemic iCa2+
Escalating Ca2+ infusion requirements
Total Ca2+:Systemic iCa2+ Ratio> 2.5:1 (increas. Ca2+ gap)
Meier-Kriesche HU et al. Crit Care Med.2001, 29:748-752
Calcium Gap
Ionizedcalcium
Totalcalcium1
2
3
mm
ol/L
Complexedcalcium
4
8
12
mg/dL
Calciumcitrate
Proteinbound
calcium
Zimmerman et al, Neph, Dial & Transpl 1999 14:2387-2391
CRRT Solutions:Bicarbonate vs. Lactate in CRRT:
Group 1 (Lactate first) Group 2 (Bicarb first)
Baseline
Bicarbonate
Lactate
16.3 + 1.5
2.4 + 0.8
18.9 + 2.0
1.4 + 0.2
0 – 48 hours
Bicarbonate
Lactate
Receiving Lactate
22.2 + 1.4
2.6 + 0.4
Receiving Bicarb
22.2 + 1.1
1.5 + 0.1
48 – 96 hours
Bicarbonate
Lactate
Receiving Bicarb
24.2 + 2.3
1.8 + 0.6
Receiving Lactate
24.8 + 0.6
3.1 + 0.7
Comparison of Lactate vs. Bicarbonate CRRT Solutions
Some studies show equivalent hemodynamics
Most show a benefit with bicarbonate-based solutions Lower lactate levels
Faster, better acid-base control
Improved hemodynamics
Which CRRT solutions are best?
Prefer Calcium-free Dialysate solution when using Citrate
Prefer physiological concentrations of electrolytes
Phosphate Hypophosphatemia occurs in up to 80% of pts on CRRT
Studies have demonstrated the safe addition of phosphorous in replacement and dialysate fluids
Broman et al retrospectively evaluated phosphorous levels in 3 groups of patients on CVVHDF: Group 1: No phosphorous added to CRRT solutions
Group 2: Phosphate in dialysate
Group 3: Phosphate in dialysate and replacement solution
Troyanov S et al. Intensive Care Med 2004; Gatchalian RA et al. Am J Kidney Dis 2000;Santiago MJ et al. Kidney Int 2009;Ricci Z et al. Nature Reviews 2009;Broman M et al. Acta Anaesthesiol Scand 2011
Phosphate
Broman M et al. Acta Anaesthesiol Scand 2011
KEY POINTS-Board ReviewPrescribing CRRT-Solutions
Solutions needed to maximize clearance
Bicarbonate seems superior to lactate
Pharmacy made solutions give greatest flexibility but have increased risks of compounding errors and costs
Commercially available solutions are the safest Two currently approved for replacement in the
U.S.
KEY POINTS-Board ReviewSummary
Modality: No overall benefit to CRRT compared to IHD, though CRRT may be better for patients at risk of increased ICP and for volume control.
Dose: No benefit to “intensive” therapy, but delivered dose of both CRRT and IHD must be monitored to ensure minimum adequate dose
Anticoagulation: Citrate is gaining wider acceptance as the preferred anticoagulation for CRRT
CRRT Solutions : Bicarbonate should be the buffer in dialysate and replacement fluid for RRT in patients with AKI, especially with liver failure and/or lactic acidemia