Many older people can experience confusion, memory problems, or a decline in their thinking after major surgery. These problems are sometimes called 'postoperative neurocognitive disorders' or PND and can affect recovery and a person's ability to live independently.

The investigators want to find out the best way to study these problems in older patients undergoing surgery. This is a 'feasibility study', which means we are testing the research methods. The investigators want to see if it is possible to ask participants to do memory tests and give blood samples before and after their operation. The investigators are hoping to include around 40 patients over 2 years in this study.

The investigators will compare performance in memory (cognitive assessment) findings before and after surgery and link this to data taken from the anaesthetic, including the types of drugs used, duration, brain features from processed electroencephalogram monitoring and standard recommended monitoring. In addition the investigators will link this to blood sample markers of brain health and function (biomarkers).

The results of this study will help the investigators plan a much larger study in the future, with the ultimate goal of making surgery safer for the brain.

SUMMARY

Older patients can experience significant difficulties with memory and thinking (known as cognitive problems) after major surgery. The specific reasons in this vulnerable group are not yet clearly understood.

CAPSULAR is a single-centre feasibility research project at the Western General Hospital, Edinburgh, that aims to find the best way to conduct detailed research into this problem.

Objectives:

Main Aim:

- To determine if it is practical and feasible to screen older participants (age ≥ 70) for cognitive problems both before surgery and up to 7 days after surgery (or before leaving hospital, if earlier).

Secondary Aims:

• Collect extra blood samples (at the same time as routine clinical blood tests) to measure markers of potential brain injury. These will be collected before, immediately after, and up to 7 days after surgery (or before leaving hospital, if earlier).
• Gather detailed data on the participant's health, frailty, and the anaesthetic technique used, including standard brain monitoring (pEEG) to monitor anaesthesia depth during the operation.
• Look for a link between anaesthesia technique and the risk of cognitive problems and blood markers of brain injury.
• Proxy outcomes to inform economic analysis in a larger planned trial e.g. impact on changes in care need, cognitive aids such as new use of a multi-compartment drug compliance aid.

We plan to recruit 40 patients aged ≥ 70 who are scheduled for colorectal or urological surgery lasting over one hour. Participants will be those already attending the POPS (Perioperative Medicine for Older People undergoing Surgery) clinic.

The study will measure success based on the percentage of eligible patients who agree to take part, complete the one-week cognitive screening, and provide all the necessary blood and data samples.

This research will provide the crucial initial evidence needed to plan future definitive trials exploring whether altering anaesthetic or surgical care can safely reduce brain problems for older and frailer patients.

2 INTRODUCTION

2.1 BACKGROUND

Postoperative neurocognitive disorders (PND) represent a spectrum of cognitive impairments that can arise after surgery, ranging from acute, reversible, postoperative delirium to more persistent, and sometimes subtle, cognitive decline. These disorders are particularly common in older adults, with reported incidence rates for postoperative delirium as high as 40% following major elective surgery. The consequences are significant, including prolonged hospital stays, increased patient morbidity and mortality, and a greater likelihood of long-term cognitive impairment, which can profoundly reduce a patient's quality of life and independence. Additionally, there may be further impact economically and upon the formal and informal care sectors for example new dependence on aids.

The investigators' previous work with the Perioperative Care for Older People Undergoing Surgery (POPS) Clinic at the Western General Hospital, Edinburgh, identified that 21% of patients scheduled for major surgery had previously unrecognised pre-operative cognitive impairment. This cohort subsequently experienced a high incidence of PND, particularly delirium, affecting 40% of those who underwent emergency surgery and 5% of those undergoing elective surgery. This highlights a vulnerable patient population in whom the risks of postoperative cognitive decline are substantial.

The pathophysiology of PND is thought to be multifactorial, involving interplay between patient-specific risk factors (e.g., advanced age, frailty, pre-existing cognitive deficits) and procedural factors, such as surgical stress, systemic inflammation, and anaesthetic technique. Previous research has often included younger and less frail individuals, leaving a critical knowledge gap concerning those elderly and frailer patients who are possibly most at risk.

Given the increasing trend towards older patients undergoing major surgery, there is therefore, an urgent need for research focused specifically on elderly and frail patients to identify reliable risk factors. This includes physiological and molecular biomarkers predictive of PND. This knowledge will enable us to better identify at-risk patients to inform consent, guide preventative resources, and stratify participants for future trials of therapeutic interventions.

2.2 RATIONALE FOR STUDY

One near-universal criticism of the existing literature in this area has been that study cohorts have not been of a sufficiently advanced age. The investigators' research location hospital and clinic stream enables them to set recruitment at 70 years of age or over, as one in five, over-75 year olds, are predicted to undergo surgery from 2030.

While the pilot data established a high incidence of PND in a high-risk cohort, the investigators now need to investigate and categorise the nature of PND with greater accuracy and determine if it is feasible to robustly investigate the impact of perioperative factors on cognitive outcomes.

This project aims to address this evidence gap. The investigators will conduct a prospective feasibility study to establish the practicalities of performing detailed, domain-specific cognitive testing in a high-risk, frail, older patient population at baseline (preoperatively) and postoperatively. This will allow them to accurately quantify the incidence of new or worsening cognitive impairment following major surgery. Furthermore, the investigators will assess the feasibility of systematically collecting detailed data on anaesthetic technique, including intra-operative processed EEG metrics, and obtaining serial blood samples for biomarker analysis. Finally the investigators will assess proxy- patient impact and economic markers such as predicted vs. actual length of stay, change to living arrangements and provision of new aids.

The investigators hypothesize that it is feasible to recruit this cohort and perform these detailed assessments. This work is critical as it will provide the foundational data necessary to design a larger, adequately powered trial to determine whether specific anaesthetic practices, such as pEEG-guided anaesthesia to minimise burst suppression, can mitigate the risk of long-lasting postoperative cognitive decline in vulnerable patients. It will inform the design of research aimed at generating data to help identify at-risk patients, possibly identify modifiable factors and quantify the incidence which would help improve the accuracy of pre-surgery counselling.

Inclusion Criteria:

• Age ≥ 70
• Seen in the Perioperative medicine for Older People undergoing Surgery (POPS) clinic
• Scheduled for colorectal or urological surgery with expected anaesthesia time over 60 minutes

Exclusion Criteria:

• Regional anaesthesia only
• Planned day surgery or expected hospital stay < 24 hours
• Expected to remain sedated and ventilated for > 24 hours postoperatively
• Participant does not wish to remain in the study if capacity is lost during the study

CO-ENROLMENT

• As this is a non-intervention study, co-enrolment will be permitted in other studies that do not conflict with this protocol.

We will conduct a prospective, single-centre feasibility cohort study over a period of 24 months, recruiting patients from the Perioperative medicine for Older People having Surgery clinic (POPS) clinic at the Western General Hospital, Edinburgh, who are scheduled for major surgery. This is a pre-surgery clinic and physician-led inpatient follow up service with discharge planning roles. Note, the nature of the clinical pathway means that patients may wait several months from POPS clinic review until surgery.