Use of dexmedetomidine during light versus deep anaesthesia on postoperative delirium among elderly patients undergoing major non-cardiac surgery: protocol for a multicentre randomised factorial trial

Abstract

Introduction

Elderly patients are at a high risk of postoperative delirium (POD), leading to increased postoperative morbidity and mortality. The use of dexmedetomidine and depth of anaesthesia may influence POD. This study aims to determine the effects of dexmedetomidine infusion versus normal saline placebo during light versus deep anaesthesia on POD among elderly patients undergoing major non-cardiac surgery.

Methods and analysis

This prospective, multicentre, randomised, controlled, factorial trial will be conducted at three tertiary hospitals in Jiangsu, China. We will recruit a total of 420 patients who are at least 60 years old and undergoing major non-cardiac surgery (thoracic, abdominal, urology, orthopaedic and spine surgery) under general anaesthesia. Patients will be randomised (1:1:1:1) to receive one of four anaesthesia regimens: (1) dexmedetomidine and light anaesthesia, (2) dexmedetomidine and deep anaesthesia, (3) placebo and light anaesthesia or (4) placebo and deep anaesthesia. Dexmedetomidine will be infused at 0.5 µg/kg/h throughout surgery, and intraoperative bispectral index target will be 55 for light anaesthesia and 40 for deep anaesthesia. The primary outcome is the occurrence of POD during the first 7 days postoperatively or until hospital discharge, assessed using the 3-min Confusion Assessment Method two times per day. The secondary outcomes include days with POD, type of POD, pain scores at rest and on movement at 24 and 48 hours postoperatively, patient-controlled intravenous fentanyl consumption during 0–24 and 24–48 hours postoperatively, hypotension, bradycardia, postoperative nausea and vomiting, non-delirium complications, length of postoperative hospital stay, 30-day cognitive function and 30-day mortality. Data will be analysed on a modified intention-to-treat basis.

Ethics and dissemination

This trial was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University and each participating centre. The trial results will be published in a peer-reviewed journal.

Trial registration

Chinese Clinical Trial Registry (ChiCTR2300073271)

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a multicentre, randomised, controlled trial with factorial design.

• This trial aims to assess the effects of two anaesthetic interventions (use of dexmedetomidine and depth of anaesthesia) on postoperative delirium in elderly patients undergoing major non-cardiac surgery.

• The study design and sample size calculation are based on data from the pilot study.

• Patients with American Society of Anaesthesiologists physical status IV and preoperative cognitive decline are not included.

• This trial is not powered for detecting the interaction between the two treatment options.

Introduction

Postoperative delirium (POD) is an acute brain dysfunction after surgery, characterised by acute deterioration in attention, cognition and consciousness.^{1 2} For elderly patients undergoing major surgery, the reported incidence of POD ranged from 13% to 50%,³ which was associated with adverse clinical outcomes including increased postoperative complications, prolonged length of hospitalisation, poor quality of life and mortality.4,6

Intraoperative anaesthetic medications and depth of anaesthesia may influence the prevalence of POD.^{2 7} Dexmedetomidine is a highly selective α2-adrenergic receptor agonist used for sedation and analgesia.⁸ Recent studies suggested that dexmedetomidine may exert a protective role against POD9,12; however, the current evidence is still insufficient.^{13 14} Regarding the depth of anaesthesia, this lack of certainty also exists. Our previous meta-analysis found that deep anaesthesia (bispectral index (BIS) values ranging 30–45) versus light anaesthesia (BIS values of 45–60) was associated with an increased risk of POD.¹⁵ However, another meta-analysis did not support such a correlation.¹⁶ There is no study assessing the effects of these two interventions (use of dexmedetomidine and depth of anaesthesia) on POD among elderly patients undergoing major surgery.

With this context in mind, we intend to conduct a multicentre randomised factorial trial in elderly patients undergoing major non-cardiac surgery. We hypothesise that (1) the administration of dexmedetomidine versus normal saline placebo would reduce the rate of POD and (2) compared with deep anaesthesia, light anaesthesia would lead to a decreased risk of POD. The feasibility of this trial has been demonstrated in our pilot study.¹⁷

Methods

Study design

This multicentre, randomised, controlled factorial trial is designed based on the recently published pilot study.¹⁷ This trial will be conducted at three tertiary hospitals in China (The First Affiliated Hospital of Soochow University, The First People’s Hospital of Taicang and Zhangjiagang First People’s Hospital). This trial protocol is reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline (online supplemental file 1).¹⁸

Study status

We plan to recruit 420 elderly patients who are scheduled to have a major non-cardiac surgery between August 2023 and July 2025. The first patient was enrolled on 1 August 2023, and we have recruited 180 patients by 30 August 2024. Patients will receive one of four combinations of dexmedetomidine and anaesthesia depth as follows: (1) dexmedetomidine infusion during light anaesthesia, (2) dexmedetomidine infusion during deep anaesthesia, (3) normal saline (placebo) infusion during light anaesthesia or (4) placebo infusion during deep anaesthesia. The flow chart of this trial is illustrated in figure 1. Patient enrolment, trial interventions and outcome measurements following the SPIRIT guideline are presented in table 1.

Figure 1. Trial flow diagram. Supporting information. DEX, dexmedetomidine.

Table 1. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) schedule of patient enrolment, trial interventions and outcome measurements.

	Study period
Timepoint	Enrolment	Allocation	Post-allocation					Closeout
	Preoperative visit	Before surgery	During surgery	Day 1	Day 2	Day 7	Hospital discharge	Day 30
Patient enrolment
Inclusion criteria	×
Exclusion criteria	×
Written informed consent	×
Baseline characteristics	×
Randomisation		×
Allocation		×
Trial interventions
DEX and light anaesthesia			×
DEX and deep anaesthesia			×
Placebo and light anaesthesia			×
Placebo and deep anaesthesia			×
Outcome measurements
Occurrence of POD				×	×	×
Days with POD				×	×	×
Type of POD				×	×	×
Pain at rest/on movement				×	×
Patient-controlled fentanyl				×	×
Hypotension			×
Bradycardia			×
Nausea and vomiting				×	×
Non-delirium complications*				×	×	×	×
Postoperative hospital stay							×
30-day cognitive function								×
30-day mortality								×

According to SPIRIT statement of defining standard protocol items for clinical trials.

^*Including hypoxaemia, pulmonary oedema, pneumonia, respiratory failure, myocardial infarction, new-onset atrial fibrillation, heart failure, gastrointestinal haemorrhage, stroke, renal failure, haemorrhagic shock, sepsis, septic shock, anastomotic leakage, and reoperation.

DEX, dexmedetomidinePODpostoperative delirium

Inclusion criteria

1. Age ≥60 years old.

2. American Society of Anaesthesiologists (ASA) physical statuses I−III.

3. Undergoing major non-cardiac surgery (thoracic, abdominal, urology, orthopaedic and spine) under general anaesthesia and receiving patient-controlled analgesia (PCA).

4. An estimated anaesthesia duration ≥1.5 hours.

5. An estimated length of postoperative hospitalisation ≥2 days.

Exclusion criteria

1. Emergency surgery.

2. Bradycardia (heart rate (HR) < 50 beats per minute), sick sinus syndrome, left ventricular ejection fraction <30%, second-degree or higher atrioventricular block without a pacemaker.

3. History of Alzheimer’s or Parkinson’s disease, Mini-Mental State Examination (MMSE) score <23¹⁹.

4. Alcohol abuse (defined by the drinker’s alcohol abuse score >8)²⁰.

5. BIS monitoring cannot be applied.

6. Declined to participate.

Randomisation and blinding

An independent researcher will perform the online randomisation with a 1:1:1:1 ratio, a block size of 8 and stratification by trial sites. According to the random number sequence, patients will be assigned to one of four study groups as aforementioned. The details of allocation will be concealed in opaque-sealed envelopes. Anaesthesiologists will be blinded to the use of dexmedetomidine and placebo, but not to the anaesthesia depth allocation. All patients, perioperative care team, postoperative outcome collectors and the statistician will remain masked to group allocation.

Study interventions

In the dexmedetomidine groups, patients will receive intravenous dexmedetomidine infusion (0.5 µg/kg/h), starting from skin incision until wound closure. We select this dosing regimen according to our pilot trial¹⁷ and recent studies in which intraoperative dexmedetomidine with or without postoperative use reduced the rate of POD.^{21 22}

Based on previous meta-analyses,^{15 16} studies defined BIS values ranging 45 to 60 as light anaesthesia and 30 to 45 as deep anaesthesia. In the present study, the BIS target will be set at 55 (with an acceptable range of 50–60) in the light anaesthesia groups and 40 (with an acceptable range of 35–45) in the deep anaesthesia groups, which is in line with the definitions in our pilot trial.¹⁷ Propofol infusion rate will be adjusted immediately if the BIS values reach the lower or upper limit of the ranges.

To ensure patient safety, anaesthesia providers will be able to pause the study drug infusion and not to pursue the BIS targets if there is a severe haemodynamic event (such as severe hypotension and bradycardia).

Anaesthesia

All patients will be monitored with electrocardiography, arterial blood pressure, pulse oximetry, temperature and BIS. Intravenous propofol (1.0–1.5 mg/kg), sufentanil (0.3 µg/kg) and cisatracurium (0.2 mg/kg) will be used to induce anaesthesia. After tracheal intubation, patients will receive mechanical ventilation. Anaesthesia will be maintained using propofol infusion (50–150 µg/kg/min). Volatiles such as sevoflurane, desflurane or nitrous oxide will not be used. Intermittent sufentanil (0.1 µg/kg) will be administered to provide sufficient analgesia. Intravenous dexamethasone (5 mg) and ondansetron (4 mg) will be given for prophylaxis of postoperative nausea and vomiting. Fluid therapy includes buffered Ringer’s solutions, colloid solutions, and erythrocytes and/or fresh frozen plasma when clinically indicated. Postoperative pain will be treated using PCA with fentanyl. Other perioperative management will be done at the discretion of the attending physicians, adhering to the institutional standard of care for elderly patients undergoing major surgery.

Baseline and perioperative data

Demographic and baseline characteristics will be recorded, including age, sex, weight, height, level of education, ASA physical status, 5-factor modified frailty index scores, Charlson comorbidity index scores, MMSE scores, types of surgery and baseline mean arterial pressure (MAP) and HR values. Baseline MAP will be calculated as the mean value of multiple blood pressure measurements obtained preoperatively. Perioperative data include intraoperative BIS values; dose of propofol, sufentanil and dexmedetomidine; intraoperative blood loss, infused fluids, transfusions and urine output; surgical time, time to extubation and length of post-anaesthesia care unit stay; and intensive care unit (ICU) admission. The researchers who assess cognitive function will receive complete training from a senior neuropsychologist.

Primary outcome

The primary outcome is the incidence of POD up to postoperative day 7 (including weekends) or until hospital discharge, whichever occurs earlier. POD assessment will be performed at 08:00–10:00 and 19:00–21:00 using the 3-min Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit (CAM-ICU) for intubated patients.^{23 24}

Secondary outcomes

The secondary outcomes that support the primary outcome include days with POD, type of POD and 30-day cognitive function. Pain-related outcomes include pain scores at rest and on movement at 24 and 48 hours postoperatively and patient-controlled intravenous fentanyl consumption during 0–24 and 24–48 hours postoperatively. Other outcomes include hypotension, bradycardia, postoperative nausea and vomiting, non-delirium complications, length of postoperative hospital stay and 30-day mortality.

Specifically, POD is classified into three types: hypoactive, hyperactive and mixed.²⁵ Postoperative pain will be assessed using a numerical rating scale which ranges from 0 (indicating no pain) to 10 (indicating the most severe pain imaginable). Hypotension is defined as a decrease in MAP >30% of baseline. Bradycardia is defined as HR <45 beats per minute. The details of non-delirium complications are available in online supplemental file 2. 30-day cognitive function will be assessed using the 10-item Telephone Interview of Cognitive Status test.^{26 27}

Data collection and monitoring

All data will be collected in the case report forms and entered into an electronic database. We have an independent Data and Safety Monitoring Board (DSMB) which consists of an attending anaesthesiologist, a senior neuropsychologist, a pharmacist and a statistician. The DSMB will perform an ongoing review of the study implementation, monitor the data quality and completeness, and ensure patient safety.

Sample size calculation

Our pilot study reported the POD incidences (7.7% with dexmedetomidine, 17.9% with placebo, 7.5% with light anaesthesia and 18.4% with deep anaesthesia) but was underpowered to assess efficacy.¹⁷ These POD incidences are in line with the literature.^{15 22} Additionally, our pilot data suggested no significant interaction between dexmedetomidine and anaesthesia depth on POD (p = 0.477). Therefore, we design this multicentre trial to determine the main effect of each treatment on POD. With a two-sided α level of 0.025 and a power of 80%, this trial should include 406 patients to detect differences in POD for dexmedetomidine versus placebo and 360 patients for light versus deep anaesthesia. We selected the sample size of 406 and considered a dropout rate of approximately 4% (the dropout rate was 2.5% in our pilot study); therefore, we decided to recruit a total of 420 patients with 105 in each of the four study groups. The sample size was calculated using the Power Analysis & Sample Size software (V.11, NCSS, Kaysville, UT, USA).

Statistical analysis

Continuous data will be assessed for normality using the Shapiro–Wilk test and reported as means (SD) or medians (interquartile ranges) depending on distribution. Categorical data will be reported as numbers (percentages). The primary and secondary outcomes will be analysed using the independent t-test, Mann–Whitney rank-sum test, Kruskal–Wallis test, χ² test or Fisher’s exact test, as appropriate, and the risk difference or mean/median difference with their 95% CI will be reported. Time to delirium data will be depicted using the Kaplan-Meier curves and analysed using the HR with its 95% CI in the cox regression. The incidences of POD across the four groups will be analysed using logistic regression and will be reported as the ORs with the 95% CI. Given the factorial design, a logistic regression model will be employed with POD as the outcome variable to assess whether an interaction exists between use of dexmedetomidine and depth of anaesthesia.

All analyses will be performed in the modified intention-to-treat population, including all randomised patients who receive surgery and have the primary outcome data available. With an overall α level of 0.05, the significance criterion for the primary outcome is 0.025 (ie, 0.05/2, Bonferroni correction) after adjusting for two treatments. For the exploratory secondary outcomes, no multiple testing adjustments will be performed. No interim analysis will be planned. As missing data were uncommon in our pilot study, we will not perform imputation for missing data in this trial. Statistical analyses will be done using the SPSS software (V.25.0, IBM SPSS Inc., Chicago, IL, USA).

Patient and public involvement

Patients and/or the public will not be involved in the design, conduct, report or dissemination plans of this research.

Discussion

This multicentre, randomised, controlled, factorial trial aims to determine the effects of two anaesthetic interventions (use of dexmedetomidine and depth of anaesthesia) on POD in elderly patients undergoing major non-cardiac surgery. We mainly focus on the main effect of each treatment option. In addition, we will explore the interaction between these two treatments using the factorial design.

According to the recommendation of design and statistical considerations for pilot studies,^{28 29} our recent work has provided a basis for this ongoing multicentre trial.¹⁷ In our pilot study, all predefined feasibility endpoints were successfully achieved, specifically a high consent rate, a low dropout rate, timely recruitment, blinding implementation, planned infusion of study medications, a high proportion of patients reaching the BIS targets and completion of scheduled POD measurements. We also estimated the rates of POD in the control arms (ie, placebo and deep anaesthesia groups) and the treatment effects of the interventional arms (ie, dexmedetomidine and light anaesthesia groups). Based on the existing evidence, the rate of POD was up to 25% in patients receiving dexmedetomidine and up to 43% in patients receiving normal saline placebo, yielding a treatment effect of risk ratio = 0.54 (95% CI 0.46 to 0.64)²² ; the incidence of POD was up to 18% after light anaesthesia and 28% after deep anaesthesia, with a risk ratio = 0.64 (95% CI 0.52 to 0.78).¹⁵ The incidences of POD observed in our pilot study are within these ranges. Based on these, we justified the sample size of this multicentre trial to answer the research question.

Dexmedetomidine has been used for optimising anaesthesia and postoperative pain management. Studies showed that dexmedetomidine infusion was associated with a reduced POD incidence in elderly patients after hip fracture surgery³⁰ and in cardiac and non-cardiac surgical patients.¹² However, a multicentre trial with 390 elderly patients undergoing major non-cardiac surgery found that dexmedetomidine did not prevent POD.³¹ In our pilot study, 7.7% of patients receiving dexmedetomidine developed POD, compared with 17.9% of patients receiving placebo, with an absolute reduction of −10% (95% CI −28% to 7%). On the other hand, BIS-guided anaesthesia management may help to reduce the risk of POD.³² Our recent meta-analysis suggested that light anaesthesia was associated with a lower incidence of POD compared with deep anaesthesia.¹⁵

Our pilot study did not have enough power to test the interventional effects; instead, we suggested the feasibility of conducting such a multicentre trial. As far as we know, this is the first multicentre, randomised, controlled trial with the factorial design to determine the effects of dexmedetomidine and anaesthesia depth on POD. With the explicitly specified primary outcome and justified sample size, reliable study results can be expected. The multicentre design would expedite the recruitment process and enhance the generalisability of the findings. If the treatment benefits are substantiated, our trial would have a significant impact on anaesthetic care and neurocognitive outcomes for elderly patients undergoing major non-cardiac surgery, as the study interventions can be easily incorporated into clinical practice.

Some limitations still exist. First, patients with ASA physical status IV and preoperative cognitive decline are not included. Second, administration of light or deep anaesthesia cannot be blinded to anaesthesiologists. Third, the rate and duration of dexmedetomidine infusion may influence the rate of POD, and thus further studies are needed to determine the optimal infusion strategy of dexmedetomidine. Fourth, we documented the duration of POD but did not measure its severity in our patients. Last, detecting the possible interaction between the two treatment options is only exploratory.

Ethics and dissemination

The trial protocol was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University (Approval No. 2023–130) and each participating centre. We registered this trial at the Chinese Clinical Trial Registry (identifier: ChiCTR2300073271; https://www.chictr.org.cn/showprojEN.html?proj=199567) prior to the enrolment of the first patient. The implementation of this study will follow the Declaration of Helsinki. Written informed consent for participation will be obtained from all patients (online supplemental file 3). The trial results will be published in a peer-reviewed journal.