REstrictive Versus LIberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury
Phase: NA
Conditions: Acute Kidney Injury, Fluid Overload, Hypotension, Dialysis; Complications, Critical Illness
Sponsor: University of Pittsburgh

 
1
   
 
 
 
 
 
 
REstrictive versus LIberal rate of 
Extracorporeal Volume removal Evaluation 
in Acute Kidney Injury  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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RELIEVE-AKI Version 1.8 
 
2 | Page  
 
 
ACRONYM: 
RELIEVE-AKI 
 
 
VERSION: 
1.8 
 
 
PROTOCOL CO-CHAIRS: 
Raghavan Murugan, MD, MS, FRCP 
Professor of Critical Care Medicine 
Department of Critical Care Medicine 
University of Pittsburgh School of Medicine 
 
 
 
Kianoush Kashani, MD, MSc, FASN 
Professor of Medicine 
Division of Nephrology and Hypertension 
Division of Pulmonary and Critical Care Medicine 
Mayo Clinic College of Medicine 
 
 
 
Paul M. Palevsky, MD 
Professor of Medicine 
Renal and Electrolyte Division 
Department of Medicine 
University of Pittsburgh School of Medicine 
 
 
 
Chung-Chou H. Chang, PhD 
Professor of Medicine, Biostatistics, and Clinical and 
Translational Science 
Division of General Internal Medicine 
University of Pittsburgh School of Medicine 
 
 
 
 
SPONSOR: 
NIDDK R01 DK 128100 
 
 
DATE: 
12/13/2023 
 
 
 

 
3
1 
TABLE OF CONTENTS 
2 
Abbreviations and Definitions ................................................................................... 6 
2.1 
Abbreviations .............................................................................................................. 6 
2.2 
Definitions ................................................................................................................... 7 
3 
Executive Summary ................................................................................................... 9 
4 
Trial Summary......................................................................................................... 10 
5 
Trial Description ...................................................................................................... 14 
5.1.1 
Background ................................................................................................................................... 14 
5.1.2 
Pathophysiologic changes during UFNET ........................................................................................ 14 
5.1.3 
Assessment of intravascular volume ............................................................................................ 15 
5.1.4 
Current clinical practice ................................................................................................................ 15 
5.2 
Preliminary Work ....................................................................................................... 16 
5.2.1 
High UFNET rates During CKRT are associated with mortality and KRT dependence ..................... 16 
5.2.2 
Higher UFNET rates in the first 48 hours of CKRT are associated with mortality ........................... 17 
5.2.3 
Lower UFNET rates are also associated with mortality in patients with fluid overload ................. 17 
5.2.4 
Bayesian heterogeneity in treatment effect associated with the UFNET rate ................................ 17 
5.2.5 
Adverse events frequently occur during continuous dialysis ....................................................... 18 
5.2.6 
Multinational survey of attitudes towards UFNET practices .......................................................... 19 
5.2.7 
Clinician Equipoise to enroll in Clinical Trial ................................................................................. 19 
5.2.8 
Feasibility of enrollment ............................................................................................................... 20 
5.2.9 
Physician equipoise to enroll at UPMC and Mayo CLinic .............................................................. 20 
5.3 
Restrictive UFNET rate Strategy .................................................................................... 20 
5.3.1 
Potential advantages .................................................................................................................... 20 
5.3.2 
Potential disadvantages ................................................................................................................ 20 
5.4 
Liberal UFNET rate Strategy .......................................................................................... 21 
5.4.1 
Potential advantages .................................................................................................................... 21 
5.4.2 
Potential disadvantages ................................................................................................................ 21 
5.5 
A trial of UFNET strategy is warranted in critically ill patients ........................................ 21 
5.6 
Potential Pitfalls of the Proposed Study Design and Alternative Trial Designs .............. 22 
5.6.1 
Potential Pitfalls of the Proposed Study Design ........................................................................... 22 
5.6.2 
Alternative Study designs ............................................................................................................. 23 
5.7 
Objectives.................................................................................................................. 23 
5.8 
End points ................................................................................................................. 24 
5.8.1 
Primary outcome .......................................................................................................................... 24 
5.8.2 
Secondary Outcomes .................................................................................................................... 25 
5.8.3 
Safety Outcomes ........................................................................................................................... 25 
6 
Study Population and Enrollment ............................................................................ 26 
6.1 
Setting ....................................................................................................................... 26 
6.2 
Education and training ............................................................................................... 26 
6.3 
Randomization .......................................................................................................... 26 
6.3.1 
Rationale ....................................................................................................................................... 26 
6.3.2 
Randomization unit ....................................................................................................................... 27 
6.4 
Screening ................................................................................................................... 27 

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6.5 
Inclusion Criteria ........................................................................................................ 28 
6.6 
Exclusion Criteria ....................................................................................................... 28 
6.6.1 
Reasons for Exclusions .................................................................................................................. 28 
6.6.2 
Assessing Physician equipoise ...................................................................................................... 29 
6.7 
Informed Consent ...................................................................................................... 30 
6.8 
Study Enrollment ....................................................................................................... 30 
6.9 
Minorities and Women .............................................................................................. 30 
7 
Study Procedures .................................................................................................... 31 
7.1 
Restrictive UFNET group ............................................................................................... 31 
7.2 
Liberal UFNET group (Control arm) ............................................................................... 32 
7.3 
Discontinuation of Study Protocol .............................................................................. 33 
7.4 
Common strategies for ALL study groups .................................................................... 33 
7.4.1 
Study startup procedures ............................................................................................................. 33 
7.4.2 
Hemodynamic Management ........................................................................................................ 34 
7.4.3 
CKRT Procedures ........................................................................................................................... 35 
7.4.4 
Ventilator procedures ................................................................................................................... 36 
7.4.5 
Conservative Fluid Management Protocol ................................................................................... 36 
7.4.6 
Rescue Procedures ........................................................................................................................ 36 
7.4.7 
Facilitating compliance ................................................................................................................. 37 
8 
Data variables......................................................................................................... 37 
8.1 
Background assessments ............................................................................................ 37 
8.2 
Baseline assessments ................................................................................................. 37 
8.3 
Assessments during study .......................................................................................... 38 
8.3.1 
Hemodynamic monitoring during study startup .......................................................................... 38 
8.3.2 
Reference measurements ............................................................................................................. 38 
9 
Statistical Considerations ........................................................................................ 40 
9.1 
Statistical Methods .................................................................................................... 40 
10 Data collection and site monitoring ......................................................................... 40 
10.1 
Data Collection .......................................................................................................... 40 
10.2 
SITE Monitoring ......................................................................................................... 41 
11 Risk Assessment ...................................................................................................... 41 
11.1 
Risks of Restrictive UFNET Rate .................................................................................... 41 
11.2 
Risks of Liberal UFNET rate ........................................................................................... 41 
11.3 
Risk of adverse events ................................................................................................ 42 
11.4 
Minimization of risks .................................................................................................. 42 
11.5 
Potential Benefits ...................................................................................................... 44 
11.6 
Risks in relation to anticipated benefits ...................................................................... 44 
11.7 
Importance of the knowledge to be gained ................................................................. 44 
12 Human Subjects ...................................................................................................... 45 

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12.1 
Selection of Subjects .................................................................................................. 45 
12.2 
Justification of including vulnerable subjects .............................................................. 45 
12.3 
Informed consent ...................................................................................................... 45 
12.4 
Continuing consent .................................................................................................... 47 
12.5 
Withdrawal of consent ............................................................................................... 47 
12.6 
Identification of legally authorized representatives .................................................... 47 
12.7 
Justification of surrogate consent ............................................................................... 48 
12.8 
Additional safeguards for vulnerable subjects ............................................................. 49 
12.9 
Confidentiality ........................................................................................................... 49 
13 Safety Monitoring ................................................................................................... 49 
13.1 
Adverse events .......................................................................................................... 49 
13.2 
Serious Adverse Events .............................................................................................. 50 
13.3 
IRB and DSMB Reporting ............................................................................................ 51 
13.3.1 
IRB reporting ............................................................................................................................ 51 
13.3.2 
DSMB reporting ........................................................................................................................ 52 
14 Appendices ............................................................................................................. 54 
A. 
Calculation of NIH Gender-Specific Predicted Body Weight ............................................. 54 
B. KDIGO Criteria for Diagnosing and Staging of Acute Kidney Injury ....................................... 55 
B1. Diagnosis of AKI ..................................................................................................................................... 55 
B2 Staging of AKI ......................................................................................................................................... 55 
C. Deidentified data elements for screened, non-enrolled subjects .......................................... 56 
D. Continuous Kidney Replacement Therapy (CKRT) Management Procedures ........................ 57 
E. SOFA scoring system........................................................................................................... 58 
F. Time-Events Schedule ......................................................................................................... 59 
F1. General Data Collection ........................................................................................................................ 59 
F2. CKRT Data collection ............................................................................................................................. 60 
G. Adverse Event Reporting and Unanticipated problems ....................................................... 62 
G1. Determining relationship of adverse events to study procedures ....................................................... 62 
G2. Unanticipated problems (UP) ............................................................................................................... 62 
H. Data and safety monitoring board ...................................................................................... 63 
I. Common reasons for Acute Kidney Injury, Fluid Overload and Rapid UFNET ........................... 64 
I1. Common causes for AKI and FO ............................................................................................................. 64 
I2. Common reasons for rapid UFNET ........................................................................................................... 64 
15 References .............................................................................................................. 65 
 
 
 
 

 
6
2 
ABBREVIATIONS AND DEFINITIONS 
2.1 
ABBREVIATIONS 
 
AKI = Acute Kidney Injury 
COVID = Coronavirus Disease 
CKRT = Continuous Kidney Replacement 
Therapy 
CMO = Comfort Measures Only 
CVVHDF = Continuous Venovenous 
Hemodiafiltration 
CVVHD = Continuous Venovenous 
Hemodialysis 
CVVH = Continuous Venovenous 
Hemofiltration 
CVP = Central Venous Pressure 
CPR = Cardiopulmonary Resuscitation 
DSMB = Data and Safety Monitoring 
Board 
DNR = Do Not Resuscitate 
DNI = Do Not Intubate 
ECMO = Extracorporeal Membrane 
Oxygenation 
EMR = Electronic Medical Records 
ESKD = End Stage Kidney Disease 
FiO2 = Fraction of Inspired Oxygen 
FO = Fluid Overload 
GCS = Glasgow Coma Scale 
GRADE = Grading of Recommendations 
Assessment, Development and Evaluation 
HR = Heart Rate 
HRPO = Human Research Protection 
Office 
ICU = Intensive Care Unit 
IDH = Intradialytic Hypotension 
IHD = Intermittent Hemodialysis 
IBW = Ideal Body Weight 
IRB = Institutional Review Board 
ITT = Intent to Treat 
KDIGO = Kidney Disease Improving Global 
Outcomes  
LAR = Legally Authorized Representative 
MAP = Mean Arterial Pressure 
MBW = Measured Body Weight 
NBAC = National Bioethics Advisory 
Commission 
NIH = National Institute of Health 
OHRP = Office of Human Research 
Protection 
PaO2 = Partial pressure of arterial oxygen 
PBW = Predicted Body Weight 
RENAL = Randomized Evaluation of 
Normal versus Augmented Level of Kidney 
Replacement Therapy 
KRT = Kidney Replacement Therapy 
SAEs = Adverse events that are serious 
and unexpected and have a reasonable 
possibility that the event was due to a 
study procedure 
SBP = Systolic Blood Pressure 
SCUF = Slow Continuous Ultrafiltration 
SpO2 = Oxygen Saturation via pulse 
oximetry 
S/F = SpO2/FiO2 ratio 
SUSAR = Serious and Unanticipated 
Suspected Adverse Reactions 
SOFA = Sequential Organ Failure 
Assessment  
SW-CRT = Stepped-wedge Cluster 
Randomized Trial 
TPN = Total Parenteral Nutrition 
UPMC = University of Pittsburgh Medical 
Center 
UFNET = Net Ultrafiltration 
 

 
7
2.2 
DEFINITIONS 
 
Adverse Event: Any untoward medical occurrence associated with the use of a drug or a 
study procedure, whether or not considered related to the drug or study procedure. 
 
Adverse Reaction: Any adverse event caused by a drug or a study procedure. An adverse 
reaction is a subset of all suspected adverse reactions where there is a reason to conclude 
that the drug or the study procedure caused the event. 
 
Continuous Kidney Replacement Therapy (CKRT): A form of continuous dialysis frequently 
used to remove solutes and fluid in critically ill patients with acute kidney injury. 
 
Continuous Venovenous Hemodiafiltration (CVVHDF): A modality of continuous dialysis in 
which solute clearance occurs by diffusion and convection. 
 
Continuous Venovenous Hemodialysis (CVVHD): A modality of continuous dialysis in which 
solute clearance occurs only by diffusion. 
 
Continuous Venovenous Hemofiltration (CVVH): A modality of continuous dialysis in which 
solute clearance occurs only by convection. 
 
Slow Continuous Ultrafiltration (SCUF): A modality of continuous dialysis in which only fluid 
is removed without any solute clearance. 
 
Funding: National Institutes of Health (National Institute of Diabetes and Digestive and 
Kidney Diseases). 
 
Intention to Treat (ITT): All eligible and consented patients who undergo randomization will 
be included in the ITT cohort for the purposes of analyzing the primary and secondary study 
outcomes. 
 
Intravascular Volume: The circulating volume of red cells and plasma within arteries and 
veins.   
 
Intermittent Hemodialysis: A modality of dialysis done intermittently in which the solute 
clearance occurs by diffusion. 
 
Legal Representative: An individual, judicial, or other body authorized under applicable law 
to consent on behalf of a prospective patient to the patient's participation in the clinical 
study. 
 
Net Ultrafiltration: The net volume of fluid removed from the patient by the dialysis 
machine after discounting fluids administered (e.g., replacement fluids and dialysate given 
during CVVHDF) via the dialysis machine for the purpose of conducting the dialysis as well as 
fluids given to the patient (e.g., IV fluids, medications). 
 

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Net Ultrafiltration Rate: The rate at which the net ultrafiltration volume is removed from 
the patient adjusted for patient body weight and unit time (i.e., milliliters/kilogram/hour). 
This is the rate of depletion of circulating intravascular volume in the patient by fluid 
removal. 
 
Stepped-Wedge Cluster Randomized Trial: A clinical trial in which randomization occurs at 
the group level (e.g., ICU) rather than the individual patient level. Each group then “crosses 
over” from control to intervention at a randomized time point and multiple “time steps” of 
data collection occur. 
 
Study Day: The day of study enrollment is study day zero. The next day is study day one etc. 
 
Study Hospital: Defined as the hospital where the patient was enrolled. 
 
Study ICU: Defined as the study ICU in which patient was enrolled. 
 
Study Withdrawal: Defined as permanent withdrawal from study before completion of 
study activities. This does not include those subjects who have completed the protocol 
procedures or stopped procedures because they have reached independence from CKRT. If 
a patient or surrogate requests withdrawal from the study the clinician will seek explicit 
permission to continue data collection. 
 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility 
that the study procedures caused the adverse event. Reasonable possibility means there is 
evidence to suggest a causal relationship between the study procedures and the adverse 
event. A suspected adverse reaction implies less certainty about causality than an adverse 
reaction (21 CFR 312.32(a)). 
 
Ultrafiltration: Ultrafiltration is the process by which plasma water devoid of cells and 
colloids is forced by hydrostatic pressure across an extracorporeal, biosynthetic, 
semipermeable, hemofiltration membrane, resulting in removal of patient intravascular 
volume.  
 

 
9
3 
EXECUTIVE SUMMARY 
“Net ultrafiltration (UFNET),” also known as net fluid removal during kidney replacement therapy, has been 
used in the treatment of fluid overload among critically ill patients with acute kidney injury (AKI) for more 
than seven decades. However, the optimal rate of fluid removal (i.e., UFNET rate) remains uncertain, 
complications such as hypotension and cardiac arrhythmias occur frequently, and more than 40% of 
patients die. Observational studies in critically ill patients receiving continuous kidney replacement therapy 
(CKRT) show that UFNET rate has a “J” shaped association with mortality with both slower and faster UFNET 
rates associated with increased risk of death compared with moderate UFNET rates. 
 
Our long-term goal is to determine whether a restrictive UFNET rate strategy is associated with lower 90-
day mortality compared with a liberal UFNET rate strategy in a multicenter, randomized, clinical trial in 
critically ill patients with AKI. The overall objective of this randomized trial is to establish the feasibility of 
maintaining patients in the restrictive UFNET rate strategy during treatment with CKRT. Our central 
hypothesis is that a restrictive UFNET rate strategy embracing a “slow and steady” approach to fluid removal 
is associated with fewer complications, including cardiac arrhythmias, hypotension, and death, compared 
with a more liberal “sprint and pause” strategy among critically ill patients. 
 
We propose a prospective, two-center, unblinded, parallel-group, 2-arm, comparative effectiveness, 
stepped-wedge cluster-randomized trial among 112 critically ill patients with AKI treated with CKRT in 10 
ICUs across two hospital systems. The trial will be conducted at 5 ICUs at University of Pittsburgh Medical 
Center in Pittsburgh, PA, as well as 5 ICUs at Mayo Clinic, Rochester, MN. ICUs will be randomized 1:1 to 
either a restrictive or a liberal UFNET rate strategy. During the first six months, all ICUs will continue with a 
liberal UFNET rate strategy. Thereafter, one ICU will be randomized to deploy the restrictive UFNET rate 
strategy using a rolling randomization strategy. In the liberal group, the UFNET rate will be titrated between 
2.0-5.0 mL/kg/h and maintained throughout fluid removal. In the restrictive group, the UFNET rate will be 
titrated between 0.5-1.5 mL/kg/h and maintained throughout fluid removal. The UFNET rates used in both 
strategies are used in current clinical practice. 
 
The primary feasibility outcomes are a.) between-group separation in mean delivered UFNET rates of a 
minimum of 0.53 mL/kg/h; b.) protocol deviation defined as UFNET rate out of range of >0.5 mL/kg/h lower 
or higher than the assigned UFNET rate range for six consecutive hours; and c.) patient recruitment of one 
patient per  time window per ICU. We will explore the effects of restrictive and liberal UFNET rate groups on 
secondary outcomes such as daily and cumulative fluid balance, duration of kidney replacement therapy 
and mechanical ventilation, organ-failure free days, ICU and hospital length of stay, hospital mortality, and 
kidney replacement therapy dependence by hospital discharge.  
 
We will also assess safety outcomes such as intradialytic hypotensive and hypertensive episodes; 
intradialytic cardiac arrhythmias; emergent use of rescue UFNET rates higher than the assigned group for 
treatment of fluid overload; severe hypophosphatemia, hypokalemia, and hypocalcemia; CKRT circuit 
downtime due to filter clotting or clogging; discontinuation of fluid removal due to hemodynamic 
instability; inability to close surgical wounds due to edema; new organ dysfunction; diastolic and systolic 
dysfunction; pulmonary edema; ileus, bowel ischemia, anastomotic break down; pressure ulceration; 
wound infections; arterial or venous thrombosis; severe anemia requiring red cell transfusion, severe 
thrombocytopenia requiring platelet transfusions; and secondary infections. 
 
This feasibility trial will be used to support the rationale and design of a future multicenter phase III 
randomized trial to examine the effects of alternative UFNET rate strategies on patient-centered clinical 
outcomes.  

 
10
4 
TRIAL SUMMARY 
Title: REstrictive versus LIberal rate of Extracorporeal Volume removal Evaluation in Acute 
Kidney Injury (RELIEVE-AKI) – a comparative-effectiveness, stepped-wedge cluster-
randomized feasibility trial. 
 
Objective: To evaluate the feasibility of alternative UFNET rate strategies among critically ill 
adults with AKI and treated with CKRT. 
 
Study Design: Two-center, prospective, unblinded, parallel-group, 2-arm, comparative 
effectiveness, stepped-wedge cluster-randomized trial (SW-CRT) of two UFNET rate strategies 
conducted across 10 ICUs. 
 
1. We will emphasize early screening and protocol initiation and enroll a maximum of 
112 patients with AKI (KDIGO stage 3) who are treated with CKRT.  
2. We will assess attending physician’s equipoise twice daily as to whether fluid should 
be removed emergently or deferred. 
3. We will emphasize safety by initiating UFNET only when fluid removal is indicated as 
determined by the attending physician. 
4. UFNET rate will be calculated based on predicted body weight (PBW) to avoid 
confounding of actual weight by fluid overload. 
5. Study protocol will be continued until the end of UFNET while on CKRT.  
6. We will allow enrollment of patients initiated on net fluid removal for less than 48 
hours. 
7. We will emphasize that the final decision to set and titrate UFNET rate is at the 
discretion of the treating clinician. 
8. We will allow not removing fluid per study protocol when the goal is to maintain 
patient in euvolemia. 
 
9. Restrictive UFNET rate strategy  
a. UFNET rate will be initiated at 0.5 mL/kg/h of patient PBW. 
b. UFNET rate will be gradually increased 0.5 mL/kg/h as tolerated to maintain 
between 0.5-1.5 mL/kg/h throughout the study period. 
c. We will recommend rescue intervention with faster UFNET rates beyond 1.5 
mL/kg/h only for emergent treatment of respiratory distress or severe 
hypoxia due to fluid overload. 
 
10. Liberal UFNET rate strategy  
a. UFNET rate will be initiated at 0.5 mL/kg/h of patient PBW. 
b. UFNET rate will be gradually increased 0.5 mL/kg/h as tolerated to maintain 
between 2.0-5.0 mL/kg/h throughout the study period. 
c. We will emphasize safety by stipulating a maximum UFNET rate of 5.0 
mL/kg/h. 
d. We will recommend rescue intervention with faster UFNET rates beyond 5.0 
mL/kg/h only for emergent treatment of respiratory distress or severe 
hypoxia due to fluid overload. 

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11. Hemodynamic management 
a. We will recommend continuous monitoring of MAP in both the study arms. 
b. We will recommend withholding of UFNET in both arms for hypotensive 
episodes as determined by bedside clinicians. 
c. We will recommend titration of vasopressors by bedside clinicians, as 
needed, during fluid removal for hemodynamic management. 
 
12. CKRT management 
a. We will protocolize solute clearance with an effluent flow rate of 20-30 
mL/kg/h. 
b. We will recommend CKRT modality, hemofilter, blood flow rate, dialysate 
use, dialysate flow rate, buffers, pre- and post-filter substitution fluids, and 
anticoagulation as determined by attending nephrologist. 
c. We will recommend that CKRT machine is functioning at least 20 hours a day. 
d. We will recommend CKRT circuit change every 48-72 hours. 
 
13. Other care 
a. We will provide recommendations for conservative fluid management in 
both study arms. 
b. We will provide criteria for initiation of rapid rescue net ultrafiltration. 
 
Inclusion Criteria 
1. Age ≥18 years 
2. Stage 3 acute kidney injury according to the KDIGO criteria  
3. Started or intending to start CKRT for volume management 
4. Attending intensivist or nephrologist intending to remove net fluid using CKRT for at 
least 48 hours 
 
Exclusion Criteria 
1. Respiratory distress due to pulmonary edema or fluid overload in un-intubated 
patients 
2. Massive volume infusion (i.e., >200 mL/h for >6 hours of continuous infusion) 
3. No intention to remove net fluid as determined by attending intensivist or 
nephrologist 
4. Attending intensivist or nephrologist believes that the protocol will not be followed 
5. Continuous net fluid removal for >48 hours prior to study enrollment 
6. Patients on chronic outpatient hemodialysis 
7. Patients with history of, or current admission for kidney transplantation 
8. Patients on comfort measures only orders (i.e., CMO) 
9. Moribund not expected to survive >24 hours 
10. Confirmed pregnancy 
11. Patients treated with extracorporeal membrane oxygenation (ECMO), ventricular 
assist device (VAD), or intra-aortic balloon pump (IABP) 
12. Organ donors with neurological determination of death (i.e., brain dead donors) 
13. Drug overdose requiring CKRT for drug clearance 

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14. Enrollment in a concurrent interventional clinical trial with direct impact on fluid 
balance (e.g., >500 mL study drug administration) 
 
Assessing Attending Physician Equipoise: After meeting inclusion and none of the exclusion 
criteria, the attending intensivist or nephrologist will be asked twice daily if she/he strongly 
believed:  
a) emergent and rapid fluid removal should occur 
 
OR 
 
b) fluid removal should be defered 
 
If the answer is negative to both questions, the patient will be considered fully eligible and 
efforts to obtain informed consent from patient or LAR will commence. If a patient’s 
eligibility is excluded by an attending physician, the patient will be reconsidered for 
participation in the trial, and the physician will be re-approached later, provided the patient 
still meets inclusion criteria and none of exclusion criteria.  
 
Study Initiation Time Window: All patients must be consented and enrolled within 48 hours 
of meeting full eligibility. Time of signing the informed consent will be the study enrollment 
time. Once enrolled, the assigned intervention must be initiated within 24 hours.  
 
Discontinuation of Study Protocol: The study protocol will be continued until one of the 
following occurs:  
1. Attending intensivist or nephrologist determines that fluid removal is no longer 
necessary using CKRT. 
2. Attending intensivist or nephrologist decides to stop CKRT and transition the patient 
to IHD. 
3. The patient or surrogate decision-makers decide to withdraw life-sustaining 
treatment. 
4. The patient dies. 
5. Day 28 after study enrollment, whichever occurs first. 
 
Primary Outcomes: The primary feasibility outcomes are as follows: 
 
1. Between-group separation in mean delivered UFNET rates of a minimum of 0.53 
mL/kg/h. 
2. Protocol deviation defined as UFNET rate out of range of >0.5 mL/kg/h lower or 
higher than the assigned UFNET rate range for six consecutive hours. 
3. Patient recruitment of one patient per  time window per ICU. 
 
Secondary Outcomes 
 
1. Daily fluid balance 
2. Cumulative fluid balance 
3. Duration of kidney replacement therapy 
4. Duration of mechanical ventilation 

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5. Organ failure free days 
6. ICU length of stay 
7. Hospital length of stay 
8. Hospital mortality  
9. Dialysis dependence at hospital discharge 
 
Safety Outcomes 
 
1. Intradialytic hypotensive episodes  
2. Intradialytic hypertensive episodes  
3. Intradialytic new onset cardiac arrhythmias including supraventricular tachycardia, 
bradycardia, atrial fibrillation, ventricular tachycardia, ventricular fibrillation, and 
cardiac arrest 
4. Emergent use of rescue UFNET with rates higher than the assigned treatment arm 
5. Severe hypophosphatemia (<0.5 mg/dL) 
6. Severe hypokalemia (<3.0 mg/dL) 
7. Severe hypocalcemia (<1.90 mg/dL or ionized calcium <0.90 mmol/L) 
8. CKRT system downtime due to filter clotting or clogging 
9. Discontinuation of UFNET due to hemodynamic instability 
10. Inability to close surgical wounds due to edema 
11. New organ dysfunction 
12. Worsening of systolic or diastolic cardiac function on echocardiogram 
13. Worsening of pulmonary edema on chest X Ray and/or CT scan 
14. Worsening of ileus on abdominal X Ray and/or CT scan 
15. Bowel ischemia or anastomotic breakdown based on intraoperative findings 
16. Pressure ulcerations 
17. New wound infections 
18. New arterial or venous thrombosis 
19. Severe anemia requiring red cell transfusions 
20. Severe thrombocytopenia requiring platelet transfusions 
21. New secondary infections 
 
Sample Size/Interim Monitoring 
 
1. Using the sample size calculation for SW-CRT design, 111 patients will have 80% 
power at a two-sided alpha of 0.05 to reject the null hypothesis that the average 
UFNET rate was at least 0.53 mL/kg/h different between the two groups, using intra-
cluster correlation coefficient of 0.01, at a standard deviation of 0.75, and assuming 
mean UFNET rate of 1.0 mL/kg/h. We will enroll 112 subjects or 56 patients per group. 
 
2. The principal analysis will be intent-to-treat based upon randomization assignment. 
 
3. The trial progress will be evaluated by an independent Data and Safety Monitoring 
Board (DSMB). Being a feasibility study there will be no interim analyses. 
 
 

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5 
TRIAL DESCRIPTION 
5.1.1 BACKGROUND 
 
Fluid overload is present in two-thirds of critically ill patients with AKI before initiation of 
KRT,1 and despite fluid removal, mortality ranges between 40% to 60%.1-3 Emerging 
evidence suggests that the UFNET rate, a process of care variable, has a “J” shaped 
association with mortality (Figure 1). Slower UFNET rates, compared with faster rates, 
increase exposure to fluid overload and organ edema.2,4,5 In contrast, faster rates compared 
with slower rates are associated with hemodynamic instability, hypotension and ischemic 
organ injury.6 Thus, both slower and faster rates are associated with mortality compared 
with moderate UFNET rates in observational studies (Section 5.2).2,6-8 Thus, it is imperative to 
determine whether the UFNET rate-mortality relationship is causal. By establishing the 
feasibility of the restrictive UFNET rate group, this proposal will be the harbinger of a phase III 
trial to examine causal effects of UFNET rate on patient-centered clinical outcomes. 
 
Figure 1: An emerging conceptual model of the association between UFNET rate and 
mortality in critically ill patients. 
 
 
5.1.2 PATHOPHYSIOLOGIC CHANGES DURING UFNET 
 
As fluid is removed from the intravascular space during extracorporeal ultrafiltration, 
vascular refill occurs due to fluid shifting from the extravascular and interstitial spaces into 
the intravascular space. When the rate of fluid removal is higher than the rate of vascular 
refill, intravascular hypovolemia results in hypotension, decreased organ perfusion and 
ischemic injury.9,10 Although there are patient-related (e.g., comorbid conditions, reduced 
vasomotor tone) and other dialysis-related factors (e.g., reduced plasma osmolality due to 
solute clearance) that contribute to hemodynamic instability (Figure 2), several studies 
indicate that there is a direct relationship between higher UFNET rate, a process of care 
variable, and subsequent risk of hypotension and mortality.11-15  
 
Figure 2: Pathophysiology of hemodynamic instability during UFNET.  

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HIRRT, Hemodynamic instability related to kidney replacement therapy; CKRT, Continuous kidney replacement 
therapy; SLED, Slow extended daily dialysis; HD, hemodialysis; KRT, Kidney replacement therapy 
 
5.1.3 ASSESSMENT OF INTRAVASCULAR VOLUME 
 
Clinical assessment of intravascular volume is the holy grail of hemodynamic management 
in critically ill patients during ultrafiltration. Conventionally used hemodynamic parameters 
such as blood pressure, central venous pressure, pulmonary artery occlusion pressures are 
insensitive to early changes in intravascular volume. Although dynamic parameters such as 
pulse pressure variation, stroke volume variation, IVC collapsibility, passive leg raising are 
used to predict fluid responsiveness in critically ill patients, these technologies have several 
pitfalls.  
 
First, assessing pulse pressure variation and stroke volume variation to predict fluid 
responsiveness require that the patient is mechanically ventilated, not on low tidal volume 
ventilation, sedated and not spontaneously breathing. Second, IVC collapsibility and passive 
leg raising tests are not feasible as they cannot be done continuously. Third, while these 
technologies have been validated for predicting fluid responsiveness in critically ill patients, 
its validity for predicting intradialytic hypotension during fluid removal in critically ill 
patients is unknown. Other technologies such as hematocrit monitoring and bioimpedance 
analysis used in outpatients undergoing hemodialysis have not been validated in critically ill 
patients for fluid removal. Thus, current assessment of intravascular volume during 
ultrafiltration is mostly clinical based on surrogate measures such as blood pressure, fluid 
balance, and physical examination of the patient (e.g., capillary refill). 
 
5.1.4 CURRENT CLINICAL PRACTICE 
 
Currently there is a wide variation in the clinical practice of UFNET.16,17 Clinicians arbitrarily 
set UFNET rates based on blood pressure and severity of FO and titrate UFNET rate as 
tolerated by patient hemodynamics. However, blood pressure is insensitive to early changes 
in intravascular volume. Thus, hypotension can occur abruptly during fluid removal when 
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rate, hypotensive episodes complicate 19% to 97% of patients during CKRT,18-20  and 
intradialytic hypotension has been independently associated with three-fold increase in 
odds of death in critically ill patients.21  
 
5.2 
PRELIMINARY WORK 
 
5.2.1 HIGH UFNET RATES DURING CKRT ARE ASSOCIATED WITH MORTALITY AND KRT 
DEPENDENCE 
 
Using the Randomized Evaluation of Normal versus Augmented Level (RENAL) of the Renal 
Replacement Therapy trial cohort,3 we examined the association of the UFNET rate with 
outcomes. Of 1,434 patients, the 90-day mortality among patients who received UFNET rate 
>1.75 vs. 1.01-1.75 vs. <1.01 mL/kg/h was: 48.6% vs. 39.2% vs. 44.9%; P=0.01, respectively. 
Using Gray model, UFNET rates >1.75 mL/kg/h compared with rates 1.01-1.75 mL/kg/h 
(adjusted HR range, 1.44-1.77, P=0.004) and rates <1.01 mL/kg/h (aHR range, 1.51-1.66; 
P=0.01) was associated with lower survival. Every 0.5 mL/kg/h increase in UFNET rate was 
associated with 7% increased odds of death (aOR, 1.07; 95%CI, 1.00-1.15; Figure 3).6 Using a 
joint model, longitudinal increase and variation in UFNET rates over time was also associated 
with risk of death (β=0.056; P<0.001). UFNET rates of >1.75 mL/kg/h, were also associated 
with an increased risk of cardiac arrhythmias requiring treatment (36.8% vs. 30.8%; P=0.08).  
After accounting for competing risk of death, UFNET rates >1.75 mL/kg/h compared with 
UFNET rates, 1.01-1.75 mL/kg/h (cause-specific aHR, 0.79, 95%CI, 0.66 – 0.95) and UFNET rates 
<1.01 mL/kg/h (aHR, 0.69, 95%CI, 0.56-0.85) was associated with lower renal recovery and 
longer dependence on KRT.22  
We also investigated whether the daily fluid balance was a mediator of the relationship 
between UFNET rate and mortality, with baseline day one fluid balance as moderator.23 We 
found that a more negative daily fluid balance attenuated the harmful mortality effect of 
high UFNET (>1.75 mL/kg/h) rate group compared with moderate (1.01-1.75 mL/kg/h) and 
low (<1.01 mL/kg/h) UFNET rate groups. However, despite this attenuation, the high UFNET 
rate (>1.75 mL/kg/h) group remained significantly and directly associated with higher 
mortality compared with the moderate UFNET rate group (average direct effect, 1.10, 95%CI, 
1.04-1.16). These data add to the scientific premise and support the further need to conduct 
a randomized trial.23 
 
Figure 3: In the RENAL cohort, a patient receiving a UFNET rate of 1 mL/kg/h had a 30.6% 
predicted risk of death and a patient receiving UFNET rate of 4.5 mL/kg/h had a 64.5% 
predicted risk of death. 

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5.2.2 HIGHER UFNET RATES IN THE FIRST 48 HOURS OF CKRT ARE ASSOCIATED WITH 
MORTALITY 
 
We also examined the association between the UFNET rate within the first 48-hours of use of 
CKRT and hospital mortality in an independent cohort of 347 critically ill patients.7 UFNET 
rates >1.75 mL/kg/h compared with rates <1.01 mL/kg/h (aHR range, 1.27-4.18, P=0.03) was 
associated with 28-day mortality. In a subsequent mediation analysis, we found that this 
higher risk of death was not mediated by fluid balance, blood pressure, vasopressors, or 
electrolytes, implying that higher UFNET rates may have a direct causal effect on the risk of 
death.24 
 
5.2.3 LOWER UFNET RATES ARE ALSO ASSOCIATED WITH MORTALITY IN PATIENTS WITH 
FLUID OVERLOAD 
 
Using the UPMC ICU database of patients with >5% fluid overload and treated with CKRT 
and IHD (n=1,075), we evaluated the association of UFNET rate over 24-hour period and 1-
year mortality.2 We found that the UFNET rates <20 mL/kg/day, compared with rates >25 
mL/kg/day, were associated with increased risk-adjusted mortality. Of the CKRT subgroup, 
hourly UFNET rates <0.5 mL/kg/h compared with rates >1.0 mL/kg/h was also associated with 
death. These findings suggest that minimum UFNET rates of >20 mL/kg/day or >1.0 mL/kg/h 
using CKRT is associated with a lower risk of death among patients with fluid overload. Using 
Mayo Clinic data, UFNET rates <35 mL/kg/day compared with ≥35 mL/kg/day were also 
associated with the risk of major adverse kidney events.8 These studies suggest that a 
minimum rate of at least 1.0 mL/kg/h is associated with reduced mortality compared with 
slower rates.  
 
5.2.4 BAYESIAN HETEROGENEITY IN TREATMENT EFFECT ASSOCIATED WITH THE UFNET RATE 
 
Using cluster analysis in RENAL, the probability of harm associated with UFNET rates >1.75 
mL/kg/h was 99.6% compared with UFNET rates of 1.01-1.75 mL/kg/h, and 32.5% compared 
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metabolic acidosis, organ edema, those treated with mechanical ventilation and 
vasopressors (Figure 4).25 The probability of harm associated with UFNET rates between 1.01-
1.75 mL/kg/h compared with the rates <1.01 mL/kg/h was only 0.2%. Of patients who are 
hemodynamically unstable with cardiovascular sequential organ failure assessment (SOFA) 
score of 3 or more, both UFNET rates >1.75 mL/kg/h and rates <1.01 mL/kg/h were 
associated with increased mortality compared with rates 1.01-1.75 mL/kg/h.25  
Figure 4: Posterior probability of the UFNET rate group treatment effect (log [HR]) in each 
cluster. The tables contain the probability that the hazard ratio for 90–day mortality in the 
high UFNET group (plots A and B) is above 0 (i.e., a hazard ratio above 1, suggestive of 
harm). 
 
5.2.5 ADVERSE EVENTS FREQUENTLY OCCUR DURING CONTINUOUS DIALYSIS 
 
In a cohort of 1,743 patients receiving continuous KRT at Mayo Clinic ICUs, intradialytic 
hypotension (IDH) occurred frequently.18 IDH was defined as MAP ≤60 mmHg, SBP 
<90mmHg or a decline in SBP >40mmHg from baseline, a positive fluid balance >500mL or 
increased vasopressor requirement. Early IDH occurred in 1,124 patients (64.6%) and was 
independently associated with mortality (Odds Ratio, 1.56, 95% CI: 1.25–1.9). IDH within the 
first hour occurred in 43% of patients, and 81% of patients had new onset of cardiac 
arrhythmias.19 Sinus tachycardia was present in 51% and atrial fibrillation in 11% (Table 1). 
 
In a multinational survey of ICU practitioners in 80 countries17 IDH was reported by 20% 
(range, 20%–38%) of practitioners. When IDH occurred, practitioners decreased the rate of 
fluid removal (70.3%; Figure 5); started or increased vasopressor dose (51.5%); completely 
stopped fluid removal (35.8%); and/or administered a fluid bolus (31.6%) for treatment.17 
Thus, IDH and interventions for IDH are common during KRT. Using the Acute Renal Failure 
Trial Network cohort,26 we found that IDH events occurred in 43.2% of patients. Of all 
hypotensive complications, hypotension requiring vasopressor use, discontinuation of KRT, 
and other interventions occurred in 13.2%, 8.4%, and 78.4%, respectively. 
 
 
Table 1: Incidence of adverse events during continuous KRT 
 

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Parameter 
No. (%) 
Hypotension 
258 (43) 
Sinus tachycardia 
306 (51) 
Atrial fibrillation 
64 (11) 
Atrial flutter 
6 (1) 
Ventricular tachycardia 
14 (2) 
Sinus bradycardia 
43 (7) 
Ventricular fibrillation 
19 (3) 
Asystole 
20 (3) 
Others 
12 (2) 
Cardiac arrest 
28 (5) 
 
 Figure 5: Reported interventions performed for intra-dialytic hypotension by critical care 
practitioners 
5.2.6 MULTINATIONAL SURVEY OF ATTITUDES TOWARDS UFNET PRACTICES 
 
In a survey of 80 countries, two-thirds of practitioners (71%, regional range, 55%-95.5%) 
reported using CKRT for volume management.16,17 In the U.S., the reported initial median 
UFNET rate prescription was 100 (IQR, 78-200) mL/h and the maximum rate was 285 (IQR, 
200-341) mL/h for hemodynamically stable patients and 51 (IQR, 25-100) mL/h for 
hemodynamically unstable patients. For an average 80-kg patient, a UFNET volume of 285 
mL/h would be equivalent to a rate of 3.56 mL/kg/h, and 341 mL/h would be equal to a rate 
of 4.26 mL/kg/h in hemodynamically stable patients. These data suggest that the UFNET rates 
used in the liberal group is within the range of clinical practice. More than 80% of critical 
care practitioners believed a protocol-based fluid removal would be useful. 
 
5.2.7 CLINICIAN EQUIPOISE TO ENROLL IN CLINICAL TRIAL 
 
In our survey, we asked critical care practitioners about attitudes towards UFNET practice and 
equipoise to enroll patients in a clinical trial of protocol based UFNET.27 Across regions, most 
practitioners (90.0%, range, 84.5% – 91.7%) agreed that early UFNET would be beneficial and 
protocol (81.4%, range, 62.3% – 88.3%) outlining the rate, volume and duration of UFNET 
would be useful. Two-thirds of clinicians (78.3%, range, 72.7% – 83.7%) indicated that they 
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5.2.8 FEASIBILITY OF ENROLLMENT 
 
In 2019, 412 unique patients were admitted to UPMC Presbyterian hospital ICUs and 
received treatment with CKRT. This averages 34 patients per month, and thus, an average of 
2 patients per month enrollment would be feasible. The average duration of treatment with 
CKRT was four days. At Mayo Clinic, approximately 15 patients per month were treated with 
CKRT across the 3 ICUs in 2020. Thus, enrolling 144 patients across six ICUs over 30 months 
is feasible. 
 
5.2.9 PHYSICIAN EQUIPOISE TO ENROLL AT UPMC AND MAYO CLINIC 
 
Both at the UPMC and the Mayo Clinic, fluid removal is co-managed by intensivists and 
nephrologists. Thus, we conducted an email survey of intensivists and nephrologists (n=43) 
at both clinical sites. An overwhelming number of physicians (n=41; 95%) were willing to 
enroll in this trial. Reasons for unwillingness included massive fluid overload with ongoing 
large infusions, refractory hypoxemia, inability to close the abdominal surgical wound due 
to edema, and the decision already made to remove fluid rapidly. Our study design already 
excludes such patients. We have also discussed the protocol with ICU directors, chiefs of 
nephrology, intensivists, and nephrologists, at the Mayo Clinic and at the UPMC, and they 
are willing to aid with screening and enrollment. 
 
5.3 
RESTRICTIVE UFNET RATE STRATEGY 
 
5.3.1 POTENTIAL ADVANTAGES 
 
There are several potential benefits to restrictive UFNET rate strategy. First, it will allow more 
time for vascular refill and will reduce blood pressure variability and hypotensive episodes 
as both intradialytic blood pressure variability and hypotensive episodes have been 
associated with ischemic organ injury and increased mortality.11,21 Second, by preventing 
hypotensive episodes, restrictive UFNET rate is likely to reduce the need for subsequent 
interventions such as completely stopping UFNET, fluid administration, starting or increasing 
the dose of new vasopressor. Both discontinuing UFNET and administering fluids will offset 
any potential benefit of UFNET and increase risk of fluid overload. Third, restrictive UFNET 
rates may preserve myocardial blood flow and prevent episodes of cardiac arrhythmias. 
Fourth, restrictive UFNET rate may reduce the workload and burden on nursing staff due to 
decreased number of interventions required to treat intradialytic hypotension.  
 
5.3.2 POTENTIAL DISADVANTAGES 
 
Restrictive UFNET rate strategy may theoretically be associated with longer tissue exposure 
to fluid overload and may increase time to achieving euvolemia. Prolonged exposure to fluid 
overload may impair kidney recovery, prolong the duration of kidney replacement therapy, 
or increase ventilator dependence. However, the risks of prolonged exposure to FO 
associated with restrictive UFNET rate strategy must be balanced against the risk of ischemic 
organ injury due to hypotensive episodes and blood pressure variability associated with 
faster and more liberal UFNET rates used in clinical practice. 

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5.4 
LIBERAL UFNET RATE STRATEGY 
 
5.4.1 POTENTIAL ADVANTAGES 
 
Liberal UFNET rate based on hemodynamics may result in better and earlier volume control 
including achieving daily negative fluid balance and overall, less positive cumulative fluid 
balance as documented in observational studies.2,6 By varying UFNET across a range of UFNET 
rates, the liberal UFNET group affords more flexibility to clinicians for rapid fluid removal for 
treatment of fluid overload.  
 
5.4.2 POTENTIAL DISADVANTAGES 
 
Liberal UFNET rate strategy might be associated with rapid and unpredictable decline in 
intravascular volume. Intravascular hypovolemia in turn reduces cardiac preload.9 Decreases 
in preload is associated with lower cardiac output and hypotension. Moreover, faster and 
frequent titration of UFNET will increase the workload for the clinicians, poor compliance 
with closer monitoring of hemodynamics, and increase subsequent interventions for 
treatment of hypotensive episodes including bolus fluid administration thereby offsetting 
potential benefits of rapid fluid removal. 
 
5.5 
A TRIAL OF UFNET STRATEGY IS WARRANTED IN CRITICALLY ILL PATIENTS 
 
There are several compelling reasons why trial of UFNET rate strategy should be conducted. 
First, the net risk-benefits of treatment of fluid overload and UFNET rate on clinical outcomes 
remains unclear as current observational studies have significant limitations. Thus, there is a 
critical need to determine the optimal process of care for patients undergoing UFNET. In the 
absence of such a knowledge, effective treatment of fluid overload and safe provision of 
UFNET among critically ill patients will be problematic. 
 
Second, the current clinical practice of UFNET is highly variable in ICUs and is not evidenced-
based. Generation of robust evidence will result in development and adoption of clinical 
practice guidelines and is likely to reduce variability in clinical practice.  
 
Third, critically ill patients are a more vulnerable population sensitive to hemodynamic 
perturbations. For instance, studies show that more than 19% to 97% of patients on CKRT 
have episodes of sudden hypotension,18-20 and IDH is associated with mortality in critically ill 
patients.21 Thus, generation of robust evidence base is needed to ensure there is no harm 
associated with current clinical practice as the existing practice is to use liberal UFNET rates in 
patients with stable hemodynamics until hypotension occurs.  
 
Fourth, more than two-thirds of critical care practitioners surveyed indicated that they have 
equipoise to enroll patients in a clinical trial of protocol-based UFNET strategy suggesting 
uncertainty as to the optimal approach to fluid removal in critically ill patients. Finally, 
several aggressive interventions in critically ill patients have not found to be associated with 
improved outcomes, and perhaps harmful, underpinning the principle of “less is more”. For 
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volume strategy was associated with increased risk of ventilator-induced lung injury and 
mortality than lower tidal volume ventilation.28 Thus, dialysis-associated organ injury due to 
faster rate of fluid removal needs further evaluation. 
 
5.6 
POTENTIAL PITFALLS OF THE PROPOSED STUDY DESIGN AND ALTERNATIVE TRIAL 
DESIGNS 
 
5.6.1 POTENTIAL PITFALLS OF THE PROPOSED STUDY DESIGN 
 
5.6.1.1 Why use Predicted Body Weight for Dosing UFNET? 
 
In this protocol, we propose to use predicted body weight (PBW) for setting UFNET rate in 
both treatment groups. PBW will be estimated using a gender-specific calculator (Appendix 
A) based on measurement of patient’s height by research staff at the time of study 
enrollment. We chose PBW for the following reasons: (i.) PBW has been used in several NIH 
sponsored ICU trials,28,29 (ii.) shown closely to approximate with IBW in males and females,30 
(iii.) free of confounding by FO and catabolism due to critical illness, and other 
measurement errors by nursing staff, (iv.) could be precisely determined at study 
enrollment from patient height accurately measured by trained research staff. 
 
We chose not to use measured body weight (MBW) and actual body weight for the 
following reasons. First, precise premorbid MBW is unknown in most critically ill patients. 
Weight documented in EMR during prior hospitalization cannot be used as a surrogate for 
premorbid weight because of confounding by underlying illness. Second, index hospital 
admission weight is likely to be confounded by the underlying condition that led to 
hospitalization (e.g., dehydration from sepsis may result in underestimation, and fluid 
overload from underlying worsening congestive heart may result in overestimation of 
MBW). Third, retrospective collection of hospital and ICU admission weights are prone to 
measurement errors31 and also confounded by daily fluid intake and output which are 
inaccurately documented on hospital wards.32 Fourth, following initiation UFNET, the patient 
MBW is likely to fluctuate widely with decreasing weight overtime due to UFNET and due to 
catabolic nature of many ICU illness.  
 
5.6.1.2 Why not use both IHD and CKRT for UFNET instead of only CKRT? 
 
We chose CKRT for this feasibility trial instead of IHD for the following reasons: (i.) our 
survey revealed that more than 70% of respondents indicated using CKRT for volume 
management in the ICU,27 (ii.) evidence suggests that CKRT is superior to IHD for volume 
control in critically ill patients due to continuous nature of ultrafiltration over a 24-hour 
period in patients with severe fluid overload,33 (iii.) the UFNET rates used during IHD would 
be very different to that of UFNET rates used during CKRT thus confounding the effect of 
UFNET rates while on CKRT, on clinical outcomes, iv.) the optimal ultrafiltration rates in 
critically ill patients with AKI treated with CKRT is uncertain; and v.) CKRT is the predominant 
modality used for volume management at the UPMC and the Mayo Clinic ICUs. 
 

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5.6.2 ALTERNATIVE STUDY DESIGNS 
 
We considered several alternative study designs in addition to the proposed study design 
(Table 2). 
 
Table 2: Strengths and Weaknesses of Alternative Study Designs 
 
Intervention 
Control 
Strengths 
Weakness 
<0.5 mL/kg/h 
>1.75 mL/kg/h 
• Less episodes of hemodynamic 
instability in the intervention 
arm 
 
• More flexibility in dosing in the 
control arm 
 
• May not be feasible to randomize to 
a rate <0.5 mL/kg/h as most 
clinicians would consider UFNET rate 
<0.5 mL/kg/h is clinically insignificant 
volume removal. 
• Exposure to wide UFNET rate ranges in 
the control arm. 
• May increase risk of hemodynamic 
instability in the control arm 
0.5 – 1.0 mL/kg/h 
1.7 – 2.2 mL/kg/h 
• More flexibility in the slower 
arm 
 
• Less episodes of hemodynamic 
instability in the intervention 
arm 
• Too narrow range in the control arm 
and does not represent current 
clinical care. 
• Most clinicians would consider UFNET 
rate <1.0 mL/kg/h is clinically 
insignificant volume removal. 
1.0 mL/kg/h 
Clinicians 
determine the 
UFNET rate 
• Mirrors clinical practice in the 
control arm 
• Variability among clinicians in 
titrating UFNET 
• May not have adequate separation 
between the two treatment arms to 
detect meaningful difference. 
1.0 – 1.7 mL/kg/h 
>2.0 mL/kg/h 
• Observational studies suggest 
lower mortality in the 
intervention arm 
• Exposure to wide UFNET rate ranges in 
the control arm 
UFNET rate guided 
by continuous 
monitoring of 
intravascular 
volume status 
(e.g., pulse 
pressure 
variation, stroke 
volume variation) 
UFNET rate guided 
by traditional 
hemodynamic 
monitoring (i.e., 
heart rate, MAP) 
• Precision UFNET rate guided by 
intravascular volume assessment 
• May reduce episodes of 
hemodynamic instability 
 
• Functional hemodynamic monitoring 
has only been validated for fluid 
administration but not fluid removal 
• Most clinicians do not use functional 
hemodynamic monitoring for fluid 
removal 
• Requires patient to be on a 
controlled mode of ventilation with 
no spontaneous respiratory effort to 
accurately assess pulse pressure and 
stroke volume variation. 
 
5.7 
OBJECTIVES 
 
Primary Objective 
 
The primary objective of this randomized trial is to assess the feasibility of maintaining 
patients in restrictive and liberal UFNET rates, adherence to the protocol, and assess 
recruitment rate in preparation for a large multicenter randomized clinical trial. 
 

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5.8 
END POINTS 
 
5.8.1 PRIMARY OUTCOME 
 
The three primary feasibility outcomes are as follows: 
 
1. The between-group difference in mean delivered UFNET rate: The primary objective is to 
measure a minimum of 0.53 mL/kg/h separation in the delivered patient mean UFNET 
rates between the restrictive and liberal UFNET rate groups. We chose between-group 
separation as a feasibility metric because it is a robust measure of adherence to complex 
protocols and has been used in ICU trials assessing the feasibility of frequently titrated 
interventions.34,35 Specifically, we reasoned that a larger study would not be feasible if 
the separation in the UFNET rates were less than 0.5 mL/kg/h. We chose 0.5 mL/kg/h as a 
clinically meaningful difference because our preliminary data indicated that a 0.50 
mL/kg/h increase in UFNET rate is associated with increased mortality.6 
 
2. Protocol adherence: Adherence assessed by protocol deviation varies as the function of 
the definition of deviation and the frequency of measurements. Thus, in this trial, we 
will define protocol deviation a priori as delivered UFNET rate that lies >0.5 mL/kg/h 
outside of the target UFNET rate range in the assigned treatment group for greater than 
six consecutive hours during fluid removal without significant changes in MAP (i.e., MAP 
<65 mmHg or ≥90 mmHg). As such, out of range UFNET rates >0.5 mL/kg/h beyond the 
target UFNET rate range in the assigned treatment group will not constitute a protocol 
deviation when the bedside team titrated the UFNET rate as required to manage the 
patient hemodynamics (i.e., when clinicians appropriately decreased rate or stopped 
fluid removal for hypotension; increased rate for hypertension or for treatment of 
respiratory distress due to fluid overload and pulmonary edema).  
 
We chose the above metric for protocol deviation because with complex interventions, 
as the frequency of monitoring increases, so does the resources required to track 
protocol adherence. Close monitoring of protocol deviations is unlikely in trials that lack 
resources, introducing a risk of ascertainment bias. In contrast, with very frequent 
monitoring of continuous interventions, the likelihood of recording protocol deviations 
increases but the clinical impact of each deviation diminishes proportionately. Similarly, 
criteria for protocol deviations that are too sensitive would exaggerate the impact of 
protocol deviations beyond what is clinically important and unduly undermine the 
apparent feasibility and internal validity of the trial.35  
 
All reasons for non-adherence will be recorded for both groups using pretested 
taxonomy distinguishing clinical reasons (e.g., hypotension, hypertension, difficulty in 
oxygenation, respiratory distress, hemodynamic instability, attending override of 
protocol) and research-related reasons (e.g., consent withdrawal). 
 
3. Recruitment rate: A successful recruitment rate will be defined as achieving an 
enrollment rate of 1 patient per ICU per time window during the trial. While this 
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will be reviewed monthly, and the numbers of missed eligible patients will be 
investigated. If applicable, we will discuss barriers to enrollment and use well-developed 
strategies to improve recruitment. Therefore, recruitment will be maximized as 
necessary over the course of the trial. The recruitment metric will be measured and 
interpreted at the end of the trial by calculating the mean number (standard deviation) 
of recruited patients per active screening month. 
 
5.8.2 SECONDARY OUTCOMES 
1. Daily fluid balance 
2. Cumulative fluid balance 
3. Duration of kidney replacement therapy 
4. Duration of mechanical ventilation 
5. Organ failure free days 
6. ICU length of stay 
7. Hospital length of stay 
8. Hospital mortality  
9. Dependence on kidney replacement at hospital discharge 
 
5.8.3 SAFETY OUTCOMES 
1. Intradialytic hypotensive episodes  
2. Intradialytic hypertensive episodes  
3. Intradialytic new onset cardiac arrhythmias including supraventricular 
tachycardia, bradycardia, atrial fibrillation, ventricular tachycardia, ventricular 
fibrillation, and cardiac arrest 
4. Emergent use of rescue UFNET with rates higher than the assigned treatment arm 
5. Severe hypophosphatemia (<0.5 mg/dL) 
6. Severe hypokalemia (<3.0 mg/dL) 
7. Severe hypocalcemia (<1.90 mg/dL or ionized calcium <0.90 mmol/L) 
8. CKRT system downtime due to hemofilter clotting or clogging 
9. Discontinuation of UFNET due to hemodynamic instability 
10. Inability to close surgical wounds due to edema 
11. New organ dysfunction  
12. Worsening of systolic or diastolic cardiac function on echocardiogram 
13. Worsening of pulmonary edema on chest X Ray and or/or CT scan 
14. Worsening of ileus on abdominal X Ray and/or CT scan 
15. Bowel ischemia or anastomotic breakdown based on intraoperative findings 
16. Pressure ulcerations 
17. New wound infections 
18. New arterial or venous thrombosis 
19. Severe anemia requiring red cell transfusions   
20. Severe thrombocytopenia requiring platelet transfusions 
21. New secondary infections 
 
 
 

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6 
STUDY POPULATION AND ENROLLMENT 
6.1 
SETTING 
 
The trial will accrue a maximum of 112 patients. Participants will be enrolled from 5 ICUs at 
the UPMC, Pittsburgh, PA, and 5 ICUs at the Mayo Clinic, Rochester, MN. At the UPMC, we 
will include the Transplant ICU, Medical ICU, and the Surgical Trauma ICU at the 
Presbyterian hospital, and the Medical-surgical ICU and Neuro-ICU (ICU8) at the Mercy 
hospital. At Mayo Clinic, we will enroll at the Medical-surgical ICU from the Methodist 
campus, and the Cardiac, Medical, Surgical, and CV Surgery ICUs at St. Mary’s campus. No 
study ICU has a protocolized approach to fluid removal, and instead, clinicians determine 
the timing and rate of UFNET. All ICUs use specialized ICU nurses trained and certified in 
delivering CKRT. We expect each ICU to recruit one or more subjects per time window based 
on annual volume and past enrollment, allowing complete enrollment in 2.0 years. 
 
6.2 
EDUCATION AND TRAINING 
 
One month before patient recruitment begins at each site, we will prepare standardized 
educational materials for academic detailing, including slide presentations, videos, and 
“virtual” sessions, prominently placed posters, and pocket cards. We will provide study 
orientation to clinicians at the study ICUs using the following methods: i.) we will create 
education materials including frequently asked questions (FAQs) and power point 
presentation that will be circulated via newsletters and emails; ii.) we will present the study 
at clinician meetings and answer questions; iii.) we will schedule webinars for the clinicians 
before study initiation and at periodic intervals; iv) we will provide just-in-time training for 
the ICU nurse before starting the study intervention; v.) we will create a short video 
regarding the study protocol that will be embedded in the web application and mounted on 
the tablet computer that the clinicians can watch at any time; and vi.) we will also provide 
impromptu training sessions, as needed. 
 
6.3 
RANDOMIZATION  
 
6.3.1 RATIONALE 
 
In a Stepped-Wedge Cluster Randomized Trial (SW-CRT)36-38 a) randomization occurs at the 
group level (e.g., ICU) rather than the individual level (e.g., patient); b) each group "crosses 
over" from the control to intervention at a randomized time point; and c) multiple “time 
steps” of data collection occur.  
We chose SW-CRT because i.) individual patient-level randomization is scientifically 
problematic due to a high risk of contamination between the two UFNET rate groups (i.e., 
Hawthorne effect), ii.) a cluster RCT is infeasible because ICUs are unwilling to continue with 
a single intervention (i.e., only restrictive or liberal UFNET rate group) during the entire study 
period, iii.) each ICU act as their control and thus fewer units or clusters are required than a 
traditional cluster-randomized trial,39 iv.) to alleviate logistical challenges associated with 
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provide adequate time for training all staff on liberal UFNET rate group before transitioning 
to the restrictive group, v.) offers the opportunity to evaluate ICU-level effectiveness of a 
new intervention, and vi.) to study the effect of time on intervention effectiveness (i.e., time 
since the introduction and delayed treatment effects). 
 
6.3.2 RANDOMIZATION UNIT 
 
Following best practice recommendations for evaluation of system-level interventions, the 
unit of randomization is the cluster (e.g., ICU) rather than the individual patient.40 During 
the first six months of data collection, all sites will continue with a liberal UFNET rate 
strategy. Thereafter, one ICU will be randomized to deploy the restrictive UFNET rate strategy 
every two months or when a maximum of 10 patients have been enrolled, whichever occurs 
first, and stay in this strategy until the end of the study (Figure 6). 
 
Figure 6: Stepped-wedge cluster-randomized trial design 
 
 
We will use a computer-generated randomization scheme to determine the order in which 
each ICU would cross over from the liberal group to the restrictive group, with new 
crossover occurring every two months or whenever 10 patients have been enrolled, 
whichever occurs first. This trial design will allow us to stagger the implementation of the 
restrictive UFNET strategy while maintaining concurrent control over data collection in the 
ICUs that were not yet using the restrictive UFNET strategy. 
 
6.4 
SCREENING 
 
The overall strategy is to screen and enroll early. Research coordinators will screen the ICU 
population at each participating site using electronic medical records with screening sweeps 
occurring in the morning and afternoon. We will screen every new ICU patient with severe 
AKI (KDIGO stage 3) and follow up with each screened patient with AKI daily for the need for 
CKRT. The coordinator will confirm the inclusion and exclusion criteria as listed in Section 
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6.5 
INCLUSION CRITERIA 
 
1. Age ≥18 years 
2. Stage 3 acute kidney injury according to KDIGO criteria (Appendix B) 
3. Started or intending to start CKRT for volume management 
4. Attending intensivist or nephrologist intending to remove net fluid using CKRT for at 
least 48 hours 
 
6.6 
EXCLUSION CRITERIA 
 
1. Respiratory distress due to pulmonary edema or fluid overload in un-intubated 
patients 
2. Massive volume infusion (i.e., >200 mL/h for >6 hours of continuous infusion) 
3. No intention to remove net fluid as determined by the attending intensivist or 
nephrologist 
4. Attending intensivist or nephrologist believes that the protocol will not be followed 
5. Continuous net fluid removal for >48 hours before study enrollment 
6. Patients on chronic outpatient hemodialysis 
7. Patients with history of, or current admission for kidney transplantation 
8. Patients on comfort measures only orders (i.e., CMO) 
9. Moribund not expected to survive >24 hours 
10. Confirmed pregnancy 
11. Patients treated with extracorporeal membrane oxygenation (ECMO), ventricular 
assist device (VAD), or intra-aortic balloon pump (IABP). 
12. Organ donors with neurological determination of death (i.e., brain dead organ 
donors) 
13. Drug overdose requiring CKRT for drug clearance 
14. Enrollment in a concurrent interventional clinical trial with direct impact on fluid 
removal (e.g., >500 mL study drug administration) 
 
6.6.1 REASONS FOR EXCLUSIONS 
 
Patients <18 years old are excluded because of limited data on UFNET rate on these 
individuals. In addition, we will only be enrolling patients from adult ICUs, and the staff may 
be less well-trained in CKRT and UFNET practices in children. Patients with severe pulmonary 
edema, respiratory distress who are not on mechanical ventilator, and massive volume 
infusion are excluded because they may have emergency indication for rapid fluid removal, 
and it would be considered unethical to randomize patients to a restrictive UFNET rate. 
Patients with anticipated net fluid removal <48 hours are excluded because KRT might be 
terminated early, or patients might be transitioned to IHD and thus the exposure to UFNET 
rate during CKRT would be minimal. Patients with UFNET for more than 48 hours are 
excluded because UFNET rates used prior to study enrollment may confound assessment of 
outcomes.  
 
Patients on chronic outpatient dialysis are excluded because the UFNET rates used in IHD are 
different than UFNET rates used in CKRT and thus would confound outcome assessment. 

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Patients with kidney transplantation are excluded because their prognoses are different 
from those of AKI or complicates the assessment of secondary outcomes (e.g., kidney 
function recovery). Criteria 9 and 10 exclude patients who may not survive to important 
study endpoints or whose underlying condition complicates assessment of at least one of 
the outcomes. Criteria 11 is excluded as there is not sufficient data on UFNET rates in 
pregnant women. Criteria 12 is excluded as ECMO, VAD, and IABP precludes UFNET rate 
titration based on hemodynamics as well as confounds the assessment of influence of UFNET 
rates on patient hemodynamics. Brain-dead organ donors are excluded as one or more of 
the outcomes cannot be assessed; and drug overdose requiring KRT is excluded because 
there is not sufficient data on UFNET rates in such patients. 
 
6.6.2 ASSESSING PHYSICIAN EQUIPOISE 
 
If all inclusion and none of the exclusion criteria are met, the patient will be considered 
provisionally eligible (Figure 7). Once provisionally eligible, the attending intensivist or 
nephrologist will be asked twice daily: a) if he/she strongly believed that emergent and 
rapid fluid removal should occur, or b) if he/she strongly believed deferral of fluid removal. 
If the answer is negative to both questions, the patient will be considered fully eligible and 
efforts to obtain informed consent will commence.  
If a patient’s eligibility is excluded by a physician, the patient will be reconsidered for 
participation in the trial, and the physician will be re-approached later, provided the patient 
still meets inclusion criteria. This approach integrates the principle of clinical equipoise in 
the trial protocol and has been successfully used in clinical trials of AKI.3,41 We will continue 
to screen patients for 7 days following initiation of CKRT but less than 24 hours of initiation 
of UFNET. 
Once the patient is fully eligible, with permission from the intensivist or nephrologist, a 
study investigator or study resident/fellow physician will discuss informed consent with the 
patient or legally authorized representative (LAR). Informed consent will be obtained within 
48 hours of meeting full eligibility. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 7: Screening and Recruitment Algorithm 
 
 
6.7 
INFORMED CONSENT 
 
Informed consent will be obtained from each patient or LAR prior to enrollment in the trial. 
No study procedures will be done prior to obtaining informed consent. All patients meeting 
inclusion criteria will be entered on a screening log. If the patient is not enrolled, the 
screening log will include information explaining why enrollment did not occur (e.g., 
exclusion criteria, attending physician denial, patient refusal) and a minimum dataset to the 
extent allowed (Appendix C). If consent is obtained by LAR and later, while still in the study, 
the enrolled patient regains capacity to self-consent, the patient will be reconsented. 
 
6.8 
STUDY ENROLLMENT 
 
Time of signing the informed consent will be the study enrollment time. Following study 
enrollment, the UFNET must be initiated according to study protocol within 24 hours.  
 
6.9 
MINORITIES AND WOMEN 
 

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No patient will be excluded from the study based on gender, race, ethnicity or sexual 
preference.  
7 
STUDY PROCEDURES 
Clinical trials should be conducted in a setting reflective of best practice that can be clearly 
described and reproduced in a clinical non-trial setting. Thus, we will ensure that there are 
no imminent indications for emergent and rapid UFNET rates after discussing with the 
attending physician. Blinding is not feasible due to the nature of the intervention. To 
calculate the UFNET rate, we will use patient predicted body weight (PBW) determined from 
patient height and has been used in several NIH sponsored ICU trials (Appendix A).42,43  
Close oversight will be provided by ICU attending and/or designee. Before initiation of 
UFNET, we will ensure i.) the CKRT is operational; ii.) a study investigator or designee will 
assess the hemodynamic appropriateness for initiation of UFNET using the following as 
guidelines: MAP ≥65 mm Hg and no fluid bolus has been administered or new vasopressor 
started or vasopressor dose increased in the last hour; iii.) study investigator or designee 
will discuss with the attending physician to ensure there are no emergency indications for 
fluid removal; and iv.) UFNET according to protocol will be initiated within 24 hours of 
enrollment in both groups. 
To calculate the correct and dynamic UFNET rate for the two intervention groups, we will use 
a web-based UFNET rate calculator located on a password protected secure database 
accessed via a tablet computer, desktop computer, or computer on wheels. This UFNET rate 
calculator will be programmed to automatically calculate the net fluid removal rate based 
on the allocation to the intervention group, predicted body weight, and rate of fluids 
infused into the patient. At all times, we will emphasize that the clinicians retain complete 
decision-making authority with respect to selecting and titrating the UFNET rate, if the 
protocol cannot be followed for patient related reasons. Thus, the final decision to set a 
UFNET rate will be at the discretion of the treating clinician.  
 
Since the goal of this protocol is to assess feasibility of intravascular volume removal at a 
given UFNET rate, the protocol will also not be applied when the clinicians do not plan to 
remove fluid but rather use CKRT to maintain euvolemia (e.g., using CKRT with a goal to 
remove administered IV fluids and medication volume rather than to achieve net negative 
fluid balance). 
 
7.1 
RESTRICTIVE UFNET GROUP  
 
Fluid removal will not be started until the MAP ≥65 mm Hg with or without the need for 
vasopressors. The initial UFNET rate will be set at 0.5 mL/kg/h and then increased 0.5 
mL/kg/h, up to a maximum of 1.5 mL/kg/h, as tolerated (Figure 8). The UFNET rate can be 
titrated and maintained between 0.5-1.5 mL/kg/h, throughout the study as per clinician 
discretion. For instance, in a patient with PBW 70 kilograms, the UFNET rate will be initiated 
at 35 mL/h (i.e., 70x0.5=35 mL/h) and increased by 35 mL/h to a maximum of 105 mL/h (i.e., 
70x1.5= 105 mL/h). The UFNET rate can then be titrated between 35-105 mL/h throughout 
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If fluid removal was started less than 48 hours before enrollment, and if the UFNET rate 
before study enrollment was <0.5 mL/kg/h, the UFNET rate will be reset at 0.5 mL/kg/h. In 
contrast, if the UFNET before enrollment was >1.5 mL/kg/h, the rate will be reset at 1.5 
mL/kg/h. If the UFNET rate before enrollment is between 0.5-1.5 mL/kg/h, it will be 
continued at that current rate between 0.5-1.5 mL/kg/h.  
 
We will also ensure that the UFNET rate is adjusted for any ongoing volume infusion in the 
patient. For instance, in a patient with PBW of 70 kilograms, if the patient is also receiving 
an infusion of 100 mL/h in fluids (e.g., medications, parenteral nutrition etc.), the initial 
UFNET rate will be set at 135 mL/h (i.e., [70x0.5]+100= 135 mL/h). The UFNET rate can be 
increased to a maximum of 205 mL/h (i.e., [70x1.5]+100= 205 mL/h) and maintained 
between 135 mL/h to 205 mL/h, as tolerated, for the duration the patient is receiving 100 
mL/h volume infusion. If the additional 100 mL/h fluid is discontinued in the patient, the 
UFNET rate will be reset between 35 mL/h and 105 mL/h. This will ensure that the net 
intravascular volume removal rate is equivalent to the set UFNET rate. 
 
7.2 
LIBERAL UFNET GROUP (CONTROL ARM) 
 
Fluid removal will not be started until the MAP ≥65 mm Hg with or without the need for 
vasopressors. The initial UFNET rate will be set at 0.5 mL/kg/h and then increased 0.5 
mL/kg/h, up to a maximum of 5.0 mL/kg/h, as tolerated (Figure 8). The UFNET rate can be 
titrated and maintained between 2.0-5.0 mL/kg/h, throughout the study as per clinician 
discretion. For instance, in a patient with PBW 70 kilograms, the UFNET rate will be initiated 
at 35 mL/h (i.e., 70x0.5=35 mL/h) and increased by 35 mL/h to a maximum of 350 mL/h (i.e., 
70x5.0= 350 mL/h) as tolerated. The UFNET rate can then be titrated between 35-350 mL/h 
throughout the study as per clinician discretion.  
 
If fluid removal was started less than 48 hours before enrollment, and if the UFNET rate 
before study enrollment was <2.0 mL/kg/h, the UFNET rate will be gradually increased to 2.0 
mL/kg/h. In contrast, if the UFNET before enrollment was >5.0 mL/kg/h, the rate will be reset 
at 5.0 mL/kg/h. If the UFNET rate before enrollment is between 2.0-5.0 mL/kg/h, it will be 
continued at that current rate between 2.0-5.0 mL/kg/h and titrated per clinician discretion.  
 
We will also ensure that the UFNET rate is adjusted for any ongoing volume infusion in the 
patient. For instance, in a patient with PBW of 70 kilograms, if the patient is also receiving 
an infusion of 100 mL/h in fluids (e.g., medications, parenteral nutrition etc.), the initial 
UFNET rate will be set at 135 mL/h (i.e., [70x0.5]+100= 135 mL/h). The UFNET rate can be 
increased and maintained between 240 mL/h (i.e., [70x2.0]+100= 240 mL/h) and 450 mL/h 
(i.e., [70x5.0]+100= 450 mL/h) for the duration the patient is receiving 100 mL/h volume 
infusion. If the additional 100 mL/h fluid is discontinued in the patient, the UFNET rate will be 
maintained between 140 mL/h (i.e., 70x2.0=140 mL/h) and 350 mL/h (i.e., 70x5.0=350 
mL/h). This will ensure that the net intravascular volume removal rate is equivalent to the 
set UFNET rate. 
 
 

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Figure 8: Study interventions 
 
 
7.3 
DISCONTINUATION OF STUDY PROTOCOL 
 
The study protocol will be continued until one of the following occurs: i.) the attending 
physician determines that fluid removal is no longer needed; ii.) a decision is made to stop 
CKRT and transition the patient to IHD; iii.) the patient or surrogate decision-makers decide 
to withdraw life-sustaining treatment; iv.) the patient dies; or v.) day 28 after study 
enrollment, whichever occurs first. 
 
7.4 
COMMON STRATEGIES FOR ALL STUDY GROUPS 
 
7.4.1 STUDY STARTUP PROCEDURES 
 
In both the study groups, we will use the following standardized, stepwise, startup 
procedures. Close oversight of study initiation will be provided by an intensive care 
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1. Ensure MAP ≥65 mmHg. 
 
2. Ensure that the CKRT is operational. 
 
3. Before starting UFNET, a study investigator or designee will determine hemodynamic 
appropriateness for UFNET using the following as guidelines: MAP ≥65 mmHg or SBP 
>90 mmHg, no fluid bolus has been administered, no new vasopressor has been 
started, or dose of vasopressor increased in the last hour. 
 
4. Study investigator or designee following discussion with the attending physician will 
ensure there are no emergency indications for fluid removal. 
 
5. In both the arms, UFNET will be initiated within 24 hours of study enrollment. 
 
6. In the restrictive UFNET rate arm, UFNET will be started at 0.5 mL/kg/h and increased 
to a maximum of 1.5 mL/kg/h. The UFNET rate can be titrated by clinicians between 
0.5-1.5 mL/kg/h, as tolerated. 
 
7. In the liberal UFNET rate arm, UFNET will be initiated at 0.5 mL/kg/h and gradually 
increased 0.5 mL/kg/h to a maximum of 5.0 mL/kg/h. The UFNET rate can be titrated 
by clinicians between 2.0-5.0 mL/kg/h, as tolerated. 
 
8. In both the study arms, UFNET rate can be decreased or stopped at the discretion of 
clinicians for hypotension. Following resolution of hypotension, UFNET rate can be 
restarted and increased as tolerated as per the assigned treatment arm. 
 
9. In both the study arms, at any given day and time, the UFNET rate as per study 
protocol can be held if the clinicians decide to use CKRT for maintaining euvolemia 
(i.e., no net fluid removal from patient). 
 
7.4.2 HEMODYNAMIC MANAGEMENT 
 
7.4.2.1 Toleration of UFNET 
 
Toleration of UFNET will be defined as the absence of hemodynamic instability following 
initiation of UFNET since there are no clinically validated tolerance parameters. We have 
chosen this construct for tolerance because in current clinical practice, tolerance to UFNET is 
based on maintaining hemodynamic stability using MAP, HR and SBP.  
 
7.4.2.2 Definition of hemodynamic instability 
 
Hemodynamic instability during UFNET will be defined as a new mean arterial pressure (MAP) 
<65 mmHg, systolic blood pressure (SBP) <90mmHg or a decline in SBP >40 mmHg, and/or a 
>30% increase in dose of existing vasopressors, initiating a new vasopressor, administration 
of fluid bolus with a goal to maintain (MAP) ≥65 mmHg, systolic blood pressure (SBP) 

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≥90mmHg or discontinuation of fluid removal during CKRT.18,19 The reason for choosing 
increased need of vasopressors, fluid bolus or discontinuation of fluid removal is to account 
for clinically significant hypotension that required an intervention.18  
 
7.4.2.3 Interventions for hemodynamic instability 
 
If hemodynamic instability develops after initiation of study treatments, we will check (i) the 
patient, the arterial tracing and heart rate and rhythm on the monitor to ensure correct 
reading; (ii) the UFNET rate on the CKRT machine to ensure that the rate is set correctly; (iii) 
the alarms on the CKRT machines; (iv) the patient does not have obvious bleeding; (v) that 
no new sedative or other medications that cause hypotension has been administered or 
existing sedation dose increased in the previous 30 minutes; and (vi) follow the 
recommendations in Table 3.  
Table 3: Interventions for managing hemodynamic instability  
 
1. 
Completely stop UFNET (i.e., no fluid removal) 
2. 
Stop or reduce the dose of sedative medication infusion 
3. 
Stop or reduce the dose of any medication that is known to cause 
hypotension 
4. 
Administer Plasmalyte or Lactated Ringers fluid bolus of 250 mL 
(may repeat as needed) 
                                AND/OR 
Start or increase norepinephrine to maintain MAP ≥65 mmHg 
 
7.4.2.4 Re-initiation of UFNET following hemodynamic instability 
 
Following resolution of hypotension and attending physician approval, the bedside clinician 
will ensure that MAP ≥65 mmHg. The UFNET rate will be set at 0.5 mL/kg/h and increased as 
tolerated per the assigned treatment arm. 
 
7.4.3 CKRT PROCEDURES 
 
We will follow specific protocols for management of CKRT to ensure uniformity of treatment 
between the patient groups. We have chosen CKRT as the primary modality for UFNET for 
this trial because (i) overall volume control is superior with CKRT compared with IHD,33 (ii) 
better hemodynamic tolerance than IHD in critically ill patients,20,21 (iii) more than 70% of 
critical care practitioners surveyed use CKRT for volume removal,44 (iv) primary modality 
used for treatment in ICU patients with severe fluid overload and multisystem organ failure 
at the UPMC and the Mayo Clinic ICUs. 
 
CKRT will be provided at the discretion of attending nephrologist (Appendix D). CKRT 
modality will either be CVVHDF, CVVHD, CVVH or SCUF. All hemofilters will be comprised of 
biocompatible synthetic hollow-fiber membranes and will be changed at least every 48-72 
hours. The electrolyte composition of the dialysate and replacement fluids and dialysate 
and replacement fluid flow rates will be prescribed by the attending nephrologist. Dialysate 
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the clinician. Effluent flow rate will be 20-30 mL/kg/h and prescribed by the attending 
nephrologist. All efforts will be made to minimize CKRT downtime and ensure that CKRT is 
functioning at least 20 hours per day. Patients would be transitioned from CKRT to IHD or no 
KRT as determined by the treating physicians. 
 
7.4.4 VENTILATOR PROCEDURES 
 
We will protocolize low tidal volume ventilation strategy and use a simplified version of the 
ARDS network 6-8 mL/kg PBW lung protective ventilation protocol. We will use a 
standardized PEEP protocols based on prior ARDS network studies. Both low tidal volume 
ventilation and standardized PEEP strategies are already in use at the UPMC and the Mayo 
Clinic ICUs. 
 
7.4.5 CONSERVATIVE FLUID MANAGEMENT PROTOCOL 
 
Fluid management during shock or treatment for hypotension will be unrestricted. 
However, in patients not in shock, a conservative fluid approach will be recommended for 
all patients enrolled in the study (Table 4). This protocol is recommended for all enrolled 
patients, to be used until cessation of UFNET. 
 
Table 4: Conservative fluid management protocol 
 
1. 
Discontinue all maintenance intravenous fluids. 
2. 
Double concentrate or use lowest possible volume for all carrier 
fluids for medications, if possible. 
3. 
Continue enteral nutrition and free water flushes 
4. 
Manage electrolytes and blood products per usual practice. 
5. 
For shock, use any combination of fluid boluses and vasopressor(s) 
to achieve MAP ≥65 mmHg as fast as possible.  
6. 
If the patient is on total parenteral nutrition (TPN), the TPN 
volume would be limited to provide the least volume required to 
administer the calories, protein, and lipids. 
7.4.6 RESCUE PROCEDURES 
 
Our goal is to respect clinician autonomy and protect patient safety, while preserving 
separation of treatment between arms. Thus, we will encourage higher UFNET rates beyond 
that which is specified by the protocol at the discretion of treating physician for emergent 
treatment of refractory hypoxia due to fluid overload or patient requiring massive volume 
infusion that requires control of fluid overload in the opinion of treating clinician (Table 5). 
However, following the resolution of emergency indication for fluid overload, UFNET rate will 
be resumed as per protocol as determined by the attending nephrologist/intensivist. Being a 
feasibility randomized trial, the use of rescue rates of UFNET will be collected as secondary 
outcomes and will not constitute a protocol violation. 
 
Table 5: Criteria for rapid rescue net ultrafiltration 
 

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1. 
Severe pulmonary edema with PaO2/FiO2 <150 and PEEP >5 cm H20 due to fluid 
overload 
2. 
Respiratory distress due to fluid overload 
3. 
Ongoing hourly volume infusion at a rate higher than the assigned treatment 
group for more than 6 hours 
4. 
Inability to close surgical wounds due to tissue edema 
5. 
Failing spontaneous breathing trial due to fluid overload at the discretion of 
attending intensivist 
PaO2, partial pressure of oxygen; FiO2, the fraction of inspired oxygen; PEEP, positive end-expiratory 
pressure. 
 
7.4.7 FACILITATING COMPLIANCE 
 
We will use educational programs and academic detailing,45 automated reminders,46 
selection of ICU staff that are local opinion leaders,47 and regular audit with feedback.48 
Study coordinators will facilitate compliance in three key roles – background operational 
logistics, clinician in-servicing, and interventional logistics (e.g., ensuring CKRT machine is 
operational; suggested UFNET rate is followed etc.). We will provide clear instruction guides 
to each coordinator and standardize work across ICUs. 
8 
DATA VARIABLES 
8.1 
BACKGROUND ASSESSMENTS 
 
1. Demographic and Admission Data (including age, sex, race and ethnicity, admission 
diagnosis including COVID status) 
2. Pertinent Medical History and Physical Examination (including Elixhauser co-
morbidity index score) 
3. Premorbid body weight and serum creatinine (if available) 
4. Time on CKRT prior to enrollment 
5. Type and location of ICU admission 
6. Risk factors for AKI (sepsis, ischemia, nephrotoxin, other) 
7. Risk factors for fluid overload (sepsis, heart failure, shock, trauma, massive 
transfusion) 
 
8.2 
BASELINE ASSESSMENTS 
 
The following information will be recorded during the 24-hour interval preceding study 
enrollment. If more than one value is available for this 24-hour period, the value closest to 
the time of study enrollment will be recorded. If no values are available from the 24 hours 
prior to enrollment, then values will be measured post enrollment but prior to initiation of 
study interventions. All values will be derived from clinically available data. 
 
1. History and physical examination 
Vital signs: heart rate (beats/min), systemic systolic, diastolic, and mean arterial 
blood pressure (mmHg), body temperature (°C), central venous pressure (cm H2O), 
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variation, if available). Measured height and actual weight of the patient. Arterial 
blood gas values, if available. 
 
2. CKRT mode, prescribed and actual blood flow rate, replacement fluid type and rate, 
dialysate type and rate, rate of ultrafiltration, UFNET rate, effluent fluid rate, venous 
access and inflow pressures, transmembrane pressure, hemofilter type, time of last 
change of filter. 
 
3.  Administration of the following medications and fluids 
a. Intravenous vasopressors and inotropes 
b. Intravenous or enteral corticosteroids  
c. Intravenous fluids and career fluids, enteral and parenteral nutrition 
 
4. APACHE II score, including the acute physiology components and laboratory values 
 
5. SOFA score: cardiovascular, kidney, respiratory, hepatic, and hematology organ 
function will be assessed using the SOFA methodology as described in Appendix E. 
 
6. Fluid intake and output before study enrollment and prior to ICU admission, if 
available. 
 
7. If receiving positive pressure ventilation, ventilator settings including set tidal 
volume, FiO2, and PEEP. 
 
8.3 
ASSESSMENTS DURING STUDY 
 
8.3.1 HEMODYNAMIC MONITORING DURING STUDY STARTUP 
 
We will record the baseline hemodynamics before initiation of UFNET, time at which UFNET is 
initiated, time at which target UFNET rate is reached. We will also record any episodes of 
hypotension, cardiac arrhythmias, administration of fluid bolus, vasopressor use, or increase 
in vasopressor dose.  
 
8.3.2 REFERENCE MEASUREMENTS 
 
The following data will provide the basis for assessing protocol compliance and safety as 
well as between-group differences. Data for each of the variables will be recorded on the 
days shown in the Time-Events schedule (Appendix F) until death, discharge from the ICU, or 
day 28, whichever occurs first. Values will be derived from clinically available data.  
 
1. UFNET rate 
 
a. Restrictive UFNET rate group 
i. Time and initial UFNET rate 
ii. Time and target UFNET rate 
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iv. Reason and duration of UFNET hold (if any) 
v. Total volume of UFNET during the study 
vi. Rescue UFNET (YES/NO) 
 
b. Liberal UFNET rate group 
i. Time and initial UFNET rate 
ii. Time and target UFNET rate 
iii. Time and hourly UFNET rate 
iv. Reason and duration of UFNET hold (if any) 
v. Total volume of UFNET during the study 
vi. Rescue UFNET (YES/NO) 
 
 
Reference measurements (Daily) 
 
The following parameters will be measured and recorded between 4:00 A.M. and 10.00 
A.M. using the values closest to 8.00 A.M. on the days specified in the Time-Events 
schedule. The following conditions will be ensured prior to measurements: no CKRT changes 
in the previous 30 minutes, no invasive procedures or ventilator changes for 30 minutes. All 
vascular pressures will be zero-referenced to the mid-axillary line. 
 
1. If receiving CKRT: CKRT mode, blood flow rate, actual rate, replacement and 
dialysate flow rate, ultrafiltration rate, UFNET rate, effluent flow rate.  
 
2. If receiving positive pressure ventilation set tidal volume, FiO2, PEEP, and plateau 
pressures. 
 
3. PaO2, PaCO2, pH, and SpO2 
 
4. Rescue procedures used 
a. Rescue UFNET rates used beyond the assigned treatment arm 
b. Vasopressors used for hypotension including dose 
c. Fluid bolus used for hypotension including volume 
 
5. Serum electrolytes 
 
6. Administration of the following fluids and medication 
a. Enteral or intravenous corticosteroids 
b. Intravenous vasopressors 
 
7. Was CKRT interrupted? (YES/NO) 
 
8. Cardiovascular SOFA score 
 
9. Fluid intake and output 
 

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9 
STATISTICAL CONSIDERATIONS 
NOTE: Detailed statistical analysis plan (SAP) will be a separate document 
 
9.1 
STATISTICAL METHODS 
 
The primary feasibility outcomes are between-group difference in mean UFNET rate, protocol 
adherence, and recruitment rate. The primary objective of this feasibility trial to measure a 
minimum of 0.53-0.57 mL/kg/h separation in the delivered patient mean UFNET rates 
between the restrictive and liberal UFNET rate groups. We estimated that, if each of the 10 
ICUs enrolled a minimum of 0.93 patient per 2 months for 24 months, we would have a total 
of 111 patients. Using the sample size calculation for SW-CRT design, we estimated that 111 
patients will have 80% power at a two-sided alpha of 0.05 to reject the null hypothesis that 
the average UFNET rate was at least 0.53-0.57 mL/kg/h different between the two groups, 
using intra-cluster correlation coefficient of 0.01, at a standard deviation of 0.75, and 
assuming mean UFNET rate of 1.0 mL/kg/h (Table 6). After accounting for a very small 
attrition rate, we plan to recruit from each of the 10 ICUs: 1 patient per 2 months for 24 
months for a total of 112 subjects or 56 patients per group. 
 
Table 6: Detectable difference in mean UFNET rates 
 
 
 
 
10 DATA COLLECTION AND SITE MONITORING 
10.1 DATA COLLECTION 
 
At the UPMC and the Mayo Clinic, the research staff will collect data and record it either on 
paper data sheets and/or enter in a secure web database. Once daily, coordinators will 
enter data that can be analyzed for consistency.  
 
In this trial, we will define protocol deviation as delivered UFNET rate that lies >0.5 mL/kg/h 
outside of the target UFNET rate range in the assigned treatment group for greater than six 
consecutive hours during fluid removal without significant changes in MAP (i.e., MAP <65 
mmHg or ≥90 mmHg). As such, out of range, UFNET rates >0.5 mL/kg/h beyond the target 
UFNET rate range in the assigned treatment group will not constitute a protocol deviation 
when the bedside team titrated the UFNET rate as required to manage the patient 
hemodynamics (i.e., when clinicians appropriately decreased rate or stopped UFNET for MAP 
<65 mm Hg or increased rate for MAP ≥90 mm Hg).  
 
Difference 
ICC 
Alpha 
Power 
N 
0.53 
0.01 
two-sided 
0.8 
111 
0.57 
0.1 
two-sided 
0.8 
111 
0.57 
0.01 
one-sided 
0.8 
126 
0.63 
0.1 
one-sided 
0.8 
126 
ICC, intra-cluster correlation coefficient 
 

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We will also calculate “%-on target” value for each center for each of the monitored 
variables (# of dates on-target for a specific variable/# of opportunities to be on-target for 
that specific variable). Principle Investigators at each site will receive monthly reports of (1) 
% on-target for each of the specific variables in the most recent month; (2) % on-target for 
each of the variables since the beginning of a trial; and (3) a list of dates/times from the past 
month, the specific data that were entered for those dates/times, and determinations of 
on- or off-target.  
 
Investigators will use these reports to identify aspects of protocol management that can be 
improved at their sites. The on-target performances of all ICUs will also be included, 
allowing investigators at each center to know how their ICU is performing related to other 
ICUs. On-target performances will be discussed during regular meetings of the Steering 
Committee.  
 
10.2 SITE MONITORING 
 
Data quality will be reviewed remotely using front end range and logic checks at the time of 
data entry and back-end monitoring of data using SAS reports. The site PIs at the two sites 
will perform random audits of up to 10% of eDCFs and verify source documents. A summary 
of the audits will be submitted to the IRB during annual renewal. Patient records and case 
report forms will be examined on a spot check basis to evaluate the accuracy of the data 
entered into the database and monitor for protocol compliance. 
 
11 RISK ASSESSMENT 
This study involves randomization to either restrictive UFNET rate, or liberal UFNET rate. 
Compared to not being part of the study, patients may have a higher, lower, or similar risk 
of adverse events.  
 
11.1 RISKS OF RESTRICTIVE UFNET RATE 
 
Restrictive UFNET rates between 0.5 to 1.5 mL/kg/h may theoretically increase the risk of 
fluid overload, increase dependence on ventilator as well as dependence on kidney 
replacement therapy by prolonging fluid overload. Myocardial edema may result in 
increased episodes of cardiac arrhythmias. Worsening oxygenation may result in increased 
use of rescue procedures. However, UFNET rates used in the restrictive group are also 
frequently used in clinical practice and our observational studies showed a lower risk of 
cardiac arrhythmias than liberal UFNET rates. 
 
11.2 RISKS OF LIBERAL UFNET RATE  
 
Liberal UFNET rates between 2.0-5.0 mL/kg/h may increase the risk of hypotensive episodes 
and cardiac arrhythmias requiring treatment similar to that encountered in current clinical 
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kidney function and longer dependence on KRT. The UFNET rates in liberal group is also 
widely used in clinical practice.  
 
11.3 RISK OF ADVERSE EVENTS 
 
It is possible that one treatment arm may lead to more adverse events, which will be 
monitored during the study. However, being a feasibility trial, the study is not powered to 
detect any statistically significant differences in adverse events. Many of the adverse events 
commonly occur during current clinical practice of fluid removal (Section 5.2.5; Table 1). 
 
11.4 MINIMIZATION OF RISKS 
 
Net ultrafiltration is currently used clinically in the treatment of patients with fluid overload 
during CKRT and hypotensive episodes occur in 19% to 97% of patients18-20 with a mortality 
rate of more than 40%.2,3,26,49 This trial will study two different approaches to fluid removal 
in order to minimize the risk of hypotension and ultimately to improve patient outcomes in 
a subsequent large multicenter randomized trial. There are several elements of study design 
inherent in the present protocol that ensures the minimization of risks greater than that 
provided during routine clinical care. Below we address the mitigation strategies used for 
each risk. 
 
Risks of the release of information: The risk of inadvertent release of confidential 
information is unlikely due to the numerous protections in place. i.) All data will be collected 
and stored in secure files both at the participating clinical sites and at the CRISMA 
coordinating center. ii.) Each enrolled study participant will be assigned a study 
identification number, and the information to be collected and submitted to the 
coordinating center will not contain any personal identifiers (protected health information). 
iii.) We will enter all data collected by the site study coordinator using electronic data 
collection forms into a secure web-based study database, which will be password protected. 
Only the site study coordinators and the PI will have access to the password for the 
database. iv.) All study personnel with access to the study database will be required to 
complete training on the web-based data collection system and have the necessary CITI 
modules completed. v.) All study participant consent forms, research data, and linkage 
information will be stored in a secure manner with access limited to the study personnel. 
The linkage will be maintained by CRISMA’s Biostatistics and Data Management Core’s Data 
Manager only and is kept in a password protected location with access to no one else. 
 
Risk of hypotension: i.) This protocol assesses attending physician equipoise to ensure safety 
before study enrollment. Subjects will not be enrolled in the study if the attending physician 
believes that fluid should not be removed due to severe hemodynamic instability. ii.) All 
patients will have continuous monitoring of blood pressure in the ICU via indwelling arterial 
line as per routine clinical care for early detection of hypotension. iii.) This protocol also 
mandates that UFNET rates do not exceed greater than 5.0 mL/kg/h in the liberal group to 
ensure that subjects are not exposed to high UFNET rates that are used in current clinical 
practice. iv.) This protocol mandates that fluid removal be completely stopped if a patient 
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hemodynamic instability (Table 3). v.) Hypotensive episodes will be treated by slowing rate 
or completely stopping fluid removal. vi.) Fluid bolus and vasopressors will be administered, 
as needed. vii.) Fluid removal will only be restarted once the patient regains hemodynamic 
stability. viii.) all ICU clinicians will undergo training on study protocol and what to do when 
hypotension occurs.  
 
Risk of hypertension: Hypertensive episodes related to severe fluid overload will be treated 
according to clinician discretion by increasing the rate of fluid removal and also with anti-
hypertensive medications, as per clinician discretion. 
 
Risk of prolonged exposure to fluid overload: i.) This protocol assesses attending physician 
equipoise to ensure safety before study enrollment. Subjects will not be enrolled in the 
study if the attending physician believes that fluid should be removed rapidly due to severe 
fluid overload. ii.) This protocol recommends conservative fluid management in both study 
arms to minimize unnecessary fluid administration (Table 4). We will recommend that all 
medications and infusions be double concentrated to reduce fluid volume. iii.) All patients 
will have daily monitoring of fluid input, output, and daily fluid balance in the ICU as part of 
routine clinical care. iv.) If severe fluid overload occurs, clinicians can increase the rate of 
fluid removal, as required, to treat fluid overload. 
 
Risk of heart failure and pulmonary edema: If a patient develops respiratory distress due to 
fluid overload, this protocol provides for the option of using rapid and rescue UFNET rates, as 
required per clinician discretion to treat fluid overload (Table 5). 
 
Cardiac arrhythmias: i.) Cardiac arrhythmias due to severe fluid overload will be treated by 
increasing the fluid removal rate as per clinician discretion. Whereas arrhythmias due to 
rapid fluid removal will be treated by slowing the fluid removal rate, as needed. ii.) Clinically 
significant cardiac arrhythmias will be treated using anti-arrhythmic agents as per clinician 
discretion. 
 
Risk of increased duration of mechanical ventilation, dialysis, ICU and hospital length of stay 
due to fluid overload will be treated by increasing fluid removal rate, as per clinician 
discretion. 
 
Risk of surgical wound edema, bowel ischemia and anastomotic break down, and ileus, 
abnormal liver function, delirium, poor wound healing due to fluid overload will be treated 
by increasing fluid removal rate as clinically indicated to treat organ edema and dysfunction 
per discretion of treating clinicians. 
 
Risk of wound infections and secondary infections: Patients will be monitored for wound 
infections due fluid overload. Wound infection will be treated using debridement or 
antibiotics as per clinician discretion. 
 
Risk of hypophosphatemia, hypokalemia, hypocalcemia: Electrolytes will be monitored 
frequently as per ICU protocol. Severe hypophosphatemia, hypokalemia, and hypocalcemia 
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Risk of arterial and venous thrombosis: Patients will be monitored for arterial and venous 
thrombosis. Arterial and deep venous thrombosis will be treated with anticoagulation, as 
per the discretion of treating clinicians. 
 
Risk of anemia, hemolysis, and thrombocytopenia: Hematology labs will be monitored daily 
in all patients. Clinically significant anemia, hemolysis, and thrombocytopenia will be treated 
with administration of blood products, as per the discretion of treating clinicians. 
 
11.5 POTENTIAL BENEFITS 
 
Study subjects may or may not receive any direct benefits from their participation in this 
study. Restrictive UFNET rates have been found to reduce risk of cardiac arrhythmias as well 
as short- and long-term mortality and KRT dependence in observational studies.6,22 
Restrictive UFNET rates may result in less hypotensive episodes and may result in overall net 
negative fluid balance and improved patient outcomes if risk of hypotension and 
subsequent fluid administration are reduced. The liberal UFNET rates may also result in 
overall reduced exposure to fluid overload, earlier liberation from mechanical ventilation 
and lower complications from fluid overload. 
 
The knowledge gained from this study may be of significant benefit to future critically ill 
patients undergoing treatment with CKRT with a restrictive or liberal UFNET rate strategy. 
Understanding the UFNET rate-outcome relationship in acutely ill patients is critical for four 
reasons: a) to ensure that the provision of current care is safe, b) to design interventions to 
reduce mortality, c) to develop evidence-based clinical practice guidelines, and d) to 
implement quality measures during treatment with CKRT. 
 
11.6 RISKS IN RELATION TO ANTICIPATED BENEFITS 
 
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable 
in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge 
that may reasonably be expected to result.” Based on the preceding assessment of risks and 
potential benefits, the risks to subjects are reasonable in relation to anticipated benefits. 
Faster and slower UFNET rates are currently used in clinical practice. There is a potential for 
benefit to the society and individual patients should one of the UFNET strategies reduce 
complications and improve outcomes in a subsequent large phase III trial. Should one of the 
UFNET rate strategies, again consistent with clinical practice, prove to be harmful, the benefit 
will be in avoiding such therapies for future patients. 
 
11.7 IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
 
The knowledge gained from this trial will be used to design a large multicenter phase III trial 
to examine alternative UFNET rate strategies and its association with patient-centered clinical 
outcomes of 90-day mortality and dependence on KRT. We will also use the knowledge 
gained from this proposal to design other interventions to reduce the risks associated with 
UFNET. Such knowledge may serve to take precautionary measures to mitigate risks and 
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This trial will also help us understand four key points, 1) whether it is feasible to maintain 
patients in the restrictive or liberal UFNET rates throughout the study; 2) an assessment of 
protocol adherence, 3) the patient recruitment rates in each center for the current trial, and 
4) the effects of alternate UFNET rate strategies on patient’s secondary clinical and safety 
outcomes. Thus, this study will enhance the scientific knowledge of understanding the UFNET 
rate-outcome relationship in critically ill patients. 
 
12 HUMAN SUBJECTS 
Each study participant or a LAR must sign and date an informed consent form. Approval for 
this feasibility trial will be obtained from the University of Pittsburgh Human Research 
Protection Office (HRPO), which will serve as the single IRB, before any subject is entered 
into the study.  
 
12.1 SELECTION OF SUBJECTS 
 
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of subjects. The ICUs 
at the UPMC and Mayo Clinic will be screened daily to determine if any patient meets 
inclusion and exclusion criteria. Data that have been collected as part of the routine 
management of the subject will be reviewed to determine eligibility. No protocol-specific 
tests or procedures will be performed as part of the screening process. If any subject meet 
criteria for study enrollment, then the attending physician will be asked for permission to 
approach the patient or his/her LAR for informed consent. Study exclusion criteria neither 
unjustly exclude classes of individuals from participation in the research nor unjustly include 
classes of individuals from participation in the research. Hence, the recruitment of subjects 
conforms to the principle of distributive justice.  
 
12.2 JUSTIFICATION OF INCLUDING VULNERABLE SUBJECTS 
 
The present research aims to investigate the feasibility of alternative UFNET strategies for 
critically ill patients. Since the subjects enrolled in this clinical trial will have fluid overload 
and one or more organ system failure (e.g., respiratory and renal failure) it is anticipated 
that most of these patients will have impaired decision-making capability. This study cannot 
be conducted if limited to enrolling only those subjects with retained decision-making 
capacity. Hence, subjects recruited for this trial are not being unfairly burdened with 
involvement in this research simply because they are easily available.  
 
12.3 INFORMED CONSENT 
 
Federal regulations 45 CFR 46.111 (a) (5) require that informed consent be sought from 
each prospective subject or the subject’s LAR. We anticipate almost all consents will be from 
the subject’s LAR, and thus the remainder of this section will focus on LARs. The one 
obtaining consent is responsible for ensuring that the LAR understands the risks and 
benefits of participating in the study and answering any questions the LAR may have 
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relevant to the LAR’s willingness to permit the subject’s continued participation in the trial. 
The consenter will make every effort to minimize coercion.  
 
All study participants or their LARs will be informed of the objectives of the study and the 
potential risks. Prior to obtaining informed consent the patient and/or LAR will also be 
provided a study brochure. The informed consent document will be used to explain the risks 
and benefits of study participation to the LAR in simple terms before the patient is entered 
into the study, and to document that the LAR is satisfied with his or her understanding of 
the risks and benefits of participating in the study and desires to participate in the study. 
The investigator is responsible for ensuring that informed consent is given by each LAR. The 
process of informed consent between a study attending physician investigator or study 
resident/fellow physician and the patient or LAR may occur face-to-face either in-person or 
virtually via a remote electronic communications platform (e.g., via ZOOM/Teams) due to 
restrictions because of hospital COVID-19 protocols. This includes obtaining the appropriate 
signatures and dates on the informed consent document prior to the performance of any 
protocol procedures. In case of virtual consent with LAR, appropriate electronic signatures 
from LAR, witness, and/or attending physician investigator or study resident/fellow 
physician will be obtained via an approved electronic consent platform. 
 
To obtain informed consent, the following information shall be provided to each patient or 
patient’s LAR: 
 
a. The name of the study. 
b. The name of the Principal Investigator. 
c. An explanation that the study involves research. 
d. An explanation that the purpose of the study is to determine feasibility of 
maintaining slow or fast fluid removal, and whether a particular strategy of fluid 
removal is associated with less fluid overload and complications. 
e. An explanation that the active treatment portion of the study will last up to 28 
days from study enrollment. 
f. A description of the restrictive and liberal UFNET rate strategies 
g. A description of benefits and risks associated with restrictive and liberal UFNET 
strategies 
h. A description of randomization at the ICU level. 
i. A description that participation in the study may require longer or shorter times 
on dialysis treatment with fluid removal.  
j. A description that the patient’s medical record number will be used to identify 
records and to track the patient during hospital stay. 
k. A description that the alternative to participation in this study will be to receive 
fluid removal during kidney replacement therapy (dialysis) as per clinician 
discretion and not as part of the study. 
l. A description that all records will be kept confidential. 
m. An explanation of whom to contact for answers to questions about the research 
and about research subject’s rights. 
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o. A statement that participation in the study is voluntary and that a decision not to 
participate or to withdraw from the study after initially agreeing to participate 
will involve no penalty, loss of benefits or reduction in access to medical care. 
p. A statement that there will be no cost for the treatments provided as part of this 
study. 
q. A statement that there will be no payment for participation in this study.  
 
12.4 CONTINUING CONSENT 
 
Subjects for whom consent was initially obtained from a LAR, but who subsequently regain 
decision-making capacity while still in hospital within the 28d post intervention period, will 
be approached for consent for continuing participation, including continuance of data 
acquisition. The consent form signed by the LAR will reflect that such consent will be 
obtained. 
 
12.5 WITHDRAWAL OF CONSENT 
 
Patients may withdraw or be withdrawn (by the LAR) from the trial at any time without 
prejudice. Data recorded up to the point of withdrawal will be included in the trial analyses 
unless consent to use their data has also been withdrawn. If a patient or LAR requests 
termination of the trial intervention during the treatment period, the intervention will be 
stopped but the patient will continue to be followed up as part of the trial. If a patient or 
LAR withdraws consent during the trial treatment, the trial intervention will be stopped but 
permission will be sought to access medical records for data related to the trial. If a patient 
or LAR wishes to withdraw from the trial after completion of trial treatment, permission to 
access medical records for trial data will be sought.  
 
12.6 IDENTIFICATION OF LEGALLY AUTHORIZED REPRESENTATIVES 
 
Many of the patients approached for participation in this research protocol will invariably 
have limitations of decision-making abilities due to their critical illness. Hence, most patients 
will not be able to provide informed consent. Accordingly, informed consent will be sought 
from the potential subject’s LAR.  
Regarding proxy consent, the existing federal research regulations (“the Common Rule”) 
states at 45 CFR 46.116 that “no investigator may involve a human being as a subject in 
research….. unless the investigator has obtained the legally effective informed consent of 
the subject or the subject’s legally authorized representative”; and defines at 45 CFR 46 102 
(2) a legally authorized representative as “an individual or judicial or other body authorized 
under applicable law to consent on behalf of a prospective subject to the subject’s 
participation in the procedures(s) involved in the research.” The Office of Human Research 
Protections (OHRP) defined examples of “applicable law” as being state statutes, 
regulations, case law, or formal opinion of a State Attorney General that addresses the issue 
of surrogate consent to medical procedures. Such “applicable law” could then be considered 
as empowering the LAR to provide consent for subject participation in the research.  
 

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According to a previous President’s Bioethics Committee (National Bioethics Advisory 
Committee [NBAC]), an investigator should accept a relative or friend of the potential 
subject who is recognized as an LAR for purposes of clinical decision making under the law 
of the state where the research takes place.50 Finally, OHRP has stated in their 
determination letters that a surrogate could serve as a LAR for research decision making if 
such an individual is authorized under applicable state law to provide consent for the 
“procedures” involved in the research study.  
 
In the state of Pennsylvania, the following individuals may be considered LARs of a potential 
research subject and capable of providing surrogate consent: 
 
• A court-appointed guardian authorized in a current court order to consent to the 
subject's participation in the research. 
• A health care agent appointed by the subject in a power of attorney. 
• A "health care representative" when the individual cannot speak for his/herself and 
where there has been no guardian appointed by the court and no health care power 
of attorney designated (PA Act 169). 
• Any of the following relatives, in descending order of priority, who is reasonably 
available, may also act as the subject’s health care representative: 
a. The spouse (unless an action for divorce is pending). 
b. Adult children (18 years of age or older). 
c. A parent. 
d. An adult sibling. 
e. An adult grandchild. 
f. An adult who has knowledge of the potential research subject’s preferences 
and values, including but not limited to religious and moral beliefs, who is 
able to assess how the patient would make decisions. 
 
12.7 JUSTIFICATION OF SURROGATE CONSENT 
 
According to the Belmont Report, respect for persons incorporates at least two ethical 
convictions; first, that individuals should be treated as autonomous agents, and second, that 
persons with diminished autonomy are entitled to protection. One method that serves to 
protect subjects is restrictions on the participation of subjects in research that presents 
greater than minimal risks. Commentators and research ethics commissions have held the 
view that it is permissible to include incapable subjects in greater than minimal risk research 
as long as there is the potential for beneficial effects and that the research presents a 
balance of risks and expected direct benefits similar to that available in the clinical setting.51 
Commentators and research ethics commissions have held the view that it is permissible to 
include incapable subjects in greater than minimal risk research as long as there is the 
potential for beneficial effects and that the research presents a balance of risks and 
expected direct benefits similar to that available in the clinical setting.51  
 
Several U.S. tasks forces have deemed it is permissible to include incapable subjects in 
research. For example, the American College of Physicians document allows surrogates to 
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participation are not substantially greater than the risks of standard treatment”.52 Finally, 
NBAC stated than an IRB may approve a protocol that presents greater than minimal risk 
but offers the prospect of direct medical benefits to the subject, provided that “the 
potential subject’s LAR gives permission…..”.50 Several U.S. tasks forces have deemed it is 
permissible to include incapable subjects in research. For example, the American College of 
Physicians document allows surrogates to consent to research involving incapable subjects 
only “if the net additional risks of participation are not substantially greater than the risks of 
standard treatment”.52 Finally, NBAC stated than an IRB may approve a protocol that 
presents greater than minimal risk but offers the prospect of direct medical benefits to the 
subject, provided that “the potential subject’s LAR gives permission…..”.50 Consistent with 
the above ethical sensibilities regarding the participation of decisional incapable subjects in 
research and the previous assessment of risks and benefits in the previous section, the 
present trial presents a balance of risks and potential direct benefits that is similar to that 
available in the clinical setting. 
 
12.8 ADDITIONAL SAFEGUARDS FOR VULNERABLE SUBJECTS 
 
The present research will involve subjects who might be vulnerable to coercion or undue 
influence. As required in 45 CFR 46.111 (b), we will use additional safeguards to protect the 
rights and welfare of these subjects. Such safeguards might include but are not limited to: i.) 
assessment of the potential subject’s capacity to provide informed consent; ii.) the 
availability of the LAR to monitor the subject’s subsequent participation and withdrawal 
from the study; and iii.) augmented consent processes. The specific nature of the additional 
safeguards will be left to the discretion of the Human Research Protection Office. 
 
12.9 CONFIDENTIALITY  
 
Federal regulations at 45 CFR 46 111 (a) (7) requires that when appropriate, there are 
adequate provisions to protect the privacy of subjects and to maintain the confidentiality of 
data. To maintain confidentiality, all evaluation forms, and reports will be identified only by 
a coded number. The coded number will be generated by a computer, and only the study 
team will have access to the codes. All records will be kept in a locked, password protected 
computer. All computer entry and networking programs will be done with coded numbers 
only. All paper case report forms will be maintained inside a locked office. Study information 
will not be released without the written permission of the patient, except as necessary for 
monitoring by the institutional Data and Safety Monitoring Board. 
13 SAFETY MONITORING 
13.1 ADVERSE EVENTS 
 
A clinical trial adverse event (AE) is defined as any untoward medical event temporally 
associated with the use of drug or study procedure in humans, whether or not it is 
considered related to a study intervention or study procedure. Assuring patient safety is an 
essential component of this protocol and the Principal Investigators have the primary 
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will monitor for all AEs from study enrollment until ICU discharge or day 28, whichever 
occurs first.  
 
Following study enrollment, AEs occurring after the patient received the study interventions 
will be evaluated at the two clinical sites by the Principal Investigators. Investigators will 
assess if there is a reasonable possibility that the study procedure caused the event, based 
on the criteria outlined in Appendix G1. 
 
If a patient’s study treatment is discontinued because of an AE, the study investigator must 
report the circumstances and data leading to discontinuation of treatment in the AE case 
report forms. AEs will be considered related or possibly related to study treatment only up 
to 24 hours following discontinuation of CKRT. AEs occurring after discontinuation of CKRT 
and after transition to IHD will not be considered related to study interventions. 
 
Investigators will also consider if the event is unanticipated or unexplained given the 
patient’s clinical course, previous medical conditions, and concomitant medications as 
outlined in Appendix G2. An adverse event is considered “unanticipated” if it is not listed in 
the study protocol (21 CFR 312.32(a)). 
 
The following adverse events will be collected in the case report forms: 
 
• Serious adverse events 
• Non-serious adverse events that are considered by the investigator to be related to 
study intervention or study procedures or of uncertain relationship (Appendix G) 
• New onset hypotensive and hypertensive episodes, cardiac arrhythmias, considered 
by the investigator to be related to rate of fluid removal during CKRT, or of uncertain 
relationship 
• Emergent use of rescue UFNET rates with rates higher than the assigned treatment 
arm 
• Severe hypophosphatemia, hypokalemia, hypocalcemia  
• CKRT system clotting, clogging, downtime, and discontinuation of fluid removal due 
to patient instability. 
• Inability to close surgical wounds due to edema 
• New organ dysfunction such as diastolic and systolic dysfunction on echocardiogram; 
pulmonary edema on chest X ray; ileus, bowel ischemia, anastomotic break down; 
wound infection, and pressure ulceration; arterial and venous thrombosis; severe 
anemia requiring red cell transfusions, and severe thrombocytopenia requiring 
platelet transfusions. 
• New secondary infections 
 
13.2 SERIOUS ADVERSE EVENTS 
 
Serious adverse event (SAE) collection begins after the patient or surrogate has signed 
informed consent and has received the study intervention or undergone study procedures. 
If a patient experiences a SAE after consent, but prior to receiving the study intervention, 
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been caused by a protocol procedure. SAEs will be collected after initiation of study 
intervention until ICU discharge or day 28, whichever occurs first, regardless of the 
investigator’s opinion of causation. Thereafter, SAEs are not required to be reported unless 
the investigator feels the events were unanticipated and related to the study procedure. If a 
determination is made that a SAE has a reasonable possibility of having been caused by a 
study procedure, it will be classified as a suspected adverse reaction. If the suspected 
adverse reaction is unanticipated, it will be classified as a serious unanticipated suspected 
adverse reaction (SUSAR). 
 
As per the FDA and NIH definitions, a SAE is any adverse event that results in one of the 
following outcomes: 
 
• Death 
• A life-threatening experience (that is, immediate risk of dying) 
• Prolonged inpatient hospitalization or rehospitalization 
 
As per https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-
adverse-event report if admission to the hospital or prolongation of hospitalization 
was a result of the adverse event. Emergency room visits that do not result in 
admission to the hospital should be evaluated for one of the other serious outcomes 
(e.g., life-threatening; required intervention to prevent permanent impairment or 
damage; other serious medically important event).  
 
• Persistent or significant disability/incapacity 
 
As per https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-
adverse-event report if the adverse event resulted in a substantial disruption of a 
person’s ability to conduct normal life functions, i.e., the adverse event resulted in a 
significant, persistent or permanent change, impairment, damage or disruption in 
the patient’s body function/structure, physical activities and/or quality of life.  
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the above definition.  
 
13.3 IRB AND DSMB REPORTING 
13.3.1 IRB REPORTING 
An AE or SAE is judged to be reportable to University of Pittsburgh HRPO, if it meets ALL of 
the following: i.) unanticipated in terms of nature, severity, or frequency; ii.) related or 
possibly related to study intervention; iii.) places subjects or others at a greater risk of 
physical, psychological, economic or social harm than was previously known or recognized.  
If the AE is judged to be reportable to the IRB based on above criteria, then the study team 
at the University of Pittsburgh will report to the HRPO within 10 working days. If it is an SAE 
and meets the above criteria, the study team will report to the HRPO within 24 hours.  
 

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All SAEs that meet above criteria and occurring at Mayo Clinic must be reported to the study 
team at University of Pittsburgh within 24 hours. All AEs that meet above criteria and 
occurring at Mayo Clinic must be reported within 5 working days to the team at University 
of Pittsburgh. The study team at University of Pittsburgh will then report all AE and SAE to 
the University of Pittsburgh HRPO within timelines shown in Table 7. The AEs that comprise 
the safety outcomes will be included in outcome reporting and will not be reported a 
second time as AEs or SAE. 
 
At both clinical sites the study personnel must alert the Principal Investigator of any serious 
and study procedure-related adverse event within 24 hours of investigator/coordinator 
awareness of the event. Please note that most AEs will not meet the definition of an 
Unanticipated Problem Involving Risk to Subjects or Others and need not be reported to the 
HRPO. Expected AEs or AEs which are determined by the investigator to be unrelated to the 
research intervention need not be reported to the IRB.  The flow chart below provides an 
algorithm for determining whether an AE meets the definition of an unanticipated problem 
involving risk to subjects or others and whether it needs to be reported to HRPO. 
 
Figure 9: Adjudication of AEs  
13.3.2 DSMB REPORTING 
All SAEs meeting the definition of unanticipated problem as stated in Section 13.3.1 will be 
reported to DSMB within 24-48 hours of investigator/coordinator awareness of the event. 
For all other AEs meeting the definition of unanticipated problem a written report will be 
sent to the DSMB within 10 working days. The DSMB will also review all AE and clinical 
outcomes during regularly scheduled meetings and at the final analyses, including frequency 
of rescue procedures and hypotension in all the study groups. If the DSMB determines that 

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the overall rate of adverse events is higher in any of the two intervention groups, University 
of Pittsburgh HRPO will be notified within 15 days of this determination. An AE table 
summarizing IRB and DSMB reporting timeline is provided below. 
 
 
Table 7: Reporting timelines  
 
Reporting 
organization 
Fatal or life-
threatening AE 
meeting definition of 
unanticipated problem 
All other AEs meeting 
definition of 
unanticipated 
problem 
AEs that are expected 
and listed as 
secondary or safety 
outcome 
Co-ordinating 
center 
24 hours 
5 working days 
No reporting 
IRB 
24 hours 
10 working days 
No reporting 
DSMB 
24-48 hours 
10 working days 
Reporting at the 
regular DSMB 
meeting 
 
 

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14 APPENDICES 
A. CALCULATION OF NIH GENDER-SPECIFIC PREDICTED BODY WEIGHT 
 
Predicted body weight (PBW) is calculated from gender and height (heel to crown) 
according to the following equations: 
 
Males: PBW (Kilograms) = 50 + 2.3 [height (inches) – 60] 
 
Females: PBW (Kilograms) = 45.5 + 2.3 [height (inches) – 60] 
 
 
 

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B. KDIGO CRITERIA FOR DIAGNOSING AND STAGING OF ACUTE KIDNEY INJURY 
 
B1. DIAGNOSIS OF AKI 
 
AKI will be diagnosed using as any of the following 
 
• Increase in serum creatinine ≥0.3 mg/dL within 48 hoursa 
OR 
• Increase in serum creatinine ≥1.5 times baseline, which is known or presumed to 
have occurred within prior 7 daysa 
OR 
• Urine volume <0.5 mL/kg/h for 6 hours 
OR 
• Increase in serum creatinine value ≥ the age, gender, and race corrected levels in 
Table B1 
a The increase in serum creatinine (absolute and relative) will be determined based on the 
lowest available serum creatinine value in the past 12 months. If no baseline value is 
available, AKI status will be determined using the age- and gender-corrected table below 
provided there is no past medical history of chronic kidney disease 
 
Table B1: Cut-off values for serum creatinine based on 1.5 times estimated normal values 
for age group 
 
Age 
(years) 
Black Male 
mg/dL 
Other Male 
mg/dL 
Black Female 
mg/dL 
Other Female 
mg/dL 
20-24 
2.3  
2.0  
1.8  
1.5  
25-29 
2.3  
1.8  
1.7  
1.5  
30-39 
2.1  
1.8  
1.7  
1.4  
40-54 
2.0  
1.7  
1.5  
1.4  
55-65 
2.0  
1.7  
1.5  
1.2  
>65 
1.8  
1.5  
1.4  
1.2  
 
B2 STAGING OF AKI 
 
Table B2: Determination of the stage of AKI  
Stage 
Serum Creatinine 
Urine Output 
1 
1.5 – 1.9 times baseline 
OR 
≥0.3 mg/dl increase 
<0.5 mL/kg/h for 6 – 12 hours 
2 
1.0 – 2.9 times baseline 
<0.5 mL/kg/h for ≥12 hours 
3 
3.0 times baseline 
OR 
Increase in serum creatinine to ≥4.0 mg/dl 
OR 
Initiation of kidney replacement therapy 
<0.3 mL/kg/h for 24 hours 
OR 
Anuria ≥12 hours 
 
 

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C. DEIDENTIFIED DATA ELEMENTS FOR SCREENED, NON-ENROLLED SUBJECTS 
 
The following data elements will be collected on screened subjects who met the inclusion 
criteria but were not enrolled. 
 
• Has CKRT been started? 
• Was UFNET commenced before screening? 
• Was the attending intensivist/nephrologist intending to start CKRT for fluid 
removal? 
• Month of year that patient met screening criteria (02-21) 
• Gender 
• Ethnicity 
• Age (if age >89, 89 will be entered as age) 
• Patient location (e.g., TICU, Medical ICU etc.) and if regularly screened 
• Reason(s) patient excluded from study 
• If not excluded, not enrolled, why? 
• Cause of acute kidney injury 
 
 

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D. CONTINUOUS KIDNEY REPLACEMENT THERAPY (CKRT) MANAGEMENT PROCEDURES 
 
General treatment parameters for the prescription of CKRT are summarized in the table 
below.  
 
Modality  
CVVHDF, CVVHD, CVVH, or SCUF 
Treatment schedule 
Continuous 
Hemofilter 
M100 or any synthetic hollow-fiber 
membranes 
Blood flow rate 
200 – 350 mL/min, prescribed by primary 
team 
Effluent flow rate 
20-30 mL/kg/h 
Dialysate 
Bicarbonate buffered; electrolyte 
composition prescribed by primary team 
Dialysate flow rate 
Prescribed by primary team 
Post-filter replacement fluid 
Bicarbonate buffered; electrolyte 
composition prescribed by primary team 
Pre-filter replacement fluid 
Bicarbonate buffered; electrolyte 
composition prescribed by primary team  
Ultrafiltration rate 
As per study protocol  
Anticoagulation 
Prescribed by primary team 
System change 
At least every 48-72 hours 
 
To deliver the targeted dose of UFNET, it is critical that periods of time during which the 
patient is off CKRT are kept as brief as possible. We recognize that patients will need to 
come off therapy for a variety of reasons, including CT scans, MRI scans, angiographic and 
surgical procedures. The ICU staff will be educated as to the importance of resuming 
treatment promptly upon the patients return to the ICU. Similarly, when systems need to be 
changed, either due to system clotting, or due to routine system changes, the time off 
therapy needs to be minimized.  
 
 
 

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E. SOFA SCORING SYSTEM 
 
 
Variables 
Sequential Organ Failure Assessment Score 
 
0 
1 
2 
3 
4 
Respiratory 
 
 
 
 
 
 
PaO2/FiO2 (mmHg) 
>400 
≤400 
≤300 
≤200a 
≤100a 
Coagulation 
 
 
 
 
 
 
Platelets (x 103/µL 
>150 
≤150 
≤100 
≤50 
≤20 
Liver 
 
 
 
 
 
 
Bilirubin 
<1.2 
1.2 – 1.9 
2.0 – 5.9 
6.0 – 11.9 
>12.0 
Cardiovascular 
 
 
 
 
 
 
MAP (mmHg) 
 ≥70 
<70 
 
 
 
 
Vasopressorb (doses 
in mcg/kg/min) 
None 
None 
Dopamine ≤5 
OR 
Dobutamine 
(any dose) 
Dopamine >5 
OR 
Epinephrine ≤0.1 
OR 
Norepinephrine ≤0.1 
Dopamine >15 
OR 
Epinephrine >0.1 
OR 
Norepinephrine >0.1  
 
 
Central Nervous System 
 
 
 
 
 
 
Glasgow Coma Scale 
15 
13 – 14 
10 – 12 
6 – 9 
<6 
Kidney 
 
 
 
 
 
 
Creatinine (mg/dL) 
<1.2 
1.2 – 1.9 
2.0 – 3.4 
3.5 – 4.9 
OR 
≥5 
OR 
 
Urine output (mL/day) 
 
 
 
<500 
<200 
 
a Values are with ventilatory support; the maximum score in patients not receiving 
ventilatory support is 2 
 
b Pressor agents administered for at least 1 hour 
 
We define a clinically significant organ failure as a new SOFA score of ≥2 
 
 

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F. TIME-EVENTS SCHEDULE 
F1. GENERAL DATA COLLECTION 
Measurement/Event Screening 
Baseline/
Day 0@ 
1 
2 
3 
4 
5 
6 
7 
8-
14 
15-
21 
22-
28 
Serum Creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics, 
History and Physical 
 
X 
 
 
 
 
 
 
 
 
 
 
AKI Cerner alerts 
X 
X 
 
 
 
 
 
 
 
 
 
 
Etiology of AKI 
 
X 
 
 
 
 
 
 
 
 
 
 
APACHE II 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily FB* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Restrictive UFNET  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liberal UFNET 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ventilator 
parametersφΨ* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CKRT parametersφΨ$ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ABG* 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
Fluids 
(intake/output)* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MAP* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CVP, CI, PPV, SVV, 
and other 
hemodynamic data* 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
Hypotensive & 
Hypertensive 
episodes$% 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac 
arrhythmias$% 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Use of rescue UFNET 
rates$ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Severe 
hypophosphatemia$ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Severe hypokalemia$ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Severe hypocalcemia 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
All lab data* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs and 
medications* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inability to close 
surgical wounds 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
New organ 
dysfunction* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Secondary infections 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SOFA score β* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Measurement/Event Screening 
Baseline/
Day 0@ 
1 
2 
3 
4 
5 
6 
7 
8-
14 
15-
21 
22-
28 
KRT Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IHD use  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X= Required 
A=When available 
Ψ=Data gathered at times indicated or until 72 hours, whichever occurs first 
β=Records clinically available creatinine, platelets, bilirubin, MAP, SBP, FiO2, fluid bolus and vasopressor use 
φ=Measure during reference period (0600 -1000); other values may be obtained closest to 0800 on the 
specified calendar date 
* = collected only if the patient is still in the ICU before day 28 and if available in the electronic health records 
$= collected only if the patient is on CKRT upto 24 hours following discontinuation of CKRT 
%=collected only if the patient is on IHD 
@ =Data collected before initiation of study intervention 
 
F2. CKRT DATA COLLECTION 
 
Measurement/ 
Event 
Initiation 
of RRT 
Baselin
e/Day 
0@ 
1 2 
3 
4 
5 
6 
7 
8-14 
15-21 
22-28 
Indication for KRT 
- Volume status 
- Serum potassium 
- Acid-base status 
- Symptoms 
- BUN 
- Hemodynamic 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
CKRT 
- Mode 
- Hemodiafilter 
- Blood flow rate 
- Dialysate flow 
rate 
- Replacement fluid 
rate 
- Ultrafiltration rate 
- Net Ultrafiltration 
rate 
- Hours of therapy 
- 24- hour effluent 
volume 
- Anticoagulation 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
Complications 
- Clogging 
- Clotting 
- Downtime  
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 

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Measurement/ 
Event 
Initiation 
of RRT 
Baselin
e/Day 
0@ 
1 2 
3 
4 
5 
6 
7 
8-14 
15-21 
22-28 
- Discontinuation of 
UFNET due to 
patient instability 
Indications for 
termination of KRT 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
@= Data collected before initiation of study intervention 
 
 
 

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G. ADVERSE EVENT REPORTING AND UNANTICIPATED PROBLEMS 
G1. DETERMINING RELATIONSHIP OF ADVERSE EVENTS TO STUDY PROCEDURES 
 
Investigators will be asked to grade the strength of the relationship of an adverse event to 
study procedures as follows: 
 
• Definitely Related: The event follows: a) A reasonable, temporal sequence from a 
study procedure; and b) cannot be explained by the known characteristics of the 
patient’s clinical state or other therapies; and c) evaluation of the patient’s clinical 
state indicates to the investigator that the experience is definitely related to study 
procedures.  
 
• Probably or Possibly Related: The event should be assessed following the same 
criteria for “Definitely Associated”. If in the investigator’s opinion at least one or 
more of the criteria are not present, then “probably” or “possibly” associated should 
be selected. 
 
• Probably Not Related: The event occurred while the patient was on the study but 
can reasonably be explained by the known characteristics of the patient’s clinical 
state or other therapies. 
 
• Definitely Not Related: The event is definitely produced by the patient’s clinical state 
or by other modes of therapy administered to the patient. 
 
• Uncertain Relationship: The event does not meet any of the criteria previously 
outlined. 
 
G2. UNANTICIPATED PROBLEMS (UP) 
 
Investigator will report Unanticipated Problems, regardless of severity, associated with the 
study procedures to University of Pittsburgh HRPO and DSMB. An unanticipated problem is 
defined as follows: any incident, experience, or outcome that meets all the following 
criteria: 
 
• Unexpected, in terms of nature, severity, or frequency, given the research 
procedures that are described in the protocol-related documents, such as the HRPO-
approved research protocol and informed consent document; and the characteristics 
of the subject population being studied. 
 
• Related or possibly related to participation in the research. Possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research. 
 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  
 

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H. DATA AND SAFETY MONITORING BOARD 
 
The principal role of the DSMB is to assure the safety of patients in this feasibility trial. They 
will regularly monitor the data from this trial, review and assess the performance of its 
operations, and make recommendations to the Principal Investigator with respect to: 
 
• Review of adverse events 
• Possible modifications in the clinical trial protocol 
 
The Clinical and Translational Science Institute at the University of Pittsburgh will appoint a 
DSMB. The DSMB will consist of members with expertise in critical care medicine, 
nephrology, and biostatistics. Appointment of all members is contingent upon the absence 
of any conflicts of interest. The Principal Investigator will be responsible for the preparation 
of all DSMB and adverse event reports. 
 
The DSMB will review the protocol and sample consent form during its first meeting. 
Subsequent DSMB meetings will be scheduled in accordance with the DSMB. When 
appropriate, face-to-face (i.e., Teams/Zoom) meetings will be held. Recommendations to 
end, modify, or continue the trial will be prepared by the DSMB executive secretary. 
Recommendations for major changes, such as stopping, will be reviewed by the DSMB and 
communicated immediately. Other recommendations will be distributed to the RELIEVE-AKI 
steering committee. 
 
 

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I. COMMON REASONS FOR ACUTE KIDNEY INJURY, FLUID OVERLOAD AND RAPID UFNET 
 
I1. COMMON CAUSES FOR AKI AND FO 
 
• Sepsis  
• Massive hemorrhage 
• Cardiac surgery 
• Major trauma 
• Acute pancreatitis 
 
I2. COMMON REASONS FOR RAPID UFNET  
 
• Severe fluid overload with impending respiratory failure 
• Acute heart failure with pulmonary edema and cardio-renal syndrome 
• Refractory hypoxemia due to fluid overload and ARDS while on mechanical 
ventilation 
• Severe fluid overload after massive septic shock resuscitation 
• Chronic kidney disease and heart failure or COPD 
 

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Martin DC, Richards GN. Predicted body weight relationships for protective 
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Bloomfield R, Steel E, MacLennan G, Noble DW. Accuracy of weight and height 
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Jeyapala S, Gerth A, Patel A, Syed N. Improving fluid balance monitoring on the 
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