The Effect of Blood Pressure on Cerebral Blood Flow During Propofol Anesthesia
Phase: NA
Conditions: Gastrointestinal Neoplasms, Anesthesia, General
Sponsor: Rigshospitalet, Denmark

Study protocol: The Effect of Blood Pressure on Cerebral Blood Flow During 
Propofol Anesthesia 
 
Brief Title: The Effect of Blood Pressure on Cerebral Blood Flow During Propofol Anesthesia  
 
Official Title: The Effect of Blood Pressure on Cerebral Blood Flow During Propofol Anesthesia  
 
Acronym: CA 
 
Clinical trials ID: NCT03309917 
 
Date: December 22 2017 
 
Unique Protocol ID: H-17021598-61256  
 
 
 
 
 
 
 
 
 
 

Ethics 
The study protocol (H-17021598-61256) was approved by the Regional Ethical Committee of the 
Copenhagen Region (De Videnskabsetiske Komiteer Region Hovedstaden, 004538666395, Email: 
vek@regionh.dk, Adress: Kongens Vænge 2, DK-3400 Hillerød, Denmark 
 
The study is monitored by the Danish Dataprotection Agency. 
 
Study is planned to be conducted from December 2017-April 2018 
 
FDA Regulated: No 
FDA Regulated Intervention: No 
Sponsor: Rigshospitalet, Denmark 
Principal investigator: Niels Damkjær Olesen, MD 
Sub-Investigator: Niels H. Secher, M.D., D.M.Sc., Prof. 
Contacts/Locations 
Central Contact:  
Niels D. Olesen, MD 
Telephone: 0045 35452674 
Email: nielsdolesen@gmail.com 
 
Central Contact Backup:  
Niels H. Secher, M.D., D.M.Sc., Prof.. 
Telephone: 0045 35452242 
Email: niels.secher@regionh.dk  

Study Officials:  
Niels D. Olesen, MD 
Study Principal Investigator 
Department of Anesthesia, Rigshospitalet 2043, DK-2100 Copenhagen Ø, Denmark 
 
Locations:  
Department of Anesthesia, Rigshospitalet 2043, DK-2100 Copenhagen Ø, Denmark 
Facility contact: Niels D. Olesen, M.D. Tel.: 0045 35452674 e-mail: nielsdolesen@gmail.com 
Short Description   
General anesthesia often reduces blood pressure whereby blood flow to the brain and other vital 
organs may become insufficient. Thus, medicine is often administered to maintain blood pressure 
but it is unclear at what level blood pressure should be aimed at during anesthesia. 
 
Thirty patients undergoing major abdominal surgery will be included. The study will start 
one hour after the start of surgery and lasts for approximately half an hour. The purpose of the study 
is to evaluate whether blood flow to the brain can be increased by maintaining blood pressure at a 
higher level than that used in clinical practice. In the study, MAP is adjusted to a high, moderate, 
and low level for a short time. The low level of blood pressure used in the study, corresponds to the 
level aimed at in clinical practice. The drug noradrenaline will be used to control blood pressure. 
Blood flow to the brain will be evaluated on the neck using ultrasound. 
Background 
Propofol anesthesia reduces cerebral blood flow (CBF) and mean arterial pressure (MAP) but it is 
unclear whether the decrease in CBF is accentuated by hypotension. Cerebral autoregulation is 

generally considered to maintain CBF when MAP is between 60-150 mmHg. Hence, vasoactive 
medication is administered if MAP decreases to below approximately 60 mmHg. 
 
It is controversial whether there is a plateau for cerebral autoregulation. Thus, middle 
cerebral artery blood velocity (MCA Vmean), as an index of CBF, is associated to MAP during 
pharmacological changes in MAP between approximately 40-125 mmHg. Similarly, CBF is 
affected by pharmacological changes in MAP between 40-80 mmHg during hypothermic 
cardiopulmonary bypass surgery in propofol anesthesia. Arterial hypertension may increase the 
lower limit of cerebral autoregulation which can be mitigated by antihypertensive 
treatment. 
 
Cognitive dysfunction and delirium are common following major surgery, particularly in 
the elderly, and may be related to hypotension and cerebral hypoperfusion. Further, hypotensive 
anesthesia is associated with an increase in markers of neuronal damage, but studies have been too 
small to detect any difference in incidence of cognitive dysfunction following hypotensive as 
compared to normotensive anesthesia. 
 
In young healthy adults, propofol anesthesia causes limited reduction in blood pressure and 
decreases CBF by approximately 50% by a reduction in neuronal activity. An increase in MAP 
from approximately 80 to 100 mmHg during propofol anesthesia does not affect CBF but it is 
unknown whether CBF can be increased by an increase in MAP from approximately 60 to 80 
mmHg. Propofol appears to maintain cerebral autoregulation but it is unknown whether the lower 
level of cerebral autoregulation is affected. The internal carotid artery supplies most of CBF and 
dilates during moderate hypotension with maintained blood flow which indicates that the vessel 
contributes to cerebral autoregulation. Further, central blood volume and cardiac output may be 
important factors for maintaining CBF. 
 
The study will include thirty patients planned for major abdominal surgery in propofol-
remifentanil anesthesia combined with epidural analgesia. Internal carotid artery blood flow will be 

evaluated on the neck using duplex ultrasound. The study will be conducted one hour after the start 
of surgery and lasts for approximately half an hour. In the study, MAP is set pharmacologically at 
80-85, 70-75 and 60-65 mmHg for a short time in random order. The level of 60-65 mmHg 
corresponds to the level at which MAP is maintained in clinical practice. Control of MAP is by 
intravenous infusion of noradrenaline, an α- and β-adrenergic agonist. 
Objective 
The purpose of the study is to evaluate whether internal carotid artery blood flow is increased by 
maintaining MAP at a higher level than that used in clinical practice during propofol anesthesia. 
Further, we evaluate whether a lower limit of cerebral autoregulation can be detected by comparing 
the slopes of linear regression of internal carotid artery blood flow and MAP at the evaluations 
when MAP is 60-65 and 70-75 mmHg and when MAP is 70-75 and 80-85 mmHg. 
Hypotheses 
· Internal carotid artery blood flow is higher when MAP is 80-85 mmHg as compared to a 
MAP of 60-65 mmHg. 
· Internal carotid artery blood flow is higher when MAP is 70-75 mmHg as compared to a 
MAP of 60-65 mmHg. 
· Internal carotid artery blood flow is higher when MAP is 80-85 mmHg as compared to a 
MAP of 70-75 mmHg. 
· The slope of linear regression between changes in MAP and internal carotid artery blood 
flow is higher for the evaluations at a MAP of 70-75 and 60-65 mmHg than for the 
evaluations at a MAP of 80-85 and 70-75 mmHg. 

Methods 
The study is a single-center, prospective cohort study of thirty consecutive patients planned for 
major abdominal surgery in propofol anesthesia. In case surgery is cancelled, or if gas anesthesia is 
used the patient will be excluded and excluded patients will be replaced. The number of dropouts 
is expected to be between zero to five patients. Patients will be recruited the day before surgery, at 
which time the internal carotid artery will be evaluated using ultrasound. In case the vessel cannot 
be visualized, e.g. due to high localization of the carotid bifurcation the patient will not be able to 
participate in the study. 
 
Anesthesia and surgery are according to clinical practice. Anesthesia is induced by 
propofol and maintained by propofol and remifentanil. A thoracic epidural catheter is placed at 
Th8/9 or Th9/10 and epidural anesthesia is initiated before surgery by bupivacaine infusion 0.5%, 5 
ml/hr. and bolus 15 mg bupivacaine that is repeated hourly. Stroke volume is optimized after 
induction of anesthesia by repeated administration of 250 ml 5% human albumin until the increase 
in stroke volume is less than 10%, and volume optimization is repeated in case of persistent 
decrease in stroke volume by more than 10%. Noradrenaline infusion (0.6 μg/kg*ml) is started 
after induction of anesthesia to maintain MAP > 60 mmHg and to avoid volume optimization when 
the circulation is dilated. 
 
Development of a so-called mesenteric traction syndrome can affect MAP in the first hour 
of major abdominal surgery. Thus, the study is conducted from 60 min after incision and lasts for 
approximately half an hour. Anesthesia reduces MAP, but the reduction varies between patients and 
is affected by administration of propofol, remifentanil, and epidural anesthesia, fluid status, and 
surgical stimulation etc. The start of the study is postponed until any larger bleeding, transfusion or 
volume optimization is treated or finished. Before the start of the study, the infusion speed of 
propofol and remifentanil must have been constant for at least 10 min, and at least 15 min must 
have elapsed since the last bolus dose bupivacaine, as any changes in anesthesia may affect both 

cerebral and central hemodynamics. In case the infusion of propofol or remifentanil is changed or 
bolus bupivacaine is administered during the study, the experiment is halted, and the study is 
restarted when the anesthesia has been stable for 10 min. The experiment can only be restarted once 
and only data from the last trial with the highest number of evaluations are used. 
 
In the experiment MAP is temporally set to 80-85, 70-75, and 60-65 mmHg by adjusting 
the infusion of noradrenaline. The order of evaluations is randomized by drawing an envelope just 
before the start of the experiment. Noradrenaline is short lasting and have no direct effect on CBF. 
The experiment lasts approximately 30 min until evaluations have been conducted at the three 
levels of MAP. If MAP does not drop to 60-65 mmHg by halting the infusion of noradrenaline this 
evaluation is not conducted but we expect that this will be the case in only few patients. In clinical 
practice noradrenaline is used to maintain MAP > 60 mmHg. The study is not an investigation of 
medicinal products as noradrenaline is used as a tool to control MAP. 
 
Administration of noradrenaline is by a central venous or large peripheral catheter, using 
an electronic infusion pump, and infusion speed is adjusted slowly until the level of MAP is 
reached. Noradrenaline is effective within 1-2 min after administration and the effect lasts only for a 
few minutes. When MAP has been stable at the desired level for at least 3 min, measurements are 
conducted during the following 2 min. When the study is finished, control of MAP will be 
according to clinical practice. We consider that there is no increased risk by a short term increase in 
MAP to 80-85 mmHg.  
Measurements  
Arterial and central venous pressure are determined invasively while stroke volume, cardiac output, 
and total peripheral resistance are evaluated by modified pulse-contour analysis of the arterial 
pressure curve (Nexfin, BMEYE, Holland). Cerebral and biceps muscle oxygenation are evaluated 

using near-infrared spectroscopy (INVOS 5100C, Somanetics, Troy, MI, USA). Depth of anesthesia 
is assessed by Bispectral Index (BIS Complete Monitoring Systems, Covidien, USA).  
 
Internal carotid artery blood flow is evaluated unilaterally on the neck using duplex 
ultrasound (Logiq E, GE Medical System, Jiangsu, Kina). Evaluation is in the longitudinal section 
at least 1.5 cm distal to the carotid bifurcation with the head turned approximately 30⁰ to the 
contralateral side. In order to limit the influence of ventilation, three recordings of approximately 
15-20 s are conducted at each level of MAP and the mean is reported. A frequency of 8-12 MHz is 
used and gain is set as high as possible while vessel lumen is echo-free. Ultrasonic adjustments are 
not changed during the study. Diameter is assessed using automatic software to track the vessel wall 
(Brachial Analyser for Research v. 6, Medical Imaging Applications LLC, Coralville, IA, USA). 
The angle-corrected time maximum flow velocity (TAVMAX) is evaluated using pulsed-wave 
Doppler at an angle of insonation ≤ 60º. The TAVMAX corresponds to twice the mean blood 
velocity and blood flow is: 0.125*60*TAVMAX*π*diameter^2. Arterial and central venous blood 
is sampled for blood gas analysis. Internal carotid artery blood flow is corrected for changes in 
PaCO2 using a factor of 18%/kPa and for the ScO2 a correction factor of 4.3%/kPa is used 
(unpublished results from the study "Cerebral Blood Flow During Propofol Anaesthesia" 
NCT02951273). 
Statistics  
Trial size: The minimal clinically important difference in internal carotid artery blood flow between 
evaluations at MAP 60-65 and 80-85 mmHg is considered to be 10% as evaluations using near-
infrared spectroscopy indicate that intraoperative cerebral deoxygenation of > 10% associates to 
postoperative cognitive dysfunction. 

 
A power calculation indicated that at least 18 patients were required to detect a difference 
in internal carotid artery blood flow of 10% corresponding to 19 ml/min assuming a standard 
deviation for the change of 27 ml/min (unpublished results from the study "Cerebral Blood Flow 
During Propofol Anaesthesia" NCT02951273) to obtain a 5% significance level and a power of 
80%. We plan to include 30 patients. 
Inclusion Criteria  
• Patient planned for Whipple’s surgery or total pancreatic resection 
• Age > 18 years 
Exclusion Criteria  
• No informed consent 
• Alcohol intake ≥ 420 g / week 
• Beard on the neck 
• Visualization of the internal carotid artery not possible, e.g. due to high 
• placement of the bifurcation 
• Stenosis that obstructs ≥ 16% of the internal carotid artery 
• Cardiac disease, including congestive heart failure (NYHA II-IV), 
• myocardial infarction, valvular heart disease or atrial fibrillation 
• Neurologic disease considered to affect cerebral blood flow, including 
• dementia, epilepsy, and apoplexy 

• Intake of moclobemide, isocarboxazid or tricyclic antidepressantsNeurologic disease 
considered 
Primary Outcome Measure: 
1. Change in internal carotid artery blood flow when mean arterial pressure (MAP) is set to 80-
85 and 60-65 mmHg 
Secondary Outcome Measures: 
2. Change in internal carotid artery blood flow when MAP is set to 70-75 and 60-65 mmHg 
 
3. Change in internal carotid artery blood flow when MAP is set to 80-85 and 70-75 mmHg 
 
4. Comparison of the slope of linear regression of MAP and internal carotid artery blood flow 
for the evaluations when MAP is set to 80-85 and 70-75 mmHg and that of the evaluations 
when MAP is set to 70-75 and 60-65 mmHg 
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