Impact of Intraoperative Ventilation With High Oxygen Content to Reduce the Incidence and Extent of Postoperative Pneumocephalus in Patients Undergoing Craniotomies
Phase: NA
Conditions: Pneumocephalus
Sponsor: Ohio State University

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Official Title of the Study:  
A Prospective Randomized Clinical Trial to Evaluate the Impact of Intraoperative Ventilation 
with High Oxygen Content on the Extent of Postoperative Pneumocephalus in Patients 
Undergoing Craniotomies 
 
NCT number: NCT02722928 
 
Last approved continuing review on: 08MAR2018  
 
IRB protocol number: 2015H0032 
- 
Initial submission approved on: 27JAN2015  
- 
IRB confirmed closure date: 26DEC2018 
 
Objectives  
Primary Objective  
We compared the rate of occurrence and volume of postoperative pneumocephalus in patients 
undergoing craniotomies (hemispheric or posterior cranial fossa tumors and microvascular 
decompression) and receiving intraoperative ventilation with pure oxygen versus a conventional 
air/oxygen 1:1 mixture during the last stage of surgery (hemostasis and wound closure)  
Secondary Objectives  
We compared the incidence and volume of postoperative pneumocephalus in patients undergoing 
surgery in sitting and supine positions. Furthermore, we compared postoperative neurological 
outcomes and intensive care unit length of stay among neurosurgical patients (posterior cranial 
fossa tumors, supratentorial tumors, and transsphenoidal /endoscopic procedures)  
 
Study Design  

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We conducted a prospective randomized single-blinded study at The Ohio State University 
Wexner Medical Center enrolling patients (≥ 18 years) with an American Society of 
Anesthesiologists (ASA) physical status of II–IV undergoing neurosurgeries (supra- and 
infratentorial tumors such as astrocytomas and glioblastoma multiforme, and microvascular 
decompression) in sitting, prone, lateral, park bench, and other positions.  
 
Sample Size and Statistical Analysis  
We estimated that a sample size of 80 patients per group would confer a greater than 80% power 
to detect a 20% decrease in volume in the intervention group with an alpha of 0.05 considering a 
mean pnemocephalus volume of 87 ml in the control group (standard deviation of 40). The 
sample size was estimated based on published data. Our proposed intervention is considered 
harmless, being applied routinely in perioperative settings. No intervention-related adverse 
events were expected during the study.  
Categorical variables were reported as frequencies and percentages and compared between 
randomization groups using Chi-square tests or Fisher’s exact tests where relevant. Continuous 
variables were reported as means and standard deviations or medians and interquartile ranges 
and compared between randomization groups using Student’s t-tests or Wilcoxon rank sum tests 
where relevant. Hypothesis testing was conducted at a 5% type 1 error rate (alpha=0.05). All 
statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).  
 
Randomization  
The study was planned and conducted according to all the required institutional and state 
regulations related to clinical research. Patients were randomly distributed (random table) into 
two groups:  
- Control Group (A): received controlled ventilation throughout the surgery with a 
conventional air/oxygen 1:1 gas mixture (FiO2 60%)  
- Interventional Group (B): received controlled ventilation with a conventional air/oxygen 
1:1 gas mixture from the beginning of the surgery and during the tumor removal 
phase. However, patients in group B were switched to controlled ventilation with 

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100% O2 once the tumor resection was completed and hemostasis started until 
extubation  
 
Study Procedures  
Both groups received supplemental oxygen via nasal cannula as a standard of care during the 
early postoperative period. A standard CT scan was performed within 6 hours post-surgery for 
both groups. CT scans were assessed and interpreted by a blinded radiologist in order to diagnose 
the frequency and the extent of postoperative pneumocephalus (quantification). TeraRecon 
Intuition software version 4.4.11.265.8092 was used, retrieving the CT scan data from the system 
and loading it into the software program. All CT data maintained a 1 mm slice increment. The air 
in the skull was identified and circled using a region of interest (ROI) tool. The area defined for 
measurements applied in this study was within the skull in any space occupied by brain. This 
excluded any air trapped between the bone from graft placement or between the skin and the 
skull. Once all the visually identified areas of “air” were circled and then selected within the 
skull, a Hounsfield unit (HU) threshold tool was used to remove any excluded tissue. The setting   
of -150 HU or less was applied, and the selected areas were presented in 2D and 3D. Only the 
areas identified within the ROI accounted for the 3D image. The volume was calculated in cm3 
using the software presented by clicking the “volume” measurement tool. Considering similarity 
of the groups and randomization, it was expected that the duration of the last part of surgery and 
the lapsing time from the end of surgery to postoperative CT acquisition to be the same for the 
control and treatment groups. The following data was considered for intergroup analysis and 
selection bias exclusion: demographics (age, gender, weight, and body mass index), oxygen 
inhalation time, the period of time elapsed from the end of surgery to CT scan completion. The 
occurrence of adverse events and neurological status were assessed before the CT scan and 
compared with the baseline evaluation. Stage 1 was defined as the interval of time (minutes) 
measured from skin incision to the onset of hemostasis (i.e. after tumor removal). Stage 2 was 
defined as the interval of time (minutes) measured from the onset of hemostasis to incision 
closure. We conducted study intervention (for group B) during stage 2. 
 
 

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DISCUSSION 
Our prospective randomize study is the first to examine the prophylactic effect of normobaric 
hyperoxygenation on limiting the extension of postoperative pnuemocephalus volume in patients 
undergoing elective neurosurgery. A total of 70 patients were included into our final analysis. 
The study showed no pneumocephalus volume reduction when higher oxygen concentration 
(FiO2 100% vs 60%) was used prophylactically during the last stage of surgery in patients 
undergoing craniotomy (p= 0.47). We estimated that our intervention would produce a 20% 
decrease in pneumocephalus volume for the interventional group. However, after enrolling 105 
(N=105) patients, an unanticipated blinded analysis showed that the variability relative to the 
pneumocephalus volume mean was much higher than initially assumed based on published data. 
Therefore, we determined that our study was underpowered and an unfeasible number of patients 
would have been required (N>400 patients/group) to be enrolled in order to detect the expected 
difference between groups. 
 

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Figure 1. CONSORT Flow Diagram 
  
 
Assessed for eligibility (n= 105) 
Excluded (n= 5) 
♦ Not meeting inclusion/exclusion criteria (n= 5) 
Excluded from analysis (n= 8): Intraoperative MRI required 
and/or surgery differed from scheduled procedure 
Control / Group “A” (n= 47) 
Intervention / Group “B” (n= 53) 
Excluded from analysis (n= 22): Intraoperative MRI required, 
postoperative CT scan not available, and/or inability to follow 
study procedures (i.e. FiO2 > 60% required) 
Randomized (n= 100) 
Analyzed (n= 39) 
Analyzed (n= 31) 

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Table 1. Demographic and Clinical Variables 
Variable 
Control 
n= 39 
Intervention 
n= 31 
p value 
Age (mean ± SD) 
46.69 (14.21) 
50.81 (13.28) 
0.2198 
Gender n (%) 
• 
Female 
• 
Male 
 
23 (58.97) 
16 (41.03) 
 
14 (45.16) 
17 (54.84) 
 
0.2501 
Race n (%) 
• 
White 
• 
African-American 
 
36 (92.31) 
3 (7.69) 
 
27 (87.10) 
4 (12.90) 
 
0.6916 
Biometrics mean ± SD 
• 
Weight (Kg ± SD) 
• 
Height (cm ± SD) 
• 
BMI (Kg/m2 ± SD) 
 
89.00 (21.69) 
168.31 (10.29) 
31.35 (7.42) 
 
94.00 (17.67) 
172.30 (10.90) 
31.94 (6.64) 
 
0.3034 
0.1208 
0.7301 
ASA n (%) 
• 
I 
• 
II 
• 
III 
• 
IV 
 
0 (0.00) 
12 (30.77) 
26 (66.67) 
1 (2.56) 
 
1 (3.23) 
9 (29.03) 
20 (64.52) 
1 (3.23) 
 
0.8874 
Preoperative Diagnosis n (%) 
• 
Supratentorial lesion 
• 
Infratentorial lesion 
 
25 (64.10) 
14 (35.90) 
 
21 (67.74) 
10 (32.26) 
 
0.7500 
 
 
n= number of patients; ASA= American Society of Anesthesiologists  
 
 
 
 
 
 
 
 

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Table 2. Perioperative Variables 
Variable 
Control 
n= 39 
Intervention 
n= 31 
p 
value 
Surgical Positioning n (%) 
Sitting 
Semi-sitting 
Prone 
Lateral 
Park bench 
Supine 
 
1 (2.56) 
0 (0.00) 
10 (25.64) 
7 (17.95) 
0 (0.00) 
21 (53.85) 
 
0 (0.00) 
0 (0.00) 
3 (9.68) 
11 (35.48) 
0 (0.00) 
17 (54.84) 
 
 
 
0.1233 
Procedure Performed n (%) 
Conventional Anterior Fossa 
Conventional Posterior Fossa 
Conventional Middle Fossa 
Minimally Invasive Anterior Fossa 
Minimally Invasive Middle 
 
23 (58.97) 
15 (38.46) 
0 (0.00) 
0 (0.00) 
1 (2.56) 
 
16 (51.61) 
11 (35.48) 
3 (9.68) 
1 (3.23) 
0 (0.00) 
 
 
 
0.1535 
Ventilatory parameters  
beginning of stage 2 [median and IQR] 
Ppeak (cm H2O) 
PEEP (cm H2O) 
EtCO2 (mm Hg) 
 
 
21.0 [19.0 – 25.0] 
4.9 [4.0 – 5.0] 
29.0 [28.0 – 32.0] 
 
 
22.0 [20.0 – 25.0] 
5.1 [4.4 – 7.0] 
30.00 [28.0 – 32.0] 
 
 
0.3734 
0.0215 
0.8726 
Length of stage 1  [median and IQR] 
177.0 [140.0 – 223.0] 
256.0 [145.0 – 344.0] 
0.0596 
Length of stage 2 [median and IQR] 
49.0 [34.00 – 63.0] 
55.0 [39.0 – 68.0] 
0.3688 
Postoperative Recovery Location 
PACU 
SICU 
 
6 (15.38) 
33 (84.62) 
 
3 (9.68) 
28 (90.32) 
 
0.7214 
Length of PACU stay (min ± SD) 
344.67 (455.51) 
178.33 (147.60) 
0.5683 
Length of SICU stay  (min ± SD) 
1,380.0 [1,112.0 – 2,096.0] 
1,524.5 [1,312.0 – 2,814.5] 
0.1880 
End of Surgery - CT scan interval 
time in minutes [median and IQR] 
89.0 [61.0 – 125.0] 
80.0 [62.0 – 127.0] 
0.8229 
Postoperative pneumocephalus in cm3 
[median and IQR] 
9.65 [3.61 – 23.20] 
7.06 [2.70 – 20.1] 
0.4768 
   n= number of patients; Ppeak= peak inspiratory pressure; PEEP= positive end-expiratory pressure; EtCO2= 
end-    tidal CO2; PACU= post-anesthesia care unit; SICU= surgical intensive care unit; CT= computed 
tomography 
 
 

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Table 3. Postoperative Pneumocephalus Volume in cm3 [median and IQR] according to Procedure Performed  
Conventional Anterior Fossa 
Control 
n= 23 
Intervention 
n= 16 
p value 
 
17.40 [6.89 – 24.40] 
13.95 [4.82 – 22.15] 
0.4797 
Conventional Posterior Fossa 
Control 
n= 15 
Intervention 
n= 11 
p value 
 
4.38 [0.81 – 10.50] 
4.00 [0.60 – 13.00] 
0.8775 
 
 
 

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Table 4. SICU LOS according to Procedure Performed (median min [IQR]).  
Conventional Anterior Fossa 
Control 
n= 23 
Intervention 
n= 16 
p value 
 
1380 [1112.0 – 1665.0] 
1489.0 [1337.0 – 2814.5] 
0.2017 
Conventional Posterior Fossa 
Control 
n= 9 
Intervention 
n= 9 
p value 
 
2059.0 [1102.0 – 3049.0] 
1342.0 [1203.0 – 1665] 
0.7943 
    SICU= surgical intensive care unit; LOS= length of stay 
 
 
 

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Table 5. Changes in Neurological Outcomes at POD 3 Compared to Preoperative Evaluation 
Neurological Outcome Variation 
n (%)  
Control 
n= 39 
Intervention 
n= 31 
p value 
Improvement 
No changes 
Deterioration 
8 (20.5) 
25 (64.1) 
6 (15.4) 
6 (19.3) 
15 (48.4) 
10 (32.3) 
 
0.23 
                     POD= postoperative day; n= number of patients