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Abstract
Introduction Postoperative neurocognitive dysfunction (PND), including postoperative delirium (POD), is a common complication in elderly patients after major surgeries, often leading to poor postoperative recovery. Although the pathological mechanism underlying PND is still unclear, postoperative pain is strongly associated with the development of PND. The ultrasound-guided serratus anterior plane block (SAPB) has been reported to relieve postoperative pain in thoracic surgery. Therefore, this prospective trial hypothesises that SAPB may reduce the incidence of PND in the elderly undergoing thoracoscopic lobectomy.
Methods and analysis This study is designed as a single-centre, double-blind, randomised controlled clinical trial. A total of 256 elderly patients scheduled to undergo thoracoscopic lobectomy at Shanghai Pulmonary Hospital will be randomly assigned to general anaesthesia group or SAPB group. The primary outcome is the incidence of PND 7 days postoperatively or before discharge from hospital. The secondary outcomes include the occurrence of POD, the postoperative pain scores, Quality of Recovery at 1–2 days postoperatively and incidence of PND at 3 months postoperatively. The levels of fasting blood glucose in peripheral blood will be examined before and 1–2 days postoperatively.
Ethics and dissemination The trial has been approved by the Clinical Research Ethics Committee of Shanghai Pulmonary Hospital (identifier: K20-290). All participants will be required to provide written informed consent before any protocol-specific procedures. Findings will be disseminated in a peer-reviewed journal and in national and/or international meetings to guide future practice.
Trial registration number ChiCTR2100052633.
- adult anaesthesia
- adult intensive & critical care
- anaesthesia in cardiology
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Introduction
Lung cancer is the malignant tumour with the highest morbidity and mortality worldwide.1 2 Surgical resection is the primary effective method for treating lung cancer. However, postoperative neurocognitive dysfunction (PND) may occur as an adverse event. PND is a common postoperative complication in elderly patients, mainly manifested as new cognitive dysfunction after anaesthesia and surgery, in areas including attention, memory, processing speed, executive inhibition, language and other cognitive dimensions.3 4 PND prolongs the patient’s hospital stay and significantly increases the risk of mortality and medical expenses 6–12 months after surgery.5 However, because the pathophysiological mechanism of PND is unclear, the diagnostic strategies and prevention methods remain minimal. How to reduce the incidence of PND is a critical clinical problem that needs to be solved urgently.
Intraoperative stimulation and inflammatory reactions can sensitise pain receptors in the spinal cord and brain, sensitising patients to postoperative pain and increasing the risk of PND.6 7 With enhanced recovery after surgery and the continuous advancement of ultrasound technology, ultrasound-guided nerve blocks are widely used in perioperative analgesic management.8 9 ,10 Blanco et al11 proposed ultrasound-guided serratus anterior plane block (SAPB), wherein, local anaesthetic is injected into the serratus anterior space, primarily blocking the lateral cutaneous branch of the intercostal nerve and the thoracic length. Blocking the nerves and thoracic dorsal nerves produce analgesia covering the anterolateral and posterior sides of the chest wall. Moreover, the advantages of SAPB over the thoracic segmental epidural block and thoracic paravertebral block include simple operation, increased safety, fewer complications and haemodynamic stability.12 Currently, ultrasound-guided SAPB has been widely used in thoracic surgery and has achieved good clinical results in postoperative analgesia.13 It has been shown that the usage of SAPB reduces pain after VATS lobectomy.14 Postoperative pain is strongly associated with the development of PND. Additionally, adequate analgesia aids pulmonary function recovery and reduces the incidence of postoperative pulmonary complications.14 15 However, it is still unclear whether SAPB can affect postoperative cognitive function in elderly patients.
STRENGTHS AND LIMITATIONS OF THIS STUDY
This randomised controlled clinical trial is designed to provide evidence on the efficacy of serratus anterior plane block in reducing postoperative neurocognitive dysfunction in elderly patients, which is fast becoming a crucial issue with increasing number of the elderly patients gaining access to surgical treatment.
To preserve homogeneity of patients, patients undergoing only thoracoscopic lobectomy will be included.
Follow-up of cognitive function at 3 months postoperatively is planned to be conducted over telephone; this may lead to lost to follow-up.
We designed a single-centre, prospective, randomised controlled trial with the aim to evaluate whether SAPB reduces PND incidence in elderly patients undergoing thoracoscopic lobectomy. To this end, the study intends to assess whether surgical anaesthesia causes acute and chronic neurocognitive dysfunction in elderly patients, investigate the effect of SAPB on PND in elderly patients. The mechanism of occurrence and the method to reduce the incidence of PND can provide critical clinical evidence.
Methods and analysis
Trial design
This is a single-centre, prospective, double-blind, randomised controlled clinical study. This study is designed and will be reported based on the Standard Protocol Items: Recommendations for Interventional Trials 2013 statement. The trial has been approved by the Clinical Research Ethics Committee of Shanghai Pulmonary Hospital. The trial has been registered at chictr.org.cn (Identifier: ChiCTR2100052633). Elderly patients undergoing thoracoscopic lobectomy at Shanghai Pulmonary Hospital will be randomly divided into general anaesthesia (GA group) or ultrasound-guided anterior serratus block combined with GA (SAPB group). All patients will be assessed for the incidence of cognitive dysfunction at 7 days postoperatively or before discharge. All procedures will be conducted in accordance with the Declaration of Helsinki throughout the study period. A flow chart for the study is shown in figure 1; the trial schedule, including enrolment, intervention and assessment, is shown in table 1.
Trial schedule
Flow chart of the study. GA, general anaesthesia; SAPB, serratus anterior plane block.
Participant recruitment
Patients will be recruited to the trial based on specific inclusion and exclusion criteria.
Inclusion criteria:
Age >65 years, without any limitation on sex.
American Society of Anesthesiologists scores I–III.
Patients undergoing elective thoracoscopic lobectomy.
Fluent in communication and able to complete the self-assessment scale independently.
Mini-Mental Status Examination (MMSE) score >19, with no evidence of cognitive dysfunction.
Voluntary participation, provision of written informed consent and ability to comply with the follow-up plan and other research requirements.
Exclusion criteria:
Presence of dementia.16
History of alcohol or drug abuse.17
History of congenital mental retardation, mental illnesses and neurological diseases that can cause brain dysfunction.
Long-term use of sedative or psychotropic drugs.
Presence of local anaesthetic allergy.
Participation in other clinical trials in the past 3 months.
Reintubation after surgery or unplanned resurgery.
Presence of severe medical conditions such as heart failure, acute myocardial infarction, respiratory failure, renal failure and liver failure.
History of chronic pain or preoperative chest puncture positioning.
Informed consent and withdrawal from participation
The study’s purpose, procedures, follow-up methods, benefits and potential risks will be fully explained to patients and families who are deemed eligible for inclusion by the investigators. Written informed consent will be obtained from all patients. The investigators would assure them that no personal information will be disclosed and that the patients’ vital signs are safe during the perioperative period. The patients will complete the signing of informed consent on the day before the surgery. During the trial, patients can withdraw at any time. Patients will be terminated from the trial if unforeseen factors change the surgical plan. The data of all such patients will be discontinued from the study and will be recorded in the case report.
Randomisation and blinding
The trial will randomise patients on a 1:1 basis and a block randomisation was applied with block length being 4. The randomisation sequence list of this trial will be designed by a statistician who does not participate in the rest of the research process and will be generated by the ‘malloc. ado’ command program through the StataMP V.15 software package.
Safety evaluation procedure
The information of randomisation was put into opaque sealed randomisation envelopes. The patients will be assigned to the experimental or control groups according to the random number in the envelope when they were enrolled. Under no circumstances can the investigator change the random number assigned to the patient and the grouping issued. Randomised patients who discontinue study participation before starting treatment will retain their numbers; these numbers will not be reused. The next patient will be assigned a different random number, even if receiving the same treatment. Randomised patients who withdraw early from the study will not be replaced.
In this study, although the anaesthetists will not be blinded due to the research design, other members of the treatment team such as ward nurses and physicians and even the patients will not be informed of the grouping status. Care would be taken to reduce the likelihood of providing different supportive care regimens after surgery. Additionally, this study will recruit blinded individuals who are not participating in the treatment process to collect and evaluate data. The statistician of the research data will not be involved in the treatment and follow-up evaluation of the patients. Data to be analysed would be masked of the actual grouping.
Interventions
General anaesthesia
GA administration would include intravenous injection of propofol 1.0–1.5 mg/kg, sufentanil 0.4 µg/kg, rocuronium 0.6 mg/kg for induction, double-lumen tracheal intubation and bronchoscopy positioning, adjustment of ventilator parameters, tidal volume 6–10 mL/kg, breathing 10–16 times/min, maintaining end-tidal carbon dioxide (ETCO2) between 35 and 45 mm Hg.
Serratus anterior plane block
SAPB administration would include intravenous injection of propofol 1.0–1.5 mg/kg, sufentanil 0.4 µg/kg, rocuronium 0.6 mg/kg for induction, double-lumen tracheal intubation and bronchoscopy positioning, adjustment of ventilator parameters, tidal volume 6–10 mL/kg, breathing 10–16 times/min, maintaining ETCO2 between 35 and 45 mm Hg.
After induction of GA, the patient will be placed in the lateral decubitus position before the surgery, and the skin on the affected side will be sterilised. An ultrasonic high-frequency linear array probe will be used to obtain the serratus anterior image. A 22-gauge nerve block needle will be used for intraplane puncture and insertion. Under real-time ultrasound guidance, the needle tip will be confirmed to reach the serratus anterior space. Overall, 1% ropivacaine mesylate (10 mL)+2% lidocaine (10 mL) will be injected after withdrawal without blood and gas. The drug is being deposited deep to the serratus anterior muscle plane, as shown in figure 2.
Ultrasound image showing the serratus anterior plane block. Yellow line indicates the path of insertion of needle. SAM,serratus anterior muscle; Rib,rib
Anaesthesia and perioperative management
All patients will be assessed using MMSE, Confusion Assessment Method (CAM) for delirium, Rey Auditory Verbal Learning Test, STROOP Colour Word Test, Wiring Test, Number Span Test, Number Symbol Replacement Test, Purdue Nailboard Test, Verbal Fluency test, Self-Rating Anxiety Scale and Depression Scale. Fasting blood glucose will be measured. Fasting is required for 8 hours before the surgery, and drinking is prohibited for 4 hours before the surgery. No preoperative medication will be used, and blood samples will be obtained before surgery. After the patients enter the operating room, blood pressure, heart rate, oxygen saturation and ECG will be routinely monitored, peripheral venous access will be opened by placing the right internal jugular vein under local anaesthesia.
Propofol, remifentanil and rocuronium bromide will be administered during the surgery for maintenance, and appropriate fluid supplementation will be provided according to blood and fluid loss. The surgery time and opioid and propofol doses will be recorded during the surgery. Intraoperatively, according to the specific conditions of vital signs, nicardipine, atropine, ephedrine and fluid replacement will be administered to maintain haemodynamic stability; the respiratory rate and tidal volume will be adjusted according to ETCO2, maintained at 35–45 mm Hg. Pleural sutures will be initiated to discontinue maintenance medication. Muscle relaxant antagonists (sugammadex sodium) will be routinely used postoperatively. The tracheal tube will be removed when spontaneous breathing returns to 10–20 times/min and tidal volume >6 mL/kg.
Postoperative pain management will adopt an intravenous patient-controlled analgesia (PCA) mode, with a formula: sufentanil 100 µg diluted to 100 mL with normal saline, background dose 1 mL/hour, self-controlled additional dose 2 mL and locking time 10 mins. Patient-controlled intravenous analgesia (PCIA) will be administered to patients with mild pain (a Visual Analogue Scal (VAS) score ≥3 cm). Patients can push the PCIA button repeatedly until they feel relief from pain. It takes about 2 days for a PCA pump to be used for postoperative analgesia. In the event that a top-up dose does not adequately relieve pain (VAS score>3 cm), a rescue analgesic of 50 mg flurbiprofen is administered intravenously, and it could be repeated as necessary. There should be no more than 200 mg of flurbiprofen per day. Prophylaxis of postoperative nausea and vomiting includes dexamethasone 5 mg at induction and ondansetron 4 mg before surgery.
Neuropsychological tests
Delirium battery
The CAM is effective for diagnosing delirium in the elderly. The CAM will be performed to evaluate the presence of delirium before surgery. Further, on postoperative days 1–2, the presence of postoperative delirium will be assessed twice daily (morning and afternoon). The interval between the two assessments per day would be no less than 6 hours. When the CAM test result indicates the presence of delirium, the Memory Delirium Assessment Scale will be used to assess the type and severity of delirium. Simultaneously, Richmond Agitation-Sedation Scale and Quality of Recovery Score (QoR-40) will be used at each evaluation 2 days after surgery.
Cognitive battery
Neurocognitive assessment is a preliminary screening and evaluation based on the cognitive status of patients. The evaluation items include orientation, concentration, language (understanding, retelling and naming), structure and organisation, memory, calculation ability, reasoning ability (similarity and judgement) and other fields, which can sensitively reflect problems in cognitive function and the degree of cognitive impairment.18 The neurocognitive assessments include the MMSE, Auditory Word Learning Test, Digit Span Forwards and Backwards test, Trail Making test, Word Fluency Test, Number Symbol Test, Stroop Colour Word Test and Purdue Pegboard Test. Neurocognitive assessment will be performed 1 day before surgery, 7 days after surgery or before discharge and 3 months after surgery. Telephone interview for cognitive status-modified which includes a 12-item questionnaire will be used to assess the global cognitive function by verbal communication via telephone. All neurocognitive assessments during this study will be performed in the thoracic surgery unit by the same anaesthesiologist researcher trained by psychiatrists and neurologists. To reduce assessment bias, two assessors trained in the Neurological Functioning Scale.
Definition for endpoints
Primary endpoint
The primary outcome of this study is neurocognitive function 7 days postoperatively or before discharge from the hospital in elderly patients undergoing thoracoscopic lobectomy under GA and SAPB.
Secondary endpoints
A secondary endpoint is the incidence of delirium 1–2 days postoperatively and the postoperative pain scores in elderly patients undergoing thoracoscopic lobectomy under SAPB versus GA. Other secondary endpoints include incidence of cognitive impairment 3 months postoperatively, quality of recovery 1–2 days after surgery, perioperative blood glucose, and intraoperative and postoperative adverse events.
Safety considerations
Adverse events are defined as any unfavourable medical event that occurs in the patients participating in this study. The events may not necessarily have a causal relationship with the treatment. The investigator (a qualified physician) will assess the causal relationship of adverse events to this study. The investigator will be required to perform a causality assessment for all adverse events.
If severe adverse events/population adverse events occur, in addition to reporting them, they will be monitored by investigators who will take appropriate measures to protect patient safety and health.
Sample size calculation
The study used the online software ‘Power and Sample Size.com’ to calculate the sample size with sample allocation ratio of 1:1 between the experimental group and control group. On reviewing previous literature, the incidence of PND was 25.8%,19 and the incidence of PND in patients administered nerve block was 9%.20 With α set to 0.05, the test power was 90%, and the calculated sample size was 102 patients per group. As all patients are hospitalised, considering a 20% lost to follow-up, this study set 128 patients in each group, and a total of 256 patients for enrolment finally.
Statistical analysis
All results will be analysed using an intention-to-treat strategy, which means that patients should be included in the assigned group for statistical analysis of efficacy regardless of whether they received or completed treatment in the group after randomisation. Baseline characteristics comparisons between the two groups will be performed using two independent samples t-test, χ2 test or Fisher’s exact test. Pearson’s χ2 test will be used for assessing the difference in the incidence of PND between the two groups. For continuous variables in the secondary endpoints, baseline-adjusted analysis of covariance will be used to analyse the differences between the two groups and calculate the 95% CI. Comparisons and analyses of repeated measures data will be performed using linear mixed-effect models. Pearson’s χ2 or Fisher’s exact test will be used for categorical variables that are secondary endpoints. Multivariate model analysis of the incidence of postoperative delirium in the GA and SAPB groups will be performed.
The primary outcome PND will be measured using a standardised composite score across the test scales. The mean and SD will be used to present the scores for each scale. Individual test scores will be normalised by subtracting the mean of the baseline scores and dividing it by the SD. The last observation carry-forward method will be used to impute missing values. Safety data will be presented with proportions to describe the occurrence, with comparisons of differences between groups, if necessary. The level of significance will be set at 0.05. SAS V.9.4 (SAS Institute) was adopted for all analyses.
Data management and monitoring
Overview of data management approaches
This study will conduct data management following common regulatory objectives applicable standards and data cleaning procedures to ensure data integrity and accuracy.
This research will use a database management system to establish an independent database of this experiment according to the content of case report forms. All data entry, review and data cleaning will strictly follow Clinical Data Interchange Standards Consortium (CDISC) standards. The serious adverse events data list and safety information will be reviewed and updated in the database every 6 months. The locking and opening of the database will be carried out in strict accordance with the data management Standard Operating Procedures (SOP) and CDISC standards; researchers and programmers need to participate in signing the relevant application forms.
Supervision requirements
Screening period
The primary researchers and anaesthesiologists will discuss and evaluate the inclusion of patients. After the patients sign the informed consent, baseline data will be collected by the research assistants.
Treatment period
Clinical data of patients during surgery and recovery will be recorded in detail by research assistants. Data will also be collected on the first postoperative day and post-treatment visits (safety follow-up visit, follow-up visit and survival visit).
Data security and monitoring plan
Quality control
By signing this study plan, the investigator agrees to be responsible for implementing and establishing quality control and assurance system following the SOP to ensure that the conduct of the trial and the generation, recording and reporting of data following the implementation, and that of all applicable laws, regulations and norms. Findings of the study will be submitted for publication in peer-reviewed scientific journals and presented at relevant medical conferences.
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.
Ethics and dissemination
The trial has been approved by the Clinical Research Ethics Committee of Shanghai Pulmonary Hospital (Identifier: K20-290). All participants will be required to provide written informed consent before any protocol-specific procedures. The data underlying this article will be shared on reasonable request to the corresponding author. Findings will be disseminated in a peer-reviewed journal and in national and/or international meetings to guide future practice.
Discussion
PND is a complication after surgical anaesthesia, especially in elderly patients. It increases economic burden and may also be associated with an increased risk of postoperative mortality.21–23 Patients with cancer undergoing thoracoscopic lobectomy can sensitise the pain receptors located in the spinal cord and brain due to intraoperative stimulation and inflammatory reactions, leading to increased postoperative pain, and in turn slower postoperative recovery and PND.24 Therefore, appropriate pain management in the perioperative period is needed for effective recovery and reduced incidence of perioperative adverse reactions.25–27
The serratus anterior is an easily identifiable superficial muscle that originates on the anterolateral side of the first to nineth ribs and inserts on the spinal edge of the scapula.28 SABP, first proposed by Blanco et al,11 is simple and blocks the lateral cutaneous branch of the sternocostal nerve (T2–T9) for analgesia on the anterolateral thoracic and abdominal wall. Moreover, the probability of pneumothorax and local anaesthetic toxicity is low.29 30 Currently, ultrasound-guided SAPB has been widely used in thoracic surgery and has achieved good clinical results in postoperative analgesia.14 Further, our preliminary study found that SAPB reduces perioperative pain scores and improves patient satisfaction; however, it is still unclear whether SAPB can affect postoperative cognitive function in elderly patients.
In this study, neuropsychological tests will be used to evaluate whether ultrasound-guided SAPB could reduce the incidence of PND in elderly patients undergoing thoracoscopic lobectomy under GA. The incidence of delirium at 1–2 days, incidence of cognitive dysfunction at 3 months after surgery, the QoR-40 score 1–2 days after surgery, perioperative blood glucose will be assessed. The changes in these factors and other indicators have previously correlated with the incidence of intraoperative and postoperative adverse events.31–33 Our results may facilitate the application of SAPB in elderly patients undergoing thoracoscopic lobectomy as an appropriate approach to improve postoperative pain and facilitate postoperative recovery.
However, the study may have associated limitations. This study intends to adopt a single-centre, prospective, randomised controlled study method. In order to protect the rights and interests of patients, we chose a no-treatment control group. In the study design, we made efforts to adhere to ethical principles and minimise unnecessary invasive procedures and potential risks to the study participants.34 35 Administering 0.9% saline for SAPB in the control group would not have any potential therapeutic effects for the individuals, but it would require additional invasive interventions. To maximise harm reduction and ensure ethical treatment of the study participants, we opted for GA as the control group. Using normal saline for SAPB as the control group may effectively achieve operator blindness and reduce research bias. The target population comprises elderly patients aged over 65 years who undergo thoracoscopic lobectomy at the Shanghai Pulmonary Hospital; therefore, the sample size is expected to be small. Further large-sample, multicentre prospective randomised controlled trials are needed to evaluate whether ultrasound-guided SAPB combined with GA can reduce PND in elderly patients following thoracoscopic lobectomy.36
Ethics statements
Patient consent for publication
Acknowledgments
We would like to thank Editage (www.editage.com) for English language editing.
References
Footnotes
D-YW and DF contributed equally.
Contributors D-YW and DF drafted the manuscript. HS designed the protocol with HX and DF. ML and WW wrote the statistical analysis plan and estimated the sample size. All authors read and approved the final manuscript.
Funding This work was supported by Shanghai Special Program for Research on Aging and Women and Children's Health (No. 2020YJZX0136) and Talent Program of Shanghai Pulmonary Hospital (No. fkgg1809).
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.