ElectroEncephalography Guided Anesthesia in Neurosurgery for decreasing the incidence of postoperative delirium- a randomized controlled trial

Research Hypothesis- Electroencephalography(EEG) guided anesthesia using dexmeditomidine-sevoflurane based anestheticregimen will result in reduction of delirium by 50 %

Primary Objective:-To compare theeffect of EEG guided anesthesia with conventional anesthesia monitoring onpostoperative delirium in patients undergoing posterior

fossa neurosurgery for resection of brain tumors.

SecondaryObjectives:-

(i) To evaluate the dominant alpha oscillatory activity during emergence

(ii) To evaluate deltadominant activity and slow wave activity

(iii)To correlate intraoperative EEG pattern with intraoperative systolic bloodpressure, 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 postoperativecognition

(v) To observe theimpact on post-operative neuroinflammation between the two groups as assessed    by thefollowing  laboratory tests:  IL-1β, IL-6, TNF****α and S100B

A Randomized, parallelgroup, open labeled, Allocation blinded, Assessor blinded trial

PICOT of this RCT

•         POPOULATION **-**Patients scheduled for posterior fossaneurosurgery for resection of brain tumors

•         INTERVENTION - Electroencephalography guidedanesthesia

•           COMPARISON - With the conventional anesthesia monitoring posterior fossa

•         neurosurgery

•         OUTCOME - Primary- occurrence of postoperative deliriumbetween 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 cohortand analysis of EEG charts

Reason for Study

•      The incidence of delirium after neurosurgery is estimated to bebetween 40% and 70% depending on the population studied and the methods used toassess delirium

•      As one of the most common complications after neurosurgery it isassociated with prolonged length of hospital and intensive care unit (ICU)stay, increased morbidity and mortality, functional and cognitive decline, andis often associated with placement in long-term care facility.

•      The target site for all theanesthetics is brain. Yet the conventional anesthesia practice is based onmonitoring the heart, lungs and renal system. This ambiguity has resulted inmiscalculation of adequate levels of anesthetics in infant, pregnant andelderly  patients. We aim to rectify thisambiguity, starting by monitoring brain during the anesthesia, and therebytailoring the anesthesia practice as per the EEG indices.

•      The results of this study shall helpin formulating a clinical practice algorithm for EEG guided anesthesiamonitoring aimed at reduction of post-operative delirium

•      Additionally, this will be the firststudy on intra-operative EEG based anesthesia practice from our state ofHimachal Pradesh

Methodology:

This study has been approved by the institutional Ethics committeesof 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 forInterventional Trials) guidelines. The checklist and figure have been attachedas annexure to this protocol.

The reporting of data pertaining to this trial will beas per the CONSORT (ConsolidatedStandards of Reporting Trials) guidelines

Recruitment- The patients scheduled for neurosurgery to operatebrain tumors in the posterior cranial fossa  at this institute, will be recruited for thisstudy after provision of a

written  informed consent by themselves or next oftheir kin.

Inclusion criteria- The  patients aged 18years and above undergoing neurosurgery for resection of brain tumors in theposterior 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-anestheticcheckup;

(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-existingpsychiatric illness.

These patients will be excluded from the study as they will not beable to participate adequately for screening delirium during pre-anestheticevaluation.

Enrollment- through pre-anesthesia clinics andalso by the visit from anesthesiologist to the ward, prior to the surgery ofpatient. They will be given a detailed information sheet (Annexure 6 and 7)explaining about the pros and cons of this research alongwith their entitlementfor compensation as per the clinical trial insurance policy. The patients whodo not give consent for participation in this study shall still get thestandard  anesthetic monitoring andsurgical treatment for their pathology.

Sample Size- Based on the number of patients operated bythe neurosurgery department over last one year (which were around 200), andkeeping the z-score of 1.65 in order to attain the confidence level of 90% andmargin 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 standarddeviations a given proportion is away from the mean.

R****andomization

Computergenerated assignment at the patient level will be used for block randomization. Patients who will be eligible and have giveninformed consent, shall be randomized to either of the two study groups i.e. Group E (EEG guidedanesthesia) and Group C(Conventional anesthesia practice). The randomization sequence will be generated by the data analysiscenter using block randomization technique.

The randomization code shall only bebroken in case the patient develops any intra-operative lethal complicationlike venous air embolism, pulmonary edema, brain herniation or cardiac arrest.

Allocation blinding

An external member (Sharath Krishnaswamy, AsterWhitefield hospital, Bengaluru, Karnataka) shall enroll participants and assignthe randomization between the two groups. He will maintain the record in aregister which shall be opened only during the allotment of randomization of thegroup. Predictability of the randomization sequence is minimized by recordingit in a separate sealed register, unavailable to the other members of theresearch team who enroll participants and assign groups. This allocator shallsend the group information to the attending anesthesiologist in the operationtheater, in order to ensure allocation blinding.

 Open labeled

The patient will be aware whetherhe/she is applied with the EEG electrodes or not. Therefore this will be anopen labeled study.

 Assessor blinding

The member analyzing the postoperativedelirium by CAM-S form will be unaware of the allocated group to the patient.

The anesthesiologist and the teamcaring for the patient intraoperatively shall thereafter perform the anesthesiaconduct as per the allotted group.

                The primary investigator enlisted fordata collection has been trained at Department of Neuroanesthesia andNeuro-critical care, NIMHANS Bangalore, to recognize the typical EEG patternsof the different levels of anesthesia seen during the usage of intravenousanesthetics with/without volatile anesthetic agents. He has also been trainedto differentiate the EEG pattern in awake patients from the EEG patterns seenduring general anesthesia.

 The co-investigator (Prof. SudhirSharma) is a dedicated Neurologist with detailed clinical expertise in EEGmonitoring of over 10 years.

 The co-investigator (Dr. VikromTakkar) is a dedicated Anaesthesiologist and Intensivist with experience ofover 8 years in this field. He will be assessing the delirium and cognition in pre-anesthesiaclinics/ neurosurgery ward and post-operatively.

 In case of any inadvertentintra-operative event like massive blood loss, cardiac arrest, embolism, thepatient data will be unblinded and the allocated intervention will be revealed.

 Implementation Plan for theMethodology

                Thepatients who are undergoing elective neurosurgery and provide informed consentby 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. Afterenrollment, they will be randomized into the two groups (i.e E and C) using block randomization technique once they meet the inclusioncriteria.

The patient will bebrought into the operation theatre and pre-oxygenated for 3 minutes.Thereafter, the patient will undergo anesthetic induction with dexmeditomidine1µg/kg/hr iv infused over 10 minutes (i.e 0.6 µg/kg/min over 10 minutes) andpreservative free lignocaine 1.5 mg/kg iv. In order to provide analgesia tocurtail the intubation response, the patient will receive fentanyl 2 µg/kg iv. Atelapse of 8 minutes after starting the dexmeditomidine infusion, facemask shallbe placed with oxygen and sevoflurane 4% on volume concentration dial in orderto deepen the plane of anesthetic induction. In order to facilitate musclerelaxation for laryngoscopy, vecuronium 0.15 mg/kg iv shall be administered.This will be followed by subsequent endotracheal intubation. Assessmentof quality of Intubation will be as per the modified Viby-Mogenson criteria21(table 1).

Anaesthesia will bemaintained using air: oxygen: sevoflurane. Analgesia during surgery will beprovided by a continuous infusion of dexmeditomidine @ 0.5 μg/kg/hr in both thestudy groups. A scalp block using 20 ml of 0.375 % bupivacaine to block nervesupply to the scalp shall also be applied to all the patients participating inthis study cohort.

An increase in meanblood pressure or heart rate by more than 30% of baseline value despite adequate anesthetic depth during surgerywill be considered a nociceptive response and it shall be treated byadministering a bolus of  fentanyl (1μg/kg i.v). The total dose of i.v. fentanyl given in the intra-operative periodwill be documented. The EEG electrodes will be applied on scalp in theinterventional arm group E. Hereafter the data will be recorded at the timepoints stated in the proforma attached alongside this form. Intraoperativetitration of anesthesia will be as per the EEG derived indices- Spectral Edgefrequency (SEF) in the intervention group E. In the conventional group C, the anesthetictitration shall be done using the minimum alveolar concentration (MAC) value.The EEG electrodes will be removed from the patient after completion ofsurgery. 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 theincidence of postoperative delirium which willbe 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) questionnairefor 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 theMATLAB software.

A data monitoring committee will not be neededfor this study as the sample size has data compatible with microsoft xcelsheets manageable at the investigator level.

The investigators have not planned forany interim analysis of this research project.

A trial audit however, will be doneafter recruitment of 50% of the study sample size.

Any amendments in this protocol willbe notified to the institutional Ethics committee and CTRI accordingly afterapproval of funds from ICMR / MRU .

The blood samples for laboratoryanalysis will be collected and stored by departments of biochemistry andpathology at Indira Gandhi Medical college.

Outcomes

Primary- occurrence of postoperativedelirium  between day 1 to 5

Secondary- Evaluationof Glasgow Outcome Score- Extended (GOS-E) at 30 days after surgery

Exploratory outcomes include covariates of delirium, functionality and postoperativecognitive impairment. Pre-specified exploratory analyses include intraoperativemediating events such as anesthetic concentrations, electroencephalogramsuppression time and hypotension duration.

Peri-operative adverse events includeundesirable intraoperative movement, awareness with recall, complications suchas major blood loss and transfusions, stroke, sepsis, dialysis, prolongedintubation and mortality rate.

Postoperative delirium

The primary outcome of the study is the incidence ofpostoperative delirium. Assessment of postoperative delirium is conducted inpatients that can be sufficiently aroused according to a Richmond Agitation andSedation Score ≥ -3. Assessment of patients for delirium is performedpostoperatively.                                                                     Theresearch works by **Card et al.**19and **Lepouse et al.**20 havepointed out numerous key elementsin the anesthesia technique whichcan lead to post-operative delirium. We will observe the EEG power andcorrelate it with our anesthesia protocol to deduct whether the post-operativedelirium (if any) is due to anesthetics or not.               A diagnosis of delirium for each patient is based on anapproach combining a standardized assessment with a chart review. Members ofthe research team who are blinded to the treatment arm of the study assesspatients 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 areunable to speak (e.g., have a tracheal tube or tracheostomy).

Postoperative Cognitive deficit

One of the secondary objectives of this trial is alsoto elucidate postoperative cognitive deficit (if any) between the two studygroups. We will use the Montreal Cognitive Assessment (MoCA) scoreassessment, preoperatively and postoperatively to determine any new onsetdeficit in cognition after surgery. This data will be collected from thosepatients who are having a GCS of 15 after surgery.

Statistical Analysis

Intervalscale and ordinal scale variables will be represented by median andinterquartile ranges, while nominal variables will be represented byfrequencies and percentages. Data  testing for normality willbe done using the Shapiro–Wilk test.  Baseline anddemographic variable differences will be analyzed using the Kruskal–Wallis testor Chi‑square test as appropriate for the variable type. Between‑group analysisfor longitudinal data will be conducted using linear mixed effect models. The correlation between the variables willbe conducted using repeated measures correlation based on generalized linearmodelling.

 Data access

The data will be present forfive years after completion of the research work and it shall be provided onlyif it is required for meta-analysis or secondary analysis.

Anciliary Care

It shall be providedby the departments of Neurosurgery, Anesthesia and Neuroanesthesia. Clinicaltrial Insurance from TATA-AIG shall provide compensation to any patient who suffers harm from trialparticipation.

Conflicts of Interests

The investigators affirm thatthey do not have any financial and other competing interests.

Funding

It will be met from the Indian Council of MedicalEducation and Research (ICMR) based extramural grant, after approval by theconcerned body.