Ultrasonographic Assessment of the Optic Nerve Sheath Diameter During Variations in PetCO2 and Controlled Internal Jugular Venous Occlusion: A Volunteer Study
Conditions: Elevated Intracranial Pressure (ICP)
Sponsor: Lashmi Venkatraghavan

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Ultrasonographic assessment of the optic nerve sheath diameter during 
variations in PetCO2 and controlled internal jugular venous occlusion: A 
volunteer study 
 
 
 
 
Principle Investigator:  
Dr. Lashmi Venkatraghavan 
 
 
 
 
Department of Anaesthesia 
Toronto Western Hospital 
339, Bathurst Street 
Toronto M5T 2S8 
 
 
Co- Investigators: 
 
 
Dr. Vincent Chan  
Department of Anaesthesia 
Toronto Western Hospital 
 
Dr. Joseph Fisher 
 
 
 
 
Department of Anaesthesia 
Toronto General Hospital 
 
Dr. Michael Dinsmore 
 
 
 
 
Department of Anaesthesia 
University of Toronto 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Background 
Elevated intracranial pressure (ICP) is a common and potentially life threatening 
condition arising from a variety of pathological conditions including traumatic brain 
injury (TBI), intracranial hemorrhage, subarachnoid hemorrhage and brain tumors.  
Monitoring the ICP is the most important aspect of the management of these 
patients and use of ventricular catheter is the gold standard method of measuring 
ICP. The potential risks of misplacement, infection, hemorrhage and obstruction 
have led to development and implementation of alternative intracranial devices and 
techniques for monitoring ICP.  However, the use of intracranial ICP monitoring 
devices is restricted to the patients in neurosurgical intensive care units and they 
often require neurosurgical team for the placement. Imaging modalities such as 
computerized tomography (CT) and magnetic resonance imaging (MRI) are used for 
the diagnosis for raised intracranial pressure but risk of radiation and accessibility 
are the main disadvantages. Recently, transorbital ultrasonography has gained 
popularity as a noninvasive bedside exam that has been shown to be useful in the 
diagnosis of raised ICP by evaluating the change in the optic nerve sheath diameter 
(ONSD). The optic nerve is surrounded by cerebrospinal fluid, which is connected to 
the intracranial subarachnoidal space. Hence any variations in the CSF pressure will 
have a direct effect on the ONSD2.  Previous histological studies have revealed that 
the region approximately 3 mm behind the papilla segment of the optic nerve is 
where maximal diameter fluctuations are seen and this is the ideal region for ONSD 
measurement.3 This has been validated by numerous studies showing significant 
correlation between ONSD and elevated ICP with good intra and inter-observer 

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reliability 4 5.  Therefore, transorbital ultrasonographic measurement of ONSD 
appears to be a noninvasive, relatively inexpensive bedside examination for the 
diagnosis of raised ICP.   
However the most of the literature on the use of changes in the ONSD for 
monitoring the changes in ICP came from the patients in the intensive care units 
with elevated intracranial pressure.2,7 Currently there are no data on how ONSD 
changes with acute increase or decrease in ICP. In addition, we don’t know how 
soon the ONSD changes with acute changes in intracranial pressure.  
Intracranial pressure is determined by the intracranial volume which in turn 
determined by the intracranial content namely, brain tissue, intracranial vessels 
(artery and veins) and the cerebrospinal fluid. There are limited non-surgical 
options that can be used to alter the ICP.  Increase in the volume of intracranial 
vessels by either arterial dilation and/or occlusion of venous drainage can lead to 
increase in intracranial pressure. Carbon dioxide (CO2) is a potent cerebral 
vasodilator, hypercapnia induced cerebral vasodilatation can lead to increase in ICP 
secondary to increase in intracranial volume. Similarly, obstruction to the cerebral 
venous drainage can also increase the intracranial pressure.  Controlling the Co2 
and improving the venous drainage are the two fundamental principles in the 
anesthesia management of patients with increased ICP. 6 8  
In order to use transorbital ultrasonographic measurement of ONSD as a method 
of monitoring changes in ICP, we need to determine how reliable the change in 
ONSD with controlled acute changes in intracranial pressure is. Controlled changes 
in ICP can be produced by either manipulation PCO2 and/or cerebral venous 

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drainage. Among the methods available for CO2 manipulation, we have shown that 
Model-based Prospective End-Tidal Targeting (MPET) system (RespirAct™- 
Thornhill research Inc) is the most reliable method for accurate and precise 
targeting of Co2. 9-10  Briefly, the RespirAct™ is a custom designed breathing circuit 
that uses computer controlled gas blending to quickly and precisely control end-
tidal carbon dioxide levels9. The RespirAct™ has two main features for this study.  
First, it is capable of rapidly and precisely targeting a series of PetCO2 independent 
of the subject’s breathing pattern10.  These changes can be induced within three 
breaths, are accurate to within ± 1 mmHg, and can be sustained at constant levels.  
Second, it has been shown in humans and animals that a unique characteristic of 
this system is that the end tidal CO2 (PetCO2) is precisely equal to arterial CO2 ( 
PaCO2).9 With regards to venous outflow obstruction, both Valsalva maneuver 
(forced inspiration with closed glottis) and /or compression of internal jugular 
veins (IJV) are the two commonly used physiological methods that can cause an 
increase in ICP.  However, compared to Valsalva maneuver which is dependent on 
the individual’s effort and a variable effect, jugular venous compression is more 
reliable and reproducible method to increase ICP.  Bilateral jugular occlusion is 
sometimes used during neurosurgical procedures during craniotomy opening 
especially in patients who are at risk of air embolism.( 11) Jugular venous occlusion 
can be done using a custom made neck collar and previous investigations have used 
a similar device in a rat model to demonstrate the protective effects on slosh-
mediated brain injury by increasing intracranial blood volume 12,13.   While the 
collars have not yet been studied on people for their effectiveness at preventing 

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concussions, many studies have looked at the effect of neck collars on both jugular 
compression and ICP.14,15 
    Aim of our study to determine the changes in ONSD with acute controlled 
changes in ICP in healthy volunteers. Transorbital ultrasound will be used for 
measuring the changes in ONSD.  The controlled changes in ICP will be produced by 
manipulating the PCO2 with the use of Respiract and jugular venous compression 
with the use of custom made neck collar.   
 
 
References 
References 
 
1. Lundberg N. Continuous recording and control of ventricular fluid pressure in 
neurosurgical practice. Acta Psychiatr Scand Suppl 1960;36(149):1-193. 
2. Rajajee V, Thyagarajan P, Rajagopalan RE. Optic nerve ultrasonography for 
detection of raised intracranial pressure when invasive monitoring is unavailable. 
Neurol India 2010;58(5):812-3. 
3. Helmke K, Hansen HC. Fundamentals of transorbital sonographic evaluation of 
optic nerve sheath expansion under intracranial hypertension II. Patient study. 
Pediatr Radiol 1996;26(10):706-10. 
4. Bauerle J, Lochner P, Kaps M, Nedelmann M. Intra- and interobsever reliability of 
sonographic assessment of the optic nerve sheath diameter in healthy adults. J 
Neuroimaging 2012;22(1):42-5. 
5. Dubourg J, Javouhey E, Geeraerts T, Messerer M, Kassai B. Ultrasonography of 
optic nerve sheath diameter for detection of raised intracranial pressure: a 
systematic review and meta-analysis. Intensive Care Med 2011;37(7):1059-68. 
6. Rossanda M, Vecchi G. Determination of cerebral autoregulatory status and pCO2 
responsiveness. Int Anesthesiol Clin 1979;17(2-3):425-38. 
7. Seo H, Kim YK, Shin WJ, Hwang GS. Ultrasonographic optic nerve sheath diameter 
is correlated with arterial carbon dioxide concentration during reperfusion in 
liver transplant recipients. Transplant Proc 2013;45(6):2272-6. 

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8. Mavrocordatos P, Bissonnette B, Ravussin P. Effects of neck position and head 
elevation on intracranial pressure in anaesthetized neurosurgical patients: 
preliminary results. J Neurosurg Anesthesiol 2000;12(1):10-4. 
9. Slessarev M, Han J, Mardimae A, Prisman E, Preiss D, Volgyesi G, et al. Prospective 
targeting and control of end-tidal CO2 and O2 concentrations. J Physiol 
2007;581(Pt 3):1207-19. 
10. Mark CI, Slessarev M, Ito S, Han J, Fisher JA, Pike GB. Precise control of end-tidal 
carbon dioxide and oxygen improves BOLD and ASL cerebrovascular reactivity 
measures. Magn Reson Med 2010;64(3):749-56. 
11. Losasso TJ, Muzzi DA, Cucchiara RF. Jugular venous compression helps to    
identify the source of venous air embolism during craniectomy in patients in the  
sitting position. Anesthesiology. 1992 Jan;76(1):156-7. 
12. Turner RC, Naser ZJ, Bailes JE, Smith DW, Fisher JA, Rosen CL. Effect of slosh 
mitigation on histologic markers of traumatic brain injury: laboratory 
investigation. J Neurosurg 2012;117(6):1110-8. 
13. Smith DW, Bailes JE, Fisher JA, Robles J, Turner RC, Mills JD. Internal jugular vein 
compression mitigates traumatic axonal injury in a rat model by reducing the 
intracranial slosh effect. Neurosurgery 2012;70(3):740-6. 
 
14. Stone MB, Tubridy CM, Curran R. The effect of rigid cervical collars on internal 
jugular vein dimensions. Acad Emerg Med. 2010 Jan;17(1):100-2.   
 
15. Davies G, Deakin C, Wilson A. The effect of a rigid collar on intracranial pressure. 
Injury. 1996 Nov;27(9):647-9 
 
 
Hypothesis   
 
Our hypothesis is that there will be a change in optic nerve sheath diameter (ONSD) 
with the raised PCO2 and internal jugular venous occlusion 
 
Objective of study 
 The main objective of this study is to determine the changes in ONSD with 
controlled increase in intracranial pressure with hypercapnia and jugular venous 
occlusion in healthy human volunteers.  
 
Proposed Methodology 
 

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The study will be conducted in accordance with guidelines set forth by the 
University of Toronto, University Health Network Ethics Committee for use of 
human subjects in research. Ethics board approval will be obtained as well as 
written consent from each subject.  
 
Study Design 
 
This will be a prospective, non-randomized, observational study.  
 
Recruitment 
Healthy volunteers will be recruited by poster advertisement around the hospital. 
They will be asked to contact Dr. Jigesh Mehta, Research coordinator for the study. 
His contact number and email will be provided. They will then be screened 
according to the inclusion and exclusion criteria’s to see if they are suitable for the 
study.  
 
Inclusion criteria 
Adult healthy volunteers who are above the age of 18 
ASA 1 
Body mass index (BMI) less than and equal to 35 
Neurologically normal subjects with no symptoms other than occasional non-severe 
headache 
 
Exclusion criteria 
BMI above 35 
Lack of informed consent 
Language barrier 
Medical students and/or anesthesia residents going through the department as part 
of their rotation 
Pregnancy 
Frequent migraine headache 
 
Informed Consent 
 
The background of the study, benefits and risks will be explained to the subject 
and the informed consent form will be signed and witnessed if the subject agrees to 
participate. 
 
Study protocol 
 Ultrasound measurement of ONSD 

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All volunteers will be fully awake throughout the study and be kept comfortable. 
The transoccular ultrasound examinations of the ONSD will be carried out using a 
SonoSite Edge (FUJI FILM SonoSite Inc. US) ultrasound system and a 7-10 MHz 
linear probe.  Two trained investigators will perform investigations on both eyes of 
all subjects independently without being aware of each other’s study results.  All 
patients will be in the supine position and the probe will be gently placed on the 
temporal part of the closed upper eyelid. Contact with the eye will be gentle at all 
times and pressure never directly applied on the globe with the probe. A Tegaderm 
film (Transparent film dressing, 3M Canada) will be applied over the eye to protect 
the patient from the ultrasound gel applied during sonography.  Once the anterior 
part of the optic nerve is depicted in the transverse/axial plane showing the papilla 
and optic nerve in its longitudinal course, the ONSD will be assessed 3 mm behind 
the papilla, as described previously (Figure 3).  Each eye will be examined 3 times 
by each investigator and the mean value of the ONSD will be used for further 
calculations. 
Carbon dioxide Manipulation 
The volunteers will don an airtight mask connected to the RespirAct™ sequential gas 
delivery breathing circuit. The subject will lie supine on a stretcher.  Gas will be 
supplied by a computerized MPET system (RespirAct™).  During control conditions, 
room air will be supplied at flows greater than the subject’s minute ventilation.  
These studies will be done at the subject’s baseline end-tidal CO2 tension (usual 
range 35 – 40 mmHg).  The PetO2 will be fixed at 100 mmHg, a normal PETO2 for 
most subjects. We will record baseline values for 120 seconds and then the PetCO2 
will be increased to +10 mmHg (Hypercapnia I) from baseline and held for 5 
minutes in order to complete ONSD measurements.  The venous compression neck 
collar will then be applied and ONSD measurements will be repeated.  Following 
measurements, the PetCO2 will be returned back to baseline (Figure 1).  This 
sequence will again be repeated increasing the PetCO2 to +15 mmHg (Hypercapnia 
II) from baseline before returning to baseline.  The subject will then have PetCO2 
decreased to -10 mmHg (Hypocapnia) from baseline before returning to normal 
capnia.  The study will stop at this point. During each cycle, the PetO2 and PetCO2 
will be controlled by delivering mixes of source gases consisting of O2, air, and 
blends of CO2, N2 and O2. The speed and accuracy of the RespirAct™ for modulating 
PetCO2 while maintaining constant PetO2 is shown in Figure 2.  
The RespirAct™ system has been used extensively in more than 15 UHN 
studies.  Over 500 spontaneously breathing human subjects have been studied 
under these approved protocols. Results have been published in abstract and peer 
reviewed form and a number of Master’s and Doctorate Theses at the University of 
Toronto (Marat Slessarev, Jay Han, Rosemary Regan, Dahlia Balaban, Anne Battisti, 
Danny Mandell, Hiroshi Sasano). The RespirAct™ is still considered an 

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investigational device and Health Canada approval will be obtained before 
beginning the study.  
Internal jugular compression using a Neck collar 
A custom made collar consisting of two (2 x 3 x 1.5 cm) soft gauze pledgets held 
over the IJV by an elastic retainer of will be applied around the patient’s neck which 
can be adjusted to the subject’s neck circumference using Velcro.( Velcro, US)  This 
will apply only minimal pressure on the neck, which is comparable to wearing a 
tight dress shirt.  In order to confirm the jugular venous occlusion with the neck 
collar, we will measure the diameter and flow in the IJV using the ultrasound in each 
subject in both sitting and supine positions with and without collar. Similarly to 
determine the lowest pressure needed to occlude the IJV, a 100 ml fluid (normal 
saline) bag which is attached to a pressure manometer will be placed on the 
subjects’ neck below the collar and the minimal pressure at which there is complete 
occlusion of IJV will be recorded The venous compression neck collar will be applied 
at each CO2 levels (normocapnia, Hypercapnia I and II and hypocapnia) and ONSD 
measurements will be measures before and after the collar.   
 
Risks 
1. Carbon dioxide 
The physiologic stresses of Co2 manipulation on this proposal can be considered 
minimal. The higher PetCO2 required will not exceed 60 mmHg nor will this change 
be sustained for long (10 minute intervals). The lower level of PetCO2 is frequently 
seen with exercise.  This range of PetCO2 is physiological and is experienced 
repeatedly by most people over a regular day.  Hyperventilation with hypocapnic 
PetCO2 is common in day-to-day living (anger, excitement, running).  Taking 
sedatives (alcohol) or even normal sleep can be associated with a PCO2 of ~ 50 
mmHg. 
2. RespirAct TM  
The inhaled gases used in this study are supplied by a computerized MPET 
system.  During control conditions, room air will be supplied at flow greater than 
the subject’s minute ventilation. The subject will be monitored continuously for 
heart rate, depth of sedation and saturation by pulse oximetry by an attending 
physician (neurosurgery/ICU or anesthesia). When there is any concern about the 
subject’s condition an alarm button on the RespirAct™ will deliver 100% oxygen to 
the subject as an extra safety feature. The re-breathing circuit can be easily removed 
from the subject’s face.  
Theoretically, CO2 manipulation can cause further impairment of perfusion in 
areas with low flow and poor reactivity, by a “steal phenomenon” – flow would be 
diverted to areas of preserved reactivity during stimulation. In spite of this 
theoretical possibility this seems to be exceedingly uncommon even in patients with 

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severe chronic ischemic conditions such as Moyamoya, where the cerebrovascular 
reactivity is frequently tested with CO2 manipulation and acetazolamide, and more 
recently at the Toronto Western Hospital, using the RespirAct™ (several protocols 
are currently approved by the UHN REB).  As well, it is anticipated that the majority 
of our subjects studied will be young and otherwise healthy. 
The device has built in safety features and alarms.  For example, 
 All source gases contain at least 6 % oxygen to limit the level of hypoxia to a 
safe and asymptomatic level in case of an error or technical problem with 
implementing the desired blend of gases 
 The blender has a “dead man’s switch” that defaults to 100% oxygen at 12 
L/min if there is any loss of communication between the blender and the 
computer such as “hanging up” of the software or computer, loss of power to 
computer or blender, any one of a series of pre-set alarm conditions are met. 
 The RespirAct™ has a large red button that if pushed switches the gasses to 
100% oxygen allowing fast and easy intervention in case of any problematic 
issue. 
 The gas delivery circuit has a rubber button with a handle accessible to the 
subject that if pulled immediately opens the circuit and provides the subject 
with room air.  
 In addition to being monitored by a physician, the RespirAct™ continuously 
assesses a series of subject and hardware parameters to assure that they stay 
within pre-set safe limits.  Some of these are: 
 Subject parameters: 
 Respiratory rate 
 Peak expired CO2 concentration 
 inspired CO2 concentration 
 expired O2 concentration 
 inspired O2 concentration 
 apnea time 
 Blender parameters 
 Delivered flow of each gas is equal to the demanded flow 
 Internal pressures and temperatures 
 Proper functioning of gas flow controllers and switches 
The RespirAct™ been used in about 500 cases at the Toronto Western Hospital in 
patients with significant impairment of the blood supply to the brain without undue 
effect or complication. 
3. Neck Collar and Jugular compression 
 The physiological effect jugular venous compressions used in this study are 
minimal and the brief period of jugular occlusion is similar to the effects produced 

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by straining, coughing and heavy lifting. Neck collar will apply only minimal 
pressure on the neck, which is comparable to wearing a tight dress shirt and a tie.  
4.  Ultrasound 
There are no risks with the use of ultrasound. Orbital ultrasound is routinely 
done in all patients coming for cataract and retinal surgery at Toronto 
Western Hospital. Around 30 patients undergo transorbital ultrasound every 
day at UHN. Ultrasound Gel can be cold on contact with skin.  
 
Data collection 
 
Data collected will include: 
 Volunteer demographics 
 Medical history 
 Vital signs- Heart rate, non-invasive blood pressure and cardiac output, 
oxygen saturation, end-tidal Co2 levels. 
 Optic nerve sheath diameter at normocapnia, 2 levels of hypercapnia and 
hypocapnia. 
 Internal jugular vein diameter and flow in supine and Siting position with 
and without the neck collar. 
 The minimal pressure needed to occlude the IJV. 
 
Data Analysis 
 
A paired t test will be used to compare the following changes in ONSD 
 Normocapnia (baseline Pco2) to hypercapnia (baseline+10 mmHg) 
 Normocapnia (baseline Pco2) to Hypercapnia (baseline+15mmHg  
  Normocapnia (baseline Pco2) to hypocapnia (baseline -10mmHg) 
 Neck collar ON and OFF  at each Co2 levels.  
 
Sample size 
 
Since this is a preliminary study to evaluate the effect of hypercapnia and 
hypocapnia and IJ compression on ONSD, only a small sample is required. We intend 
to enroll 15 subjects in this initial phase. Given the fact that the CO2 manipulation 
technique using the RespirAct™ is a new method developed at the University of 
Toronto and not yet widely available, the lack of information in the literature 
regarding its utilization for this purpose is obvious. We believe that this small 
sample will be sufficient to demonstrate the feasibility of the test and set the stage 
for larger studies. 

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 Project Feasibility 
We anticipate no difficulty in obtaining 15 volunteers to participate in this study. 
The RespirAct™ gas blender used for CO2 manipulation has been installed at 10 sites 
including John’s Hopkins, University of Colorado, Duke University, University of 
Nottingham, University of Montreal, University of Texas, and McGill University. The 
device has a proven track record with regard to clinical implementation.  
 
Figures 
 
Figure 1:  Experimental protocol demonstrating target PetCO2 levels with 
measurements being performed both while the venous compression collar is off and 
then subsequently applied.   
 

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Figure 2: An experiment of end-tidal CO2 (PetCO2) manipulation using MPET 
(RespirAct™).  Please note the stable O2 levels and the precision control of PetCO2 
levels. 

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Figure 3:  Two-dimensional ocular sonography.  A diagram showing the ultrasound 
probe, the ocular globe and the optic nerve with the optic nerve sheath diameter 
(ONSD) which was measured 3 mm behind the papilla using an electronic caliper 
(A X LONG measure ) and an axis perpendicular to the optic nerve (B + LONG 
measure).