initiation and discontinuation of crrt
TRANSCRIPT
Initiation and Discontinuation of CRRT
Sean M Bagshaw, MD, MSc
Department of Critical Care Medicine, University of Alberta, Edmonton,
Canada
37th Vicenza Course on AKI & CRRT
Vicenza, Italy
Wednesday, May 29, 2019 ~ 10:00 – 10:20
2019 Disclosures
•Salary: Canada/Alberta government
•Grant: Canada/Alberta government, Baxter
•Consulting: Baxter, CNA Diagnostics, Spectral Medical
•Data Safety Monitoring: CytoPherx
•Co-PI: STARRT-AKI trial
Parsons et al Lancet 1961
This is an
decades old
dilemma in
acute care
nephrology!
Wald et al AJKD 2014; Hsu et al JASN 2013
Temporal trends for greater RRT utilization for ICU patients with AKI
“Conventional” Indications for Starting RRT
Oligo-anuria Urine output <200mL/12 hr or anuria
Azotemia Urea>36 mmol/L or uremic organ complications
Hyperkalemia K+ >6.5 and/or rapidly rising and/or ECG abnormalities
Metabolic acidosis pH <7.15
Sodium disorders Progressive and/or uncontrolled hypo/hypernatremia
Thermoregulation Uncontrolled hyperthermia and/or hypothermia (>39.5 C)
Volume overload Clinically significant, diuretic-unresponsive organ edema
Overdose Drug overdose with dialyzable toxin
Any Critical Care or Nephrology Textbook
Liborio et al CJASN 2015
Retrospective analysis of MIMIC II project database (n=18,410) - AKI occurred in 10,245 (55.6%)
Determinants of excess hospital mortality
associated with AKI was attenuated by:• Metabolic acidosis
• Cumulative fluid balance
RRT ↑ hospital survival in the following
AKI groups:• Hyperkalemia (OR 0.55)
• Metabolic acidosis (OR 0.70)
• FO >5% (OR 0.60)
• Azotemia (OR 0.57)
• 5.1.1: Initiate RRT emergently when life-threatening changes in fluid, electrolyte, and acid-base balance exist. (Not Graded)
• 5.1.2: Consider the broader clinical context, the presence of conditions that can be modified with RRT, and trends of laboratory tests—rather than single BUN and creatinine thresholds alone—when making the decision to start RRT. (Not Graded)
KDIGO CPG for AKI_KI (suppl) 2012
Earlier Start to RRT in AKI
Benefits
• Azotemic control
• Electrolyte/acid-base homeostasis
• Fluid balance homeostasis
• Prevent complications of AKI
• Nutritional support
• Immunomodulation
Risks
• CVC insertion
• Extracorporeal circuit
• Anticoagulation
• Micronutrient depletion
• Added bedside resources
• Impaired/disrupted recovery*
Balance of decision to start based on indications and perception of whether of there
will be greater benefit relative to potential harm
• Decision to start is largely subjective based
on the spectrum of clinical information and
provider bias:• Providers start when confronted with “life-
threatening” complications
• Wide variation in the “minimum” severity of
indications prompting start of RRT
• Many factors modify the decision: age,
comorbidity, responsiveness to a diuretic
challenge, illness severity (predicted mortality),
prescribing service, time of day, day of week
• DESIGN: Multi-centre, unblinded, parallel group, randomized trial
• POPULATION: 620 ICU patients with AKI (KDIGO stage 3) with no absolute
indication and supported with mechanical ventilation and/or vasoactive therapy
• INTERVENTIONS (STRATEGIES):
• EARLY = RRT within 6 hr of KDIGO stage 3 AKI (98% at 4.3 hr)
• DELAYED = RRT for clinical criteria & complications (51% at 57 hr)
• PRIMARY ENDPOINT: Mortality at 60-days Gaudry et al NEJM 2016
Survival at 60-days RRT-free at 28-days
Mortality at 60-days: 48.5% vs. 49.7% (p=0.79)
49% of DELAYED group did not receive RRTGaudry et al NEJM 2016
• DESIGN: Single-centre, open-label, parallel group, randomized trial
• POPULATION: 231 critically ill patients with AKI (KDIGO stage 2) + pNGAL >
150 ng/mL + one of (sepsis; vasoactives; refractory FO; worsening SOFA)
• INTERVENTIONS (stratified by SOFA + oliguria):
• EARLY = RRT within 8 hr of KDIGO stage 2
• DELAYED = RRT within 12 hr of KDIGO stage 3
• PRIMARY ENDPOINT: Mortality at 90-daysZarbock et al JAMA 2015
Mortality at 90-days:
EARLY 39.3%
vs
DELAYED 53.6%
(ARR -15.4%)
(HR 0.66, 0.45-0.97)
Zarbock et al JAMA 2015
RCT – 864 patients with septic shock – allocated to early RRT (<12 hr after
RIFLE F onset) v. delayed RRT (>48 hr after RIFLE F onset) on 90-d mortality
TERMINATED PREMATURELY after 56.4% enrollment for futility
Barbar et al NEJM 2018
STandard versus Accelerated initiation of Renal
Replacement Therapy in Acute Kidney Injury
Multi-centre (15 countries; 164 sites), open-label,
randomized controlled trial of accelerated vs.
conservative strategies for initiation of RRT in 3,000
critically ill patients with severe AKI
ClinicalTrials.gov Identifier: NCT02568722
https://www.ualberta.ca/critical-care/research/current-research/starrtaki
Does accelerated (or early) RRT initiation in critically
ill patients with AKI reduce 90-day all-cause
mortality and non-recovery of kidney function?
•Active Sites: 164 (Canada, Austria,
Australia, Belgium, Brazil, China,
France, Finland, Germany, Ireland, Italy,
New Zealand, Switzerland, United
Kingdom, US)
•Randomized: 2,823 (94.1%)(weekly
enrollment ~ 15-20)
Feature ELAIN AKIKI IDEAL-ICU STARRT-AKI
Country Germany France France Multiple (15+)
No. of Sites 1 31 29 >135
Participants 231 620 488 2,866*
Case-mix Mostly surgical Mostly medical Septic Mixed
Sample calculation (ARR) 18% 15% 10% 6%
Clinician Equipoise No No No Yes
Interventions:
EARLY KDIGO stage 2 KDIGO stage 3 KDIGO stage 3 KDIGO stage 2
DELAYED KDIGO stage 3 Specific criteria 48 hours Specific criteria*
Primary Endpoint 90-day mortality 60-day mortality 90-day mortality 90-day mortality
DELAYED Death Rate 54.7% 49.7% 54% 37.0%*
Final Thoughts….
The decision to start RRT is complex, represents a significant escalation in support, and can be influenced by many factors (i.e., patient-specific, clinician-specific and health system-related)
There is wide variation in clinical practice
The issue of who, when and under what circumstance to ideally start RRT for critically ill patients with AKI (in the absence of life threatening complications) remains an important evidence care gap
Additional randomized trials are needed to guide clinical practice
KDIGO CPG for AKI_KI (suppl) 2012
http://www.adqi.org/
Uchino et al CCM 2009
Uncertain whether “failed liberation” or “re-initiation” per se associated with incremental risk
Readiness for RRT Liberation?
Evidence of clinical stabilization/readiness for de-escalation
Resolution/stabilization of precipitating acute event
Reduction in acuity and improvement in multi-organ dysfunction
Increasing kidney function capacity (i.e., urine output, CL)
Capable of managing obligatory fluid requirements
Capable of maintaining acid-base and metabolic homeostasis
Withdrawal of life sustaining therapy/change in goals-of-care
Patient Factors Associated with Likelihood of Successful RRT Liberation
Age
Organ Failure
Urine output
Duration of RRT
Wu V et al ICM 2008; Uchino S et al CCM 2009; Katayama et al Anaesth Intensive Care 2016; Heist et al JCTS 2012
Causland et al CJASN 2016
RRT-free days through day 28: 10.42 for INT v. 12.95 Less INT;
mean difference -2.53; p=0.028 Vijayan A et al KI Rep 2017
Additional Diagnostic Measures to Predict Successful RRT Liberation
DAILY URINARY UREA EXCRETION
2-HOUR CREATININE CLEARANCE
DAILY URINARY CREATININE
KINETIC GFR FUROSEMIDE CHALLENGE
KIDNEY BIOMARKERS
(NGAL, SERUM IL-8, SERUM CYSC)
Frohlich et al J Crit Care 2012; Viallet et al Ann Intensive Care 2016;Aniort et al Crit Care 2016; Pike et al
CJASN 2015; Kim et al Kidney Blood Press Res 2018
Systematic Review of Factors Associated with RRT Discontinuation
Urine Output: Sensitivity: 67%; Specificity: 77%
Katulka R et al: Under Review
Final Thoughts….
Appropriate “liberation” from RRT is critical to minimize exposure to unnecessary RRT and reduce resource use
Selected clinical parameters may help target patients for a “weaning trial” of RRT liberation:
Restoration of urine output AND another measures of clearance (i.e., CrCl, urea excretion, kinetic eGFR etc.)
Studies general small (single centre) and warrant replication
Role of novel biomarkers promising for incremental value
