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Abstract
Introduction Parkinson’s disease is one of the most common neurodegenerative diseases. Deep brain stimulation (DBS) can improve motor symptoms in patients with middle and late Parkinson’s disease, reduce the use of levodopa, and thus reduce drug-related side effects. Postoperative delirium can significantly reduce the short-term and long-term quality of life in elderly patients, which can be alleviated by dexmedetomidine (DEX). However, whether prophylactic DEX could reduce the incidence of postoperative delirium in patients with Parkinson’s disease was still unknown.
Methods and analysis This is a single-centre, randomised, double-blinded, placebo-controlled group trial. A total of 292 patients aged 60 years and above elected for DBS will be stratified according to DBS procedure, subthalamic nucleus or globus pallidus interna, then randomly allocated to the DEX group or the placebo control group with a 1:1 ratio, respectively. In the DEX group, patients will be injected with the DEX continuously with an electronic pump at a rate of 0.1 µg/kg/hour for 48 hours at the beginning of general anaesthesia induction. In the control group, normal saline will be administered at the same rate for patients as in the DEX group. The primary endpoint is the incidence of postoperative delirium within 5 days after surgery. Postoperative delirium is assessed by the combination of the Richmond Anxiety Scale and the Confusion Assessment Method (CAM) for the intensive care unit or the 3-minute diagnostic interview for CAM as applicable. The secondary endpoints include the incidence of adverse events and non-delirium complications, the length of stay in the intensive care unit and hospital and all-cause 30-day mortality after the operation.
Ethics and dissemination The protocol has been approved by the Ethics Committee of Beijing Tiantan Hospital of Capital Medical University (KY2022-003-03). The results of this study will be disseminated through presentation at scientific conferences and publication in scientific journals.
Trial registration number NCT05197439.
- anaesthesia in neurology
- adult anaesthesia
- Parkinson's disease
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STRENGTH AND LIMITATION OF THIS STUDY
This prospective, randomised, double-blinded, placebo-controlled group trial is designed to investigate the effect of DEX on delirium in elderly patients with Parkinson’s disease after deep brain stimulation (DBS).
This study adopts proper dose of dexmedetomidine (DEX), standardised randomisation and blinding, definite inclusion and exclusion criteria, rigorous anaesthesia management protocol, thorough adverse event management and experienced investigators in each procedure.
One limitation of the study is that this is a single-centre trial focusing on elderly patients undergoing DBS, which might limit the generalisation of the conclusion.
The inclusion criteria in this study are strict, so the results may only be applicable to a specific population.
DEX may slow heart rate and lower blood pressure, leading to blind weakening.
Introduction
Delirium is a clinical syndrome characterised by acute and typically reversible failure of cognitive and attentional functions.1 2 Those with delirium can be classified into three motoric subtypes: hyperactive, hypoactive or mixed.2 3 Although postoperative delirium usually recovers within a week, it is associated with increased mortality, cognitive and functional decline, increased hospital length of stay, healthcare costs and decreased long-term quality of life.3
Parkinson’s disease is a common neurodegenerative disease with more than 6 million patients worldwide,4 which is characterised by motor symptoms, including bradykinesia, rigidity, rest tremor and postural instability, as well as non-motor symptoms, such as olfactory loss, sleep dysfunction, autonomic dysfunction, psychiatric disturbances, cognitive impairment and others.5 Diagnosis of Parkinson’s disease is based on history and physical examination. Prodromal symptoms, family history and current concerns will be considered, and physical examination must show the core features of bradykinesia and rigidity and/or tremor. Once these are confirmed, the physician assesses the patient’s response to levodopa to confirm the diagnosis.5 Deep brain stimulation (DBS) has become an established therapeutic tool for treating patients with advanced Parkinson’s disease with pharmaco-resistant motor fluctuations and dyskinesias refractory. The procedure consists of two steps, electrode implantation and impulse generator implantation. Subthalamic nucleus and globus pallidus interna are two common nuclei to be stimulated during the procedural. In various studies, the incidence of postoperative delirium after DBS surgery varied from 11% to 60%. Age, non-motor symptoms, disease severity, brain atrophy and surgery effect are risk factors for delirium in patients with Parkinson’s disease.6–10
Dexmedetomidine (DEX) is a highly selective α2 adreno receptor agonist which could provide sedation, anxiolysis and additional analgesia with minimal respiratory depression. A preliminary study of 11 consecutive patients who received continuous low-dose DEX infusion during unilateral DBS of the hypothalamic nucleus confirmed that the use of DEX is safe and effective, with no haemorrhagic complications and no postoperative side effects.11 The use of DEX perioperatively has been shown to significantly reduce the incidence of postoperative delirium in elderly surgical patients.12–14 However, the effect of DEX on postoperative delirium in patients with Parkinson’s disease after DBS is rarely reported.
DEX is usually used as an adjunct to postoperative analgesia in wards, and the dose ranged from 0.04 µg/kg/hour to 0.08 µg/kg/hour.15–17 A randomised controlled trial about the impact of DEX supplemented analgesia on delirium in patients underwent orthopaedic surgery showed that supplementing sufentanil intravenous analgesia with low-dose DEX did not reduce delirium significantly,15 which may account for the low dose of DEX (DEX 200 µg diluted with 0.9% saline to 160 mL). Otherwise, in a randomised controlled trial including 700 patients older than 65 years who were admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose DEX (0.1 µg/kg/hour) significantly decreases the occurrence of delirium during the first 7 days after surgery, and the therapy was safe.14 Therefore, the dose of DEX in this study was set as 0.1 µg/kg/hour.
Current literature supports the use of DEX in DBS.11 18 In a randomised placebo-controlled trial, overnight prophylactic low dose of DEX decreased delirium incidence in patients aged 65 years and older after non-cardiac surgery.12 16 This provided a rationale for the long duration of infusing DEX in our study. Our study design is a continuous infusion of DEX will be started at the beginning of general anaesthesia and last for 48 hours.
Therefore, we hypothesised that using low-dose DEX during and after DBS could safely decrease the incidence of delirium in patients with Parkinson’s disease following DBS surgery.
Methods
Study design
This prospective, single centre, randomised, placebo-controlled, double-blinded trial with two parallel arms will be conducted at Beijing Tiantan Hospital, Capital Medical University. The overall flow chart is shown in figure 1. The study protocol was approved by the local Institutional Review Board (KY2022-003-03) and registered at ClinicalTrials.gov (NCT05197439). Data will be collected from consecutive patients admitted to Functional Neurosurgery ward and written informed consent will be obtained from patients or their legal representatives.
Flow chart of the study. PD, Parkinson’s disease; POD, postoperative delirium.
Participants
Patients diagnosed with Parkinson’s disease aged 60 and older with non-motor symptoms, available to provide consent and scheduled for elective DBS, will be screened for eligibility. Diagnosis of Parkinson’s disease is based on patient’s history and physical examination5 and will be confirmed by the neurosurgeon before the patient is admitted into our functional neurosurgery ward. Non-motor symptoms include olfactory loss, sleep dysfunction, autonomic dysfunction, psychiatric disturbances and cognitive impairment, which will be assessed during bedside visiting and chart review preoperatively.
If the following criteria exist, the patients will be excluded from this study: preoperative severe cognitive impairment (Montreal Cognitive Assessment <18), history of psychoactive, allergic or intolerant to DEX, severe bradycardia (heart rate lower than 40 beats per minute) or sick sinus syndrome, second-degree or third-degree atrioventricular block, severe hepatic dysfunction (Child-Pugh class C), severe renal dysfunction requiring renal replacement therapy before the surgery and medical records documented inability to communicate in the preoperative period due to language barrier or other situations.
Randomisation and blinding
Stratified block randomisation of size 6 by different DBS procedure (nuclei stimulated) will be applied in the trial with a distribution ratio of 1:1. Randomisation will be carried out by an independent research assistant using a computer-generated table. The study agents (DEX 200 µg/2 mL) will be diluted to 100 mL with normal saline and injected into an electronic pump at the dosage of 4.8 µg/kg before being labelled as ‘trial drug’. Patients, investigators who perform data collection and follow-up, anaesthesiologists and other healthcare providers responsible for patients’ care will be blinded to the randomisation and group allocation. Blinding will be maintained throughout the entire research period.
Grouping and intervention
DEX will be diluted to 4.8 µg/kg in 100 mL normal saline and pump 2 mL/hour by an electronical pump at the beginning of DBS and last for 48 hours.14 Patients in the control group will receive the identical volume of saline in the same setting.
Anaesthesia protocol
Standard routine monitoring will be instituted, including non-invasive blood pressure, electrocardiography, pulse oxygen saturation, end-tidal carbon dioxide and so on. Local anaesthesia and bilateral supraorbital and auriculotemporal nerve block with 0.3% ropivacaine will be performed during electrode implantation. Patients will receive general anaesthesia, induced with propofol, sufentanil and cis-atracurium during impulse generator implantation. Anaesthesia will be maintained with propofol and remifentanil to keep bispectral index (BIS) at 40–60. Since the duration of the second step of DBS is short, sufentanil and cis-atracurium will no longer be added.
Mechanical ventilation will be established after the oral insertion of the laryngeal mask. A tidal volume of 6–8 mL/kg, respiratory frequency of 12–15 breaths per minute, inspiration to expiration ratio of 1:1.5–2 and positive end-expiratory pressur (PEEP) of 5 cmH2O will be used in all groups. All patients will be administered 60% oxygen at 2 L/min total flow, and respiratory rates were adjusted to maintain partial pressure of carbon dioxide (PaCO2) at 35–45 mm Hg.
Orthostatic hypotension, due to the impaired baroreflex function and the vasodilating effects of anti-Parkinson medications, is a common non-motor feature of Parkinson’s disease.19 In this study, we need to be alert to the bradycardia and hypotension events caused by prolonged DEX infusion in the elderly. We aim for a mean blood pressure within 20% above and below the patient’s baseline, and administer fluids and vasoactive medications as necessary.
Objectives
This study aims to determine whether DEX infusion could alleviate postoperative delirium in elderly patients with Parkinson’s disease and non-motor symptoms.
Primary outcome
The primary outcome is the incidence of postoperative delirium. Postoperative delirium is assessed by the combination of the Richmond Anxiety Sedation Scale (RASS) and the Confusion Assessment Method of the Intensive Care Unit (CAM-ICU) or 3-minute Diagnostic Intensive for CAM (3D-CAM) as applicable two times per day within 5 days after surgery. Patients will be evaluated with RASS and 3D-CAM in the general ward. The arousal level will be first assessed through RASS in ICU. If the patient is not responsive to verbal stimuli (RASS Score ≤−4), the remaining assessment will be aborted and recorded as comatose. Otherwise, delirium will be evaluated by CAM-ICU. Researchers will be routinely trained to use the above-mentioned assessments.20
Secondary outcomes
The secondary outcomes include other efficacy and safety outcomes.
The severity of postoperative delirium will be assessed by Delirium Rating Scale-Revised-98 within 5 days after surgery.
Postoperative pain will be assessed with Numerical Rating Scale (NRS) on the day of surgery and daily for 3 days after surgery. NRS ranges from 0 to 10, with the highest score indicating the worst pain. Postoperative analgesia will be recorded.
Quality of recovery will be evaluated on the first day after surgery with 15-Item Quality of Recovery Questionnaire (QoR-15). The QoR-15 Score ranges from 0 (extremely poor recovery) to 150 (excellent recovery). The patient acceptable symptom state for the QoR-15 is 118.21
Quality of sleep will be evaluated with the Richards Campbell Sleep Questionnaire (RCSQ) on the second and the third day after surgery. The scale evaluates perceptions of the depth of sleep, sleep onset latency, number of awakenings, time spent awake and overall sleep quality. The 0–100 mm Visual Analogue Scale (1 mm=1 point) is used. The total score of the scale is divided into five items, and the higher the score, the better the sleep quality. The scale has been validated in a population of critical care patients between the ages of 55 and 79. The RCSQ total parameter with a cut-off of 50 (RCSQ total ≥50 good sleep/RCSQ total <50 poor sleep) was suitable for discrimination of subjectively perceived sleep quality in ICU patients.
Cognitive function will be assessed using the Mini-Mental State Examination and the Montreal Cognitive Assessment-Basic before surgery and 5 days after surgery. The scale includes seven items: time orientation, place orientation, immediate memory, attention and calculation, delayed memory, language and visual space. A total of 30 questions will be asked, 1 point for each correct answer, 0 point for a wrong answer or unknown answer and the total scores range from 0 to 30. Higher score indicates better cognitive function.
Anxiety and depression will be evaluated before surgery and 5 days after surgery using Generalised Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 items (PHQ-9). The GAD-7 summed score ranges from 0 to 21, with cut-off points of 5, 10 and 15, allowing researchers to classify the anxiety as none/normal (0–4), mild (5–9), moderate (10–14) and severe.15–22 The PHQ-9 Depression Scale, a valid self-administered depression screening and diagnostic tool, was used to measure depression symptoms. Major depression is considered present if the patient reports five or more depressive symptoms with at least one symptom being anhedonia or depressed mood. Minor depression is defined by two to four depressive symptoms with at least one symptom being anhedonia or depressed mood.23
Parkinson’s disease-related status will be evaluated before surgery and 5 days after surgery by Movement Disorder Society-Sponsored Revision Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). The MDS-UPDRS consists of the following four segments: (1) non-motor experiences of daily living, (2) motor experience of daily living, (3) motor examination and (4) motor complication. It ranked on a 5-point Likert Scale (0=normal, 1=slight, 2=mild, 3=moderate and 4=severe).24 We used this scale to access the changes of both motor and non-motor symptoms before and after operation.
Statistical plan and sample size calculation
The incidence of postoperative delirium in patients with Parkinson’s disease who underwent DBS surgery was about 40% in the previous study.8 A meta-analysis of non-cardiac surgery patients showed that the incidence of postoperative delirium reduced by approximately half when DEX was used perioperatively.25 We estimated that 162 participants would provide a power of 90% to detect a 50% difference using a two-tailed alpha of 0.05. After continuous correction, the final sample size was 182. Considering a dropout rate of 5%, we plan to enrol 192 patients, each group with 96 participants.
Categorical variables will be presented as numbers and percentages, and analysed by the Χ2 test or Fisher’s exact test. Continuous variables will be checked for normal distribution and presented as mean±SD or median and IQR as appropriate. Comparison of continuous variables will be performed by Student’s t-test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. Time-to-event variables will be analysed by survival analysis, with the difference between groups assessed with log-rank test. We will adjust the primary outcome by the parameter which is not comparable between groups. Confounding factors will be selected from the risk factors of delirium in patients with Parkinson’s disease, such as age, severity and medication for Parkinson’s disease, as well as baseline data that were unbalanced between the two groups and finally confirmed based on their significance in univariate analysis and evidence from previous studies. Multiple logistics regression will be applied to determine the influence of these confounding factors on the primary outcome. All analyses will be conducted according to the intention-to-treat principle. SPSS software (V.22.0) was used for statistical analysis. A p value less than 0.05 is considered statistically significant.
Data management and monitoring
The time points for enrolment, intervention and assessment are shown in figure 2. Two independent investigators unaware of the allocation will conduct the outcome assessment and data management. To ensure the quality of the assessment, the study team will perform training on data collection, especially in the use of the outcome questionnaire scales. We will collect raw data on paper, and all information will be kept confidential. Final data will be entered to EpiData by two investigators independently to ensure data accuracy.
Data collection process and patient follow-up. CAM, Confusion Assessment Method; MDS-UPDRS, Movement Disorder Society-Sponsored Revision Unified Parkinson’s Disease Rating Scale; NRS, Numerical Rating Scale; PD, Parkinson’s disease.
Management of adverse events
Adverse events will be monitored from the start of study agent infusion until 48 hours or the pump discharge. Investigators should record all the adverse events including the type, diagnosis time, duration and consequences. In the present study, predicted adverse events include bradycardia (defined as heart rate lower than 50 beats per minute), hypotension (defined as systolic blood pressure lower than 90 mm Hg) and hypoxaemia (defined as pulse oxygen saturation lower than 90%).
Intraoperative hypotension is common in patients with Parkinson’s disease, especially those who underwent general anaesthesia. Furthermore, DEX-induced bradycardia and hypotension are dose-dependent. Attending surgeons can stop the study agent infusion in the following cases. Heart rate lower than 40 beats per minute after atropine in 0.25 mg intravenous bolus. Systolic blood pressure lower than 90 mm Hg after fluid resuscitation with 250 mL crystalloid solution infusion within 15 min. Peripheral pulse oxygen saturation lower than 90% after administration of oxygen and adjustment of mechanical ventilation for patients without and with endotracheal intubation, respectively. Other conditions deemed necessary by the surgeon.
Patient and public involvement
No patient involved.
Ethics and dissemination
The study protocol was approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (KY2022-003-03) and registered at ClinicalTrials.gov (NCT05197439). In these cases, the reasons that lead to any protocol interruption are documented and reported to the local Institutional Review Board within 24 hours. Patients with study protocol interruption will be included in the intention-to-treat analysis. The trial results will be presented at national and international conferences relevant to the subject fields and submitted to international peer-reviewed journals.
Trial status
At the time of manuscript submission, the study is in the preparation phase for recruitment. We expect to start the recruitment in 1 December 2023 and complete the study by December 2024.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors JY and ZS wrote the first draft. HJ and TM registered the protocol at ClinicalTrial.gov. JW revised the draft. SL, MZ and XL planned the statistical strategy and was actively involved in the sample size calculations and random allocation. YP conceived and designed the study. All authors read and approved the final protocol. All authors were involved in editing the protocol for critically important contexts and have approved the final version of the manuscript.
Funding This work was supported by the National Key Research and Development Program of China (Grant No. 2018YFC2001901).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.