Effect of anesthesia depth on postoperative clinical outcome in patients with supratentorial tumor (DEPTH): study protocol for a randomized controlled trial.

INTRODUCTION: Recent studies have shown that deep anaesthesia is associated with poor outcomes. However, no randomised controlled trials have been conducted to test the causality in patients undergoing brain tumour resection. METHODS AND ANALYSIS: DEPTH is a multicenter, randomised, parallel-group, blind trial. The depth of general anaesthesia will be monitored using the bispectral index (BIS). Patients elected for supratentorial tumour resection will be randomly allocated to the deep or the light anaesthesia group in which the target BIS value is 35 or 50, respectively. BIS will be maintained at the target value for more than 90% of the total anaesthesia period. The primary outcome is the disability-free survival rate at postoperative 30 days and 1 year. The secondary outcomes are the mortality and morbidity within 30 days after surgery. ETHICS APPROVAL AND DISSEMINATION: Ethical approval has been granted by the Medical Ethics Committee of Beijing Tiantan Hospital, Capital Medicine University. The reference number is KY2016-059-02. The results of this study will be disseminated through presentations at scientific conferences and publication in scientific journals. TRIAL REGISTRATION: NCT03033693. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

To date, DEPTH is the first randomised controlled trial to test the causal relationship between anaesthesia depth and postoperative outcomes in patients undergoing supratentorial tumour surgery.

There are nearly six thousand cases of supratentorial tumour every year at Beijing Tiantan Hospital, Capital Medical University. It is feasible and reasonable to complete the trial with a large sample size in 3 years.

This study is not a double-blind study. It is not practical for the anesthesiologists to be blinded to the grouping. However, the patients and the outcome assessors will be blinded to anaesthesia depth.

There is no conclusive information about BIS monitoring in patients with supratentorial brain tumours undergoing craniotomy, which will be the secondary analysis of DEPTH.

Background

A recent study shows that the average incidence of intracranial tumours in China is approximately twenty-five per hundred thousand,1 most of which are supratentorial tumours. The clinical outcomes are very poor, placing a tremendous burden on families and society.2 Therefore, increased perioperative attention is being paid to ways to increase the disability-free survival rate in patients undergoing brain tumour resection.

There are many factors associated with the survival of patients undergoing supratentorial tumour resection. Age, histologic type, the presence of seizures, tumour volume, and Karnofsky performance status (KPS) score have been confirmed as associated with overall and cause-specific survival.3 Haydon et al 4 indicated that total resection improved the recurrence-free outcome and increased the postoperative survival rate. Soliman et al 5 showed that continuous intraoperative infusion of dexmedetomidine improved clinical outcomes in patients undergoing craniotomy. The anaesthesia method also affected the postoperative clinical outcomes.6 However, there is still a lack of evidence regarding the association between anaesthesia depth and the postoperative clinical outcome in patients undergoing supratentorial tumour surgery.

Anaesthesia depth is defined as the degree of drug-induced non-responsiveness to stimulation under general anaesthesia.7 The bispectral index (BIS), which is calculated from the original electroencephalography (EEG), is widely used to measure the depth of anaesthesia.8–11 The BIS value ranges between 0 and 100, which represent burst suppression and full awakeness, respectively. Watson et al 12 found a higher long-term mortality for patients who showed EEG burst suppression compared with those who did not (59% vs. 33%) during sedation in an intensive care unit (ICU). Chan13 and colleagues showed that BIS-guided anaesthesia decreased the risk of postoperative cognitive dysfunction (POCD) at 3 months. Recent studies have suggested that deeper anaesthesia was associated with worse outcomes in surgical patients.12 14–16 However, there are no such studies involving patients with supratentorial tumours.

Under deep anaesthesia, the circulatory system is inhibited; hence, cerebral blood flow, cerebral perfusion, brain electric activity, and energy metabolism are reduced.17 The HR of postoperative mortality was 1.29 in patients with a persistent low BIS. When a BIS lower than 45 was maintained for an hour, the risk of death increased by 29%.18 Leslie et al 19 found similar results. Monk et al 20 showed that the cumulative time of deep hypnosis and intraoperative hypotension were independent predictors of mortality. However, Sessler DI et al 21 performed a study of the depth of anaesthesia in 24 120 patients undergoing non-cardiac surgery that indicated that low BIS was not the only risk factor associated with high postoperative mortality. Willingham et al 22 indicated that intraoperative EEG suppression was a predictor of postoperative mortality only if mean arterial pressure (MAP) was also low. The postoperative 30 day mortality doubled when both low MAP and a low minimum alveolar concentration (MAC) were present.21 However, targeting anaesthesia depth23 at a specific BIS threshold did not decrease postoperative mortality.

There is still a lack of randomised controlled trials with a large sample size examining the effect of anaesthesia depth on postoperative outcomes in patients undergoing supratentorial tumour surgery. Based on the current literature, we propose the hypothesis that compared with light anaesthesia, deep anaesthesia leads to worse clinical outcomes in these patients. The disability-free survival rate at postoperative 30 days and 1 year will be the primary outcome. A randomised controlled trial will be designed to test this hypothesis.

Methods

Study design

DEPTH is a multicenter, randomised, parallel-group, blind trial. The data will be collected from consecutive patients admitted to neurosurgery wards.

Objectives

The aim of DEPTH is to determine whether there is a causal relationship between anaesthesia depth and postoperative clinical outcome in patients undergoing supratentorial tumour surgery.

Inclusion criteria

Patients scheduled to undergo elective supratentorial tumour resection under general anaesthesia from 2017 to 2019 will be recruited for the trial. The inclusion criteria include age between 18 and 80 years, American Society of Anesthesiologists (ASA) physical status III-IV, surgery duration expected to be 3 hours or longer, postoperative hospital stay expected to be five nights or longer, and BIS monitoring throughout anaesthesia.

Exclusion criteria

Patients who undergo emergency or awake craniotomy surgery or are unable to provide written consent will be excluded from the trial. Patients whose incision site conflicts with the placement of BIS electrodes on the frontal and temporal lobes will also be excluded from the study.

Randomization and blinding

Permuted randomization will be used and stratified by age (older or younger than 50 years). Patients who meet the criteria will be randomly allocated to the deep group (BIS=35) or the light group (BIS=50). The distribution ratio will be 1:1. The anesthesiologists will not be blinded to the grouping. However, the patients and the outcome assessors will be blinded to the intervention.

Grouping

Based on the depth of anaesthesia monitored by BIS (BIS Complete Monitoring System; Coviden Ireland Limited, Dublin, Ireland), the patients will be randomly divided into the deep group or the light group, in which the BIS value will be targeted at 35 or 50, respectively. Research assistants will generate the allocation sequence and assign the participants to interventions. The anaesthesia depth in the deep group will begin to be adjusted when the BIS equals 32 or 38; in the light group, the anaesthesia depth will be adjusted when the BIS is 47 or 53. In this way, BIS will be maintained at no more than five units outside the targeted range for more than 5 min. The target BIS value will be maintained for 90% of the total time from the induction to the cessation of anaesthesia.

Anaesthesia induction and management

Standard routine monitoring will be instituted, including non-invasive blood pressure (NBP), electrocardiography (ECG), pulse oxygen saturation (SPO2), end-tidal carbon dioxide PaO2 (ETCO2), BIS, body temperature, continuous arterial pressure and urine output. All patients will be premedicated with midazolam 0.05 mg/kg intravenously. Total intravenous anaesthesia (TIVA) will be performed for all patients undergoing supratentorial tumour resections. No inhalational agent will be used. Ketamine and dexmedetomidine will not be used in DEPTH. Anaesthesia will be induced with sufentanil, rocuronium or cisatracurium and propofol or etomidate. After tracheal intubation, mechanical ventilation will be performed with a tidal volume of 8–10 mL/kg, a respiratory rate of 12–15/min, an inspiration and expiration ratio of 1:2, a fraction of inhaled fresh gas of 60% and a flow rate of fresh gas of 1–2 L/min to maintain normocapnia. Anaesthesia will be maintained with intravenous propofol and remifentanil and supplemented with intravenous rocuronium or cisatracurium for muscle relaxation. Sufentanil will be administered to attenuate potent stress responses induced by noxious stimuli at certain time points during skull opening, such as scalp incision and skull drilling. Crystalloid infusion and colloid infusion will be used as needed. The comorbidities, the dosage of anaesthetic drugs, and the physical parameters will be recorded. Fluid input and output will also be closely monitored and recorded.

At the end of the surgery, ondansetron will be administered to prevent postoperative nausea and vomiting. Neostigmine and atropine will be used to antagonise remnant muscle relaxation. Postoperative patient-controlled intravenous analgesia (PCIA) formulation will be set as sufentanil (1–2 µg/kg) combined with ondansetron (16 mg) diluted to a total volume of 100 mL in 0.9% saline. The PCIA device provides a basal infusion of 2 mL/h and a bolus (0.5 mL, 15 min lock-out time). The patient will be delivered to the post-anaesthesia care unit (PACU) after the surgery.

Blood pressure management

The blood pressure will be maintained at the target value during the surgery. The baseline value is defined as the average MAP of the first three values measured after the patient enters operating room and before induction. The target value is defined as the range from below 15% to more than 20% of the baseline value. Blood pressure will be measured at 3 min intervals. When MAP is outside the target range, measures will be taken including adjusting the infusion rate of remifentanil and administering sufentanil and vasoactive agents (such as phenylephrine, norepinephrine and perdipine). The initial doses of norepinephrine and phenylephrine will be 0.01 µg/kg/min and 0.5 µg/kg/min, respectively.

Conversion between the groups

Anaesthesia will be deepened if body movement or intraoperative bucking occurs to ensure the safety of patients when the BIS value cannot be maintained within the target range anymore. If the intraoperative MAP is difficult to maintain within the target range after the standard operational procedure, the depth of anaesthesia will also be changed. The decision to convert will be made by the chief investigator for each medical centre, and the reason will be recorded.

Primary outcome

The primary outcome is the disability-free survival rate at postoperative 30 days. The WHO Disability Assessment Schedule 2.0 Scale (WHODAS 2.0) will be used to assess the disability before surgery and 30 days and 3 months after surgery.24 Disability is defined as a 4-point reduction in the WHODAS score.

Outcome assessment will be conducted by research members who have been trained before the study and are blinded to the grouping.

Intraoperative awareness: the modified Brice questionnaire25–27 will be administered to assess intraoperative awareness at 1 day and 30 days after surgery.

Postoperative delirium: the Confusion Assessment Method for the Intensive Care Unit scale (CAM-ICU) will be applied to assess postoperative delirium within 1 day in the PACU or the ICU.

Postoperative cognitive dysfunction: The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and cognitive function assessment scale for dementia will be used 1 day before and 30 days after surgery to evaluate cognitive function.

Recovery quality: the postoperative Quality of Recovery-15 score (QoR-15) will be applied to assess the quality of awakeness in the PACU.

All-cause mortality: the incidence and the reason for mortality will be recorded at 30 days.

The incidence of comorbidity will be recorded within the first three and 30 days after surgery. Morbidity28 includes the incidence of myocardial infarction, cardiac arrest, pulmonary embolism, stroke, sepsis, surgical site infection and persistent postoperative pain.

The progression-free survival rate and the survival rate at postoperative 1 year will be assessed.

Sample size calculation

Based on the previous literature,29–31 we estimate that the disability-free survival rate at 30 days after surgery is approximately 80%, and we expect the survival rate of the patients in the light anaesthesia group to increase by 5%. We estimate that 2504 participants would provide 90% power to detect a 5% difference (80% vs. 85%) in the disability-free survival rate using a two-tailed alpha of 0.05.32 Considering a drop-out rate of 20%, the total sample size was calculated as 3004.

Statistical plan

SPSS software (version 19.0) will be used for statistical analysis. The categorical data will be expressed as the number of patients (percentage) or median (IQR (IQR)) and analysed using chi-square tests or Fisher’s exact test. The continuous data will be expressed as the mean ± SD and analysed using the Mann-Whitney U test or independent t test.

The disability-free survival rate at postoperative 30 days and 3 months will be compared using the chi-square test. The progression-free survival rate and survival rate at postoperative 1 year will be compared through chi-square test. The incidence of myocardial infarction, cardiac arrest, stroke, pulmonary embolism, sepsis, surgical site infection, intraoperative awareness and persistent post-operative pain will be analysed using chi-square tests or Fisher’s exact test. The QoR-15 score, CAM-ICU score, WHODAS score, MMSE score, and cognitive function assessment scale for dementia score will be analysed by using the Mann-Whitney U test or independent t test.

Subgroup analysis will be performed for age, comorbidities, histological type of tumour, duration of anaesthesia, and resection degree. Multiple logistics regression will be applied to determine the influence of these confounding factors on the primary outcome. All analyses will be based on the intention-to-treat (ITT) and per-protocol (PP) principles. The final conclusion will be based on the ITT principle. A p-value less than 0.05 will be considered to have statistical significance.

The project will be monitored by a data monitoring committee (DMC) composed of specialists in ethics, anesthesiology, statistics, and methodology. When the follow-up visits of 1500 participants are completed (estimated to occur after 1 year of recruitment), the interim analysis will be conducted to evaluate the efficacy of the primary outcome. The p-value for the analysis will be set at p<0.001.

Adverse events

All adverse events will be monitored and recorded until they are resolved. Once any adverse event occurs, it will be immediately reported to the endpoint adjudication committee, which will determine the severity and causality of the adverse events. The chief investigator will be responsible for all adverse events reported. The incidence of adverse events will be summarised for each group and compared using the chi-square test or Fisher’s exact test.

Discussion

DEPTH is a large randomised, multicenter, parallel-group, blind trial aiming to test the hypothesis that light anaesthesia will increase the disability-free survival rate at 30 days after surgery in patients undergoing supratentorial tumour surgery. It is recommended that the BIS value be maintained between 40 and 60 during routine general anaesthesia. However, BIS monitoring is not a routine procedure in clinical work. When anaesthesia was conducted with the BIS value hidden from the anaesthetist, patients were commonly anaesthetised at BIS levels between 30 and 50.33 34 Moreover, the BALANCED study (registration number: ACTRN12612000632897) is an ongoing randomised controlled trial that aims to observe the effect of anaesthesia depth on the outcome of patients undergoing major surgery28; in that study, the targeted BIS value of the light anaesthesia group is also targeted at 35. Data suggest that the longer the BIS value remains below 40, the higher the risk of mortality; however, at present, there is no conclusive evidence that deep anaesthesia is associated with poor clinical outcomes in patients undergoing supratentorial tumour resection. Based on the existing references and the BALANCED study, the ethics committee of Beijing Tiantan Hospital approved the target BIS value of 35 for the light anaesthesia group in the DEPTH study. The BALANCED study focused on the 1 year all-cause mortality in patients older than 60 years who were scheduled to undergo major surgery.

Many studies have proven that BIS can monitor the depth of anaesthesia during craniotomy.35 36 However, during neurosurgery in particular, the recommended placement of electrodes sometimes conflicts with the incision site. BIS can alternatively be monitored at the occipital lobe when the neurosurgical incision is located on the frontal lobe.37 However, the monitored BIS values in the frontal and occipital lobes differ in the same person. Therefore, it is not suitable to use these two different monitoring sites in the DEPTH study, in which BIS value is the main intervention. Consequently, patients whose surgery site conflicts with the BIS monitoring sites on the frontal and temporal lobes will be excluded from the study. There will be no alternative set-ups.

Anaesthesia depth also has an impact on the other outcomes in patients undergoing surgery. Myles et al 26 performed a study of intraoperative awareness during anaesthesia in 2463 patients that showed that BIS-guided anaesthesia reduced the risk of intraoperative awareness in patients undergoing general anaesthesia. Messina et al 38 found that higher doses of anaesthetics reduced the risk of awareness. Law et al 39 conducted a randomised controlled trial on the effect of anaesthesia depth on postoperative pain in 135 patients. There was no clinically useful analgesic effect in the deep anaesthesia regimen. However, Sahni et al 40 performed a prospective observational study and found that keeping the BIS at 45 to 40 throughout the anaesthesia resulted in better postoperative pain relief in patients undergoing laparoscopic cholecystectomy. Farag et al 41 reported less POCD in patients undergoing deep anaesthesia. Similarly, An et al 42 also indicated that deeper TIVA decreased the incidence of cognitive dysfunction during the early postoperative period. However, no study has examined the effect of anaesthesia depth on the incidence of awareness, POCD, and postoperative pain in patients undergoing supratentorial tumour resection. Hence, differences in intraoperative awareness, POCD, and postoperative pain between the different depths of anaesthesia will be the secondary outcomes of the DEPTH study.

In summary, DEPTH is a large randomised, multicenter, parallel-group, blind trial that aims to test the hypothesis that light anaesthesia will increase the disability-free survival rate at 30 days after surgery in patients undergoing supratentorial tumour surgery. If the results from the BALANCED and DEPTH studies, both of which have large sample sizes, are positive, they will provide strong evidence of the contribution of anaesthesia to the clinical outcomes in surgical patients.

Dissemination

The results of this study will be disseminated through a presentation at scientific conferences and a publication in scientific journals.

Timeline

The study will take approximately three years to complete enrollment and outcome assessment. The recruitment started on February 1, 2017. The completion date will be December 31, 2019.

Audits

The DMC will audit through regular interviews, letters or telephones. The DMC reserves the right to audit the recruitment of patients at any time. The auditing process will be independent from the investigators.

Amendments to the protocol

Amendments to the protocol will only be made by academic committee and with the approval of the Medical Ethics Committee, Beijing Tiantan Hospital, Capital Medical University. All modifications will be recorded. Any modifications will be applied to all subsequent patients, and the registration record will be updated.