STRENGTHS AND LIMITATIONS OF THIS STUDY
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BISCAR protocol is a multicentric randomised controlled trial evaluating the effect of anaesthesia depth on perioperative neurocognitive disorders in planned cardiac surgery.
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BISCAR protocol is the first study that will include very elderly patients in cardiac surgery.
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Anaesthesia depth will be monitored with a simple and reproducible method: the Bispectral Index.
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Only 200 patients will be included.
Introduction
The occurrence of cognitive dysfunction after surgery has been described since the first anaesthesia was performed in the 19th century.1 An International Nomenclature Consensus Working Group has recently recommended a change in the terminology used to describe perioperative neurocognitive disorders (NCDs) to include three essential entities: the progression of a pre-existing neurocognitive lesion, the occurrence of postoperative delirium (POD) and, finally, a postoperative NCD classified as mild or severe.2
POD is defined as an acute confusional state associated with altered consciousness, cognitive and psychomotor disorders, disturbances to the sleep cycle and psychomotor disorders, which present rapidly, fluctuate in severity and can manifest in any age group. It affects up to 20–45% of older patients undergoing surgery.3 4 NCD is mainly manifested in the form of memory, attention and language disorders or psychomotor impairments assessed via specific tests and which impact daily life. NCD is an entity that occurs from the 30th postoperative day after complete recovery from surgery. These disorders can be moderate or severe and are experienced by 20–50% of older patients 3 months after cardiac surgery and by 5–55% of those undergoing other major surgeries.5 6
It is well documented that POD represents an important independent risk factor for morbidity and mortality.7 Furthermore, delirium is linked to an increase in the length of hospital stays and a heightened prevalence of long-term cognitive impairment.8 Consequently, the prevention of POD represents a significant objective within the perioperative context. The pathophysiology of POD remains incompletely understood; several hypotheses have been proposed to explain this phenomenon, primarily linked to systemic and neurological inflammation.9
A plethora of perioperative risk factors have been identified in the literature as being predictive of POD, including obstructive preoperative altered cognitive status, history of neurologic (stroke) or psychiatric disease (depression), alcohol or drug use, metabolic disorders, hypotension and uncontrolled postoperative pain.10 However, the most robust risk factor for POD remains age, with elderly patients (>60 years) being the most vulnerable.11 Moreover, the type of surgery, particularly cardiac and emergency surgery, is a major risk factor for POD. The advent of highly reliable clinical tools has enabled the detection of delirium at the patient’s bedside. The reference scale used is the Confusion Assessment Method (CAM) Scale.12
Recently, there has been increased interest in the relationship among POD, NCD and the depth of anaesthesia.13 Indeed, the Bispectral Index (BIS) has found that depressed cerebral activity in major surgery is associated with POD and NCD.14
The elderly, defined as patients aged 60 years or above, are increasingly undergoing cardiac surgery, particularly in Western countries; and they are the demographic group most vulnerable to the development of delirium. Accordingly, it is imperative to devote attention to these patients and to develop therapeutic alternatives to prevent POD.
We are therefore proposing a randomised clinical trial to assess the benefits of reducing the depth of anaesthesia monitored with BIS to prevent short-term cognitive impairment after cardiac surgery in a population of patients over 75 years.
Methods and analysis
Study design and aim
The aim of the study is to investigate whether a deep level of anaesthesia (BIS 35) compared with a lower level of anaesthesia maintained in the standard range (BIS 55) reduces the prevalence of POD in patients aged 75 years and above undergoing planned cardiac surgery (heart valve surgery, coronary artery bypass graft surgery, aortic surgery or combined surgery). The study will be overseen by the coordinating centre located at Centre Cardiologique du Nord, Saint Denis, France, and is a multicentre (Centre Cardiologique du Nord, Clinique de la Porte de Paris and Groupe Hospitalier Privé Ambroise Paré-Hartmann), controlled and randomised trial involving two parallel groups (BIS 35 vs 55), with a follow-up study on NCD conducted solely with patients enrolled at the Centre Cardiologique du Nord. This entails assessments of POD using the CAM for the Intensive Care Unit (CAM-ICU Scale) and cognitive status using the Montreal Cognitive Assessment (MoCA) Score at 3 months post enrolment.
Study population and eligibility criteria
The target demographic for the inclusion criteria is adults aged between 75 and 85 years old and scheduled to undergo one of three programmed cardiac surgeries: valvular, coronary bypass, aortic surgery or a combined procedure. All participants had to be affiliated with the French health system. Patients were excluded from the study and therefore were not included in the final sample for the following reasons: they refused consent; they were unable to read, write or understand French; they were vulnerable patients, as defined by French law, or patients of full age placed under guardianship or legal protection; they were incapable of providing personal consent in accordance with Article L1121-8 of the French Public Health Code (CSP); patients with postoperative stroke and associated major neurological or cognitive dysfunction, or they had already participated in the present study.
Any subject included in the study may withdraw their consent to participate at any time and for any reason without the obligation to provide justification. Moreover, the medical investigator can interrupt the subject’s participation in the research for any reason that affects the subject’s safety.
Recruitment
Patients who will undergo planned cardiac surgery, including heart valve surgery, coronary artery bypass graft surgery, aortic surgery or combined surgery, and who meet the eligibility criteria will be identified. Oral and detailed written information about the study will be provided by the investigating physician in each participating centre. A necessary and sufficient delay will be granted to patients who agree to participate, and a written informed consent form will be collected (online supplemental material S1). The investigating physician will also sign the informed consent form and indicate the inclusion of the patient in the medical file as well as their randomisation arm. Patients will be randomly allocated to one of two study arms (group 55 and group 35) on enrolment, following the signing of the informed consent form. The randomisation protocol will be conducted using the ENNOV Clinical software (Paris, France).
Participant timeline and intervention
Participant inclusion started in January 2024, and the study is expected to continue for 24 months with 200 patients expected to be included, 100 in each group. A preoperative MoCA (online supplemental material S2) will be completed following randomisation the day before intervention in patients included in the Centre Cardiologique du Nord. On the day of surgery, each group will receive anaesthetic protocol in order to reach allocated BIS target (35 vs 55). Anaesthetic protocol remains at the discretion of the supervising anaesthesiologist. Hypnotic protocol was based on continuous propofol infusion or inhaled sevoflurane. Continuous ketamine or lidocaine infusion is prohibited in order to avoid any BIS interaction or associated postoperative confusion. To ensure the most appropriate and balanced allocation of patients, the randomisation sequence will be stratified according to the following variables: participating centre, type of surgery (valvular vs coronary bypass vs aortic surgery vs combined surgery) and patient age (75–80 years vs 81–85 years). Moreover, the Euroscore 2 score at the time of inclusion will be considered (a predicted mortality risk of ≥30% vs <30%). The trial design schematic, as illustrated in figure 1, will define the flow chart. The patient timeline is represented in figure 2. All haemodynamic, respiratory and cardiopulmonary bypass parameters with associated infused drugs (flow, pressure, temperature) are recorded every 15 min. BIS, burst suppression ratio, electromyogram signal analysis and quality of signal associated with BIS monitoring are also recorded every 15 min. Patients will be followed for the first 3 days after their surgical intervention to complete the CAM-ICU. CAM-ICU is realised once a day by our research nurses. In case of any major neurological fluctuation observed during the day, the nurse in charge of the patient readministers the CAM-ICU. The CAM-ICU is part of the routine neurological evaluation in our intensive care unit. The CAM-ICU is considered a positive test, and delirium is present if criteria 1 and 2 are present alongside criterion 3 or 4. Before their hospital discharge, patients will receive clinical examinations. 3 months after their hospital discharge, an MoCA test to evaluate cognitive dysfunction and a vital status assessment will be conducted among patients included in the Centre Cardiologique du Nord. MoCA is stratified into four scales according to the severity of cognitive decline. We consider a significant modification in the cognitive function if there is a jump to a lower scale.
Trial design flow chart. BIS, Bispectral Index; CAM-ICU, Confusion Assessment Method for the Intensive Care Unit; ICU, intensive care unit.
Patient timeline. BIS, Bispectral Index; CAM-ICU, Confusion Assessment Method for the Intensive Care Unit; MoCA, Montreal Cognitive Assessment.
Outcomes measures
The primary endpoint of the present study is to evaluate the prevalence of delirium during the first 3 days after surgery with the CAM-ICU Scale. Secondary endpoints were hypnotics, opioids and neuromuscular block agents used, as well as dosages during the intervention and in the intensive care unit, length of ICU stay, length of hospital stay, duration of delirium, days free of mechanical duration of mechanical ventilation and rate of reintubation and 3-month mortality rate. The MoCA will be used to evaluate the cognitive status between enrolment and the third month after hospital discharge.
Data collection and management
In accordance with the provisions concerning the confidentiality of data to which the persons responsible for the quality control of research involving human beings have access (Article L.1121-3 of the CSP), persons with direct access will take all necessary precautions to ensure the confidentiality of information relating to the persons who participate in the research, particularly with regard to their identity and the results obtained. These persons, such as the investigators themselves, are subject to confidentiality (according to French law). During research involving human beings, the data collected regarding the persons who participate will be pseudonymised and entered into an electronic case report form. They will be authenticated via the electronic signature of the investigator. As part of this research, the participants will be identified by a patient code defined by the sponsor. The sponsor will ensure that each person who participates in the research has given their written consent for access to individual data concerning them that is strictly necessary for the quality control of the research. The computerised processing of personal data is in compliance with French and European legislation on data protection. In accordance with the requirements of the Commission Nationale de l’Informatique et des Libertés, the French commission of data protection and liberties (CNIL) and the European General Data Protection Regulation, the persons participating in this research will be informed via the information notice and the consent form:
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Of the nature and purpose of the data collected as part of the research, as well as the storage period of their data.
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Of the possibility of terminating the study and the collected personal data.
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Of their rights of access, rectification, opposition, limitation and deletion of the data collected as part of the research. These rights may be exercised at any time during the research, either by making a request to the physician who is monitoring the research or by submitting a request to the sponsor’s Data Protection Officer.
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The possibility, in case of a disagreement, of making a complaint to the CNIL.
Anonymised data from the study may be made available on reasonable request addressed to the principal investigator. Each request will be subject to ethical and regulatory review. Data will be shared solely for research purposes, contingent on the signing of a data transfer agreement.
Statistical methods
The statistical analysis will incorporate all the elements required by the Consolidated Standards of Reporting Trials statement. Statistical analysis will be performed in an intention-to-treat population, including all the randomised patients except for patients who withdraw their consent, who are protected or not covered by the French statutory healthcare insurance system or who have no main outcome recorded on an electronic case report form. A perprotocol analysis will then be performed, excluding the patients with major deviations. Major deviations are defined by variations of ±15% of the BIS during the procedure. Each case will be reviewed by the scientific committee during the blind review. All analyses will be conducted using statistical software (R, V.4.3.3). A two-sided p<0.05 will be considered to indicate statistical significance.
In order to demonstrate a minimal difference in the rate of subjects with POD (according to the CAM-ICU) of 20 points: 50% expected in the BIS 35 arm versus 30% in the BIS 55 arm, these rates correspond to those observed in a retrospective series at our centre and with a two-sided type 1 risk of 5% and a minimum power of 80%, 186 analysable subjects (93 per arm) are required. To account for possible loss to follow-up, we propose to include a total of 200 subjects (100 per arm) in this study.
The baseline features of the overall population and of each group will be described. Categorical variables will be reported as frequencies and percentages and continuous variables as either means with SDs or medians with IQRs.
A corrected χ2 test will be used for primary outcome analysis. A logistic regression will be used for the analysis of the primary outcome with OR calculation, before and after adjustments for confounding variables despite the randomisation. Covariates will be defined as binary variables and continuous variables dichotomised according to their median tested in the model; they will be selected a priori and limited according to the number of primary outcome events and then presented as adjusted ORs or adjusted HRs with 95% CIs. A centre effect will be checked using a mixed effect model, considering the centre both as a random and then a fixed variable. Interactions between variables will be tested. Subsequently, unadjusted stratified and subgroups analyses will be performed according to the variable of stratification.
Continuous outcomes will be compared with the Student’s t-test or Mann-Whitney rank-sum test according to the conditions of application and categorical variables with the χ2 test or the Fisher’s exact test, according to the conditions of application. This trial will not be planned without any interim analysis. Based on prior trials in similar settings, we anticipate less than 5% missing data for the primary outcome. For the primary analysis, missing data will not be imputed. We have prespecified a single primary analysis of a single primary outcome. For the exploratory outcomes, a false discovery rate method will be used.
Expected results and impact
A reduction in the depth of anaesthesia through a decrease in the administration of hypnotic agents intraoperatively, with monitoring using the BIS, would facilitate a reduction in POD in the very elderly patients undergoing planned cardiac surgery. This approach could also be beneficial in reducing long-term cognitive dysfunction in this particularly vulnerable population. Indeed, elderly subjects frequently exhibit an early, subclinical or even progressive decline in cognitive function. POD is a source of increased morbidity and mortality, particularly as a result of infectious complications and the increased use of sedative drugs (benzodiazepines, neuroleptics, etc), which in turn cause cognitive dysfunction. As a result, patients stay longer in intensive care and in the hospital. Postoperative rehabilitation is delayed and impaired, sometimes leading to significant dependency, which in turn results in significant additional costs. If the results of our study are confirmed, it could significantly change anaesthetic practice in cardiac surgery in the very elderly and thus improve overall management, with more effective and efficient postoperative rehabilitation and a significant reduction in postoperative complications and mortality.
Ethics and dissemination
The research is conducted in adherence to the Declaration of Helsinki and in compliance with current French laws relating to research involving human beings (Law No. 2012-300 of 5 March 2012, Loi Jardé). Moreover, this study respects French laws related to data files, liberties and personal data protection with regard to the processing and the free movement of such data, and repealing Directive 95/46/EC.
This type of research is defined in Article 2° of Article L.1121-1 of the CSP (Category 2 of the Jardé law). The study protocol has been approved by the relevant French medical review board, the French Committee for Protection of Persons (ID: 2022-A02200-43, Comité de protection des personnes Est III) and the trial is registered at ClinicalTrials.gov (NCT05877326).
Prior to conducting such research involving human beings, the free, informed consent of the subject must be obtained after being informed by the investigator during a consultation and after a sufficient period of reflection. The information intended for trial participants must include all the elements defined in the Jardé Law and must be written in a simple manner in a language that the participant can understand.
An independent committee will be responsible for adjudicating causes of death and adverse events. Additionally, a data and safety monitoring board, appointed by the Committee for the Protection of Individuals, will supervise the trial’s progress.
Study results will be disseminated in peer-reviewed journals as soon as possible and presented at relevant conferences.
Patient and public involvement statement
No patient and/or public involvement was realised for this study.
Discussion
‘Perioperative NCDs’ is now an overarching term used for cognitive impairment identified in the preoperative and postoperative state that encompasses three essential elements: the progression of a pre-existing neurocognitive lesion, the occurrence of POD and, finally, postoperative NCD classified as mild or major.2
POD is associated with a prolonged hospital stay, higher readmission rates, long-term cognitive decline with associated healthcare needs and costs and increased mortality.15 Delirium is usually assessed using the CAM in the general ward and a specific scale for the intensive care unit, namely the CAM-ICU. The CAM-ICU was used in our study because it remains the reference method; however, a more recent assessment scale, the 3D-CAM, could be more suitable for patients able to speak. The evaluation of NCDs is more sensitive and requires the evaluation of perceptual motor function, language, executive function, complex attention, learning and memory and social cognition. In our study, we decided to use the MoCA Scale to evaluate NCD. Indeed, MoCA is an easy and reproducible scale that is translated into French.
Many risk factors are associated with POD and NCD, including cognitive impairment prior to surgery, anaemia, dehydration, electrolyte abnormalities, signs of malnutrition and specific medications such as antihypertensives, anticholinergics, antidepressants, benzodiazepines and opioids.16–19 However, advanced age is, in numerous studies, the most important independent risk factor for perioperative NCDs.16 20 This is secondary to structural cerebral changes and neurotransmitter alterations.21 22 In this context, the elderly are more sensitive to neuronal injury, as their cognitive reserves are more limited.
The underlying mechanisms behind perioperative NCD and specifically POD are not fully understood. Several hypotheses exist for the pathophysiology of delirium, such as systemic inflammation secondary to surgery and tissue trauma and neuroinflammation with neurotransmitter dysregulation.23 24 Cardiac surgery has some specifications with associated microemboli, flow alteration and enhanced associated inflammation. Anaesthesia depth was recently hypothesised as being related to POD and NCD, specifically in terms of the temporary deactivation or depression of cerebral functions. Indeed, a deeper anaesthesia level was associated with an increased level of POD and NCD. Moreover, anaesthetic agents could amplify the effects of the harms associated with major surgery and particularly cardiac surgery.
BIS is a reliable and simple method used to evaluate anaesthesia depth. In cardiac surgery, it is used frequently to optimise anaesthesia depth and reduce anaesthetic agents’ haemodynamic disturbance. In this context, the close monitoring of anaesthesia depth with BIS could reduce associated POD and NCD.