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Does CRRT Improve Renal Recovery and Outcomes?
UK Kidney Research Keynote Lecture
Patrick D Brophy, MD, MHCDS
Director Pediatric Nephrology
Professor
The University of Iowa
London 2015
UnEqual
Many questions remain unanswered
• What therapy should we use?• When should we start it?• What are we trying to achieve?• How much therapy is enough?• When do we stop/switch?• Can we improve outcomes?• Throughout the conference these are
the basic questions we have tried to address!
Overview
• Impact of Acute Kidney Injury in the PICU• Therapies Comparison in brief
– IRRT, CRRT & Hybrid therapies -SLEDD• Solute clearance with IRRT v CRRT v SLEDD• Dose-outcome relationships & IRRT v CRRT• Summary & thoughts
Pediatric AKI: Definition
Past: So many definitions….
Risk Injury Failure End-Stage Kidney Disease (RIFLE)
Pediatric RIFLE (pRIFLE)
Acute Kidney Injury Network definition
Crit Care. 2005; 9(5): 523–527
Pediatric AKI: Incidence in PICUPopulation & Definition-dependent
Cardiac Surgery
Kidney Int. 2009 Oct;76(8):885-92 Anesth Analg 2009;109:45–52(Aprotinin study)
N = 395 N=395
AKI: 21%AKI: 34%
Pediatric AKI: Incidence in PICUPopulation & Definition-dependent
General PICU
Pediatr Crit Care Med 2007; 8:29 –35 Al-Kandari et al, ASN, 2008
Kid Int 2007; 71: 1028-35
82% AKI4.5% AKI 42% AKI
Most Critically ill childrenVasopressors/VentilatedUrinary catheter
pRIFLE
All PICU Admx SCr baseline
SCr Doubling (pRIFLE I)
All PICU stay>48hrs
pRIFLE
Pediatric AKI: Changing Epidemiology
Pediatric ARF Causes
Num
ber
of P
atie
nts
0
10
20
30
40
50
60
Unk
now
n
AG
N
Hem
oglo
binu
ria
Sep
sis
Hem
Cys
titis
AT
N-D
ehyr
datio
n
Con
geni
tal H
eart
Flu
id O
verl
oad
Neo
plas
m
Low
Alb
HU
S
Chr
onic
Ren
al D
z
Con
gest
ive
hear
t
Rha
bdom
yoly
sis
AR
DS
Pye
lone
phri
tis
Vas
culit
is
Nep
hrot
oxic
Med
Stickle SH et al: Am J Kid Dis 45:96-101, 2005
Previously: Primary renal diseases
CRRT Diagnoses
RRT Options
Hemodialysis, Peritoneal Dialysis, CRRT, SLEDD Each has advantages & disadvantages Choice is guided by
Patient Characteristics o Disease/Symptomso Hemodynamic stability
Goals of therapyo Fluid removalo Electrolyte correctiono Both
Availability, expertise and cost
Pediatr Nephrol (2009) 24:37–48
Trends in Pediatric RRT
Warady et al, Pediatr Neph 2000, 15:11-3
CRRT Increasing 12-US Multicentre ppCRRTMost include Dialysis
Why CRRT?
Reduces hemodynamic instability preventing secondary ischemia Precise Volume control/immediately adaptable Uremic toxin removal Effective control of uremia, hypophosphatemia,
hyperkalemia Acid base balance
Rapid control of metabolic acidosis Electrolyte management
Control of electrolyte imbalances Allows for improved provision of nutritional support Management of sepsis/plasma cytokine filter Safer for patients with head injuries
Indications for Pediatric RRT
Electrolyte (metabolic) imbalance Uremia with bleeding and or
encephalopathy Acuity/Degree of Kidney Injury
reduction in GFR/elevated creatinine
reduction in urine output Nutritional support Intoxications, Inborn errors of
Metabolism (IEM)
Fluid Overload (hypervolemia with pulmonary edema/respiratory failure)
Implications of the available data
Major Renal Replacement Techniques
Intermittent ContinuousHybrid
IHDIntermittent
haemodialysis
IUFIsolated
Ultrafiltration
SLEDDSustained (or
slow) low efficiency daily
dialysis
SLEDD-FSustained (or
slow) low efficiency daily
dialysis with filtration
CVVHContinuous veno-
venous haemofiltration
CVVHDContinuous veno-
venous haemodialysis
CVVHDFContinuous veno-
venous haemodiafiltration
SCUFSlow continuous
ultrafiltration
Intermittent Therapies - PRO
Intermittent Therapies - CON
Intradialytic Hypotension: Risk Factors
• Age < 5, weight < 10 kg• Pressor requirement, Low Predialysis SBP • Cardiac disease- congenital repairs• Poor nutritional status / hypoalbuminaemia• Uremic neuropathy or autonomic dysfunction• Severe anemia• High volume ultrafiltration requirements
Managing Intra-dialytic Hypotension
Dialysate temperature modelingLow temperature dialysate
Dialysate sodium profilingHypertonic Na at start decreasing to 135 by endPrevents plasma volume decrease
Midodrine if not on pressorsUF profilingColloid/crystalloid bolusesReducing dosing
2005 National Kidney Foundation K/DOQI GUIDELINES
Continuous Therapies - PRO
** Depends on strategy and management
Continuous Therapies - CON
SLED(D) & SLED(D)-F : Hybrid therapy
Conventional dialysis equipment Online dialysis fluid preparation Excellent small molecule detoxification Cardiovascular stability maybe as good
as CRRT Reduced anticoagulation requirement Decreased costs compared to CRRT? Phosphate supplementation required like
CRRT
Fliser, T & Kielstein JT. Nature Clin Practice Neph 2006; 2: 32-39 Berbece, AN & Richardson, RMA. Kidney International 2006; 70: 963-968
Uremia Control
Liao, Z et al. Artificial Organs 2003; 27: 802-807
Large molecule clearance
Liao, Z et al. Artificial Organs 2003; 27: 802-807
Comparison of IHD and CVVH
John, S & Eckardt K-U. Seminars in Dialysis 2006; 19: 455-464
RRT for Acute Kidney Injury
• There is some evidence for a relationship between higher therapy dose and better outcome, at least up to a point
• This is true for IHD* and for CVVH**• There is no definitive evidence for superiority
of one therapy over another, and wide practice variation exists***
• Accepted indications for RTT vary• No definitive evidence on timing of RRT
*Schiffl, H et al. NEJM 2002; 346: 305-310 ** Ronco, C et al. Lancet 2000; 355: 26-30*** Uchino, S. Curr Opin Crit Care 2006; 12: 538-543
Therapy Dose in IRRT
p = 0.01
p = 0.001
Schiffl, H et al. NEJM 2002; 346: 305-310
The “Ronco Study”Improved survival
in all patients with convective clearance of 35mL/kg/hr
Trend towards improved survival in septic patients with convective clearance of 45mL/kg/hrRonco, C et al. Lancet 2000; 355: 26-30
Therapy Dose in CVVH
The “ATN Study” 1124 adults in the ICU
563 had intensive therapy 561 had less-intensive therapy
ATN Study
ATN Study
Intensity of CRRT in Critically Ill Patients (The “RENAL” Study)
NEJM 361(17); Oct 2009
NEJM 361(17); Oct 2009
Intensity of CRRT in Critically Ill Patients (The “RENAL” Study)
Outcome with IRRT vs CRRT
Trial quality low: many non-randomized
Therapy dosing variable
Illness severity variable or details missing
Small numbers Uncontrolled
technique, membrane Definitive trial would
require 660 patients in each arm!
Unvalidated instrument for sensitivity analysis
Kellum, J et al. Intensive Care Med 2002; 28: 29-37
“there is insufficient evidence to establish whether CRRT is associated with improved survival in critically ill patients with ARF when compared with IRRT”
Outcome with IRRT vs CRRT
Tonelli, M et al. Am J Kidney Dis 2002; 40: 875-885
• No mortality difference between therapies• No renal recovery difference between
therapies• Unselected patient populations• Majority of studies were unpublished
Outcome with IRRT vs CRRT
Vinsonneau, S et al. Lancet 2006; 368: 379-385
Summary
There is some evidence for a relationship between higher therapy dose and better outcome for IHD
There is no definitive evidence for beneficial effects of high dose CRRT despite major attempts to do so
Trials have demonstrated it is difficult to deliver this dose due to unpredictable breaks in treatment-clotting, bag changes, nursing (Vesconi 2009)
Modern IHD approaches may reduce overt hemodynamic instability even in unstable ITU patients
CRRT greater exposure to anticoagulation
*Schiffl, H et al. NEJM 2002; 346: 305-310 ** Ronco, C et al. Lancet 2000; 355: 26-30*** Uchino, S. Curr Opin Crit Care 2006; 12: 538-543
Summary
RCT (Uchino 2009) 3-5% incidence of significant bleeding problems as opposed to 1% with IHD
HIT
Filter downtime up to 8 hours per day due to clotting problems and short filter life
Delayed procedures, tests,surgery
The legion of alternatives used emphasize the problem **citrate looks promising
Costs– although this is variable (Srisawat N et al. Crit Care. (2010))
DeathDeath
Approach to Pediatric AKI
NormalNormal Increasedrisk
Increasedrisk
Kidneyfailure
KidneyfailureDamageDamage GFR GFR
AntecedentsIntermediate StageAKIOutcomes
EGDT
Defend Blood PressureRestore & Optimize PerfusionUse inotropes with careMitigate Inflammatory Injury
Optimize RRT
Reference Tools
Adqi.net-web site for information on CRRT Crrtonline.com-web site for info on Dr Mehta’s meeting www.PCRRT.com Pediatric CRRT with links to other meetings,
protocols, industry PCRRT list serve (contact Bunchman)