ASN Board Review: Acute Renal Replacement Therapies Ashita Tolwani, M.D., M.Sc. University of Alabama at Birmingham 2014 Key issues for 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 for initiation of RRT Appropriate timing of initiation of RRT Conventional Indications Refractory fluid overload Metabolic acidosis Hyperkalemia Uremia 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 (%) Early vs Late Initiation of CVVH RCT Bouman CS, et al. Critical Care Med 2002; 30:2205-2211 Early High Volume Group (n = 35) Early Low Volume Group (n = 35) Late Low Volume Group (n = 36) Time between inclusion and RRT (hrs) 6.0 (3.0 – 9.7) 7.0 (5.0 – 10.0) 41.8 (21.4 – 72.0) Predialysis BUN (mg/dl) 45.7 (38.4 – 57.7) 47.9 (40.3 – 65.8) 104.8 (61.6 -116.0) Survival (%) (p = 0.8) 74.3 68.8 75 Earlier-Start vs Usual-Start Dialysis in Patients with Community-Acquired AKI: A RCT 208 patients with community-acquired AKI randomized to early- vs. usual-start RRT IHD Early-start RRT: BUN >70 mg/dL and/or serum creatinine >7.0 mg/dL Usual-start RRT: refractory hyperkalemia, volume overload, acidosis, nausea, anorexia, etc. Mortality: 20.5% for early-start; 12.2% for usual-start (RR, 1.67; 95% CI, 0.88-3.17; P = 0.2) Jamale TE et al. Am J Kidney Dis. 2013
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ASN Board Review:Acute Renal Replacement
Therapies
Ashita Tolwani, M.D., M.Sc.
University of Alabama at Birmingham
2014
Key issues for 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 for initiation of RRT Appropriate timing of initiation of RRT
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
Tumor lysis
Respiratory acidosis in ARDS
Fluid management in multi-organ failure
Fluid Accumulation in Critically Ill Children with AKI
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‐
survivorsP
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-UpdatesVolume 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.
RRT should be initiated prior to the development of overt symptoms and signs of renal failure
Key issues for 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
RRT MODALITIES
Intermittent
IHD PIRRT
Continuous
CRRT
SCUFSCUF
CVVHCVVH
CVVHDCVVHD
CVVHDFCVVHDF
PD
CRRT
Potential Advantages
Hemodynamic stability
Increased clearance
Increased fluid removal
Fewer fluctuations in
intracranial pressure
Potential Disadvantages
Labor intensive
Requires ICU level care
Patient Immobility
Requires continuous
anticoagulation
Access
Return
Effluent
SCUFNo solute clearance;
Used for fluid removal
CVVHSolute clearance: convection;
Operative fluid: RF
CVVHDSolute clearance: diffusion;
Operative fluid: dialysate
CVVHDFSolute clearance: diffusion & convection;
Operative fluids: RF & dialysate
CRRT Modalities
Replacement(pre or post dilution)
Access
Return
Effluent
Access
Return
Effluent
Dialysate
Replacement(pre orpost dilution)I
Access
Return
Effluent
Dialysate
CRRT in Management of ICP
Davenport, A. Sem Dialysis, 2009
Fa
ll in
ser
um o
smo
lalit
yIn
trac
rani
al p
ress
ure
mm
Hg
Fluid Balance: CRRT vs IHDAugustine et al, AJKD 2004
IHD CVVHD
Hemodynamic Stability: CRRT vs IHDAugustine et al, AJKD 2004
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
Choice of RRT Modality and Dialysis Dependence after AKI: A Systematic Review and Meta-analysis
Schneider AG et al. 2013
SLED Using a Single Pass Batch System in AKI RCT
Schwenger et al. Critical Care 2012, 16:R140
SLED Using a Single Pass Batch System in AKI RCT
Schwenger et al. Critical Care 2012, 16:R140
SLED Using a Single Pass Batch System in AKI RCT
Schwenger et al. Critical Care 2012, 16:R140
SLED Using a Single Pass Batch System in AKI RCT
Schwenger et al. Critical Care 2012, 16:R140
Conclusion: SLED associated with reduced nursing time and costs compared to CRRT
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
Use of Peritoneal Dialysis in AKI: A Systematic Review
24 studies identified
19/24 from Asia, Africa, and South America
13 studies with PD only
11 studies with PD and EBP
7 observational
4 randomized
Chionh CY, et al. Clin J Am Soc Nephrol 8: 1649–1660, 2013
Key issues for 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
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
Kellum JA and Ronco C Nature Reviews Nephrology; 2010
Delivered RRT Dose and Survival 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 ATN trial (VA/NIH Acute Renal Failure Trial Network, 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 for 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
Prescribed vs Delivered Dose 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
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
Calcium-freedialysate
Citrate chelatesfree ionized Ca2+
Citrate
Effluent
Post filter iCa2+ is monitoredand used to titrate citrate rateto assure anticoagulation
Citrate is metabolizedprimarily in liver to HCO3
-
Bound Ca2+ is released
Calcium is infusedthrough a separatecentral line to replaceCa2+ lost in ultrafiltrate
Returning blood combineswith venous blood in body,normalizing iCa2+ and preventingsystemic anticoagulation
Citrate Anticoagulation in CRRT: Regional Effect in the Circuit
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
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