Hypotension Prediction Index (HPI) Software Guided Hemodynamic Management for Noncardiac Surgery Patients - Blood Pressure Trial (National PI: Kamal Maheshwari, MD, MPH)
Phase: NA
Conditions: Moderate to High-risk Noncardiac Surgery
Sponsor: Edwards Lifesciences

 
 
 
 
 
NCT05105477 
 
 
 
Hypotension Prediction Index Software Guided 
Hemodynamic Management for Noncardiac Surgery 
Patients - Blood Pressure Trial – 
HPI SMART- BP Trial 
A Multicenter, Interventional, Randomized comparison of intraoperative hemodynamic 
management with or without Hypotension Prediction Index software guidance on postoperative 
complications 
 
 
Clinical Trial Protocol and Statistical Analysis Plan 
 
Clinical Trial Protocol version: December 17, 2021 
Statistical Analysis Plan version: May 11, 2022 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 1 of 68 
CONFIDENTIAL 
 
 
 
 
 
 
Hypotension Prediction Index Software Guided Hemodynamic 
Management for Noncardiac Surgery Patients - Blood Pressure 
Trial 
HPI SMART- BP Trial 
 
A Multicenter, Interventional, Randomized comparison of intraoperative hemodynamic management with 
or without Hypotension Prediction Index software guidance on postoperative complications 
 
Clinical Trial Protocol 
Trial Number: 2021-04 
 
 
 
 
 
Revision: C 
Date: 17DEC21 
 
 
 
 
Edwards Lifesciences LLC 
One Edwards Ways 
Irvine, CA 92614 USA 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 2 of 68 
CONFIDENTIAL 
 
 
 
 
Revision B Change Summary 
Please note: Punctuation, formatting or clerical changes are not included in the table. 
Section 
(Page) 
Change and Reason for Change 
Synopsis and Trial Objective 
(7 & 17) 
Updated trial objective to the following: To determine if the use of a 
protocolized strategy using advanced hemodynamic monitoring with 
Hypotension Prediction Index (HPI) software guidance for intraoperative 
hemodynamic management reduces postoperative complication rate in 
moderate- to high-risk non-cardiac surgery.” 
Reason: To provide further clarification. 
Synopsis, Background & General Design 
(7,10 & 23) 
Added “The control arm will be blinded to advanced hemodynamic 
monitoring with and will only receive blood pressure monitoring data from 
the arterial line, as per the standard of care.” 
Reason: To provide further clarification for control arm design. 
Synopsis, Procedure, and Sample size 
Justification 
(7, 35 & 37) 
Updated total enrollment to 1486 
Reason: To align with statistical analysis plan. 
Synopsis, Additional Evaluation (Trial 
Objective and Endpoints) Additional 
Evaluation (Statistical Methods) 
(8,17 & 38) 
Updated item 9 to following: Amount of vasoactive drugs; mg (e.g.: 
phenylephrine, ephedrine, norepinephrine, epinephrine, dobutamine) 
Added item 10: Amount of intraoperative intravenous analgesics and 
sedatives 
Added item 12: Verification of the incidence of the listed postoperative 
complications may be performed at each site by reviewing historic data up to 
6 months prior to study initiation. 
Reason: To provide further clarification. 
Synopsis and Treatment Protocol 
(8 &24) 
Edited Alert phase to state: HPI greater than 85 ➔ alert ➔ treatment per 
protocol recommendation 
Edited treatment protocol’s figure to display the targeted treatment plan. 
Reason: To provide further clarification. 
Schedule of Events 
(34) 
Added footnote for Creatinine labs to be collected on post-op day 1,2 or 3. 
Reason: To provide further clarification. 

HPI SMART-BP 
Protocol #2021-04 
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of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 3 of 68 
CONFIDENTIAL 
 
 
Revision C Change Summary 
Please note: Punctuation, formatting or clerical changes are not included in the table. 
Section 
(Page) 
Change and Reason for Change 
Synopsis & Treatment Protocol 
(9 & 24) 
Added “Clinicians should validate the appropriateness of protocol 
recommendations, and provide treatment based upon their clinical judgment.” 
Reason: To provide further clarification that clinical judgement is key to treatment. 
Additional Evaluations 
(17 & 39) 
Added additional datapoints for analysis 
Reason: Sensitivity analysis for any missing 30-Day follow-up and treatment 
protocol compliance analysis 
Synopsis, Schema, Schedule of Events & 
Procedures 
(10, 27,32) 
Removed MoCA; Added: Preo-op Surgical Risk Assessment, Post-Op 
Neurocognitive Assessments 
Reason: Change in assessment type 
General Design 
(24) 
Added “The HPI Pressure & Flow Optimization Protocol provides 
recommendations for treatment. Clinicians are instructed to validate the 
appropriateness of protocol recommendations, and provide treatment based 
upon their clinical judgment” 
Reason: Clarification on non-significant risk reasons. 
Randomization and Blinding 
(25) 
Changed “Study investigators and staff will be blinded up until the time of the 
surgery. The staff member(s) involved in the consenting of the patient will be 
blinded to the randomization assignment and will not be involved in the care of 
the Trial subject.” to “Study investigators will be blinded up until the time of the 
surgery. The clinician(s) involved in the consenting of the patient will be blinded 
to the randomization assignment and will not be involved in the care of the Trial 
subject.” 
Reason: To clarify the randomization and blinding. 
Roll-in Subjects 
(30) 
Updated the roll-ins to a max of 5 at a site. The total roll-in cases remain at 60. 
Reason: To allow for additional roll-in cases at sites that need them. 
Procedure 
(35) 
Added “Interventions conducted per treatment protocol and/or outside the 
treatment protocol will be documented on the eCRF(s). Clinicians should validate 
the appropriateness of protocol recommendations, and provide treatment based 
upon their clinical judgment.” 
Reason: To clarify the intervention data that will be collected. 
Additional Evaluations 
(39) 
Added “Sensitivity analysis including the review of any influence of surgical 
position, type of anesthesia, tidal volume etc., on the primary outcome measure, 
are specified in the SAP.” 
Reason: Clarification on sensitivity analysis. 
Anticipated Risks 
(42) 
Added risks related to associated with HPI Pressure and Flow Optimization Protocol 
Reason: To clarify risks that may be associated with treatment protocol. 

HPI SMART-BP 
Protocol #2021-04 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 4 of 68 
CONFIDENTIAL 
 
 
 
 
INVESTIGATOR’S SIGNATURE PAGE 
 
This trial will be carried out in accordance with the protocol, International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), applicable state, local and federal regulatory requirements as well as 45 CFR Part 
46, 21 CFR Parts 11, 50, 54, 56 and 812. 
 
I will provide copies of the protocol to the Institutional Review Board and all members of the Research team 
responsible to me who participate in the trial. I will discuss this material with them to ensure that all 
participating personnel at the Research Site are fully informed regarding the conduct of the protocol. 
Once the Institutional Review Board approves the protocol, I will not modify this protocol without obtaining 
the prior approval of both the Sponsor and the Institutional Review Board. I will submit the protocol 
modifications and/or any informed consent modifications to the Sponsor and the Institutional Review Board, 
as applicable, and approval will be obtained before any modifications are implemented. A determination will 
be made regarding whether a new consent needs to be obtained from participants who provided consent, 
using a previously approved consent form. 
 
I will conduct the trial as detailed in the protocol and in accordance with conditions of the approval imposed 
by the Institutional Review Board and all applicable regulations. I will maintain adequate source 
documentation records throughout the trial and make them available as requested during monitoring visits. 
I will maintain device accountability records and will supervise the use of the device involving human subjects. 
In addition, I will provide all the information requested in the electronic Case Report Forms presented to me 
by the Sponsor in a manner to assure completeness and accuracy. 
 
I will ensure that the requirements for obtaining informed consent are met. Additionally, I will disclose 
financial interests in accordance with 21 CFR 54, and certify that such financial interests, if any, will not 
interfere with my responsibilities as an investigator or influence trial outcomes under my supervision. 
 
I have read the attached protocol and hereby agree that it contains all the necessary details for performing 
the trial. 
 
 
Investigator's Signature 
Date 
Investigator’s Printed Name 
Trial Site Name 
STATEMENT OF COMPLIANCE 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 5 of 68 
CONFIDENTIAL 
 
 
Table of Content 
Statement of Compliance ..................................................................................................................... 4 
Synopsis ................................................................................................................................................. 8 
1. Introduction .................................................................................................................................... 11 
Background ....................................................................................................................................................... 11 
2. Medical Devices ............................................................................................................................. 13 
Device Names ................................................................................................................................................... 13 
Device Descriptions, Contraindications, and Intended Uses ............................................................................ 13 
AcumenTM HPI Feature Software .......................................................................................................................... 13 
Acumen IQ Sensor Technology ............................................................................................................................ 14 
FloTrac Technology .............................................................................................................................................. 15 
ForeSight Elite Oximetry Technology ................................................................................................................... 16 
3. Trial Objective and Endpoints ...................................................................................................... 17 
Trial Primary Objective ...................................................................................................................................... 17 
Additional Evaluations ....................................................................................................................................... 17 
Trial Endpoints .................................................................................................................................................. 18 
Outcome definitions .......................................................................................................................................... 18 
MACE .................................................................................................................................................................... 18 
Myocardial injury ............................................................................................................................................... 18 
Nonfatal cardiac arrest ...................................................................................................................................... 19 
Stroke................................................................................................................................................................ 19 
Death ................................................................................................................................................................ 19 
Serious Infections .................................................................................................................................................. 20 
Surgical site infection (deep surgical site) ......................................................................................................... 20 
Surgical site infection (organ/space) ................................................................................................................. 20 
Pneumonia ........................................................................................................................................................ 20 
Sepsis ............................................................................................................................................................... 21 
AKI ........................................................................................................................................................................ 21 
4. Trial Design .................................................................................................................................... 23 
General Design ................................................................................................................................................. 23 
Treatment Protocol ........................................................................................................................................... 24 
Randomization and Blinding ............................................................................................................................. 25 
Schema ............................................................................................................................................................. 26 
5. Subject Consent, Selection, and Withdrawal .............................................................................. 28 
General Characteristics of the Proposed Subject Selection ............................................................................. 28 
Informed Consent ............................................................................................................................................. 28 
Subject Eligibility ............................................................................................................................................... 28 
Screen Failures [or Late Screen Failures] ........................................................................................................ 30 
Enrolled Subjects .............................................................................................................................................. 30 
Roll-in Subjects ................................................................................................................................................. 30 
Early Withdrawal of Subjects ............................................................................................................................ 31 
Lost to Follow-Up .............................................................................................................................................. 31 
6. Schedule of Events & Procedures ................................................................................................ 32 
Screening .......................................................................................................................................................... 32 
Pre-Procedure ................................................................................................................................................... 32 
DAY 1 (DAY OF SURGERY) ............................................................................................................................ 32 
DAYS 2-4 (POD 1-3)......................................................................................................................................... 33 
Discharge from the ICU / hospital ..................................................................................................................... 33 
30-Day Follow-up .............................................................................................................................................. 33 
Schedule of Events (SoE) ................................................................................................................................. 34 
Procedure ......................................................................................................................................................... 35 

HPI SMART-BP 
Protocol #2021-04 
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of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 6 of 68 
CONFIDENTIAL 
 
 
7. Statistical Methods ........................................................................................................................ 37 
Statistical Analysis Plan (SAP) ......................................................................................................................... 37 
Primary Outcome Endpoint ............................................................................................................................... 37 
Sample Size Justification .................................................................................................................................. 38 
Analysis Populations ......................................................................................................................................... 38 
Analysis Methods .............................................................................................................................................. 38 
Additional Evaluations ....................................................................................................................................... 39 
Planned Interim Analyses ................................................................................................................................. 40 
8. Risk Analysis .................................................................................................................................. 41 
Anticipated Risks .............................................................................................................................................. 41 
Risk Management ............................................................................................................................................. 43 
Benefits ................................................................................................................................................................. 43 
9. Reportable Events .......................................................................................................................... 44 
Recording and Reporting of Adverse Events .................................................................................................... 44 
Severity of an AE .............................................................................................................................................. 44 
Relationship of an AE ....................................................................................................................................... 44 
Recording and Reporting of Adverse Device Effects ........................................................................................ 45 
Recording and Reporting of Serious Adverse Event ........................................................................................ 45 
Recording and Reporting of Serious Adverse Device Effects ........................................................................... 45 
Recording and Reporting of Unanticipated Adverse Device Events ................................................................. 46 
Recording and Reporting of Deaths.................................................................................................................. 46 
Recording and Reporting of Adverse Events Associated with Commercial Components ................................ 46 
Recording and Reporting of Pre-Existing Conditions ........................................................................................ 47 
Reporting Adverse Events to the FDA .............................................................................................................. 47 
Reporting Adverse Events to the Responsible IRB .......................................................................................... 47 
Recording and Reporting AE Time Period ........................................................................................................ 47 
10. Independent Safety Committees .................................................................................................. 48 
Medical Reviewer .............................................................................................................................................. 48 
Data Safety Monitoring Board .......................................................................................................................... 48 
Stopping Rules ...................................................................................................................................................... 49 
11. Receiving, Storage, and Return of devices ................................................................................. 50 
Receipt of Device Supplies ............................................................................................................................... 50 
Storage ............................................................................................................................................................. 50 
Device Accountability ........................................................................................................................................ 50 
Return of Devices ............................................................................................................................................. 50 
12. Confidentiality and Privacy ........................................................................................................... 51 
13. Data Handling and Record Keeping ............................................................................................. 52 
Source............................................................................................................................................................... 52 
Data Entry Timelines ........................................................................................................................................ 52 
14. Changes to the Protocol ................................................................................................................ 53 
15. Protocol Deviation ......................................................................................................................... 54 
16. Data Collection Methods ............................................................................................................... 55 
17. Record Retention ........................................................................................................................... 56 
18. Trial Documentation ...................................................................................................................... 57 
Trial Records ..................................................................................................................................................... 57 
Trial Reports ..................................................................................................................................................... 57 
Communication Procedures .............................................................................................................................. 58 
19. Trial Monitoring, Auditing, and Inspecting .................................................................................. 59 
Site Selection .................................................................................................................................................... 59 
Trial Monitoring Plan ......................................................................................................................................... 59 
Interim Monitoring Activities .................................................................................................................................. 59 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 7 of 68 
CONFIDENTIAL 
 
 
Site Close-Out Visit ............................................................................................................................................... 60 
Auditing and Inspecting ..................................................................................................................................... 60 
20. Trial Early Termination .................................................................................................................. 61 
21. Ethics .............................................................................................................................................. 62 
Ethical and Scientific Conduct of the Clinical Research Trial ........................................................................... 62 
22. Financial Disclosures .................................................................................................................... 63 
23. Conflict of Interest Policy .............................................................................................................. 64 
24. Publications .................................................................................................................................... 65 
25. Acronyms and Abbreviations ....................................................................................................... 66 
26. References ...................................................................................................................................... 67 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 8 of 68 
CONFIDENTIAL 
 
 
SYNOPSIS 
 
 
Title: 
Hypotension Prediction Index (HPI) Software Guided Hemodynamic 
Management for Noncardiac Surgery Patients – Blood Pressure Trial 
Short Title: 
HPI SMART-BP Trial 
Trial 
 
Description: 
A multicenter, interventional, randomized trial 
Trial Objective: 
To determine if the use of a protocolized strategy using advanced 
hemodynamic monitoring with Hypotension Prediction Index (HPI) software 
guidance for intraoperative hemodynamic management reduces 
postoperative complication rate in moderate- to high-risk non-cardiac 
surgery. 
Primary 
Effectiveness 
Endpoint: 
The primary hypothesis is that the administration of advanced hemodynamic 
monitoring utilizing the Hypotension Prediction Index (HPI) with a 
protocolized strategy during moderate-to-high-risk noncardiac surgery 
reduces composite of severe postoperative complications at 30 days. The 
composite includes: Major adverse cardiac events MACE (myocardial injury, 
stroke, non-fatal cardiac arrest, and death), acute kidney injury (AKI), and 
serious infection. Specifically, we seek to evaluate if the treatment protocol 
utilizing the technology from Edwards Lifesciences will result in a relative 
change of at least 25% in the composite complication score when compared 
to the control arm that will receive an arterial line with only blood pressure 
monitoring, as per the standard of care. 
Trial Devices: 
HemoSphere Advanced Monitor, AcumenTM HPI Feature Software, Acumen 
IQ sensor, FloTrac sensor, and ForeSight Elite Oximetry sensor. 
Overall Design: 
A multicenter, randomized comparison of intraoperative hemodynamic 
management with or without a protocolized strategy utilizing Hypotension 
Prediction Index (HPI) software guidance during moderate-to-high-risk 
noncardiac surgery. 
Trial 
Population: 
Up to 1486 adults undergoing moderate-to-high-risk noncardiac surgery who 
will be receiving pressure monitoring with an arterial line. 
Number of 
Sites: 
Up to Twenty (20) U.S. Sites 
Trial Duration: 
Total of 24 to 36 months 
Participation 
Duration: 
Screening/Baseline; Procedure; Post-Op Days 1-3; ICU; hospital discharge; 
30-day Telephone Follow-Up Visit 
Inclusion/ 
Exclusion 
Criteria 
Inclusion Criteria: 
1. Signed informed consent; 
2. Age ≥ 18 years; 

HPI SMART-BP 
Protocol #2021-04 
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of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 9 of 68 
CONFIDENTIAL 
 
 
 
3. ASA Physical Status ≥ 2; 
4. Noncardiac surgery with expected surgery duration ≥ 2 hours 
(example include: orthopedic, spine, urology, and general surgery) 
5. Planned blood pressure monitoring with an arterial line catheter; 
6. General anesthesia; 
Exclusion Criteria: 
1. Participating in another interventional Trial; 
2. Contraindication to arterial blood pressure monitoring; 
3. Subjects with a physical site area too limited for proper Sensor 
placement 
4. Serum creatine > 175 µmol/L (>2.0 mg/dL) or CKD stage > 3A 
5. Scheduled for intracranial surgery with permissive hypotension; 
6. Patient who is confirmed to be pregnant and/or nursing mothers; 
7. Patients with an intra-aortic balloon pump (IABP) or ventricular 
assist device(s); 
8. Have a condition that precludes routine or tight blood pressure 
management such as surgeon request for relative hypotension; 
9. Emergency surgery; 
10. Require beach-chair positioning; 
11. Scheduled for cardiac surgeries 
12. Have previously participated in the SMART-BP trial. 
Treatment 
Protocol: 
Alert Phase: HPI greater than 85 ➔ alert ➔ treatment per protocol 
recommendation 
Monitoring Phase: HPI 50 – 85➔ evaluate flow / vascular tone indices and fluid 
responsive state. 
Clinicians should validate the appropriateness of protocol recommendations, 
and provide treatment based upon their clinical judgment. 
Primary Outcome: 
A composite of 30-day moderate-to-severe perfusion related postoperative 
complications. The composite includes: 
1. MACE (myocardial injury, stroke, non-fatal cardiac arrest, and death) 
2. Acute kidney injury (KDIGO stage 2-3) 
3. Serious Infections: pneumonia, deep surgical site or organ space 
infections, and sepsis 
Preoperative 
Assessments: 
Creatinine, Surgical Risk Assessment (NSQIP1), Troponin, NT-proBNP 

HPI SMART-BP 
Protocol #2021-04 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 10 of 68 
CONFIDENTIAL 
 
 
 
Postoperative 
Assessments: 
Troponin and Post-Op delirium assessment POD 1,2,3; Creatinine POD 2, 
Post-Operative Morbidity Survey (POMS7) POD 3, 30-day Follow-up, World 
Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.019) 
Trial Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 USA 

HPI SMART-BP 
Protocol #2021-04 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 11 of 68 
CONFIDENTIAL 
 
 
 
 
With advancements in treating disease, the number of patients undergoing major surgery worldwide is 
growing.6 Despite this fact, many patients still experience severe perioperative complications or post- 
operative mortality.6 Each year roughly 240 million anesthesia cases are performed worldwide.3 About 10% 
of these cases are high risk patients who account for >80% of perioperative deaths.3 The more common 
moderate-risk surgery constitutes 40% of surgeries. Of these, about 30% of patients experience minor post- 
operative complications.3 
 
The perioperative period is characterized by hemodynamic instability. Various degrees of hypotension are 
common during anesthesia, which may cause organ ischemia.8 There is accumulating evidence that 
intraoperative hypotension is associated with injury to the heart, kidney, and brain and carries an increased 
likelihood of mortality in moderate-to high-risk patients.6 Recent studies have demonstrated a connection 
between hypotension and adverse outcome events such as acute kidney injury (AKI) and myocardial injury 
(MI).20 Post-operative complications, even the minor ones, extend hospital stay and surge healthcare costs, 
and, more importantly, can reduce long-term survival.3 
 
Recent studies have looked at the effects that intraoperative hypotension have on post-operative 
complications. Long periods of hemodynamic flow-base optimization through cardiac output has shown 
improvements to reduce complications. One of these trials was the OPTIMISE I trial that aimed to assess the 
clinical effectiveness of cardiac output-guided hemodynamic therapy during the perioperative period.14 The 
meta-analysis for the study indicated that hemodynamic intervention was linked to a reduction in 
complication rates (intervention 31.5% versus control 41.6%).14 
 
In another randomized trial, the effect of individual blood pressure management on reducing organ damage 
was analyzed.6 Based on the trial results, only 46.3% patients in the individualized treatment group reported 
postoperative organ dysfunction compared to that of the standard treatment group which was 63.4%. This 
study was able to demonstrate a total of 17.1% post-operative organ dysfunction reduction for subjects who 
received individualized blood pressure management.6 
 
The duration of hypotension may have an effect on the resulting organ damage as well.20 The Hypotension 
Prediction Index (HPI) algorithm predicts hypotension, which is defined as MAP <65 mmHg for at least one 
minute, by collecting information from arterial waveform features such as waveform time, amplitude, area, 
segment slopes, and complexity features.10 In the HYPE trial, a randomized controlled trial, it was shown that 
using Hypotension Prediction Index (HPI) software for hemodynamic management reduces intraoperative 
hypotension compared with the standard of care for patients undergoing elective noncardiac surgery.21 Based 
on the results, the subjects in the intervention group experienced a median of 8.0 minutes of hypotension 
compared to that of the control group which was 32.7 minutes.21 There was a mean total reduction of 75.5% 
of hypotension. In another single-center feasibility randomized, blinded prospective interventional trial, there 
was a substantial reduction of intraoperative hypotension in the HPI group. The rate of hypotensive events 
in the HPI group was 48%, while the rates in the routine anesthetic care and historic control groups were 
87.5% and 80%, respectively. 16 
Background 
1. INTRODUCTION 

HPI SMART-BP 
Protocol #2021-04 
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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Currently, there is a minimal amount of evidence linking a reduction in intraoperative hypotension to patient 
outcome. Moreover, the inclusion of comprehensive flow and hypotension management strategies has also 
not been evaluated in a robust manner in improving patient postoperative AKI outcome. Precise treatment of 
perioperative hypotension should be based on a reference to the patient’s baseline measurements of BP, 
cardiac output, stroke volume, heart rate, and systemic vascular resistance (SVR).11 
 
Tissue oxygenation will also be measured during the trial using ForeSight Elite oximetry sensors for only 
observation purposes. Changes in cardiovascular dynamics are induced during major surgery that includes 
anesthesia. These changes in cardiovascular dynamics can lead to reduction in perfusion of vital organs and 
contribute to post-operative complications.12 Different cardiovascular variables besides arterial pressure 
including arterial oxygen content and cardiac output are regulating and inducing tissue perfusion ad 
oxygenation. Thus, maintaining or restoring tissue perfusion and oxygenation by optimizing global 
cardiovascular dynamics can be a propitious concept in improving postoperative outcomes for patients 
undergoing surgery.12 
 
This trial seeks to evaluate the benefit of a protocolized blood pressure management strategy that utilizes a 
hypotension prediction tool along with a comprehensive advanced hemodynamic assessment to reduce a 
composite of postoperative complications in patients undergoing non-cardiac surgery. Based onthe literature, 
6,10,14 the estimated incidence of the composite primary outcome is expected to be at least 31%. This trial is 
targeting a relative reduction of at least 25% in the composite outcome within the treatment arm as compared 
to the control arm control arm that will receive an arterial line with only blood pressure monitoring, as per 
the standard of care. 

HPI SMART-BP 
Protocol #2021-04 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 13 of 68 
CONFIDENTIAL 
 
 
Device Descriptions, Contraindications, and Intended Uses 
 
 
• 
AcumenTM HPI Feature Software 
• 
Acumen IQ sensor 
• 
FloTrac sensor 
• 
ForeSight Elite oximetry sensors 
• 
HemoSphere advanced monitoring platform 
 
 
AcumenTM HPI Feature Software 
Description 
The AcumenTM HPI Feature Software was initially granted marketing clearance via a de novo request 
(DEN160044) by the Food and Drug Administration (FDA) on March 16, 2018. It was initially cleared for 
use on the HemoSphere advanced monitoring platform on November 16, 2018. 
 
The AcumenTM HPI Feature Software provides the clinician with physiological insight into a patient’s 
likelihood of trending toward a hypotensive event (defined as mean arterial pressure ≤ 65 mmHg for at 
least one minute) and the associated hemodynamic parameters. The Acumen TM HPI Feature Software is 
intended for use in surgical and non-surgical patients receiving advanced hemodynamic monitoring. The 
AcumenTM HPI Feature Software is used as decision support to supplement the clinician’s assessment of 
the patient’s physiological condition. No therapeutic decisions should be made based solely on the 
AcumenTM HPI parameter. 
 
The AcumenTM HPI Feature Software, on the HemoSphere advanced monitoring platform, is enabled by the 
minimally invasive Acumen IQ sensor. The Acumen IQ sensor is the hardware which is connected to an 
existing radial arterial catheter. Hemodynamic information is calculated and presented on the Edwards 
HemoSphere advanced monitoring platform. The entire system is comprised of: 
• 
Acumen IQ sensor (hardware): Acumen IQ is the sensor which is connected to the standard arterial 
catheter tubing from the patient. The sensor relays information to the standard anesthesia 
monitor in the form of continuous arterial pressure waveform. The sensor also relays information 
to the AcumenTM HPI Feature Software-enabled HemoSphere Platform. 
• 
AcumenTM HPI Feature Software: The software consists of the Hypotension Prediction Index and 
other advanced hemodynamic parameters. 
• 
HemoSphere advanced monitoring platform: This is the system monitor which displays the 
continuous arterial pressure monitoring, HPI, and other advanced hemodynamic parameters. 
Device Names 
2. MEDICAL DEVICES 

HPI SMART-BP 
Protocol #2021-04 
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Protocol # 2021-04 
Page 14 of 68 
CONFIDENTIAL 
 
 
Acumen IQ Sensor Technology 
Description 
The Acumen IQ sensor is a sterile, single use kit that monitors pressures when attached to pressure 
monitoring catheters. When connected to a compatible monitor, the Acumen IQ sensor minimally- 
invasively measures cardiac output and key hemodynamic parameters, which assist the clinician in 
assessing the patient’s physiologic status and support clinical decisions related to hemodynamic 
optimization. The disposable sterile cable with a red connector interfaces exclusively with an Edwards 
cable that is specifically wired for the pressure monitor being used. The disposable sterile cable with a 
green connector interfaces exclusively with the Edwards cables for use with the Edwards arterial pressure 
based cardiac output monitoring devices or hardware. 
 
The Acumen IQ sensor has a straight, flow-through design across the pressure sensors with an integral 
flush device. 
 
Device performance, including functional characteristics, has been verified in a comprehensive series of 
testing to support the safety and performance of the device for its intended use when used in accordance 
with the established Instructions for Use. 
 
When used with a compatible monitoring platform, the Acumen IQ sensor provides information regarding 
the hemodynamic status of the patient, which may lead to improved data driven clinical decision making 
for medically necessary intervention and/or clinical re-evaluation. When used in conjunction with HPI 
software, the Acumen IQ sensor assists in providing information regarding the likelihood of a patient 
trending toward a hypotensive event (defined as mean arterial pressure ≤ 65 mmHg for at least one 
minute). 
 
 
Contraindications 
There are no absolute contraindications for using the Acumen IQ sensor in patients requiring invasive 
pressure monitoring. 

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Protocol # 2021-04 
Page 15 of 68 
CONFIDENTIAL 
 
 
 
Acumen IQ Sensor Cleared Indications 
The Acumen IQ sensor is indicated for use in intravascular pressure monitoring. It is also indicated 
for use with the Edwards arterial pressure based cardiac output monitoring devices or hardware to 
measure cardiac output. 
HemoSphere Advanced Monitor with HemoSphere Pressure Cable Cleared Indications (For Use with 
Acumen IQ Sensor) 
The HemoSphere advanced monitor when used with the HemoSphere pressure cable is indicated for use in 
critical care patients in which the balance between cardiac function, fluid status, vascular resistance and 
pressure needs continuous assessment. It may be used for monitoring of hemodynamic parameters in 
conjunction with a perioperative goal directed therapy protocol in a hospital environment. 
 
 
FloTrac Technology 
Description 
The FloTrac sensor is a sterile, single use kit that monitors pressures when attached to pressure 
monitoring catheters. When connected to a compatible monitor, the FloTrac sensor minimally-invasively 
measures cardiac output and key hemodynamic parameters, which assist the clinician in assessing the 
patient’s physiologic status and support clinical decisions related to hemodynamic optimization. The 
disposable sterile cable with a red connector interfaces exclusively with an Edwards cable that is 
specifically wired for the pressure monitor being used. The disposable sterile cable with a green connector 
interfaces exclusively with the Edwards cables for use with the Edwards arterial pressure based cardiac 
output monitoring devices or hardware. 
The FloTrac sensor has a straight, flow-through design across the pressure sensors with an integral flush 
device. 
 
 
FloTrac Sensor Cleared Indications 
The FloTrac sensor is indicated for use in intravascular pressure monitoring. It is also indicated for use with 
the Edwards arterial pressure based cardiac output monitoring devices or hardware to measure cardiac 
output. 
The FloTrac Sensors are cleared for use with the HemoSphere Advanced Monitor with HemoSphere 
Pressure Cable. 
 
 
Contraindications 
There are no absolute contraindications for using the FloTrac sensor in patients requiring invasive pressure 
monitoring. 

HPI SMART-BP 
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Protocol # 2021-04 
Page 16 of 68 
CONFIDENTIAL 
 
 
HemoSphere Advanced Monitor with HemoSphere Pressure Cable Cleared Indications (For Use with 
FloTrac) 
The HemoSphere advanced monitor when used with the HemoSphere pressure cable is indicated for use 
in critical care patients in which the balance between cardiac function, fluid status, vascular resistance and 
pressure needs continuous assessment. It may be used for monitoring of hemodynamic parameters in 
conjunction with a perioperative goal directed therapy protocol in a hospital environment. 
 
ForeSight Elite Oximetry Technology 
Description 
The Sensor, when used in combination with the ForeSight Elite tissue oximeter module or in combination 
with the ForeSight Elite absolute tissue oximeter, is a single use applied part that allows the clinician to 
continuously and accurately determine absolute levels of blood oxygenation saturation in the tissue (StO2). 
ForeSight Elite Oximetry Sensors (Large) Cleared Indications 
When used in conjunction with the ForeSight Elite absolute tissue oximeter or ForeSight Elite tissue 
oximetry module: The large Sensor is indicated for monitoring of absolute regional hemoglobin oxygen 
saturation of blood under the sensor in individuals at risk for reduced flow or no-flow ischemic states. It is 
intended for use on adults and transitional adolescents ≥ 40 kg. 
It is included in the Trial only to obtain reference information under its currently cleared indications. 
Contraindications 
The ForeSight Elite oximetry sensor is contraindicated for use on patients: 
• 
With a physical site area too limited for proper sensor placement 
• 
With allergic reactions to sensor adhesive 
• 
Undergoing an MRI scan because of associate risk of injury 
The ForeSight Elite sensors are cleared for use with the HemoSphere advanced monitor with HemoSphere 
Tissue Oximetry Module in both pediatric and adult population on the HemoSphere advanced monitoring 
platform. 
 
HemoSphere Advanced Monitor with HemoSphere Tissue Oximetry Module Cleared Indications 
The noninvasive ForeSight Elite tissue oximeter module is intended for use as an adjunct monitor of 
absolute regional hemoglobin oxygen saturation of blood under the sensors in individuals at risk for 
reduced-flow or no-flow ischemic states. The ForeSight Elite tissue oximeter module is intended to allow 
for the display of StO2 on the HemoSphere advanced monitor. It is indicated for use as follows: 
• 
When used with large sensors, the ForeSight Elite tissue oximeter module is indicated for use on adults 
and transitional adolescents ≥40 kg. 

HPI SMART-BP 
Protocol #2021-04 
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Protocol # 2021-04 
Page 17 of 68 
CONFIDENTIAL 
 
 
Trial Primary Objective 
Additional Evaluations 
 
 
 
The primary objective is to determine if the use of a protocolized strategy using advanced hemodynamic 
monitoring with Hypotension Prediction Index (HPI) software guidance for intraoperative hemodynamic 
management reduces postoperative complication rate in moderate- to high-risk non-cardiac surgery. 
 
 
 
1. Time-to-Adverse Event (Complications) Analysis 
a. Non-Parametric Survival Analysis (KM approach) 
b. Cox Proportional Hazard Model 
c. Mixed effect Cox Proportional Hazard Model 
d. Stratification analysis through applying study sites, gender, race as the stratification factor 
e. Fixed/Mixed effective Poisson regression model applying the count of events as the response 
f. Mixed effective survival model to assess the multiple event cases within patient 
2. Hypotension management analysis 
a. Time from alert event to intervention 
b. % alerts with no intervention 
c. 
Reasons for nonintervention 
d. Amount of hypotension removing nonintervention segments 
e. Agreement analysis; clinical decision vs. treatment algorithm 
f. Overall treatment protocol compliance 
3. Area under the curve AUC MAP under the threshold of 55,65,75 mmHg 
4. Time Weighted Average (TWA) of intraoperative hypotension (mmHg) 
5. Time in target SVV <13% (for valid SVV readings = no arrythmia) 
6. Time in target CI >2.5 L/min/m15 
7. Postoperative morbidity survey (POMS) on postoperative day 3 
8. Transfusion requirement (mL packed red blood cells) 
9. Amounts of intraoperative crystalloid and colloid and vasoactive drugs; mL 
10. Amount of vasoactive drugs; mg (e.g.: phenylephrine, ephedrine, norepinephrine, epinephrine, 
dobutamine) 
11. Amount of intraoperative intravenous analgesics and sedatives 
12. Brain oxygen saturation – StO2 using ForeSight Elite tissue oximetry system, time in target 
13. Verification of the incidence of the listed postoperative complications may be performed at each site by 
reviewing historic data up to 6 months prior to study initiation 
14. Cost of care 
15. Hospital length of stay 
16. Hospital readmission within 30 days 
3. TRIAL OBJECTIVE AND ENDPOINTS 

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Protocol # 2021-04 
Page 18 of 68 
CONFIDENTIAL 
 
 
Outcome definitions 
Myocardial injury 
 
 
 
 
The primary outcome endpoint is to demonstrate that adding an advanced hemodynamic monitoring 
utilizing the Hypotension Prediction Index (HPI) with a protocolized strategy to the information provided by 
the invasive arterial pressure monitoring during moderate-to-high-risk noncardiac surgery impacts the 
composite of moderate and severe postoperative complications at 30 days. 
 
A reduction in the composite outcome of least 25% in the treatment arm as compared to the control arm is 
expected. The composite includes MACE (myocardial injury, stroke, non-fatal cardiac arrest, and death), AKI 
(KDIGO stage 2-3), and serious infections (pneumonia, deep and organ space surgical site infections, and 
sepsis). 
 
MACE 
The components and definition of MACE as a post-operative composite outcome are defined below. 
 
Myocardial injury after non-cardiac surgery will be diagnosed by objective screening based on troponin 
concentrations preoperatively and on the first three postoperative days so long as patients remain 
hospitalized. MINS is defined as any myocardial infarction (i.e., 4th Universal Definition of myocardial 
infarction17), and any elevated troponin judged to be due to myocardial ischemia (i.e., without evidence of 
a non-ischemic etiology, e.g. chronic elevation, pulmonary embolism, sepsis, cardioversion, others) that 
occurred within the first 30 days after surgery. 
Myocardial injury will be considered when a postoperative troponin concentration is elevated and believed 
to be consequent to myocardial ischemia. The thresholds differ depending on the assay generation and 
type. The following thresholds based on available literature will be used: 
1. non-high sensitivity (fourth generation) troponin T ≥0.03 ng/mL; 
2. high-sensitivity troponin T ≥65 ng/L; or high-sensitivity troponin T 20-64 ng/L and an increase ≥5 ng/L from 
baseline; 
3. high-sensitivity troponin I (Abbott assay) is ≥60 ng/L4; 
4. high-sensitivity troponin I (Siemens assay) is ≥75 ng/L (Borges, unpublished); 
5. troponin I (other assays) is at least twice local 99th percentiles; 
6. an increase of at least 20% in patients who have preoperative high-sensitivity troponin concentrations 
that exceed 80% of the relevant thresholds in items 2-5. 
Occasionally, patients will have preoperative troponin concentrations exceeding the thresholds in items 2-5. 
When that happens, clinicians should try to distinguish acute myocardial injury from chronic elevations. 
Whenever possible, troponin should be resampled because concentrations will usually change substantially 
in patients having an acute injury but otherwise remain nearly constant if they represent chronic elevation. 
For patients with a chronic elevation or an acute injury before surgery, a new myocardial injury after surgery 
requires identification of a new elevated troponin after surgery as per points 1-5 above, and the troponin 
Trial Endpoints 

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Protocol # 2021-04 
Page 19 of 68 
CONFIDENTIAL 
 
 
Nonfatal cardiac arrest 
Stroke 
Death 
elevation must be a 20% rise beyond the chronic troponin value or beyond the last measurement of the acute 
preoperative myocardial injury that was clearly demonstrated to have peaked and was coming down. 
 
Nonfatal cardiac arrest will be defined as successful resuscitation from either documented or presumed 
ventricular fibrillation, sustained ventricular tachycardia, asystole, or pulseless electrical activity requiring 
cardiopulmonary resuscitation, pharmacological therapy, or cardiac defibrillation. 
 
Strokes will be detected from clinical symptoms lasting at least 24 hours and require imaging evidence 
consistent with new-onset cerebral ischemic or hemorrhagic injury. 
 
Death will be defined as all-cause mortality through the 30-day follow-up (up to 30-days post-operative). 

HPI SMART-BP 
Protocol #2021-04 
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Protocol # 2021-04 
Page 20 of 68 
CONFIDENTIAL 
 
 
Surgical site infection (deep surgical site) 
Surgical site infection (organ/space) 
Pneumonia 
Serious Infections 
Serious infections (pneumonia, deep surgical site, organ/space, and sepsis) within 30 days after the 
operative procedure is defined according Clavien-Dindo grade II or greater: 
 
• 
An infection at the surgical incision site which meets the following criteria: 
o Involves deep soft tissues (e.g., fascial and muscle layers) of the incision and 
o The patient has at least one of the following: 
▪ 
Purulent drainage from the deep incision but not from the organ/space 
component of the surgical site 
▪ 
A deep incision spontaneously dehisces or is deliberately opened by a surgeon and 
is culture-positive or not cultured when the patient has at least one of the 
following symptoms or signs: fever (>38ᵒC), or localized pain or tenderness. A 
culture-negative finding does not meet this criterion. 
▪ 
An abscess or other evidence of infection involving the deep incision is found on 
direct examination, during surgery, or by histopathologic or radiologic examination 
▪ 
Diagnosis of an incisional surgical site infection by a surgeon or attending physician 
organ space surgical site infection 
 
 
• 
An infection at the surgical incision site, excluding the fascia or muscle layers, which appears to be 
related to the surgical procedure and involves any part of the body, excluding the skin incision, 
fascia, or muscle layers, that is opened or manipulated during the operative procedure and the 
patient has at least one of the following: 
o Purulent drainage from a drain that is placed through a stab wound into the organ/space 
o Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/ 
space 
o An abscess or other evidence of infection involving the organ/space that is found on direct 
examination, during reoperation, or by histopathologic or radiologic examination 
Diagnosis of an organ/space surgical site infection by a surgeon or attending physician 
 
• 
This is defined as two or more serial chest radiographs with at least one of the following (one 
radiograph is sufficient for patients with no underlying pulmonary or cardiac disease): 
o New or progressive and persistent infiltrates 
o Consolidation 
o Cavitation 
• 
And at least one of the following: 
o Fever (>38°C) with no other recognized cause 
o Leucopenia (<4,000 white blood cells/mm3) or leucocytosis (>12,000 cells/mm3) 
o For adults >70 years old, altered mental status with no other recognized cause 

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Protocol # 2021-04 
Page 21 of 68 
CONFIDENTIAL 
 
 
Sepsis 
• 
And at least two of the following: 
o New onset of purulent sputum or change in character of sputum, or increased respiratory 
secretions, or increased suctioning requirements 
o New onset or worsening cough, or dyspnoea, or tachypnoea 
o Rales or bronchial breath sounds 
o Worsening gas exchange (hypoxia, increased oxygen requirement, increased ventilator 
demand) 
 
Sepsis within 30 days after the operative procedure is defined according to the criteria of the Centers for 
Disease Control and Prevention (CDC) 
Sepsis, severe sepsis, and septic shock criteria 
• 
Sepsis is defined as: 
o Defined focus of infection and 
o At least two systemic inflammatory response syndrome (SIRS) criteria.2 
▪ 
Criteria for Systemic Inflammatory Response Syndrome (SIRS) 
SIRS is defined by two or more of the following: 
1. Core temperature >38°C or <36°C. (Core temperature was rectal or 
tympanic). If oral, inguinal, or axillary temperatures were used, 0.5°C were 
added to the measured value 
2. Heart rate >90/min. If patient had an atrial arrhythmia, record the 
ventricular rate. If patients have a known medical condition or are 
receiving treatment that would prevent tachycardia (for example, heart 
block or beta blockers), they must meet two of the remaining three SIRS 
criteria. 
3. Respiratory rate > 20/min or a PaCO2 <32 mmHg (4.3 kPa) or mechanical 
ventilation for an acute process. 
4. White Blood Cell (WBC) count of >12 x 109/l or <4 x 109/l. 
• 
Defined focus of infection is indicated by either an organism grown in blood or sterile site, or an 
abscess or infected tissue (e.g., pneumonia, peritonitis, urinary tract, vascular line infection, soft 
tissue, etc.). 
• 
Severe sepsis is defined by sepsis plus at least one organ failure, hypotension or hypoperfusion. 
Septic shock was sepsis-induced hypotension despite adequate fluid resuscitation along with the 
presence of perfusion abnormalities 
AKI 
Postoperative Acute Kidney Injury will be defined by Kidney Disease Improving Global Guidelines (KDIGO) 
Clinical Practice Guidelines.9 
AKI is defined as any of the following: 
• 
Increase in SCr by ≥0.3 mg/dL (≥26.5 Lmol/L) within 48 hours; or 
• 
Increase in SCr to≥1.5 times baseline, which is known or presumed to have occurred within the 
prior 7 days; or 

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Protocol # 2021-04 
Page 22 of 68 
CONFIDENTIAL 
 
 
• 
Urine volume ˂0.5 mL/kg/h for 6 hours. 
 
 
AKI is staged for severity according to the following serum criteria (Table 1). 
 
Table 1 Staging of AKI 
 
Stage 
Serum creatinine 
1 
1.5–1.9 times baseline 
OR 
≥0.3 mg/dL (≥26.5 mmol/l) increase 
2 
2.0–2.9 times baseline 
3 
3.0 times baseline 
OR 
Increase in serum creatinine to ≥4.0 mg/dL (≥353.6 mmol/l) 
OR 
Initiation of renal replacement therapy 
OR, In patients ˂18 years, decrease in eGFR to ˂35 mL/min per 1.73 m2 

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Protocol #2021-04 
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of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 23 of 68 
CONFIDENTIAL 
 
 
 
 
A multicenter, interventional, randomized comparison of intraoperative hemodynamic management to 
determine whether use of a protocolized strategy using advanced hemodynamic monitoring with Hypotension 
Prediction Index (HPI) software guidance for intraoperative hemodynamic management reduces 
postoperative complication rate in moderate- to high-risk non-cardiac surgery. There will be two arms in this 
trial, with both arms receiving arterial line monitoring. The treatment arm will receive guidance from a 
protocolized strategy using advanced hemodynamic monitoring with Hypotension Prediction Index (HPI) 
software guidance for intraoperative hemodynamic management. The control arm will be blinded to 
advanced hemodynamic monitoring and will only receive blood pressure monitoring data from the arterial 
line, as per the standard of care. 
A subject will be considered enrolled in the treatment arm once the subject has signed the informed consent 
and an Acumen IQ sensor has been connected. 
A subject will be considered enrolled in the control arm once they signed informed consent and a FloTrac 
sensor has been connected. 
Subjects will be assigned a 6-7-digit Trial Identification Number (Trial ID). The first three-four numbers will 
identify the site, and the second set of numbers will identify the subject identification number. 
For subjects in the treatment arm an Acumen IQ sensor and ForeSight Elite oximetry sensors will be placed 
prior to the start of the procedure. All advanced hemodynamic parameters including cardiac output (CO), 
systemic vascular resistance (SVR), stroke volume (SV), stroke volume variation (SVV), EaDyn, dP/dt and vital 
signs will be collected throughout the duration of the procedure and analyzed according to the Statistical 
Analysis Plan (SAP). 
For subjects in the control arm a FloTrac sensor and ForeSight Elite oximetry sensors will be placed prior to 
the start of the procedure. The control arm will be blinded to advanced hemodynamic monitoring obtained 
from the FloTrac and ForeSight sensors and will only receive blood pressure monitoring data from the arterial 
line, as per the standard of care. All vital signs will be collected throughout the duration of the procedure and 
analyzed according to the SAP. 
Subject participation will include preoperative Trial eligibility screening and consent, planned surgical 
intervention, post intervention follow up through discharge, and 30 days post procedure. Discontinued 
subject data will be analyzed under intent-to-treat and data will be used for safety and performance analyses. 
 
This Trial will be conducted in a manner that is consistent with the applicable regulations and in accordance 
with current Good Clinical Practice (GCP). 
In accordance with 21 CFR 812.3(m), this Trial does not meet the definition of a significant risk investigation 
for the following reasons: 
• 
The devices in the treatment arm are being studied in accordance with the indications for use and 
intended use granted by FDA and therefore are not investigational devices; 
General Design 
4. TRIAL DESIGN 

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Protocol # 2021-04 
Page 24 of 68 
CONFIDENTIAL 
 
 
Treatment Protocol 
Note: Clinicians should validate the appropriateness of protocol recommendations, and provide treatment based upon their clinical judgment. 
• 
The devices in the treatment arm are not implants; 
• 
The devices in the treatment arm do not present a potential for serious risk to the health, safety, or 
welfare of a subject as only subjects requiring an arterial line will be eligible for enrollment in the 
Trial and; 
• 
The devices in the treatment arm are of substantial importance in diagnosing, mitigating, or treating 
disease, or otherwise preventing impairment of human health and the general and class II (special) 
controls provide a reasonable assurance of the safety and effectiveness of adjunctive predictive 
cardiovascular indicators; 
• 
The Trial relies on the intervention of a learned intermediary prior to initiation of treatment, as the 
clinicians are utilizing their own clinical judgment in deciding appropriate treatment; 
• 
The HPI Pressure & Flow Optimization Protocol provides recommendations for treatment. Clinicians 
are instructed to validate the appropriateness of protocol recommendations, and provide treatment 
based upon their clinical judgment; 
• 
The devices in the treatment arm are not of substantial importance in curing a disease. 
 
Subjects assigned to treatment arm will receive treatment per following guidelines: 
 
• 
Alert Phase: HPI greater than 85 ➔ alert ➔ treatment per protocol recommendation 
• 
Monitoring Phase: HPI 50 – 85 ➔ evaluate flow / vascular tone indices and fluid responsive state. 
Figure 1 : Treatment Protocol for Subjects Enrolled in the Treatment Arm 
 
 

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Protocol # 2021-04 
Page 25 of 68 
CONFIDENTIAL 
 
 
 
 
The randomization for this Trial will be implemented using an Interactive Web Response Systems (IWRS). The 
Sponsor will be blinded to the randomization codes. Participants will be randomized to either the control or 
treatment arm at enrollment. Study investigators will be blinded up until the time of the surgery. The 
clinician(s) involved in the consenting of the patient will be blinded to the randomization assignment and will 
not be involved in the care of the Trial subject. Once the intent of arterial line placement is confirmed with 
the anesthesia team, before surgery (the day before or in the morning of surgery), the subject will be 
randomized to either the treatment or control arm. The arterial line will then be placed. Randomization will 
be allocated in 1:1 ratio, stratified by site. 
 
Throughout the Trial, the randomization assignment will remain blinded to all parties, with the study 
investigators and staff being blinded up until the time to surgery. Randomization assignment can be unblinded 
in the case of a medical emergency that requires the treatment assignment to be known. In this case, an 
individual subject blind may be broken via the Code Break Module by the Investigator or Medical Reviewer. 
When possible, the Investigator is to consult with the Medical Reviewer, or designee, prior to breaking the 
code. The Investigator is to capture the date, time, and reason for breaking the blind in the subject’s source 
notes. Additionally, an independent biostatistician will be unblinded to the randomization codes in order to 
conduct the interim analysis. All other parties will be blinded to the randomization at time of the interim. 
After completion of the Trial, the randomization codes will be unblinded, post database lock and with the Trial 
Sponsor’s approval to unblind. 
Randomization and Blinding 

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Protocol # 2021-04 
Page 26 of 68 
CONFIDENTIAL 
 
 
Screening 
No 
Eligible 
Excluded from 
Trial 
Yes 
No 
ICF Signed 
Refuse to Sign ICF 
Yes 
Intent to Place 
Arterial Line 
 
 No 
Yes 
Randomized to 
Trial Group 
Treatment Arm 
Control Arm 
Receive HPI 
Guidance 
Receive Standard 
of Care 
 
 
 
Figure 2 Enrollment Flow Diagram 
 
Schema 

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Protocol # 2021-04 
Page 27 of 68 
CONFIDENTIAL 
 
 
 
Figure 3 Enrollment Timeline Diagram 
 
Day -7 to Day 0 
Screening and Consent 
 
 
Day 1 
Randomization* 
 
 
Pre-Op and Procedure 
 
Intervention 
n =713 
Control 
n =713 
Day 1 
 
Day 2 
 
 
Day 3 
 
 
Day 4 
 
 
 
Day 2+ 
Labs: Creatinine, Troponin, NT-proBNP 
Surgical Risk Assessment (NSQIP) 
POD 1: 
Labs: Troponin 
Post-Op Delirium Assessment 
POD 2 
Labs: Troponin & Creatinine 
Post-Op Delirium Assessment 
 
 POD 3: 
Labs: Troponin 
POMS Survey 
Post-Op Delirium Assessment 
Hospital Discharge 
 
Day 15-44 
30-day Follow-up Phone Call 
WHODAS 2.0 
 
*Roll-ins not included. 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Informed Consent 
Subject Eligibility 
 
 
Adults with an ASA classification of ≥ 2 undergoing moderate-to-high-risk noncardiac surgery with expected 
surgery duration > 2 hours who will be receiving pressure monitoring with an arterial line will be screened 
for inclusion into the Trial. Only subjects meeting all inclusion criteria will be enrolled. Prior to any Trial 
procedures, an IRB-approved informed consent form must be signed and dated by the subject or legal 
guardian. Subjects who have been screened but do not sign an informed consent form will not be 
considered enrolled and will not have any eCRFs (electronic Case Report Forms) completed. 
 
Before a subject undergoes any Trial procedures, an informed consent will be obtained utilizing the IRB 
approved consent form. All consent procedures will be conducted in a manner that is consistent with the 
applicable regulations and in accordance with Good Clinical Practice (GCP). 
During the consent procedure, each potential subject will be given ample time to discuss participation in the 
Trial and to have any questions or concerns addressed by the Principal Investigator or Investigator. Each 
subject will be provided with a copy of the IRB approved consent. 
 
 
All eligible subjects should be screened for Trial eligibility. The Investigator and/or Designee(s) at the Trial 
site shall review the candidate’s eligibility. The Trial site should maintain a cumulative log of all screened 
subjects in the EDC system. 
 
Inclusion Criteria: 
1. Signed informed consent; 
2. Age ≥ 18 years; 
3. ASA Physical Status ≥ 2; 
4. Noncardiac surgery with expected surgery duration ≥ 2 hours (example include: orthopedic, spine, 
urology, and general surgery) 
5. Planned blood pressure monitoring with an arterial line catheter; 
6. General anesthesia; 
General Characteristics of the Proposed Subject Selection 
5.  SUBJECT CONSENT, SELECTION, AND WITHDRAWAL 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
 
 
 
Exclusion Criteria: 
1. Participating in another interventional Trial; 
2. Contraindication to arterial blood pressure monitoring; 
3. Subjects with a physical site area too limited for proper Sensor placement 
4. Serum creatine > 175 µmol/L (>2.0 mg/dL) or CKD stage > 3A 
5. Scheduled for intracranial surgery with permissive hypotension; 
6. Patient who is confirmed to be pregnant and/or nursing mothers; 
7. Patients with an intra-aortic balloon pump (IABP) or ventricular assist device(s); 
8. Have a condition that precludes routine or tight blood pressure management such as surgeon 
request for relative hypotension; 
9. Emergency surgery; 
10. Require beach-chair positioning; 
11. Scheduled for cardiac surgeries 
12. Have previously participated in the SMART-BP trial. 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Enrolled Subjects 
Roll-in Subjects 
 
 
 
 
All eligible subjects should be screened for Study eligibility. The Investigator and/or Designee(s) at the 
Study site shall review the candidate’s eligibility. The Trial site should maintain a cumulative log of all 
screened subjects in the EDC system. 
 
Early Screen Failure 
Early Screen Failures are patients who do not meet the inclusion criteria for participation in this trial 
(screen failure). Patient may be rescreened if they meet inclusion criteria at a later time. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
 
Late Screen Failure 
Late Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the Trial intervention or entered in the Trial. 
 
A Trial ID will be assigned to early screen failures and late screen failures. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demographics, screen failure details, and 
eligibility criteria. 
 
 
A subject will be considered enrolled in the Trial once the subject has signed the informed consent, has 
been assigned a Trial ID, and an arterial line with either a FloTrac sensor (control arm) or Acumen IQ sensor 
(treatment arm) has been connected. The Trial ID will be a [6-7-digit] number, the first three-four numbers 
will identify the site, and the second set of numbers will identify the subject identification number. 
 
 
In order to avoid a learning curve bias, up to five (5) Roll-in cases may be performed at a site, as needed, 
with a maximum total of 60 Roll-in cases in the Trial. Roll-in cases will be analyzed separately from the 
pivotal cohort. 
Screen Failures [or Late Screen Failures] 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Lost to Follow-Up 
 
 
 
Subjects may voluntarily withdraw consent at any time during the Trial with no loss of benefit or penalty. 
The Investigator may withdraw any subject if they determine that continued participation in the Trial may 
be detrimental to the subject’s safety and welfare. Subjects withdrawn due to a device complaint or 
adverse event will be followed through the 30-day telephone follow-up. In addition, if the procedure is 
aborted early, but after the subject is connected to Trial devices, the subject will be followed for 30 days 
after the aborted procedure. Each subject withdrawal will be documented on the appropriate eCRF. 
 
 
A participant will be considered lost to follow-up if he or she cannot be reached for the 30-day phone 
follow-up by the Trial site staff. 
 
The following actions must be taken before a subject is deemed to lost to follow-up: 
 
• 
The investigator or designee will make every effort to contact with the subject (where possible, 
three (3) telephone calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
subject’s medical record or electronic Trial Master File (eTMF). 
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the Trial with a primary reason of lost to follow-up. 
Early Withdrawal of Subjects 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Pre-Procedure 
DAY 1 (DAY OF SURGERY) 
 
 
 
The study staff will review the subject’s medical history for eligibility. Once the potential eligibility has been 
determined, the study will be discussed with the subject and interest in study participation will be 
determined. Subjects who fulfill all eligibility criteria will be scheduled for surgery within 30 days of the 
screening visit. 
 
During the pre-procedure period the following data will be collected: 
• 
Labs: 
o Creatinine 
o Troponin 
o NT-proBNP 
• 
Survey 
o Surgical Risk Assessment (NSQIP) 
 
 
On the day of the surgery, clinicians will be asked to follow the recommended treatment protocol for 
subjects enrolled in the treatment arm to reduce the subject’s susceptibility to hypotension, (defined as 
MAP < 65 mmHg for at least one (1) minute), with guidance for decision support from the Hypotension 
Prediction Index (HPI) Feature Software. There is no restriction on the type of general anesthesia with or 
without regional anesthesia administered during the surgery. 
The subjects in the treatment arm who are undergoing the planned non-cardiac surgery will have a radial 
arterial catheter inserted for pressure monitoring. The catheter will be connected to an Acumen IQ sensor 
and to the HemoSphere advanced monitoring platform with the Hypotension Prediction Index (HPI) Feature 
Software. The ForeSight Elite oximetry sensors will also be placed on subject’s forehead to collect tissue 
oximetry data for observational purposes. 
The subjects enrolled in the control arm will have a radial arterial catheter inserted for pressure monitoring 
and will have ForeSight Elite oximetry sensors placed on their forehead. The catheter will be connected to a 
FloTrac sensor and to the HemoSphere advanced monitoring platform, however the clinician will not be able 
to visualize the HemoSphere advanced monitoring platform and will not have information from FloTrac and 
ForeSight sensors. The subjects will be treated per standard of care, which includes radial arterial catheter 
monitoring for blood pressure monitoring. 
The study staff may access intraoperative care data from the electronic anesthesia information management 
system. A designated study staff will be present during the procedures to collect data live. At the completion 
of the surgery, the hemodynamic monitoring data will be downloaded from HemoSphere advanced 
monitoring platform. 
Screening 
6.  SCHEDULE OF EVENTS & PROCEDURES 

HPI SMART-BP 
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Protocol # 2021-04 
Page 33 of 68 
CONFIDENTIAL 
 
 
Discharge from the ICU / hospital 
30-Day Follow-up 
 
 
 
The following data will be collected post-operation at Days (POD) 1, 2 & 3: 
• 
Post-Operative Day 1 
o Any fluid and vasoactive medications 
o Obtain post-operative complications 
o Labs: Troponin 
o Post-Op delirium assessment (4AT5 or 3D-CAM17) 
• 
Post-Operative Day 2 
o Obtain post-operative complications 
o Record adverse events 
o Labs: Creatinine and Troponin 
o Post-Op delirium assessment (4AT or 3D-CAM) 
• 
Post-Operative Day 3 
o Obtain post-operative complications 
o Record adverse events 
o Labs: Troponin 
o POMS survey post-operation 
o Post-Op delirium assessment (4AT or 3D-CAM) 
If the subject is discharged prior to any of the above schedule of events, a telephone call is sufficient to 
collect the appropriate required data. 
 
 
The following data will be collected at discharge from the ICU / hospital: 
• 
Obtain post-operative complications 
• 
Record adverse events 
• 
Concomitant Medications: medication that was administered post-operation 
 
 
The following data will be collected at 30 days post-procedure via telephone if the subject is no longer 
in the hospital: 
• 
Obtain post-operative complications 
• 
Record adverse events 
• 
Mortality determination 
• 
WHODAS 2.0 Survey 
DAYS 2-4 (POD 1-3) 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
 
 
 
Table 2: Schedule of Events 
 
Trial Procedure / Exam 
Subject 
Screening 
Pre- 
Procedure 
Procedure 
Post-OP 
Day 1 
Post-OP 
Day 2 
Post-OP 
Day 3 
Discharge 
30-Day Follow 
Up 
(±14 Days) 
Obtain Informed Consent 
X 
Perform Inclusion / Exclusion 
Evaluation 
X 
Obtain Medical History / 
Subject Demographics 1 
0F0F0F0F 
X 
Assign Subject ID 
X 
Assign Trial Arm 
X 
Enter Subject Data into 
Monitor3 
X 
Vital Signs 
X 
Monitoring Duration 
X 
Data download from 
Monitor3 
X 
Obtain Fluid and Vasoactive 
Medication Administration 
Record 2 
1F1F1F1F 
X 
X 
Obtain post-operative 
complications, if applicable 
X 
X 
X 
X 
X 
X 
Labs: Creatinine 4 
X 
X 
Labs: Troponin 
X 
X 
X 
X 
Labs: NT-proBNP 
X 
POMS 5 
X 
NSQIP Surgical Risk 
Assessment5 
X 
Post-Op delirium assessment 
(e.g., 4AT or 3D-CAM)5 
X 
X 
X 
WHODAS 2.05 
X 
Complete eCRFs 
X 
X 
X 
X 
X 
X 
X 
X 
Record Adverse Events, if 
applicable 
X 
X 
X 
X 
X 
X 
Obtain ICU / Hospital 
discharge Information 
X 
X 
Phone Contact 30-day follow 
up / Mortality Determination 
X 
 
 
 
 
1 Medical History / Subject Demographics / Surgical and Clinician Demographics can be obtained prior to procedure, either at the 
screening visit or on the day of procedure. 
2 Can be collected via the hospital record system anytime on the day of procedure or thereafter. 
3 To be conducted for subjects assigned to treatment arm 
4 To be collected on post-op day 1, 2 or 3. 
5 To be collected if data or subject is available. 
Schedule of Events (SoE) 

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Protocol # 2021-04 
Page 35 of 68 
CONFIDENTIAL 
 
 
 
 
The HPI SMART-BP Trial will collect data from up to 1486 subjects at up to 20 study sites across the United 
States. Up to 60 subjects may be included as roll-ins and will be analyzed separately from the pivotal cohort. 
Subjects will be randomly assigned to the interventional or control arms. The maximum number of subjects 
enrolled at each site will not exceed 20% of the total study population. 
A subject will be considered enrolled in the Trial once the subject has signed the informed consent, has been 
assigned a Trial ID, an arterial line with either a FloTrac sensor (control arm) or Acumen IQ sensor (treatment 
arm) has been connected. Subjects may be screened for eligibility and consented on the day of surgery. 
 
Subject participation will include preoperative study eligibility screening and consent, planned surgical 
intervention, Post-Op Day 1-3, ICU, hospital discharge, and 30 days post-procedure. Discontinued subject 
data will be analyzed under intent-to-treat and data will be used for safety and performance analyses. 
 
The subjects enrolled in the treatment arm will have a radial arterial catheter inserted for pressure 
monitoring and will have ForeSight Elite oximetry sensors placed on their forehead. The catheter will be 
connected to an Acumen IQ sensor and to the HemoSphere advanced monitoring platform which includes 
the AcumenTM Hypotension Prediction Index (HPI) feature software. The Acumen HPI software will provide 
clinicians with information and physiological insight regarding the likelihood of a subject trending towards a 
hypotensive event (defined as mean arterial pressure ≤ 65 mmHg for at least one minute). A secondary 
screen with associated hemodynamic parameters is available to the clinicians for additional quantitative 
information regarding the subject’s physiological condition. When the Hypotension Prediction Index (HPI) 
exceeds 85 for two consecutive 20-second updates or reaches 100 at any time, a popup alert will appear on 
the monitor and clinicians can activate the secondary screen to review all hemodynamic parameters. The 
anesthesia team will receive a protocolized hemodynamic management strategy and will determine the 
amount and timing of intravenous fluids and vasopressor or ionotropic drugs to be given to subject. 
Interventions conducted per treatment protocol and/or outside the treatment protocol will be documented 
on the eCRF(s). Clinicians should validate the appropriateness of protocol recommendations, and provide 
treatment based upon their clinical judgment. 
 
The subjects enrolled in the control arm will have a radial arterial catheter inserted for pressure monitoring 
and will have ForeSight Elite oximetry sensors placed on their forehead. The catheter will be connected to a 
FloTrac sensor and to the HemoSphere advanced monitoring platform; however, the clinician will not be 
able to visualize the HemoSphere advanced monitoring platform and will not have information from FloTrac 
and ForeSight sensors. The subjects will be treated per standard of care, which includes radial arterial 
catheter monitoring for blood pressure monitoring. Patients in the control arm will not have a defined MAP 
threshold for hypotension and will not receive protocolized hemodynamic management. The anesthesia 
team will determine the amount and timing of intravenous fluids and vasopressor or inotropic drugs to be 
given to subject. 
Procedure 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
For subjects enrolled in both arms, creatinine values and Surgical Risk Assessment (NSQIP) will be collected 
during the perioperative period. Troponin values and Post-Op delirium assessment (4AT or 3D-CAM) for POD 
1-3, creatinine values for POD 2, POMS survey for POD 3, and 30-day survey will be accessed post 
operatively. 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Primary Outcome Endpoint 
 
 
There will be a formal SAP, separate from this Trial protocol. A formal SAP will be completed prior to 
database lock and the analysis of any Trial endpoints data. The SAP will detail the planned statistical 
analyses. The subsections below summarize the planned analyses. 
 
 
The primary outcome endpoint is to determine if the use of a protocolized strategy using advanced 
hemodynamic monitoring with Hypotension Prediction Index (HPI) software guidance for intraoperative 
hemodynamic management reduces postoperative complication rate in moderate- to high-risk non-cardiac 
surgery. The composite includes MACE (myocardial injury, stroke, non-fatal cardiac arrest, and death), AKI, 
and serious infections (pneumonia, deep and organ space surgical site infections, and sepsis). 
Statistical Analysis Plan (SAP) 
7.  STATISTICAL METHODS 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Analysis Populations 
Analysis Methods 
 
 
 
 
The goal of this study is to assess if the use of Hypotension Prediction Index (HPI) software guidance impacts 
the incidence of postoperative morbidity and mortality in the adult population undergoing moderate-to- 
high-risk noncardiac surgery (with a pressure monitoring with an arterial line). A relative reduction in the 
composite outcome within the treatment arm is expected. For a group sequential analysis, following the 
O'Brien and Fleming methodology, a sample size was calculated for a two-sample comparison of rates (two- 
sided). The hypothesis are as follows: 
H0: p0-p1 ≥0 
H1: p0≠p1 
 
Assuming at least a 25% relative change in rate for the treatment (p1) arm, a type I error (0.05), a power of 
80%, and a reference rate of 0.31 (p0) based on a meta-analysis 6,10,14 , a sample size of 1426 subjects are 
needed. An additional 60 subjects may be included as roll-ins, which results in a total enrollment potential 
of 1486 subjects. 
 
 
Modified Intent-to-treat (mITT) 
Modified Intent-to-treat (mITT) is defined as the study subjects who were exposed to the study product and 
will therefore be included in the effectiveness and safety analysis datasets. All randomized study subjects 
who have satisfied the population criteria will be classified in the designated population and will only be 
included in analyses for which they have available data. The mITT population will also be used to present 
exploratory analyses by the randomized treatment arm. The safety population is defined as all randomized 
subjects who were exposed to the study product; thus, the safety population will therefore be identical to 
the mITT population if all randomized subjects are exposed to the study product. The safety population will 
be used to present the safety summaries by actual treatment received. 
 
Per Protocol Analysis 
A per protocol analysis is defined as a dataset of subjects who completed enrollment as written in the 
protocol, (e.g., No protocol deviations occurred during the non-cardiac surgical procedures). 
 
 
The following z-statistic will be used to judge if the Hypotension Prediction Index (HPI) software can reduce 
postoperative morbidity and mortality: 
𝑝̂0 − 𝑝̂1 − 0 
𝑧 = 
 
 
√(𝑥0 + 𝑥1 ) (1 − 𝑥0 + 𝑥1) ( 1  +  1 ) 
𝑛0 + 𝑛1 
𝑛0 + 𝑛1 
𝑛0 
𝑛1 
Sample Size Justification 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
 
Here 𝑥0 and 𝑥1 are the amount of events that occurred in the reference arm and test arm respectively, thus, 
𝑝̂ = 
𝑥0 , 𝑝̂ = 
𝑥1 are the proportion of events that occurred in the reference arm and test arm, respectively, 
0 
𝑛0 
1 
𝑛1 
𝑛0, 𝑛1 are the number of subjects in reference arm and test arm respectively. The pooled standard error is 
given by √(x0+x1 )(1 − 
x0+x1 )( 1 + 
1 ) . The z-statistic will be calculated using data from the complete 
n0 +n1 
n0 +n1 
n0 
n1 
case population and it will be compared to the critical z-value (𝑧(𝛼′, 𝑛0 + 𝑛1 − 2) to judge if the null 
hypothesis can be rejected. Here 𝛼′ is the adjusted type I error rate (adjusted for interim analysis). 
Moreover, the degree of freedom is given by, 𝑛0 + 𝑛1 − 2. The 95% CI is given by 𝑝̂0 − 𝑝̂1 ± 
𝑧 ′√(𝑥0+𝑥1 )(1 − 𝑥0+𝑥1 )( 1 + 1 ) The other analysis methods are detailed in the statistical analysis plan. 
𝛼 
𝑛0+𝑛1 
𝑛0 +𝑛1 
𝑛0 
𝑛1 
 
 
 
The continuous variables will be evaluated using the parametric two sample t-test (or the Welsh t-test if 
unequal variance or the Wilcox-Mann Whitney test if non-normally distributed) and categorical/binary 
variables will be evaluated using a chi-squared test (Fisher’s exact if low counts). Logistic regression will be 
used to evaluate incidence of AKI with other variables being used as co-variates. Time-to-event variables will 
be evaluated by survival analysis models (Kaplan-Meier or Cox Proportional Hazards). Summary statistics and 
statistical comparison will be presented in tables with point estimates (odds ratios or log odds), standardized 
errors, and 95% CI. There will be no multiplicity adjustment for performing multiple hypothesis tests of 
exploratory outcomes, unless specified otherwise. 
 
Sensitivity analysis including the review of any influence of surgical position, type of anesthesia, tidal volume 
etc., on the primary outcome measure, are specified in the SAP. 
 
The following data will also be explored: 
 
1. Time-to-Adverse Event (Complications) Analysis 
a. Non-Parametric Survival Analysis (KM approach) 
b. Cox Proportional Hazard Model 
c. Mixed effect Cox Proportional Hazard Model 
d. Stratification analysis through applying study sites, gender, race as the stratification factor 
e. Fixed/Mixed effective Poisson regression model applying the count of events as the response 
f. Mixed effective survival model to assess the multiple event cases within patient 
2. Hypotension management analysis 
a. Time from alert event to intervention 
b. % alerts with no intervention 
c. 
Reasons for nonintervention 
d. Amount of hypotension removing nonintervention segments 
e. Agreement analysis; clinical decision vs. treatment algorithm 
f. Overall treatment protocol compliance 
3. Area under the curve AUC MAP under the threshold of 55,65,75 mmHg 
Additional Evaluations 

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Protocol # 2021-04 
Page 40 of 68 
CONFIDENTIAL 
 
 
Planned Interim Analyses 
4. Time Weighted Average (TWA) of intraoperative hypotension (mmHg) 
5. Time in target SVV <13% (for valid SVV readings = no arrythmia) 
6. Time in target CI >2.5 L/min/m15 
7. Postoperative morbidity survey (POMS) on postoperative day 3 
8. Transfusion requirement (mL packed red blood cells) 
9. Amounts of intraoperative crystalloid and colloid and vasoactive drugs; mL 
10. Amount of vasoactive drugs; mg (e.g.: phenylephrine, ephedrine, norepinephrine, epinephrine, 
dobutamine) 
11. Amount of intraoperative intravenous analgesics and sedatives 
12. Brain oxygen saturation – StO2 using ForeSight Elite tissue oximetry system, time in target 
13. Verification of the incidence of the listed postoperative complications may be performed at each site by 
reviewing historic data up to 6 months prior to study initiation 
14. Cost of care 
15. Hospital length of stay 
16. Hospital readmission within 30 days 
 
 
 
Assuming a power of 80% and a relative reduction of at least 25% in the composite score (reference 
proportion=0.31) with three total looks (two interim analysis, one final), the critical values for each time point 
were chosen to preserve an overall type-1 error rate of 0.05. The O'Brien and Fleming methodology was used 
to determine the boundary rule for deciding when to stop the trial prematurely. Futility was included. A relative 
reduction in the composite outcome within the treatment arm is expected. The alpha at each interim and the 
maximum number of observations are chosen so that the overall significance level is the probability of 
detecting the treatment difference under the null hypothesis. The table below shows the critical values: 
 
Analysis 
Information 
Rate 
Effectiveness Boundary 
z-value 
(Upper, Lower) 
Futility Boundary 
z-value 
(Upper, Lower) 
First Interim Analysis 
50% 
(2.96259, -2.96259) 
(0.40273, -0.40273) 
Second Interim 
75% 
(2.35898, -2.35898) 
(1.12741, -1.12741) 
Final Analysis 
100% 
(2.01404, -2.01404) 
(2.01404, -2.01404) 

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CONFIDENTIAL 
 
 
 
 
Edwards will monitor for safety, which includes those potentially associated with the use of Trial devices and 
their components. There may be additional risks and discomforts that are not known at this time. 
Any events associated with the Trial devices will be reported in accordance with the Medical Device 
Reporting (Complaints) regulation (21 CFR Part 803). 
 
Below is a list of general anticipated risks associated with the type of surgeries and procedures, which may 
be conducted as standard of care. 
 
• 
Risks related to transplantation of donor organ: 
o Death 
o Explant of donor organ 
o Hemorrhage 
o Organ transplant failure 
o Respiratory Failure 
o Sepsis/Infection 
• 
Risks related to other surgical or patient factors: 
o 30-day mortality 
o Cardiac arrest 
o Cardiac arrhythmia 
o Hemorrhage 
o Ileus 
o Nausea and vomiting 
o Pneumonia 
o Prolonged Hospital length of stay 
o Prolonged ICU length of stay 
o Pulmonary embolism 
o Sepsis 
o Transfusion need 
o Wound infection 
Anticipated Risks 
8.  RISK ANALYSIS 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Below is a list of anticipated risks that may be associated with the use of the Acumen IQ/FloTrac sensor: 
The vascular access obtained is standard clinical care for the adult population and the addition of the 
Acumen IQ/FloTrac sensor is and is not expected to impose any additional risk to the patient. There is no 
measurable increased infectious risk with the temporary use of the Acumen IQ/FloTrac sensor. 
 
Below is a list of anticipated risks that may be associated with the use of ForeSight Elite oximetry Sensors: 
• 
Allergic reaction to adhesive on sensors 
• 
Skin irritation 
 
In addition to the risks mentioned above, use of the HPI Pressure & Flow Optimization Protocol may lead to 
undertreatment or overtreatment with vasoactive drugs or fluids. 
Under- or overtreatment may result in the following anticipated risks: 
• 
Heart failure 
• 
Profound hypotension 
• 
Hypertension 
• 
Cardiac ischemia 
• 
Tachyarrhythmia 
• 
Bradycardia 

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Protocol # 2021-04 
Page 43 of 68 
CONFIDENTIAL 
 
 
 
 
The HemoSphere advanced monitoring platform, Acumen IQ sensor, FloTrac sensor, ForeSight Elite oximetry 
sensor and Hypotension Prediction Index (HPI) Feature Software have been tested to an established regimen 
of safety and performance testing (as applicable) required prior to use in human subjects in these clinical 
studies. This regimen includes requirements under applicable standards and regulations for packaging, shelf 
life, biocompatibility, microbiology, chemistry, sterility, electrical, mechanical and fatigue testing. 
 
The indications and intended use of the HemoSphere advanced monitoring platform with AcumenTM 
Hypotension Prediction Index (HPI) feature software and Acumen IQ sensor remain unchanged from those 
previously cleared by FDA. 
 
Table 3: Trial Devices and Indication for use 
 
Device 
Indication for use 
HemoSphere Advance 
Monitoring Platform with 
Acumen Hypotension 
Prediction Index 
The Acumen HPI feature software is intended for use in surgical or non-surgical 
patients receiving advanced hemodynamic monitoring. The Acumen HPI feature is 
considered to be additional quantitative information regarding the patient’s 
physiological condition for reference only and no therapeutic decisions should be 
made based solely on the Acumen Hypotension Prediction Index (HPI) parameter. 
Acumen IQ Sensor 
The Acumen IQ sensor is indicated for use in intravascular pressure monitoring. It is 
also indicated for use with the Edwards arterial pressure based cardiac output 
monitoring devices or hardware to measure cardiac output. 
FloTrac Sensor 
The FloTrac sensor is indicated for use in intravascular pressure monitoring. It is also 
indicated for use with the Edwards arterial pressure based cardiac output monitoring 
devices or hardware to measure cardiac output. 
The FloTrac Sensors are cleared for use with the HemoSphere Advanced Monitor with 
HemoSphere Pressure Cable. 
ForeSight Elite oximetry 
Sensor 
The large ForeSight Elite oximetry Sensor is indicated for monitoring of absolute 
regional hemoglobin oxygen saturation of blood under the sensor in individuals at 
risk for reduced flow or no-flow ischemic states. It is intended for use on adults and 
transitional adolescents ≥ 40 kg. 
 
 
Benefits 
There are no guaranteed benefits to Trial participation. However, this will be the first prospective, 
multicenter, interventional, randomized controlled Trial that will highlight the potential effect the 
Hypotension Prediction Index (HPI) plus a treatment protocol has on morbidity and mortality. 
Risk Management 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Severity of an AE 
Relationship of an AE 
 
 
The Investigator and/or Designee(s) will determine whether any adverse events (AEs) have occurred. An 
AE is defined as any untoward medical occurrence in a clinical Trial of a Trial Device regardless of the 
causal relationship of the problem with the device or, if applicable, other Trial treatment or diagnostic 
product(s). Information for AEs with the Trial devices will be collected from the time a subject begins the 
Trial related procedure and/or is exposed to Trial product(s). AEs will also be collected during surgical 
intervention, post intervention, discharge and through the follow-up. AEs may be volunteered by 
subjects, clinicians, elicited from questioning by Investigator and/or Designee(s), or collected via 
observation. When a device or Trial related AE is suspected all available event information and will be 
provided to the Clinical Events Committee. 
Once an AE/SAE/UADE is confirmed as such, event, date of onset, severity, duration, treatment (if 
required), resolution (or ongoing), assessment of seriousness, relationship to Trial procedure and 
relationship to device will be recorded on the appropriate eCRF or SAE Report Form and submitted as 
necessary by the Investigator and/or Designee(s). Any suspected AEs related to the Trial Device or Trial 
procedure must be reported to the Sponsor or Designee within 24 hours of first awareness of the event. 
 
 
The following guidelines will be used to describe the severity of the AE: 
• 
Mild – Event requires minimal or no treatment and do not interfere with the subject’s daily 
activities. 
• 
Moderate – Event results in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Event interrupts a subject’s usual daily activity and may require systemic drug therapy or 
other intervention. Severe events are usually potentially life-threatening or incapacitating. Of 
note, the term “severe” does not necessarily equate to “serious.” 
 
The evaluation of relatedness must consider etiologies such as natural history of the underlying disease, 
concurrent illness, concomitant therapy, Trial-related procedures, accidents, and other external factors. In 
a device Trial, the Trial product(s) must always be suspect. 
 
Causality of relationship to the Trial product(s) will be judged by the Investigator who examines and 
evaluates the subject based on temporal relationship and his/her clinical judgment. Causality of 
relationship will also be reviewed by the Investigator, and independently by a Medical Reviewer, as 
follows: 
Recording and Reporting of Adverse Events 
9.  REPORTABLE EVENTS 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Recording and Reporting of Adverse Device Effects 
Recording and Reporting of Serious Adverse Event 
Recording and Reporting of Serious Adverse Device Effects 
Not related: 
• 
An event is clearly not and cannot be related to the Trial product(s), and/or evidence exists that 
the event is definitely related to another etiology. Note: Reporting of these events to the Sponsor 
or designee within 5 working days of first awareness of the event is not required unless the event 
was related to the Investigational Device or Trial. 
Possibly Related: 
• 
There is some evidence to suggest a causal relationship may exist; however, the event could have 
been produced by another cause (e.g., treatment, condition). Note: Reporting of these events to 
the Sponsor or designee within 5 working days of first awareness of the event is required. 
Related: 
• 
A relationship can be directly attributed to the use of the Investigational Device. Note: Reporting 
of these events to the Sponsor or designee within 24 hours of first awareness of the event is 
required. 
 
 
An adverse device effect (ADE) is defined as an AE related to the use of a Trial medical device. This 
definition includes AEs resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation or operation, or any malfunction of the investigation device. It also includes any 
AE resulting from use error or from intentional misuse of the Trial Device. 
ADEs must be reported to the Sponsor or designee, within 24 hours of first awareness of the event. 
Notification should be done via email, fax, telephone, or direct communication followed by direct entry of 
AE/SAE data into the eCRF. In addition, the Trial site will report confirmed ADEs related to their IRB in 
accordance with the IRB’s/IEC’s requirements. ADEs will also be reported to the FDA, as required. 
 
A serious adverse event (SAE) is defined as an AE that results in any of the following outcomes: death, a 
life-threatening adverse event, inpatient hospitalization, or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect. 
 
A serious adverse device effect (SADE) is an ADE that has resulted in any of the consequences or 
characteristics of a SAE. 
 
SADEs must be reported to the Sponsor or designee, within 24 hours of first awareness of the event. 
Notification should be done via email, fax, telephone, or direct communication followed by direct entry of 
AE/SAE data into the eCRF. In addition, the Trial site will report confirmed SADEs their IRB in accordance 
with the IRB’s/IEC’S requirements. SADEs will also be reported to the FDA, as required. 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Recording and Reporting of Deaths 
Recording and Reporting of Adverse Events Associated with Commercial Components 
 
 
 
Unanticipated adverse device effect (UADE) is defined in 21 CFR 812.3(s) as 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 supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. In contrast, an anticipated adverse device effect is an effect which by its nature, incidence, 
severity, or outcome has been identified in the risk analysis report. 
 
UADEs must be reported to the Sponsor or designee within 24 hours and submitted to the reviewing IRB as 
soon as possible, but in no event later than 10 working days after the Investigator first learns of the effect. 
 
All AEs related to the Trial Device or Trial will be reviewed by the Investigator and/or Designee(s) and 
Sponsor. These AEs will be followed until they are adequately resolved, explained by the Investigator 
and/or Designee(s), until subject has completed follow-up, terminated the Trial early, is lost to follow-up or 
has been withdrawn from the Trial. 
 
 
Events resulting in death during the subject’s enrollment in this Trial are not expected to occur as a result 
of participation in the Trial. In the event of subject death, every reasonable effort should be made to 
obtain a copy of the autopsy report and/or death summary. Information on the date and cause of death 
and its relationship to the Trial device will be determined by the Investigator and/or Designee and 
recorded on the appropriate AE eCRF and submitted on an SAE Report Form as necessary. 
 
 
Any adverse event associated with an FDA cleared component will be recorded as a device complaint and 
reported via the MDR program (21 CFR Part 803). Complaints will also be reported to the IRB in 
accordance with each IRB’s/IEC’s requirements. Device complaints should be reported to the Sponsor as 
soon as the site becomes aware of the complaint. The Sponsor may request further information and 
documentation from the site when complications and/or malfunctions are observed and reported. 
Recording and Reporting of Unanticipated Adverse Device Events 

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CONFIDENTIAL 
 
 
Reporting Adverse Events to the FDA 
Reporting Adverse Events to the Responsible IRB 
Recording and Reporting AE Time Period 
 
 
 
 
Pre-existing medical conditions and symptoms due to pre-existing medical conditions, surgery or 
admission to ICU will not be recorded as adverse events. The admission of a critically ill patient in the 
intensive care unit is commonly due to one or several serious medical conditions and/or a major surgery, 
which may cause changes and abnormalities of blood chemistry, diagnostic and physiological parameters. 
In the event there is a deterioration of a pre-existing medical condition or symptoms due to the use of the 
Trial product(s) or a Trial related procedure, then the review of the event will be initiated, and an AE will 
be recorded if it meets the definition. Any events occurring prior to the exposure to the Trial product(s) or 
Trial related procedure will be recorded as medical history. 
 
Confirmed UADEs will be evaluated by the Medical Reviewer. The FDA, all participating principal 
investigators, and their reviewing IRBs/IECs will be informed no later than 10 working days after Edwards 
Lifesciences or designee first becomes aware of the effect. 
 
 
In accordance with applicable policies of the IRB, the Investigator will report, any observed or volunteered 
confirmed adverse event that is determined to be (1) unexpected; (2) related or possibly related to the 
research; and/or (3) involves increased or greater risk of harm to participant(s) or others than was 
previously known or approved by the IRB. AE reports will be submitted to the IRB in accordance with the 
IRB policies and procedures. 
 
Confirmed UADEs will be evaluated, and the reviewing IRB will be informed of the results of the Trial no 
later than 10 working days after Edwards or when the designee first becomes aware of the effect. 
 
At each Trial visit, the Investigator and/or Designee(s) will inquire about the occurrence of 
AE/SAEs/ADEs/SADEs/UADEs since the last visit. AE/SAEs/ADEs/SADEs/UADEs will be followed until they 
are adequately resolved, explained by the Investigator and/or Designee(s), until subject has completed 
follow-up, terminated the Trial early, is lost to follow-up or has been withdrawn from the Trial. 
Recording and Reporting of Pre-Existing Conditions 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Data Safety Monitoring Board 
 
 
The role of the Medical Reviewer is to adjudicate pre-specified adverse events in a consistent and unbiased 
manner throughout the course of the trial. The Medical Reviewer is an independent, qualified physician 
whose medical specialty may include anesthesiology. The Medical Reviewer will adjudicate serious adverse 
events that are possibly related to the surgical procedure or the Acumen™ Hypotension Prediction Index 
(HPI) Feature Software or death. The Medical Reviewer will notify the site or Sponsor if additional potential 
adverse events are identified during the adjudication process. 
 
An independent (4-Member) Data Safety Monitoring Board (DSMB) will be established to oversee the Trial 
outcome. Members of the DSMB must be free of significant conflicts of interest ( e.g., Financial, intellectual, 
professional, or regulatory), or measures should be in place to minimize perceived conflict of interest. 
Members of the DSMB are also experts in all scientific disciplines needed to interpret the data and ensure 
Trial participant safety, including an independent biostatistician. The DSMB will meet via teleconference a 
minimum of semiannually or at least two (2) times over the course of the Trial. The DSMB manual of 
operation (MOP) will be maintained by the Sponsor as part of the clinical Trial project plan. The DSMB MOP 
will outline membership and voting procedures as well as DSMB Meeting documentation and 
communication. The DSMB meetings will include an open session where the Sponsor will present Trial 
updates, review trends for device malfunctions, protocol deviations and subject withdrawal reasons to 
communicate Trial progress. The Investigators may attend the open session. 
 
In addition to the open portion of the DSMB meetings, there will be closed sessions that will only be 
attended by the DSMB members. 
The DSMB will perform the following activities during the closed session of the meetings: 
• 
Assess primary safety endpoint 
• 
Assess participant risk versus benefit, performance of Trial sites, and other factors that can affect 
Trial safety outcome 
• 
Review factors external to the Trial when interpreting the data, such as scientific or therapeutic 
developments that may have an impact on the safety of the participants or the ethics of the Trial 
• 
Make recommendations to Edwards Lifesciences, IRB, and investigators concerning continuation 
or conclusion of the Trial based solely on safety evaluation 
• 
Protect the confidentiality of the Trial data and the results of monitoring 
 
To mitigate any potential release of Trial results, the analysis of safety endpoint will be led by the 
independent biostatistician serving on the DSMB. The biostatistician will have no contact with the Sponsor 
or any Trial sites. Furthermore, the identification of the other DSMB members will not be shared with the 
sites during the conduct of the Trial. 
Medical Reviewer 
10. INDEPENDENT SAFETY COMMITTEES 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
 
Stopping Rules 
Continuation or discontinuation of the trial will be based upon the DSMB’s evaluation of trial safety. 
This study will be stopped prior to its completion if: (1) the intervention is associated with adverse events 
that call into question the safety of the intervention, (2) any new information becomes available during the 
trial that necessitates stopping the trial and/or (3) Based on the results of interim analysis. 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Storage 
Device Accountability 
Return of Devices 
 
 
A packing list will accompany all device shipments. This list will include the inventoried product with receipt 
date and investigator and/or designee signature. 
 
 
The HemoSphere advanced monitoring platform and all Trial product(s) shall be stored in a secure and clean 
area complying with the storage instructions provided in the labeling. 
 
The Investigator and/or delegated-Trial personnel shall keep records documenting the receipt, use, return, 
and disposal of the devices. Only the Investigator, delegated-Trial Personnel and/or designee(s) (i.e., 
Assisting Clinician(s)) may use the devices. The Investigator will supervise the use of the devices in Trial 
subjects. The Trial site shall account for which system/device was used for which subject as well as for the 
return of the system/device. 
 
 
The Principal Investigator or designee is responsible for returning the unused product back to the Sponsor. 
Receipt of Device Supplies 
11. RECEIVING, STORAGE, AND RETURN OF DEVICES 

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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
 
 
Information about Trial subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). Consistent with these regulations, a 
signed authorization will be obtained that informs each subject of the following: 
• 
What protected health information (PHI) will be collected from subjects in this Trial 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI 
No subject demographic data or medical information will be used or shared outside the Sponsor and site 
staff unless an unanticipated adverse device effect (UADE) is reported. If a UADE is reported, all efforts will 
be made to keep subject information confidential. The Sponsor is dedicated to maintaining the 
confidentiality and privacy of subjects who volunteer to participate in the Trial. The Trial Investigator and 
the Trial site personnel are responsible for maintaining confidentiality throughout the clinical Trial. The 
Sponsor and Sponsor designated Trial personnel will have access to the data collected. The hard copies of 
the source documentation are to be maintained in a secure area with limited access. 
 
To protect subject confidentiality, the subject’s name must not appear anywhere on CRFs, or supporting 
documentation removed from the site. All subject identifiers (e.g., social security number) will be 
obliterated from all photocopies of source documents that have been removed from the site. All Trial 
documents will identify the subject by a subject Trial identification number and Protocol number assigned 
by the Sponsor (if applicable). 
In the event that a subject revokes authorization to collect or use PHI, the Investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization. For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e., that the subject is alive) at the end of their scheduled Trial period. 
12. CONFIDENTIALITY AND PRIVACY 

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13. DATA HANDLING AND RECORD KEEPING 
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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
Data Entry Timelines 
 
 
Source data are all information, original records of clinical findings, observations, or other activities in a Trial 
necessary for the reconstruction and evaluation of the Trial. Source data are contained in source 
documents. Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, source worksheets that have been certified as source, and records kept at the pharmacy, at the 
laboratories, and at medical-technical departments involved in the Trial. 
Required data for this Trial are to be recorded in the subject’s file and/or via eSource and/or on worksheets, 
certified as source, for source documentation and data verification. Some of the source documentation 
generated during the Trial may also be the electronic data from the Monitor, laboratory data, or printout 
from Radiometer and YSI. Data may also be entered directly onto the eCRF during the visit. Because of the 
potential for errors, inaccuracies, and illegibility in transcribing data onto eCRFs, the Investigator must 
permit inspection of source documents by the Sponsor, and inspection by local and regulatory authorities. 
 
 
It is recommended that electronic case report forms (eCRFs) be completed within 24 hours of data 
availability, but not more than 10 working days after completion of assessments. 
Source 

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Protocol #2021-04 
14. 
CHANGES TO THE PROTOCOL 
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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
 
Changes to the research covered by this protocol must be implemented by formal protocol amendment. All 
amendments to the protocol must be initiated by the Sponsor. 
Protocol amendments must not be implemented without prior IRB approval. Documentation of amendment 
approval by the Investigator and IRB or IEC must be provided to the Sponsor or its authorized representative. 
When the change(s) involve only logistic or administrative aspects of the Trial, the IRB only needs to be 
notified. 

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15. 
PROTOCOL DEVIATION 
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Protocol # 2021-04 
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CONFIDENTIAL 
 
 
 
Any deviations from the protocol will be documented on the protocol deviation eCRF. The Investigator/or 
Designee shall be responsible for the reporting of any deviations deemed reportable to the IRB. 
Deviations shall be reported to the Sponsor, regardless of whether they are medically justifiable, pre-approved 
by the sponsor, or taken to protect the subject in an emergency. Subject-specific deviations will be reported 
on the appropriate eCRF. 
 
Non-subject specific deviations (e.g., unauthorized use of a device outside the Trial, etc.) will be reported in 
writing. The investigator will also adhere to procedures for reporting Trial and subject specific deviations to 
their IR/IEC in accordance with their specific IRB’s/ IEC’s reporting policies and procedures. 

HPI SMART-BP 
Protocol #2021-04 
16. DATA COLLECTION METHODS 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
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of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 55 of 68 
CONFIDENTIAL 
 
 
 
Trial data will be captured utilizing electronic Case Report Forms (eCRFs) including the 30-day follow-up call 
as well as downloaded files captured directly via the use of the HemoSphere advanced monitor. Data collected 
from the HemoSphere advanced monitor will be downloaded at the end of each catheterization procedure 
and stored on a USB stick. USBs will be stored in a secure location at the site, accessible only to Trial site 
personnel. The HemoSphere data on USBs may be shipped to the Sponsor at any point in time of the Trial per 
the request of the Sponsor. 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 56 of 68 
CONFIDENTIAL 
 
 
 
17. RECORD RETENTION 
 
It is the Investigator’s responsibility to retain Trial essential documents during the investigation and for a 
minimum period of two (2) years after the investigation is terminated or completed, or the records are no 
longer required for the purposes of supporting a premarket approval application or a notice of completion of 
a product development protocol. These documents should be retained for a longer period if required by an 
agreement with the Sponsor. In such an instance, it is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 57 of 68 
CONFIDENTIAL 
 
 
Trial Reports 
 
 
Edwards will maintain accurate, complete, and current records relating to the conduct of the Trial. 
Records to be maintained by Edwards Lifesciences and the Trial site include but are not limited to: 
• 
Trial protocol and all amendments, if applicable 
• 
IRB approved Informed Consent 
• 
IRB approval letter, including informed consent form 
• 
IRB membership list, or alternative notification of IRB being duly constituted or Department of Health 
and Human Services Multiple Projects Assurance Number 
• 
IRB correspondences 
• 
Trial training logs 
• 
Device accountability records 
• 
Required reports, if applicable 
The following records must be maintained for each subject enrolled in the Trial: 
• 
Signed informed consent form 
• 
All completed eCRFs 
• 
Supporting documentation of any adverse events 
 
 
Designated site personnel shall prepare and submit the following accurate and complete reports in a timely 
manner to the IRB and FDA, if applicable: 
• 
Report of an Unanticipated Adverse Device Effects (UADEs) as soon as possible, but in no event later 
than 10 working daysafter the first awareness of the event. After an internal evaluation, Edwards shall 
report the results of such evaluation to FDA and to all reviewing IRBs/IECs and participating 
investigators within 10 working days after receipt of notice of the effect. 
• 
Withdrawal of IRB approval within 5 working days to Edwards. Thereafter, Edwards shall notify FDA 
and all reviewing IRBs/IECs and participating investigators of any withdrawal of approval of an 
investigation or a part of an investigation by a reviewing IRB within 5 working days after receipt of the 
notification of withdrawal of approval. 
• 
Progress reports will be submitted to the IRB as required and no less than yearly. 
• 
Deviation from the Trial protocol to protect the subject’s life or physical well-being in an emergency 
will be reported to Edwards as soon as possible, but in no event later than 5 working days after the 
emergency occurred. Non-emergency deviations will be reported to the IRB, as required. If deviations 
may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA 
and IRB shall be notified. 
• 
A final written report is submitted to the IRB within 6 months after completion or termination of the 
Trial as required. 
• 
Upon request by the reviewing IRB or FDA, Edwards will provide accurate, complete, and current 
information about any aspect of the investigation. 
• 
Use of the Trial device without informed consent will be reported to Edwards and the IRB within 5 
working days after the use occurs. Thereafter, Edwards shall notify FDA within 5 days of receipt of 
notice. 
Trial Records 
18. TRIAL DOCUMENTATION 

HPI SMART-BP 
Protocol #2021-04 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
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Protocol # 2021-04 
Page 58 of 68 
CONFIDENTIAL 
 
 
 
 
 
 
Edwards will utilize an electronic regulatory binder to maintain required Trial documentation including 
applicable correspondences during the course of the Trial. 
Communication Procedures 

HPI SMART-BP 
Protocol #2021-04 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
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of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 59 of 68 
CONFIDENTIAL 
 
 
Trial Monitoring Plan 
 
 
The Trial site(s) for this Trial will be pre-screened by the Sponsor. The Principal Investigator will be 
selected based on their training and experience with this type of research activity and available subject 
population. The Sponsor will provide the Investigator with information, Trial specific training, and supplies 
necessary to conduct the Trial. 
 
 
A Monitoring Plan will be created to address monitoring arrangements and the extent of source data 
verification. A Trial monitor will be assigned to monitor the progress of the Trial by the Sponsor. The Trial 
monitor may be either an employee of the Sponsor or contracted. The Trial monitor will be responsible for 
reviewing eCRFs and monitoring the Trial site routinely to observe Trial progress and to verify that the Trial 
is conducted, and data are generated, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements. The Investigator must permit inspection of the source documents, regulatory 
binders and other Trial related documents provided by the Sponsor. 
Trial monitoring visits will be scheduled throughout the duration of the Trial between the Trial monitor and 
the Investigator and/or Designee at a mutually convenient and available time. These visits will assure that 
the facilities are still acceptable, the Protocol and investigational plan are being followed, the IRB has been 
notified of approved Protocol changes as required, complete records are being maintained, appropriate 
timely reports have been made to the Sponsor and the IRB, device and device inventory are secure and the 
Investigator is carrying out all agreed activities. Any personnel changes must be reported to the Trial 
monitor immediately. 
All eCRFs will be maintained in a validated EDC system and data anomalies, missing data, or unclear data 
will be queried as necessary throughout the Trial for clarification/resolution by the Principal Investigato r or 
delegated-site personnel. 
Interim Monitoring Activities 
The Sponsor has the obligation to monitor the conduct of this Trial to ensure that the Trial is conducted in 
accordance with the protocol, Edwards Lifesciences procedures and 21 CFR 812.46 Monitoring 
Investigations. 
 
Interim monitoring visits (onsite or remote) will be conducted to evaluate the progress of the Trial, verify 
the rights, well-being, and protection of the patients, and verify that the reported clinical Trial data is 
accurate, complete, and verifiable from the electronic medical records and source documents. Monitoring 
visits will be made in accordance with the Monitoring Plan. 
Site Selection 
19. TRIAL MONITORING, AUDITING, AND INSPECTING 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
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of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 60 of 68 
CONFIDENTIAL 
 
 
Auditing and Inspecting 
 
Site Close-Out Visit 
The Investigator will be notified in writing upon termination or completion of the Trial. The Sponsor 
retains the right to suspend or prematurely terminate this clinical investigation at any time. Upon 
completion or premature termination of the Trial, the Trial monitor will perform a close-out visit. 
A site will be considered closed when the following criteria are met: 
• 
Last subject completes 30-day follow-up 
• 
All data queries are resolved 
• 
A site closeout visit is completed 
• 
The IRB is notified in writing of site and Trial closure in accordance with their requirements 
 
In the event that audits are initiated by the Sponsor or national/international regulatory authorities, the 
Investigator shall allow access to the original medical records and provide all requested information, as 
applicable. The Investigator will permit Trial-related monitoring, audits, and inspections by the Research 
Quality Assurance Office, IRB, the Sponsor, and government regulatory bodies, of all Trial related documents 
(e.g., source documents, regulatory documents, data collection instruments, Trial data etc.). The 
Investigator will ensure the capability for inspections of applicable Trial-related facilities (e.g., pharmacy, 
diagnostic laboratory, etc.). 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 61 of 68 
CONFIDENTIAL 
 
 
 
 
Edwards retains the right to temporarily suspend or prematurely terminate this Trial at any time if there is 
sufficient reasonable cause. Written notification, documenting the reason for Trial suspension or termination, 
will be provided by the Sponsor to Principal Investigator and regulatory authorities. If the Trial is prematurely 
terminated or suspended, the Principal Investigator will promptly inform Trial subjects, and the IRB, and will 
provide the reason(s) for the termination or suspension. 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or when so instructed 
by the IRB or regulatory authorities, Edwards shall suspend the Trial while the risk is assessed by the Data 
Safety Monitoring Board (DSMB). Edwards shall terminate the clinical investigation if an unacceptable risk is 
confirmed. 
20. 
TRIAL EARLY TERMINATION 

HPI SMART-BP 
Protocol #2021-04 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 62 of 68 
CONFIDENTIAL 
 
 
 
 
The Trial may only commence once IRB approval and regulatory approval, as applicable, are received. This 
Trial will be conducted in compliance with the Protocol approved by the IRB, the relevant federal 
regulations, and IRB policies and procedures and according to Good Clinical Practice standards. 
 
The Investigator shall ensure that all work and services described herein, or incidental to those described 
herein, shall be conducted in accordance with the highest standards of medical and clinical research practice 
and the applicable regulations. The Investigator will provide copies of the current Trial Protocol to all Trial 
site personnel responsible for Trial conduct. 
As the Sponsor of this clinical Trial, Edwards Lifesciences has the overall responsibility for the conduct of the 
Trial, including assurance that the Trial meets the regulatory requirements of the pertinent regulatory 
agencies. Edwards Lifesciences will also ensure compliance with the signed clinical agreement, the Protocol, 
the requirements of applicable regulations, and any conditions of Trial approval by the IRB. 
The Sponsor may transfer Trial related duties and functions to a CRO. Transferred duties and functions will 
be specified in a written agreement. Ultimate responsibility for the quality and integrity of the Trial resides 
with the Sponsor. 
Ethical and Scientific Conduct of the Clinical Research Trial 
21. ETHICS 

HPI SMART-BP 
Protocol #2021-04 
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 63 of 68 
CONFIDENTIAL 
 
 
 
 
Appropriate financial disclosures will be obtained from all Principal Investigators and Sub-Investigators and 
additional personnel listed on the Statement of the Investigator. The Investigator will provide sufficient and 
accurate financial disclosure information to the Sponsor prior to Trial start-up, and again during the course of 
the trial. The Principal Investigators and Sub-Investigators shall promptly update the Sponsor if any relevant 
changes occur during the course of the investigation. 
22. FINANCIAL DISCLOSURES 

HPI SMART-BP 
Protocol #2021-04 
23. CONFLICT OF INTEREST POLICY 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 64 of 68 
CONFIDENTIAL 
 
 
 
The independence of this Trial from any actual or perceived influence is critical. Therefore, any actual conflict 
of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this Trial 
will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The Sponsor requires that all conflicts of interest be disclosed and will establish a 
mechanism for the management of all reported dualities of interest. 

HPI SMART-BP 
Protocol #2021-04 
24. PUBLICATIONS 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 65 of 68 
CONFIDENTIAL 
 
 
 
At the conclusion of the Trial, a manuscript may be prepared for publication in a scientific journal. The Sponsor 
reserves the right to review any manuscripts prior to submission. The Trial will be entered into a 
clinicaltrials.gov. 

HPI SMART-BP 
Protocol #2021-04 
25. ACRONYMS AND ABBREVIATIONS 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
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of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 66 of 68 
CONFIDENTIAL 
 
 
 
Acronym 
Entire Word 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ASA 
American Society of Anesthesiologists 
BP 
Blood Pressure 
CI 
Cardiac Index 
CO 
Cardiac Output 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
GCP or gCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HPI 
Hypotension Prediction Index 
HR 
Heart Rate 
Hr 
Hour 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
KDIGO 
Kidney Disease: Improving Global Outcomes 
MI 
Myocardial injury 
MINS 
Myocardial Injury after Noncardiac Surgery 
mL 
Milliliters 
mITT 
Modified Intent-to-Treat 
N 
Total Sample Size 
NCT 
National Clinical Trial 
NSQIP 
National Surgical Quality Improvement Program 
PI 
Principal Investigator 
POD 
Post-Operative Day 
POM 
Postoperative morbidity survey 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
StO2 
Peripheral tissue oxygen saturation 
Sub-I 
Sub-Investigator 
SV 
Stroke Volume 
SVI 
Stroke Volume Index 
SVV 
Stroke Volume Variation 
SVR 
Systemic Vascular Resistance 
UADE 
Unanticipated Adverse Device Effect 
3D-CAM 
3-Minute Diagnostic Interview for Confusion Assessment Method defined Delirium 
4AT 
4 A's Test 

HPI SMART-BP 
Protocol #2021-04 
26. REFERENCES 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 67 of 68 
CONFIDENTIAL 
 
 
 
1. American College of Surgeons National Surgical Quality Improvement Program, 
https://riskcalculator.facs.org/RiskCalculator/. 
2. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of 
innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of 
Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644-1655. 
3. Calvo-Vecino, J. M., Ripolles-Melchor, J., Mythen, M. G., Casans-Frances, R., Balik, A., Artacho, J. P., 
Martinez-Hurtado, E., Serrano Romero, A., Fernandez Perez, C., Asuero de Lis, S., & Group, F. T. I. (2018). 
Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk 
surgical patients: a multicentre randomised controlled trial (FEDORA trial). Br J Anaesth, 120(4), 734- 
744. https://doi.org/10.1016/j.bja.2017.12.018 
4. Duceppe, E., et al., Association between high-sensitivity troponin I and major cardiovascular events after 
non-cardiac surgery (abstrract). Journal of the American College of Cardiology, 2020. 75(11). 
5. 4AT. (n.d.). Retrieved from https://www.the4at.com/. 
6. Futier, E., Lefrant, J. Y., Guinot, P. G., Godet, T., Lorne, E., Cuvillon, P., Bertran, S., Leone, M., Pastene, B., 
Piriou, V., Molliex, S., Albanese, J., Julia, J. M., Tavernier, B., Imhoff, E., Bazin, J. E., Constantin, J. M., 
Pereira, B., Jaber, S., & Group, I. S. (2017). Effect of Individualized vs Standard Blood Pressure 
Management Strategies on Postoperative Organ Dysfunction Among High-Risk Patients Undergoing 
Major Surgery: A Randomized Clinical Trial. JAMA, 318(14), 1346-1357. 
https://doi.org/10.1001/jama.2017.14172 
7. Grocott, M.P.W., Browne, J.P., Van der Meulen, J., Matejowsky, C., Mutch, M., Hamilton, M.A., Levett, 
D.Z.H., Emberton, M., Haddad, F.S. and Mythen, M.G. (2007) The Postoperative Morbidity Survey was 
validated and used to describe morbidity after major surgery. Journal of Clinical Epidemiology, 60 (9), 
919-928. (doi:10.1016/j.jclinepi.2006.12.003). (PMID:17689808) 
8. JE., G. A. a. H. Overview of the circulation: Medical physics of pressure, flow, and resistance. In E. S. 
Elsevier (Ed.), Textbook of Medical Physiology (11th edition ed., pp. 161–170). 
9. Khwaja, A., KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract, 2012. 120(4): 
p. c179-84. 
10. Maheshwari, K., Shimada, T., Yang, D., Khanna, S., Cywinski, J. B., Irefin, S. A., Ayad, S., Turan, A., 
Ruetzler, K., Qiu, Y., Saha, P., Mascha, E. J., & Sessler, D. I. (2020). Hypotension Prediction Index for 
Prevention of Hypotension during Moderate- to High-risk Noncardiac Surgery. Anesthesiology, 133(6), 
1214-1222. https://doi.org/10.1097/ALN.0000000000003557 
11. Meng, L., Yu, W., Wang, T., Zhang, L., Heerdt, P. M., & Gelb, A. W. (2018). Blood Pressure Targets in 
Perioperative Care. Hypertension, 72(4), 806-817. 
https://doi.org/10.1161/HYPERTENSIONAHA.118.11688 
12. Molnar Z, Benes J, Saugel B. Intraoperative hypotension is just the tip of the iceberg: a call for 
multimodal, individualised, contextualised management of intraoperative cardiovascular dynamics. Br J 
Anaesth. 2020 Oct;125(4):419-423. doi: 10.1016/j.bja.2020.05.048. Epub 2020 Jul 18. 
13. Muller, H. H., & Schafer, H. (2001). Adaptive group sequential designs for clinical trials: combining the 
advantages of adaptive and of classical group sequential approaches. Biometrics, 57(3), 886-891. 
https://doi.org/10.1111/j.0006-341x.2001.00886.x 

HPI SMART-BP 
Protocol #2021-04 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC. IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Acumen, Acumen IQ, FloTrac, and ForeSight Elite oximetry Sensor are trademarks 
of Edwards Lifesciences Corporation. 
Protocol # 2021-04 
Page 68 of 68 
CONFIDENTIAL 
 
 
14. Pearse, R. M., Harrison, D. A., MacDonald, N., Gillies, M. A., Blunt, M., Ackland, G., Grocott, M. P., Ahern, 
A., Griggs, K., Scott, R., Hinds, C., Rowan, K., & Group, O. S. (2014). Effect of a perioperative, cardiac 
output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a 
randomized clinical trial and systematic review. JAMA, 311(21), 2181-2190. 
https://doi.org/10.1001/jama.2014.5305 
15. Rodseth RN, Biccard BM, Le Manach Y, Sessler DI, Lurati Buse GA, Thabane L, Schutt RC, Bolliger D, Cagini 
L, Cardinale D, Chong CP, Chu R, Cnotliwy M, Di Somma S, Fahrner R, Lim WK, Mahla E, Manikandan R, 
Puma F, Pyun WB, Radovic M, Rajagopalan S, Suttie S, Vanniyasingam T, van Gaal WJ, Waliszek M, 
Devereaux PJ: The prognostic value of pre-operative and post-operative B-type natriuretic peptides in 
patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B- 
type natriuretic peptide: a systematic review and individual patient data meta-analysis. J Am Coll Cardiol 
2014; 63: 170-80 
16. Schneck E, Schulte D, Habig L, Ruhrmann S, Edinger F, Markmann M, Habicher M, Rickert M, Koch C, 
Sander M. Hypotension Prediction Index based protocolized haemodynamic management reduces the 
incidence and duration of intraoperative hypotension in primary total hip arthroplasty: a single centre 
feasibility randomised blinded prospective interventional trial. J Clin Monit Comput. 2020 
Dec;34(6):1149-1158. doi: 10.1007/s10877-019-00433-6. Epub 2019 Nov 29. PMID: 31784852. 
17. 3D-CAM. (2021). American Geriatrics Society. https://help.agscocare.org/chapter- 
abstract/chapter/H00101/H00101_PART001_006 
18. Thygesen, K., et al., Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol, 2018. 
19. Üstün, T. B., & World Health Organization. (2010). Measuring health and disability: Manual for WHO 
Disability Assessment Schedule WHODAS 2.0. Geneva: World Health Organization. 
20. Wesselink, E. M., Kappen, T. H., Torn, H. M., Slooter, A. J. C., & van Klei, W. A. (2018). Intraoperative 
hypotension and the risk of postoperative adverse outcomes: a systematic review. Br J Anaesth, 121(4), 
706-721. https://doi.org/10.1016/j.bja.2018.04.036 
21. Wijnberge, M., Geerts, B. F., Hol, L., Lemmers, N., Mulder, M. P., Berge, P., Schenk, J., Terwindt, L. E., 
Hollmann, M. W., Vlaar, A. P., & Veelo, D. P. (2020). Effect of a Machine Learning-Derived Early Warning 
System for Intraoperative Hypotension vs Standard Care on Depth and Duration of Intraoperative 
Hypotension During Elective Noncardiac Surgery: The HYPE Randomized Clinical Trial. JAMA, 323(11), 
1052-1060. https://doi.org/10.1001/jama.2020.0592 

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Title 
Statistical Analysis Plan for HPI SMART-BP Trial 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Protocol Title: 
Hypotension Prediction Index Software Guided Hemodynamic Management 
for Noncardiac Surgery Patients - Blood Pressure 
Protocol Number: 
2021-04 
SAP Version: 
A 
SAP Date: 
May 11, 2022 
 
 
 
 
 
 
 
CONFIDENTIAL 

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Revision Date: May 11, 2022 
Rev 
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For Use Only by 
Affiliates of 
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Page 2 of 19 
Title 
Statistical Analysis Plan for HPI SMART-BP Trial 
TABLE OF CONTENTS 
1. 
INTRODUCTION 
4 
2. 
STUDY DESIGN 
4 
2.1 
Study Objectives 
4 
2.2 
Overall Study Design and Plan 
4 
2.3 
Sample Size Consideration 
5 
2.4 
Randomization and Blinding 
7 
3. 
STUDY ENDPOINT 
7 
3.1 
Primary Effectiveness Endpoint 
7 
3.2 
Exploratory Analysis Datapoints 
7 
4. 
ANALYSIS POPULATIONS 
8 
4.1 
Modified Intent-to-treat (mITT) 
8 
4.2 
Full Analysis Population (FAS) 
9 
4.3 
Per Protocol Population (PP) 
9 
4.4 
Complete (Evaluable) Case Population (CC) 
9 
4.5 
Roll-in Subject 
9 
4.6 
Screen Failures 
9 
5. 
DEFINITIONS 
9 
5.1 
Analysis Dates and Days 
9 
5.2 
Analysis Window 
9 
6. 
DATA AND ANALYSIS CONVENTIONS 
10 
6.1 
General Conventions 
10 
6.2 
Handling of Missing Data 
10 
7. 
SUMMARY OF BASELINE INFORMATION 
11 
7.1 
Patient Enrollment and Accountability 
11 
7.2 
Demographics and Baseline Characteristics 
11 
7.3 
Medical History and Prior Intervention 
11 
7.4 
Baseline Risk Assessments 
12 
7.5 
Procedural Information 
12 
8. 
STATISTICAL ANALYSIS OF STUDY ENDPOINTS 
12 
8.1 
Primary Effectiveness Endpoint 
12 
8.2 
Exploratory Evaluations 
13 
8.3 
Outliers 
13 
8.4 
Sensitivity Analysis 
13 
9. 
ANALYSIS OF SAFETY 
14 
9.1 
Deaths 
14 
9.2 
Adverse Events 
14 
10. CHANGES FROM PROTOCOL SPECIFIED ANALYSES 
14 
11. REFERENCES 
15 
12. APPENDIX 
16 
12.1 Alternative Computation of the Reference 
16 
12.2 Fleiss’s Inverse Variance 
17 
12.3 Time Weighted Average (TWA) Computation 
18 
13. PEER REVIEW REQUEST, PER SAP INSTRUCTION (DOC-0089205) 
19 

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Statistical Analysis Plan for HPI SMART-BP Trial 
Glossary of Terms 
 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
AKI 
Acute kidney injury 
AUC 
Area Under Curve 
Alpha (α) 
Type I error 
𝛼′ 
Adjusted type I error 
Beta (β) 
Type II error 
CC 
Complete case population 
CEC 
Clinical Events Committee 
CI 
Confidence Intervals 
CSR 
Clinical study report 
dpt 
Disposable Blood Pressure Transducer 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ES 
Effect Size 
ESKD 
End Stage Kidney Disease 
GCP 
Good Clinical Practice 
GSD 
Group Sequential Design 
H0 
Null hypothesis 
H1 
Alternative hypothesis 
HPI 
Hypotension Prediction Index 
IRB 
Institutional Review Board 
KDIGO 
Kidney Disease Improving Global Outcomes 
MACE 
Major Adverse Cardiovascular Events 
MAP 
Mean Arterial Pressure 
mITT 
Modified Intention-To-Treat 
MINS 
Myocardial Injury After Noncardiac Surgery 
MOCA 
Montreal Cognitive Assessment 
POMS 
Postoperative Morbidity Survey 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
TWA 
Time weighted average 

 
 
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Statistical Analysis Plan for HPI SMART-BP Trial 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the analysis of data collected 
within the scope of Edwards Lifesciences’s Protocol 2021-04, Hypotension Prediction Index Software Guided 
Hemodynamic Management for Noncardiac Surgery Patients-Blood Pressure Trial and provides detailed instructions as to 
how clinical data analysis will be performed. 
All statistical analysis will be performed using SAS 9.4 or later version. Results obtained from the analyses specified in the 
SAP will become the basis of the clinical study report (CSR) for this protocol. Any deviations from the SAP must be 
documented in the CSR. 
2. 
STUDY DESIGN 
2.1 
Study Objectives 
The primary objective of this study is to evaluate the benefit of a protocolized blood pressure management strategy that 
utilizes a HPI along with a comprehensive advanced hemodynamic assessment to reduce a composite of postoperative 
complications in patients undergoing non-cardiac surgery. The study population is subjects ≥ 18 years of age undergoing 
moderate-to-high-risk non-cardiac surgery with pressure monitoring with an arterial line. 
2.2 
Overall Study Design and Plan 
This is a multicenter, interventional, randomized clinical study with treatment and control arms focusing on intraoperative 
hemodynamic management with or without hypotension prediction index software guidance. A noncardiac surgery 
patient will be enrolled in the study once the subject has signed the informed consent form, has been assigned a study 
identification number, an arterial line has been placed and the subject is randomized to the treatment or control arm. In 
The subjects enrolled in the treatment arm will have a radial arterial catheter inserted for pressure monitoring. The 
catheter will be connected to an Acumen IQ sensor and to the HemoSphere advanced monitoring platform which includes 
the Acumen™ Hypotension Prediction Index (HPI) feature software. In the control arm, the physician will use standard of 
care (with a FloTrac sensor) management per physician judgement. Section 5 in study protocol lists all inclusion/ exclusion 
criteria used to screen and enroll study patients. Section 4 of the protocol details the trial design. 
An adapted group sequential design will be utilized for this clinical study, and to determine stopping rules, or to re- 
estimate the sample size by interim analysis outcomes [10, 12, 14, 17]. Adapted group sequential study design allows for one or 
more planned interim analyses when a prespecified stopping criteria is chosen. If the first interim analysis outcomes 
provide evidence for the necessity to enroll more patients, study sample size will be reassessed to determine the new 
appropriate sample size [1,10]. When there is sufficient evidence from study data collected at present stage in addition to 
the data collected from previous study stage, the clinical trial could be stopped early for already achieving the study 
objectives. A type I error (𝛼) spending function will be used to design stopping boundaries for effectiveness, while allowing 
flexibility in how many interim analyses are designed, and at what time point they are conducted [4]. The methodology 
from O'Brien, Harrington, and Fleming [16] will be used to determine the effectiveness stopping criteria for prespecified 
first interim analysis, the secondary interim analysis, and the final analysis with 50%, 75%, and 100% information 
respectively. Many literatures proposed different methodologies from weighted combining test statistics to weighted 
combining p value from interim analyses to preserve type I error (𝛼). The O’Brien-Fleming methodology, the conservative 
approach, spend little type I error (𝛼) at the time of interim analyses and lead to boundary values at the final stage that 
 
 
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I Statistical Analysis Plan for HP/ SMART-BP Trial 
are close to those from fixed sample designls, 161. The O'Brien-Fleming formulae (to preserve the familywise error rate, a) is 
denoted as follows, PH0(IZ11< Ci,  ... , IZk-il < ck-l• IZkl ::?: ck) 
= ak, where ci = cp(K,a), where ci represents the 
positive critical values corresponding to stopping boundaries and the trial stops at an interim-i where IZiI ::?: ci. In this 
clinical trial, the O'Brien-Fleming methodology will be used to split the type I error (a) for each interim analysis, and also 
used to calculate critical value to judge if receives or rejects the null hypothesis. If the Z-statistic is close to the critical 
boundary value but the null hypothesis could not be rejected. By adapted group sequential study design principles, the 
study sample size will be re-assessed for the purpose to achieve the study objective by a third-party, independent, un- 
blinded statistician who will not unblind the study statistician and hence does not involve and alpha penalty. It is noted 
that a group sequential design with one(50%) interim analysis can reduce the expected sample size of a clinical trial by 
roughly 15% l3, 11,171. 
 
2.3 Sample Size Consideration 
Meta-analysis approach is used to optimally integrate the valid information collected from literature. Here, the statistics 
(pooled effect sizes (ES)) from the meta-analysis construct the composite endpoint for the reference (control) group. 
Composite endpoint is comprised of the following components: (1) MACE (myocardial injury l2I, stroke, non-fatal cardiac 
arrest, and death), (2) AKI (KDIGO stage 2-3), and (3) infection (pneumonia, deep surgical site, and organ space surgical 
site). 
The event rate (pooled effect size) of the control arm to be given is 0.31. This event rate was calculated using the weighted 
average methodology where the final event rate is based on the sample sizes as the weight from following manuscripts, 
Futier et al. 171, Pearse et al. l13I, and Maheshwari et al. l9I_The algorithm formula is: ES = r.c;eight xEs)_ Moreover, for 
weight 
manuscripts in which individuals who experienced MINS, stroke or death simultaneously were observed, an adjustment 
was conducted so that there is no overcounting within the meta-analysis. The event rate for the components MACE, AKI, 
and infection is as 0.06788, 0.10217, and 0.17182 respectively. Please see algorithm listed below the table using in the 
meta-analysis and final composite endpoint computation. 
- 
Compilation Composite= 1 - (1- 0.06788) * (1 - 0.10217) * (1- 0.17182) = 0.30690 
Although there are other derivations of the meta-analysis including Fleiss' s inverse variance methodology 151(Please see 
appendix section 12.1, 12.2, and 12.3), this conservative control arm final composite endpoint estimate (0.31) is selected 
to estimate sample size for this clinical trial, due to this being more reflective of what is observed in clinical practice. A 25% 
reduction of the composite endpoint by the treatment arm is expected for this trial, which is used in sample size 
 
' Did not report deep alone, this statistic was merged with other infection types. 
2 MINS rate was adjusted for overcounting, original rate for MINS 7/108 (6 7%) 
5/108 (4.6%) 
3 Deep Surgical Site Infection rate was adjusted for overcounting, original rate 35/108 (32.4%) 
34/108 (315%) 
Sample 
Size 
.,...  
AKI(%) 
Infection (%) 
Renal 
Deep Surgical 
Site 
Organ Space 
Sure:ical Site 
n=145 
aT 
Q. 
$;.5 
17.9 
0 
24.8 
n =364 
2.'2' 
Q 
3.0 
4.7 
01 
9.9 
n =108 
·4::0: 
1.4, 
(J:1)3 
18.5 
31.5 3 
0 
Composite 
6.288 
10.217 
17.182 

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estimation, and is supported by the integrated evidence from physician clinical experience, scientific publications, and 
previous clinical trial results. 
The hypothesis setting for this study used in sample size estimation is: 
Ho: Pi 2:: Po 
H1:P1 < Po 
where p1 and p0 are the proportions of composite endpoint in treatment arm and control arm, respectively. 
 
Moreover, two interim analyses will be designed at 50% and 75% subject enrollment with 30-day follow-up data, to assess 
the composite endpoint (pooled event rate) between treatment and control arms. To determine when the trial can be 
stopped prematurely for effectiveness, the O'Brien-Fleming methodology 1161was used to determine the stopping 
boundary (alpha spending function). The O'Brien-Fleming methodology preserves the overall type I error across all interim 
analysesl16l. The overall type I error used for this one tail hypothesis test study is 0.025. If the Z-statistics is close to 
boundary value but could not reject null hypothesis, possibly the study sample size will be reassessed for the purpose to 
achieve study objective. 
With these trial parameter and hypothesis settings, and two designed interim analyses plus a final analysis,1486 subjects 
(including 15% attrition, including a maximum of 60 roll-ins) are needed for this clinical trial. The sample size is estimated 
with PASS2021. The critical Z value and the corresponding p value for effectiveness boundary are displayed in the 
following table for interim analysis and final analysis. By the study objective and experiment design, in effectiveness 
analysis if the Z value calculated by the data available at each study stage (interim analysis and final analysis) is less or 
equal the critical Z value listed in effectiveness boundary column, the null hypothesis will be rejected, and the study stops 
for the study objective is achieved. To simplify the interim analysis decision making procedure, the lower limit of the 
reference arm accumulated subjects with complication, and the upper limit of treatment arm accumulated subjects with 
complication are designed by the study design parameters, the study arm accumulated sample size at each analysis stage, 
and effectiveness boundary (critical Z value) estimated by O'Brien-Fleming methodology. 
 
Analysis 
Information 
Rate 
Alpha Spending 
Function 
Effectiveness 
Boundary 
Critical Z value 
P-Value 
First Interim 
50% 
O'Brien-Fleming 
-2.96259 
0.00153 
Second Interim 
75% 
O'Brien-Fleming 
-2.35898 
0.00916 
Final Analysis 
100% 
O'Brien-Fleming 
-2.01404 
0.02200 
 
Analysis 
Information 
Rate 
Proportion of 
Control Subject 
with Complications 
Required 
Reduction 
Rate 
Control 
Arm Limit 
(2::) 
Treatment 
Arm Limit 
(<) 
Subject 
Ratio(<)* 
First Interim 
50% 
0.31 
0.33 
111 
74 
0.67 
Second Interim 
75% 
0.31 
0.21 
167 
131 
0.78 
Final Analysis 
100% 
0.31 
0.16 
222 
186 
0.84 
Note:* Subject Ratio=Treatment Arm Limit/Control Arm Limit. 

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2.4 
Randomization and Blinding 
The enrolled subjects will be randomized to treatment arm and control arm with 1:1 ratio. To avoid the selection bias 
caused by study team, the randomization will be done automatically by the Electronic Data Capture (EDC) system. 
Randomization will occur after verifying an arterial line that is placed during the study procedure. A block randomization 
scheme with alternating block sizes of 4 and 6 subjects will be generated by study subject enrolled at each study site. No 
other stratification factors will be considered in randomization. By the random number generated for each subject within 
the randomization block, the web-based program will produce a cutoff value to ensure equal allocation between the 
treatment and control arms. The randomization code for each subject will be maintained by the study coordinator at the 
study site. The treatment allocation will be unblinded once the surgery operation starts. 
3. 
STUDY ENDPOINT 
The primary hypothesis is that the administration of advanced hemodynamic monitoring utilizing the Hypotension 
Prediction Index (HPI) with a protocolized strategy during moderate-to-high-risk noncardiac surgery reduces composite of 
severe postoperative complications. 
3.1 Primary Effectiveness Endpoint 
The primary objective of this study is that the administration of a protocolized strategy utilizing advanced hemodynamic 
monitoring with a hypotension prediction index software reduces composite of severe postoperative complications 
identified within 30 days post-operative period. 
The primary outcome variable is a composite endpoint that includes major adverse cardiac events (MACE), acute kidney 
injury (AKI), and serious infection (pneumonia, deep surgical site, sepsis, and organ space surgical site infection). 
Myocardial injury will be diagnosed based on troponin concentrations preoperatively. MINS is defined as any myocardial 
infarction (i.e., 4th Universal Definition of myocardial infarction17), and any elevated troponin judged to be due to 
myocardial ischemia (i.e., without evidence of a non-ischemic etiology, e.g. chronic elevation, pulmonary embolism, sepsis, 
cardioversion, others) that occurred within the first 30 days after surgery. Strokes will be detected from clinical symptoms 
lasting at least 24 hours. Mortality is confined to a 30-day post-operative window. Postoperative acute kidney injury will 
be defined by the Kidney Disease Improving Global Guidelines (KDIGO). Surgical infection site (pneumonia, deep surgical 
site, and organ space) within 30 days after the operative procedure is defined according Clavien-Dindo grade II or greater. 
Please see the study protocol for more detailed criteria. 
3.2 Exploratory Analysis Datapoints 
The following measures will also be investigated for this study: 
1. Time-to-Adverse Event (Complications) Analysis 
a. 
Non-Parametric Survival Analysis (KM approach) 
b. Cox Proportional Hazard Model 
c. 
Mixed effect Cox Proportional Hazard Model 
d. Stratification analysis through applying study sites, gender, race as the stratification factor 
e. Fixed/Mixed effective Poisson regression model applying the count of events as the response 
f. 
Mixed effective survival model to assess the multiple event cases within patient 

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2. Hypotension management analysis 
a. 
Time from alert event to intervention 
b. % alerts with no intervention 
c. 
Reasons for nonintervention 
d. Amount of hypotension removing nonintervention segments 
e. Agreement analysis; clinical decision vs. treatment algorithm 
f. 
Overall treatment protocol compliance 
3. Hypotension duration (minute) is the summation of hypotension instance duration, defined as the consecutive 
measurements with MAP<65 lasting at least 1 minute. 
4. Area under the curve (AUC) with the MAP threshold of 55,65,75 mmHg 
5. Time Weighted Average (TWA) of intraoperative hypotension (mmHg) 
6. Time in target SVV <13% (for valid SVV readings = no arrythmia) 
7. Time in target CI >2.5 L/min/m15 
8. Postoperative morbidity survey (POMS) on postoperative day 3 
9. Transfusion requirement (mL packed red blood cells) 
10. Amounts of intraoperative crystalloid and colloid and vasoactive drugs; mL 
11. Amount of vasoactive drugs; mg (e.g.: phenylephrine, ephedrine, norepinephrine, epinephrine, dobutamine) 
12. Amount of intraoperative intravenous analgesics and sedatives 
13. Brain oxygen saturation – StO2 using ForeSight Elite tissue oximetry system, time in target 
14. Verification of the incidence of the listed postoperative complications may be performed at each site by reviewing 
historic data up to 6 months prior to study initiation 
15. Cost of care 
16. Hospital length of stay 
17. Hospital readmission within 30 days 
Please see appendix section 12.9 for TWA calculation. 
4. 
ANALYSIS POPULATIONS 
4.1 
Modified Intent-to-treat (mITT) 
Modified Intent-to-treat (mITT) is defined as the study subjects who were exposed to the study product and will therefore 
be included in the effectiveness and safety analysis datasets. All randomized study subjects who have satisfied the 
population criteria will be classified in the designated population and will only be included in analyses for which they have 
available data. The mITT population will also be used to present exploratory analyses by the randomized treatment arm. 
The safety population is defined as all randomized subjects who were exposed to the study product; thus, the safety 
population will therefore be identical to the mITT population if all randomized subjects are exposed to the study product. 
In this clinical study, the primary effectiveness endpoint is a composite measurement of MINS, AKI, and serious infection 
adverse events, mITT will be the target population in interim, and final effectiveness analysis. The Roll-in subjects designed 
for the training purpose to avoid a learning curve bias will be analyzed separately. The safety population will be used to 
present the safety summaries by actual treatment received. 

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4.2 
Full Analysis Population (FAS) 
The full analysis population is defined as all pivotal subjects with valid intra-operative measurements during non-cardiac 
surgery, and with at least one valid post-operative measurement. It will be applied in primary and secondary effectiveness 
sensitivity analysis. 
4.3 
Per Protocol Population (PP) 
A per protocol analysis population is defined as a group of pivotal subjects who enrolled into study and completed all 
operations as written in the protocol (e.g., No major protocol deviations occurred during the non-cardiac surgical 
procedures). It will be applied in primary and secondary effectiveness sensitivity analysis. 
4.4 Complete (Evaluable) Case Population (CC) 
The complete case population is defined as all pivotal subjects who complete surgery, have valid post-operative data and 
follow-up records, and exit this study by designed procedure within protocol. It is the population used in primary and 
secondary effectiveness endpoint sensitivity analysis in final analysis. 
4.5 
Roll-in Subject 
To prevent a learning curve bias, up to five (5) Roll-in cases may be performed at a site, as needed, with a maximum total 
of 60 Roll-in cases in the Trial. Roll-in cases will be analyzed separately from the pivotal cohort. 
4.6 
Screen Failures 
Late screen failures are defined as subjects who consent to participate in the clinical trial and but are not subsequently 
randomly assigned to the trial intervention or entered in the trial. So, the subjects are not exposed to FloTrac sensor or 
Acumen IQ sensor and are not treated as part of the study. Late screen failures will be represented in summary tables by 
counts and percentages. Please see study protocol for more detailed criteria. 
 
5. 
DEFINITIONS 
5.1 
Analysis Dates and Days 
Subjects who fulfill all eligibility criteria will be scheduled for surgery and followed for 30 days post-surgery. The 30-day 
follow-up has a ±14-day window (see protocol for more detailed information). Pre-procedure data collection includes: (1) 
Pre-op Surgical Risk Assessment, and (2) the lab values: creatine, troponin, and NT-proBNP. On post-op day 1 the following 
data will be collected: (1) the lab value troponin, (2) post-op complication, and (3) fluid and vasoactive medications. On 
post-op day 2 the following data will be collected: (1) the lab values: creatinine and troponin, (2) adverse events, and (3) 
post-operative complications. The POMS will be given on postoperative day 3, further, the POMS may be entered into the 
system until after the third day. Other post-op day 3 data include: (1) the lab value troponin, (2) Post-Op Neurocognitive 
Assessments, (3) post-op complications, (4) adverse events, and (5) post-op complications. Lastly, for 30-day follow up the 
following will be evaluated: (1) post-op complications, (2) adverse events, and (3) the WHODAS 2.0 survey. 
5.2 
Analysis Window 
There is no analysis window for this study. Please see the protocol for more detailed procedure information. 

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6. 
DATA AND ANALYSIS CONVENTIONS 
6.1 
General Conventions 
The baseline characteristics and demographics, the medical history data of each study subject will be collected during the 
subject screening process and recorded on an electronic case report form (eCRF). The hemodynamic measurement data 
will be downloaded from HemoSphere advanced monitoring platform. 
All endpoints will be presented using descriptive statistics by assigned treatment group; continuous variable will be 
summarized with the mean, standard deviation (SD), median, and interquartile range (IQR); binary and categorical 
variables will be presented using count and percentage. 
Other summaries (e.g., minimum, maximum, standard error, 95% intervals, coefficient of variation (CV) or %CV, odd ratio) 
will be used as appropriate. Sample sizes shown with summary statistics are the number (n) of patients with non-missing 
values. All percentages should be rounded and reported to a single decimal place (xx.x%). If percentages are reported as 
integers, percentages greater than 0% but <1% will be reported as <1%, whereas percentages greater than 99% but <100% 
will be reported as >99%. A percentage of 100% will be reported as 100%. 
For categorical endpoints, logistic regression and the approximate Z test will be performed on the primary outcomes and 
exploratory analysis. Summary statistics and p-values from the statistical comparison will be displayed in result report. The 
p-value will present with three decimals. P-values less than 0.001 will be reported as <0.001. Additionally, ad-hoc analyses 
may be conducted as deemed appropriate. 
An independent Data Safety Monitoring Board (DSMB) will evaluate the data at interim. 
6.2 
Handling of Missing Data 
Missing data are defined as those instances in which data collection was attempted yet failed for some reason (i.e., due to 
technological, procedural, and/or subject dropout). Demographic and baseline characteristics are collected from the study 
subjects as part of screening. Subjects who do not meet all criteria will not be enrolled into this study. Subjects who are 
not randomized are considered as screening failures. Data for screening failure subject will not be captured. 
If missing data are not related to the subject’s eligibility criteria, missing data will be presented as not reported in the 
demographic and baseline characteristics summary statistics table. These subjects will be included in all analysis. However, 
if the missing data are related to the subject’s eligibility, this will be considered a protocol deviation, and in this case, the 
study data from this subject will be reviewed internally, to determine if the subject should be excluded from analysis set. 
The hemodynamic measurements are downloaded from the monitor platform. Theoretically, there should be no missing 
data. If there are missing values in the hemodynamic parameters download from monitor platform caused by any reason, 
the last value will be carried forward. 
For binary or categorical data that are missing as defined above, single imputation will be used. For continuous data that 
are missing as defined above, statistical imputation using the multiple imputation (MI) method. 
By the data from similar clinical trial sponsored by Edwards LifeSciences, missing value of the primary effectiveness 
endpoint is really rare (less than 1%). In case, more than 5% study subjects with missing primary effectiveness endpoint, 
imputation techniques with different missing mechanisms (multiple imputation approach with assumption missing at 
complete random, missing at random, or tipping point analysis approach for missing not at random), mentioned in 
National Research Council publication [18], will apply to impute the missed values. Sensitivity analysis for primary 

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effectiveness endpoint will conduct on pivotal mITT data with imputed values to check the robustness of statistical analysis 
outcome. 
With assumption missing primary effectiveness endpoint at random or complete at random (missing primary effectiveness 
endpoint unrelated to the actual value of primary effectiveness endpoint), 20 different datasets will be exported from 
multiple imputation approach. With exact the same statistical analysis method, the p value from the sensitivity analysis on 
imputed data should be consistent to the statistical hypothesis test result with valid pivotal mITT dataset. 
With tipping point analysis approach for the missing primary effectiveness endpoint related to actual primary endpoint 
value, multiple imputed datasets are exported corresponding to all possible imputations. By the p-value from statistical 
analysis on all these imputed datasets, if a reasonable majority of statistical hypothesis tests have the same outcome as it 
from valid pivotal mITT dataset statistical hypothesis test, this statistical outcome would be considered robust. 
Please see section 8.3 and 8.4 for outliers and sensitivity analysis. 
 
7. 
SUMMARY OF BASELINE INFORMATION 
7.1 
Patient Enrollment and Accountability 
The following will be tabulated via frequency and percentage into a summary table: 
• 
Number of included and randomized patients 
• 
Number of randomized patients by treatment groups 
• 
Number of active sites 
• 
Number of included and randomized patients by treatment groups 
• 
Number of included and randomized patients by site 
• 
Number and percentage of patients having finished the study normally by treatment groups 
• 
Reason of withdrawal will also be tabulated and a listing of reason of withdrawal will be produced 
• 
Normal study end (yes/no) and if no, reason 
Moreover, subjects who withdraw from the study will be tabulated with the reasons for the withdrawal. Compliance with 
study visits will also be presented. Please refer to section 4 for enrolled subject definition. Also, please see the protocol for 
the enrollment diagram and enrollment timeline diagram. 
7.2 
Demographics and Baseline Characteristics 
The baseline characteristics and demographics of each study subject will be collected during the subject screening process. 
For subject demographics, age, sex, race, ethnicity, and other demographic variables will be used for each summary. All 
outcomes will be presented using descriptive statistics; normally distributed data by the mean and standard deviation (SD) 
and skewed distributions by the median and interquartile range (IQR). The sample size of non-missing values will be 
reported for summary tables as well as frequency (count and percentage) of illegible and eligible will be represent by a 
Consolidated Standards of Reporting Trials (CONSORT) consort diagram. The number and reasons for drop-out, lost-to- 
follow-up, or withdrawal will be presented by frequency and percentage. 
7.3 
Medical History and Prior Intervention 
The subject’s medical historical data will be recorded on an electronic case report form (eCRF). Historical data will be 
summarized into tables with continuous variables being represented by medians and interquartile ranges and categorical 

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variables being represented by counts and percentages. 
7.4 
Baseline Risk Assessments 
Demographic data will be summarized into tables with continuous variables represented by median and interquartile 
ranges. Categorical demographic variables will be represented by counts and percentages 
The vascular access obtained is standard clinical care for the adult population and the addition of the Acumen IQ sensor or 
FloTrac sensor is not expected to impose any additional risk to the patient. There is no measurable increased infectious 
risk with the temporary use of the Acumen IQ sensor or FloTrac sensor. Below is a list of anticipated risks that may be 
associated with the use of the ForeSight Oximetry Sensors: 
• 
Allergic reaction to adhesive on sensors 
• 
Skin irritation 
7.5 
Procedural Information 
Procedural data (procedure setting and procedure measurements) will be summarized into tables with continuous 
variables being represented by medians and interquartile ranges and categorical variables being represented by counts 
and percentages. Moreover, a specifications document is created for each statistical output (table, listing, or figure) and it 
will contain, at the minimum: 
• 
Title and footnote information 
• 
Column headers 
• 
If the output includes a figure then a detailed description of the figure 
• 
Variables, procedures, and/or calculation logic used in the statistical output 
• 
Ad Hoc or Post Hoc analyses 
• 
Formulas for derived procedures 
 
 
8. 
STATISTICAL ANALYSIS OF STUDY ENDPOINTS 
8.1 
Primary Effectiveness Endpoint 
The primary objective is to determine if the use of a protocolized strategy using advanced hemodynamic monitoring with 
Hypotension Prediction Index (HPI) software guidance for intraoperative hemodynamic management reduces 
postoperative complication rate in moderate- to high-risk non-cardiac surgery patient. The treatment group (Acumen ID 
sensor) will be compared to control arm receiving standard of care (FloTrac sensor). This analysis will be conducted on the 
mITT population only with pivotal study subject. With null hypothesis, the Z-statistic will be used to judge if the 
hypotension prediction index software can reduce postoperative morbidity and mortality: 
𝑝̂1 − 𝑝̂0 
𝑍 = 
 
 
√𝑝̂1 ∗ (1 − 𝑝̂1 )  + 𝑝̂0 ∗ (1 − 𝑝̂0 )  
𝑛1 
𝑛0 
Here 𝑥 and 𝑥 are composite endpoint events in the reference arm and treatment arm respectively; thus, 𝑝̂ = 
𝑥0 , 𝑝̂ = 
0 
1 
0 
𝑛0 
1 
𝑥1 are the proportion of events in the reference arm and treatment arm, respectively; 𝑛 , 𝑛 
are the number of subjects in 
𝑛1 
0  1 

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reference arm and treatment arm respectively; 
𝑝̂0∗(1−𝑝̂0) , 
 𝑝̂1∗(1−𝑝̂1) is the variances of the proportion of events in reference 
𝑛0 
𝑛1 
arm ( 𝑝̂0 ) ,  and in test arm ( 𝑝̂1 )  respectively. The Z-statistic will compare to the critical Z-value to judge if the null hypothesis 
could be rejected. 
By the study designed parameter table in section 2.3 and the Z statistic calculated at each study stage with the trial data 
collected at present stage in addition to data collected in previous stage or stages, following judgement will be conducted 
for interim analysis and final analysis. For first and second interim analyses, if the calculated Z value is equal to or less than 
the critical Z value in the effectiveness boundary column, the null hypothesis will be rejected, and the study will stop for 
achieving the study objective; if the calculated Z statistic is greater than critical Z value for effectiveness but it is close to 
the critical value but could not reject null hypothesis, the study continues to next step, and the study sample seize will be 
reassessed by the principles of adapted group sequential study design. If it is necessary, more study subject will be 
enrolled for the purpose to achieve the study objectives. For final analysis, if the calculated Z statistic is equal to or less 
than the critical Z value listed in effectiveness boundary column, the null hypothesis will be rejected, and the alternative 
hypothesis will accept, the study objective is achieved, otherwise, the null hypothesis will accept, the study objective will 
be not achieved. 
8.2 
Exploratory Evaluations 
For all endpoints listed in section 3.2, the continuous variables will be evaluated with linear fixed/mixed effect regression 
model on the treatment effectiveness adjusted by subject’s baseline and demographic, medical history variables, and 
surgery related covariates. The categorical/binary variables, and count variables will be evaluated with generalized linear 
model or mixed generalized linear model on the effectiveness of treatment adjusted by all relevant covariates. Time-to- 
event variables will be evaluated by survival analysis models (Kaplan-Meier or Cox Proportional Hazards). The re-current 
time to event variable will be analyzed with frailty cox proportion hazard model. Sub-group analysis will be conducted 
based upon study design factors and baseline characteristics. 
8.3 
Outliers 
Suspected outliers for this study will be considered as the observation that lie outside of the pre-defined clinical bounds. 
Outliers may be evaluated via summary statistics (interquartile or standard deviation rules), graphical methods (boxplots 
or histograms) or statistical test. For continuous outcomes, formal statistical test includes the Grubbs (or Dixon’s Q), or 
Tietjen-Moore test can be used as well as the cutoff observation being within 1.5 units of the interquartile range. All 
methods of measurements will be recorded for all devices and included as part of the data set. Once outliers are 
identified, the principal investigator will assess the validity of the data. 
8.4 
Sensitivity Analysis 
Sensitivity analysis will be performed for primary endpoint. For primary effective endpoint, sensitivity analysis will be 
conducted with all study subjects from FAS, PP, or CC population to check if the similar conclusion could be drawn. If there 
are more than 5% study subjects with missing primary endpoint in test arm, the imputed endpoint with missing at 
complete random, or missing not at random will replace the missing value for each study subject, the sensitivity analysis 
on this imputed mITT pivotal dataset will be conducted to check if the similar conclusion could be drawn. Then check if the 
variation among study sites will affect the statistical comparison between study arms. Next check if the study cohorts (roll- 

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in, pivotal) will change the analytical conclusion. Finally, bootstrap approach will be applied to check if sample size effect 
the analytical result. 
The effect of the following factors on the primary effectiveness endpoint will be analyzed: 
▪ 
MAP threshold (<55, 60, 70 mmHg) and the length of time in hypotension episode definition (20, 40, and 80 
seconds) 
▪ 
NSQIP score vs ASA score 
▪ 
Regional anesthesia vs general anesthesia 
▪ 
Surgery technique (open or laparoscopic) vs hemodynamic changes 
▪ 
Patient positioning vs hemodynamic changes 
▪ 
Surgery type vs hemodynamic changes 
▪ 
Survival analysis 
▪ 
Arterial line vs Arterial line + CVP monitoring 
▪ 
Onset of HPI Alert vs time of intervention 
▪ 
Amount of vasopressors/fluids/inotropes administered vs time of intervention (start & stop time) 
– 
Stratified by cohort 
▪ 
Tidal volume 
 
9. ANALYSIS OF SAFETY 
9.1 Deaths 
Any deaths that occur during this study will be summarized by frequencies and percentages. The frequency distribution 
and percentage of death related to a specific medical device will be presented. Evaluation of death has a 30-day post-op 
window. Death is considered an unexpected serious adverse event in the context of this study. 
9.2 Adverse Events 
The safety data will be summarized for all subjects in the safety population. Safety will be assessed through summary of 
adverse events. The frequency and percentage of AEs and SAEs will be reported in summary tables by treatment group. 
Plots showing the incidence of AEs and SAEs and their relative risk (with 95% confidence interval) will also be produced. 
Any other serious adverse events that occur during this study will be summarized by frequencies and percentages. The 
frequency distribution and percentage of any adverse events related to a specific medical device will be presented. The 
following categories will be on the summary table: 
• 
AEs-All 
• 
AEs-Serious 
• 
AEs Treatment-related 
• 
AEs by seriousness criterion 
• 
AEs that lead to study withdrawal 
10. CHANGES FROM PROTOCOL SPECIFIED ANALYSES 
There are no changes to the protocol specified analyses at this time. If protocol deviations occur during the study, they will 
be tabulated via frequency and percentage and presented in a summary table. Definition of minor and major deviations 
can be found in the protocol. 

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11. 
REFERENCES 
1. Bothwell LE, Avorn J, Khan NF, Kesselheim AS. Adaptive design clinical trials: a review of the literature and 
ClinicalTrials.gov. BMJ Open. 2018;8(2): e018320. Published 2018 Feb 10. doi:10.1136/bmjopen-2017-018320 
2. Calvo-Vecino JM, Ripolles-Melchor J, Mythen MG, Casans-Frances R, Balik A, Artacho JP, Martinez-Hurtado E, Serrano 
Romero A, Fernandez Perez C, Asuero de Lis S, Group FTI: Effect of goal-directed haemodynamic therapy on 
postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial 
(FEDORA trial). Br J Anaesth 2018; 120: 734-744 
3. Chen, Y. H., DeMets, D. L., & Gordon Lan, K. K. (2004). Increasing the sample size when the unblinded interim result 
is promising [Abstract]. Statistics in Medicine, 23(7), 1023-1038. doi:10.1002/sim.1688 
4. Demets, D. L., & Lan, K. G. (1994). Interim analysis: the alpha spending function approach. Statistics in medicine, 
13(13‐14), 1341-1352. 
5. Duceppe E, Borges FK, Tiboni M, Pearse R, Chan MTV, Srinathan S, Kavsak P, Szalay D, Garg A, Sessler D, Sapsford R, 
Pettit S, Vasquez J, Devereaux PJ: Association between high-sensitivity troponin I and major cardiovascular events 
after non-cardiac surgery (abstrract). Journal of the American College of Cardiology 2020; 75 
6. Fleiss, J. (1993). The statistical basis of meta-analysis. Statistical Methods in Medical Research 2: 121-145. 
7. Futier, E., Lefrant, J., Guinot, P., Godet, T., Lorne, E., Cuvillon, P., . . . Jaber, S. (2017). Effect of individualized vs 
standard blood pressure management strategies on postoperative organ dysfunction among high-risk patients 
undergoing major surgery. JAMA, 318(14), 1346. doi:10.1001/jama.2017.14172 
8. Kumar, A., & Chakraborty, B. S. (2016). Interim analysis: A rational approach of decision making in clinical trial. 
Journal of advanced pharmaceutical technology & research, 7(4), 118–122. https://doi.org/10.4103/2231- 
4040.191414 
9. Maheshwari, K., Shimada, T., Yang, D., Khanna, S., Cywinski, J. B., Irefin, S. A., . . . Sessler, D. I. (2020). Hypotension 
prediction index for prevention of Hypotension During moderate- to High-risk Noncardiac surgery [Abstract]. 
Anesthesiology, 133(6), 1214-1222. doi:10.1097/aln.0000000000003557 
10. Mehta, C. R., & Pocock, S. J. (2010). Adaptive increase in sample size when interim results are promising: A practical 
guide with examples [Abstract]. Statistics in Medicine, 30(28), 3267-3284. doi:10.1002/sim.4102 
11. Muller HH, Schafer H: Adaptive group sequential designs for clinical trials: combining the advantages of adaptive and 
of classical group sequential approaches. Biometrics 2001; 57: 886-91 
12. Pallmann, P., Bedding, A. W., Choodari-Oskooei, B., Dimairo, M., Flight, L., Hampson, L. V., . . . Jaki, T. (2018). 
Adaptive designs in clinical trials: Why use them, and how to run and report them. BMC Medicine, 16(1). 
doi:10.1186/s12916-018-1017-7 
13. Pearse, R. M., Harrison, D. A., MacDonald, N., Gillies, M. A., Blunt, M., Ackland, G., . . . Rowan, K. (2014). Effect of a 
PERIOPERATIVE, cardiac OUTPUT–GUIDED Hemodynamic Therapy algorithm on Outcomes following major 
Gastrointestinal Surgery [Abstract]. JAMA, 311(21), 2181. doi:10.1001/jama.2014.5305 
14. Thorlund, K., Haggstrom, J., Park, J. J., & Mills, E. J. (2018). Key design considerations for adaptive clinical trials: A 
primer for physicians [Abstract]. BMJ. doi:10.1136/bmj.k698 
15. Tufanaru, C., Munn, Z., Stephenson, M., & Aromataris, E. (2015). Fixed or random effects meta-analysis? Common 
methodological issues in systematic reviews of effectiveness. International journal of evidence-based healthcare, 
13(3), 196-207. 
16. Fleming, T. R., Harrington, D. P., & O'Brien, P. C. (1984). Designs for group sequential tests. Controlled clinical trials, 
5(4), 348-361. 

 
--- 
17. United States, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). (2019, November). Retrieved 
from https://www.fda.gov/ regulatory-information/ search-f da-guidance-documents/adaptive-design-clinicaI-trials- 
drugs-and-biologics-guidance-industry Docket Number: FDA-2018-D-3124 
18. National Research Council. (2010). The Prevention and Treatment of Missing Data in Clinical Trials. Panel on 
Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social Sciences 
and Education. Washington, DC: The National Academies Press. 
 
12. 
APPENDIX 
.. 
12.1 Alternative Computation of the Reference 
 
 
- 
 
12.1.1 MACE, AKI, Infection (Sepsis, Pneumonia, Deep, and Organ) 
 
This composite contains: (1) MINS, (2) Stroke, (3) Death, (4) AKI, (5) Sepsis, (6) Pneumonia, (7) Deep Surgical Site Infection, 
and (8) Organ Space Surgical Site Infection. The composite score is given by 0.55. 
145(0.007 + 0.000 + 0.055) + 364(0.022 + 0.000 + 0.030) + 108(0.046 + 0.074 + 0.0093) 
MACE= 
145+ 364+ 108 
145(0.179) + 364(0.047) + 108(0.185) 
AKI= 
145 + 364 + 108 
. 
145(0.262 + 0.110 + 0.000 + 0.248) + 364(0.107 + 0.099) + 108(0.315 + 0.000) 
Infection= 
145+ 364+ 108 
 
 
AKI Composite 
Infection Composite 
a-- 
0.10217 
0.38549 
Composite Score= 1 - ((1 - 0.06788) * (1 - 0.10217) * (1 - 0.38549)) = 0.55554 
 
12.1.2 MACE, AKI, Infection {Pneumonia, Deep, and Organ) 
 
This composite contains: (1) MINS, (2) Stroke, (3) Death, (4) AKI, (5) Pneumonia, (6) Deep Surgical Site Infection, and (7) 
 
4 Did not report deep alone, this statistic was merged with other infection types. 
5 MINS rate was adjusted for overcounting, original rate for MINS 7/108 (6 7%) 
5/108 (4.6%) 
6 Deep Surgical Site Infection rate was adjusted for overcounting, original rate 35/108 (32.4%) 
34/108 (315%) 
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Sample 
Size 
.. 
i., 
AKI(%) 
Infection (%) 
... -- ...., 
Renal 
Sepsis 
Pneumonia 
Deep 
Surgical Site 
Infection 
Organ Space 
Surgical Site 
Infection 
n=145 
0396,° 
., 
s...- 
17.9% 
26.2% 
11.0% 
0% 
24.8% 
n =364 
, - 
·a.mt. 
4.7% 
NA 
10.7% 
0%4 
9.9% 
n=108 
1ε 
0;93K 
18.5% 
NA 
NA 
31.5%6 
0% 

 
--- 
Organ Space Surgical Site Infection. The composite score is given by 0.49. 
 
145(0.007 + 0.000 + 0.055) + 364(0.022 + 0.000 + 0.030) + 108(0.046 + 0.074 + 0.0093) 
MACE= 
145 + 364 + 108 
145(0.179) + 364(0.047) + 108(0.185) 
AKI= 
145+364+108 
145(0.110 + 0.000 + 0.248) + 364(0.107 + 0.099) + 108(0.315 + 0.000) 
Infection = 
+ 
145 
+ 
364 
108 
 
 
Composite Score = 1 - ((1 - 0.06788)* (1 - 0.10217)* (1 - 0.32392)) = 0.49397 
 
12.2 Fleiss's Inverse Variance 
 
All the meta-analysis, using the weighted mean effect sizes will be compared to Fleiss's inverse variance methodology (6). 
This methodology allows for aggregates over multiple variables while minimizing the variance of the weighted average. It 
is noted that when the variances are equal, then the inverse variance average becomes the traditional average. The 
k 
formula (pooled effect size), for binary outcomes is represented as follows, 0 = L ? wke\ where wk  is the reciprocal of 
k=1Wk 
the variance and 0 represents a measure of the generic effect size for each k-study. Moreover, each variable is weighted in 
inverse proportion to its variance, this is considered the inverse standard error. Moreover, for manuscripts in which 
individuals who experienced MINS or stroke, or death simultaneously were observed, an adjustment was made so that 
there is no overcounting within the meta-analysis. 
 
Sample 
Size 
'Mgff4' 
AKI(%) 
Infection (%) 
MINS _. .h.a,t.h, 
Renal 
Sepsis7 
Pneumonia 
Deep Surgical 
Site Infection 
Organ Space 
Surgical Site 
Infection 
n=145 
0:.1" 
 
5.5'6 
17.9% 
26.2% 
11.0% 
0% 
24.8% 
n =364 
l •- 
 
3ml 
4.7% 
NA 
10.7% 
0%8 
9.9% 
n =108 . uw- 
)!;fl 
0 9395· 
18.5% 
NA 
NA 
31.5%10 
0% 
 
...... 
 
 
 
Component 
 
 
 
 
7 Cannot run inversive variance method on, only 1 paper reported statistics on this measure. 
8 Did not report deep alone, this statistic was merged with other infection types. 
9 MINS rate was adjusted for overcounting, original rate for MINS 7/108 (6 7%) 
5/108 (4.6%) 
10 Deep Surgical Site Infection rate was adjusted for overcounting, original rate 35/108 (32.4%) 
34/108 (31.5%) 
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Composite Value 
Model 
Tau2 
Test of Heterogeneity 
(p Value) 
. 
D.OB& _......, 
...Effeds 
0.0001 
0.1004 
0o
..0o
0m
41 
Randonf - 
<dOtJOl 
llOl36 
·- 
AKI 
0.1332 
Effects:: 
Random Effects 
0.0088 
0,0568 
< 0.0001 
Sepsis 
0.2620 
---- 
- 
---- 
Pneumonia 
0.1080 
Random Effects 
0.0000 
0.9168 

 
.Ul=l 
60 
t us, 
IS given y. 
--- 
 
 
 
Deep Surgical Site Infection 
0.0346 
Random Effects 
0.0006 
<0.0001 
Organ Space Surgical Site Infection 
0.1102 
Random Effects 
0.0089 
< 0.0001 
If heterogeneity was present in the meta-analysis, this was adjusted for by using a random effects model. It is noted the 
following for random effects: (1) results apply beyond the included studies, (2) there is no common fixed parameter, and 
(3) the summary effect is an estimate of the mean distribution of the true effects. [15) Moreover, the DerSimonian-Laird 
estimator was used to estimate Tau11. 
 
For this study, a more conservative methodology of weighted sums was selected based upon the sample sizes due to this 
being more reflective of what is observed in clinical practice. 
 
12.2.1 MACE, AKI, Infection (Deep and Organ) 
The individual event rates for the components MACE, AKI, and infection are as follows, 0.0506, 0.1332 and 0.1448. The 
composite score is given by 0.2962. 
Composite Score = 1 - ((1 - 0.0506)* (1 - 0.1332)* (1 - 0.1448)) = 0.2962 
12.2.2 MACE, AKI, Infection (Pneumonia, Deep, and Organ) 
The individual event rates for the components MACE, AKI, and infection are as follows, 0.0506, 0.1332, and 0.2528. The 
composite score is given by 0.3851. 
Composite Score = 1 - ((1 - 0.0506) * (1- 0.1332) * (1 - 0.2528)) = 0.3851 
12.2.3 MACE, AKI, Infection (Sepsis, Pneumonia, Deep, and Organ) 
The individual event rates for the components MACE, AKI, and infection are as follows, 0.0506, 0.1332, and 0.5148. The 
composite score is given by 0.6007. 
Composite Score = 1 - ((1 - 0.0506) * (1 - 0.1332) * (1 - 0.5148)) = 0.6007 
 
12.3 Time Weighted Average (TWA) Computation 
 
AUC (minute*mmHg) for a hypotension instance is calculated by the following: 
 
Aue=  '°m  (t,+1-t,) * (65 - MAPi+MAPi+1)  h 
TWA. 
• 
b . 
2 
TWA= 
Im 
Where the unit of TWA isgiven by mmHg and 4nis the length of measurement of study subject in minutes given by: 
4n = last valid EV1000 measure time - first valid EV1000 measure time 
 
 
 
 
 
 
11 This is a test for between-study heterogeneity; Occurs when, Tau2>0% 
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Name of Reviewer: 
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Reason Peer Review not Needed: 
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