Clinical trial NCT02439164
Conditions: Glioma
Keywords: sedation eloquent area glioma neurologic function
Sponsor: Beijing Tiantan Hospital
Start date: 2015-05-26; Completion date: 2017-03-21
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Sedation in the operating room, the Post Anesthesia Care Unit and the Intensive Care Unit is common and often necessary for patients with intracranial brain tumor. Repeated neurological function assessments is needed in those locations, especially in patients with tumors in or near eloquent regions, this is to monitor their neurologic performance to determine if there are alterations that require treatment. Some slowly infiltrative low-grade gliomas near eloquent regions do not show any detectable neurologic deficits, perhaps from reorganization, but with sedation by some sedatives such as benzodiazepine midazolam and anesthetic hypnotic propofol, the disease may seem much worse resulting in inappropriately aggressive treatment. This may be especially problematic in patients undergoing awake craniotomy for tumors in eloquent regions.

This is a single-center perspective study. Patients will be mildly sedated to keep them responsive and cooperative. Motor and sensory function will be evaluated before and after mild sedation. Specific benzodiazepine antagonist will be used if sedated by midazolam.

The purpose of this study is to observe if commonly used benzodiazepine midazolam exacerbates or unmasks motor and sensory function in patients with intracranial eloquent area gliomas.

Hypothesis:

mild sedation can unmasks or exacerbate motor and sensory deficits in patients with eloquent area glioma but not in non-neurosurgical patients/healthy volunteers. If the neurologic deficits induced by benzodiazepine agonist, then can be reversed by flumazenil.

Detailed description:

Arms: arm 1: Patients in this group will be administered sedatives (midazolam or propofol or dexmedetomidine) titrating to mild sedation. arm 2: patients in this group will be administered the same sedative midazolam as compared glioma group, and titrate to mild sedation.
Interventions: intervention 1: Midazolam
Intervention descriptions: intervention 1: specific benzodiazepine agonist midazolam will be used titrate to desired sedation level, its specific antagonist flumazenil will also be used

Protocol documents:
Prot_000.pdf: 
Protocol for Sedatives' Effects on Neurological Function in Patients With 
Eloquent Area Glioma 
April 1st,2016 
 
Background  
Sedation in the operating room, the Post Anesthesia Care Unit, and the Intensive 
Care Unit (PACU) is common and often necessary for patients with intracranial brain 
tumors. Repeated neurological function assessments are needed, especially in 
patients with tumors in or near eloquent regions. This is to monitor neurologic 
performance to determine if there are alterations that require treatment1. Some 
slowly infiltrative low-grade gliomas near eloquent regions do not show any 
clinically detectable neurologic deficits, perhaps from neuronal reorganization2,3. 
However, with sedation by some GABAergic sedatives the disease may manifest or 
seem much worse resulting in inappropriately aggressive treatment4. This may be 
especially problematic in patients undergoing awaked craniotomy for tumors in 
eloquent regions.  
 
Midazolam sedation has been found to profoundly exacerbated or unmask motor 
deficits in patients with supratentorial mass lesions, and these deficits primarily 
involved limb motor function or ataxia according to our previous study using 
National Institutes of Health Stroke Scale (NIHSS) evaluation5, and neither the 
mechanism nor the reversibility of effects will be investigated in that study. However, 
limb ataxia will be shown the worst reliability in stroke a patient under NIHSS, in a 
modified NIHSS, limb ataxia will be removed with other 3 items (consciousness, 
facial palsy, dysarthria) 6,7. For patients with brain tumor with positive change in 
limb ataxia, it is hard to conclude an unreliable false positive or truly impaired ataxia 
that may indicate the disrupted motor-sensory function integrity. Nine-hole peg test 
has good reliability to test upper limb dexterity and motor co-ordination, hand/eye 
co-ordination as well as ability to follow simple directions8,9, it can be applied to test 
midazolam induced motor deficits effects and reversibility.  
 
This will be a single-center prospective non-randomized study. Patients will be 
mildly sedated to keep them responsive and cooperative. Motor and sensory 
function will be evaluated before and after mild sedation as well as after midazolam 
reversal by the specific benzodiazepine antagonist flumazenil. 9-hole peg test will be 
used to test the motor-sensory function because it requires motor coordination, 
accurate reading and sensorimotor integration.  
 
The aim of the study is to (1) determine whether the neuronal deficits are mediated 
specifically through benzodiazepine sites by demonstrating reversibility with 
flumazenil; (2) more precisely document the midazolam induced motor-sensory 


function and coordination worsening; (3) investigate how specific patient 
populations with eloquent areas gliomas react to mild midazolam sedation. 
 
We hypothesized that mild sedation by midazolam can unmask or exacerbate upper 
limb’s motor and sensory deficits in patients with eloquent area gliomas but not in 
non-neurosurgical patients; the neurologic deficits induced by midazolam can be 
reversed by antagonist flumazenil. 
 
Materials and Methods 
 
Study Design  
This will be an interventional, parallel assignment, interventional non-randomized 
trial and will be approved by the Institutional Review Board of Beijing Tiantan 
Hospital, Capital Medical University (approval number: KY2014-040-03). This study 
was registered in ClinicalTrials.gov (registration No. is NCT02439164). 
 
Population 
Elective neurosurgery patients with supratentorial eloquent area gliomas diagnosed 
by Magnetic Resonance Imaging (MRI) will be eligible for this study.  
 
Inclusion Criteria and Exclusion Criteria 
The inclusion criteria will be the age between 18 and 60 with American Society of 
Anesthesiology (ASA) status I~II. The control group enrolled volunteers in the same 
age but without neuro-diseases. The exclusion criteria will be based on the hospital 
record documentation screening: unable to comprehend and cooperate with the 
neurologic examination, impaired mental status, taking sedative drugs by any way in 
the past 24 hours, taking any type of pain reliever by any way in the past 24 hours, 
drug and/or alcohol abuse, pregnant and/or lactating women, recurrent glioma, 
multiple brain glioma, accepting radiotherapy or chemotherapy, complicated with 
intracranial trauma and vascular diseases, complicated with grand mal epilepsy, 
complicated with neuromuscular diseases and complicated with cutaneous 
paresthesia. 
 
Study interventions 
Patients’ demographic characteristics, clinical manifestations and past history will 
be obtained before the study. On the day of study, subjects will be admitted into the 
operating room in supine position with the head up at 60 degree. Nasal cannula will 
be used for providing oxygen. Vital signs including blood pressure (BP), heart rate 
(HR), pulse oxygen saturation (SpO2) will be monitored and recorded before and 
after the treatment. Observer’s Assessment of Alertness and Sedation (OAA/S) will 
be evaluated and recorded before and after drugs administration, OAA/S is from 1 to 


5 indicating deep sleep to fully alert (5 = alert, 4 = lethargic, 3 = aroused by voice, 2 = 
aroused by shaking, 1 = deep sleep). Nine-Hole Peg Test (Rolyan® A851-5, United 
Kingdom) will be used to evaluate motor function after midazolam sedation and 
flumazenil reversal in each hand. After obtaining the baseline vital signs and 9-Hole 
Peg Test data, small dose of midazolam from 0.02mg/kg as initial dose will be given 
intravenously to get OAA/S=4 which will be arousalble and fully cooperative 
sedation, if the sedation level will be not reached, additional titration dose of 
0.01mg/kg will be given, waited for 3-5 minutes to allow reaching peak effect after 
each administration and ensured OAA/S =4 as well as fully cooperative, 9-Hope Peg 
Test will be then repeated. After the evaluation, specific benzodiazepine receptor 
antagonist flumazenil at 4μ/kg will be given intravenously to reverse midazolam’s 
sedation till OAA/S=5, 9-Hole Peg Test will be then repeated again to test the motor 
function as shown below. Other drugs (e.g. atropine for bradycardia) prescribed as 
needed, will be also recorded. Detailed descriptions of the lesion in MRI will be 
obtained. The lesions’ pathologic diagnoses will be obtained two weeks after the 
tumor removal. 
 
 
 
The interventions will be stopped if any of the following occurs: systolic blood 
pressure less than 90mmHg or more than 180mmHg after the drugs, heart rate less 
than 50bpm after 0.5mg atropine, SpO2 less than 90%, over sedated as indicated by 
OAA/S equal or less than 3, any of the drug related side effect occurred such as 
respiratory depression, unstable hemodynamic, agitation etc.  
 
Nine-Hole Peg Test9 will be the major task for upper extremities evaluation in this 
study. It is to test motor coordination, eye/hand coordination and the ability to 
follow simple directions, and it requires brain sensorimotor integration. The testing 
board is a square board with 9 holes that are spaced 1.25 inches apart in a 3×3 
array, each hole is 0.5 inches deep; each peg is 1.25 inches long and 0.25 inches in 
diameter. The pegboard will be centered in front of the subjects with the container 
holding the pegs placed on the hand being tested. The instruction will be provided 
while the demonstration will be shown. Subjects will be instructed to pick up the 
pegs one at a time using testing hand and put them into the holes in any order as 
quickly as they can until all the holes will be filled, and then remove the pegs one at 
a time and return them to the container in the full speed, the un-testing hand will be 


used to stabilize the peg board. After the subjects performed the practice trials, they 
will be instructed the actual test as before. The outcome measure will be the length 
of time from the first peg subject touches to the last peg hits the container. The 
ipsilesional hand will be firstly tested in glioma patients group and dominant hand 
will be firstly tested in normal control group; after the first testing, the container will 
be placed on the opposite side of the pegboard and repeated the testing with the 
contralesional hand in glioma group and with non-dominant hand in control group. 
Timing will be performed with a stopwatch and recorded in seconds by a same 
nurse during whole study period. Patients and the doctors who administered drug 
will be blinded of the timing. This test will be firstly performed before the 
administration of medication at baseline, as well as after midazolam and flumazenil 
administered to each patient.  
 
The primary outcomes will be the changes of task performing time after 
midazolam sedation and flumazenil reversal compared to the normal control.  
 
The secondary outcomes will be the differences of performing time among 
baseline, midazolam sedation and flumazenil reversal; as well as the differences of 
time changes between two types of gliomas. 
 
Sample size justification 
Based on a previous study, with an estimated standard deviation of 10.0 and with a 
significance level (alpha) of 0.05 using a two-sided one-sample t-test. The minimum 
number of cases will be 15 in one group achieves 95% power to detect a possible 
statistical difference between any of two groups. Allowing 20% rate of drop-out, we 
raised the case number to 18 for each group, as 1:1 assignment in experimental 
group and control group, we aimed to enroll at least 36 subjects in total. Sample size 
will be calculated by PASS11.0.2 (Copyright © 1983-2011. NCSS Statistical Software, 
Kaysville, Utah) 
 
 
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Anaesthesiol 2007; 21: 431-47 
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SAP_001.pdf: 
Statistical analysis for the study of Sedatives' Effects on Neurological Function in 
Patients With Eloquent Area Glioma 
 
April 1st, 2016 
 
Kolmogorov-Smirnov testing will be used for evaluating if the continuous variables 
are having a normal distribution or not. The normally distributed data will be 
described as mean and standard deviation and student's t-test will be conducted to 
compare the mean value between glioma and control group at baseline and after the 
administration of medication. The non-normally distributed data will be presented 
as median and interquartile range (IQR), Mann-Whitney U test will be used to 
compare the difference between glioma and control group. For categorical variables, 
numbers or percentage will be described; Chi-square or fisher exact test will be used 
to analyze the difference between groups. Paired t-test will be used to analyze the 
change before and after sedation, as well as to test for the change before and after 
sedation reversal. Oneway ANOVA will be used to test the difference among hands in 
a certain time point. To analyze the time difference of completion of 9-hole peg test 
before and after drug administration, general linear model for repeated measures 
ANOVA will be used. Statistical significance will be defined as P-value < 0.05. 
Analyses will be conducted using Statistical Package for the Social Sciences (SPSS) 
version 17.0 (Chicago, IL, USA).