Cerebral Blood Flow During Propofol Anaesthesia
Conditions: Gastrointestinal Neoplasms
Sponsor: Rigshospitalet, Denmark

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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Cerebral blood flow during propofol anaesthesia  
 
Study protocol  
 
Clinicaltrials.gov id: NCT02951273 
 
Date: 19 November 2017 
 
 

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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Detailed Description:  
Background 
General anaesthesia reduces blood pressure, but cerebral autoregulation is considered to maintain its 
blood flow if mean arterial pressure (MAP) is between 60-150 mmHg. Thus, vasoactive medication 
is administered to treat anaesthesia-induced hypotension if MAP decreases to below approximately 
60 mmHg. In young healthy adults, propofol anaesthesia, with limited reduction in blood pressure, 
decreases cerebral blood flow by approximately 50% by a decrease in neuronal activity. However, it 
is unknown whether the anaesthesia-induced reduction in cerebral blood flow is affected by a 
marked decrease in MAP and whether propofol anaesthesia affects the lower level of cerebral 
autoregulation.  
 
If central blood volume is maintained, cerebral oxygenation may be unaffected by a decrease in 
MAP to ~40 mmHg whereas a reduction in central blood volume and cardiac output (CO) during 
orthostasis or bleeding, reduces cerebral oxygenation when MAP is lower than approximately 80 
mmHg. Thus, CO may affect cerebral blood flow and the ability to increase CO is likely of 
importance for maintaining a sufficient cerebral blood flow.  
 
During anaesthesia, cerebral blood flow and MAP may be affected by various factors including 
release of vasoactive substances. Manipulation of the abdominal organs may induce a so-called 
mesenteric traction syndrome (MTS) encompassing a triad of flushing, hypotension, and 
tachycardia in about half of the patients who undergo major abdominal surgery. MTS typically 
develops 15-20 min after the start of surgery and the haemodynamic manifestations, that appear to 
be mediated by prostaglandin I2, last for approximately 30 min. The effect of MTS on cerebral 
blood flow is unknown. Prostaglandin I2 dilates cerebral arteries in vitro but does not affect cerebral 
blood flow when administered to healthy subjects. In a previous study we found that MTS increases 
near-infrared spectroscopy determined frontal lobe oxygenation possibly due to an increase in 
extracranial circulation while there was no effect on middle cerebral artery mean flow velocity as an 
index of changes in cerebral blood flow.  
 
Propofol anaesthesia appears not to affect the CO2 reactivity of the middle cerebral artery as 
determined by transcranial Doppler ultrasonography, but the CO2 reactivity of the internal carotid 
artery during propofol anaesthesia is unknown.  

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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Objective 
The purpose of this study is to evaluate how internal carotid artery blood flow is affected by 
propofol anaesthesia and related hypotension, and by administration of phenylephrine as standard 
care to treat anaesthesia-induced hypotension. Further, the study will assess whether internal carotid 
artery blood flow is affected by development of MTS and whether propofol anaesthesia affects the 
CO2 reactivity of the internal carotid artery.  
 
Hypotheses 
1) Propofol anaesthesia and related anaesthesia-induced hypotension (MAP < 65 mmHg) reduces 
internal carotid artery blood flow 
2) Treatment of anaesthesia-induced hypotension by administration of phenylephrine increases 
internal carotid artery blood flow 
3) Development of MTS increases near-infrared spectroscopy determined frontal lobe oxygenation 
due to an increase in forehead skin blood flow and oxygenation with no effect on internal carotid 
artery blood flow  
4) Propofol anaesthesia lowers the CO2 reactivity of the internal carotid artery 
 
Methods 
The study will include thirty patients undergoing oesophageal- or ventricular resection. The study 
was approved by the Regional Ethical Committee (De Videnskabsetiske Komiteer Region 
Hovedstaden id: H-16036250) and the Danish Dataprotection Agency. The study lasts from when 
the patient arrives to the operating room and until two hours after the start of surgery. As part of 
standard care all patients will be instrumented with arterial and central venous catheters. 
Anaesthesia will be induced by propofol and maintained by propofol and remifentanil combined 
with epidural anaesthesia. Development of MTS is defined by flushing within the first 60 min of 
surgery. Measurements include unilateral internal carotid artery blood flow evaluated by duplex 
ultrasound, MAP and heart rate as recorded by a transducer connected to the arterial line, central 
haemodynamics (stroke volume, CO, and total peripheral resistance) evaluated by pulse contour 
analysis of the arterial pressure curve, frontal lobe and muscle oxygenation as determined by near-
infrared spectroscopy, forehead skin blood flow, haemoglobin concentrations, and oxygenation 

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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assessed by laser Doppler flowmetry, and depth of anaesthesia determined by Bispectral Index. 
Arterial blood will be drawn for analysis of the arterial CO2 tension (PaCO2).  
 
During the study PaCO2 will be maintained at the value before induction of anaesthesia by 
ventilator adjustments. Internal carotid artery CO2 reactivity before induction of anaesthesia will be 
determined by evaluations of blood flow and PaCO2 during normoventilation and during 
hyperventilation to reduce PaCO2 by 1.5 kPa as guided by end-tidal CO2 tension (PetCO2) and 
measurements will be conducted when PetCO2 has been stable for 5 min. The CO2 reactivity during 
anaesthesia will be determined by evaluations of internal carotid artery blood flow and PaCO2 at a 
PaCO2 at the value before induction of anaesthesia and 1.5 kPa above and below that value as 
guided by PetCO2 and measurements will be conducted when PetCO2 has been stable for 5 min. 
The CO2 reactivity before and during anaesthesia is calculated as the percentage change in internal 
carotid artery blood flow per kPa change in PaCO2. Analysis of internal carotid blood flow will be 
after correction for CO2 reactivity.  
 
Blood samples for analysis of markers of MTS (6-keto-prostaglandin-F1, pro-ANP, ACTH, 
cortisone, IL-1, IL-6, and TNF-α) will be drawn before induction of anaesthesia and 20 and 60 min 
after the start of surgery. Total amount of blood samples will be no more than 75 ml. Patients will 
be excluded if the planned surgery is cancelled and excluded patients will be replaced.  
 
Measurements will be conducted and arterial blood drawn at the following time points:  
- Before induction of anaesthesia during normoventilation and hyperventilation 
- After induction of anaesthesia  
- During anaesthesia-induced hypotension (MAP < 65 mmHg)  
- After treatment of anaesthesia-induced hypotension by administration of phenylephrine  
- 5 min before and after incision and 0, 20, 40 and 70 min after development of MTS and 20, 40, 60 
and 90 min after the start of surgery in patients who did not develop MTS  
- During normo-, hyper-, and hypocapnia during anaesthesia in random order  
 
Statistics  
Trial size: The minimal clinically important difference in internal carotid artery blood flow by 
treatment of anaesthesia-induced hypotension is considered to be 10%, corresponding to 

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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approximately 24 ml/min, and twenty-seven patients were considered required assuming a 42 
ml/min SD with a 5% significance level and a power of 80%. 
 
Outcome Measures 
Primary Outcome Measures: 
1. Changes in internal carotid artery blood flow by treatment of anaesthesia-induced 
hypotension 
Time Frame: Two measurements; during anaesthesia 
Designated as safety issue: No 
Unilateral internal carotid artery blood flow [ml/min] assessed by duplex ultrasound as 
determined during anaesthesia-induced hypotension (mean arterial pressure < 65 mmHg) 
and after administration of phenylephrine. 
 
Secondary Outcome Measures: 
2. Changes in internal carotid artery blood flow by induction of anaesthesia 
Time Frame: Two measurements; before and after induction of anaesthesia 
Designated as safety issue: No 
Unilateral internal carotid artery blood flow [ml/min] assessed by duplex ultrasound as 
determined before and after induction of anaesthesia. 
 
3. Association between changes in internal carotid artery blood flow, mean arterial pressure 
and cardiac output by treatment of anaesthesia-induced hypotension 
Time Frame: Two measurements; during anaesthesia 
Designated as safety issue: No 
Association between changes in unilateral internal carotid artery blood flow [ml/min] 
assessed by duplex ultrasound, mean arterial pressure [mmHg] as recorded by a transducer 
connected to an arterial line, and cardiac output [l/min] evaluated by pulse contour analysis 
of the arterial pressure curve (Modelflow) as determined before and after treatment of 
anaesthesia-induced hypotension (mean arterial pressure < 65 mmHg) by administration of 
phenylephrine. 

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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4. Changes in frontal lobe oxygenation by development of mesenteric traction syndrome 
Time frame: Six measurements; during anaesthesia 
Designated as safety issue: No 
Near-infrared spectroscopy determined frontal lobe oxygenation [%] as compared between 
those patients who develop mesenteric traction syndrome (defined as flushing within 60 min 
after the start of surgery) and those who do not as determined 5 min before and after incision 
and 0, 20, 40, and 70 min after flushing and 20, 40, 60, and 90 min after the start of surgery 
in those who do not develop mesenteric traction syndrome.  
 
5. Changes in forehead skin blood flow by development of mesenteric traction syndrome 
Time frame: Six measurements; during anaesthesia 
Designated as safety issue: No 
Forehead skin blood flow [PU] assessed by laser Doppler flowmetry as compared between 
those patients who develop mesenteric traction syndrome (defined as flushing within 60 min 
after the start of surgery) and those who do not as determined 5 min before and after incision 
and 0, 20, 40, and 70 min after flushing and 20, 40, 60, and 90 min after the start of surgery 
in those who do not develop mesenteric traction syndrome.  
 
6. Changes in forehead skin oxygenation by development of mesenteric traction syndrome 
Time frame: Six measurements; during anaesthesia 
Designated as safety issue: No 
Forehead skin oxygenation [%] assessed by laser Doppler flowmetry as compared between 
those patients who develop mesenteric traction syndrome (defined as flushing within 60 min 
after the start of surgery) and those who do not as determined 5 min before and after incision 
and 0, 20, 40, and 70 min after flushing and 20, 40, 60, and 90 min after the start of surgery 
in those who do not develop mesenteric traction syndrome.  
 
7. Changes in internal carotid artery blood flow by development of mesenteric traction 
syndrome 
Time frame: Six measurements; during anaesthesia 
Designated as safety issue: No 

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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Unilateral internal carotid artery blood flow [ml/min] assessed by duplex ultrasound as 
compared between those patients who develop mesenteric traction syndrome (defined as 
flushing within 60 min after the start of surgery) and those who do not as determined 5 min 
before and after incision and 0, 20, 40, and 70 min after flushing and 20, 40, 60, and 90 min 
after the start of surgery in those who do not develop mesenteric traction syndrome.  
 
8. Changes in the CO2 reactivity of the internal carotid artery from before to after induction of 
anaesthesia 
Time frame: Five measurements; before and during anaesthesia 
Designated as safety issue: No 
Unilateral internal carotid artery blood flow [ml/min] assessed by duplex ultrasound and 
arterial CO2 tension (PaCO2) [kPa] are evaluated before induction of anaesthesia during 
normoventilation and hyperventilation to reduce PaCO2 by 1.5 kPa and during anaesthesia at 
a PaCO2 at the value before induction of anaesthesia and 1.5 kPa above and below that 
value. The CO2 reactivity before and during anaesthesia is calculated as the percentage 
change in internal carotid artery blood flow per kPa change in PaCO2 and the values are 
compared.  
 
9. Changes in heart rate from baseline 
Time Frame: Continuous measurements before induction of anaesthesia and during 
anaesthesia 
Designated as safety issue: No 
Heart rate [bpm] as recorded continuously by a transducer connected to an arterial line.  
 
10. Changes in mean arterial pressure from baseline  
Time Frame: Continuous measurements before induction of anaesthesia and during 
anaesthesia 
Designated as safety issue: No 
Mean arterial pressure [mmHg] as recorded continuously by a transducer connected to an 
arterial line.  
 

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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11. Changes in cardiac output from baseline 
Time Frame: Continuous measurements before induction of anaesthesia and during 
anaesthesia 
Designated as safety issue: No 
Cardiac output [l/min] as evaluated continuously by pulse contour analysis of the arterial 
pressure curve (Modelflow).  
 
12. Changes in stroke volume from baseline 
Time Frame: Continuous measurements before induction of anaesthesia and during 
anaesthesia 
Designated as safety issue: No 
Stroke volume [ml] as evaluated continuously by pulse contour analysis of the arterial 
pressure curve (Modelflow).  
 
Inclusion Criteria  
 - Patients planned for major abdominal surgery that require placement of an arterial line and 
central venous catheter, including oesophageal- or ventricular resection 
 - Age ≥ 18 years.  
 
Exclusion Criteria  
 - No informed consent 
 - Robotic assisted procedures 
 - Treatment with anti-inflammatory medication, including NSAID and corticosteroids 
 - Atherosclerosis of the internal carotid artery that obstructs ≥ 30% of the vessel lumen 
 - Neurologic disease considered to affect cerebral blood flow, including dementia, epilepsy, and 
apoplexy 
 
Contacts/Locations 
Niels D. Olesen, MD 
Study Principal Investigator 

Cerebral blood flow during propofol anaesthesia. Study protocol.  
Date: 19 November 2017 
 
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Telephone: 0045 35452674 
Email: nielsdolesen@gmail.com 
 
Niels H. Secher, MD, D.M.Sc. 
Telephone: 0045 35452242 
Email: niels.secher@regionh.dk  
 
Location: Department of Anaesthesia, Rigshospitalet 2043, DK-2100 Copenhagen Ø, Denmark 
 
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