Conditions: Advanced Chronic Rhinosinusitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 72
Healthy volunteers: yes

Brief summary:
Utilization of total intravenous anesthesia (TIVA) has been proposed as a method to improve visualization during endoscopic sinus surgery (ESS), largely due to its physiologic decrease in cardiac output without the peripheral smooth muscle relaxation and resultant vasodilation associated with inhaled anesthetics. This may be especially important in cases of advanced inflammatory sinus disease, when visualization may be most compromised. The goal of this study is to improve clinical practice paradigms by evaluating the use of TIVA versus inhaled anesthetic for maintenance of anesthesia in ESS for advanced paranasal sinus disease.

Detailed description:
Specific Aims:

1. Determine the effect of total intravenous versus inhaled anesthesia on intraoperative visual field in endoscopic sinus surgery for advanced paranasal sinus disease
2. Evaluate clinical outcomes associated with choice of total intravenous versus inhaled anesthesia in endoscopic sinus surgery

General Design:

Double blind, randomized controlled trial of total intravenous versus inhaled anesthetic for maintenance of anesthesia during endoscopic sinus surgery.

Subject Recruitment and Screening:

Patients will be screened for study inclusion by the principal investigator (EDM) during their preoperative visit in the Department of Otolaryngology. Those meeting inclusion criteria will be introduced to the study at this time. A full description of the research purpose, personnel, procedures, risks and benefits will be presented, and a copy of the study consent documentation will be provided for home review.

Method for Assigning Subjects to Treatment Groups:

On the day of surgery, eligible participants will be admitted to the Day of Surgery Department, where a member of the Anesthesia team will review study information and confirm informed consent. A randomly assigned, sealed envelope will then be opened to assign participants to either the TIVA, or inhaled anesthetic cohort. At no time will the patient or surgeon be made aware of the patient's cohort.

Blinding of Study Drug:

At no time will the patient or surgeon be made aware of the patient's cohort. During the procedure the surgeon is blinded to the type of anesthesia by placement of a high drape at the head of the operative table. Study reviewers will be blinded to treatment arm without cohort assignment at time of review for determination of visual field score.

Study Procedures:

Participants make no clinic/hospital visits for purposes of study completion as all patient interaction limited to visits and surveys completed as part of routine clinical care. Clinic visits will include a baseline preoperative visit, and visits at 1 week, 4 weeks, and 10 weeks after surgery.

Arms:
arm 1: Intravenous propofol for maintenance of anesthesia arm 2: Inhaled volatile anesthetic for maintenance of anesthesia

Interventions: intervention 1: Propofol intervention 2: Sevoflurane
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
Ochsner Clinic Foundation 
Ochsner Health System 
 
 
 
 
 
 
 
TOTAL INTRAVENOUS VERSUS INHALED ANESTHESIA IN ENDOSCOPIC SINUS SURGERY FOR 
ADVANCED PARANASAL DISEASE 
 
 
Regulatory Sponsor: 
Edward D. McCoul, MD, MPH 
Ochsner Clinic Foundation, Department of Otolaryngology 
1514 Jefferson Highway  
New Orleans, LA 70121  
Phone: (504) 842-4080  
 
Funding Sponsor: 
None 
Study Product: 
Propofol (Diprivan) 
Protocol Number: 
Pro00011453 
IND Number: 
NA 
Document Date: 
February 08, 2017 
 
 
 
 
 
 
 
 


 
 
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Date: 
 
Amended: 
 
Administrative Change: 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the Ochsner Clinic Foundation.  No part 
of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 


 
 
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Table of Contents 
STUDY SUMMARY ................................................................................................................................................... 1 
1 
INTRODUCTION .............................................................................................................................................. 3 
1.1 
BACKGROUND .................................................................................................................................................. 3 
1.2 
PRECLINICAL DATA ......................................................................................................................................... 4 
1.3 
CLINICAL DATA TO DATE ................................................................................................................................ 4 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................................ 4 
2 
STUDY OBJECTIVES ...................................................................................................................................... 4 
3 
STUDY DESIGN ................................................................................................................................................ 5 
3.1 
GENERAL DESIGN ............................................................................................................................................ 5 
3.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................................... 5 
3.3 
SECONDARY STUDY ENDPOINTS ...................................................................................................................... 5 
3.4 
PRIMARY SAFETY ENDPOINTS .......................................................................................................................... 5 
4 
SUBJECT SELECTION AND WITHDRAWAL............................................................................................ 5 
4.1 
INCLUSION CRITERIA ....................................................................................................................................... 5 
4.2 
EXCLUSION CRITERIA ...................................................................................................................................... 6 
4.3 
SUBJECT RECRUITMENT AND SCREENING ........................................................................................................ 6 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................................. 6 
4.4.1 
When and How to Withdraw Subjects .................................................................................................... 6 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ....................................................................... 6 
5 
STUDY DRUG ................................................................................................................................................... 6 
5.1 
DESCRIPTION ................................................................................................................................................... 6 
5.2 
TREATMENT REGIMEN ..................................................................................................................................... 6 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................................... 8 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................................... 8 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................................... 8 
5.6 
PRIOR AND CONCOMITANT THERAPY .............................................................................................................. 8 
5.7 
PACKAGING...................................................................................................................................................... 8 
5.8 
BLINDING OF STUDY DRUG .............................................................................................................................. 8 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................................ 8 
5.9.1 
Receipt of Drug Supplies ....................................................................................................................... 8 
5.9.2 
Storage ................................................................................................................................................... 8 
5.9.3 
Dispensing of Study Drug ...................................................................................................................... 9 
6 
STUDY PROCEDURES .................................................................................................................................... 9 
6.1 
VISIT 1 ............................................................................................................................................................. 9 
6.2 
VISIT 2 ............................................................................................................................................................. 9 
6.3 
VISIT 3 ............................................................................................................................................................. 9 
6.4 
VISIT 4 ............................................................................................................................................................. 9 
6.5 
VISIT 5 ............................................................................................................................................................. 9 
6.6 
VISIT 5 ............................................................................................................................................................. 9 
7 
STATISTICAL PLAN ..................................................................................................................................... 10 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................................... 10 
7.2 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................................... 10 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 10 
8.1 
DEFINITIONS .................................................................................................................................................. 10 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................................. 12 
8.2.1 
EC/IRB Notification by Investigator .................................................................................................... 12 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 12 


 
 
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9.1 
CONFIDENTIALITY .......................................................................................................................................... 12 
9.2 
SOURCE DOCUMENTS ..................................................................................................................................... 12 
9.3 
RECORDS RETENTION .................................................................................................................................... 13 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 13 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 13 
10.2 
AUDITING AND INSPECTING ....................................................................................................................... 13 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 13 
12 
STUDY FINANCES ......................................................................................................................................... 14 
12.1 
FUNDING SOURCE ..................................................................................................................................... 14 
12.2 
CONFLICT OF INTEREST ............................................................................................................................. 14 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................................ 14 
13 
PUBLICATION PLAN .................................................................................................................................... 14 
14 
REFERENCES ................................................................................................................................................. 15 
15 
ATTACHMENTS ............................................................................................................................................ 16 
 


 
 
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List of Abbreviations 
 
 
CRS- Chronic Rhinosinusitis 
IA- Inhaled Anesthesia 
PONV- Postoperative nausea and vomiting 
TIVA- Total Intravenous Anesthesia 
 
 


 
 
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Study Summary 
Title 
Total Intravenous versus Inhaled Anesthesia in Endoscopic Sinus 
Surgery for Advanced Paranasal Disease 
Short Title 
TIVA in high-risk endoscopic sinus surgery 
Protocol Number 
Pro00011453 
Phase 
 
Methodology 
Randomized controlled trial 
Study Duration 
18 months 
Study Center(s) 
Ochsner Clinic Foundation 
Objectives 
Evaluate the role of TIVA for maintenance of anesthesia during 
endoscopic sinus surgery. Outcome measures of operative visual field, 
change in sinus related quality-of-life, surgical time, complications and 
postoperative nausea and vomiting will be collected with subgroup 
analysis of patients with advanced paranasal sinus disease.  
Number of Subjects 
110 
Diagnosis and Main 
Inclusion Criteria 
Chronic rhinosinusitis. English speaking patients undergoing 
endoscopic sinus surgery for treatment of inflammatory paranasal sinus 
disease. 
Study Product, 
Dose, Route, 
Regimen 
Propofol, 100-200 mcg/kg/min IV for maintenance of anesthesia with 
goal mean arterial pressure of 70-80 mmHg 
Duration of 
administration 
Limited to maintenance of anesthesia during endoscopic sinus surgery 
Reference therapy 
Inhaled anesthesia 


 
 
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Statistical 
Methodology 
All parametric data is tested for normal distribution and 
characterized by mean +/-􏰃 standard deviation. Differences 
between the visual field and change in quality-of-life measure for 
the two treatment groups are evaluated using a t-test. The 
association between the treatment groups and surgical procedure 
is tested using the chi-square test. The association between the 
treatment groups and pathological groups is tested using Fisher’s 
exact test.  
 


 
 
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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1 Background 
 
Successful endoscopic sinus surgery (ESS) is largely dependent on identification of 
anatomic landmarks within a visually limited surgical field. Tight structural spaces, 
inflammatory tissues and intraoperative bleeding combine to decrease surgical exposure, with 
resultant increases in operative time, total blood loss and intraoperative complications. 
Maneuvers to improve the endoscopic visual field include reverse Trendelenburg positioning, 
nasal decongestion and infiltration of the lateral nasal wall with vasoactive epinephrine, and are 
currently accepted as standard of care1. Utilization of total intravenous anesthesia (TIVA) has 
been proposed as an additional method to improve visualization during ESS, largely due to its 
physiologic decrease in cardiac output without the peripheral smooth muscle relaxation and 
resultant vasodilation associated with inhaled anesthetics (IA)2. Propofol, when utilized for 
maintenance of anesthesia, is associated with decreased blood loss in several orthopedic and 
obstetric procedures3-5. However, despite this physiologic basis for improved intraoperative 
visualization with TIVA, conclusive evidence remains elusive6-10. While two recently published 
meta-analyses cite suggestive evidence for improved visual fields in ESS with TIVA, definitive 
recommendations could not be made due to limitations in the constituent studies11, 12. The 
objective of this study is therefore to evaluate the effects of TIVA versus IA on intraoperative 
visual field in ESS.  
 
This application seeks to improve clinical practice paradigms by evaluating the use of 
TIVA for maintenance of anesthesia in ESS for advanced paranasal sinus disease. Despite 
several previous studies evaluating the effect of TIVA on endoscopic visual field in ESS, limited 
study sizes and heterogeneous outcome measures prevent definitive recommendations. 
Additionally, the role of TIVA has not been reported among a subset of patients with advanced 
paranasal sinus disease. This study seeks to address these concerns, and will utilize the validated 
Wormald Visual Scale13 as a standardized outcome measure with the sensitivity to detect 
changes in visual field not recognized by other means (Boezaart Grading Scale, total blood loss).  
 
 
 
 


 
 
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Investigational Agent 
Propofol (Diprivan) 
1.2 Preclinical Data 
Since its introduction in the 1970s, propofol has become the most widely used IV hypnotic in 
clinical use today. Building on work on the sedative properties of phenol derivatives in mice, 
propofol was developed in the United Kingdom by Imperial Chemical Industries as ICI 35868. 
The current formulation was launched in 198614.  
1.3 Clinical Data to Date 
Propofol is used for induction and maintenance of anesthesia and for sedation in and outside the 
operating room. Its mechanism of action is likely the enhancement of γ-aminobutyric acid 
(GABA)-induced chloride currents. Propofol causes a dose-dependent decrease in arterial blood 
pressure through a decrease in cardiac output and systemic vascular resistance and produces 
moderate respiratory depression. A unique action of propofol is its antiemetic effect, even at 
concentrations less than those producing sedation14. 
1.4 Dose Rationale and Risk/Benefits 
Propofol is suitable for the induction and maintenance of anesthesia.  
The IV induction dose is 1 to 2.5 mg/kg.  
Maintenance dose is 50-150 μg/kg/min IV combined with N2O or an opiate. The infusion rate is 
titrated to individual requirements and the surgical stimulus14. 
Induction of anesthesia with propofol is often associated with pain on injection, apnea, 
hypotension, and, rarely, thrombophlebitis of the vein into which propofol is injected14. 
2 Study Objectives 
The objective of this study is to evaluate the effects of TIVA versus IA on intraoperative visual 
field in ESS for the treatment of advanced paranasal sinus disease.  
SPECIFIC AIMS 
1. Determine the effect of total intravenous versus inhaled anesthesia on intraoperative 
visual field in endoscopic sinus surgery for advanced paranasal sinus disease 
This study seeks to evaluate the effect of total intravenous anesthesia (TIVA) on the 
intraoperative visual field during endoscopic sinus surgery (ESS). Subgroup analysis of patients 
with allergic fungal sinusitis, pan-sinus opacification and nasal polyposis will further evaluate 
the role of TIVA in advanced sinus disease.  
 


 
 
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2. Evaluate clinical outcomes associated with choice of total intravenous versus inhaled 
anesthesia in endoscopic sinus surgery  
Clinical outcomes among patients receiving TIVA versus IA will be made with assessment of 
change in quality of life scores, pharmacologic effects (postoperative nausea and vomiting, 
recovery time) and surgical complications.  
 
3. Evaluate relative costs associated with total intravenous versus inhaled anesthesia in 
endoscopic sinus surgery  
Comparative cost analysis will be included to evaluate potential barriers to implementation of 
total intravenous anesthesia in endoscopic sinus surgery.  
 
3 Study Design 
3.1 General Design 
Double blind, randomized controlled trial of total intravenous versus inhaled anesthetic for 
maintenance of anesthesia during endoscopic sinus surgery. 
3.2 Primary Study Endpoints 
110 patients will be enrolled for study participation. Validated measure of intraoperative visual 
field will be utilized for primary outcome measure. 
3.3 Secondary Study Endpoints 
Secondary outcome measures include change in sinus-related quality-of-life, intraoperative 
bleeding, surgical time, post anesthesia care unit recovery time, postoperative nausea and 
vomiting (PONV), complications and response duration. 
3.4 Primary Safety Endpoints 
Safety endpoints include adverse surgical (intraoperative orbital/dural injury and postoperative 
hemorrhage/cerebrospinal fluid leak) and pharmacologic (severe PONV) events.  
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
Inclusion criteria include English-speaking patients undergoing endoscopic sinus surgery for the 
treatment of inflammatory paranasal sinus disease, including subgroups of patients with allergic 
fungal sinusitis, chronic rhinosinusitis with nasal polyposis, chronic rhinosinusitis with 
eosinophilia and rhinosinusitis with pan-sinus opacification. 


 
 
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4.2 Exclusion Criteria 
Exclusion criteria includes noninflammatory sinonasal disease, disease extending through the 
skull base or orbital wall, patients <18 years old, American Society of Anesthesiologists 
Preoperative Health Status >II, known non-pharmacologic coagulopathy (platelet < 50000/mL, 
INR>1.2), preoperative anticoagulants within 7 days of surgery and allergy to one of the study 
medications. 
4.3 Subject Recruitment and Screening 
Patients will be screened for study inclusion by the principal investigator (EDM) during their 
preoperative visit in the Department of Otolaryngology. Those meeting inclusion criteria will be 
introduced to the study at this time. A full description of the research purpose, personnel, 
procedures, risks and benefits will be presented, and a copy of the study consent documentation 
will be provided for home review. 
 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Study personnel will remain available to participants at all times during the study period, and 
may be reached via the hospital operator. Withdraw notification can be given at any time, and 
will be immediately reported to the clinical coordinator for documentation. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Completion of study participation will have no bearing on clinical follow-up. Withdrawn 
subjects will complete follow-up as clinically indicated, without further data collection. 
5 Study Drug  
5.1 Description 
Propofol (Diprivan) 
5.2 Treatment Regimen 
Anesthesia Protocol  
 
Preoperative medications may be given according to routine clinical care, which may 
include Midazolam 1-2 mg IV prior to being taken to the operating room. Standard ASA 
monitors will be placed. Induction of general anesthesia will follow the normal standard of care. 
Induction of anesthesia for both groups will include: Propofol 2 mg/kg, Lidocaine 0.5-1 mg/kg, 
Fentanyl 1-2 mcg/kg, with muscle relaxation with either Succinylcholine 1-2 mg/kg or 
Cisatracurium 0.15-0.2 mg/kg for intubation. Maintenance of anesthesia will consist of 
Cisatracurium 0.03- 0.04 mg/kg and the appropriate anesthetic per protocol described below. 


 
 
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Patients in the inhaled anesthesia group will receive Sevoflurane in an end expiratory 
concentration of 1.4% to 3% corresponding to near minimum alveolar concentration (MAC) of 
~0.5-1.5%. The carrier gas flow for both groups will consist of a combination of oxygen and air 
to a total flow rate of 2 l/m to maintain oxygenation per standard of care. Patients in the TIVA 
group will receive an infusion of Propofol in a dose of 100-200 mcg/kg/min for maintenance. IA 
group will adjust the Sevoflurane concentration and TIVA group will adjust the Propofol and 
Remifentanil dosing with the goal of maintaining mean arterial pressure 70 -80 mmHg.  
 
Both groups will be allowed to utilize Phenylephrine, Ephedrine, Labetalol or Esmolol as 
needed to maintain target blood pressure. Patients will be reversed with Neostigmine and 
Glycopyrrolate at the conclusion of the case. Post-operative pain relief will include either 
Morphine or Dilaudid per standard of care. No Acetaminophen may be given for either group for 
pain control.  
 
Surgical Protocol  
 
All patients are placed in 30 degree Reverse Trendelenberg positioning. 10 minutes prior 
to start of surgery, patients are pretreated with 4% cocaine-soaked nasal pledgets and local 
injection of 1% xylocaine with 1:100,000 epinephrine into the submucosa at the anterior 
attachment of the middle turbinate and crista ethmoidalis. Topical thrombin and epinephrine 
soaked pledgets will be available for intraoperative maintenance of hemostasis. Endoscopic sinus 
surgery will be completed following the modified Messerklinger technique, with utilization of 
endoscopic surgical equipment for video documentation of the surgical field. Recording 
equipment includes the Storz 4mm 0° rigid endoscope (Karl Storz, Tuttlingen, Germany) 
connected to a high definition camera and Olympus Evis Extra II light source. The video is 
recorded in MPEG2 digital format and transferred to the password protected study database. 
Visual field is recorded following the standardized method reported by Wormald et al., with the 
protocol as follows:  
Prior to completion of surgery, old blood is suctioned from the nasal cavity with care not to 
traumatize mucosal surfaces and reinitiate bleeding. The surgical field is then recorded in a 
systematic fashion, with observation of four intranasal structures. Moving from anterior/superior 
to posterior/inferior, the frontal recess, ethmoidal cavity (endoscope positioned just anterior to 
the middle meatus), sphenoidal recess, and postnasal space are serially recorded for ten seconds 
each.  
 
Following completion of surgery total blood loss will be calculated by the nursing 
circulator, with subtraction of the volume of intraoperative irrigation from the total volume 
contained in all suction canisters and saturated towels. The patient will be transferred to post-
operative recovery and released home upon meeting established criteria. Patients will undergo 
routine postoperative follow-up, with evaluation at 1, 2, 4 weeks and as needed. A new SNOT-
22 questionnaire will be completed as part of the postoperative week 2 and 4 visit.  


 
 
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5.3 Method for Assigning Subjects to Treatment Groups 
On the day of surgery, eligible participants will be admitted to the Day of Surgery Department, 
where a member of the Anesthesia team will review study information and confirm informed 
consent. A randomly assigned, sealed envelope will then be opened to assign participants to 
either the TIVA, or IA cohort. At no time will the patient or surgeon be made aware of the 
patient's cohort.  
5.4 Preparation and Administration of Study Drug 
Staff in the department of Anesthesia will administer perioperative medications in accordance 
with surgical standard of care. 
5.5 Subject Compliance Monitoring 
N/A as study intervention limited to perioperative maintenance of anesthesia. 
5.6 Prior and Concomitant Therapy 
Medications for induction, maintenance of anesthesia, reversal and postoperative recovery will 
be given as described in the “Anesthesia Protocol” (section 5.2). 
5.7 Packaging 
Packaging of study medication will be concealed from surgeons and study participants. 
5.8 Blinding of Study Drug 
At no time will the patient or surgeon be made aware of the patient's cohort. During the 
procedure the surgeon is blinded to the type of anesthesia by placement of a high drape at the 
head of the operative table. Study reviewers will be blinded to treatment arm without cohort 
assignment at time of review for determination of visual field score. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a 
drug receipt log filled out and signed by the person accepting the shipment.  It is important 
that the designated study staff counts and verifies that the shipment contains all the items 
noted in the shipment inventory.  Any damaged or unusable study drug in a given shipment 
(active drug or comparator) will be documented in the study files.  The investigator must 
notify study sponsor of any damaged or unusable study treatments that were supplied to the 
investigator’s site. 
5.9.2 Storage 
The study medication will be stored in the hospital pharmacy and distributed to Anesthesia 
personnel in accordance with surgical standard of care. 


 
 
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5.9.3 Dispensing of Study Drug 
Staff anesthesiologists will dispense study drug in the perioperative setting. Drug 
administration will be recorded and maintained in the surgical record. 
6 Study Procedures 
Participants make no clinic/hospital visits for purposes of study completion as all patient 
interaction limited to visits and surveys completed as part of routine clinical care. 
6.1 Visit 1 
Clinic presentation: A 22-item Sinonasal Outcome Test (SNOT-22) survey is completed per 
routine clinical care. Patients considering endoscopic sinus surgery for treatment of 
inflammatory paranasal sinus disease are initially screened for study participation. The principal 
investigator (EDM) presents the research purpose, personnel, procedures, risks and benefits of 
the study, and provides a written copy of the study consent for home review. 
6.2 Visit 2 
Preoperative visit: Study consent reviewed with an investigator and signed at this time. 
Enrolled patients will be assigned a randomly generated unique study identification number. The 
patient's demographic information will then be entered into the password- protected study 
database (Excel, Microsoft, Redwood, WA), which will be maintained on a HIPAA compliant 
server with access restricted to identified study computer maintained in the department of 
Otolaryngology. 
6.3 Visit 3 
Day of Surgery: Study consent reviewed and treatment group assigned. Intervention limited to 
perioperative maintenance of anesthesia with recording of deidentified endonasal endoscopic 
video for independent analysis of surgical visual field. 
6.4 Visit 4 
Routine 1-week postoperative follow-up. 
6.5 Visit 5 
Routine follow-up 4 weeks after date of surgery with completion of SNOT-22 survey. 
6.6 Visit 5 
Routine follow-up 12 weeks after date of surgery with completion of SNOT-22 survey. 
 


 
 
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7 Statistical Plan 
7.1 Sample Size Determination 
Sample size determination was calculated using the OpenEpi Sample Size Tool (Available: 
http://www.openepi.com/SampleSize/SSCohort.htm). The Wormald visual field has not been 
used to evaluate the effect of TIVA versus IA on endoscopic visual field, so previous reports 
using the Boezzart scale were used to estimate the mean size difference12. This calculation 
provided a n=52 per cohort, or sample size of 104. Sample size increased to 110 to allow for 
patient dropout. 
7.2 Subject Population(s) for Analysis 
Subgroup analysis will be completed of patients deemed “high risk” for endoscopic sinus 
surgery. This includes patients with diagnoses of allergic fungal sinusitis, CRS with nasal 
polyposis, CRS with eosinophilia and advanced paranasal sinus disease (LM>12).  The analysis 
plan has been reviewed by an in-house statistician. 
8 Safety and Adverse Events 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study.  Intercurrent illnesses or injuries should be regarded 
as adverse events.  Abnormal results of diagnostic procedures are considered to be adverse 
events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 


 
 
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• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the 
period from the initiation of any study procedures to the end of the study treatment follow-
up.  For this study, the study treatment follow-up is defined as 30 days following surgery.  
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise 
in this protocol.  Any condition responsible for surgery should be documented as an 
adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or diagnostic 
and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 


 
 
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8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
8.2.1 EC/IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be submitted to the 
EC/IRB within 10 working days.  Copies of each report and documentation of EC/IRB notification 
and receipt will be kept in the Clinical Investigator’s binder. 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• 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.  
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 study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical 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, 


 
 
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This material is the property of Ochsner Clinic Foundation.  Do not disclose or use except as authorized in writing by the study sponsor 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
9.3 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  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.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The Investigator will ensure that the monitor or other compliance or quality assurance reviewer 
is given access to all the above noted study-related documents and study related facilities, and 
has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices.  The protocol will be registered on clinicaltrials.gov in accordance with regulation. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 


 
 
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This material is the property of Ochsner Clinic Foundation.  Do not disclose or use except as authorized in writing by the study sponsor 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  See Attachment A for a copy of the Subject Informed Consent Form.  This consent form 
will be submitted with the protocol for review and approval by the EC/IRB for the study.  The 
formal consent of a subject, using the EC/IRB-approved consent form, must be obtained before 
that subject is submitted to any study procedure.  This consent form must be signed by the 
subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
 
12 Study Finances 
12.1 Funding Source 
There is no financial sponsor for the study at this time. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor 
prior to participation in this study.  All Ochsner investigators will follow the institutional conflict 
of interest policy. 
12.3 Subject Stipends or Payments 
No incentives are associated with study participation. 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
 


 
 
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14 References 
1. 
Leigh JM. The history of controlled hypotension. British journal of anaesthesia 1975; 
47:745-749. 
2. 
Blackwell KE, Ross DA, Kapur P, et al. Propofol for maintenance of general anesthesia: 
a technique to limit blood loss during endoscopic sinus surgery. American Journal of 
Otolaryngology--Head and Neck Medicine and Surgery 1993; 14:262-266. 
3. 
Hall JE, Ng WS, and Smith S. Blood loss during first trimester termination of pregnancy: 
comparison of two anaesthetic techniques. British journal of anaesthesia 1997; 78:172-
174. 
4. 
Kumarasinghe N, Harpin R, and Stewart AW. Blood loss during suction termination of 
pregnancy with two different anaesthetic techniques. Anaesthesia and intensive care 
1997; 25:48-50. 
5. 
Yoshimoto H, Nagashima K, Sato S, et al. A prospective evaluation of anesthesia for 
posterior lumbar spine fusion: the effectiveness of preoperative epidural anesthesia with 
morphine. Spine 2005; 30:863-869. 
6. 
Beule A, Wilhelmi F, KUHNEL T, et al. Propofol versus sevoflurane: Bleeding in 
endoscopic sinus surgery. Otolaryngology -- Head and Neck Surgery 2007; 136:45-50. 
7. 
Pavlin JD, Colley PS, Weymuller EA, et al. Propofol versus isoflurane for endoscopic 
sinus surgery. American Journal of Otolaryngology--Head and Neck Medicine and 
Surgery 1999; 20:96-101. 
8. 
Manola M, De Luca E, Moscillo L, et al. Using remifentanil and sufentanil in functional 
endoscopic sinus surgery to improve surgical conditions. ORL; journal for oto-rhino-
laryngology and its related specialties 2005; 67:83-86. 
9. 
Wormald PJ, van Renen G, Perks J, et al. The effect of the total intravenous anesthesia 
compared with inhalational anesthesia on the surgical field during endoscopic sinus 
surgery. American journal of rhinology 2005; 19:514-520. 
10. 
Eberhart LHJ, Folz BJ, Wulf H, et al. Intravenous anesthesia provides optimal surgical 
conditions during microscopic and endoscopic sinus surgery. The Laryngoscope 2003; 
113:1369-1373. 
11. 
Kelly EA, Gollapudy S, Riess ML, et al. Quality of surgical field during endoscopic sinus 
surgery: a systematic literature review of the effect of total intravenous compared to 
inhalational anesthesia. International Forum of Allergy &amp; Rhinology 2012; 3:474-
481. 
12. 
DeConde AS, Thompson CF, Wu EC, et al. Systematic review and meta-analysis of total 
intravenous anesthesia and endoscopic sinus surgery. International Forum of Allergy 
&amp; Rhinology 2013; 3:848-854. 


 
 
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13. 
Athanasiadis T, Beule A, Embate J, et al. Standardized Video-Endoscopy and Surgical 
Field Grading Scale for Endoscopic Sinus Surgery: A Multi-Centre Study. The 
Laryngoscope 2008; 118:314-319. 
14. 
Miller RD. Miller's anesthesia. Philadelphia, PA: Elsevier/Saunders, 2015. 
 
 
 
15  Attachments 
 
A. Subject informed consent form 
B. HIPAA authorization 
C. Table 1. Collected Data 
D. Study Monitoring Plan