Research Hypothesis- Electroencephalography
(EEG) guided anesthesia using dexmeditomidine-sevoflurane based anesthetic
regimen will result in reduction of delirium by 50 %
Primary Objective:- To compare the
effect of EEG guided anesthesia with conventional anesthesia monitoring on
postoperative delirium in patients undergoing posterior
fossa neurosurgery for resection of brain tumors.
Secondary
Objectives:- (i) To evaluate the dominant alpha oscillatory activity during emergence (ii) To evaluate delta
dominant activity and slow wave activity
(iii)
To correlate intraoperative EEG pattern with intraoperative systolic blood
pressure, diastolic blood pressure, intraoperative peripheral oxygen saturation
(SpO2), end tidal carbon di-oxide (EtCO2) levels,
fraction of inspired oxygen (FiO2). (iv) To compare the effect on postoperative
cognition (v) To observe the
impact on post-operative neuroinflammation between the two groups as assessed by the
following laboratory tests: IL-1β, IL-6, TNFα and S100B
A Randomized, parallel
group, open labeled, Allocation blinded, Assessor blinded trial
PICOT of this RCT
•
POPOULATION -Patients scheduled for posterior fossa
neurosurgery for resection of brain tumors
•
INTERVENTION - Electroencephalography guided
anesthesia
• COMPARISON - With the conventional anesthesia monitoring posterior fossa
•
neurosurgery
•
OUTCOME - Primary- occurrence of postoperative delirium
between day 1 to 5 - -Secondary-
Evaluation of Glasgow Outcome Score- Extended . (GOS-E) at 30 days after surgery
•
TIME FRAME - . 5 days for primary outcome ; 30 days for secondary outcome ;
2 years for completion of sample size in the study cohort
and analysis of EEG charts
Reason for Study
•
The incidence of delirium after neurosurgery is estimated to be
between 40% and 70% depending on the population studied and the methods used to
assess delirium
•
As one of the most common complications after neurosurgery it is
associated with prolonged length of hospital and intensive care unit (ICU)
stay, increased morbidity and mortality, functional and cognitive decline, and
is often associated with placement in long-term care facility.
•
The target site for all the
anesthetics is brain. Yet the conventional anesthesia practice is based on
monitoring the heart, lungs and renal system. This ambiguity has resulted in
miscalculation of adequate levels of anesthetics in infant, pregnant and
elderly patients. We aim to rectify this
ambiguity, starting by monitoring brain during the anesthesia, and thereby
tailoring the anesthesia practice as per the EEG indices.
•
The results of this study shall help
in formulating a clinical practice algorithm for EEG guided anesthesia
monitoring aimed at reduction of post-operative delirium
•
Additionally, this will be the first
study on intra-operative EEG based anesthesia practice from our state of
Himachal Pradesh
Methodology:
This study has been approved by the institutional Ethics committees
of the Indira Gandhi Medical College, Shimla vide letter number HFW(MC-II)B(12)
ETHICS/2024/6783 This study protocol meets the SPIRIT
(Standard Protocol Items: Recommendations for
Interventional Trials) guidelines. The checklist and figure have been attached
as annexure to this protocol.
The reporting of data pertaining to this trial will be
as per the CONSORT (Consolidated
Standards of Reporting Trials) guidelines
Recruitment- The patients scheduled for neurosurgery to operate
brain tumors in the posterior cranial fossa at this institute, will be recruited for this
study after provision of a
written informed consent by themselves or next of
their kin.
Inclusion criteria- The patients aged 18
years and above undergoing neurosurgery for resection of brain tumors in the
posterior cranial fossa will be included in this study.
Exclusion criteria-
(1) preoperative Glasgow coma scale
(GCS) score less than 15 or presence of confusion during pre-anesthetic
checkup;
(2) patients with auditory impairment;
(3) patient with loss of vision;
(4) patient with aphasia;
(5) patient with prior history of epilepsy;
(6) patient with pre-existing
psychiatric illness.
These patients will be excluded from the study as they will not be
able to participate adequately for screening delirium during pre-anesthetic
evaluation.
Enrollment- through pre-anesthesia clinics and
also by the visit from anesthesiologist to the ward, prior to the surgery of
patient. They will be given a detailed information sheet (Annexure 6 and 7)
explaining about the pros and cons of this research alongwith their entitlement
for compensation as per the clinical trial insurance policy. The patients who
do not give consent for participation in this study shall still get the
standard anesthetic monitoring and
surgical treatment for their pathology.
Sample Size- Based on the number of patients operated by
the neurosurgery department over last one year (which were around 200), and
keeping the z-score of 1.65 in order to attain the confidence level of 90% and
margin of error 5%, we estimated the sample size by the Z-formula to be 116. where:- N =
population size; e = Margin of error
(percentage in decimal form) ; z = z-score. The z-score is the number of standard
deviations a given proportion is away from the mean.
Randomization
Computer
generated assignment at the patient level will be used for block randomization. Patients who will be eligible and have given
informed consent, shall be randomized to either of the two study groups i.e. Group E (EEG guided
anesthesia) and Group C
(Conventional anesthesia practice). The randomization sequence will be generated by the data analysis
center using block randomization technique.
The randomization code shall only be
broken in case the patient develops any intra-operative lethal complication
like venous air embolism, pulmonary edema, brain herniation or cardiac arrest.
Allocation blinding
An external member (Sharath Krishnaswamy, Aster
Whitefield hospital, Bengaluru, Karnataka) shall enroll participants and assign
the randomization between the two groups. He will maintain the record in a
register which shall be opened only during the
allotment of randomization of the
group. Predictability of the randomization sequence is minimized by recording
it in a separate sealed register, unavailable to the other members of the
research team who enroll participants and assign groups. This allocator shall
send the group information to the attending anesthesiologist in the operation
theater, in order to ensure allocation blinding.
Open labeled
The patient will be aware whether
he/she is applied with the EEG electrodes or not. Therefore this will be an
open labeled study.
Assessor blinding
The member analyzing the postoperative
delirium by CAM-S form will be unaware of the allocated group to the patient.
The anesthesiologist and the team
caring for the patient intraoperatively shall thereafter perform the anesthesia
conduct as per the allotted group.
The primary investigator enlisted for
data collection has been trained at Department of Neuroanesthesia and
Neuro-critical care, NIMHANS Bangalore, to recognize the typical EEG patterns
of the different levels of anesthesia seen during the usage of intravenous
anesthetics with/without volatile anesthetic agents. He has also been trained
to differentiate the EEG pattern in awake patients from the EEG patterns seen
during general anesthesia.
The co-investigator (Prof. Sudhir
Sharma) is a dedicated Neurologist with detailed clinical expertise in EEG
monitoring of over 10 years.
The co-investigator (Dr. Vikrom
Takkar) is a dedicated Anaesthesiologist and Intensivist with experience of
over 8 years in this field. He will be assessing the delirium and cognition in pre-anesthesia
clinics/ neurosurgery ward and post-operatively.
In case of any inadvertent
intra-operative event like massive blood loss, cardiac arrest, embolism, the
patient data will be unblinded and the allocated intervention will be revealed.
Implementation Plan for the
Methodology
The
patients who are undergoing elective neurosurgery and provide informed consent
by themselves or next of their kin, are eligible to be included in the study.
The calculated sample size for this study came out to be 116 patients. After
enrollment, they will be randomized into the two groups (i.e E and C) using block randomization technique once they meet the inclusion
criteria.
The patient will be
brought into the operation theatre and pre-oxygenated for 3 minutes.
Thereafter, the patient will undergo anesthetic induction with dexmeditomidine
1µg/kg/hr iv infused over 10 minutes (i.e 0.6 µg/kg/min over 10 minutes) and
preservative free lignocaine 1.5 mg/kg iv. In order to provide analgesia to
curtail the intubation response, the patient will receive fentanyl 2 µg/kg iv. At
elapse of 8 minutes after starting the dexmeditomidine infusion, facemask shall
be placed with oxygen and sevoflurane 4% on volume concentration dial in order
to deepen the plane of anesthetic induction. In order to facilitate muscle
relaxation for laryngoscopy, vecuronium 0.15 mg/kg iv shall be administered.
This will be followed by subsequent endotracheal
intubation. Assessment
of quality of Intubation will be as per the modified Viby-Mogenson criteria21
(table 1).
Anaesthesia will be
maintained using air: oxygen: sevoflurane. Analgesia during surgery will be
provided by a continuous infusion of dexmeditomidine @ 0.5 μg/kg/hr in both the
study groups. A scalp block using 20 ml of 0.375 % bupivacaine to block nerve
supply to the scalp shall also be applied to all the patients participating in
this study cohort.
An increase in mean
blood pressure or heart rate by more than
30% of baseline value despite adequate anesthetic depth during surgery
will be considered a nociceptive response and it shall be treated by
administering a bolus of fentanyl (1
μg/kg i.v). The total dose of i.v. fentanyl given in the intra-operative period
will be documented. The EEG electrodes will be applied on scalp in the
interventional arm group E. Hereafter the data will be recorded at the time
points stated in the proforma attached alongside this form. Intraoperative
titration of anesthesia will be as per the EEG derived indices- Spectral Edge
frequency (SEF) in the intervention group E. In the conventional group C, the anesthetic
titration shall be done using the minimum alveolar concentration (MAC) value.
The EEG electrodes will be removed from the patient after completion of
surgery. Blood samples will be collected to assess the markers of neuroinflammation
(IL-1β (interleukin 1), IL-6 (interleukin 6), TNFα (tumor necrosis factor alpha),
S100B (S100 calcium-binding protein B)} in the entire study cohort.
The primary outcome will be the
incidence of postoperative delirium which will
be assessed using Confusion Assessment Method (CAM-S) short form (Annexure 2)
for extubated patients and Confusion Assessment Method for the intensive care unit (CAM-ICU) questionnaire
for intubated patients shifted to ICU/HDU (Annexure 3) by a blinded assessor. Additionally,
this blinded assessor shall also perform the scoring of cognition using the Montreal Cognitive Assessment (MoCA) score
(Annexure 4)
EEG charts will be reviewed using the
MATLAB software.
A data monitoring committee will not be needed
for this study as the sample size has data compatible with microsoft xcel
sheets manageable at the investigator level.
The investigators have not planned for
any interim analysis of this research project.
A trial audit however, will be done
after recruitment of 50% of the study sample size.
Any amendments in this protocol will
be notified to the institutional Ethics committee and CTRI accordingly after
approval of funds from ICMR / MRU .
The blood samples for laboratory
analysis will be collected and stored by departments of biochemistry and
pathology at Indira Gandhi Medical college.
Outcomes
Primary- occurrence of postoperative
delirium between day 1 to 5 Secondary- Evaluation
of Glasgow Outcome Score- Extended (GOS-E) at 30 days after surgery
Exploratory outcomes include covariates of delirium, functionality and postoperative
cognitive impairment. Pre-specified exploratory analyses include intraoperative
mediating events such as anesthetic concentrations, electroencephalogram
suppression time and hypotension duration.
Peri-operative adverse events include
undesirable intraoperative movement, awareness with recall, complications such
as major blood loss and transfusions, stroke, sepsis, dialysis, prolonged
intubation and mortality rate.
Postoperative delirium
The primary outcome of the study is the incidence of
postoperative delirium. Assessment of postoperative delirium is conducted in
patients that can be sufficiently aroused according to a Richmond Agitation and
Sedation Score ≥ -3. Assessment of patients for delirium is performed
postoperatively. The
research works by Card et al.19
and Lepouse et al.20 have
pointed out numerous key elements in the anesthesia technique which
can lead to post-operative delirium. We will observe the EEG power and
correlate it with our anesthesia protocol to deduct whether the post-operative
delirium (if any) is due to anesthetics or not. A diagnosis of delirium for each patient is based on an
approach combining a standardized assessment with a chart review. Members of
the research team who are blinded to the treatment arm of the study assess
patients for delirium using the Confusion Assessment Method short (CAM-S) form,
or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) for patients who are
unable to speak (e.g., have a tracheal tube or tracheostomy).
Postoperative Cognitive deficit
One of the secondary objectives of this trial is also
to elucidate postoperative cognitive deficit (if any) between the two study
groups. We will use the Montreal Cognitive Assessment (MoCA) score
assessment, preoperatively and postoperatively to determine any new onset
deficit in cognition after surgery. This data will be collected from those
patients who are having a GCS of 15 after surgery.
Statistical Analysis
Interval
scale and ordinal scale variables will be represented by median and
interquartile ranges, while nominal variables will be represented by
frequencies and percentages. Data testing for normality will
be done using the Shapiro–Wilk test. Baseline and
demographic variable differences will be analyzed using the Kruskal–Wallis test
or Chi‑square test as appropriate for the variable type. Between‑group analysis
for longitudinal data will be conducted using linear mixed effect models. The correlation between the variables will
be conducted using repeated measures correlation based on generalized linear
modelling.
Data access
The data will be present for
five years after completion of the research work and it shall be provided only
if it is required for meta-analysis or secondary analysis.
Anciliary Care
It shall be provided
by the departments of Neurosurgery, Anesthesia and Neuroanesthesia. Clinical
trial Insurance from TATA-AIG shall provide compensation to any patient who suffers harm from trial
participation.
Conflicts of Interests
The investigators affirm that
they do not have any financial and other competing interests.
Funding
It will be met from the Indian Council of Medical
Education and Research (ICMR) based extramural grant, after approval by the
concerned body.
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