Preventing Delirium and Promoting Long-Term Brain Health: A Clinical Trial Design for the Perioperative Cognitive Enhancement (PROTECT) Trial

Abstract

Background:

Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are common in older adults and, for many, precipitate functional decline and/or dementia.

Objective:

In this protocol, we describe a novel multidisciplinary, multicomponent perioperative intervention that seeks to prevent or reduce POD and associated cognitive decline.

Methods:

We will conduct a prospective, single-blind, pragmatic, randomized-controlled trial to compare our tailored multi-disciplinary perioperative pathway against current standard of care practices. We will recruit a total of 692 elective surgical patients aged 65 years or more and randomize them in a 1:1 design. Our perioperative intervention targets delirium risk reduction strategies by emphasizing the importance of early mobilization, nutrition, hydration, cognitive orientation, sensory aids, and avoiding polypharmacy. To promote healthy behavior change, we will provide a tailored psychoeducation program both pre- and postoperatively, focusing on cardiovascular and psychosocial risks for cognitive and functional decline.

Results:

Our primary outcome is the incidence of any PND (encapsulating POD and mild or major postoperative neurocognitive disorder) at three months postoperative. Secondary outcomes include any incidence of POD or neurocognitive disorder at 12 months. A specialized delirium screening instrument, the Confusion Assessment Method (3D-CAM), and a neuropsychological test battery, will inform our primary and secondary outcomes.

Conclusion:

Delirium is a common and debilitating postoperative complication that contributes to the cognitive and functional decline of older adults. By adopting a multicomponent, multidisciplinary approach to perioperative delirium prevention, we seek to reduce the burden of delirium and subsequent dementia in older adults.

Keywords

Anesthesia and analgesia cognition delirium dementia healthy aging perioperative medicine prehabilitation preventive medicine rehabilitation

INTRODUCTION

Older adults undergo surgery and anesthesia to manage disease, improve quality of life, and reduce pain. It is clearly established, albeit not sufficiently recognized, that for older adults, surgery and anesthesia are associated with perioperative neurocog-nitive disorders (PND). PND encapsulates several adverse, potentially preventable, neurocognitive seq-uelae occurring within the first 12 months of the perioperative period, including postoperative delirium (POD), delayed neurocognitive recovery (dNCR), and longer-term cognitive decline (postoperative neurocognitive disorders) [1].

POD, a condition characterized by altered consciousness and disturbances in attention, is now recognized as a major contributor to poor health outcomes in older people [2, 3]. Adverse outcomes of POD include increased risk of hospital complications, lengthier hospital admissions, long-term cognitive decline [4, 5], loss of functional independence [6], early institutionalization [7], dementia [8], and mortality [9]. It is estimated that more than 10%of community dementia may be a direct result of delirium [3]. The incidence of delirium following anesthesia and surgery is high, with up to 65%of older adult surgical patients experiencing an episode of POD [10]. The incidence of delirium is expected to increase as the population ages and the demand for surgical procedures increases [11]. In Australia, older adults account for 15%of the population but make up 42%of hospital admissions. This equates to an estimated 1.5 million older adults exposed to anesthesia, surgery, and perioperative neurocognitive sequelae each year [12]. The high incidence of POD and subsequent adverse outcomes highlight the social and economic burden of the condition, and the search for effective interventions is now a key priority area of public health policy and government funding [13].

Up to 30–40%of POD cases may be prevented [2] suggesting that the adverse neurocognitive outcomes resulting from an episode of POD may also be preventable [5]. Presently, the only effective interventions to prevent POD are non-pharmacological, multi-modal strategies targeting modifiable delirium risk factors [2 , 14–16]. The Hospital Elder Life Program (HELP) is a widely established intervention that emphasizes reorientation, early mobilization, hydration, nutrition, sleep promotion, and the provision of sensory aids as key modifiable delirium risk factors among elderly patients. [17]. A large body of work reliably demonstrates the social and financial advantages of the HELP program in medically hospitalized patients [18 –20] but the program does not specifically address the pre- or post-operative needs of people who are undergoing anesthesia and surgery. Evidence for multi-modal prevention programs in elective surgery is sparse. Of the few studies documenting delirium prevention programs, most focus on physical- or cognitive- interventions in isolation rather than a complete multi-modal package of care addressing physical, cognitive, and mental health that continues post discharge [21 –23].

Dementia prevention literature supports the advantages of behavioral interventions, highlighting that early interventions are considered more effective than current pharmacological therapies (for a review see Lancet Commission: Dementia Prevention, Intervention and Care [24]). Alongside POD, modifiable dementia risk factors include physical inactivity, diabetes, social isolation, and depression [3 , 25] and are an increasing focus of community-based interventions aimed at preventing cognitive decline [26 –32]. We know that many patients experience an accelerated rate of long-term cognitive decline in the postoperative period, even after an initial return to preoperative baseline abilities [4, 5]. Thus, applying multimodal community-based interventions to older adults in the perioperative period is an important avenue of research that to-date has received little attention.

The perioperative period provides a unique opportunity to educate older adults alongside their families or care person, about how to mitigate the risks of POD and possible long-term cognitive decline [32]. Moreover, the perioperative period is an opportune time to involve older adults in lifestyle modification strategies as they are engaged in a healthcare service and may be motivated to make positive lifestyle changes [32]. Here, we describe the design and implementation of a multi-modal, multi-disciplinary package of care, tailored to older adults undergoing anesthesia and surgery that is ultimately aimed at reducing the incidence of delirium and subsequent cognitive decline.

METHODS AND MATERIALS

Study design

The PeRiOperaTive Enhancement of Cognitive Trajectory (PROTECT) trial is a randomized-con-trolled, multicenter, single-blind, pragmatic clinical trial. The study will assess the efficacy of a multicomponent, multidisciplinary individualized package of care in older adults undergoing elective surgical procedures. We will compare this package of care, which targets preventable causes of POD and modifiable risk factors of long-term cognitive decline, with routine management. We have prepared this protocol to align with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist [33].

The aims of the PROTECT trial are to identify whether patients receiving a specialized package of care:

Demonstrate a lower incidence of POD and other perioperative neurocognitive disorders (PND) up to three months postoperatively, relative to patients receiving current standard of care

Demonstrate a lower incidence of new mild or major postoperative neurocognitive disorder (NCD) (mild cognitive impairment (MCI) or dementia, respectively) at 12 months postoperatively, relative to patients receiving current standard of care

Setting

Study initiation will take place at St Vincent’s Hospital Melbourne (SVHM), Australia. SVHM is a large tertiary hospital that performs approximately 15,000 elective surgical procedures per year. To ensure recruitment targets are met, in addition to ensuring generalizability of the study, multiple study sites will subsequently be involved in the project, including the co-located St Vincent’s Private Hospital Melbourne. An up-to-date list of study sites may be obtained from http://cognition.org.au/wp/.

Recruitment

We will screen the eligibility of all elective surgical patients scheduled at the relevant study site. Research assistants will perform an initial screen of patient eligibility by reviewing the patients’ medical history (i.e., to establish age, geographical location, English proficiency). We will contact patients who pass this initial screen via telephone to further determine eligibility and interest in participation. Patients who express interest will be sent a study brochure with study details and provided sufficient time to make an informed and voluntary decision regarding their participation. If informed consent is obtained, participants will be recruited, enrolled, and randomly allocated to one of the two study arms.

Participants

Participants are allocated to one of two parallel study arms: 1) specialized individual care intervention; or 2) standard of care (control). We will review participant feedback and compliance six months after study commencement and make protocol adjustments if required. The primary outcome of the study is the incidence of PND, encompassing the presence of POD, or NCD at three-months postoperatively. Secondary outcomes include mild or major NCD and functional disability measured with the WHODAS 2.0 at a 12-month postoperative follow-up assessment.

We obtained ethical approval for the PROTECT trial via the St Vincent’s Hospital Melbourne (SVHM) Human Research Ethics Committee (HREC 205/19). Research ethics or governance approval for each additional study site will be obtained from the relevant Institutional Review Board. The PROTECT trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619001778178p). All participants will provide written informed consent in accordance with the Declaration of Helsinki. We designed our consent forms to ensure participants would remain blinded to their group allocation and the specific details of the alternative care package. The National Health and Medical Research Council (NHMRC) of Australia provided funding for this trial (APP1171174).

Inclusion criteria

Patients scheduled for elective cardiac or non-cardiac surgery of greater than 60 min, who are aged 65 years or older, with an expected hospital admission of at a least one night, and who reside within 60 min of the recruiting hospital (to enable follow-up assessment). In addition, we will only recruit patients who are scheduled for surgery approximately 14 days after enrolment thereby allowing sufficient time to implement the study protocol. We opted for a minimum 14-day lead in time to provide participants with sufficient time to engage in the intervention materials, and to standardize, as far as possible, the pre-education period.

Exclusion criteria

Patients who have pre-existing neurological injury (e.g., traumatic brain injury), undergoing intracranial neurosurgical procedures or cerebrovascular surgery (e.g., carotid endarterectomy), advanced dementia of any etiology defined by a lack of capacity to provide informed consent (e.g., Alzheimer’s disease, Parkinson’s disease), contraindication to neuropsychological testing (e.g., limited English proficiency, severe hand tremor, blindness or deafness), significant immobility precluding study interventions, or medical illness that may reasonably lead to significant complications and subsequent loss to follow-up.

Specialized care intervention arm

We will implement the following interventions at each stage of the perioperative period:

Perioperative education

Participants randomized to the intervention arm will receive a specialized package of care throughout the preoperative period. This package will commence approximately 14 days prior to surgery and will include verbal and written psychoeducation and delirium risk reduction strategies. Our verbal and written materials include a pre-operative health diary encouraging compliance with nutrition, hydration, exercise, and stress management recommendations, alongside preoperative anxiety management techniques with audio-recorded relaxation practices. Health diaries will be complemented with a health guide that includes accessible information and resources we have specifically tailored to older adults. Prompts to promote cardiovascular and brain health will be sent via text message (SMS), four times per week (i.e., eight SMS’ preoperatively).

Intraoperative pathway

All intervention arm participants will be seen at the preoperative anesthesia clinic for optimization prior to surgery. At this appointment, we will conduct a pharmacological review of medications with an emphasis on minimizing polypharmacy and identifying high risk medications that may be safely reduced prior to surgery (e.g., see American Geriatrics Society Beers Criteria) [34]. Perioperative anesthesia care will include avoidance of benzodiazepines and centrally acting anti-cholinergic drugs, targeting a lighter depth of anesthesia with guidance from processed EEG monitoring, and minimizing opioid analgesic use with a multimodal analgesia protocol [32, 35].

Postoperative inpatient care

We will refer all participants in the intervention arm to the physical therapy department who will encourage early mobility as clinically appropriate, assisted where possible by research staff. Participants will be added to the hospital’s acute pain service to ensure appropriate pain management and ongoing analgesia review to ensure, where possible, limited use of opioids, especially slow release opioids [36]. Daily visits from research staff will ensure participants have access to sensory aids as required, are oriented to time and place, and have access to cognitive stimulation. If necessary, participants will be provided with talking clocks to alert them to the day and time at more frequent intervals. Research staff will also encourage visiting family members to assist the patient by reinforcing the use of sensory aids and cognitive orientation.

Post discharge care

At discharge, we will interview participants, providing an opportunity to debrief about their perioperative experience. In this interview, we will apply motivational interviewing techniques to encourage positive behavior change upon discharge, alongside psychoeducation pertaining to brain health. We will invite participants and a member of their family (if possible) to attend fortnightly group education sessions that target different modifiable risk factors of cognitive decline [24]. Six fortnightly group sessions will commence one to three months post-operatively (allowing sufficient physical recovery from surgery) and address: cognition, nutrition, physical activity, sleep, social engagement, and the management of stress, anxiety, and depression. Participants are encouraged to apply the session content within the context of their own health needs. In doing so, the intervention components are individualized to each participant. Group sessions were designed by a neuropsychologist (KA) who is a key leader of the research team, with the support of a senior clinical neuropsychologist (KP) who has extensive expertise in developing and facilitating group psychoeducation for older adults [37 –39]. Group sessions reinforce the written education materials provided pre-operatively and participants will track their engagement with health behaviors in a post-operative health diary completed at the time of engagement with the group sessions. Four times weekly text messages in the first four weeks after discharge will provide participants with interim support (i.e., 16 SMS’ post-discharge), which will be reinforced with a monthly phone call (up to 12 months post-operatively) from a member of the research team. Phone calls will address facilitators and barriers to engaging in the recommended brain health behaviors. All intervention components are displayed graphically in Fig. 1.

Fig. 1

Schematic of the Specialized Package of Care Provided to Participants in the Intervention Arm.

Standard of care control arm

Participants randomized to the control arm will transition through the perioperative period following the usual standard of care, which currently does not include psychoeducation specific to delirium prevention or detailed recommendations for improving or maintaining brain health. Control participants will undergo a routine clinical preoperative evaluation. Perioperative anesthesia and analgesic management will be as decided by the anesthetist and other treating physicians. Input from physiotherapy and other allied health services will be determined by nursing and medical staff. Post-discharge follow-up will occur as indicated by the surgical unit. By using current standard of care (SOC) as a comparator, we aim to provide evidence that supports the implementation of our intervention strategies; even as clinical care standards change. We will document key elements of SOC to identify departures from—or advances in—SOC and account for any site-to-site variations in practice. Key elements of care that we will record include: pre-operative anesthetic review, analgesic or pharmacy review, referral and daily input from physiotherapists and referral to allied health. In addition, we will implement daily charting to monitor mobilization, ambulatory independence, independence with personal activities of daily living and oral intake. All aspects of care monitoring and charting are consistent across both study arms.

All participants

Participants in both study arms will receive a research-grade triaxle accelerometer (GENEActivtrademark device; ActivInsights Ltd., Kimbolton, Cambridgeshire, United Kingdom) to wear two weeks prior to their expected surgical date, throughout the perioperative period and a further four weeks following their discharge. This will enable us to identify levels of motor activity, in addition to sleep-wake cycles.

Cognitive and delirium assessments will be undertaken at baseline and at the subsequent pre-determined time-points detailed below and shown in Fig. 2.

Fig. 2

Flow chart of the intervention in the context of initial and follow-up assessments.

2.6 Study outcomes

2.6.1 Initial review

We will conduct an initial review six months post study commencement to evaluate participant recruitment and compliance. In this review, we will consider the length of the lead-in education period, compliance with delirium prevention strategies and engagement with education recommendations and group education sessions (assessed by completion of pre- and post-operative diaries and attendance at group education sessions). Qualitative feedback from participants in the intervention group will also be sought to inform any necessary adjustments.

Primary outcome

The primary outcome is the incidence of any perioperative neurocognitive disorder up to three months post-operatively [1]. Perioperative neurocognitive disorders of interest include postoperative delirium (POD), and the presence of postoperative mild or major NCD. Postoperative NCD has been defined as the onset of a neurocognitive disorder (either mild or major) within 12 months of the surgical period [1]. We will assess delirium using the method of Inouye et al. [5], using the 3D-CAM [40] at baseline, daily during hospitalization and at three-months postoperatively, alongside obtaining information from the patient, family and staff, and thorough chart review. Throughout hospitalization, the 3D-CAM will be performed in the morning, between 7:00am to 11:00am local time. Similar to our previous studies of cognitive decline associated with anesthesia and surgery [41] we will use a cognitive test battery commonly used in the perioperative setting to establish the presence of PND/NCD (Table 1). We will define mild pNCD as a z-score on any cognitive test that is one, but no more than two, standard deviations below a previously established normative group [42, 43]. Major pNCD is defined by a z-score of two or more standard deviations below our normative mean. In accordance with the Diagnostic and Statistical Manual of Mental Disorder (5th ed.) [1, 43], mild and major NCD require a subjective decline in cognition, which we will determine by asking a structured question of the participant and, if available, an informant such as a spouse, partner, or care person. We will determine the presence of functional decline using the self- and informant- rated questionnaires described below in materials and shown in Table 1.

Table 1

Primary and secondary outcome measures and associated domain of interest

Neuropsychological Test	Domain Assessed
3D-CAM	Delirium
Wechsler Test of Adult Reading (WTAR)	Pre-morbid IQ
MoCA	General cognition
CERAD WLT	Memory
Trail Making Test (A + B)	Attention, processing speed, executive function
Digit Symbol Substitution Test	Processing speed, attention
COWAT Phonemic Fluency	Executive function
Semantic Fluency	Semantic memory
Clock Drawing Test	Attention, visuospatial abilities, executive function
Grooved Pegboard	Motor dexterity, psychomotor speed
Self-Report Measure	Domain Assessed
WHODAS 2.0	Global disability
SF-12¹	Health related quality of life
Neuro-QoL Cognitive Function²	Cognition related quality of life
ADL-PI³	Instrumental activities of daily living
AES-SF⁴	Apathy
GDS⁵	Depression
FRAIL Scale	Frailty
Biological Samples	Analyses
Saliva	APOE4
Accelerometry	Domain Assessed
GENEActiv Ambulatory Monitoring	Physical Activity^*

3D-CAM, 3-Dimensional Confusion Assessment Method; MoCA, Montreal Cognitive Assessment; CERAD WLT, CERAD World Learning Test; COWAT Phonemic Fluency, Controlled Oral Word Association Test; WHODAS 2.0, World Health Organization Disability Health Schedule. ¹Short Form Health Survey. ²Quality of Life in Neurological Disorders: Cognitive Function. ³Assessment of Instrumental Daily Activities. ⁴Apathy Evaluation Scale –Short Form. ⁵ Geriatric Depression Scale. ^*Minutes spent in sedentary, light, moderate and vigorous physical activity.

Secondary outcomes

We will evaluate the following secondary outcomes using a combination of information obtained through patient medical records, cognitive test performance, and self- and informant-ratings at 12-months postoperatively:

Mild or major NCD at 12 months (MCI/de-mentia);

Incidence of 30-day readmission to hospital or specified medical or surgical complications;

Days alive and out of hospital at day 30 [44];

World Health Organization Disability Assessment Schedule (WHODAS 2.0) disability at 12 months [45];

Mortality at 12 months;

Quality of Life at 12 months;

Additional measures

In addition to our primary and secondary outcomes, we will obtain saliva samples from all participants allowing genotyping for APOE4, a known genetic risk factor of cognitive decline [46]. The inclusion of APOE4 status is intended to provide greater characterization of our sample, facilitating comparison between our surgical population and people with cognitive decline in the community. Accelerometer data will allow us to calculate metrics of physical activity aggregated into minutes of sedentary, light, moderate, and vigorous physical activity [47]. Between group comparisons will be used to identify whether the intervention has been effective in increasing activity pre- and post-operatively, and any differences in sleep-wake cycles. Accelerometer data may also inform sub-study analyses to examine the relationship between delirium and physical activity and sleep quality both pre- and post-operatively. These additional measures and the timeline of their collection are shown in Fig. 3.

Fig. 3

Timeline of the PROTECT trial.

Materials

Adherence measures

Adherence to protocol will be evaluated throughout the perioperative period by trained research assistants who will review the patients’ medical chart (for key elements including visits from pharmacy, physiotherapy, and nutritional intake) and daily discussions with the participant throughout their admission (tolerance to meals and daily mobility).

In the 14 days pre-operatively, and the first 30 days post-discharge participants record their physical activity, dietary intake, sleep duration, cognitive engagement, and socialization with simple checkbox responses in pre- and post-operative health diaries. Pre-operative health diaries are collected by the research coordinator at admission. Participants return their post-operative health diaries via a postage paid mailing envelope provided to them at discharge by the research coordinator or by the research coordinator at the final group education session.

Delirium

Three Minute-Diagnostic Confusion Assessment Method (3D-CAM) [40]. Blinded research assistants, formally trained in administration and overseen by a registered Neuropsychologist, will perform the 3D-CAM daily during the first three postoperative days. In the case that a patient is admitted to the ICU, we will use the CAM-ICU. For consistency, all delirium assessments will take place in the morning, between 7:00am and 11:00am local time. If delirium is present at any time on days one to three, we will continue to administer the 3D-CAM until the sooner of: 1) five days postoperatively or 2) discharge. The 3D-CAM is an extensively used assessment of delirium that takes approximately 3 min to administer. The tool consists of ten questions, directed to the patient, pertaining to orientation, mental control, and self-reported symptoms. A further ten questions are completed by the assessor based on the patient’s presentation throughout the interview. Thorough chart reviews will complement the 3D-CAM to capture episodes of delirium that may not be present at the time of assessment, alongside discussions with relevant nursing staff regarding the previous 24 h. The Richmond Agitation-Sedation Scale (RASS) will monitor patients’ degree of arousal and will be recorded at each 3D-CAM assessment [48].

Self-report measures

World Health Organization Disability Assessment Schedule [45]. We will use the World Health Organization Disability Assessment Schedule (WHODAS 2.0) to evaluate disability at baseline and 12-months. The WHODAS 2.0 is a 36-item self-report measure of health and disability. The tool evaluates the following six domains of function: cognition, mobility, self-care, social interaction, activities of daily living, and community participation. Both self- and informant-reports are available, we will use both versions in this trial as secondary outcomes of disability.

SF-12 [49]. The SF-12 Short Form Health Survey is adapted from the original SF-36 to evaluate eight domains of physical and mental health including: General Health, Physical Functioning, Physical Activities, Pain, Vitality, Social Functioning, Emotional Functioning, and Mental Health. In older adults the SF-12 converges with other measures of chronic illness and physical and mental health [50].

Geriatric Depression Scale (GDS) Short form [51]. The GDS short form is a 15-item self-report measure of depression that avoids somatic symptoms, making it appropriate for use with older adults. Respondents rate each item on a dichotomous “Yes” or “No” scale to indicate the presence or absence of depressive symptoms within the preceding 30 days. Summated items result in a possible total score range of 0–15, with scores of 6 or more indicative of mild depressive symptoms and scores greater than 11 suggestive of severe depression symptomology.

Apathy Evaluation Scale –Short Form (AES-SF) [52]. The AES-SF is adapted from the original 18-item Apathy Evaluation Scale [53] and includes 10-items deemed most appropriate for older adults [52]. Higher scores indicate a greater number of apathy symptoms.

Quality of Life in Neurological Disorders (NeuroQoL) –Cognitive Function [54]. The NeuroQoL Cognitive Function scale includes seven items, which respondent’s rate on a 5-point Likert scale. Items address the respondent’s perceived cognitive abilities or the application of these abilities to daily activities. Example items include “In the past 7 days, I had to read something several times to understand it” and “How much difficulty do you currently have managing your time to do most of your daily activities”. Summated items produce an overall scale score that is converted to a standardized T-score. Higher scores indicate better self-reported health.

Sample size

Based on an estimated POD incidence of 30%in perioperative populations [10 , 55–58], and accounting for a possible reduction in the occurrence of delirium, given the nature of our trial [17], this study is powered to detect a baseline change of 33%, yielding an incidence of 20%in the intervention group, while maintaining alpha of 0.05 and power of 0.8. Allowing an attrition rate of 15%, we will recruit 692 participants (346 per group) across study sites.

Allocation and blinding

After completing an initial baseline assessment, participants will be randomly allocated into the intervention care pathway or SOC by a computer-generated, random sequence block allocation. Using a block size of four, we will stratify randomization by site. Group allocation will be obtained from an online secure server, accessible only to key research personnel who are not involved in data collection. Participants, surgeons, resident medical staff providing care, and the research assistants collecting outcome data will be blinded to study arm. In-hospital and community intervention components will be undertaken by un-blinded research staff under the guidance of the research coordinator. Unblinded research staff members will not perform assessments that inform the primary and secondary outcomes of the study. Due to the prescribed care recommendations outlined in the study protocol, it will not be possible to blind anesthesiologists, pharmacists, key nursing staff, and allied health professionals to participants in the intervention group, however these staff will not be involved in data collection. As participants in the control arm receive current SOC, clinical staff within the hospital will not be made specifically aware of their involvement in the trial.

DISCUSSION

Delirium is a common, yet frequently preventable, perioperative complication that we know precipitates long-term cognitive decline, dementia, and functional disability [2–5 , 59]. Recent literature reflects the importance of preventing POD, with an increasing number of pharmacological, perioperative, and behavioral interventions targeting delirium prevention but few include a complete multi-modal package of care in the perioperative period [15 , 60–66]. Outside the perioperative setting, behavioral strategies show promise and are currently the most effective method of prevention and thus the focus of this trial [2 , 14–16]. The perioperative period provides a unique opportunity to engage older adults in lifestyle modification strategies as they transition through the healthcare system. Accordingly, by engaging surgical patients, our trial will extend existing community-based behavioral interventions by providing psychoeducation and perioperative maximization approaches, alongside postoperative lifestyle modification strategies to reduce cardiovascular and dementia risk factors in the community.

We have designed this study to enable wide scale implementation across multiple study sites. If successful, a major strength of the study will be the ability to generalize and implement our behavioral interventions across many health care settings. Currently, although rarely implemented, multi-domain interventions to simultaneously address multiple delirium risk factors are the gold-standard of perioperative care [2, 14]. Reflecting this, our study includes the modification of specific delirium risk factors using a multicomponent, multidisciplinary approach with input from geriatricians, anesthesiologists, neuropsychologists, clinical neuroscientists, physiotherapists, pharmacists, and nursing staff. A further strength of our study is the inclusion of a comprehensive neuropsychological test battery to measure cognitive function, rather than relying on the cognitive screening tools that are common in the perioperative literature [22, 67]. Aligning with trial recommendations for older adults [68], we will administer our cognitive battery at three time points, up to 12 months post-operatively, allowing us to observe differences in the long-term cognitive trajectories of participants in each study arm.

A potential limitation of our trial is the degree of fidelity to protocol within and across study sites. To improve fidelity, detailed study manuals are available outlining how each component of the intervention is implemented. Group education and a subset of one-on-one education sessions will be recorded to monitor fidelity of education across participants and as a training tool for new research staff. An initial six-month review will allow un-blinded research staff to determine compliance to interventions across both clinical staff and research participants. Any necessary adjustments will be made at this point to maximize the protocol’s suitability across study sites. Additionally, we will monitor the key elements of each pathway, alongside participant engagement, to determine any changes in behavior that may bias our results during enrolment. Finally, we have opted to assess delirium on the first three post-operative days, and to cease delirium assessment at this time if no positive episode is documented. Although, this temporal window of assessment may result in missed cases, it is well informed by our previous work (pending submission) in which we assessed for delirium twice daily for five days and found that new episodes of delirium after day 3 occurred in only 1%of patients.

On balance, although resource intensive, we be-lieve that if effective in reducing the incidence of POD and subsequent adverse cognitive and functional outcomes, our intervention strategies are economically advantageous and internationally generalizable [3]. As each component of our protocol builds upon an existing element of care, our intervention may easily become the future ‘standard of care’ without significantly expanding the need for hospital resources.

Footnotes

ACKNOWLEDGMENTS

This study is generously supported by the National Health and Medical Research Council of Australia, Boosting Dementia Grant; #1171174.

Authors’ disclosures available online ().

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