asn board review: acute renal replacement therapies · 2013. 12. 17. · asn board review: acute...

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)

rrussell

Sticky Note

Marked set by rrussell

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


Effect of Dialysis Modality on Fluid Balance


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.





•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







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



•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


Wald et al. CriticalCare 2012, 16:R205


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.


•When should therapy be initiated



•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

asn board review: acute renal replacement therapies · 2013. 12. 17. · asn board review: acute...

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