targeting abdominal perfusion pressure in septic shock ...confidential protocol: crd -062615 rev c...

Confidential Protocol: CRD-06-2615 Rev C

CRD-06-2615 Rev C Confidential & Proprietary 1

Targeting Abdominal Perfusion Pressure in Septic Shock (The MAP APP Study)

PROTOCOL NUMBER: CRD-06-2615

Revision C Product: Potrero Medical Accuryn™ Monitoring System Sponsor: Potrero Medical, Inc. 101 Mississippi Street San Francisco, CA 94107 www.potreromed.com 415-926-8616 Confidentiality Statement The information contained in this document is the confidential and proprietary information/property of Potrero Medical, Inc. (Potrero Medical), and, except as may be required by federal, state or local laws or regulations, may not be disclosed to others without prior written permission of Potrero Medical. The Principal Investigator may disclose such information to supervised individuals involved with the Accuryn™ Monitoring System clinical trial.



INVESTIGATOR’S AGREEMENT

I have read the protocol Targeting Abdominal Perfusion Pressure in Septic Shock’, and agree that it contains all necessary details for carrying out this clinical trial as described. I will conduct the clinical trial as outlined herein, including all statements of confidentiality, and will make every reasonable effort to complete the trial within the time designated. I will provide copies of this protocol and all pertinent information to individuals responsible to me who assist in the conduct of this trial. I will discuss this information with them to ensure that they are fully informed regarding the device, its operation and the conduct of the clinical trial. I will fulfill all responsibilities for submitting pertinent information to the Ethics Committee (EC) or Institutional Review Board (IRB) responsible for this clinical trial. I will use only the informed consent form approved by Potrero Medical, the IRB or EC, or its designees. I further agree that Potrero Medical or its designee shall have access to source records identified in the informed consent form from which clinical trial subject record information may have been obtained. This clinical trial will be conducted according to principles of Good Clinical Practice as described in International Conference on Harmonization guidelines. _____________________________________ PI Name _____________________________________ Signature of Investigator _________________________ Date



KEY PERSONNEL

Study PIs:

Daniel Burnett, MD, MBA Chief Medical Officer Potrero Medical, Inc. San Francisco, CA Phone: (415) 926 8616 [email protected] Michael J. Connor, Jr., MD Associate Professor - Critical Care Medicine & Nephrology Division of Pulmonary, Allergy, Critical Care, & Sleep Medicine Emory Critical Care Center & Grady Memorial Hospital Emory University School of Medicine Atlanta, GA Phone: (404) 616-0184 [email protected] Luis A. Juncos, MD Professor-Clinical Nephrology University of Arkansas Medical Center Central Arkansas Veterans Health System John L. McClellan Memorial Veterans Hospital 4300 West 7th Street Little Rock, AR 72205 Phone: (501) 257-1000 [email protected]

Please note that this study adopts a multiple PI model. All PIs above will share administrative responsibility and general oversight of the study.



Sponsor Contacts:

Reem Yunis, PhD Senior Clinical Trial Manager Potrero Medical, Inc. San Francisco, CA P: (415) 926 8616 C: (650) 279 7769 [email protected]



TABLEOFCONTENTS1. Protocol Synopsis ........................................................................................................................................................ 7 2. Objectives ................................................................................................................................................................. 15 3. Background ............................................................................................................................................................... 16

3.1 Significance ....................................................................................................................................................... 16 3.2 Device Description ............................................................................................................................................ 16

3.2.1 Accuryn™ Sensing Urinary Catheter ......................................................................................................... 18 3.2.2 Accuryn™ Urine Collection Set .................................................................................................................. 19 3.2.3 Accuryn™ Monitor .................................................................................................................................... 19

3.2.3.1 Electrical Urometer UO volume and temperature measurements ...................................................... 20

3.2.3.2 Pressure lumen measurement .............................................................................................................. 20

4. Study Overview ......................................................................................................................................................... 20 4.1 Objectives of Clinical Trial ................................................................................................................................. 20 4.2 Study population for the Accuryn™ Monitoring System .................................................................................. 21

5. Criteria for Subject Selection .................................................................................................................................... 21 5.1 Number of Subjects and Sites ........................................................................................................................... 21 5.2 Inclusion Criteria and Exclusion Criteria ........................................................................................................... 21

5.2.1 Inclusion Criteria ....................................................................................................................................... 21 5.2.2 Exclusion Criteria ...................................................................................................................................... 22

6. Study Plan ................................................................................................................................................................. 22 6.1 Overview ........................................................................................................................................................... 22

6.1.1 Screening & Enrollment ............................................................................................................................ 22 6.1.2 Randomization .......................................................................................................................................... 23 6.1.3 Intra-Abdominal Pressure Measurements ................................................................................................ 24 6.1.4 Targeted Resuscitation in Intervention Phases ........................................................................................ 25 6.1.5 Data Collection & Follow-up ..................................................................................................................... 25

6.2 Study Flow ........................................................................................................................................................ 26 6.3 Endpoints and Additional Analyses ................................................................................................................... 27 Statistical methods ....................................................................................................................................................... 28

6.3.1 Study Power .............................................................................................................................................. 28 6.3.2 Endpoint Analyses ..................................................................................................................................... 28

7. Data Management .................................................................................................................................................... 29 7.1 Data Recording Methods .................................................................................................................................. 29

7.1.1 Case Report Forms .................................................................................................................................... 29 7.2 Data Storage, Confidentiality, and quality assurance ....................................................................................... 29

7.2.1 Data Storage ............................................................................................................................................. 29



7.2.2 Data Confidentiality .................................................................................................................................. 29 7.3 Data Monitoring and quality assurance ............................................................................................................ 30

8. Event Reporting ........................................................................................................................................................ 30 Definition of adverse event and Serious Adverse Event ....................................................................................... 30 8.1 ................................................................................................................................................................................. 30 8.2 Anticipated Adverse Events .............................................................................................................................. 31 8.3 8.3 Anticipated Serious Adverse Events ........................................................................................................... 32 8.4 Reporting of Events .......................................................................................................................................... 32 8.5 Safety Assessment ............................................................................................................................................ 32

9. Risk/Benefit Assessment .......................................................................................................................................... 32 9.1 Risks Associated with the Study Procedures .................................................................................................... 32 9.2 Risk Category .................................................................................................................................................... 33 9.3 Protections Against Risks .................................................................................................................................. 33 9.4 Risk Benefit Rationale ....................................................................................................................................... 33

10. Subject Identification, Recruitment, And Consent/Assent ....................................................................................... 33 10.1 Method of Subject Identification and Recruitment .......................................................................................... 33 10.2 Informed Consent ............................................................................................................................................. 33 10.3 Cost to the Subject ............................................................................................................................................ 34 10.4 Payment for Participation ................................................................................................................................. 34

11. References ................................................................................................................................................................ 35



1. PROTOCOL SYNOPSIS

Title Targeting Abdominal Perfusion Pressure in Septic Shock (The MAP APP Study)

Sponsor Potrero Medical, Inc.

Required Device

Accuryn™ Monitoring System (510k cleared device)

Protocol Number

CRD-06-2615 Rev C 20180926 (APP-001)

Background and Rationale

Intra-abdominal pressure (IAP) has proven to be an important physiologic parameter in critically ill patients. Elevated IAP is termed intra-abdominal hypertension (IAH). Literature suggests that IAH is common in patients with septic shock and that there is an association between the presence of IAH and acute kidney injury (AKI) in this group. Mean arterial pressure (MAP) and IAP together help determine the abdominal perfusion pressure (APP) of organs and tissues within the abdominal cavity. Current clinical guidelines for septic shock encourage targeting mean arterial pressure (MAP) of 65-70 mmHg with the use of vasopressors after volume resuscitation. However, it remains unclear if hemodynamic support targeting APP: (a) reduces development of acute kidney injury (AKI), (b) decreases progression of AKI, or (c) improves renal recovery rate compared to standard care for severe septic shock patients. Potrero Medical, Inc. has developed a novel Foley catheter and monitoring device, the Accuryn™ Monitoring System, capable of detecting physiologic changes in temperature, urine output (UO) and intra-abdominal pressure (IAP). These data streams are captured continuously by a device that is minimally invasive and at a high frequency which, in combination with MAP, allow for a simple calculation of abdominal perfusion pressure (APP).

Study Objectives

Primary Objective: To study kidney function and recovery in patients with septic shock and elevated IAP as measured by timed creatinine clearance on calendar days 1-7 when targeting treatment to maintain APP ≥ 60 mmHg with a variable MAP target as compared to standard of care with a fixed MAP target. Creatinine clearance on calendar day 7 post-intervention or on day of ICU discharge, whichever is earliest, is the primary endpoint.

Secondary Objective: To study the incidence, progression and recovery of AKI as well as patient-centered outcomes among patients treated by APP target versus standard of care. To study renal injury and recovery and patient-centered outcomes among septic shock patients with or without IAH.

Study Design Multicenter, randomized, controlled trial

Study Population

Hospitalized critically ill patients with septic shock who remain dependent on vasopressor therapy 12 hours after being diagnosed with septic shock following an earlier resuscitation period.

Study Groups (1) “Monitoring group” (IAP < 8 mmHg receiving sepsis standard of care of MAP-targeted resuscitation) (2) “MAP group” (IAP ≥ 8 mmHg receiving sepsis standard of care of MAP-targeted resuscitation) (3) “APP group” (IAP ≥ 8 mmHg receiving sepsis treatment of APP-targeted resuscitation) (See Figure 1: Study Flow)



Study Interventions

Monitoring Group – This group maintains IAP < 8 mmHg and receives management of septic shock per Surviving Sepsis Campaign 2016 Guidelines. This group is monitored for peak AKI stage during hospitalization and other outcomes, such as a need for acute renal replacement therapy and mortality. MAP Group – This group develops IAP ≥ 8 mmHg and receives management of septic shock per Surviving Sepsis Campaign 2016 Guidelines to target MAP ≥ 65 mmHg (or individualized goal as determined by ICU attending physician). APP Group – This group develops IAP ≥ 8 mmHg and receives management of septic shock per Surviving Sepsis Campaign 2016 Guidelines EXCEPT target MAP will vary dynamically to target and maintain APP ≥ 60 mmHg.

Number of sites

Three (3) sites are planned to participate – additional sites may be added if enrollment is slower than anticipated at primary three sites.

Number of subjects

Following a roll-in period for each site to introduce use of the Accuryn™ Monitoring System, an initial target sample size of 200 subjects will be enrolled in the trial. Sample size adjustment (if necessary) will take place at an interim assessment occurring after approximately 100 subjects are enrolled.

Safety assessment

Continuous monitoring of subject safety will occur using an independent medical monitor. All subject adverse events and serious adverse events will be recorded as soon as the study team becomes aware. Each site's study investigator will also be reviewing the events on a regular interval and will alert the sponsor of any unanticipated adverse events related to the monitor and form of treatment.



Patients diagnosed with septic shock requiring vasopressor therapy in the ED

Standard clinical care per Surviving Sepsis 2016 protocols (or similar)

Resu

scita

tion

Perio

d(t

= 0

to t

= 12

hr)

Patient screened for eligibilityIf potentially eligible, AccurynTM catheter placed

IAP < 8 mmHg IAP ≥ 8 mmHg

Subject enters into the INTERVENTION PHASE

Subject enters into the MONITORING

PHASE

Monitoring GroupSubjects receive regular

standard of care treatment and are monitored throughout

hospitalization for:• Presence of AKI• Peak stage of AKI

(KDIGO creatinine criteria)

• Need for acute RRT

Patient assigned treatment arm (based on randomization at

time of consent)

MAP Group

• Maintain MAP ≥ 65or

• ICU Attg MD determined individualized goal (i.e. in pt with baseline HTN)

APP Group

• Measure IAP Q4H and

• Adjust MAP targets every 4 hrs to maintain APP ≥ 60*

*APP = MAP - IAP

Targeting Abdominal Perfusion Pressure in Septic ShockPROTOCOL NUMBER: CRD-06-2615

Figure 1: Study Flow

If, at any time during the Observational Period, IAP ≥ 8mmHgOb

serv

atio

nal P

erio

d(t

= 12

to t

= 48

hr)

Mon

itorin

g Ph

ase

(t =

48 h

rto

Disc

harg

e)

Intervention Phase (Entry into Intervention Phase to Discharge)

Observational Period(t = 12 hrto Entry into Intervention

Phase)

Patient consented, enrolled and randomized 1:1 (MAP/APP). After consent, Accuryn Catheter placed if not present. This may involve a catheter swap



Inclusion Criteria

FOR RESUSCITATION AND OBSERVATIONAL PERIODS OF STUDY 1. Adult (age ≥ 18) 2. Septic shock – identified as early as possible following admission into or from referring

emergency department (ED: may be diagnosed with initiation of care/resuscitation in ED). As evidenced by:

a. Clinical diagnosis of sepsis defined as documented or suspected infection with the use of antibiotic administration OR

b. Meets qSOFA (Quick Sequential Organ Failure Assessment) Criteria per the Sepsis-3 definitions:

i. Respiratory rate ≥ 22/min ii. Altered mentation

iii. Systolic blood pressure £ 100 mmHg AND c. Shock dependent on vasopressor therapy following initial 12-hour Resuscitation Period

refractory to further volume expansion as assessed by clinical treatment team; this may be supported by either:

i. Lack of blood pressure response following fluid bolus or passive leg raise ii. Hemodynamic data as available (e.g. PPV, SVV, echo, PAOP, right-heart

catheterization, etc.) Patient must meet either (a + c) or (b + c) to be eligible

3. Indication for a urinary bladder catheter (or one currently in place) 4. Indication for an arterial line (or one currently in place at any site)

FOR MONITORING PHASE OF STUDY (MONITORING GROUP)

1. All of the above criteria for the Resuscitation and Observational Periods of the study 2. Intra-abdominal pressure < 8 mmHg

FOR INTERVENTION PHASE OF STUDY (APP VS MAP GROUPS) 1. All of the above criteria for the Resuscitation and Observational Periods of the study 2. Intra-abdominal pressure ≥ 8 mmHg



Exclusion Criteria

1. Inability to receive a urinary bladder catheter 2. Chronic suprapubic catheter in place 3. Cirrhosis/end stage liver disease, including Child-Pugh class C 4. Severe AKI as defined by life-threatening electrolyte, acidemia, or other indication for imminent

emergent dialysis needs within 12 hours of hospital admission 5. Evidence of chronic renal failure stage 5 (including serum creatinine values consistent with CKD

5 or dialysis dependence) in 12-months prior to enrollment 6. Active gastrointestinal bleed likely causing/contributing to the hemodynamic instability 7. Acute intra-abdominal trauma (including intraabdominal surgery within the prior 30 days) 8. Acute pancreatitis with no established source of infection 9. Treating physician deems aggressive care is unsuitable, or has decided to de-escalate care

[Do Not Resuscitate (DNR) patients receiving standard care are still eligible] 10. In the opinion of the treating attending physician the patient is unsuitable for the study for any

legitimate reason including lack of equipoise, anticipated imminent significant deterioration, anticipated imminent recovery, incarceration, pre-existing medical or psychiatric condition that treating attending physician deems not appropriate for study, or interfering medications

11. Known previous or concurrent enrollment in a treatment clinical trial that, in the opinion of the investigator, might interfere with the objectives/endpoints of this clinical trial

12. Known contraindication to bladder pressure measurement 13. Known pregnancy 14. Suspected or known increased intracranial pressure requiring active neurosurgical consultation 15. Cardiogenic shock requiring extracorporeal support 16. Any requirement for chest compressions prior to enrollment



Study Procedures

Screening and Randomization 1. Septic shock patient identified as early as possible following admission into emergency department

(ED) or from referring ED (patient may be diagnosed with septic shock with initiation of care/resuscitation begun in ED)

2. No study related interventions during the initial 12 hour* Resuscitation Period. During these initial 12 hours, MAP targets for resuscitation are guided by primary clinical team usually using MAP target ≥ 65 mmHg per Surviving Sepsis Campaign 2016 Guidelines.

3. Patient pre-screened for eligibility during the first 12 hours* of presentation with septic shock • If potentially eligible, then Accuryn™ catheter is placed (if not already present) for simple IAP

monitoring – no consent necessary for initial catheter placement as the Accuryn™ System is FDA approved device to monitor UO, temperature (T), and IAP.

4. Patient (or surrogate) offered enrollment and consented for possible catheter swap for Accuryn™ catheter and for entry into both the MONITORING and INTERVENTION PHASES of the study. Patient (or surrogate) may be offered enrollment and consented during the 12-hour Resuscitation Period if care team determine eligibility (see #6).

5. After enrollment, the subject will be randomized and observed up to 48 hours of sepsis diagnosis: • Monitoring Phase - If IAP remains < 8 during the 48 hours from sepsis diagnosis, subjects in

this Phase will receive standard of care and de-identified EMR data (daily urine output, peak AKI stage, need for and duration of acute renal replacement therapy (RRT), and hospital mortality) will be monitored and recorded. Continuous IAP, urine output and physiological data streams are recorded via the Accuryn™ Monitoring System (on the internal device SD card) while in situ.

• Intervention Phase - If IAP ≥ 8 within 48 hours from sepsis diagnosis, then subject will enter Intervention Phase of study and be assigned to one of two treatment arms (based on randomization at time of consent):

i. MAP Group - Standard of Care arm – titrate clinical treatment to maintain MAP target ≥ 65 mmHg per Surviving Sepsis Campaign 2016 Guidelines

ii. APP Group – APP arm – IAP recorded every 4 hours and MAP targets adjusted to maintain APP ≥ 60 mmHg

6. If subjects are enrolled and randomized during the 12-hours Resuscitation Period, and their IAP ≥ 8 before completion of initial 12-hours, subjects will not begin their assigned intervention treatment before the conclusion of the 12 hours of standard resuscitation treatment. If subjects are already beyond the 12 hours of standard care, then Intervention Phase treatment will begin immediately.

* 12-hour clock starts at the time “sepsis” bundles began (i.e. first antibiotic order).

Device Setup Accuryn™ will be placed in potentially eligible septic shock patients regardless of study entry at the earliest possible time point). All potentially eligible patients can have IAP requested up to 48 hours after sepsis diagnosis. For all subjects enrolled into the Intervention Phase, IAP will be requested only if the subject is randomized to the APP arm. After enrollment, the patients participating in the MAP group will have the IAP display blinded on the Accuryn™ device. The continuous IAP recording will be captured on the internal SD card of the device (but not be visible or retrievable by the clinical user).



Targeted Resuscitation in Intervention Phases

1. MAP group will target MAP ≥ 65 mmHg per Surviving Sepsis Campaign 2016 Guidelines (or MAP target set by ICU attending [i.e. possibly higher in patient with chronic hypertension or other disease state]).

2. APP group will target APP ≥ 60 mmHg (or APP target set by ICU attending [i.e. possibly higher in patient with chronic hypertension or other disease state per standard care]).

Data Collection and Follow-up

1. Demographic patient characteristics including pre-study renal function/medical conditions/medications

2. Sepsis diagnosis 3. Hemodynamic and ventilator variables and laboratory values and special samples (i.e. timed 6-hour

urine creatinine clearance, Urinary [TIMP-2] x [IGFBP7] (NephroCheckÒ, Astute Medical, San Diego, CA), additional serum biomarkers) as outlined in analyses section

4. Vasoactive infusions and diuretic medications (dose and duration) will be documented as will cumulative fluid resuscitation/daily balance since hospital presentation

5. Receipt of RRT (including confirmation of prior RRT and indication for new RRT) 6. Follow-up points will be hospital discharge, 30 days post-enrollment, and 90 days post-enrollment 7. Patients will remain in the study until 90-day post-enrollment or death 8. Significant protocol deviation will be documented but the study will be conducted in accordance to

intention-to-treat guidelines. A “per protocol” analysis may be performed • Sites and enrollment will be assessed for protocol compliance at regular intervals

9. Data will be downloaded directly from the Accuryn™ Device every 2-3 patients’ usage of the Accuryn™ Monitoring System.

10. Statistical analyses will be performed for each of the measurement parameters as outlined below Primary endpoint will be assessed after first 100 subjects enrolled, then after every 50 additional subjects enrolled (as necessary) to adjust sample size and assess efficacy/futility.

Additional Study Requirements

1. Site principal investigators, research coordinators/nurses, and ICU nurses in participating ICUs will undergo study protocol and device training prior to initiating study enrollment. A predetermined “roll-in” period of standard device use at each site will be established prior to study initiation. The “roll-in” period will be of a minimum duration as determined by the site study team to ensure proficiency with all aspects of routine device use.

2. Per good clinical practices (GCP), sites will participate in all phases of clinical trial monitoring.



Analyses Primary Endpoint: Creatinine clearance (CrCl) on calendar day 7 post-intervention as informed by daily 6-hour timed creatinine clearance over first seven (7) days of intervention phase OR to device discharge, whichever is earliest with the following caveats: (a) patients who have died will be assigned a CrCl of 0, (b) patients who remain admitted to participating study hospital and dependent on RRT will be assigned a CrCl of 0 unless they are making > 500 ml/day of urine whereby a timed 6-hour urine creatinine clearance will be performed.

Secondary Analyses:

• Patient characteristics in each group at enrollment:

o Demographics including age, gender, BMI o SOFA scores o Medical and surgical co-morbidities and ‘renal’ medications (diuretic and

antihypertensive medications), antibiotics, and all other medications o Source of sepsis (blood, respiratory, urinary, GI/abdominal, skin/soft tissue, bone,

etc.) o Hemodynamic variables, labs (including lactate), vasoactive infusions (mean dose),

ventilation/oxygen requirement o Total fluid therapy (and fluid therapy stratified by total given in resuscitation period

and observation period) o AKI/IAP variables (baseline creatinine on ED admission and enrollment, and median

in 12 months prior to admission)

• Renal function measurements: o Serum creatinine at minimum Q24H (q = ‘every’) until discharge – will

document all creatinine values that are acquired for routine clinical use o Urine output Q4H (automatically captured by Accuryn™ device)

• A separate analysis factoring in diuretic use will be completed o Baseline urinary [TIMP-2] x [IGFBP7] (NephroCheckÒ) at study enrollment and

Q24H for 5 days after initiation of intervention phase of study o Biomarkers of renal insult (proenkephalin (PENK) and/or other) in banked

serum and urine samples at enrollment and during the intervention phase at Day 3, and 7 (or ICU discharge). Blood draw will not to exceed a total of 30 mL per patient

o Peak AKI stage by KDIGO during hospital stay o Composite endpoint of major adverse kidney events (MAKE) at 30 days post-

enrollment and 90-days post-enrollment: death, persistent RRT dependence, and >200% increase in baseline serum creatinine (as available)



• Resuscitation effectiveness measurements o Vital sign parameters including HR and MAP are recorded at Q2H from

admission to Day 7 or device removal, then at Q4H to Q6H until discharge. IAP is recorded at Q4H all throughout the study.

o Daily net fluid balance o Days on vasoactive medication o Mean daily dose of vasopressor i.e. mg/day of norepinephrine o Lactate Q6H until two successive levels <2mmol/L, daily ICU lab parameters o CVP, cardiac output indices (if available) o Ventilator days o Mean SOFA at 72 hours post-intervention o Any serious adverse event (MI, VAP, afib/VT/VF, cardiac arrest, bleeding

requiring transfusion, digital or mesenteric ischemia, neurologic sequelae (CVA, seizure)

• Patient-centered outcome measurements o In-hospital mortality o In-hospital new RRT o 30-day mortality OR continued RRT o 90-day mortality OR continued RRT o ICU length of stay (LOS) o Hospital LOS o Number and site of any hospital acquired infections o Number and reason of readmissions within 90 days o Post-hospital discharge to skilled nursing facility or rehabilitation LOS within 90

days Adverse Event Reporting

The definitions of an AE or SAE is found in Section 8. Events should be reported as an AE or SAE according to the definitions in Section 8.

The investigator or their designees are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE.

2. OBJECTIVES

Primary Objective: To study kidney function and recovery in patients with septic shock and elevated IAP as measured by timed creatinine clearance on calendar days 1-7 when targeting treatment to maintain APP ≥ 60 mmHg with a variable MAP target as compared to standard of care with a fixed MAP target. Creatinine clearance on calendar day 7 post-intervention or on day of ICU discharge, whichever is earliest, is the primary endpoint.

Secondary Objective:

To study the incidence, progression and recovery of AKI as well as patient-centered outcomes among patients with IAH treated by APP target versus standard of care in severe septic shock. To study renal injury and recovery and patient-centered outcomes among septic shock patients with or without IAH.



3. BACKGROUND

3.1 SIGNIFICANCE Potrero Medical, Inc. has developed a novel urinary catheter and monitoring device, the Accuryn™ Monitoring System, capable of accurately and continuously measuring patient temperature (T), urine output (UO), and intra-abdominal pressure (IAP). The UO measurement and digital readout reflects accurate, real-time urine output due to an automatic airlock clearing mechanism preventing urinary retention and stagnant columns of urine in the drainage tubing. Furthermore, IAP is continuously monitored using a pressure-sensing balloon, which allows for an easy one-touch IAP assessment by the caregiver. The device received FDA 510k clearance in April 2016. IAP has proven to be an important physiologic parameter, and in a critically ill patient is considered normal at approximately 4-7 mmHg. Elevated IAP is termed intra-abdominal hypertension (IAH; IAP ≥ 12 mmHg) with higher levels of IAH being referred to abdominal compartment syndrome when IAP ≥ 20 mmHg in the presence of new or worsening end-organ dysfunction1. Mean arterial pressure (MAP) and IAP together help determine the perfusion pressure of organs and tissues within the abdominal cavity. The abdominal perfusion pressure (APP; APP=MAP-IAP) is a way to estimate this perfusion and is an analogous concept to the cerebral perfusion pressure (CPP; CPP=MAP-Intracranial Pressure (ICP)) used to care for critical neurologic conditions. An APP of ≥ 60 mmHg is considered a desirable target for most patients1. Elevated IAP has been shown to have physiologic effects outside the abdominal cavity2. For example, elevated IAP affects the cardiovascular system by decreasing venous return, increasing afterload3 and thereby lowering cardiac output. Elevated IAP also increases pulmonary pressures leading to altered gas exchange dynamics and undesirable ventilator settings. ICP can also become elevated from increased IAP. Within the abdominal cavity, high IAP causes poor perfusion of the bowel wall leading to ischemia/inflammation and bacterial translocation4. Release of cytokines creates further capillary leak and edema, which spurs a vicious cycle of increasing IAP. Elevated IAP also profoundly affects the kidney increasing renal venous pressure with resultant decrease in renal perfusion pressure and renal parenchymal damage. This has been shown to trigger renal inflammation and decreased glomerular filtration rate (GFR) with oliguria, proteinuria, and diuretic resistance. Fluid overload has been shown to be a consistent source of elevated IAP5. The initial approach to treating septic shock patients is early goal-directed fluid resuscitation6 and, although fluid administration is critical to maintaining blood pressure, fluid overload is a nearly ubiquitous consequence in patients with septic shock7 . Indeed, patients with septic shock have been found to have an incidence of IAH of 40-80%8 . Furthermore, given that current clinical guidelines recommend a MAP target of ≥ 65 mmHg in those with septic shock6, patients with IAH will consequently suffer low APP. The incidence of acute kidney injury in septic shock is approximately 50%9. Therefore, we hypothesize that (1) IAH with subsequent poor renal perfusion be a significant source of AKI in patients with septic shock, and (2) that adjusting MAP targets to keep APP ≥ 60 mmHg will mitigate the decline in GFR and thus decrease the peak severity of AKI. This clinical treatment algorithm may also decrease acute RRT needs, ICU stay, and hospital mortality compared with current standard of care using fixed MAP targets in septic shock.

3.2 DEVICE DESCRIPTION The Accuryn™ Monitoring System is intended for use in the drainage and/or collection of urine, and in the monitoring of urine output and core body temperature in degrees Fahrenheit and degrees Celsius. The Accuryn™ Monitoring System is also intended for use in the monitoring of intra-abdominal pressure (IAP). The measured pressures can be used as an aid in the diagnosis of intra-abdominal hypertension (IAH) and the associated clinical syndrome of abdominal compartment syndrome (ACS). The Accuryn™ Sensing Urinary Catheter is a single use device intended for short-term use (less than 30 days).



The Accuryn™ Monitoring System clears airlocks in the drain line to maintain urine flow into the urine cassette reservoir. This reduces urine flow impediments due to airlocks, thereby providing a more accurate measurement of urine volume. The Accuryn™ Monitoring System received 510k clearance from the FDA under K153655. The Accuryn™ Monitoring System consists of the Accuryn™ Monitor and the Accuryn™ Urinary Catheter Kit, which contains the Catheter, Urine Collection Set and insertion supplies. A system diagram showing the interaction of the components is shown below in Figure 2. The kit is packaged and distributed by Medline Industries, while the Accuryn™ Monitor is packaged and distributed by Potrero Medical. For additional information on the Accuryn™ Catheter and Monitor, refer to the commercially available Instructions for Use (IFU-06-2845 Commercial Manual, Accuryn™ Monitor Gen 2.0).

The system is manufactured by Potrero Medical, Inc. and consists of three components listed below:

Accuryn™ Sensing Urinary Catheter

A 16 Fr two-way silicone urinary catheter with four lumens: the first lumen for the retention balloon, the second lumen for urine drainage, the third lumen embedded with a thermistor, and the fourth with a port to measure IAP and other physiologic signals (Figure 3 and 4).

Accuryn™ Urine Collection Set

The Urine Collection Set, distally* pre-connected to the Accuryn™ Sensing Urinary Catheter drainage lumen, conveys urine to a urine measurement cassette at the proximal end that is placed into the Accuryn™ Monitor and feeds into a urine collection bag (Figure 4).

Accuryn™ Monitor The Accuryn™ Monitor maintains urine flow from the Urine Collection Set, measures the urine output volume in the measurement cassette and displays the urine output. The Accuryn™ Monitor also measures and displays the temperature from the thermistor lumen and the intra-abdominal pressure (IAP) from the pressure lumen (Figure 4).

*Note: the words proximal and distal will be used in this document as follows: “proximal” will refer to the portion of the device towards the healthcare professional user (e.g. nurse/physician), whereas “distal” will refer to the portion of the device farther away from this user (e.g. distal tip of catheter within bladder).

A system diagram showing the interaction of components is shown below in Figure 2.

Figure 2. Accuryn™ Monitoring System with patient use scenario



3.2.1 ACCURYN™ SENSING URINARY CATHETER

The Accuryn™ Sensing Urinary Catheter is a single use, disposable, sterile medical device. The catheter is manufactured in a Class 100,000 clean room using well-known, medical grade materials. The Accuryn™ Sensing Urinary Catheter, in its single use package, is sterilized using ethylene oxide. The Accuryn™ Sensing Urinary Catheter is a 16 French, multi-lumen urinary bladder catheter (Figure 3), consisting of individual lumens for retention balloon inflation, urine drainage, thermistor/temperature measurement, and IAP monitoring. The Accuryn™ Sensing Urinary Catheter is designed pre-connected to the Accuryn™ Urinary Collection Set, which feeds into the Accuryn™ Monitor. The Accuryn™ Sensing Urinary Catheter is illustrated in Figures 3 and 4 below:

Figure 3. Accuryn™ Sensing Urinary Catheter cross section with (A) Retention balloon lumen, (B) Urine drainage lumen, (C) Thermistor lumen, and (D) Intra-abdominal pressure sensing lumen.

Figure 4. Accuryn™ Sensing Urinary Catheter pre-connected to Accuryn™ Urine Collection Set. (A) Pressure sensing balloon, (B) Urine drainage holes, (C) Retention balloon, (D) Retention balloon Valve, (E) Sampling port, (F) Drainage Tube, (G) Thermistor port connector, (H) Urine reservoir cassette

Materials of the Accuryn™ Sensing Urinary Catheter that contact the bladder mucosa and urethra are medical grade silicone and medical grade polyurethane. The profile of the Catheter is identical to that of all 16 French Foley

A B

C

D E F

G H

A

B

C DD

16 Fr



catheters containing a thermistor lumen, with the exception of an additional lumen that terminates in a pressure balloon, which is bonded to the catheter shaft.

The pressure balloon is collapsed when packaged and ready for catheter insertion. After placement of the Accuryn™ Sensing Urinary Catheter, the pressure balloon is inflated. The increased catheter outer diameter with inflation of the catheter tip pressure capsule is only about 20% of the diameter of the inflated retention balloon and is in compliance with French sizing standards defined in ASTM F623, Standard Performance Specification for Foley Catheters. The entire Accuryn™ Sensing Urinary Catheter is tested to this standard and performance is verified for flow rate through the urine lumens, balloon integrity (resistance to rupture), balloon bond strength, inflated retention balloon response to traction, balloon volume maintenance, balloon size and shaft size, deflation reliability and biocompatibility.

Accuryn™ Sensing Urinary Catheter placement will be done by a trained nurse, physician or physician extender using standard clinical technique. Catheter insertion and use training will be provided by the sponsor to appropriate study personnel prior to the onset of enrollment during a pre-study “roll-in” period. Details on the set-up procedure and device usage are available in the Instructions for Use (IFU-06-2638 IFU, Accuryn™ Urinary Catheter Kit, Gen 2.0). 3.2.2 ACCURYN™ URINE COLLECTION SET

The Accuryn™ Urine Collection Set comes pre-connected to the Accuryn™ Sensing Urinary Catheter, and hence is also a single use, disposable medical device in a package, sterilized using ethylene oxide. Like the Sensing Urinary Catheter, the Urine Collection Set is manufactured in a Class 100,000 clean room using well known, medical grade materials for all components that are patient contacting. The Accuryn™ Urine Collection Set is an accessory to a urine flow or volume measuring system which is classified as a Class II, 510(k) exempt device per 21 CFR 876.1800 (Urine flow or volume measuring system).

The drainage tube conveys urine from the catheter to a urine cassette reservoir that is placed into the Accuryn™ Monitor and feeds into a urine collection bag. Urine output volume can be measured visually using the measurement gradations on the urine collection bag or on the display of the Accuryn™ Monitor. A needle free urine sampling port (Figure 3E) located on the drainage tube at the connection with the proximal end of the Accuryn™ Catheter provides sterile access to urine from the urinary bladder and manual measurement of IAP using an IAP measurement kit. Verification and validation testing of the Accuryn™ Urine Collection Set demonstrates that it meets its performance requirements and specifications. 3.2.3 ACCURYN™ MONITOR

The Accuryn™ Monitor (Figure 5) is a reusable, non-patient contacting component of the Accuryn™ Monitoring System. The monitor, when connected to the Accuryn™ Sensing Urinary Catheter through the Accuryn™ Urine Collection Set, measures and displays the IAP, temperature and urine output volume and maintains urine flow in the drainage tube. The Accuryn™ Monitor has been developed in compliance with the Potrero Medical quality system standard operating procedures and adheres to FDA Quality System guidelines (21 CFR § 820) necessary for a Class II device. Verification and validation testing of the Accuryn™ Monitor demonstrates that it meets its performance requirements and specifications.

Device setup and use training will be provided by the sponsor to appropriate study personnel prior to the onset of enrollment during a pre-study “roll-in” period. Details on the set-up procedure, device usage and cleaning are available in the Instructions for Use (IFU-06-2845 Commercial Manual, Accuryn™ Monitor Gen 2.0).

External features of the Accuryn™ Monitor include an external touchscreen display (for UO, temperature and IAP measurements), power ON/OFF button switch, a temperature connector and urine cassette reservoir holder (Figure 5). Internal components of the Accuryn™ Monitor include urine flow pump and Accuryn™ Sensing Urinary Catheter pressure balloon inflation control pump, an SD card to record data, and associated electronic transducer and power supply parts. The external features of this device are illustrated in Figure 5.



Figure 5. Accuryn™ Monitor. Left Panel – Front view. Right Panel –Zoom in of touch screen monitor. NOTE: Values are arbitrary and for screen representation purpose only.

3.2.3.1 Electrical Urometer, UO volume, and temperature measurements

The Accuryn™ Monitoring System clears airlocks in the drain line to maintain urine flow into the urine cassette reservoir. This reduces urine flow impediments due to airlocks, thereby providing a more accurate measurement of urine volume.

The Accuryn™ Monitor works in conjunction with the Accuryn™ Urine Collection Set cassette reservoir to measure urine output volume. The volume in the cassette is added to the total volume and displayed on the touchscreen monitor. Total volume displayed includes previously measured volume until reset.

A safety overflow passage in the cassette also allows for urine to directly flow into the urine collection bag. Both the cassette and the urine bag are clear to allow the operator to see the urine fill level and graduation marks to approximate urine volume. The drainage urine bag holds at least 2000 mL of urine.

The temperature-sensing component of the Accuryn™ Sensing Urinary Catheter can also be connected to the Accuryn™ Monitor to display the core body temperature of the patient. Temperature accuracy is per the Accuryn™ Sensing Urinary Catheter thermistor lumen specifications (accuracy of ±0.3°C, range of 32 to 42°C). The Accuryn™ Monitor also allows for temperature values to be displayed on an external monitor through a pass-through cable.

3.2.3.2 Pressure lumen measurement

The Accuryn™ Monitor is also able to record signals from the Accuryn™ Sensing Urinary Catheter pressure lumen. The pressure lumen on the Accuryn™ Sensing Urinary Catheter is connected to the Accuryn™ Monitor (Figure 4). The recorded pressure is displayed on the monitor, and the data from this port is stored on the SD card for analysis offline.

The Accuryn™ Monitor operates on 100V to 240V wall power. When it is not connected to a wall outlet, the Monitor is powered through a rechargeable battery. Urine output, pressure and temperature data will be recorded on the SD card for offline analysis.

4. STUDY OVERVIEW

4.1 OBJECTIVES OF CLINICAL TRIAL

Primary Objective: To study the impact on kidney function and recovery as measured by timed creatinine clearance on calendar days 1-7 when targeting treatment to maintain APP ≥ 60 mmHg with a variable MAP target,



based on measured IAP compared to standard of care, with a fixed MAP target in critically ill patients with septic shock and elevated IAP. Creatinine clearance on calendar day 7 post-intervention or on day of ICU discharge, whichever is earliest, is the primary endpoint. Secondary Objectives: To study the incidence, progression and recovery of AKI as well as patient-centered outcomes among patients treated by APP target versus standard of care. To study renal injury and recovery and patient-centered outcomes among septic shock patients with or without IAH.

4.2 STUDY POPULATION FOR THE ACCURYN™ MONITORING SYSTEM Adult patients with septic shock admitted to the intensive care unit from the emergency department (ED) or referring hospitals that remain in shock and dependent on vasopressor therapy following initial 12-hour acute resuscitation period.

5. CRITERIA FOR SUBJECT SELECTION

5.1 NUMBER OF SUBJECTS AND SITES Three (3) sites are planned to participate – additional sites may be added if enrollment is slower than anticipated at primary 3 sites. All sites will work under the identical protocol version for the duration of this study. Following a roll-in period for each site to introduce use of the Accuryn™ Monitoring System, an initial target sample size of 200 subjects will be enrolled in the trial. Sample size adjustment (if necessary) will take place at an interim assessment occurring after approximately 100 subjects are enrolled.

5.2 INCLUSION CRITERIA AND EXCLUSION CRITERIA 5.2.1 INCLUSION CRITERIA

FOR RESUSCITATION AND OBSERVATIONAL PERIODS OF STUDY 1. Adult (age ≥ 18) 2. Septic shock – identified as early as possible following admission into or from referring ED (may be diagnosed

with initiation of care/resuscitation in ED). As evidenced by: a. Clinical diagnosis of sepsis defined as documented or suspected infection with the use of antibiotic

administration OR b. Meets qSOFA (Quick Sequential Organ Failure Assessment) Criteria per the Sepsis-3 definitions10:

i. Respiratory rate ≥ 22/min ii. Altered mentation

iii. Systolic blood pressure £ 100 mmHg AND c. Shock dependent on vasopressor therapy following initial 12-hour Resuscitation Period refractory to

further volume expansion as assessed by clinical treatment team; this may be supported by either: i. Lack of blood pressure response following fluid bolus or passive leg raise ii. Hemodynamic data as available [e.g. indices of cardiac output or filling including but not

limited to pulse pressure variation (PPV), stroke volume variation (SVV), transthoracic or transesophageal echocardiographic measurements, pulmonary artery occlusion pressures (PAOP), right-heart catheterization measurements, etc.]

Patient must meet either (a + c) or (b + c) to be eligible



3. Requirement for a urinary bladder catheter (or one currently in place) 4. Requirement for an arterial line (or one currently in place at any site)

FOR MONITORING PHASE OF STUDY (MONITORING GROUP) 1. All of the above criteria for the Resuscitation and Observational Periods of the study 2. Intra-abdominal pressure < 8 mmHg

FOR INTERVENTION PHASE OF STUDY (APP VS MAP GROUPS)

1. All of the above criteria for the Resuscitation and Observational Periods of the study 2. Intra-abdominal pressure ≥ 8 mmHg

5.2.2 EXCLUSION CRITERIA

1. Inability to receive a urinary bladder catheter 2. chronic suprapubic catheter in place 3. Cirrhosis/end stage liver disease, including Child-Pugh class C 4. Severe AKI as defined by life-threatening electrolyte or acidemia, or other indication for imminent emergent

dialysis needs within 12 hours of hospital admission. 5. Evidence of chronic renal failure stage 5 (including serum creatinine values consistent with CKD 5 and/or

dialysis dependence) in 12-months prior to enrollment 6. Active gastrointestinal bleed likely causing/contributing to the hemodynamic instability 7. Acute intra-abdominal trauma (including intraabdominal surgery within the prior 30 days) 8. Acute pancreatitis with no established source of infection 9. Treating physician deems aggressive care unsuitable or has decided to de-escalate care

[Do Not Resuscitate (DNR) patients receiving standard care are still eligible] 10. In the opinion of the treating attending physician the patient is unsuitable for the study for any legitimate

reason including lack of equipoise, anticipated imminent significant deterioration, anticipated imminent recovery, incarceration, pre-existing medical or psychiatric condition that treating attending physician deems not appropriate for study, or interfering medications

11. Known previous or concurrent enrollment in a treatment clinical trial that, in the opinion of the investigator, may interfere with the objectives/endpoints of this clinical trial

12. Known contraindication to bladder pressure measurement 13. Known pregnancy 14. Suspected or known increased intracranial pressure requiring neurosurgical consultation 15. Cardiogenic shock requiring extracorporeal support 16. Any requirement for chest compressions

6. STUDY PLAN

6.1 OVERVIEW This study is a multi-center, randomized-controlled trial in septic shock patients that examines the impact of abdominal perfusion pressure (APP) target versus mean arterial perfusion (MAP) target on renal and patient-centered outcome measures. 6.1.1 SCREENING & ENROLLMENT 1. Septic shock patient identified as early as possible following admission into emergency department (ED) or from

referring ED (patient may be diagnosed with septic shock with initiation of care/resuscitation begun in ED).



2. No study related interventions during the initial 12 hour* Resuscitation Period. During these initial 12 hours, MAP targets for resuscitation will be guided by primary clinical team usually using MAP target ≥ 65 mmHg per Surviving Sepsis Campaign 2016 Guidelines11. * 12-hour clock starts at the time “sepsis” bundles begun (i.e. first antibiotics order)

3. Patients are pre-screened for eligibility during the first 12 hours* of presentation with septic shock. • If potentially eligible, then Accuryn™ catheter is placed (if an AccurynTM catheter is not already present) for

simple UO, temperature (T), and IAP monitoring – no consent is necessary for initial catheter placement as the Accuryn™ Monitoring System is an FDA cleared device.

4. Patient (or legal surrogate) is offered enrollment and consented after the 12-hour Resuscitation Period – consent includes possible catheter swap for Accuryn™ catheter and for entry into both the MONITORING and INTERVENTION PHASES of the study. Patient (or surrogate) may be offered enrollment and consented during the 12-hour Resuscitation Period if care team determines eligibility, but will not initiate interventional treatment before the conclusion of the 12-hour resuscitation period.

5. After enrollment, the subject will be randomized to either the MAP or APP group and observed up to 48 hours of sepsis diagnosis. Patients IAP will be monitored during this Observational Period.

a. Monitoring Phase - If IAP remains < 8 mmHg within 48 hours of sepsis diagnosis, subjects in this Phase will receive standard of care and de-identified electronic medical record (EMR) data [urine output, laboratory values (including serum creatinine and lactate), KDIGO staging, need for and duration of acute renal replacement therapy (RRT), and hospital mortality] will be monitored and recorded. Continuous IAP, urine output and physiological data streams are recorded via the Accuryn™ Monitoring System (on the internal device SD card) while in situ. Additional patient-centered outcomes including ICU and hospital length of stay (LOS) as well as RRT requirement and death at 30- and 90-days post enrollment will be recorded.

b. Intervention Phase - If IAP ≥ 8 mmHg within 48 hours of sepsis diagnosis, then subject will enter Intervention Phase of study and be treated according to one of two treatment arms specified by randomization:

i. MAP Group - Standard of Care arm – titrate clinical treatment to maintain MAP target ≥ 65 mmHg per Surviving Sepsis Campaign 2016 Guidelines11

ii. APP Group – APP arm – IAP recorded every 4 hours and MAP targets adjusted to maintain APP ≥ 60 mmHg

6. If subjects are randomized before the end of the 12-hours Resuscitation Period, and their IAP ≥ 8 before completion of initial 12-hours resuscitation, subjects will begin their intervention assignment only after the Resuscitation Period is completed. If subjects are already beyond the 12 hours of standard care, then Intervention Phase treatment will begin immediately.

7. As enrollment proceeds at the sites, best practices and pitfalls will be shared via coordinated biweekly conference calls. If enrollment is deemed inadequate at one or more sites, additional sites may be recruited with input from all study primary investigators.

6.1.2 RANDOMIZATION After a subject is consented, the subject will be randomized to one of two treatment arms: the MAP Group or APP Group. Subjects will be randomized via the online electronic data capture (EDC) system, with instructions provided as part of electronic case report form (eCRF) completion. The EDC system will randomize subjects 1:1 to the MAP Group or APP Group. No patient identifiers will be entered for randomization. Randomization will be stratified by presence of pre-hospital hypertension (in prior 12 months) and presence of pre-hospital chronic kidney disease (CKD; any stage documented in prior 12 months or serum creatinine consistent with CKD stage 2 or greater); treatment assignment will be balanced within each site according to these strata. If the EDC is inaccessible and randomization is required, a manual contingency plan will be specified (i.e. blinded envelopes for treatment assignment) and the patient data and designation entered into the EDC post hoc. If the patient does not meet criteria for entering the Intervention Phase of the study, the patient will proceed with the Monitoring group protocol despite their initial



randomization assignment. Only patients that qualify for the Intervention Phase will be included in the data analyses according to the statistical analysis plan. 6.1.3 INTRA-ABDOMINAL PRESSURE (IAP) MEASUREMENTS For the purposes of this study, IAP will be measured via the Accuryn™ Monitoring System. All enrolled subjects will have an Accuryn™ Urinary Catheter connected to the Accuryn™ Monitor. Each subject’s care team should see the Instructions for Use (IFU) manual for the Accuryn™ Monitoring System for full instructions for measuring IAP. Briefly, IAP can be measured by pressing the IAP button on the Monitor, waiting for measurement to be completed, and pressing “OK” to accept the measured IAP value. These accepted IAP measurements can be displayed in the “List” screen on the monitor user interface. The Accuryn™ Monitoring System will also trend IAP in the background, without any manual handling of the monitor, and this trend graph can be displayed via the “IAP Graph” screen on the monitor user interface. At any time during a patient’s care, if the IAP > 20 mmHg, the monitor will alarm to alert care team; this alarm can be dismissed but will re-alarm every 12 hours if IAP continues to be > 20 mmHg. For the Observational Period of this study, IAP will be measured every 4 hours and recorded in the patient’s chart and/or EMR. The care team will also note subject’s position on the bed (head of bed, 30 degrees, supine, etc.) for each IAP measurement. Throughout all phases, all recorded IAP values should be documented in the 30-degree head elevation position in accordance with standard of practice ICU care (to prevent aspiration events and ventilator associated pneumonia). Life-threatening clinical events supersede this positional requirement (i.e. profound hypotension or cardiac arrest that merit supine or Trendelenburg positioning). For the Monitoring and Interventional Phases of the study, IAP will be measured or trended as below. The frequency of measurements is outlined in the manual of procedure.

1. Monitoring Group – IAP will be trended in the background within the Accuryn™ monitor. Care team will note subject’s position on the bed (head of bed at 30 degrees, supine, etc.). Care team will be blinded to this IAP trend and will continue to practice standard of care. If the subject’s IAP > 20 mmHg and the Accuryn™ monitor alerts the care team, the care team should follow the instructions to break protocol (detailed in this protocol).

2. MAP Group – IAP will be trended in the background within the Accuryn™ monitor. Care team will note subject’s position on the bed (head of bed, 30 degrees, supine, etc.). Care team will be blinded to the IAP trend and will continue to practice standard of care. If the subject’s IAP > 20 mmHg and the Accuryn™ monitor alerts the care team, the care team should follow the instructions for “Protocol Break” (detailed in this protocol as #4 below).

3. APP Group – IAP will be measured using the Accuryn™ Monitoring System. The care team will measure IAP at 30

degrees of head of bed elevation by pressing the IAP button on the Monitor, waiting for the measurement to be completed, and pressing “OK” to accept the measured IAP value. The care team will also be able to view the IAP trend graph and the IAP list screens on the monitor. The IAP will be measured and recorded and utilized to calculate APP every 4 hours (more frequent IAP measurements are allowed at the discretion of the treating clinical team). If the subject’s IAP > 20 mmHg and the Accuryn™ monitor alerts the care team, the care team should follow the instructions to break protocol (detailed in this protocol).

4. IAP > 20 mmHg Protocol Break – If the IAP > 20 mmHg for any patient enrolled in either the Monitoring Group,

MAP Group or APP Group, the treating clinician will be notified within 4 hours of alarm. The treating clinician has the discretion to decide whether to continue or withdraw the patient from the protocol. If the patient is not withdrawn from the study, they will continue on their assigned treatment plan. Furthermore, if the patient remains in the study, open label IAP monitoring will be available at the discretion of the treating clinician.



6.1.4 TARGETED RESUSCITATION IN INTERVENTION PHASES 1. MAP group will target MAP ≥ 65 mmHg per Surviving Sepsis Campaign 2016 Guidelines11 (or MAP target set

by ICU attending [i.e. possibly higher in patient with chronic hypertension or clinical condition that merits higher systemic perfusion pressures])

2. APP group will target APP ≥ 60 mmHg (or APP target set by ICU attending [i.e. possibly higher in patient with chronic hypertension or clinical condition that merits higher systemic perfusion pressures])

a. In accordance with Surviving Sepsis evidence, norepinephrine will be the vasoactive infusion of first choice.

b. Fluid resuscitation in both groups should be maintained as per standard care and at the discretion of the primary treatment team and Surviving Sepsis Campaign 2016 Guidelines.

3. Duration: The intervention phase will continue until vasopressor and fluid support are no longer clinically indicated or until patient discharge from the ICU, death, withdrawal of consent, transfer to another facility, or device discontinuation.

6.1.5 DATA COLLECTION & FOLLOW-UP Routine clinical care data will be collected either by manual review or electronic extraction of the EMR at the investigator sites. If electronic data extraction is employed, a fraction of the electronic data extraction from the EMR will be validated against standard manual chart review for accuracy. All data will be stored in site data management systems in a confidential and secure fashion. Data collection will include:

1. Demographic patient characteristics including pre-study renal function/medical conditions/medications 2. Admission location and sepsis diagnosis 3. Hemodynamic and ventilator variables and laboratory values and special samples (i.e. timed 6-hour urine

creatinine clearance, Urinary [TIMP-2] x [IGFBP7] (NephroCheckÒ, Astute Medical, San Diego, CA), additional serum biomarkers) as outlined in analyses section

4. Vasoactive infusions and diuretic medications (dose and duration) will be documented as will cumulative fluid resuscitation/daily balance since hospital presentation

5. Receipt of RRT (including confirmation of prior RRT and indication for new RRT) 6. Follow-up points will be hospital discharge, 30 days post-enrollment, and 90 days post-enrollment 7. Patients will remain in the study until 90-day post-enrollment or death, whichever occurs first 8. Significant protocol deviation will be documented but the study will be conducted in accordance to intention-to-

treat guidelines. A “per protocol” analysis may be performed • Sites and enrollment will be assessed for protocol compliance at regular intervals

9. Data will be downloaded directly from the Accuryn™ Device every 2-3 patients’ usage of the Accuryn™ Monitoring System.

10. Statistical analyses will be performed for each of the measurement parameters as outlined below Primary endpoint will be assessed after approximately 100 subjects are enrolled, then after every 50 additional subjects enrolled (if necessary) to adjust sample size and assess efficacy/futility.



6.2 STUDY FLOW A summary diagram depicting the study flow is shown below:

Patients diagnosed with septic shock requiring vasopressor therapy in the ED

Standard clinical care per Surviving Sepsis 2016 protocols (or similar)

Resu

scita

tion

Perio

d(t

= 0

to t

= 12

hr)

Patient screened for eligibilityIf potentially eligible, AccurynTM catheter placed

IAP < 8 mmHg IAP ≥ 8 mmHg

Subject enters into the INTERVENTION PHASE

Subject enters into the MONITORING

PHASE

Monitoring GroupSubjects receive regular

standard of care treatment and are monitored throughout

hospitalization for:• Presence of AKI• Peak stage of AKI

(KDIGO creatinine criteria)

• Need for acute RRT

Patient assigned treatment arm (based on randomization at

time of consent)

MAP Group

• Maintain MAP ≥ 65or

• ICU Attg MD determined individualized goal (i.e. in pt with baseline HTN)

APP Group

• Measure IAP Q4H and

• Adjust MAP targets every 4 hrs to maintain APP ≥ 60*

*APP = MAP - IAP

Targeting Abdominal Perfusion Pressure in Septic ShockPROTOCOL NUMBER: CRD-06-2615

Figure 1: Study Flow

If, at any time during the Observational Period, IAP ≥ 8mmHgOb

serv

atio

nal P

erio

d(t

= 12

to t

= 48

hr)

Mon

itorin

g Ph

ase

(t =

48 h

rto

Disc

harg

e)

Intervention Phase (Entry into Intervention Phase to Discharge)

Observational Period(t = 12 hrto Entry into Intervention

Phase)

Patient consented, enrolled and randomized 1:1 (MAP/APP). After consent, Accuryn Catheter placed if not present. This may involve a catheter swap



6.3 ENDPOINTS AND ADDITIONAL ANALYSES Primary Endpoint: To study kidney function and recovery in patients with septic shock and elevated IAP as measured by timed creatinine clearance on calendar days 1-7 when targeting treatment to maintain APP ≥ 60 mmHg with a variable MAP target compared to standard of care with a fixed MAP target. Creatinine clearance on calendar day 7 post-intervention or day of ICU discharge, whichever is earliest, is the primary endpoint. Patients who have died will be assigned a CrCl of 0 and patients who remain admitted to participating study hospital and dependent on RRT will be assigned a CrCl of 0 unless they are making > 500 ml/day of urine whereby a timed 6-hour urine creatinine clearance will be performed. Secondary Analyses:

• Patient characteristics in each group at enrollment: o Demographics including age, gender, weight, height, BMI o SOFA score o Medical and surgical co-morbidities and ‘renal’ medications (diuretic and antihypertensive

medications), antibiotics, and all other medications o Source of sepsis (respiratory, urinary tract, GI/abdominal, skin/soft tissue, bone, etc.) o Hemodynamic variables, laboratory variables (including lactate), vasoactive infusions (dose and

duration), ventilation/oxygen requirement o Total fluid therapy (and fluid therapy stratified by total given in resuscitation period and

observation period) o AKI/IAP variables (baseline serum creatinine on ED admission and enrollment, and median in 12

months prior to admission) • If no creatinine values are available between 12 months prior to admission and

enrollment, a baseline creatinine value will be calculated with the previously described formula, creatinine = 0.74 – 0.2 (if female) + 0.08 (if African-American) + 0.003 x age (years)

• Renal function measurements:

o Serum creatinine at minimum Q24H until discharge – will document all creatinine values that are acquired for routine clinical use

o Urine output Q4H (automatically captured by Accuryn™ device) • A separate analysis factoring in diuretic use will be completed

o Urinary [TIMP-2] x [IGFBP7] (NephrocheckÒ), at enrollment (baseline) and Q24H during intervention Days 1-5

o Biomarkers of renal insult (proenkephalin (PENK) and/or other) in banked serum and urine samples at enrollment and interventional Day 3, and 7 (or ICU discharge). Blood draws will not exceed a total of 30 mL blood per patient

o Peak AKI stage in-hospital, 30-days post-enrollment, 90-days post-enrollment (if serum creatinine available)

o Composite endpoint of major adverse kidney events (MAKE) within 30 days and 90 days post-enrollment: death, persistent RRT dependence, and >200% increase in baseline serum creatinine (if available)

o Data above reflect anticipated extraction from consented patients’ medical record and/or additional patient (or surrogate) contact. We may request patient or surrogate to obtain outside medical records. No additional clinical visits or tests outside standard clinical care



once discharged from the initial hospital/ICU encounter are planned

• Resuscitation effectiveness measurements o Vital sign parameters including HR and MAP are recorded at Q2H from admission to Day 7 or

device removal, then at Q4H to Q6H until discharge. IAP is recorded at Q4H all throughout the study.

o Daily net fluid balance o Days on vasoactive medication o Mean daily dose of vasopressor i.e. mg/day of norepinephrine o Lactate is recorded at Q6H until two successive levels <2mmol/L; daily critical care laboratory

values o CVP and/or cardiac output indices (if available) o Ventilator days, parameters and complications (as applicable) o Mean SOFA at 72 hours post-enrollment o Serious adverse events including but not limited to myocardial infarction or ischemia,

ventilator associated pneumonia, new arrhythmias including atrial fibrillation/ventricular tachycardia or fibrillation, cardiac arrest, significant bleeding requiring transfusion, digital or mesenteric ischemia, neurologic sequelae including cerebral vascular accident or seizure

6.3.1 STATISTICAL METHODS

6.3.1.1 Study Power

When evaluating arterial perfusion targets in severe sepsis, timed creatinine clearance has not been rigorously studied. Some studies examining lower time-adjusted MAP in septic shock demonstrate an increase in KDIGO rank by at least one stage during the first 5 days of ICU admission12. As the difference between either RIFLE or KDIGO stages of kidney injury may imply a decline in creatinine clearance (or estimated glomerular filtration rate) of approximately 25%13, we estimate that a 20% absolute difference between the creatinine clearance at calendar day 7 of our treatment groups (assuming a standard deviation of 20% for a one-sided test with 80% power and 2.5% type I error rate) necessitates a sample size in each intervention group of at least 63 patients. Enrollment predictions for study sites are also informed by the incidence of AKI in septic shock. Given the variability in prior definitions of AKI staging, there is discrepancy in the historical incidence of stage 2 or 3 (injury and failure) AKI in septic shock patients; the range spans 25.0-61.5%. The incidence of AKI varies significantly in different hospitals, and we believe a historical incidence of 40% is most closely represented at our clinical sites. Following interim analysis conducted by an independent medical monitor and/or consultant biostatistician, there is potential for an adjustment of patient sample size. Based on initial power calculations, there will be a total of 200 patients to achieve statistical significance assuming a 10% dropout rate. Following the initial 100 patients, an interim analysis will be conducted, and it may be determined at this point that there is a need for an extension of our study to meet the appropriate sample size. 6.3.2 ENDPOINT ANALYSES Analysis of the data will be conducted by comparing the two intervention groups (IAH at enrollment and randomization to either MAP and APP groups). The mean creatinine clearance and standard deviation at calendar day 7 post-intervention will be reported for each group as well as the creatinine clearance for each calendar day from intervention initiation to day 7. We presume that the MAP-APP study population will encompass several exposure variables including the study intervention, the baseline patient characteristics that may alter the risk of the primary



outcome, and physiologically distinct patient subgroups. Secondary analyses will account for repeatedly measured variables and utilize linear mixed-effects models. Descriptive statistics will be reported for the Monitoring group. Analyses will occur at the level of the individual patient during a discrete clinical time course in an intention-to-treat fashion unless otherwise specified. Continuous variables will be reported as mean ± SD, mean and 95% CI, or median and IQR and analyzed with the Mann-Whitney rank sum test for continuous variables. Categorical variables will be reported as frequencies or proportion and analyzed with the chi-squared test. A two-sided P value <0.05 will be considered statistically significant.

7. DATA MANAGEMENT

7.1 DATA RECORDING METHODS All data will be entered into a customized and validated database (Castor EDC: electronic data capture, Amsterdam, The Netherlands; US server hosted by Amazon web services, Seattle, WA) and will be processed in accordance with Potrero Medical’s procedural documentation. This electronic data capture system is validated and compliant with US Title 21 Code of Federal Regulations (CFR) Part 11. All procedures for the handling and analysis of data will be conducted using good computing practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 7.1.1 CASE REPORT FORMS Data may be collected via source documents or case report forms (CRFs)–CRFs will be maintained in a secure, PHI-protected Castor EDC. Data from CRFs and source document will be entered into the Castor EDC system. After a subject has exited the study, the de-identified data may be collected by either querying the EMR and/or by manual chart review at the institutional site by study collaborators.

7.2 DATA STORAGE, CONFIDENTIALITY, AND QUALITY ASSURANCE

7.2.1 DATA STORAGE Data obtained from the CRFs will be stored securely and maintained by Potrero Medical, Inc. at Potrero Medical facilities or through the EDC system associated storage service. Data from the EDC, EMR, and that collected prospectively and retrospectively by the Accuryn™ monitor will be stored at Potrero. 7.2.2 DATA CONFIDENTIALITY Potrero Medical maintains the overall responsibility for this study including ensuring that the study is conducted according to the regulatory requirements of Good Clinical Practice (GCP), the Declaration of Helsinki, and other applicable regulatory requirements, the Protocol, and any conditions of approval imposed by the applicable Institutional Review Board(s) (IRBs). Potrero Medical will adhere to Sponsor general duties as outlined by GCP and 21 CFR 812. ISO 14155 (2011) has been used as guidance for this protocol. All data and information collected during this study will be considered confidential by Potrero Medical, investigators, and research staff at study sites. All data used in the analysis and summary of this study will be anonymous, and without reference to specific study subject names. Access to study subject files will be limited to authorized personnel or designees of Potrero Medical, the Investigator, and research staff. Authorized regulatory personnel have the right to inspect and copy all records pertinent to this study. Federal and state regulations regarding confidentiality will be followed, as appropriate.



7.3 DATA MONITORING AND QUALITY ASSURANCE The Investigators will make study data accessible to the monitor, other authorized representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request. A file for each subject will be maintained that includes the signed Informed Consent and copies of all source documentation related to that subject. The Investigators will ensure the reliability and availability of source documents from which the information on the CRF was derived. After all data reviews and EDC query resolutions are complete, the statistical analysis plan approved and signed, the database will be locked. All study documents (subject files, signed informed consent forms, copies of CRFs, Study File Notebook, etc.) will be kept secured for a period of two years after termination of the study per FDA guidelines (21 CFR § 812.40). There may be other circumstances for which the Sponsor is required to maintain study records and, therefore, the Sponsor will be contacted prior to removing study records for any reason. Monitoring visits will be conducted by representatives of the Sponsor based on GCP. By signing this protocol, the Investigators grant permission to the Sponsor (or designee), and appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate study documentation.

8. EVENT REPORTING

8.1 DEFINITION OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT Definitions are guided by the United States Code of Federal Regulations [21 CFR § 812.50]. Adverse Event (AE) Adverse events are any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research. All AEs will be recorded in the eCRF from the time of patient consent to the time of device discontinuation. AEs will be graded as mild, moderate or severe and relationship to the study device or protocol be listed as unrelated, possible, probable, or definite based on clinical decision at time on completion of the eCRF. Serious Adverse Event (SAE) Serious adverse events are untoward medical occurrences in a human subject that are not related to the device but that meet the criteria “serious”:

• Death • Serious deterioration in the health of the subject that

o Resulted in a life-threatening illness or injury, or o Resulted in a permanent impairment of body structure or body function, or o Required in-patient hospitalization or prolongation of existing hospitalization, or o Resulted in medical or surgical intervention to prevent life-threatening illness, life-threatening injury,

or permanent impairment to a body structure or function Device Deficiency Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or performance (including malfunctions, use errors, and inadequate labeling). Unanticipated Adverse Device Effect (UADE) Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with,



a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

8.2 ANTICIPATED ADVERSE EVENTS Anticipated adverse events include all events secondary to the subject’s underlying condition and associated medical/surgical treatment plus any adverse events secondary to the risks outlined in Section 9.1 For purposes of this study, anticipated Adverse Events are considered events due to an increased exposure and duration of vasopressor therapy and fluid administration and events due to an increased need for urinary bladder catheter exchange. AEs due to an increase exposure and duration of vasopressor therapy include:

• Myocardial infarction (any STEMI, NSTEMI requiring clinical intervention) • Ventricular arrhythmia including ventricular fibrillation or ventricular tachycardia requiring external electrical

shock or antiarrhythmic therapy • New onset atrial fibrillation or atrial flutter • Mesenteric ischemia • Ischemia of the distal limb and/or digits • Cerebral vascular accident • Excessive bleeding • Nosocomial infection • Worsening multisystem organ failure due to septic shock progression and sequelae

Since the study subjects will be in septic shock dependent on vasopressors, they are by definition critically ill. Such patients experience frequent complications and events that can cause deterioration in function of any and all vital organs. Specific risks associated with this research protocol are limited to possible complications related to an increase cumulative dose of vasopressor medications that the APP group of the INTERVENTION PHASE is anticipated to receive as opposed to the MAP group. Importantly, a previous study was performed comparing high vs usual MAP targets in septic shock with the high MAP group having significantly higher exposure to vasopressor medications6. This study demonstrated that there was no significant increase rate of adverse events between the two groups, with the exception of a slightly higher rate of new onset atrial fibrillation in the high MAP group, which could possibly be explained by the increased exposure to catecholamine medications. Therefore, we believe that this study introduces minimal additional or new risks to the subject beyond the risks of organ failure and/or death as a result of the underlying infection and septic shock. AEs due to a potential increase in need for urinary bladder catheter exchange include:

• Risk of new or worsening infection • Risk of new or worsening trauma to urethra and bladder

These risks are the same risks regardless of brand of urinary catheter being inserted and are not device-specific risks associated with the Accuryn™ catheter. If at any time during the study, the subject needs the insertion of another urinary bladder catheter as part of the subject’s regular care, these risks apply as well.

• Laboratory and vital sign abnormalities qualify as AEs if medical intervention is required to treat or address the abnormality AND it is not considered an expected event in patients with septic shock and its sequelae, if the patient must be discontinued from the study due to the abnormality, or if the value exceeds specific limits defined by the standard-of-care as qualifying it as an AE.



• An elective procedure/surgery that occurs during the course of a study but is being performed for a documented pre-existing condition and was pre-planned prior to study entry will not qualify as an AE. If, however, the pre-existing condition unexpectedly deteriorates during the study, requiring the procedure/surgery to be performed earlier than planned, the condition for which the procedure/surgery is being performed will qualify as an AE.

8.3 ANTICIPATED SERIOUS ADVERSE EVENTS Death in septic shock patients is often expected or unavoidable, and considered a very common serious adverse event and therefore is an anticipated SAE. The mortality rate in patients with septic shock varies but may be up to 40% to 70%4,6.

8.4 REPORTING OF EVENTS The Accuryn™ Monitoring System is being used on-label within its intended specifications and any device-related incidences will be reported to Potrero Medical, Inc. via complaint handling and medical device reporting procedures. In the event that a UADE occurs, the event will be reported by the Investigator in writing within 10 business days after the investigator first learns of the event to the Sponsor and the reviewing IRB for the site where it occurred per the applicable IRB reporting requirements. As the sponsor, Potrero Medical, Inc. will immediately conduct an evaluation of the UADE and report the results of the evaluation to the FDA, all reviewing IRBs, and participating investigators within 10 working days after the sponsor first receives notice of the effect. AEs and SAEs related to the study will be captured in case report forms, reported as necessary, and assessed for relatedness to the study procedures.

8.5 SAFETY ASSESSMENT Continuous monitoring of subject safety will occur using an independent medical monitor. All subject adverse events and serious adverse events will be recorded as soon as the study site is aware. Each site's study investigator will also be reviewing the events on a regular basis and alert the sponsor of any unanticipated adverse events.

9. RISK/BENEFIT ASSESSMENT

9.1 RISKS ASSOCIATED WITH THE STUDY PROCEDURES • Risks associated with additional urinary bladder catheter insertions (for those patients who do not initially

receive the Accuryn™ urinary catheter): o Infection o Trauma to urethra or bladder that could necessitate additional procedures and/or treatments o Patient discomfort

• Risks associated with additional vasopressor therapy for subjects in the APP Group versus MAP Group:

o Myocardial infarction (any STEMI, NSTEMI requiring clinical intervention) o New onset cardiac arrhythmia including atrial fibrillation requiring cardioversion and/or additional

medication o Ventricular fibrillation or ventricular tachycardia requiring external electrical shock or antiarrhythmic

therapy o Mesenteric ischemia o Ischemia of the distal limbs or digits o Cerebral vascular accident



o Excessive bleeding o Nosocomial infection o Worsening multisystem organ failure due to progression of septic shock

9.2 RISK CATEGORY This study uses the Accuryn™ Monitoring System, a Class II FDA 510k cleared device. The study is conducted in septic shock patients that would already be receiving a Foley catheter. The risks to the patients do not increase with the use of the Accuryn™ Urinary Catheter and the magnitude of harm or discomfort anticipated in the research is not greater than those ordinarily encountered for these critically ill ICU patients during the performance of routine physical examinations. Hence the risks to the patient beyond standard of care are minimal.

9.3 PROTECTIONS AGAINST RISKS The APP Group, in which management of septic shock will be per Surviving Sepsis Campaign 2016 Guidelines11, with the exception that the target MAP, will vary dynamically to target and maintain a APP ≥ 60 mmHg, and will have continuous monitoring of MAP values. The subject’s care team will be aware of MAP values and be able to monitor the subject accordingly.

9.4 RISK BENEFIT RATIONALE The device being used to monitor IAP data for APP, the Accuryn™ Monitoring System, is a 510k commercially available device. The risks of this device are similar to those posed by other urinary catheters and drainage systems typically used in this critically ill population. Therefore, the Accuryn™ Monitoring System does not introduce any new risks beyond that of the standard urinary catheter that critically ill patients with septic shock receive in the ICU. The main risks of the study derive from being treated using MAP guided resuscitation vs. APP guided resuscitation.

10. SUBJECT IDENTIFICATION, RECRUITMENT, AND CONSENT/ASSENT

10.1 METHOD OF SUBJECT IDENTIFICATION AND RECRUITMENT The site research staff will identify potential participants. When a potential subject has been identified, the subject will be approached for screening and consent.

10.2 INFORMED CONSENT Patients, or their legally authorized representative (LAR), will only be asked to sign the Informed Consent document once the study has been fully approved by the IRB and the Sponsor has received and reviewed the specific IRB-approved Informed Consent document to be used by the site. Once the patient’s eligibility for trial has been determined, the Investigator, or person designated by the Investigator who has been trained to the Protocol, will explain the nature and scope of the study, discuss potential risks and benefits of participation, and answer questions from the patient or LAR. The study will be explained to the study patient/LAR in lay terms. If there is an agreement to participate, the Informed Consent must be personally signed and dated by the patient or LAR and the Investigator or person designated by the Investigator. Any additional persons required by the IRB to sign the Informed Consent will also do so. If a patient or their LAR chooses not to sign the consent, then any and all eligibility and screening assessments of the patient will be disregarded. A copy of the signed



and dated Informed Consent will be provided to the study subject or LAR. Study subjects and their LAR will be assured that they may withdraw from the study at any time and for any reason. The reason for withdrawal with date/time stamp will be documented. Failure to obtain a signed and dated Informed Consent from an individual or their LAR prior to the patient participating in the study procedures constitutes a major protocol deviation. Patients will be offered enrollment and consent obtained during or after the 12-hour Resuscitation Period. Eligible patients can be consented and randomized prior to the end of the 12-hour Resuscitation Period but will begin their intervention assignment only after the Resuscitation Period is completed. The consent process will include explanation of the two (2) arms of the study (MONITORING PHASE and INTERVENTION PHASE) and that the consent will allow for 1) possible catheter swap for Accuryn™ catheter and for randomization and treatment per assigned group if/when patients qualify for the INTERVENTION PHASE on the basis of IAP ≥ 8 mmHg; 2) if IAP remains < 8 mmHg, basic outcome data will be collected such as presence of AKI, survival to hospital discharge, etc.

10.3 COST TO THE SUBJECT Study related procedures separate from standard of care will not be billed to the subject or their insurance company. This includes Accuryn™ Monitoring System and additional lab tests beyond standard of care for critically ill patients with septic shock (i.e. urinary biomarkers Q24H, serum biomarkers, daily 6h timed urinary creatinine clearance, etc.). However, use of vasopressor therapy and all other ICU related interventions that are standard of care for septic shock will not be covered by the study and will be billed as usual to subject or their insurance company.

10.4 PAYMENT FOR PARTICIPATION Subjects will not be reimbursed for participation in the study.



11. REFERENCES 1. Dalfino, L., Tullo, L., Donadio, I., Malcangi, V., and Brienza, N. (2008). Intra-abdominal hypertension and acute

renal failure in critically ill patients. Intensive Care Med 34, 707–713. 2. Honore, P.M., Jacobs, R., Hendrickx, I., Bagshaw, S.M., Joannes-Boyau, O., Boer, W., De Waele, E., Van Gorp,

V., and Spapen, H.D. (2015). Prevention and treatment of sepsis-induced acute kidney injury: an update. Ann Intensive Care 5, 51.

3. Kirkpatrick, A.W., Roberts, D.J., De Waele, J., Jaeschke, R., Malbrain, M.L.N.G., De Keulenaer, B., Duchesne, J., Bjorck, M., Leppaniemi, A., Ejike, J.C., et al. (2013). Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome. Intensive Care Med 39, 1190–1206.

4. Leone, M., Asfar, P., Radermacher, P., Vincent, J.-L., and Martin, C. (2015). Optimizing mean arterial pressure in septic shock: a critical reappraisal of the literature. Crit Care 19, 101.

5. Malbrain, M.L.N.G., De Waele, J.J., and De Keulenaer, B.L. (2015). What every ICU clinician needs to know about the cardiovascular effects caused by abdominal hypertension. Anaesthesiol Intensive Ther 47, 388–399.

6. Asfar, P., Meziani, F., Hamel, J.-F., Grelon, F., Megarbane, B., Anguel, N., Mira, J.-P., Dequin, P.-F., Gergaud, S., Weiss, N., et al. (2014). High versus Low Blood-Pressure Target in Patients with Septic Shock. New England Journal of Medicine 370, 1583–1593.

7. Mitchell, K.H., Carlbom, D., Caldwell, E., Leary, P.J., Himmelfarb, J., and Hough, C.L. (2015). Volume Overload: Prevalence, Risk Factors, and Functional Outcome in Survivors of Septic Shock. Ann Am Thorac Soc 12, 1837–1844.

8. Papavramidis, T.S., Marinis, A.D., Pliakos, I., Kesisoglou, I., and Papavramidou, N. (2011). Abdominal compartment syndrome - Intra-abdominal hypertension: Defining, diagnosing, and managing. J Emerg Trauma Shock 4, 279–291.

9. Patel, D.M., and Connor, M.J. (2016). Intra-Abdominal Hypertension and Abdominal Compartment Syndrome: An Underappreciated Cause of Acute Kidney Injury. Adv Chronic Kidney Dis 23, 160–166.

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11. Rhodes, A., Evans, L.E., Alhazzani, W., Levy, M.M., Antonelli, M., Ferrer, R., Kumar, A., Sevransky, J.E., Sprung, C.L., Nunnally, M.E., et al. (2017). Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit. Care Med. 45, 486–552.

12. Poukkanen, M, Wilkman E, Vaara ST, Pettilä V, Kaukonen KM, Korhonen AM, Uusaro A, Hovilehto S, Inkinen O, Laru-Sompa R, Hautamäki R, Kuitunen A, Karlsson S, FINNAKI Study Group. (2013). Hemodynamic variables and progression of acute kidney injury in critically ill patients with severe sepsis: data from the prospective observational FINNAKI study. Crit Care.17(6): R295.

13. KDIGO Clinical Practice Guideline for Acute Kidney Injury (2012). Kidney International Suppl.

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