Proposal for Intraoperative Administration of Intravenous Indocyanine Green to Evaluate Position of the Optic Canal, Position of the Internal Carotid Arteries, Tumor Vascularization, and Vessel Encasement in Endoscopic Endonasal Cranial Base Surgery
Phase: NA
Conditions: Skull Base Neoplasms, Skull Neoplasms, Bone Neoplasm, Neoplasms, Bone Diseases, Musculoskeletal Disease
Sponsor: Ohio State University

IRB Protocol Number: 2016H0193 
Version: 4.0 
IRB Approval Date: 11/27/2017 
1 
 
 
 
Proposal for Intraoperative Administration of 
Intravenous Indocyanine Green to Evaluate Position of 
the Optic Canal, Position of the Internal Carotid Arteries, 
Tumor Vascularization, and Vessel Encasement in 
Endoscopic Endonasal Cranial Base Surgery. 
 
 
PI: Daniel Prevedello, MD 
Department of Neurological Surgery 
 
 
 
Objective 
 
We intend to demonstrate the feasibility of using a nasal endoscope to perform 
intraoperative angiography of surgical field, with the goals to evaluate anatomical 
landmarks and tumor characteristics during skull base surgery and publish a technical 
note. 
 
 
Background and Rationale 
 
The expanded endoscopic endonasal approach (EEA) to the cranial base is increasingly 
being utilized to address a variety of cranial base pathologies.1-7  The more severe 
complications and morbidities associated with EEA are related to vascular and cranial 
nerve injury. 8, 9   
 
The sphenoid sinus is the center and starting point for all the expanded EEA to the ventral 
skull base. Skull base surgeons rely on anatomical landmarks and neuro-navigation to 
perform a safe procedure. However, sphenoid sinus pneumatization may vary and 
anatomical landmarks may not be readily identifiable. In addition, surgeons may not rely 
exclusively on neuro-navigation since it is not always accurate and precise.  
 
Originally FDA approved for human use in 1959, indocyanine green (ICG) is a 
tricarbocyanine dye with near-infrared fluorescence that has been routinely used in a 
variety of cerebrovascular procedures since 1972 for real-time noninvasive intraoperative 
angiography with a multiple-decades-long safety history.10-14  It is administered as an 
intravenous bolus, typically in a dose of 25 milligrams dissolved in 10 milliliters of sterile 
water. It binds to large plasma proteins within 2 seconds and remains intravascular. ICG is 
metabolized exclusively by the liver with a plasma half-life of 150 seconds and is excreted 

IRB Protocol Number: 2016H0193 
Version: 4.0 
IRB Approval Date: 11/27/2017 
2 
 
in bile.15  Angiography is typically most useful approximately 45 seconds after ICG 
administration in distinct arterial, capillary, and venous phases.15 
 
There are only a few reports in the literature describing the use of ICG and the Karl Storz 
nasal endoscope in EEA for benign ventral skull base lesions.15-18 Litvack at al.15 described 
the intraoperative use of ICG to successfully differentiate relatively avascular tumor from 
the capillary-rich normal pituitary gland as well as relatively hypervascular regions of 
dural invasion without complication. Hide et al. 16-17 that the real-time observation of the 
blood supply to the optic nerves and pituitary helps to predict the preservation of their 
function. Inoue et al.18 used preoperative 3D-CT and MRI fusion models with intraoperative 
ICG endoscopy and concluded that the technique allowed distinct visualization of vital 
structures in cases where tumors had extensively infiltrated the sphenoidal sinus. 
Additionally, the ICG endoscope was a useful real-time monitoring tool for ETSS. 
 
There are no other reports of ICG use in any EEA approaches to the cranial base, nor are 
there any reports of ICG use to characterize the tumor vascularization and its relationship 
to optic nerves and arteries.   
 
The usefulness of the intraoperative ICG in cranial nerve preservation was recently studied 
in microscopic lateral skull base approaches.19 The authors concluded that the course of 
the facial nerve can be confirmed during mastoidectomy, which reduces the possibility of 
iatrogenic facial nerve dysfunction. This fluorescence technique is especially helpful in 
establishing 
confidence 
and 
shortening 
the 
learning 
curve 
for 
beginners 
at 
mastoidectomies. We believe that the same strategy can be useful to identify the optic 
nerves during expanded EEA.  
 
Proposal 
 
Based on the positive experience of our Pilot study where ICG accurately demonstrated 
visualization of perfusion of the pedicled flap posterior nasal arteries and mucosal flap 
during endoscopic endonasal approaches, we now propose a study in which we will 
administer ICG during routine EEA for cranial base pathologies in which optic canal 
decompression, intradural tumor dissection, or dissection of tumor around the internal 
carotid artery will be necessary.   
 
We anticipate needing no more than thirty-five patients to obtain the necessary 
information and will either seek further IRB approval or terminate this feasibility study if 
the necessary information cannot be obtained by the thirty-fifth patient.  All surgeries will 
be performed in a team with Dr. Daniel Prevedello (Neurological Surgery) and either Dr. 
Ricardo Carrau (Otolaryngology) or Dr. Bradley Otto (Otolaryngology).  We will use the 
Storz nasal endoscope, which is already purchased and routinely used at The Ohio State 
University (OSU), modified as described by Litvack et al.15 to visualize the proposed real-
time angiograms. These modifications include a custom xenon light source that produces 
both the standard white light as well as near-infrared (690-780 nm wavelength) light and a 
selectable near-infrared filter for the nasal endoscope, both of which will be provided by 

IRB Protocol Number: 2016H0193 
Version: 4.0 
IRB Approval Date: 11/27/2017 
3 
 
Karl Storz free of charge.  We intend to administer ICG, which is already widely used during 
open neurosurgical procedures, to identify anatomical landmarks (such as vascular 
structures leading to the optic canal and internal carotid arteries) and tumor 
characteristics (such as tumor vascularization, tissue differentiation, and vessel 
encasement) during skull base surgery at different stages of endonasal cranial base surgery 
and tumor dissection: before intradural dissection and during tumor dissection.   
 
 
Eligibility 
 
All adult patients selected to undergo an EEA for cranial base pathology that will require 
any of the following will be eligible for the study: optic canal decompression, intradural 
tumor dissection, dissection of tumor around the internal carotid artery.   
 
Exclusion criteria will include patient age less than 18 years; history of sulfa, iodide, or 
penicillin allergy; previous anaphylactic reaction to ICG; women currently pregnant or 
nursing. Patients of child bearing potential are routinely screened for pregnancy before the 
surgery using urinary or blood beta-HCG test.  
 
 
Management of Adverse Experiences 
 
1. Adverse Events 
 
1.1. 
Adverse Event Definition 
 
An adverse event (AE) will be considered any undesirable sign, symptom or medical condition 
considered related to the intervention. Medical condition/diseases present before starting the 
intervention will be considered AEs only if they worsen after starting the study and that 
worsening is considered related to the study intervention. An AE is also any undesirable and 
unintended effect of research occurring in human subjects as a result of the collection of 
identifiable private information under the research. AEs will be recorded up to the day of the 
final follow-up visit, and if still present, they will be recorded as “ongoing” at the end of the 
study. The occurrence of AEs should be sought by non-directive questioning of the patient at 
each visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits. 
 
Risk and Benefit Assessment 
 
Per the 2006 FDA label for ICG, the only listed risks of ICG administration are urticarial or 
anaphylactic reactions, which are rare.  ICG contains sodium iodide, so caution is recommended 
in patients with a history of iodide allergy.  Per this FDA label, “There are no data available 
describing the signs, symptoms, or laboratory findings accompanying overdosage. The LD 50 
after I.V. administration ranges between 60 and 80 mg/kg in mice, 50 and 70 mg/kg in rats and 
50 and 80 mg/kg in rabbits.”  The FDA arbitrarily suggests a maximum dose of 2mg/kg for 
human use, and this would be our dosage maximum.  The main risk to our study population 

IRB Protocol Number: 2016H0193 
Version: 4.0 
IRB Approval Date: 11/27/2017 
4 
 
would be a small increase in operative time under general anesthesia, which we estimate at an 
additional 15 minutes.  Litvack et al. estimated that ICG angiography during their pituitary 
surgeries required an extra 15-20 minutes of operative time under general anesthesia, which 
supports our estimation.15 
 
The benefits to our study will be visualization of important structures that may be encased by 
the tumor to avoid injury including the optic nerves, the internal carotids and minor feeding 
vessels. Also, determination of any residual tumor that may be left during tumor dissection 
helps prevent or recurrence of the tumor, which will overall decrease the morbidity of these 
kind of surgeries. We feel that the benefits to the study population markedly outweigh the 
risks.  
 
 
Human Subjects 
 
1. Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document and any subsequent modifications will 
be reviewed and approved by the IRB or ethics committee responsible for oversight of the 
study.  A signed consent form will be obtained from the subject.  The consent form will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits 
of participation, and the rights of the participant.  A copy of the consent form will be given 
to the subject and this fact will be documented in the subject’s record. 
 
The Principal Investigator or the Study Coordinator will be responsible for submitting any 
changes to the project to the IRB for approval prior to implementation of the changes.  The 
study will also be submitted for continuing review by the IRB at periods determined by the 
IRB, at lease annually, for the duration of the study. 
 
2. Subject Confidentiality 
 
Subject data records will be identified by a study specific identification number.   
All subject records will be kept in a locked file cabinet.  All computer entry and networking 
programs will be done using study specific identification number only.  Clinical information 
will not be released without written permission of the subject, except as necessary for 
monitoring by IRB, the FDA, the OHRP, the sponsor, or the sponsor’s designee. 
 
3. Subjects’ Rights 
 
Subjects will have the right to withdraw from the study at any time without penalty or lose 
of any of their usual benefits.  
 
Data Collection 
 
Specifically, patient demographic/clinical information to be included in this feasibility 
study will include: 

IRB Protocol Number: 2016H0193 
Version: 4.0 
IRB Approval Date: 11/27/2017 
5 
 
 
a. Age 
b. Gender 
c. Race 
d. Vital Signs 
e. Diagnosis 
f. Duration of Disease 
g. Brief Medical History 
h. Description of Surgical Approach 
i. Description and Images of Intraoperative Angiography 
 
Medical imaging data to be presented will include pre- and post-operative CT and MR 
studies in addition to intraoperative angiography and intraoperative endoscopic images of 
the surgical site.  
 
If, during the course of the procedure, the operator determines that it would be in patient's 
best interest to prematurely abort the procedure due to unforeseen events, it will be under the 
discretion of the PI to use the data from the prematurely aborted procedure. If patient has a 
second procedure after the first procedure was prematurely aborted, it is up to the PI 
discretion to re-dose patient with the ICG dye and complete the study procedures and collect 
study data from the second procedure. The PI may decide whether to use the data from the 
first procedure in this circumstance.  ICG dye half-life is 3-4 minutes and does not pose a threat 
of overdosing. 
 
In summary, this novel technique for performing real-time endoscopic intranasal 
angiography could substantially improve the safety of surgery by precisely locating the 
optic canal and internal carotid arteries; by providing additional information on tumor 
characteristics such as vascularization and vessel encasement.  
This information may prompt further surgical action to avoid the complications associated 
with optic canal decompression, dissection near the internal carotid and tumor dissection.  
Presentation of this feasibility study in the literature will likely lead to wide acceptance and 
implementation of this technique due to the highly useful information it will yield as well as 
its high degree of feasibility, as institutions performing EEA procedures already possess the 
materials necessary to perform it.  
 
 
 
References 
 
1. 
Kassam A, Snyderman CH, Mintz A, Gardner P, Carrau RL. Expanded endonasal 
approach: the rostrocaudal axis. Part I. Crista galli to the sella turcica. Neurosurgical 
focus. Jul 15 2005;19(1):E3. 
2. 
Kassam A, Snyderman CH, Mintz A, Gardner P, Carrau RL. Expanded endonasal 
approach: the rostrocaudal axis. Part II. Posterior clinoids to the foramen magnum. 
Neurosurgical focus. Jul 15 2005;19(1):E4. 

IRB Protocol Number: 2016H0193 
Version: 4.0 
IRB Approval Date: 11/27/2017 
6 
 
3. 
Attia M, Kandasamy J, Jakimovski D, et al. The importance and timing of optic canal 
exploration and decompression during endoscopic endonasal resection of 
tuberculum sella and planum sphenoidale meningiomas. Neurosurgery. Sep 
2012;71(1 Suppl Operative):58-67. 
4. 
Zada G, Du R, Laws ER, Jr. Defining the "edge of the envelope": patient selection in 
treating complex sellar-based neoplasms via transsphenoidal versus open 
craniotomy. Journal of neurosurgery. Feb 2011;114(2):286-300. 
5. 
Cavallo LM, Solari D, Esposito F, Cappabianca P. The endoscopic endonasal approach 
for the management of craniopharyngiomas involving the third ventricle. 
Neurosurgical review. Jan 2013;36(1):27-37; discussion 38. 
6. 
Schmidt RF, Choudhry OJ, Raviv J, et al. Surgical nuances for the endoscopic 
endonasal transpterygoid approach to lateral sphenoid sinus encephaloceles. 
Neurosurgical focus. Jun 2012;32(6):E5. 
7. 
McLaughlin N, Bresson D, Ditzel Filho LF, et al. Vidian nerve neurofibroma removed 
via a transpterygoid approach. Minimally invasive neurosurgery : MIN. Oct 
2011;54(5-6):250-252. 
8. 
AlQahtani A, Castelnuovo P, Nicolai P, Prevedello DM, Locatelli D, Carrau RL. Injury 
of the Internal Carotid Artery During Endoscopic Skull Base Surgery: Prevention and 
Management Protocol. Otolaryngol Clin North Am. 2016 Feb;49(1):237-52. doi: 
10.1016/j.otc.2015.09.009  
9. 
Horowitz PM, DiNapoli V, Su SY, Raza SM.Complication Avoidance in Endoscopic 
Skull Base Surgery. Otolaryngol Clin North Am. 2016 Feb;49(1):227-35. doi: 
10.1016/j.otc.2015.09.014 
10. 
Son YJ, Kim JE, Park SB, Lee SH, Chung YS, Yang HJ. Quantitative analysis of 
intraoperative indocyanine green video angiography in aneurysm surgery. Journal 
of cerebrovascular and endovascular neurosurgery. Jun 2013;15(2):76-84. 
11. 
Wilson EM, Halsey JH, Jr., Vitek JJ. Validation of jugular venous flow as an index of 
total cerebral blood flow. Stroke; a journal of cerebral circulation. May-Jun 
1972;3(3):300-321. 
12. 
Imizu S, Kato Y, Sangli A, Oguri D, Sano H. Assessment of incomplete clipping of 
aneurysms 
intraoperatively 
by 
a 
near-infrared 
indocyanine 
green-video 
angiography (Niicg-Va) integrated microscope. Minimally invasive neurosurgery : 
MIN. Aug 2008;51(4):199-203. 
13. 
Kim DL, Cohen-Gadol AA. Indocyanine-green videoangiogram to assess collateral 
circulation before arterial sacrifice for management of complex vascular and 
neoplastic lesions: technical note. World neurosurgery. Feb 2013;79(2):404 e401-
406. 
14. 
Ambekar S, Babu A, Pandey P, Devi IB. Intraoperative assessment of STA-MCA 
bypass patency using near-infrared indocyanine green video-angiography: a 
preliminary study. Neurology India. Nov-Dec 2012;60(6):604-607. 
15. 
Litvack ZN, Zada G, Laws ER, Jr. Indocyanine green fluorescence endoscopy for 
visual differentiation of pituitary tumor from surrounding structures. Journal of 
neurosurgery. May 2012;116(5):935-941. 

IRB Protocol Number: 2016H0193 
Version: 4.0 
IRB Approval Date: 11/27/2017 
7 
 
16. 
Hide T, Yano S, Shinojima N, Kuratsu J. Usefulness of the indocyanine green 
fluorescence endoscope in endonasal transsphenoidal surgery. J Neurosurg. 2015 
May;122(5):1185-92. doi: 10.3171/2014.9.JNS14599 
17. 
Hide T, Yano S, Kuratsu J. Indocyanine green fluorescence endoscopy at endonasal 
transsphenoidal surgery for an intracavernous sinus dermoid cyst: case report. 
Neurol Med Chir (Tokyo). 2014;54(12):999-1003. 
18. 
Inoue A, Ohnishi T, Kohno S, Nishida N, Nakamura Y, Ohtsuka Y, Matsumoto S, Ohue 
S. Usefulness of an Image Fusion Model Using Three-Dimensional CT and MRI with 
Indocyanine Green Fluorescence Endoscopy as a Multimodal Assistant System in 
Endoscopic Transsphenoidal Surgery. Int J Endocrinol. 2015;2015:694273. doi: 
10.1155/2015/694273. 
19. 
Chen SC, Wang MC, Wang WH, Lee CC, Yang TF, Lin CF, Wang JT, Liao CH, Chang CC, 
Chen MH, Shih YH, Hsu SP. Fluorescence-assisted visualization of facial nerve during 
mastoidectomy: A novel technique for preventing iatrogenic facial paralysis. Auris 
Nasus Larynx. 2015 Apr;42(2):113-8. doi: 10.1016/j.anl.2014.08.008