Transcript The Prospective Pediatric CRRT (ppCRRT) Registry

The Prospective Pediatric CRRT (ppCRRT) Registry
Timothy E. Bunchman
Professor
Nephrology & Transplantation
Grand Rapids, MI
Outline
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Why is the ppCRRT Registry needed?
Study aims
Registry design
Data acquisition and transfer
Grant funding and distribution
IRB requirement variations
Registry database fields and definitions
Published data
Future projects
ppCRRT Registry Rationale
• No single pediatric center cares for enough CRRT
patients annually to analyze the effect of more
than a few variables on patient outcome
• Mitigate geographical and institutional effects on
– Patient demographics
– CRRT practice patterns
• SHARE INFORMATION
• Generate hypotheses for future RCT’s
ppCRRT Rational: The Need For Power
• An adequately powered study to detect the
differences in percent fluid overload
between survivors (16.4% +/- 13.8%) and
non-survivors (34.0% +/- 21.0%) observed
in a previous study1 requires 25 patients
• To control for severity of illness and
perform multivariate analysis requires more
patients for each variable assessed
1. Pediatrics. 2001 107:1309-12
ppCRRT Registry: Phase 1 Aims
• Assess for potential associations between various
practices and pediatric patient outcomes
• Assess for potential associations between varying
practices and CRRT machine functioning
• Determine CRRT clearance rates of various SIRS
and CARS cytokines in children with sepsis
ppCRRT Registry Design
• Prospective, observational format
• Informed consent required
• All centers practice according to their local
protocol with respect to
– initiation and termination criteria
– modality
– prescription
• clearance
• fluids
• anticoagulation
• Centers agree to collect the same data on
standardized forms
ppCRRT Data Decision #1:
Primary Disease Definitions
• ARF causes are often multi-factorial
• To prevent artificial biases toward reporting of
particular disease entities
– no a priori primary disease classifications established at
ppCRRT inception
– site PI’s given full latitude to classify their patients’
primary diseases
• Site PI diagnoses left unchanged for abstract reports
• For manuscripts, ppCRRT PI reviews all
diagnoses and created a standard definition list
– list reviewed by each center PI who then have final
option to reassign their patients
ppCRRT Data Decision #2:
How to Control for Severity of Illness
• Large single center pediatric CRRT study showed
higher mortality in children with ARF on inotropes
• Controlling for illness severity critical to make any
valid statements regarding outcome
• Many scoring systems all with different attributes
• ppCRRT needs a severity of illness scoring system
to control for SOI, NOT to predict outcome
• SOI to be assessed at ICU admission and CRRT
initiation
1. Bunchman TE et al: Ped Neph 16:1067-1071, 2001
ppCRRT Data Acquisition and Transfer
• Each site sent a PC database program and an
electronic database file via e-mail
• Data coordinator from each site in contact with SLG
by phone to enter first data set to ensure consistency
• Data entered into program on PC or on hardcopy
• Completed patient files e-mailed or faxed back to
SLG at Texas Children’s Hospital
• Site data merged into single ppCRRT database,
which resides solely at Texas Children’s Hospital
• Database modifications, based upon suggestions
from the group, e-mailed back to sites
Grant Funding: Another ppCRRT Decision
• Funding equally divided among all active centers as of
January 1st of each year following date of grant award
– Active IRB status
– At least one patient enrolled
• SLG provides frequent updates regarding grant awards,
funding dates and amounts
• Grants are for unrestricted use at the discretion of each site
PI within the constraints of PI’s institution
• No contracts exist between sites, only contract is between
funding sources and SLG/Texas Children’s Hospital
Presentations/Abstracts/Manuscripts
• All active ppCRRT members will have the
opportunity to participate in ppCRRT
related academic endeavors
• First authorship to ppCRRT who performs
data analysis and prepares
abstract/manuscript
• SLG edits all work to ensure format
consistency
ppCRRT Data Collected
• Divided into three electronic or paper forms
– Pre-Initiation/Demographic Data
– ICU data
– Filter data
• Each patient has unique identifier to describe
center site and patient number (e.g., the third
Texas Children’s patient is #1003)
• Some sites’ IRB’s prevent listing date of birth, so
investigator calculates age
Pre-CRRT Registry Data
• Demographics
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primary disease leading to CRRT
co-morbid illness
MODS (yes/no)
gender
days in PICU prior to CRRT
ICU admit weight and height/length
• CRRT specifics
– Modality
– CRRT reason(s)
• Treatment or prevention of fluid overload and/or
• Treatment or prevention of electrolyte imbalance
– Access size, configuration and site
• Pediatric Risk of Mortality 2 (PRISM 2) score
PRISM 2 score
• 14 variables, 5 organ domains
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Cardiovascular (SBP, DBP, pulse)
Respiratory (Resp rate, pO2, pCO2)
Neurological (Glasgow Coma score, pupillary reaction)
Hepatic (bilirubin)
Metabolic (potassium, calcium, total CO2, glucose)
• Direct assessment of renal function not included
• Easy to calculate
• Data remains with ppCRRT and not sent
elsewhere for analysis
Pollack M: Crit Care Med. 1988 16:1110-6
Pre-CRRT Registry Data:
CRRT Initiation
• Renal failure indices at CRRT initiation
– GFR (Schwartz)
– Urine output in previous 24 hours
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Percent fluid overload (%FO)
PRISM 2 score
CVP
Mean airway pressure
Number of inotropic agents used
Diuretics? (yes/no)
Percent Fluid Overload Calculation
[
% FO at CVVH initiation =
Fluid In - Fluid Out
ICU Admit Weight
]
* 100%
Fluid In = Total Input from ICU admit to CRRT initiation
Fluid Out = Total Output from ICU admit to CRRT initiation
Goldstein SL et al: Pediatrics 2001 107:1309-12
Registry PICU Data
• Cardiopulmonary
– Maximum inotrope doses
– Pressors weaned? (yes/no)
– MAP change
• ICU length of stay
ppCRRT Registry Circuit Data
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Separate dataset for each circuit
Machine brand
Extracorporeal circuit volume
Priming fluid
Dialysis or replacement fluid composition
Anticoagulation
– Citrate
– Heparin rate
• ACT measured per hour
• Mean ACT
• # ACT < 180 seconds
ppCRRT Registry Circuit Data
• Clearance prescription
– CVVH versus CVVHD versus CVVHDF
– ml/1.73m2/hour
• Nutrition prescription at each circuit initiation
– Kcal/kg/day
– Grams protein/kg/day
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Total fluid intake
Total fluid output
Total and net ultrafiltration
Percent blood volume UF’d per hour
ppCRRT Cytokine Clearance Study
• Include patients with documented bacterial sepsis
• Exclude patients receiving pharamacological immunosuppression
or with an immunodeficiency
• Measure cytokine levels from access port, post filter and
dialysate/filtrate prior to, 1 and 24 hours after CRRT initiation
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TNF-alpha
IL-1beta
IL-6
IL-10
GCSF
ppCRRT Registry Patient Data:
Outcome
• Survival versus death (discharge from PICU)
• Attainment of target dry weight
• Reason to discontinue CRRT
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Death
Regained renal function
Underlying illness resolved
Tolerates intermittent hemodialysis
ppCRRT Registry Circuit Data:
Outcome
• Filter life-span (hours)
• Reason for circuit change
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clotting
access malfunction
machine malfunction
unrelated patient indication (e.g., needs CT scan)
CRRT discontinued
The ppCRRT Data
• Center and Patient Demographics
• Patient Sub-Populations
– Infants
– BMT
• Circuit Function
• MODS
ppCRRT Experience
• First patient enrolled on 1/1/01
• 370 patients entered into database as of 07/12/05
• Currently 13 active pediatric centers
–Texas Children’s
–Boston Children’s
–Seattle Children’s
–UAB
–University of Michigan
–Mercy Children’s, KC
–Egleston Children’s, Atlanta
–All Children’s, St. Petersburg
–DC Children’s
–Columbus Children’s
–Packard Children’s, Palo Alto
–DeVos Children’s, Grand Rapids
–Cleveland Clinic
Site Census
39
36
33
Patients Enrolled
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24
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15
12
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Houston
Boston
Columbus
UAB
Atlanta
Devos
Stanford
Tampa
Seattle
Michigan
Missouri
Site
Patient Demographics
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Newborn to 25 years
59% males
Weights 1.3 – 160kg (mean 33.5 kg)
Mean 6.5 days in ICU prior to CRRT
– (range 0 – 135 days, median 2)
• Modality
– CVVH (33%)
– CVVHD (54%)
– CVVHDF (13%)
ppCRRT Data: Size Distribution
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ppCRRT Demographics
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Survivors
Non-Survivors
% Survival
Indications for CRRT:
Fluid overload and electrolyte imbalance
Fluid overload only
Electrolyte imbalance only
Prevent fluid overload to allow intake
Other
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41
19
8
12
29
25
11
6
8
31
16
8
2
4
48
61
58
75
67
Diagnoses:
Sepsis
Cardiac disease/transplant
Bone marrow transplant
Malignancy
Liver disease/transplant
Renal failure
Inborn error of metabolism
Pulmonary failure
Hypovolemic Shock
Drug toxicity
Other
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21
13
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6
12
6
10
4
3
13
20
13
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6
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9
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62
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100
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CRRT for Infants < 10kg
• Previous retrospective data1 from 85 infants
who received CRRT from 1993 to 2001
– 38% patients survived
– 25% patients < 3 kg survived
1. Symons JM et al : Am J Kidney Dis. 2003 May;41(5):984-9
ppCRRT Data: Infants < 10 kg
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28 children < 10 kg
14 boys; 14 girls
Median age 40 days old
range 3 days to 2.9 years old
Median weight 4.1 kg
range 1.3 to 9.5 kg
Indication for CRRT:
75% fluid and electrolyte imbalance
25% metabolic anomaly or toxin
CRRT vascular access location:
67% femoral vein
18% internal jugular vein
15% subclavian vein
ppCRRT Infant Prescription Data
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Modality: CVVHD (25/28 children) and CVVH (3/28)
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Median blood flow: 9 ml/kg/min
(range 0 to ml/kg/min)
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Median dialysate or replacement fluid rates:
2600 ml/hr/1.73M2
(range 0 to 12,700 ml/hr/1.73M2)
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Median net ultrafiltration: 780 ml/kg
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Median CRRT duration 4 days
(range 1-99 days)
ppCRRT Infant Survival Data
Weight
Survivors
% Surviving
Children < 5 kg
7/17
41%
Children 5 – 10 kg
7/11
64%
All Children < 10 kg
14/28
50%
All Children > 10 kg
48/92
55%
ppCRRT Infant Data: Clinical Variables
Clinical Variable
Survivors
Non-Survivors
p
MAP - CRRT End
8.9
16.8
0.04
Days in ICU pre-CRRT
22
6.4
0.04
PRISM Score - CRRT Start
21
29
<0.08
PRISM Score - ICU Admit
20
28
0.08
11%
40%
0.10
11
15
0.24
Male Gender
5/14
9/14
0.26
Multiorgan Failure
10/14
12/14
0.32
102 days
182 days
0.38
Urine output - CRRT Start
2.2
1.4
0.38
Maximal Pressors
1.3
1.6
0.39
Duration of CRRT
5.5 days
11.5 days
0.43
4.6
4.8
0.77
2900 ml
3100 ml
0.83
26
24
0.86
Fluid Overload - CRRT Start
MAP - CRRT Start
Age
Weight
Dialysate/Replacement Rate
GFR - CRRT Start
Pediatric BMT/ARF Data
• Single center trials demonstrate survival rates of
42% for patients needing RRT1,2
• Recent study suggests maintenance of fluid
overload < 12% important for survival2
• Recent study showed aggressive CRRT in
intubated BMT patients helpful3
1. Bunchman TE et al: Pediatr Nephrol. 2001 16:1067-71
2. Michael M et al: Pediatr Nephrol. 2004 19:91-5
3. Alexander SA et al: Blood Purification 21:2003 (CRRT meeting)
ppCRRT BMT Patient Data
• 22 patients
– Median age 9.45 years (range 2.2 - 23.5 years)
• CRRT modalities
– CVVHD (45%)
– CVVH (41%)
– CVVHDF (14%)
• Diagnoses leading to CRRT
– Sepsis (18%)
– Hepatorenal syndrome (14%)
– No single Dx (54%)
• 8/22 (36%) patients survived
ppCRRT BMT Data: Clinical Variables
Survivors Non-Survivors
p
ICU days to CRRT
10.1+1.8
15.1+10
0.4
CRRT duration (days)
4.2+0.6
8.6+1.7
0.07
% Fluid Overload
3.8+2.0
16.1+4.0
<0.05
PRISM 2 at ICU admit
10.7+2.4
15.6+2.1
0.17
UOP (ml/kg/hr)
5.1+3.6
1.7+0.3
0.18
GFR
63.8+9.2
61.5+14.4
0.89
ppCRRT MODS Data
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ppCRRT MODS Data
BASELINE DEMOGRAPHICS
134 patients entered (1/1/2001 to 5/15/03)
102/134 (76%) with MODS (2+ organs involved)
Mean age 8.8 + 7.1 years (2 days to 25.1 years)
Mean weight 34.1 + 23.6 kg (3.2 to 95.4 kg)
Mean GFR 36.9+ 28.7 at CRRT initiation
Median 3 ICU days prior to CRRT initiation
Range 0 to 103 days
66/102 (65%) less than 7 days
ppCRRT MODS Data
MOST COMMON PRIMARY DISEASES
Sepsis (28.4%)
Cardiovascular shock (21.6%)
BMT/Malignancy (13.6%)
ppCRRT MODS Data: Modality
70
55.9%
60
Patient Number
50
40
31.4%
30
20
12.7%
10
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CVVH
CVVH-DF
MODALITY
CVVH-D
ppCRRT MODS Data: Survival
60
54.0%
Patient Number
50
46.0%
40
30
20
10
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Death
Survival
OUTCOME
ppCRRT MODS Data
BASELINE DEMOGRAPHICS
157 patients entered (1/1/2001 to 5/31/04)
116 with MODS (2+ organs involved)
Mean age 8.5 + 6.8 years (2 days to 25.1 years)
Mean weight 33.7 + 25.1 kg (1.9 to 160 kg)
Median 3 ICU days prior to CRRT initiation
Range 0 to 103 days
67%less than 7 days
Goldstein SL et al: Kidney International 2005
ppCRRT MODS Data: Clinical Variables
Variable (values mean +/- SD)
Survivors
NonSurvivors
Age (years)
8.5+6.7
8.5+7.2
NS
Weight (kg)
34.2+25.4
31.7+25.8
NS
PRISM at ICU Admit
14.3 + 8.2
16.2 + 9.7
NS
PRISM at CRRT Initiation
13.9 + 8.2
18.6 + 7.2
<0.001
CVP at CRRT Initiation
16.5 + 21.2
21.2+6.6
<0.003
GFR at CRRT Initiation
36.3 + 32.2 41.4 + 32.2
NS
% FO at CRRT Initiation
14.2 + 15.9 25.4 + 32.9
<0.005
No. of Pressors
1.4 + 1.0
1.7 + 1.1
Goldstein SL et al: Kidney International 2005
p-value
(t-test)
NS
ppCRRT MODS Data: Other Analyses
 77% of non-survivors die within 3 weeks
of ICU admission
 Survival rates similar by CRRT modality
(H 57%), (DF 53%), (HD 50%)
 Survival rates similar for patients on: 01 (53%), 2 (54%) or 3+ (39%) pressors
 Survival rates better for patients with:
<20% FO (59%) versus >20% FO (35%) at
CRRT initiation (p<0.001)
Goldstein SL et al: Kidney International 2005
ppCRRT: Anticoagulation
HepACG Protocol and Data Analyzed
 Heparin rates and boluses adjusted to keep activated
clotting times (ACT) 180-240 seconds
 Mean heparin rate (units/kg/hour)
 ACT measurement rate (#ACT’s/hour)
 #ACT’s less than 180 seconds
CitACG Protocol
 Regional citACG in CVVH-D mode
 ACD-A infusion into circuit arterial line to keep circuit
ionized calcium 0.25-0.5 mmol/L
 Central calcium chloride infusion to keep patient
ionized calcium between 1.1 and 1.3 mmol/L
ppCRRT: Anticoagulation
Complications
 Circuit clotting
 Patient systemic bleeding
 Metabolic
 Alkalosis
 Citrate lock: elevated total serum calcium with
decreased serum ionized calcium
Statistical Analysis
 Log-rank analysis comparing circuit survival between
hepACG, citACG, and noACG
 Circuit survival data censored for log-rank analysis
included circuits discontinued for: patient test, patient
death, change to hemodialysis, or scheduled circuit
change
ppCRRT- Anticoagulation
Center, Patient and Circuit Demographics
 Data collected from 1/1/01 through 10/31/02
 HepACG only:
3 centers (1 CVVH, 2 CVVHD)
 CitACG only:
2 centers
 HepACG changed to CitACG: 2 centers
 138 patients total
 18208 hours of CRRT circuit time
 230 hepACG circuits (52%) (9468.hrs)
 158 citACG circuits (36%) (6545 hrs)
 54 noACGcircuits (12%) (2185 hrs)
ppCRRT-Anticoagulation
Reasons for Circuit Change
ppCRRT: Anticoagulation
Cumulative Proportion Surviving (Kaplan-Meier)
Complete
Censored
1.0
Cumulative Proportion Surviving
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
20
40
60
80
100
120
140
Circuit Survival Time (hours)
160
180
200
220
Hep
Cit
No
ppCRRT Data: Anticoagulation
Mean duration
(hours)
% functioning @
60 hours
HepACG
CitACG
p
NoACG
p
NS
Hep or
CitACG
43+32
42+27
44+36
27+22
<0.01
69
69
NS
69
28
<0.01
ppCRRT: Anticoagulation
 43/158 citACG vs 58/230 hepACG clotted (NS)
 9 pts (hepACG) had systemic bleeding; 4 led to hepACG
discontinuation
 1 pt (hepACG) developed Thrombocytopenia leading to
hepACG discontinuation
 No systemic bleeding side effects were reported with
citACG; 4 pts developed alkalosis and 2 pts with hepatic
failure developed citrate lock.
 No correlation between circuit survival and (1) mean
hepACG rate (2) #ACT/hour or (3) # ACT’s less 180
seconds
ppCRRT Data: Anticoagulation
 HepACG and citACG protocols lead to
similar circuit survival times
 Side effects were rare for both but the
systemic bleeding noted with hepACG did
not occur with citACG
 CitACG is preferable for pediatric patients
at-risk for systemic bleeding
ppCRRT: Future Projects
• Cytokine clearance (3 patients entered)
• M10 PRISMA® filter study
• Nutrition and outcome
– Amino acid clearance
• Pharmacokinetic study
• Medication prescription based on volume of
distribution
• Bioimpedance
ppCRRT Sponsors
The ppCRRT Registry receives
grant funding from
Gambro Renal Products
Dialysis Solutions, Incorporated
Baxter Healthcare