Impact of CO2 on Cerebral Blood Flow in Infants Less Than 6 Months During General Anaesthesia
Phase: NA
Conditions: Anesthesia, General, Infant
Sponsor: St. Justine's Hospital

Research Protocol
Impact of CO2 on cerebral blood flow in infants under 6 months of age
during general anesthesia
Principal investigator:
Dr. Ossam Rhondali 
Anesthesiologist, CHU Sainte-Justine.
1.
Hypothesis
Optimal cerebral perfusion is an essential objective during anesthesia, especially in infants, whose 
brains  are immature.  A number  of  factors influence  cerebral blood  flow (CBF)  and  cerebral 
oxygenation: arterial pressure, PaCO2 and hemoglobin.
We previously showed that a mean arterial pressure (MAP) of between 35 and 45 mm Hg was an 
intraoperative objective for maintaining safe cerebral oxygenation in normocapnic conditions and in 
the absence of anemia in infants under 6 months of age. (1-3)
CO2 influences cerebral vascular tone. Hypocapnia causes vasoconstriction, a decrease in CBF 
and a risk of cerebral ischemia, while hypercapnia causes vasodilation and an increase in CBF. (4)
Mechanical  ventilation  during  general  anesthesia  changes  PaCO2.  Furthermore,  mechanical 
ventilation can be tricky in cases of lung disease in children requiring the use of high-frequency 
oscillatory ventilation. As well, surgery can influence mechanical ventilation as a result of pressure 
exerted on the lungs, either directly (thoracotomy or thoracoscopy) or indirectly via the abdomen 
(laparoscopy). Endoscopic techniques use insufflation with CO2, a gas that readily diffuses through 
the pleura or peritoneum to the infant’s blood compartment. 
Like hypotension, an unsuitable intraoperative PaCO2 can cause serious neurological sequelae. (5-
7)
2.
Objectives
Our primary objective is to determine the impact of varying EtCO2 and, therefore, PaCO2 on CBF 
and cerebral oxygenation with a MAP of between 35 and 40 mm Hg in infants under 6 months of 
age during general anaesthesia 
3.
Methodology
This will be a prospective study involving infants under the age of 6 months admitted to the surgical 
suite for surgery requiring mechanical ventilation.
During the anesthesia consultation, explanations will be provided regarding the anesthesia protocol 
used, with special focus on the following:
- The standard anesthesia technique, no change in the drugs administered, especially with regard 
to sedation and analgesia. 
- The noninvasive, painless and adverse effect-free technique for evaluating cerebral perfusion. 
- Changing cerebral perfusion in the direction of improvement (increase in EtCO2 and increase in 

CBF).
An information and consent form will be drafted using the REB’s template (see appendix). 
Cerebral perfusion will be evaluated by:
• Measuring  the  systolic,  diastolic  and  mean  velocities  in  the  middle  cerebral  artery  using 
transcranial Doppler ultrasound (see example below). 
Infant awake and then under general anesthesia. Systolic and diastolic flow is observed in the awake infant. This flow 
disappears after the induction of general anesthesia.
• Measuring cerebral oxygen saturation using a tissue oxygen saturation sensor placed in the 
frontal region.
INVOS™ OxyAlert™ NIRSensors
Near-infrared spectroscopy (NIRS) is used to noninvasively evaluate regional cerebral oxygen 
saturation (rSO2c). It reflects the balance between cerebral oxygen supply and consumption (8). A 
decrease in rSO2c indicates either an increase in cerebral oxygen consumption (CMRO2) and/or 
inadequate oxygen supply (decrease in CBF). On the other hand, an increase in rSO2c could 
indicate either an increase in CBF or a decrease in CMRO2 caused, for example, by general 
anesthesia. 
Description of study (diagram below)

We will perform a first measurement in the infant while awake. After the induction of general 
anesthesia and airway control, a series of measurements (Doppler and cerebral oxygen saturation) 
will be made. The following parameters usually used in anesthesia in infants under 6 months of 
age will be used for the mechanical ventilation: tidal volume, 8 ml/kg; positive expiratory pressure, 
5 mm Hg; and a baseline respiratory rate of 25 to 40 cycles per minute, depending on the infant’s 
age. If necessary, a bolus of ephedrine, 0.5 mg/kg, will be administered if the MAP is less than 35 
mm Hg after the induction of anesthesia. Subsequently, two series of measurements with a MAP 
greater than 35 mm Hg will be made after modifications to the ventilation to effect an increase of 5 
mm Hg in the EtCO2 value. The Doppler and cerebral oxygen saturation measurements and both 
controlled modifications to the mechanical ventilation are specific to this protocol. All the other 
aspects of the management are based on standard pediatric anesthetic care.
4.
Description of population
• Inclusion criteria
This will be a prospective study involving infants under 6 months of age admitted to the surgical 
suite for surgery requiring orotracheal intubation.
• Exclusion criteria
The exclusion criteria will be as follows: infant over 6 months of age, infant with intracranial 
pathology or a chronic respiratory disease that causes  hypercapnia, parental refusal and surgical 
emergency.

 
✓Anticipated benefits for participants.
The Doppler and cerebral oxygen saturation measurements are noninvasive and painless. The 
measurements will be made at different CO2 levels within a range usually observed during general 
anesthesia in infants (9). In our study, we will vary the CO2 in the direction of optimizing cerebral 
perfusion. (Example below with transcranial Doppler: diastolic velocity zero after intubation, and 
normalization after correcting the MAP and CO2).
Infant awake
After induction:
EtCO2 = 29
After increase in
EtCO2 to 40
5.
Statistical analysis
We will analyze the impact of changes in CO2  on cerebral oxygen saturation and velocities. The 
Spearman coefficient of correlation will be used to study the correlations between the cerebral 
perfusion parameters (cerebral velocities and rSO2c) and EtCO2. An ANOVA will be performed to 
determine the significant differences in rSO2c and cerebral velocities according to EtCO2.
A change in EtCO2 of +10 mm Hg could result in a relative increase in rSO2c of +10%. Therefore, 
with a mean standard deviation of rSO2c of 13% observed in the previous studies, we calculate the 
necessary number of subjects to be 36 (alpha risk = 5%; beta risk = 90%). To ensure that we will 
be able to analyze 36 patients, we hope to include 60 patients in the study. An interim analysis of 
the results will be performed after 20 patients have been included.
6.
Timetable and funding
For the number of patients to be included (n=60), based on the volume of activity in the CHU 
Sainte Justine’s surgical suite, we estimate that the duration of the study will need to be 18 months 
(3 to 5 patients a month).
The company Covidien is lending the cerebral oxygen saturation monitor and is providing the 60 

sensors needed for the study. We will use the Department of Anesthesiology’s sonograph.
Patient recruitment, parent explanations and the signing of the consent forms will be looked after 
by the anesthesiologist/principal investigator.
7.
References
1. Rhondali O, Pouyau A, Mahr A  et al.  Sevoflurane anesthesia and brain perfusion. Paediatr 
Anaesth. 2015 Feb;25(2):180-5.
2. Rhondali O, Juhel S, Mathews S et al. Impact of sevoflurane anesthesia on brain oxygenation in
children younger than 2 years. Paediatr Anaesth. 2014 Jul;24(7):734-40.
3. Rhondali O, Mahr A, Simonin-Lansiaux S et al. Impact of sevoflurane anesthesia on cerebral
blood flow in children younger than 2 years. Paediatr Anaesth. 2013 Oct;23(10):946-51.
4. Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. 2002 Jul 4; 347(1):43-53.
5. Weiss M, Vutskits L, Hansen TG et al.  Safe Anesthesia For Every Tot - The SAFETOTS 
initiative. Curr Opin Anaesthesiol. 2015 Jun;28(3):302-7.
6. McCann ME, Schouten AN, Dobija N et al. Infantile postoperative encephalopathy: perioperative
factors as a cause for concern. Pediatrics. 2014 Mar;133(3):e751-7.
7. McCann ME, Schouten AN. Beyond survival; influences of blood pressure, cerebral perfusion
and anesthesia on neurodevelopment. Paediatr Anaesth. 2014 Jan;24(1):68-73.
8. Bernal NP, Hoffman GM, Ghanayem NS et al. Cerebral and somatic near-infrared spectroscopy
in normal newborns. J Pediatr Surg 2010; 45: 1306–1310.
9. Hilly J, Pailleret C, Fromentin M et al. Use of near-infrared spectroscopy in predicting response 
to  intravenous  fluid  load  in  anaesthetized  infants.  Anaesth  Crit  Care  Pain  Med.  2015  Oct; 
34(5):265-70.
8.
Appendix

INFORMATION ABOUT THE RESEARCH, AND CONSENT FORM
 
Title: Impact of CO2 on cerebral blood flow in infants under 6 months of age during general 
anaesthesia.
Persons in charge:
CHU Sainte-Justine: Dr. Ossam Rhondali and Dr. Bruno Greff
Funding source: Department of Anesthesiology. The equipment is being provided by the company 
Covidien.
WHY ARE YOU BEING INVITED TO PARTICIPATE IN THIS RESEARCH PROJECT?
The CHU Sainte-Justine’s Department of Anesthesiology is taking part in research projects aimed 
at improving the quality of care and the safety of children in the surgical suite. We are today 
requesting your participation. Please read this information form in order to decide if you are 
interested in participating in this research project. It is important that you fully understand this form. 
Please feel free to ask questions. Take all the time you need to make a decision.
In this consent form, “you” refers to you or your child.
WHY IS THIS RESEARCH PROJECT BEING CONDUCTED?
Background and relevance of this research
Brain oxygenation is an essential objective during anesthesia, and a number of factors influence it: 
arterial pressure, hemoglobin and breathing.
During general anesthesia, your child’s breathing will be controlled by a respirator, which, in turn, 
will be adjusted and controlled by an anesthesiologist. Breathing permits oxygen supply to the 
body and the elimination of carbon dioxide gas (CO2).
Carbon dioxide influences oxygen supply to the brain. A decrease in CO2 causes a decrease in the 
oxygen supply, while an increase in CO2 causes an increase in oxygen supply.
Objectives of this research
We are inviting you to participate in this research project, which is aimed at studying the impact of 
the CO2 level on cerebral perfusion during anaesthesia.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS RESEARCH PROJECT?
About 60 participants will take part in this project at our facility.

HOW WILL THIS RESEARCH PROJECT PROCEED?
This study involves infants under 6 months of age admitted to the surgical suite for surgery 
requiring general anesthesia. The management of the anesthesia will be the same as that usually 
provided in infants under 6 months of age.
What is added in this research project is the evaluation of brain perfusion, which will be done by 
means of ultrasound and a cerebral oxygen saturation sensor placed on the forehead. Both 
techniques are painless and noninvasive and are frequently used for neurological monitoring in 
intensive care and cardiac surgery.
Brain perfusion will be evaluated at different CO2 levels, which will depend on the ventilation 
controlled by the anesthesiologist. The anesthesiologist will control the ventilation to maintain the 
CO2 values at physiological levels (levels expected for the child).
WHAT IS THE DURATION OF PARTICIPATION IN THIS RESEARCH PROJECT?
Your child will participate in the project during anesthesia but will not require any monitoring or 
change in his/her postoperative management in connection with his/her participation in the project.
WHAT ARE THE RISKS?
Doppler and brain oxygen saturation measurements are noninvasive and painless. The Doppler 
ultrasound measurements will be made intermittently and will not involve any risks. Measuring 
brain oxygen saturation will require the use of a sensor attached to your child’s forehead. When the 
sensor is removed, slight redness of the skin due to the sensor’s adhesive may persist. It is the 
same phenomenon observed when an adhesive bandage is removed. The measurements will be 
made at different CO2 levels within a range usually observed during general anesthesia in infants. 
Furthermore, our study will vary the CO2 level in the direction of optimizing brain perfusion.
ARE THERE ANY BENEFITS IN PARTICIPATING IN THIS RESEARCH PROJECT? 
There  would  be no direct benefit for your child in participating  in this  study.  However, your 
participation will help provide us with a better knowledge of the brain and further improve care 
quality and safety.
HOW WILL CONFIDENTIALITY BE ENSURED?
All the information gathered will remain confidential to the extent permitted by law. Your child’s 
identity will be protected by replacing your name with a research code. Only your hospital’s 
research team will have access to the link between the code and your name. The company 
Covidien will not have access to the data obtained during this research.
To check that the research is proceeding properly and to ensure your protection, the Hôpital 
Sainte-Justine Research Ethics Board may consult your research file and your medical record.
If the overall results of this research project are published or presented at scientific conferences, 
your name and other personal information will not be used.
The research data will be stored in a secure manner for 7 years under the responsibility of the 
principal investigator at your hospital.
ARE YOU FREE TO PARTICIPATE?
Yes. Participation in this research project is voluntary. You are free to choose not to participate in 
this research project. If you do not participate in this research project, this would not affect the 
quality of care provided to your child.

RESOURCE PERSONS
If you have any questions about this research project or experience a problem that you believe is 
related to your participation in the project, you can contact the investigator in charge of the project 
at your hospital:
- CHU Sainte-Justine: Dr. Ossam Rhondali, Anesthesiology. 514-345-4733.
For any information about your rights, you can contact the Local Ombudsman and Service Quality 
Commissioner:
- CHU Sainte-Justine: 514-345-4749. 
WHERE CAN I OBTAIN ADDITIONAL INFORMATION?
Clinical  Trials  (in  English  only):  A  description  of  this  clinical  trial  will  be  available  at 
http://www.clinicaltrials.gov in accordance with the provisions of US and Canadian law. This site 
will not contain any information by which you could be identified. At most, the site will present a 
summary of the results. You can search the site at any time.
You can request a summary of the results of this research project. They will be available only after 
the project is completely finished. 
You will receive a signed copy of this form. You can ask the research team questions at any time.
RESEARCH ETHICS BOARD
The Hôpital Sainte-Justine Research Ethics Board has approved this research project and is 
monitoring it.

CONSENT
Title of research project
Impact of CO2 on cerebral blood flow in infants under 6 months of age during general 
anaesthesia
The nature and conduct of this research project have been explained to me. I have read the 
consent form and have been given a copy of it. I have had the opportunity to ask questions, and 
they have been answered. After due consideration, I agree to my child participating in this research 
project.
I authorize the research team to consult my child’s medical record in order to obtain information 
relevant to this project.
In signing this consent form, you are not waiving any of your legal rights. Furthermore, you are not 
releasing the investigators and the sponsor from their legal and professional liability in the event of 
a situation that causes you harm.
Your child’s name:
Date: 
Name of parent or guardian:
Consent  (signature)
Date:
(Printed) 
I have explained all the relevant aspects of the research to the parents and answered the 
questions they asked me. I have explained to them that participation in this research project is free 
and voluntary and that participation can be terminated at any time. 
Name of person obtaining consent: 
(signature)
Date:
(Printed)