Changes in Cerebral Oxygenation Based on Intraoperative Ventilation Strategy
Conditions: Posterior Spinal Fusion
Sponsor: Joseph D. Tobias

Official title: Changes in cerebral oxygenation based on intraoperative ventilation strategy 
 
 
Short title:  NIRS and Ventilation  
 
NCT: NCT02651103 
May 15, 2017 
 
 
Authors:  
Elisabeth Dewhirst, MBBS1 
 
 
Hina Walia, MBBS1 
Walter Samora, MD2 
Alan Beebe, MD2 
Jan E. Klamar, MD2 
Joseph D. Tobias, MD1,3 
 
 
Affiliations:  
1. Department of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital, 
Columbus, Ohio 
2. Department of Orthopedic Surgery, Nationwide Children’s Hospital & The Ohio State 
University, Columbus, Ohio 
3. Department of Anesthesiology & Pain Medicine, The Ohio State University, Columbus, 
Ohio 
 
Address correspondence to: 
Elisabeth Dewhirst MD 
Department of Anesthesiology & Pain Medicine 
Nationwide Children's Hospital 
700 Children's Drive 
Columbus, Ohio, USA 43205 
Phone: (614) 722-4200 
FAX: (614) 722-4203 
E-mail: Elisabeth.Dewhirst@nationwidechildrens.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Abstract 
Introduction: Cerebral oxygenation can be monitored clinically by cerebral oximetry 
(rSO2) using near infrared spectroscopy (NIRS). Changes in rSO2 have been shown to precede 
changes in pulse oximetry, providing earlier detection of clinical deterioration.  Cerebral oximetry 
values may be affected by various factors, including changes in ventilation. The current study 
evaluates changes in rSO2 during intraoperative changes in mechanical ventilation.  
Methods: Following IRB approval, tissue and cerebral oxygenation were monitored 
intraoperatively using NIRS. Prior to anesthetic induction, the NIRS monitor was placed on the 
forehead and over the deltoid muscle to obtain baseline values.  NIRS measurements were 
recorded each minute over a 5-minute period during general anesthesia at four phases of 
ventilation: 1) normocarbia (35-40 mmHg) with a low fraction of inspired oxygen (FiO2) of 0.3; 2) 
hypocarbia (25-30 mmHg) and low FiO2 of 0.3; 3) hypocarbia and a high FiO2 of 0.6; and 4) 
normocarbia and a high FiO2. NIRS measurements during each phase were compared to 
sequential phases using paired t-tests. 
Results: The study cohort included 30 adolescents. Baseline cerebral and tissue 
oxygenation were 81 ± 9 and 87 ± 5, respectively.  During phase 1, cerebral rSO2 was 83 ± 8 
and decreased to 79 ± 8 in phase 2 (hypocarbia and low FiO2).  Cerebral oxygenation partially 
recovered during phase 3 (81 ± 9) with the increase in FiO2 and then returned to baseline 
during phase 4 (83 ± 8). Each sequential change (e.g., phase 1 to phase 2) in cerebral 
oxygenation was statistically significant (p<0.01). Tissue oxygenation was unchanged during the 
study phases and remained at 87-88 throughout. 
Discussion: Cerebral oxygenation declined during general anesthesia with the 
transition from normocarbia to hypocarbic conditions. The rSO2 decrease related to hypocarbia 
was easily reversed with a return to baseline values by the administration of supplemental 
oxygen (60% versus 30%).  

Introduction 
A key component of intraoperative care is the assurance of adequate cardiac output and 
delivery of oxygen to the tissues. While routine intraoperative care includes monitoring of blood 
pressure and systemic oxygenation (pulse oximetry), there is clinical interest in measuring end-
organ tissue oxygenation. As such, monitors of tissue oxygenation such as cerebral oximetry 
using near infrared spectroscopy (NIRS) are being used more commonly in anesthesia practice.  
The NIRS monitor consists of a non-invasive adhesive sensor with a laser light source and two 
photodetectors. Using optical technology based on the relative absorption of infrared light by 
different hemoglobin species, the monitor generates a measurement of regional tissue oxygen 
saturation (rSO2).1 Most commonly applied to the forehead, the device measures cerebral 
oxygenation, but can be used to detect regional tissue saturation elsewhere in the body. Data in 
both adult and pediatric literature suggest that monitoring and maintaining cerebral oxygenation 
may improve perioperative neurological outcomes.2,3  Most established and applied during 
cardiac surgery, the NIRS monitor is being used increasingly in the operating room and 
intensive care unit (ICU) to monitor cerebral perfusion and guide management in various clinical 
scenarios. A decrease in cerebral oxygenation correlates with events of clinical deterioration 
such as arrhythmia, hypotension, and hypoxia.4 Changes in cerebral oxygenation have been 
shown to precede those in pulse oximetry, providing an earlier detection of clinical 
deterioration.5 
In the adult population, alterations in inspired oxygen concentration and expired carbon 
dioxide have been shown to influence cerebral oxygenation.6  Various patient, surgical, and 
anesthetic factors may influence intraoperative ventilation choices (minute ventilation and the 
fraction of inspired oxygen) and the resultant arterial partial pressure of oxygen (PaO2) and 
carbon dioxide (PaCO2).7-11 Examples include laparoscopic surgery, intrathoracic surgery, 
airway surgery, patient positioning, and co-morbid condtions.8,9  Furthermore, various factors 

including a decrease in the metabolic rate related to general anesthesia may result in 
inadvertent hyperventilation during routine intraoperative care.9  Understanding how ventilation 
affects cerebral oxygenation is of clinical importance, especially when faced with other 
physiologic changes such as anemia and decreased cardiac output that may impact tissue and 
cerebral oxygen delivery. The relationship between ventilation and cerebral rSO2 has not been 
examined in the pediatric population. The current study seeks to evaluate changes in cerebral 
and tissue rSO2 during intraoperative changes in mechanical ventilation parameters. 
 
Methods 
Institutional Review Board approval and verbal consent from a parent and assent from 
the patient were obtained.  This study was registered with ClinicalTrials.gov (NCT02651103).  
Enrolled patients were children undergoing a major surgical procedure requiring placement of 
an arterial cannula. Prior to anesthetic induction, the NIRS monitor was placed on the forehead 
and over the deltoid muscle, in addition to standard American Society of Anesthesiologists 
(ASA) monitors.  Baseline values for cerebral and tissue oxygenation were obtained using 
NIRS.  After the induction of general anesthesia and placement of an endotracheal tube, an 
arterial cannula was placed and NIRS values were again measured at the following four phases 
of ventilation with variation of the inspired oxygen concentration (FiO2) and end-tidal carbon 
dioxide value (ETCO2): 
1) normocarbia (ETCO2 35-40 mmHg) and low FiO2 (0.3); 
2) hypocarbia (ETCO2 = 25-30 mmHg ) and low FiO2 (0.3);  
3) hypocarbia (EICO2 = 25-30 mmHg) and high FiO2 (0.6); and  
4) normocarbia (ETCO2 = 35-40 mmHg) and high FiO2 (0.6). 
 

To ensure the accuracy of the ETCO2 value, arterial blood gas was obtained prior to the 
start of the study and the ETCO2 was validated using the PaCO2 measurement.  At baseline 
and during each phase of ventilation, NIRS measurements were recorded every minute over a 
5-minute period. Heart rate (HR) and blood pressure (BP) were recorded at each of the 
sampling intervals and hemodynamic variables maintained constant by adjustments in the 
continuous infusion of remifentanil.  Depth of anesthesia was maintained at a constant value 
with the administration of inhaled desflurane which was titrated to maintain the bispectral index 
(BIS) at 50-60.   
The average of available NIRS measurements within each ventilation phase was 
obtained and used to compare sequential phases with paired t-tests. A planned sample size of 
30 patients was selected to be comparable to previous studies in the adult population, and to be 
consistent with study feasibility and projected patient enrollment.  Due to the exploratory nature 
of this investigation in a pediatric population, no a priori power analysis was performed. Data 
analysis was performed in Stata/IC 13.1 (College Station, TX: StataCorp LP), and two-tailed 
p<0.05 was considered statistically significant. 
 
Results 
The study cohort included 30 patients (13 males and 17 females, age 15 ± 3 years, and 
weight 55 ± 15 kg). Cohort characteristics are summarized in Table 1.  Changes in heart rate 
and blood pressure over the course of the study are summarized in Table 2. The peripheral 
oxygen saturation by pulse oximetry remained at 99-100% throughout the study. The baseline 
cerebral and tissue rSO2, prior to anesthetic induction while breathing room air, were 81 ± 9 and 
87 ± 5, respectively. During phase 1, cerebral rSO2 was 83 ± 8 and decreased to 79 ± 8 in 
phase 2 (hypocarbia and low FiO2).  Cerebral oxygenation recovered, returning to baseline 
values, during phase 3 (81 ± 9) and phase 4 (83 ± 8). Each sequential change (e.g., phase 1 to 

phase 2) in cerebral oxygenation was statistically significant (p<0.01; Table 3). Tissue 
oxygenation increased from 87 ± 8 in phase 1 to 88 ± 7 in phase 2 (p=0.002); remained at 88 ± 
7 in phase 3; and decreased to 87 ± 8 in phase 4 (p=0.023; Table 3). 
 
Discussion  
Cerebral oxygenation as measured by NIRS may provide valuable information regarding 
cerebral oxygen delivery and utilization in critically ill patients both in the operating room and the 
ICU settings.  Intraoperatively, it may help guide anesthetic care, as studies in adults have 
shown that maintaining adequate values on NIRS may improve neurological outcomes.2,12 One 
of the primary regulators of cerebral blood flow is PaCO2.  Hypocarbia results in a direct effect 
on the cerebral vasculature with vasoconstriction and a decrease in cerebral blood flow (CBF).  
For every 1 mmHg change in PaCO2, CBF changes by 1-2 mL/100 gm/minute. As there is no 
impact on the cerebral metabolic rate for oxygen related to changes in PaCO2, the decrease in 
CBF may lead to a decrease in cerebral oxygenation.  In our study, cerebral oxygenation as 
measured by NIRS declined during general anesthesia with the transition from normocarbia to 
hypocarbic conditions.  Despite this decrease, no clinical impact would be expected as the 
starting rSO2 was high, the change with hyperventilation was small, and the resultant value 
remained well above the reported threshold for concern. 
Our data demonstrate that even in clinically stable patients, PaCO2 remains an 
important determinant of CBF and cerebral oxygenation.  Changes in CBF related to alterations 
in intraoperative ventilation may have a greater impact in critically ill patients when other factors 
which impact rSO2, such as hemoglobin values and cardiac output, may be affected.  We have 
previously noted the potential impact of the combination of anemia, hypotension and hypocarbia 
on rSO2, suggesting that close attention to control of ventilation is important during 
intraoperative care where inadvertent hyperventilation is commonplace.7,13   

 
Additionally, these data demonstrate that the rSO2 decrease related to hypocarbia was 
reversed by the administration of supplemental oxygen (60% versus 30%). In clinical scenarios 
where hyperventilation is required, such as to reduce intracranial pressure when there is 
impending cerebral herniation or to blunt the respiratory drive, increasing the FiO2 may be 
pertinent to offset any reduction in cerebral oxygenation related to decreases in CBF. 
Thiagarajan et al. evaluated 18 adults with traumatic brain injury to determine the changes in 
cerebral jugular venous oxygen saturation (SjvO2) and arteriovenous oxygen content difference 
(AVDO2) in response to changes in PaO2 and PaCO2.14  SjvO2 decreased from 66% ± 3% to 
56% ± 3% when PaCO2 decreased from 30 to 25 mmHg at a PaO2 of 100-150 mmHg. The 
SjvO2 values were significantly greater when the PaO2 was 200-250 mmHg (77% ± 4% and 
64% ± 3%) at PaCO2 values of both 30 and 25 mmHg. The authors concluded, as we did in our 
study, that decreases in cerebral oxygenation (manifested as decreases in SjvO2) associated 
with a decrease in PaCO2, were offset by increasing the PaO2. These data are particularly 
relevant given the literature demonstrating episodes of cerebral ischemia and worse neurologic 
outcome in patients with traumatic brain injury who are exposed to hypocarbia.15 
 
Similar results have been noted in the adult population by other investigators using 
various monitors of cerebral oxygenation. All of these studies have demonstrated that both 
alterations in inspired oxygen concentration and expired carbon dioxide impact cerebral tissue 
oxygenation. Tisdall et al. measured the cerebral tissue oxygenation index (TOI) in 15 adults 
under hypoxic, hyperoxic, hypo- and hyper-carbic conditions.6 Hypoxemic and hypocarbic 
conditions resulted in a decrease of the TOI by 7.1% and 2.1% respectively while hyperoxia and 
hypercarbia led to increases of 2.3% and 2.6%.   Picton et al. reported a 7% decrease of rSO2 
after beach-chair positioning in adults maintained at an FiO2 of 0.3 and ETCO2 of 30 mmHg 
which was reversible by decreasing ventilation and increasing the FiO2.10 The same 
investigators reported that the rSO2 was an average of 8% higher with an FiO2 of 1.0 versus 

0.3 at an ETCO2 of 30-35 mmHg. Bouzat et al reported a 5% reduction in rSO2 with 
hyperventilation in adult patients recovering from cardiac arrest.16   
Our literature search revealed no previous studies in the pediatric age range that 
examined the effect of ventilation on cerebral oxygenation.  When compared to some of the 
adult studies, it is not surprising that the decrease in cerebral oxygenation that we noted was 
smaller than that seen in the adult population, as our patients lacked co-morbid conditions, such 
as atherosclerotic disease, which might affect CBF.  When evaluating intraoperative studies, 
including the present work, one must also consider the impact that the anesthetic agents may 
have on the findings as specific anesthetic agents may affect cerebral metabolic rate for 
oxygenation and thereby mitigate the effects of the decrease in CBF on cerebral oxygenation.17  
As the current study focused on adolescents, extrapolation of these data to younger populations 
is likely infeasible, and additional trials are needed in these age groups to determine the impact 
of changes in ventilation on cerebral rSO2.   
As expected, no major changes in tissue oxygenation were noted related to 
hyperventilation, and the changes in cerebral rSO2 under the specific study conditions had no 
clinical impact.  The change from baseline was minimal, and the low value even under 
hypobaric conditions was well above the NIRS monitor’s low threshold value for concern. 
However, the impact of hypocarbia must be considered when co-morbid conditions or ongoing 
acute issues, such as anemia or hypotension, may further impact cerebral oxygenation.  In 
specific clinical scenarios where hyperventilation is clinically indicated, the impact on cerebral 
oxygenation can be mitigated by increasing the FiO2.  
 

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Table 1. Study cohort characteristics 
 
Variable 
N (%) or Mean (SD) 
Gender 
 
     Male 
13 (43%) 
     Female 
17 (57%) 
Age (years) 
15 (3) 
Weight (kg) 
55 (15) 
ASA status 
 
     1   
5 (17%) 
     2 
16 (53%) 
     3 
8 (27%) 
     4 
1 (3%) 
 
 
 

Table 2. Hemodynamic parameters during the four study phases 
 
Variable 
Baseline 
Phase 1 
Phase 2 
Phase 3 
Phase 4 
Heart rate (beats/minute) 
90 (16) 
82 (14) 
83 (14) 
82 (13) 
78 (11) 
sBP (mmHg) 
100 (22) 
87 (14) 
86 (11) 
90 (11) 
87 (12) 
dBP (mmHg) 
62 (15) 
53 (9) 
53 (9) 
55 (7) 
51 (7) 
MAP (mmHg) 
73 (16) 
64 (10) 
64 (9) 
66 (8) 
64 (8) 
HR = heart rare; sBP = systolic blood pressure; dBP = diastolic blood pressure; MAP = mean arterial pressure 
 

Table 3. Cerebral and tissue oxygenation during study phases 
 
rSO2 
Study phase 
P-value 
 
Baseline 
 
Phase 1 
Phase 2 
Phase 3 
Phase 4 
2 vs. 1 
3 vs. 2 
4 vs.3 
Tissue 
87 (5) 
87 (8) 
88 (7) 
88 (7) 
87 (8) 
0.002 
0.776 
0.023 
Cerebral 
81 (9) 
83 (8) 
79 (8) 
81 (9) 
83 (8) 
<0.001 
0.007 
0.009