Correlating Brain Tissue Oxygen Tension (PbrO2) and Regional Cerebral Oximetry (rSO2) in Normal Human Brain Under the Conditions of Changing Ventilation Strategy
Phase: NA
Conditions: Stroke
Sponsor: University of Michigan

Title: Correlating brain tissue oxygen tension (PbrO2) and regional cerebral 
oximetry (rSO2) in normal human brain under the conditions of changing 
ventilation strategy 
PI: Paul Picton, MB ChB, MRCP, FRCA, University of Michigan  
ID:  HUM00105648 
NCT:  NCT03128957 
Date:  10/10/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 

ACRC Proposal 
Correlating brain tissue oxygen tension (PbrO2) and regional 
cerebral oximetry (rSO2) in normal human brain under the 
conditions of changing ventilation strategy 
Paul Picton, MB ChB, MRCP, FRCA – Primary Investigator 
Philip Vlisides, MD – Co-investigator 
Magnus Teig, MB ChB, MRCP, FRCA - Co-investigator 
Jason A. Heth, MD – Co-investigator 
Shelley Housey, MPH- Statistician 
Amy McKinney, MA - study coordinator 
George A. Mashour, MD, PhD – Senior author and project mentor 
 
Hypothesis: We will test the hypothesis that there is a positive correlation between brain tissue 
oxygen (PbrO2) and regional cerebral oximetry (rSO2). Confirmation of this hypothesis would 
provide evidence that rSO2 is a clinically useful surrogate marker of brain tissue oxygen.  
Study type: Prospective cohort study. 
Study population: Adult patients attending the University of Michigan Neurosurgical Unit for 
elective excision of secondary cerebral metastases. 
Outcome measures: The change in brain tissue and regional cerebral oxygenation (dependent 
variables) resultant upon changes in inspired oxygen fraction and the partial pressure of carbon 
dioxide in arterial blood (independent variables). 
 

Correlating brain tissue oxygen tension (PbrO2) and regional cerebral oximetry (rSO2) in 
normal human brain under conditions of changing ventilation strategy 
 
Authors: Paul Picton1 MB ChB, MRCP, FRCA, Philip Vlisides2, MD, Magnus Teig3, MB ChB, MRCP, 
Jason A Heth4 MD, Shelley Housey5, MPH, Amy McKinney, MA6 George A. Mashour1 MD PhD 
1Associate Professor, 2Lecturer, 3Assistant Professor, 5Statistician, 6Study Coordinator, 
Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan, 
USA 
4Associate Professor, Department of Neurosurgery, University of Michigan Medical School, Ann 
Arbor, Michigan, USA 
Corresponding Author: Paul Picton, Tel: 734 936 4280, Fax: 734 936 9091, email: 
ppicton@med.umich.edu 
 
 

Introduction 
Controversy surrounds the use of regional cerebral oximetry (rSO2) as a measure of true 
cerebral oxygenation because extracranial contamination has been demonstrated for cerebral 
oximeters from several manufacturers.1  An additional major concern is the unmeasured 
confounding effect of cerebral a:v ratio2 which is assumed fixed within mathematical algorithms 
used in device software.  Yet, cerebral oximetry has been employed in multiple clinical settings3-
5 and decreases below an absolute measure of 50% or relative decreases of 20% appear to 
correlate to cerebral ischemia.2  Furthermore, low baseline values are associated with poor 
outcome.6 
The measurement of brain tissue oxygen (PbrO2) has been used in routine neurosurgery7 and 
has been shown to reliably demonstrate cerebral hypoxia following severe head injury.8  It is 
the most direct measure of cerebral oxygenation but probe insertion is highly invasive and 
hence precludes use outside of the neurosurgical or neurocritical care setting.  Correlation 
between rSO2 and jugular bulb monitoring has been demonstrated under conditions of varying 
inspired oxygen fraction (FIO2) in both uninjured9 and injured human brain10 but no study has 
been specifically designed to compare PbrO2 (the most reliable) and rSO2 (the least invasive) as 
measures of cerebral oxygenation.  Here, we test the hypothesis that there is a correlation 
between PbrO2 and rSO2 under conditions of varying inspired oxygen fraction and the varying 
partial pressure of carbon dioxide in arterial blood in uninjured, normal human brain.  This 
study has the potential for a positive impact because confirmation of the hypothesis would 
validate cerebral oximetry as a surrogate of cerebral oxygenation.  
 

Methods/Design 
The primary aim of this prospective cohort study is to evaluate for correlation between PbrO2 
and rSO2.  The secondary aim is to investigate the relationship between combined changes in 
FIO2 and the partial pressure of carbon dioxide in arterial blood (PaCO2) with both PbrO2 and 
rSO2 in un-injured human brain during general anesthesia.   
Patients who are scheduled for elective removal of secondary cerebral metastases under 
general anesthesia will be recruited following written informed consent obtained by a study 
team member during their preoperative evaluation. This evaluation typically takes place at the 
surgeon’s office or at a separate pre-operative clinic within 30 days of the scheduled surgical 
procedure. Patients will be excluded if they refuse to give consent, have evidence of elevated 
intracranial pressure on preoperative CT scan, have coagulopathy, are taking therapeutic agents 
known to increase bleeding risk, have a history of cardiovascular disease, cerebrovascular 
disease, suffer from respiratory failure, are scheduled for surgery in the prone position, or are 
not fluent English speakers.  Since skin pigmentation may impact rSO2 values11 and the study is 
small, recruitment will be limited to Caucasian patients. All patients will undergo the same 2 
step variation in ventilation strategy designed to maximize the potential changes in brain 
oxygenation.  
Following pre-oxygenation, anesthesia will be induced using fentanyl (1-2mcg/kg) and propofol 
(0.5-2mg/kg).  Muscle relaxation will be initiated and maintained with an appropriate 
combination of succinylcholine and non-depolarizing muscle relaxants as deemed necessary by 
their anesthesiologist and as dictated by the requirements of the particular surgical procedure.  

The patient’s trachea will be intubated and their lungs will be ventilated to achieve an FIO2 and 
PaCO2 determined by the study protocol.  General anesthesia will be maintained by total 
intravenous anesthesia (TIVA) with a combination of propofol (80-150 mcg/kg/min) and 
remifentanil (0.05-0.1 mcg/kg/min) targeted to a Bispectral Index range 40-60 (BIS; Covidien, 
Boulder, CO).   
Routine perioperative monitoring and invasive blood pressure monitoring will be used for all 
patients.  rSO2 will be measured using the INVOS 5100B monitor (Somanetics Corporation, Troy, 
MI) and PbO2 using the LICOX brain tissue oxygen monitoring system (Integra LifeSciences 
Corporation, Plainsboro, NJ).  BIS and rSO2 optodes will be applied, before induction of 
anesthesia, by a single researcher on both sides of the patient’s forehead, as recommended by 
the manufacturer.  Baseline readings will be recorded in the pre-operative holding room with 
the patient sitting and breathing room air.  
Following craniotomy, the LICOX probe will be placed under direct vision into an area of normal 
brain within the tumor excision canal by the attending neurosurgeon.  The probe will secured in 
place and allowed to equilibrate as directed by the manufacturer.  The starting tidal volume will 
be set at 6-8 mls/kg and adjustments will be made by changing respiratory rate rather than 
manipulating tidal volume further.  During a pause in surgery FIO2 and minute ventilation will 
be sequentially adjusted to achieve the following pairs of ventilation set points:  
1) FIO2 0.3 and paCO2 30mmHg 
2) FIO2 1.0 and paCO2 40mmHg 

Changes in rSO2 are complete and stable within 5 minutes following a change in inspired gas 
composition;4 LICOX responds more rapidly.  Thus, after ≥5 minutes at each set point FIO2, 
PaCO2, rSO2 and PbrO2 will be recorded as a “snap-shot”. Blood pressure, heart rate, 
hematocrit, BIS value and propofol and remifentanil infusion rates will also be recorded at each 
set point.  The anesthesiologist caring for the patient will be blinded to the measures of 
cerebral oxygenation. N2O, a possible confounding factor, will be avoided.  Bolus dose 
phenylephrine is associated with a 2.8% reduction in rSO2 of approximately 8 minutes 
duration1121 and if required, the recording of results will be delayed in order to minimize this 
potential confounding effect.  A total of two blood samples (2 teaspoons each) will be collected 
during the surgery through the arterial line, which is already in place for surgery.  This will allow 
us to measure arterial blood gas and hematocrit levels.  Demographic and intra-operative data 
will be retrieved from the patient’s electronic anesthetic and medical records.  The preliminary 
de-identified electronic data captured in this study will be retained for future use in a larger-
scale study.  No specimens will be retained for any reason as part of the research study. 
Statistical analysis 
A sample size of 15 achieves an 80% power with a one-sided type I error of 5% to detect a positive 
correlation of 0.6 (from the null hypothesis of no correlation) between changes in PbrO2 and 
changes in rSO2 subsequent on alterations made in ventilation strategy.  Correlation will be 
measured using Pearson’s Correlation.  P values < 0.05 will be considered statistically significant. 
Licox probe insertion and risk  

PbrO2 monitoring is most typically utilized to guide blood pressure, oxygenation and intracranial 
pressure (ICP) management in patients with severe head injury; probes are inserted into the least 
injured cerebral hemisphere.8,10  Device placement in head injured patients requires bolt 
placement through the skull.  The Licox probe penetrates the dura, via the bolt and is held 1-2cm 
within brain parenchyma.  Even with this highly invasive approach the technique is reported to 
be safe,13 the main complication being hematoma which occurs in < 2% patients.14  We anticipate 
that the risk of placing the probes under direct vision, following the craniotomy portion of 
surgery, into brain tissue that will ultimately be excised would be extremely low.  In fact, despite 
extensive use within the operating room environment7,15,16 complications have not been 
reported. 
 
 

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