Clinical trial NCT01866657
Conditions: Hypoxia
Keywords: cerebral oximetry randomized controlled pilot study thoracic surgery single lung ventilation
Sponsor: University Hospitals Cleveland Medical Center
Start date: 2013-06-01; Completion date: 2016-11-10
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, randomized controlled pilot study of cerebral oximetry use in elderly patients undergoing thoracic surgical procedures that require the use of single lung ventilation. The hypothesis is that subjects randomized to open cerebral oximetry monitoring that have active intervention to mitigate observed desaturations will have measurable postoperative clinical outcome benefits when compared to the patients randomized to blinded cerebral oximetry monitoring with no active interventions to mitigate desaturations.

Detailed description:
Study Rationale The use of bi-frontal, near infrared spectrophotometry (NIRS) based cerebral oximetry monitoring has been demonstrated to result in improved clinical outcomes in both general surgery patients and cardiac surgical patients using prospective, randomized controlled trial methodology. Elderly thoracic surgical patients undergoing procedures that involve single lung ventilation may also stand to benefit from the application of intraoperative and early postoperative NIRS cerebral oximetry monitoring. Cerebral oximetry has not been established as a standard of care monitoring modality in this patient population, thus permitting the application of randomized, controlled testing methodology to assess the potential impact of this monitoring modality upon these patients.

Hypothesis and Objectives:

The primary hypothesis in this pilot study of elderly thoracic surgical patients undergoing procedures involving single lung ventilation (SLV) is that there will be a measurable and significant clinical benefit (as assessed by a broad range of postoperative clinical outcome measures) to the subjects randomized to the intervention cohort (open bi-frontal NIRS based cerebral oximetry monitoring with a standardized intervention protocol) vs. the control cohort (blinded bi-frontal NIRS based cerebral oximetry monitoring).

The primary objective of this pilot study is to identify the most relevant clinical outcome variables which significantly diverge as a result of being randomized to the intervention cohort vs. the control cohort so that a larger, multicenter, prospective, randomized controlled clinical trial can be designed to further test the primary hypothesis as stated in the preceding section. The subsequent larger, multicenter trial will be conducted to definitively demonstrate the ability of INVOS® 5100 guided NIRS-based bi-frontal monitoring to improve clinical outcomes in this surgical patient group and potentially establish a new U.S. Food and Drug Administration cleared indication for this monitoring modality. The clinical outcome variables being assessed as the primary objective are many and a detailed list of these variables can be found in the OUTCOME MEASURES - Primary Outcome Measure Section of this submission.

Secondary objectives of this pilot study include the following:

1. Assess the frequency of cerebral desaturations in both the intervention and control cohorts by examining both the total number of patients experiencing any cerebral desaturation as well as the total number of events among patients experiencing any cerebral desaturation (of at least 5% below baseline and progressively larger desaturations). These analyses will be conducted on the entire study population as well as upon each cohort. The Area Under the Curve (AUC) analysis technique \[incremental desaturation categories will be assessed based upon 5 to 50% decreases, measured in 5% increments, from established room air pre-incision baseline as well as oxygen supplemented pre-incision baseline as well as desaturations below absolute measured rSO2 values\] will be employed to conduct these analyses.
2. Assess the frequency of adverse clinical events and serious adverse events overall and in each cohort.
3. Perform a comprehensive assessment of the frequency and efficacy of predefined rSO2 desaturation mitigation interventions and their collective ability to affect the observed cerebral oximetry values.
4. Assess the interventional cohort's preoperative demographics and collected covariates for association with the ease or difficulty of mitigating observed cerebral desaturation events.

Exploratory analyses will include performing all possible comparisons of the two groups based upon all collected perioperative variables to examine the potentially significant relationships between the collected clinical variables representing surrogates of organ perfusion/function and cerebral oximetry desaturations (AUCrSO2). The following exploratory endpoints will be assessed:

1. Logistic regression analysis to determine the most relevant AUCrSO2 desaturation value(s) associated with any detrimental clinical outcome(s) monitored in this study
2. Logistic regression analysis to determine the most relevant AUC blood pressure values associated with any detrimental clinical outcome(s) monitored in this study
3. Comparison of baseline rSO2 values (room air and oxygen supplemented) to all collected clinical variables to assess for possibly significant associations
4. Explore the potential impact of rSO2 monitoring on changing the surgical conduct of the procedure Methodology: Single center, prospective, randomized, controlled clinical pilot study Number of Subjects: 100 subjects with balanced randomization (1:1) to control (blinded NIRS data) or intervention (open NIRS data) cohorts Main Criteria for Inclusion: Elderly patients (\> 65 years of age) scheduled for a thoracic surgical procedure at UHCMC that will involve SLV.

Duration of Treatment: Cerebral oximetry monitoring will begin with an assessment of both room air and oxygen supplemented bi-frontal baseline NIRS values and continue through the surgery to either PACU discharge or the initial 12 hours of post surgical ICU treatment. Mini Mental Status exam testing and Delirium testing with the Confusion Assessment Method will occur preoperatively and postoperatively through post-operative day (POD) #3 (or discharge if that occurs sooner than POD #3). Enrolled subjects will be followed during the index hospitalization and will undergo a 30 day follow up telephone interview to assess their progress following hospital discharge.

Criteria for Evaluation:

A large number of intraoperative and postoperative clinical variables that include cerebral oximetry, pulse oximetry, blood pressure, a composite outcome measure and clinical variables representing organ function will be assessed with the primary endpoint being the determination of which clinical variables are improved, if any, as a result of being randomized to open NIRS data monitoring with a predefined desaturation intervention algorithm guideline. The Mini Mental Status exam and Confusion Assessment Method test will be used to determine if any measured clinical variables have an effect upon neuropsychological outcomes. The frequency and effectiveness of the various cerebral desaturation mitigating interventions will be assessed in the intervention cohort.

Additional Safety Observations:

The frequency and severity of adverse clinical events and serious adverse clinical events will be assessed to determine if the use of open NIRS data bi-frontal cerebral monitoring is associated with any significant change in the observation of such events.

Statistical Methods:

Preoperative demographics and clinical variables will be compared in the two groups to assess for significant differences using the independent t-test. Differences in the observed clinical data between groups will be determined with the Wilcoxon rank-sum test. Stepwise, forward, multivariable logistic regression analysis will be performed to assess for relationships between cerebral desaturations and any of the measured clinical variables with a p value \< 0.05 being considered significant

Arms: arm 1: Open cerebral oximetry monitoring; observed desaturations will be treated with an intervention algorithm including increase FiO2, head/neck repositioning,vasoconstrictor agents, IV fluid bolus, increase ETCO2, additional anesthesia, RBC transfusion. arm 2: These subjects will have continous cerebral oximetry monitoring like the experimental cohort but the values will be blinded to all clinicians and research staff. There will be no cerebral desaturation interventions in this group because the clinicians will not be aware of a desaturation as the monitor's output is blinded in this group.
Interventions: intervention 1: Vasoconstrictor Agents intervention 2: Head/neck repositioning intervention 3: Increase ETCO2 intervention 4: IV fluid bolus intervention 5: Additional anesthesia intervention 6: RBC transfusion intervention 7: Increase FiO2
Intervention descriptions: intervention 1: cerebral desaturations may be treated with IV vasoactives to increase blood pressure or cardiac output at attending physician's descretion. intervention 2: Assure that arterial and venous neck blood flow is not obstructed related to patient positioning intervention 3: Allow normalization or slight increase in end tidal CO2 to cause selective cerebral vasodilation and increased tissue blood flow/O2 delivery intervention 4: Administer IV fluids to increase preload and cardiac output intervention 5: By deepening anesthetic there will be a decrease in cerebral metabolic oxygen consumption. intervention 6: By administering RBCs there will be a increase in intravascular volume and cardiac preload and an increase in oxygen carrying capacity intervention 7: Increase FiO2 to improve oxygen delivery to tissue

Protocol documents:
Prot_SAP_000.pdf: 
1 | Page 
 
Near Infra-Red Spectrophotometry (NIRS)-Based Cerebral Oximetry Monitoring in Elderly 
Thoracic Surgical Patients Undergoing Single Lung Ventilation Procedures: A Single Center, 
Prospective, Randomized Controlled Pilot Study Assessing the Clinical Impact of NIRS-Guided 
Intervention 
Co-Principal Investigators 
Philip Linden, M.D. 
 
Protocol Author 
Edwin G. Avery, M.D., C.P.I. 
 
Co-Investigators 
Edwin G. Avery, M.D.
 
Nurse Coordinators 
Stacey Mazzurco, R.N, Nadine Norton,, R.N. 
 
Research Assistant 
TBA 
Version 01.05.2013 
Revised 09.04.2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
The confidential information in the following document is provided to you as an investigator, potential 
investigator, or consultant, for review by you, your staff, and applicable institutional review boards. It is 
understood that the information and ideas contained within this document are the intellectual property of 


2 | Page 
 
the protocol author, Edwin G. Avery, IV, M.D., C.P.I., and will not be disclosed to others without the 
written authorization of the protocol author, except to the extent necessary to obtain informed consent 
from those persons who may be enrolled in this protocol.
1 
PROTOCOL APPROVAL 
 
Protocol Title: 
NIRS-Based Cerebral Oximetry Monitoring in Elderly Thoracic Surgical Patients Undergoing 
Single Lung Ventilation Procedures: A Single Center, Prospective, Randomized Controlled Pilot 
Study Assessing the Clinical Impact of NIRS-Guided Intervention 
Protocol Version: 5 January 2013 
Revised 04 September 2018 
 
 
 
 
 
 
 
 
 
Philip Linden, M.D. 
 
 
 
 
 
 
 
Date 


3 | Page 
 
2 
STUDY SYNOPSIS 
 
Name of Sponsor: Investigator initiated – Philip Linden, M.D. 
 
Name of Product: INVOS® 5100 Near Infra-Red Spectrophotometer (Covidien, Boulder, CO) 
 
Title of Study: Near Infra-Red Spectrophotometry (NIRS)-Based Cerebral Oximetry Monitoring in 
Elderly Thoracic Surgical Patients Undergoing Single Lung Ventilation Procedures: A Single Center, 
Prospective, Randomized Controlled Pilot Study Assessing the Clinical Impact of NIRS-Guided 
Intervention 
Study Center: University Hospitals Case Medical Center (UHCMC), Cleveland, OH – Case Western 
Reserve University School of Medicine (CWRUSOM) 
Study Rationale 
The use of bi-frontal, near infrared spectrophotometry (NIRS) based cerebral oximetry monitoring has 
been demonstrated to result in improved clinical outcomes in both general surgery patients and cardiac 
surgical patients using prospective, randomized controlled trial methodology. Elderly thoracic surgical 
patients undergoing procedures that involve single lung ventilation may also stand to benefit from the 
application of intraoperative and early postoperative NIRS cerebral oximetry monitoring. Cerebral 
oximetry has not been established as a standard of care monitoring modality in this patient population, 
thus permitting the application of randomized, controlled testing methodology to assess the potential 
impact of this monitoring modality upon these patients. 
 
Hypothesis and Objectives: 
The primary hypothesis in this pilot study of elderly thoracic surgical patients undergoing procedures 
involving single lung ventilation (SLV) is that there will be a measurable and significant clinical benefit 
(as assessed by a broad range of postoperative clinical outcome measures) to the subjects randomized to 
the intervention cohort (open bi-frontal NIRS based cerebral oximetry monitoring with a standardized 
intervention protocol) vs. the control cohort (blinded bi-frontal NIRS based cerebral oximetry 
monitoring). 
The primary objective of this pilot study is to identify the most relevant clinical outcome variables which 
significantly diverge as a result of being randomized to the intervention cohort vs. the control cohort so 
that a larger, multicenter, prospective, randomized controlled clinical trial can be designed to further test 
the primary hypothesis as stated in the preceding section. The subsequent larger, multicenter trial will be 
conducted to definitively demonstrate the ability of INVOS® 5100 guided NIRS-based bi-frontal 
monitoring to improve clinical outcomes in this surgical patient group and potentially establish a new 
U.S. Food and Drug Administration cleared indication for this monitoring modality.  
Secondary objectives of this pilot study include the following:  
1)
Assess the frequency of cerebral desaturations in both the intervention and control cohorts by 
examining both the total number of patients experiencing any cerebral desaturation as well as the total 
number of events among patients experiencing any cerebral desaturation (of at least 5% below 


4 | Page 
 
baseline and progressively larger desaturations). These analyses will be conducted on the entire study 
population as well as upon each cohort. The Area Under the Curve (AUC) analysis technique 
[incremental desaturation categories will be assessed based upon 5 to 50% decreases, measured in 5% 
increments, from established room air pre-incision baseline as well as oxygen supplemented 
preincision baseline as well as desaturations below absolute measured rSO2 values] will be employed 
to conduct these analyses.  
2)
Assess the frequency of adverse clinical events and serious adverse events overall and in each cohort.  
3)
Perform a comprehensive assessment of the frequency and efficacy of predefined rSO2 desaturation 
mitigation interventions and their collective ability to affect the observed cerebral oximetry values.  
4)
Assess the interventional cohort’s preoperative demographics and collected covariates for association 
with the ease or difficulty of mitigating observed cerebral desaturation events. 
Exploratory analyses will include performing all possible comparisons of the two groups based upon all 
collected perioperative variables to examine the potentially significant relationships between the collected 
clinical variables representing surrogates of organ perfusion/function and cerebral oximetry desaturations 
(AUCrSO2). The following exploratory endpoints will be assessed: 
•
Logistic regression analysis to determine the most relevant AUCrSO2 desaturation value(s) associated 
with any detrimental clinical outcome(s) monitored in this study 
•
Logistic regression analysis to determine the most relevant AUC blood pressure values associated 
with any detrimental clinical outcome(s) monitored in this study 
•
Comparison of baseline rSO2 values (room air and oxygen supplemented) to all collected clinical 
variables to assess for possibly significant associations 
•
Explore the potential impact of rSO2 monitoring on changing the surgical conduct of the procedure 
Methodology: Single center, prospective, randomized, controlled clinical pilot study 
Number of Subjects: 100 subjects with balanced randomization (1:1) to control (blinded NIRS data) or 
intervention (open NIRS data) cohorts 
Main Criteria for Inclusion: Elderly patients (> 65 years of age) scheduled for a thoracic surgical 
procedure at UHCMC that will involve SLV.  
 
Duration of Treatment: Cerebral oximetry monitoring will begin with an assessment of both room air 
and oxygen supplemented bi-frontal baseline NIRS values and continue through the surgery to either 
PACU discharge or the initial 12 hours of post surgical ICU treatment. Mini Mental Status exam testing 
and Delirium testing with the Confusion Assessment Method will occur preoperatively and 
postoperatively through post-operative day (POD) #3 (or discharge if that occurs sooner than POD #3). 


5 | Page 
 
Enrolled subjects will be followed during the index hospitalization and will undergo a 30 day follow up 
telephone interview to assess their progress following hospital discharge. 
 
Criteria for Evaluation: 
A large number of intraoperative and postoperative clinical variables that include cerebral oximetry, pulse 
oximetry, blood pressure, a composite outcome measure and clinical variables representing organ 
function will be assessed with the primary endpoint being the determination of which clinical variables 
are improved, if any, as a result of being randomized to open NIRS data monitoring with a predefined 
desaturation intervention algorithm guideline. The Mini Mental Status exam and Confusion Assessment 
Method test will be used to determine if any measured clinical variables have an effect upon 
neuropsychological outcomes. The frequency and effectiveness of the various cerebral desaturation 
mitigating interventions will be assessed in the intervention cohort. 
 
Additional Safety Observations: 
The frequency and severity of adverse clinical events and serious adverse clinical events will be assessed 
to determine if the use of open NIRS data bi-frontal cerebral monitoring is associated with any significant 
change in the observation of such events. 
 
Statistical Methods: 
Preoperative demographics and clinical variables will be compared in the two groups to assess for 
significant differences using the independent t-test. Differences in the observed clinical data between 
groups will be determined with the Wilcoxon rank-sum test. Stepwise, forward, multivariable logistic 
regression analysis will be performed to assess for relationships between cerebral desaturations and any 
of the measured clinical variables with a p value < 0.05 being considered significant.  


6 | Page 
 
3 
TABLE OF CONTENTS 
 
1 PROTOCOL APPROVAL……………………………………………………………….2 2 
STUDY 
SYNOPSIS……………………………………………………………………….3 
3 
TABLE 
OF 
CONTENTS…………………………………………………………………6 
4 
LIST OF ABBREVIATONS AND DEFINITIONS OF TERMS……………………....8 5 
BACKGROUND  AND RATIONALE …………………………………………………. 9 
5.1 Introduction 
5.2 Background 
5.3 Clinical Studies 
5.4 Study Rationale 
6 
TRIAL OBJECTIVES AND PURPOSE………………………………………………..10 
6.1  Primary Hypothesis 
6.2  Primary Objective 
6.3  Secondary Objectives 
6.4  Exploratory Objectives 
7 
STUDY DESIGN………………………………………………………………………….11 
 
7.1 Study Design 
 
7.2 Study Periods 
 
 
7.2.1 Screening Period 
 
 
7.2.2 Baseline Acquisition Period 
 
 
7.2.3 Intraoperative and Immediate Postoperative Period 
 
 
7.2.4 Postoperative Follow Up Period 
 
7.3 Schematic Diagram of Trial Design 
 
7.4 Study Variables 
 
 
7.4.1 Primary Endpoints 
 
 
 
7.4.1.1 Intraoperative 
 
 
 
7.4.1.2 Postoperative 
8 
STUDY DEVICE…….……………………………………………………………………19 
8.1 Device Description 
8.2 Indications for Use 
8.3 Food and Drug Administration Status 
8.4 Technological Characteristics 
8.5 Device Image 
9 
SUBJECT SELECTION………………………………………………………….20 
 
9.1 Study Population 
 
 
9.1.1 Inclusion Criteria 
 
 
9.1.2 Exclusion Criteria 
 
9.2 Withdrawal Criteria 
10 
TREATMENT OF SUBJECTS…………………………………………………..21 
 
10.1 Study Device 
 
10.2 Intervention Group 
 
10.3 Control Group 


7 | Page 
 
11 
PROTOCOL ASSESSMENTS AND PROCEDURES …………………………………22 
 
11.1 Protocol Assessments and Procedures – Screening Period 
 
 
11.1.1 General Screening Period Description 
 
 
11.1.2 Informed Consent 
 
 
11.1.3 Randomization and Preoperative Variables Collected 
 
 
 
11.1.3.1 Demographics and Clinical Variables Collected 
11.2 Protocol Assessments and Procedures – Baseline Acquisition Period 
 
 
11.2.1 General Baseline Acquisition Period Description 
11.2.2 Randomization 
 
 
11.2.3 MMSE and CAM Baseline Exams Obtained 
 
 
11.2.4 Baseline rSO2 data acquisition 
 
 
 
11.2.4.1 Room Air Baseline rSO2 
 
 
 
11.2.4.2 Oxygen Supplemented Baseline rSO2 
 
 
 
11.2.4.3 Blinding of Control Group 
 
11.3 Protocol Assessments and Procedures – Intraoperative and Immediate Postoperative Period 
 
 
11.3.1 General Intra/Immediate Post-operative Period Description 
11.3.2 Serial rSO2, SpO2 and Blood Pressure Data Collection 
 
 
11.3.3 Intraoperative and Immediate Postoperative Clinical Variables Data Collection 
 
 
 
11.3.3.1 Intraoperative Clinical Variables Data Collection 
 
 
 
11.3.3.2 Immediate Postoperative Clinical Variables Collected 
 
11.4 Protocol Assessments and Procedures – Postoperative Follow Up Period 
 
 
11.4.1 General Postoperative Follow Up Period Description 
 
 
11.4.2 Postoperative Day 1 and  3 MMSE and CAM Assessments 
 
 
11.4.3 Postoperative Clinical Variables Collected 
 
 
 
11.4.3.1 Postoperative Clinical Variables Collected 
 
 
11.4.4 Postoperative 4 week Telephone Interview 
12
TRIAL SAFETY…………………………………………………………………………..29 
 
12.1 Expert Clinician Unbiased Trial Safety Assessment 
13 
ADVERSE EVENTS………………………………………………………………………29 
 
13.1 Definitions 
 
 
13.1.1 Adverse Event 
 
 
13.1.2 Serious Adverse Event 
 
13.2 Procedures for Adverse Event Reporting 
14 PROTOCOL DEVIATIONS……………………………………………………………..30 15 
STATISTICAL 
PLAN 
……………………………………………………………………31 
16  
RECORDS 
RETENTION……….………………………………………………………..31 
17 
ETHICS AND RESPONSIBILITY…..…………………………………………………..31 
 
17.1 Informed Consent 
 
17.2 Institutional Review Board 
18
CONFIDENTIALITY …………………………………………………………………….32 
19
REFERENCES…………………………………………………………………………….32 
 
 
 
 
 
 


8 | Page 
 
 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
 
Adverse Event 
AUC  
Area Under the Curve 
CAM  
Confusion Assessment Method test 
CI 
 
Confidence Interval 
CWRUSOM Case Western Reserve University School of Medicine 
GCP 
 
Good Clinical Practices 
H-LOS
Hospital Length of Stay 
ICU 
 
Intensive Care Unit 
MMSE
Mini Mental Status Examination 
MOMM 
Major Organ Morbidity and Mortality 
NIRS   
Near Infra-Red Spectrophotometry 
OR 
 
Odds Ratio 
POD  
Post Operative Day 
rSO2  
Regional Oxygen Saturation (frontal lobe) 
SAE 
 
Serious Adverse Event 
SLV 
 
Single Lung Ventilation 
STS 
 
Society of Thoracic Surgeons 
UHCMC 
University Hospitals Case Medical Center


9 | Page 
 
5 
Background and Rationale 
 
5.1  Introduction 
This protocol is a pilot study designed to assess the clinical impact of the intraoperative and immediate 
postoperative use of regional, near infra-red spectrophotometric (NIRS) monitoring using the INVOS® 
5100 to assess bi-frontal cerebral oxygenation in elderly thoracic surgical patients undergoing procedures 
involving single lung ventilation (SLV). We seek to determine the impact of NIRS bi-frontal monitoring 
on any relevant clinical variables in the selected patient population in order to most efficiently design a 
multicenter, prospective, randomized controlled trial to definitively describe the potential clinical impact 
of this monitoring modality in the postoperative period.   
This study will be conducted in compliance with Good Clinical Practices (GCP) including the 
Declaration of Helsinki and all applicable regulatory requirements. 
5.2 Background 
Cerebral oximetry monitoring has been in clinical use for over thirty years and has been commercially 
available to clinicians for over two decades. (Jobsis FF) The use of specific wavelengths of near infrared 
light along with an understanding of the Lambert-Beer Law permits determination of a regional, venous 
weighted saturation (75% venous : 25% arterial with the INVOS® device) of tissue beneath the sensor. 
Specifically, the device is measuring the percentage of oxygenated hemoglobin in blood vessels less than 
100 microns in diameter (i.e. the exchange vessels including arterioles, capillaries and venules). (Avery 
EG) The venous weighted nature of the measurement allows for the determination of the oxygen balance 
within the interrogated tissue. For example, desaturated tissue will have lower regional saturation values 
as a result of decreased oxygen delivery and/or increased oxygen extraction.  
5.3 Clinical Studies 
Since this technology was made commercially available to practitioners several clinical studies 
including prospective, randomized controlled trials, both prospective and retrospective observational 
studies as well as a number of case reports have been published that support the use of NIRS-based 
cerebral and somatic tissue oximetry in surgical and critically ill patients. These clinical studies have been 
conducted in diverse groups of surgical patients which have demonstrated clinically beneficial outcomes 
for subjects who were monitored with this technology along with the implementation of standardized 
interventional algorithms designed to mitigate any observed desaturations. Among the patient groups that 
have been studied are general, vascular, adult cardiac, pediatric cardiac, adult thoracic surgical and 
neurocritical care patients. (Casati A  et al, Murkin JM et al, Slater JP et al, Kasman N et al, Tang L et al) 
The use of these devices has been associated with improved clinical outcomes (decreased intensive care 
unit (ICU) and hospital length of stay (LOS), decreased stroke, decreased incidence of well accepted 
composite endpoints [i.e. the Society of Thoracic Surgery (STS) Major Organ Morbidity and Mortality 
(MOMM) composite endpoint that includes death, stroke, renal dialysis, surgical re-exploration, 
prolonged ventilation and mediastinitis] as well as decreased incidence of neurocognitive dysfunction) in 
observational studies as well as in prospective, randomized controlled trials which suggests more than an 
associative relationship between the use of NIRS cerebral monitoring and these improved outcomes.  


10 | Page 
 
Active testing of this technology over the past decade has brought forth the concept that by placing the 
sensors over the frontal lobe cerebral tissue and actively working to reverse the observed desaturations 
clinicians are very likely protecting the oxygen balance in all of the body’s vital organs by using the brain 
as an index organ of adequate perfusion and oxygenation. (Grocott HP) Indeed, the improved clinical 
outcomes that have been published in the peer reviewed literature suggest a diffuse effect of generalized 
organ protection (e.g., decreased hospital LOS, decreased ICU LOS, decreased STS MOMM). It appears 
that despite the regional nature of the small amount of tissue that is monitored (i.e. 15 mm3 of frontal lobe 
cortical gray matter) that this highly metabolically active cerebral tissue may be the most desirable tissue 
to assess and use as an index organ for providing adequate oxygen balance in the rest of the body.  
Clinicians caring for perioperative cardiac surgical patients (e.g., cardiac anesthesiologists, cardiac 
surgeons and perfusionists) were early adopters of this technology related to the compromised 
cardiovascular status inherent to their patient population and the complex nature of the surgical 
procedures they perform (e.g., extracorporeal circulation and deep hypothermic circulatory arrest).   
 
Study Rationale 
There are presently two prospective, randomized controlled trials which strongly support the notion 
that these devices improve perioperative clinical outcomes in surgical patients as well as a large number 
of observational studies which strengthen the association of the use these devices to improved outcomes. 
(Murkin JM et al, Cassati A et al, Goldman S et al, Heringlake M et al, Schoen J et al) However, there is 
only one published observational study performed to date involving the use of NIRS-based regional 
cerebral oximetry of thoracic surgical patients undergoing SLV. That study only assessed the association 
of NIRS-based cerebral oximetry to postoperative neurocognitive dysfunction and did find a positive 
relationship between observed cerebral oximetry data and postoperative cognitive dysfunction (i.e. 29% 
of patients had significantly decreased Mini Mental Status Exam scores at 3 hours postoperatively and a 
↓rSO2 <65% for even just 5 minutes was associated with ↑OR 2.03 [95% CI: 0.74 – 5.59]) for developing 
early neurocognitive dysfunction. (Tang L) 
Elderly thoracic surgical patients undergoing SLV related procedures were not included in any of the 
prospective randomized controlled trials and only the single, small observational study referenced above 
assessing postoperative neurocognitive dysfunction exists to test the hypothesis that NIRS based bifrontal 
cerebral monitoring has the potential to affect any clinical outcome in this subpopulation of surgical 
patients. Further, NIRS based bi-frontal cerebral monitoring is not accepted as a standard of care in 
thoracic surgical patients which permits the employment of randomized, controlled testing methodology 
in this patient population.  
The establishment of cause and effect in clinical medicine is largely dictated by the conduct of 
multicenter, prospective, randomized controlled trials. This pilot study is intended to define the optimal 
clinical endpoints and statistical design needed to establish the potential benefits of NIRS based bi-frontal 
regional cerebral oximetry monitoring in elderly thoracic surgical patients undergoing procedures 
involving SLV.  
This pilot study involves the collection not only of cerebral oximetry data but also of blood pressure 
and pulse oximetry data as well as a number of clinically relevant outcome measures that can reflect the 
adequacy of organ protection during the intraoperative and immediate postoperative period. Having serial 


11 | Page 
 
blood pressure and pulse oximetry data will allow for any possible correlations that exist between these 
standard physiologic parameters and the observed clinical outcomes to be assessed as it has been 
previously established that blood pressure control is associated with clinical outcomes in cardiac surgical 
patients (Weir M et al). Further, by collecting this data it will be possible to quantify the relative strength 
of any potential correlations of these standard physiologic parameters as well as cerebral oximetry data to 
the observed clinical outcomes potentially permitting a direct comparison of how useful optimizing these 
parameters may be in the postoperative period. Finally, we will potentially be able to establish the effect 
of blood pressure variability on observed cerebral oxygen balance in a real time clinical environment 
which could reveal that commonly used perioperative blood pressure goals alone are inadequate measures 
to optimally protect vital organs in our study population. A series of clinical experiments assessing 
cerebral autoregulation has recently been published by Dr. C. Hogue’s group which strongly suggests that 
by using conventional medical approaches clinicians may do a poor job of predicting the lower limits of 
cerebral autoregulation and providing adequate cerebral blood flow in patients with advanced 
cardiovascular disease undergoing procedures involving the use of cardiopulmonary bypass. (Joshi B et 
al.) Our study has the ability to help solidify Dr. Hogue’s findings which suggest that widely accepted 
discretionary blood pressure goals (e.g. maintaining mean arterial pressure within 20% of the 
preoperatively observed values) may not be adequate for optimal cerebral protection. 
6 
TRIAL OBJECTIVES AND PURPOSE 
6.1  
Primary Hypothesis 
The primary hypothesis in this pilot study of elderly thoracic surgical patients undergoing procedures 
involving SLV is that there will be a measurable and significant clinical benefit (as assessed by a broad 
range of postoperative clinical outcome measures) to the subjects randomized to the intervention cohort 
(open bi-frontal NIRS based cerebral oximetry monitoring with a standardized intervention protocol) vs. 
the control cohort (blinded bi-frontal NIRS based cerebral oximetry monitoring). 
6.2 
Primary Objective 
The primary objective of this pilot study is to identify the most relevant clinical outcome variables which 
significantly diverge as a result of being randomized to the intervention cohort vs. the control cohort so 
that a larger, multicenter, prospective, randomized controlled clinical trial can be designed to further test 
the primary hypothesis as stated in the preceding section. The subsequent larger, multicenter trial will be 
conducted to definitively demonstrate the ability of INVOS® 5100 guided NIRS-based bi-frontal 
monitoring to improve clinical outcomes in this surgical patient group and potentially establish a new 
U.S. Food and Drug Administration cleared indication for this monitoring modality.  
6.3 
Secondary Objectives 
Secondary objectives of this pilot study include the following:  
1)
Assess the frequency of cerebral desaturations in both the intervention and control cohorts by 
examining both the total number of patients experiencing any cerebral desaturation as well as the 
total number of events among patients experiencing any cerebral desaturation (of at least 5% 
below baseline and progressively larger desaturations). These analyses will be conducted on the 
entire study population as well as upon each cohort. The Area Under the Curve (AUC) analysis 


12 | Page 
 
technique [incremental desaturation categories will be assessed based upon 5 to 50% decreases, 
measured in 5% increments, from established room air baseline as well as oxygen supplemented 
pre-incision baselines as well as desaturations below absolute measured rSO2 values] will be 
employed to conduct these analyses.  
2)
Assess the frequency of adverse clinical events and serious adverse events overall and in each 
cohort.  
3)
Perform a comprehensive assessment of the frequency and efficacy of predefined rSO2 
desaturation mitigation interventions and their collective ability to affect the observed cerebral 
oximetry values.  
4)
Assess the interventional cohort’s preoperative demographics and collected covariates for 
association with the ease or difficulty of mitigating observed cerebral desaturation events. 
6.4 
Exploratory Objectives 
Exploratory objectives will include performing all possible comparisons of the two groups based upon all 
collected perioperative variables to examine the potentially significant relationships between the collected 
clinical variables representing surrogates of organ perfusion/function and cerebral oximetry desaturations 
(AUCrSO2). The following exploratory endpoints will be assessed: 
o
Logistic regression analysis to determine the most relevant AUCrSO2 desaturation value(s) 
associated with any detrimental clinical outcome(s) monitored in this study 
o
Logistic regression analysis to determine the most relevant AUC blood pressure values associated 
with any detrimental clinical outcome(s) monitored in this study 
o
Comparison of baseline rSO2 values (room air and oxygen supplemented) to all collected clinical 
variables to assess for possibly significant associations 
7 
STUDY DESIGN 
7.1 
Study Design 
This study is a single center (University Hospitals Case Medical Center), prospective, randomized, 
controlled pilot study of elderly thoracic surgical patients undergoing procedures involving the use of 
SLV. A total of 100 eligible subjects will be randomized in a balanced fashion (1:1) to either the control 
cohort that will have electronically blinded bi-frontal cerebral oximetry monitoring or the intervention 
cohort that will have open bi-frontal cerebral oximetry monitoring with a predefined intervention protocol 
for observed desaturations of greater than 20% of established oxygen supplemented baseline values (see 
Appendix C). Both the control and intervention groups will have baseline NIRS data obtained in an 
unblinded fashion. The study will be divided into four separate periods that include screening, baseline 
acquisition, intraoperative and immediate postoperative and the postoperative follow up period. 


13 | Page 
 
7.2 
Study Periods 
7.2.1 
Screening Period 
Assessing patient’s suitability for enrollment based upon defined inclusion and exclusion 
criteria. The informed consent process and enrollment will occur during this period after 
which preoperative demographics and study defined covariates will be recorded.  
7.2.2 
Baseline Acquisition Period 
 Following randomization using an envelope randomization technique to either the 
control or intervention cohort enrolled subjects will undergo baseline testing with the 
MMSE and CAM assessment tools. Subsequently all subjects will have acquisition of 
bifrontal NIRS cerebral oximetric readings on both room air and with 100% oxygen 
supplementation. The control group and the intervention group will have open NIRS 
baseline data collection. This will allow all enrolled subjects to demonstrate that a set of 
baseline rSO2 values can be obtained and thus reduce the probability of unreadable 
outliers (i.e. subjects with anomalously located frontal sinuses) being studied in the 
control group. The baseline acquisition will occur in the operating room just prior to 
anesthesia induction. 
7.2.3 
Intraoperative and Immediate Postoperative Period 
The intraoperative period will occur immediately following completion of the Baseline 
Acquisition Period. Subjects randomized to the control group will be induced into 
general anesthesia with electronically blinded rSO2 monitoring while those randomized 
to the intervention cohort will undergo open rSO2 monitoring with the application of a 
standardized interventional protocol (Appendix D) for any observed significant cerebral 
desaturations. Significant cerebral desaturations are defined as any desaturation ≥ 10% of 
established room air baseline values for each individual subject. This period will continue 
through the end of the surgical procedure to PACU discharge or if the subject goes to the 
ICU through the first 12 hours of ICU admission. 
7.2.4 
Postoperative Follow Up Period 
The postoperative follow up period will continue from PACU or ICU discharge until the 
patient telephone interview 4 weeks after the surgical procedure. The active elements of 
the study protocol which involve direct subject interaction during this period include a 
postoperative day 1 and 3 MMSE and CAM delirium assessments as well as the 4 week 
post-procedure follow up telephone interview to assess the patient’s general state of 
health following surgery including a query of any need for hospital readmission. 
 
Schematic Diagram of Trial Design 
 


14 | Page 
 
Screening
Inclusion/Exclusion assessment, informed
consent, enrollment, demographic/preoperative
data collection
Baseline Acquisition Period
Randomization, MMSE & CAM baseline exams,
room air & O2 supplemented rSO2 baseline
lue collectio
va
n  
Intraoperative & Immediate
Postoperative Period
rSO2 data & clinical variables data collection
Intervention Cohort
Open rSO2 monitoring +
Intervention Protocol
Postoperative Follow Up Period
Day 1 &3 MMSE & CAM exams, AE & SAE
monitoring, clinical variables data collection, 4‐
week postoperative telephone interview
Control Cohort
Blinded rSO2 monitoring
 
 
 
 
 
 


15 | Page 
 
7.4 
 Study Variables 
7.4.1  
Primary Endpoints 
The relationship between the observed cerebral oximetry data and a number of predefined 
intraoperative and postoperative clinical variables will serve as the primary endpoints of 
this trial. The clinical variables will include the following intraoperative and 
postoperative (PACU or initial 12 hours of the ICU stay) parameters: 
7.4.1.1 Intraoperative: 
 Area under the curve of cumulative rSO2 desaturations (AUCrSO2) of progressive 
categorical degrees that will include the following:  
o
< 5% of established room air baseline and oxygen 
supplemented baseline o < 10% of established room air 
baseline and oxygen supplemented baseline o < 15% of 
established room air baseline and oxygen supplemented 
baseline o < 20% of established room air baseline and oxygen 
supplemented baseline o < 25% of established room air 
baseline and oxygen supplemented baseline o < 30% of 
established room air baseline and oxygen supplemented 
baseline o < 35% of established room air baseline and oxygen 
supplemented baseline o < 40% of established room air 
baseline and oxygen supplemented baseline o < 60% of 
absolute measured value (if baseline > 60%) o < 55% of 
absolute measured value (if baseline > 55%) o < 50% of 
absolute measured value (if baseline > 50%) o < 45% of 
absolute measured value (if baseline > 45%) o < 40% of 
absolute measured value o < 35% of absolute measured value 


16 | Page 
 
o < 30% of absolute measured value o < 25% of absolute 
measured value o < 20% of absolute measured value 
 Area under the curve for cumulative, high and low intraoperative values outside of 
preestablished, individualized patient blood pressure goals based upon preoperatively 
observed blood pressure values as well as values clinically accepted to provide adequate 
organ perfusion. This analysis will be performed for systolic, diastolic and mean arterial 
pressures (AUCSBP-hi, AUCSBP-low, AUCSBP-cum, AUCDBP-hi, AUCDBP-low, AUCDBP-cum, 
AUCMAP-hi, AUCMAP-low, AUCMAP-cum). All intraoperative pressure data will be collected 
with either invasive arterial catheterization [Q30 secs] or non-invasive blood pressure 
monitoring [Q3 min] as determined by the attending anesthesiologist caring for the 
subject. 
 Area under the curve of intraoperative progressive categorical pulse oximetry (SpO2) 
desaturations (AUCSpO2) including the following: 
o
AUCSpO2 < 95% regardless of intraoperative FiO2 values o 
AUCSpO2 < 90% regardless of intraoperative FiO2 values o 
AUCSpO2 < 85% regardless of intraoperative FiO2 values o 
AUCSpO2 < 80% regardless of intraoperative FiO2 values o 
AUCSpO2 < 75% regardless of intraoperative FiO2 values o 
AUCSpO2 < 70% regardless of intraoperative FiO2 values 
 Use of any intraoperative, intravenous vasopressor and/or inotropic agent (as assessed by 
amount of time in minutes on any IV drug support regardless of dose and assessed by 
total dose of drug to delivered to patient) 
 Intraoperative urine output in any patient with an indwelling foley catheter as assessed by 
mLs urine/kg/hr for total time in operating room 
 Need for intraoperative red blood cell transfusion (as assessed by number of RBC units 
transfused) 
 Observed desaturation prompted change in surgical procedure (e.g., the surgery was 
paused to inflate the collapsed lung to improve systemic tissue oxygenation)  
Occurrence of any intraoperative stroke or transient ischemic attack (as assessed by 
documented clinical neurological assessment or cerebral imaging study)  Any 


17 | Page 
 
observed intraoperative myocardial ischemia or infarction (as assessed by 
intraoperative ECG changes and/or myocardial biomarkers (i.e. troponin increase) 
 Area under the curve of any observed intraoperative hyperglycemia (AUCGlu > 110 mg/dL) 
in patients with a documented history of either type I or II diabetes mellitus  Any 
occurrence of intraoperative atrial fibrillation (capturing duration of atrial fibrillation and 
whether treatment was required) 
 Total time spent in operating room 
 Total amount of narcotic administered in the operating room 
 Total volume of crystalloid administered in the operating room 
 Total volume of colloid administered in the operating room 
 Anti-emetic medications administered in the operating room 
 Surgical procedure performed 
 Time on single lung ventilation  
Intraoperative Use of epidural catheter 
7.4.1.2 Postoperative: 
 Area under the curve of rSO2 desaturations (AUCrSO2) of progressive categorical degrees 
that will include the following:  
o
< 5% of established room air baseline and oxygen 
supplemented baseline o < 10% of established room air 
baseline and oxygen supplemented baseline o < 15% of 
established room air baseline and oxygen supplemented 
baseline o < 20% of established room air baseline and oxygen 
supplemented baseline o < 25% of established room air 
baseline and oxygen supplemented baseline o < 30% of 
established room air baseline and oxygen supplemented 


18 | Page 
 
baseline o < 35% of established room air baseline and oxygen 
supplemented baseline o < 40% of established room air 
baseline and oxygen supplemented baseline o < 60% of 
absolute measured value (if baseline > 60%) o < 55% of 
absolute measured value (if baseline > 55%) o < 50% of 
absolute measured value (if baseline > 50%) o < 45% of 
absolute measured value (if baseline > 45%) o < 40% of 
absolute measured value o < 35% of absolute measured value 
o < 30% of absolute measured value 
o
< 25% of absolute measured value o < 20% of absolute 
measured value 
 Area under the curve for cumulative, high and low postoperative values outside of 
preestablished, individualized patient blood pressure goals based upon preoperatively 
observed blood pressure values as well as values clinically accepted to provide adequate 
organ perfusion. This analysis will be performed for systolic, diastolic and mean arterial 
pressures (AUCSBP-hi, AUCSBP-low, AUCSBP-cum, AUCDBP-hi, AUCDBP-low, AUCDBP-cum, 
AUCMAP-hi, AUCMAP-low, AUCMAP-cum). All postoperative blood pressure data will be 
collected with either invasive arterial catheterization [Q30 secs] or non-invasive blood 
pressure monitoring [Q15 min] as determined by the attending anesthesiologist caring for 
the subject in the PACU. 
 Area under the curve of postoperative progressive categorical pulse oximetry (SpO2) 
desaturations (AUCSpO2) including the following: 
o
AUCSpO2 < 95% regardless of intraoperative FiO2 values o 
AUCSpO2 < 90% regardless of intraoperative FiO2 values o 
AUCSpO2 < 85% regardless of intraoperative FiO2 values o 
AUCSpO2 < 80% regardless of intraoperative FiO2 values o 


19 | Page 
 
AUCSpO2 < 75% regardless of intraoperative FiO2 values o 
AUCSpO2 < 70% regardless of intraoperative FiO2 values 
 Time from procedure completion to arrival in the post anesthesia care unit (PACU) or ICU 
 Temperature upon PACU/ICU arrival 
 Aldrete score upon PACU/ICU arrival and at 30 & 60 (or at discharge) min post-PACU 
arrival (See Appendix A) 
 Any occurrence of  immediate postoperative atrial fibrillation 
 Any myocardial ischemia in the immediate postoperative period 
 Any need for allogeneic RBC transfusion in the immediate postoperative period 
 Any observed stroke or TIA in the immediate postoperative period 
 Time to clinical readiness for PACU discharge as assessed by established institutional 
discharge criteria (see Appendix B)  
 Frequency and severity of nausea and vomiting observed in the PACU and/or ICU as 
assessed by an accepted postoperative nausea and vomiting scale 
 ICU length of stay (ICU-LOS) [anticipated to be at least 10-20 evaluable subjects for this 
parameter if 100 patients are enrolled] which will be defined as time to clinical readiness 
for ICU discharge as assessed by the clinical team caring for the patient 
 Postoperative mechanical ventilation time if still intubated and admitted to the ICU 
following the surgical procedure 
 Use of any immediate postoperative, intravenous vasopressor and/or inotropic agent (as 
assessed by amount of time in minutes on any IV drug support regardless of dose and 
assessed by total dose of drug to delivered to patient) 
 Immediate postoperative urine output in any patient with an indwelling foley catheter as 
assessed by mLs urine/kg/hr for total time in operating room 
 Hospital length of stay (H-LOS) 
 Need for skilled nursing facility/rehabilitation hospital admission upon discharge from 
index hospitalization 
 Length of time spent in a skilled nursing facility/rehabilitation hospital upon discharge 
from index hospitalization if a relevant data point for each subject 


20 | Page 
 
 Need for hospital readmission for any reason within 30 days of surgical procedure  
Observed change from preoperative baseline Mini-mental Status Examination (MMSE) 
score (including postoperative day #1 and postoperative day #3 or discharge scores)  
Presence/absence of postoperative delirium (as assessed by the CAM Delirium assessment 
tool results obtained preoperatively and postoperatively upon PACU discharge, Day#1 and 3 
[or hospital discharge]) 
 Change in baseline renal function (as assessed by ΔGFR from baseline compared to 
inhospital nadir postoperative GFR estimated by the Cockroft-Galt method, 
Δpreoperative serum creatinine obtained within 6 weeks of surgical procedure to nadir 
postoperative value and any new need for any form of renal replacement therapy) 
 Postoperative use of epidural catheter 
 Documented return of bowel function time (as assessed by time to first bowel movement 
following surgical procedure) 
 Need for postoperative (any time from transfer from OR to discharge) red blood cell 
transfusion (as assessed by number of RBC units transfused) 
 Occurrence of any postoperative (any time from transfer from OR to discharge) stroke or 
transient ischemic attack (as assessed by documented clinical neurological assessment or 
cerebral imaging study) 
 Any observed postoperative (any time from transfer from OR to discharge) myocardial 
ischemia or infarction (as assessed by physical examination, intraoperative ECG changes 
and/or myocardial biomarkers [i.e. troponin increase]) 
 Postoperative (any time from transfer from OR to discharge) occurrence of any form 
infectious complication up to POD 30 
 Postoperative time to wean from supplemental oxygen 
 Postoperative (any time from transfer from OR to discharge) composite endpoint that 
includes any subject with at least one of the following: new onset atrial fibrillation, 
≥Grade 2 PONV, HLOS≥4.5 days, PACU LOS≥2 hours, any infectious complication, 
death, stroke, myocardial infarction, greater 0.5 mg/dL increase in creatinine or new need 
for renal dialysis, postoperative need for intravenous inotropes or vasoactive medications 
8 
STUDY DEVICE 
8.1 
Device Description 
The INVOS® 5100C is a 2 wavelength, diffuse reflectance spectroscopy system employing near 


21 | Page 
 
infrared light to estimate the percentage of hemoglobin saturated with oxygen in tissue 
underneath the sensor. This is similar to the noninvasive technology widely used in pulse 
oximeters to monitor oxygen saturated hemoglobin percentage in arterial blood. 
An adhesive sensor containing a light source and 2 photodiodes is applied to the skin over the 
tissue of interest and the returning light is analyzed for hemoglobin and deoxyhemoglobin light 
absorption. Absorption signals from the photodiode closer to the light source are subtracted from 
those from the farther photodiode where the returning photons penetrate more deeply in the 
tissue. This suppresses absorption events originating in the outer layers of tissue that are 
common to both photodiodes, including the effects of skin pigmentation and subcutaneous 
tissues. 
The INVOS® 5100C tissue oximeter is a multichannel monitor with continuous recording and 
display of readings of regional tissue hemoglobin oxygen saturation from 4 separate sensors 
simultaneously. The monitor is connected to 2 preamplifiers, each of which in turn supports 2 
sensors. It has USB connectivity for dynamic data capture, storage and transfer as well as a 
digital output port. 
 
8.2 
Indications for Use 
 
The noninvasive INVOS® 5100C is intended for use as a monitor which provides accurate, 
immediate feedback of regional hemoglobin oxygen saturation of blood in the brain or in other 
tissue beneath the sensor. It is intended for use in any individual at risk for reduced-flow or 
noflow ischemic states. The prospective clinical value of data from the INVOS® System has not 
been demonstrated in disease states. The INVOS® System should not be used as the sole basis 
for diagnosis or therapy. 
 
8.3 
Food and Drug Administration Status 
 
510K cleared (#K080769) April 2009 
 
8.4 
Technological Characteristics 
 
The INVOS® 5100C is an in vivo optical spectrometer using two wavelengths(730 and 810 nm) 
of near infrared light that is projected into any tissue beneath the sensor. A portion of the emitted 
light is reflected back to one of two fixed distance photodiodes (30 and 40 mm from the LED 
light source). Returning light signals are processed with a technique known as spatial resolution 
which permits removal of the majority of saturation data obtained in the more superficial scalp 
tissue and thus the final reading is thought to reflect primarily a venous weighted saturation 
(75% venous to 25% arterial) of hemoglobin below the sensor pads. The data processing occurs 
in the device preamplifier and is then sent to the display module for graphic display and storage. 
Device data can be directly transferred to a collection system via a serial cable or can be 
downloaded to a USB memory stick and further processed for analysis with an Excel® macros. 
The device has the capacity to simultaneously monitor, display and store 4 separate sets of 
monitoring data. 


22 | Page 
 
 
8.5 
 Device Image 
 
8.6  
Device Modification 
The subjects randomized to the control group will be monitored with a modified device following the 
acquisition of the baseline NIRS data. The modification involves electronic blinding of the data via an 
adjustment made to the device by the manufacturer that prevents the active display of the current data and 
graphic trends on the display console. However, the modified device will still electronically store the 
acquired NIRS data for later analysis. The use of this modified version of the device will help to reduce 
investigator bias that might be introduced if a blinder were affixed to the display console. 
 
9 
SUBJECT SELECTION 
9.1  
Study Population 
A total of 100 evaluable subjects will be enrolled into this protocol. Patients at least 65 years of age who 
are scheduled to undergo non-emergent, thoracic surgical procedures planned to involve the use of single 
lung ventilation will be evaluated in this study. 
9.1.1 Inclusion Criteria: 
1.
Any male or female patient ≥ 65 years of age and able to provide informed consent (or consent 
may be provided by a legally authorized representative) who is scheduled for a thoracic surgical 
procedure that is expected to involve the use of intraoperative single lung ventilation (SLV) 
2.
Able to adequately complete a baseline mini-mental status examination (MMSE)  


23 | Page 
 
3.
Able to complete a baseline confusion assessment method (CAM) examination 
4.
Able to obtain bi-frontal baseline rSO2 values prior to induction of anesthesia 
9.1.2 Exclusion criteria: 
1.
Any patient who has participated in a clinical study of an investigational drug or device in the 
past 30 days 
2.
Any patient who the principal investigator feels at any time or for any reason should not 
participate in this clinical study 
3.
Withdrawal of informed consent for any reason 
9.2 
Withdrawal Criteria 
All patients have the right to withdraw any point during the trial without prejudice. The 
investigator can discontinue any subject at any time if medically necessary. If the ability to 
monitor the cerebral oximetry is data is lost during the conduct of the study for a significant 
period of time that precludes useful data analysis then the subject will be withdrawn by the 
principal investigator.  
10  
TREATMENT OF SUBJECTS 
10.1 
Study Device 
The study device, INVOS® 5100C, is described in Section 8. Enrolled subjects will be 
randomized in a balanced fashion (1:1) to either the control group (blinded cerebral oximetry 
monitoring intraoperatively and in the immediate postoperative period) or to the intervention 
group (open cerebral oximetry monitoring with the use of a standardized intervention protocol 
for observed desaturations greater than 20%).  
10.2 
Control Group 
The control group will have both room air and oxygen supplemented baselines obtained in an 
antecedent fashion to establish that they can produce reliable bilateral cerebral oximetry 
readings. Because it is known that the device may not be able to produce a valid reading in some 
individuals with pigmented skin or aberrantly located frontal sinuses this step is necessary to 
insure that all subjects in the control group will produce useful NIRS data. Once the baseline 
values have been recorded the cerebral oximetry will be monitored in an electronically blinded 
manner. Specifically, the device will capture data but neither the current values nor the trend will 
be displayed on the device’s display console. The use of this modified version of the device will help 
to reduce investigator bias that might be introduced if a blinder were affixed to the display console. The 
baseline values will be obtained prior to the induction of general anesthesia. 


24 | Page 
 
10.3 
Intervention Group 
The intervention group will have baseline NIRS values obtained in a manner analogous to the 
control group. Following recording of the baseline values the subjects will be induced into 
general anesthesia and the clinicians as well as an IRB registered research assistant will be able 
to openly monitor the NIRS data. Upon observed cerebral desaturations greater than 20% of the 
oxygen supplemented baseline on either frontal hemisphere the research assistant will inform the 
anesthesia clinician that a significant cerebral desaturation is occurring and requires treatment. At 
this point a standardized interventional protocol will be followed that is detailed in Appendix C. 
The clinicians caring for the subject will have the ability to override the study intervention 
algorithm based upon the patient’s physical condition at the time.  
The intervention protocol for observed desaturations >20% will involve insuring that the 
subject’s head vessels are not kinked or obstructed, increasing the mean arterial pressure via an 
intravenous fluid bolus  or administration of a vasoconstrictor (i.e.  henylephrine or ephedrine) 
as deemed appropriate by the anesthesia clinician caring for the subject, normalizing PaCO2 to a 
value between 40 to 50 mmHg, or alternatively normalizing end tidal CO2 to a value of 35 to 45 
mmHg. Subsequent interventions may include increasing the FiO2, especially if the SpO2 is 
below 98% or administering an intravenous inotropic agent if a low flow state is suspected. 
Administration of an inotrope will occur as judged by the clinician caring for the subject. Finally, 
in cases where the subject’s hematocrit is known or suspected to critically low transfusion of 
allogeneic blood will be considered. The decision to transfuse allogeneic blood will be made by 
the anesthesia and surgery clinicians caring for the subject. 
11 
PROTOCOL ASSESSMENTS AND PROCEDURES 
The Schedule of Assessments which details the sequence of assessments and procedures is 
presented in Table 1. Note that as described in Section 7.2 there are four separate periods that 
this study is divided into that include the following: screening, baseline , intraoperative and 
immediate postoperative and postoperative follow up. 


Table 1: Schedule of Assessments 
  
Screening 
Baseline 
Acquisition 
Intraoperative and Immediate 
Postoperative 
Postoperative Follow 
Up 
Study Assessment 
  
  
  
  
  
  
  
  
  
Review of inclusion/exclusion criteria 
X 
  
  
  
Informed consent 
X 
  
  
  
Demographics 
X 
  
  
  
Medical history 
X 
  
  
  
Randomization 
  
X 
  
  
  
  
  
  
MMSE & CAM testing 
  
X 
  
X 
Serum creatinine 
X 
  
  
X 
Obtain baseline room air and O2 supplemented rSO2
 
  
X 
  
  
Continuous rSO2, SpO2, blood pressure data collection 
  
  
X 
  
Employ rSO2 desaturation algorithm (intervention group 
only) 
  
  
  
X 
  
  
Continuous intra/immediate post-operative clinical 
variable collection 
  
  
X 
  
PACU and ICU clinical variable collection 
  
  
X 
  
Postoperative clinical variable collection 
  
  
  
X 
X 
Adverse and Serious Adverse Event Monitoring 
  
X 
X 
X 
Telephone interview 
  
  
  
X 
 


25 | Page 
 


27 | Page 
 
11.1 
Protocol Assessments and Procedures – Screening Period 
11.1.1 
General Screening Period Description 
Screening of potential subjects will occur prior to the planned surgical procedure to allow 
individuals time to consider their participation. Subjects will be screened from the daily 
Mather Operating Room printed schedule. Subjects scheduled to undergo surgical procedures 
that appear to meet the primary inclusion criteria will be approached for additional screening 
in the Mather Preoperative Area. An IRB registered investigator or nurse coordinator will 
approach the patient if they are willing to consider listening to a brief description of the 
study. Patients who verbally agree to learn more about the study will then have a discussion 
with the IRB registered study investigator or nurse coordinator which includes the details of 
the study explained in clear and concise language. During this conversation the voluntary 
nature of any individual’s participation will be clearly communicated. Additionally, the 
discussion will include a description of what the patient’s participation will entail, including 
the voluntary nature of their participation, their ability to withdraw at any time, the 
confidential nature of their participation, the procedures that will occur among study 
participants, the information that will be collected from participants and all of the risks and 
benefits associated with their participation in the trial. Additionally, the study staff will 
explain to the patient how their hospital care may be different if they choose to participate in 
the study, including the fact that they will be randomized to either the control group or the 
intervention group with a 50% chance of being assigned to either group. The implications of 
being assigned to either group will be discussed. 
11.1.2 
Informed Consent 
Patients will also be given the opportunity to ask questions of the study investigator or nurse 
coordinator and express their personal concerns about what their participation may entail. If 
the patient wishes to participate then the study investigator will then review the study consent 
form in a page-by-page manner to insure that they understand all aspects of what their 
participation will include. At this point additional time to personally review the consent form 
document will be given to each potential subject.  Following this, potential participants will 
then be given another opportunity to ask questions and once all of them have been 
satisfactorily addressed the subject and the study investigator will sign, time and date the 
consent form. A copy of the consent will be placed in the patient’s chart and given to the 
patient’s family/escort or will be secured and given to the patient after their surgical 
procedure.  
11.1.3 
 Preoperative Variables Collected 
Following finalization of informed consent the patient’s chart will be reviewed to ensure that they 
are appropriate for participation based upon the study’s inclusion and exclusion criteria. 


28 | Page 
 
Additionally, the patient’s records will be reviewed and key demographics and 
clinical variables will be collected using a standardized data collection tool.  11.1.3.1 
Demographics and clinical variables collected 
Age 
Gender 
Race 
Height 
Weight 
BMI 
Serum creatinine 
Hemoglobin 
LVEF 
+/- Vascular disease 
+/- Stroke/TIA 
+/- CAD 
+/- Recent MI 
+/- CHF 
+/- DM Type II (insulin) 
+/- DM Type II (non-insulin) 
+/- Renal Insufficiency 
+/- COPD 
+/- OSA 
+/- Dementia 
+/- Alcohol use 
+/- Tobacco use 
+/- Illicit drug use
 
11.2 
Protocol Assessments and Procedures – Baseline Acquisition Period 
 
11.2.1 
General Baseline Acquisition Period Description 
 
During the baseline acquisition period each subject will be randomized and then the neurocognitive 
baseline exams will be obtained. Additionally, the baseline rSO2 data will be collected. 
 
11.2.2 
Randomization 
 
Next, each subject will be randomized in a balanced fashion (1:1) to either the control group or 
the intervention group. Randomization will occur through the use of a blinded envelope 
technique at which time each subject will acquire a unique study identifier for their study 
records. 
 
11.2.3 
MMSE and CAM Baseline Exams Performed 
 
The mini-mental status examination and the confusion assessment method examination will be 
performed upon each subject to establish baseline performance prior to entering the operating 
room for their surgical procedure. A trained study investigator will conduct these two exams.  
 
11.2.4 
Baseline rSO2 Data Acquisition 
Once in the operating room the patient will have standard monitors applied as well as bilateral 
rSO2 sensor pads to the glabrous skin of the forehead just above the eyebrow line. The 
application of the pads will be preceded by swabbing the skin with an alcohol pad and 
applying both mastisol and clear tape to promote pad adhesion throughout the collection of 
NIRS data.  


29 | Page 
 
11.2.4.1 
Room Air Baseline rSO2 
Once the pads are in place approximately one minute will elapse to insure 
that a reliable NIRS signal is obtained and that it is producing stable 
values bilaterally while they are in the supine position just prior to the 
preoxygenation period of anesthesia induction. Both the left and right 
baseline values will then be recorded. The time of this event will be 
recorded on the study data collection tool. 
11.2.4.2 
Oxygen Supplemented Baseline rSO2 
Once that subject has been breathing 100% oxygen for a full two minutes 
as assessed by the research assistant’s timer the oxygen supplemented rSO2 baselines will 
be recorded when the NIRS data is stable bilaterally. The time of this event will be 
recorded on the study data collection tool. 11.2.4.3 Blinding of Control Group 
After recording the two sets of baseline rSO2 data the subjects that have 
been randomized to the control group will have their rSO2 data 
electronically blinded via activation of a device modification that will 
have been previously performed by the device manufacturer.  
11.3 
Protocol Assessments and Procedures – Intraoperative and Immediate Postoperative 
Period 
11.3.1 
General Intraoperative and Immediate Postoperative Period Description 
During this period a host of clinical variables will be collected on each subject that will serve as 
the primary endpoints of this pilot study. 
11.3.2 
Serial rSO2, SpO2 and Blood Pressure Data Collection 
Anesthesia induction will be accompanied by continuous electronic acquisition of the rSO2, 
SpO2 and MAP data. PICIS will be used to collect blood pressure data as well as rSO2 data in 
individuals randomized to the intervention group.  The INVOS devices will also be collecting 
the rSO2 data in both groups of subjects for download at a later time. Note that the time on 
the oximeter will be synchronized with the time on the PICIS Anesthesia Computer prior to 
the collection of any NIRS or hemodynamic data.   
 
11.3.3 
Intraoperative and Immediate Postoperative Clinical Variable Data Collection 
 
11.3.3.1  
Intraoperative Clinical Variables Collected 
 
Vasopressor use 
Amount of narcotic administered
Inotrope use 
Time on single lung ventilation 


30 | Page 
 
Urine output 
Anti-emetic medication administered 
Myocardial ischemia 
Total crystalloid administered 
Stroke or TIA 
Total colloid administered 
Hyperglycemia AUCGlu > 110 
Total transfused allogeneic RBCs Atrial 
fibrillation 
Use of epidural catheter 
Surgical procedure 
rSO2 prompted change in surgery 
Time spent in operating room 
 
 
11.3.3.2 
Immediate Postoperative Clinical Variables Collected 
Vasopressor use 
Antiemetic medication administered 
Inotrope use 
Total crystalloid administered 
Urine output 
Total colloid administered 
Myocardial ischemia 
Temperature on arrival 
Stroke or TIA 
Aldrete score (arrival, 30 & 60 min) 
Hyperglycemia AUCGlu > 110 
PONV Severity 
Atrial fibrillation 
Time to PACU d/c readiness 
Time spent in PACU/ICU 
Time on mechanical ventilation 
Amount of narcotic administered 
 
 
11.4 
Protocol Assessments and Procedures – Postoperative Follow Up Period 
11.4.1 
General Description Postoperative Follow Up Period 
 
During this period each subject will undergo repeat neuropsychological testing and a host of 
postoperative clinical variables will be collected prior to their discharge from the hospital. 
Additionally, this period includes a 4 week postoperative follow up telephone interview with 
each subject. 
 
11.4.2 
Postoperative Day 1 and  3 MMSE and CAM Assessments 
 
The MMSE and the CAM assessment will be repeated on each subject on postoperative days 1 
and 3.  
 
11.4.3 
Postoperative Clinical Variables Collected 
 
 
11.4.3.1 
Postoperative Clinical Variables Collected 
 
ICU-LOS 
Hospital-LOS 
Atrial fibrillation 
SNF or Rehab transfer on d/c 


31 | Page 
Time spent in SNF/Rehab 
Need for hospital readmission 
Change in baseline renal function 
Return of bowel function time 
Postoperative stroke or TIA 
Postoperative myocardial 
ischemia 
Postoperative RBC transfusion 
Any postoperative infection 
Postoperative composite 
endpoint 
 
11.4.4 Postoperative 4 Week Telephone Interview 
 
At 4 weeks (+/- 5 days) from the day of the surgical procedure a study team member will 
make a telephone call to the subject with the goal of assessing overall well being, if there 
was any need for hospital readmission or emergency ward visit, and if applicable how 
many days the subject remained in a skilled nursing facility or rehabilitation hospital. 
 
12 
TRIAL SAFETY 
 
12.1 
Expert Clinician Unbiased Trial Safety Assessment 
 
 
This trial will not employ a data safety monitoring board as three clinical trials 
with a similar design, sicker patients and larger (n) values have been previously 
conducted using the same cerebral oximetry device without evidence of safety 
concerns. (Ref Casati, Murkin, Slater) Instead, there will be two planned interim 
assessments of the collected adverse event data that will be reviewed by a clinical 
expert in the care of thoracic surgical patients as well as in clinical trial design 
and execution. Professor Manuel L. Fontes, M.D. of the Department of 
Anesthesiology at Duke University School of Medicine will perform a review of 
collected adverse event data after enrollment of 25 subjects and 50 subjects. If Dr. 
Fontes has concerns additional analyses will be performed on the collected 
clinical data to determine in any real safety issues exist for the subjects 
participating in this trial. Dr. Fontes will provide a report to detail his conclusions 
and recommendations based upon the data he reviews. This data will be shared 
with the UHCMC IRB. 
 
13 
ADVERSE EVENTS 
13.1 
DEFINITIONS 
13.1.1 Adverse Event 
 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product or procedure and which does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal lab finding), symptom or disease 
temporarily associated with the use of a medicinal product or procedure, whether or not 
considered related to this treatment.  


32 | Page 
 
 
Planned hospital admissions and/or surgical operations for an illness or disease that 
existed before the drug or procedure was given to the subject or the subject was randomized 
in a clinical study are not to be considered AEs. 
The severity of an AE and the relationship to study drug will be assessed by the 
investigator. The investigator will ensure that any patient experiencing an AE receives 
appropriate medical support until the event resolves. 
 
13.1.2 Serious Adverse Events 
 
A serious adverse event (SAE) is any untoward medical occurrence that: 
results in death, 
is life threatening, i.e., the subject was,, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred (It does not include an 
event that, had it occurred in a more severe form, might have caused death), 
results in a persistent or significant disability/incapacity, is 
a congenital anomaly/birth defect, or 
is another medically significant event that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
A distinction should be drawn between serious and severe AEs. Severity is an estimate or 
measure of the intensity of an AE, while the criteria for serious AEs are indications of 
adverse subject outcomes for regulatory reporting purposes. A severe AE need not 
necessarily be considered serious and a serious AE need not be considered severe. 
 
13.2 
PROCEDURES FOR ADVERSE EVENT RECORDING 
 
An AE report will be created for each observed event and keep with the study 
records. Both co-PIs will review and sign all generated AE reports. At the time 
the AE is reported the causality relationship to the study procedures will be 
determined by the co-PIs. The AE reports will be reviewed by an external, 
unbiased expert at defined intervals as described in Section 12.1.  
 
Additionally, all observed SAEs will prompt the creation of a report which will be 
handled in a similar manner to that described for any observed AE. All SAE 
reports will be completed within 24-48 hours of learning of their occurrence. The 
SAE reports will also be shared with the IRB once they are completed. 
 
14 
PROTOCOL DEVIATIONS 
   
 


33 | Page 
 
 
This trial will be conducted as described in this protocol, except for an emergency 
situation in which the protection, safety, and well being of the subject requires immediate 
intervention, based on the judgment of the investigator. In the event of a significant deviation 
from the protocol due to an emergency, accident, or mistake, the investigator or designee will 
report the deviation to the UHCMC IRB in a timely manner (i.e. within approximately one 
business week from learning of the deviation). The UHCMC IRB will be informed of all 
protocol changes by the principle investigator in accordance with established procedure. No 
deviations of any type will be made without complying with all the UHCMC IRB established 
procedures.  
 
15 
STATISTICAL PLAN 
 
All collected data in the case report form will be transferred into a customized electronic 
database upon completion of the study for the purpose of facilitating statistical analysis. 
Preoperative demographics and clinical variables will be compared in the two groups to 
assess for significant differences using the independent t-test. Differences in the observed clinical 
data between groups will be determined with the Wilcoxon rank-sum test. Stepwise, forward, 
multivariable logistic regression analysis will be performed to assess for relationships between 
cerebral desaturations and any of the measured clinical variables with a p value < 0.05 being 
considered significant.  
 
16  
RECORDS RETENTION 
 
 
Study records will be retained for a period of at least five years following completion of 
this clinical study and, if applicable for at least two years after a new indication application is 
submitted to the US FDA based on this data. All records will be kept in limited access areas of 
UHCMC in locked offices or will be transferred to secure file storage facilities. All electronic 
data will be kept on UHCMC password protected computer hard drives that are located in locked 
office space. 
 
17 
ETHICS AND RESPONSIBILITY 
 
 
This study will be conducted in compliance with the protocol, with US FDA regulations, 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, 
Declaration of Helsinki and with the UHCMC IRB procedures.  
 
17.1 
INFORMED CONSENT 
 
Written informed consent will be obtained from all patients (or their guardian or 
legally authorized representative) before any study-related procedures (including 
any pre-treatment procedures) are performed. The investigator(s) has both the 
ethical and legal responsibility to ensure that each patient being considered for 
inclusion in this study is given a full explanation of the protocol. This shall be 
documented on a written informed consent form, which shall be approved by the 


34 | Page 
 
UHCMC IRB. Each informed consent shall include the elements required by 
FDA regulations in 21 CFR Part 50 and ICH, Part E6, Section 4.8.  
 
Once the appropriate essential information  has been provided to the patient and 
fully explained by the investigators (or qualified designee) and it is felt that the 
patient understands the implications of participating , the patient and the 
investigator (or designee) shall sign the IRB-approved written informed consent 
form. The patient shall be given a copy of the signed informed consent, a second 
copy will be placed in the subject’s medical records, and the original shall be kept 
in the site’s regulatory file or the patient’s medical record.  
 
17.2 
INSTITUTIONAL REVIEW BOARD 
 
This protocol and the written informed consent shall be submitted to the UHCMC 
IRB. Notification in writing of approval must come from the UHCMC IRB to the 
principal investigators as a letter.  The investigator will submit continuing review 
reports to the UHCMC IRB when applicable per regulations. The UHCMC IRB 
will be notified in writing of the interruption or completion of the study by the 
principal investigator. The principal investigator will maintain accurate and 
complete set of all written correspondence to and received from the UHCMC 
IRB. 
 
18 
CONFIDENTIALITY 
 
 
All information generated in this study will be considered highly confidential and will not 
be disclosed to any persons not directly concerned with the study without written prior 
permission. However, authorized regulatory officials will be allowed full access to the records. 
Only the subjects initials and a unique subject identification number that will be documented in 
the source records and the CRF will be used to identify patients as study subjects.  
 
19  
REFERENCES 
 
Weir M, Aronson S, Avery EG, et al. Acute kidney injury following cardiac surgery: the role of 
acute blood pressure control. American Journal of Nephrology 2011;33(5):438-52. 
 
Avery EG. Cerebral oximetry is frequently a “first alert” indicator of adverse outcomes. White 
paper. October 2010. http://www.somanetics.com/images/stories/pdfs/white-paper-series.pdf 
Last accessed   08-05-2012 
 
Casati A, Fanelli G, Pietropaoli P, et al. Continuous monitoring of cerebral oxygen saturation in 
elderly patients undergoing major abdominal surgery minimizes brain exposure to potential 
hypoxia. Anesthesia and Analgesia 2005;101(3):740-7. 
 


35 | Page 
 
Goldman S, Sutter F, Ferdinand F, et al. Optimizing cerebral oxygen delivery using noninvasive 
cerebral oximetry decreases the incidence of stroke for cardiac surgical patients. Heart Surgery 
Forum 2004;7(5):E376-81. 
 
Grocott HP. Avoid hypotension and hypoxia: an old anesthetic adage with renewed relevance 
from cerebral oximetry monitoring. Canadian Journal of Anesthesia 2011;58:697-702. 
 
Heringlake M, Garbers C, Kabler J, et al. Anesthesiology 2011;114(1):58-69. 
 
Jobsis, FF. Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and 
circulatory parameters. Science 1977;198(4323):1264-7. 
 
Joshi B, Ono M, Brown C, et al. Predicting the limits of cerebral autoregulation during 
cardiopulmonary bypass. Anesthesia and Analgesia 2012;114:503-10. 
 
Kasman N, Brady K. Cerebral oximetry for pediatric anesthesia: why do intelligent clinicians 
disagree? Pediatric Anesthesia 2011;21(5):473-8 
 
Murkin JM, Adams SJ, Novick RJ, et al. Monitoring brain oxygen saturation during coronary 
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Schoen J, Meyerrose J, Paarmann H, et al. Preoperative regional cerebral oxygen saturation  is a 
predictor of postoperative delirium in on-pump cardiac surgery patients: a prospective 
observational trial. Critical Care 2011;15:R218 
 
Slater JP, Guarino T, Stack J, et al. Cerebral oxygen desaturation predicts cognitive decline and 
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Tang L, Kazan R, Taddei R, et al. Reduced cerebral oxygen saturation during thoracic surgery 
predicts early postoperative cognitive dysfunction. British Journal of Anaesthesia 
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