The Prospective Pediatric CRRT ppCRRT Registry

1
The Prospective Pediatric CRRT (ppCRRT) Registry
Timothy E. BunchmanProfessor Nephrology
TransplantationGrand Rapids, MI
2
Outline

• 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

3
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 RCTs

4
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 1071309-12
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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

6
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

7
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 PIs 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

8
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 161067-1071, 2001
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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 Childrens Hospital
• Site data merged into single ppCRRT database,
  which resides solely at Texas Childrens Hospital
• Database modifications, based upon suggestions
  from the group, e-mailed back to sites

10
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 PIs
  institution
• No contracts exist between sites, only contract
  is between funding sources and SLG/Texas
  Childrens Hospital

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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

12
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 Childrens patient is 1003)
• Some sites IRBs prevent listing date of birth,
  so investigator calculates age

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Pre-CRRT Registry Data

• Demographics
• 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

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PRISM 2 score

• 14 variables, 5 organ domains
• 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 161110-6
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Pre-CRRT Registry Data CRRT Initiation

• Renal failure indices at CRRT initiation
• GFR (Schwartz)
• Urine output in previous 24 hours
• Percent fluid overload (FO)
• PRISM 2 score
• CVP
• Mean airway pressure
• Number of inotropic agents used
• Diuretics? (yes/no)

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Percent Fluid Overload Calculation


Fluid In - Fluid Out ICU Admit Weight
100
FO at CVVH initiation
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 1071309-12
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Registry PICU Data

• Cardiopulmonary
• Maximum inotrope doses
• Pressors weaned? (yes/no)
• MAP change
• ICU length of stay

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ppCRRT Registry Circuit Data

• 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 lt 180 seconds

19
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
• Total fluid intake
• Total fluid output
• Total and net ultrafiltration
• Percent blood volume UFd per hour

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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
• TNF-alpha
• IL-1beta
• IL-6
• IL-10
• GCSF

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ppCRRT Registry Patient Data Outcome

• Survival versus death (discharge from PICU)
• Attainment of target dry weight
• Reason to discontinue CRRT
• Death
• Regained renal function
• Underlying illness resolved
• Tolerates intermittent hemodialysis

22
ppCRRT Registry Circuit Data Outcome

• Filter life-span (hours)
• Reason for circuit change
• clotting
• access malfunction
• machine malfunction
• unrelated patient indication (e.g., needs CT
  scan)
• CRRT discontinued

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The ppCRRT Data

• Center and Patient Demographics
• Patient Sub-Populations
• Infants
• BMT
• Circuit Function
• MODS

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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 Childrens
• Boston Childrens
• Seattle Childrens
• UAB
• University of Michigan
• Mercy Childrens, KC
• Egleston Childrens, Atlanta

• All Childrens, St. Petersburg
• DC Childrens
• Columbus Childrens
• Packard Childrens, Palo Alto
• DeVos Childrens, Grand Rapids
• Cleveland Clinic

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Site Census
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Patient Demographics

• 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)

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ppCRRT Data Size Distribution
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ppCRRT Demographics
6

5

1

83


Pulmon
ary failure

10

7

3

70


Hypovolemic Shock

4

3

1

75


Drug toxicity

3

3

0

100


Other

13

7

6

54


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CRRT for Infants lt 10kg

• Previous retrospective data1 from 85 infants who
  received CRRT from 1993 to 2001
• 38 patients survived
• 25 patients lt 3 kg survived

1. Symons JM et al Am J Kidney Dis. 2003
May41(5)984-9
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ppCRRT Data Infants lt 10 kg

• 28 children lt 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

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ppCRRT Infant Prescription Data

• Modality CVVHD (25/28 children) and CVVH (3/28)
• Median blood flow 9 ml/kg/min
• (range 0 to ml/kg/min)
• Median dialysate or replacement fluid rates
• 2600 ml/hr/1.73M2
• (range 0 to 12,700 ml/hr/1.73M2)
• Median net ultrafiltration 780 ml/kg
• Median CRRT duration 4 days
• (range 1-99 days)

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ppCRRT Infant Survival Data
33
ppCRRT Infant Data Clinical Variables
34
Pediatric BMT/ARF Data

• Single center trials demonstrate survival rates
  of 42 for patients needing RRT1,2
• Recent study suggests maintenance of fluid
  overload lt 12 important for survival2
• Recent study showed aggressive CRRT in intubated
  BMT patients helpful3

1. Bunchman TE et al Pediatr Nephrol. 2001
161067-71 2. Michael M et al Pediatr Nephrol.
2004 1991-5 3. Alexander SA et al Blood
Purification 212003 (CRRT meeting)
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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

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ppCRRT BMT Data Clinical Variables
37
ppCRRT MODS Data
38
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

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ppCRRT MODS Data

• MOST COMMON PRIMARY DISEASES
• Sepsis (28.4)
• Cardiovascular shock (21.6)
• BMT/Malignancy (13.6)

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ppCRRT MODS Data Modality
41
ppCRRT MODS Data Survival
42
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
• 67less than 7 days

Goldstein SL et al Kidney International 2005
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ppCRRT MODS Data Clinical Variables
Goldstein SL et al Kidney International 2005
44
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 0-1
  (53), 2 (54) or 3 (39) pressors
• Survival rates better for patients with lt20 FO
  (59) versus gt20 FO (35) at CRRT initiation
  (plt0.001)

Goldstein SL et al Kidney International 2005
45
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 (ACTs/hour)
• ACTs 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

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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

47
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)

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ppCRRT-Anticoagulation
Reasons for Circuit Change
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ppCRRT Anticoagulation
50
ppCRRT Data Anticoagulation
51
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) ACTs
  less 180 seconds

52
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

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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

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ppCRRT Sponsors
The ppCRRT Registry receives grant funding from
Gambro Renal Products Dialysis Solutions,
Incorporated Baxter Healthcare