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Abstract
Introduction Besides the comorbid risk factors shared by older and younger patients, older individuals may also experience malnutrition, as well as cognitive or functional impairments. The accumulation of frailty and various geriatric syndromes in older individuals results in decreased physiological reserves, which makes the recovery process after spine surgery particularly challenging. Theoretically, combining the presurgery optimisation provided by a multimodal prehabilitation programme with the reduction of surgical stress provided by an enhanced recovery after surgery (ERAS) programme could improve postoperative recovery of older patients.
Methods and analysis This is a prospective, multicentre, assessor-blinded, randomised controlled study. Patients who are 75 years of age or older and are scheduled for spinal fusion surgery will be enrolled on three academic medical centres. Regular preadmission education and perioperative ERAS care will be given to participants who were randomised to the control group. Participants randomised to the intervention group will receive multimodal prehabilitation combined with ERAS (PREERAS) management. We will include 164 patients with spinal fusion in three hospitals in China. All included patients will be followed for 90 days after surgery or until death. The primary outcome is the Comprehensive Complication Index (CCI), which ranges from 0 to 100, where a score of 100 indicates death due to complications. Secondary outcomes include length of stay and non-home discharge, rates of postoperative complications and unplanned readmission, North American Spine Society satisfaction, and Oswestry Disability Index/Neck disability index. Ninety-day CCI will be compared between groups using linear regression. Other continuous or categorical outcomes will be compared using linear or logistic regression.
Ethics and dissemination This study has received ethical approval from the Xuanwu Hospital of Capital Medical University Ethics Committees (2024-088-001). The findings will be submitted to a peer-reviewed journal for publication.
Trial registration number NCT06140797.
- SURGERY
- Spine
- Rehabilitation medicine
- GERIATRIC MEDICINE
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This study employs a robust multicentre, prospective, assessor-blinded, randomised controlled trial design, which enhances the reliability and generalisability of the findings.
The investigation focuses on comparing the impact of multimodal prehabilitation combined with perioperative enhanced recovery after surgery (PREERAS) care against ERAS care alone in elderly patients (aged 75 years and older), a population that is often understudied.
The study represents an important contribution to the field by exploring the potential of multimodal prehabilitation to mitigate postoperative complications specifically in the context of spinal fusion surgery.
Owing to the type of interventions, blinding of the patients and treatment providers is not possible.
Introduction
With an unprecedented ageing population and increased life expectancy, the burden of degenerative spinal diseases has increased substantially.1 These conditions can lead to the compression of the spinal cord or nerve roots, resulting in limb pain, limited mobility In severe cases, they can significantly impair a patient’s ability to perform daily activities and work, thereby diminishing their quality of life.2 One of the most commonly used treatments for degenerative spinal diseases is spinal fusion surgery.3 Recent research using multicentre data has shown that the increase in the incidence of spinal fusion procedures for spinal degenerative diseases was most pronounced among patients aged 75 years and older.4 Besides the comorbid risk factors shared by older and younger patients, older individuals may also experience malnutrition, as well as cognitive or functional impairments. The accumulation of frailty and various geriatric syndromes in older individuals results in decreased physiological reserves, which makes their recovery process after spine surgery particularly challenging.5 6 The incidence of major complications in older patients (≥75 years) is about 1.5 times higher than in younger patients, which leads to a significant increase in mortality rates and healthcare costs associated with spinal surgery.7 8
Enhanced recovery after surgery (ERAS) involves multidisciplinary perioperative interventions aimed at reducing surgical stress responses and improving perioperative outcomes as well as postoperative recovery.9 10 However, ERAS does not include preoperative comprehensive interventions to address or optimise the comorbidities, insufficient nutrient, decreased functional capacity that are commonly present in older patients.11 Without adequate physiological reserve to sustain the systemic response to stress, a patient might not be able to meet the additional demands of surgery and could have a poor surgical outcome as a result.12 Symptomatic degenerative spinal diseases are associated with an elevated prevalence and incidence of frailty among the elderly in the community.13 Walking intolerance caused by pain or numbness due to degenerative spinal disorders may lead to decreased physical activity, which might subsequently worsen age-related muscle weakness and frailty. Therefore, personalised preoperative optimisation strategies should focus on medical, functional, cognitive and nutritional factors in spine surgery.14
Prehabilitation programmes aim to strengthen patients physically and mentally before surgery. By addressing modifiable risk factors during the preoperative period while they are waiting for surgery, these programmes help to fill the existing gap.11 Emerging evidence indicates that prehabilitation, a comprehensive and structured exercise and conditioning programme, can confer significant benefits to patients undergoing major abdominal and cardiothoracic surgeries.15 16 Individuals over the age of 75 with spine conditions are at a higher risk of concurrent frailty and additional comorbidities, potentially diminishing their capacity to withstand surgical trauma and leading to delayed recovery postoperatively.17 Theoretically, combining the preoperative optimisation provided by a multimodal prehabilitation programme with the reduction of surgical stress provided by an ERAS programme could further improve postoperative recovery of older patients.11 18 Nevertheless, high-level evidence supporting the integration of prehabilitation into ERAS programme is still limited, particularly within the context of spine surgery.
Methods
Aims
The aim of this work is to examine the effect of multimodal prehabilitation combined with perioperative ERAS care (PREERAS) compared with only ERAS in older patients (aged 75 years and older) scheduled for spinal fusion surgery. We hypothesise that the PREERAS programme will be more effective than only-ERAS care in improving postoperative clinical outcomes and patient-reported outcomes (figure 1).
Overall study design and hypothesis. ERAS, enhanced recovery after surgery; PREERAS, perioperative ERAS.
Study design
This study is a multicentre, prospective, assessor-blinded, randomised controlled trial (RCT) (figure 2). Due to the intrinsic nature of the intervention, it is not feasible to blind all participants and staff members within the prehabilitation centres. Therefore, outcome assessors, surgeons and statisticians will be masked to treatment assignment, which will help to minimise bias caused by non-preoperative factors. The study is prospectively registered with ClinicalTrials.gov (NCT06140797). The study was planned and performed in agreement with the Declaration of Helsinki (Version Fortaleza 2013).19 All adverse events that occur during the study will be systematically recorded and reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials guidelines (table 1).
Flow chart of patient enrolment, randomisation and follow-up. ERAS, enhanced recovery after surgery; PREERAS, perioperative ERAS.
Schedule of enrolment, interventions and assessments
Eligibility criteria
Patients who are 75 years of age or older and are scheduled for spinal fusion surgery will be enrolled on three academic medical centres. The inclusion criteria are as follows: (1) patients who voluntarily sign the informed consent form; (2) elective spinal fusion surgery for degenerative spinal disorders and (3) no severe cognitive impairment. Patients will be excluded if they (1) are scheduled to undergo emergency or day surgery, (2) have urgent condition that needs to be managed before the surgery, (3) are unable to cooperate with preoperative assessment, (4) have spinal fractures, metastasis and spinal infections, (5) unable to understand or participate safely in intervention programme and (6) participate in another study that may affect the study. Participants are afforded the right to withdraw their consent for participation in the research study at any time, without affecting subsequent treatment. Eligibility screening will be completed by the research team at the initiating institution. Patients awaiting spinal fusion surgery, who are 75 years of age or older, and who have at least 5 weeks until their scheduled operation, will be identified by the healthcare team. They will then receive a study packet that includes information materials, a questionnaire for preliminary screening, and an informational leaflet. After a period of 24–48 hours for contemplation, a study staff member will call the patients to ascertain their willingness to join the study.
Randomisation and allocation
Patients who are willing to participate will be invited to attend the case report form at the initiating institution to provide the research team with written informed consent (see online supplemental appendix 1) and for baseline testing. After completion of the baseline assessment and registration, participants will be randomised in a 1:1 ratio to either the PREERAS intervention arm or to ERAS care group. Randomisation will be stratified based on surgical type (cervical or lumbar/ thoracic surgery) to ensure balance between the two arms of our study. To avoid the contamination between the intervention and control groups, the patients in the same group are placed in the same ward. This randomisation process will be conducted using a computer-generated randomisation list. An independent coprincipal investigator will oversee the randomisation process, ensuring its integrity and maintaining blinding to the treatment allocation. This investigator will not have any direct involvement in the implementation of the trial.
Supplemental material
Only ERAS care (control group)
Participants randomised to the control group will receive ERAS care. The ERAS programme consists of preadmission and perioperative multimodal management and was implemented by the orthopaedic department in January 2019 (box 1). The detailed pathway and efficacy of our ERAS programme have been previously reported.20–22
Perioperative ERAS care
Preadmission
Education on smoking and excessive drinking cessation.
Available counselling services at any time.
Appropriate optimisation of chronic disease in outpatient and inpatient settings.
Nutritional assessment and support.
Preoperative
Informing patients and relatives about risk and discomfort related to procedure in greater detail.
Ensuring that each patient learns and understands the ERAS pathway.
Prehabilitation includes moderate aerobic exercise, nutritional intervention and psychosocial support.
Avoiding mechanical bowel preparation and use of gastric tube.
Drinking oral carbohydrate beverage 2 hours before surgery; no prolonged fasting.
Oral administration of 150 mg of pregabalin.
Intraoperative
Infiltration of local anaesthesia with a mixture of 10 mL 2% lidocaine and 10 mL 1% ropivacaine into the musculature prior to incision and after skin closure.
Antibiotic prophylaxis within 1 hour of incision.
Intravenous infusion of tranexamic acid.
Maintenance of normothermia and maintaining fluid balance.
Postoperative
Early intake of fluid on the day of surgery (after recovery from anaesthesia).
Early physical function rehabilitation on the day of surgery and ambulate on POD 1.
Prevention of deep venous thrombosis and postoperative nausea and vomiting.
Removal of urinary catheters on the day of surgery and removal of drain tube on POD 2.
Multimodal analgesia and opioid-sparing analgesia.
Intake of oral nutrition powder for every meal.
Postoperative prevention of bacterial infection.
ERAS, enhanced recovery after surgery.
PREERAS programme (intervention group)
Introduction
Participants randomised to the intervention group will receive PREERAS management. During the planning phase of the study, we assembled a multidisciplinary team consisting of geriatrician, spine surgeons, nurses, rehabilitation specialists, anaesthesiologists, neurologists, nutritionist and social workers. Then, the PREERAS programme was conducted based on previous studies and surgical guideline.23 24 PREERAS mainly consists of Vivifrail multicomponent exercise,23 nutritional intervention,25 26 cognitive prehabilitation and brain protection27 (see online supplemental appendix 2).
Supplemental material
Sessions
Patients in the intervention group will receive twice 90 min supervised group sessions (4–6 patients) consisting of 60 min of education and 30 min discussion with one session every 2 weeks. Participants allocated to the intervention group will receive an information booklet, which includes content on the instruction of prehabilitation, intervention plan, and record of daily exercise and nutrition intake. We will also provide participants with a video lesson, which can be downloaded or accessed from the online website (https://mp.weixin.qq.com/mp/homepage?__biz=MzI5OTczNjQ2MQ==&hid=3&sn=10960353bc71a1b4b75f38d67fd010d2&scene=1&devicetype=Windows+11+x64&version=63090a13&lang=zh_CN&nettype=WIFI&ascene=0&session_us=gh_127ea8bd4d71&fontScale=100&uin=&key=). The current video lesson is available only in Chinese.
Multicomponent exercise
Vivifrail is a multicomponent intervention designed to promote exercise in older population through individualised programmes. The Vivifrail programme has proved to be efficient in improving the health status of older adults and is one of the strategies in the European Union to promote healthy ageing.23 The PREERAS includes seven Vivifrail exercises (Walking, getting up from a chair, squeeze a ball, pretend to sit, walking on tip toes and heels, arm stretching and twist a towel), two pectoralis muscles exercises (chest press and chest expansion) and two paravertebral muscles exercises (supine gluteal bridge and back muscle exercise). Patients will be advised to complete the wheel for three non-consecutive days per week. If a type of exercise cannot be completed, the frequency of other types of exercise can be increased.
Nutritional intervention
The Mini Nutritional Assessment (MNA) score will be used to evaluate nutritional risk. This validated screening tool attributes scores of different levels of nutritional status to older patients based on cognitive impairment and depression, mobility, acute disease or psychological stress, weight loss, food intake and limb circumference.28 Patients are categorised into two groups: those at high nutritional risk or malnourished (with a score below 24) and those at low risk (with a score of 24 or higher). Individuals who are well-nourished receive guidance on meeting specific nutritional goals, which include an energy intake of 25–30 kcal/kg per day and a protein intake of 1.2–1.5 g/kg per day.26
Patients at high risk for being malnourished (MNA score <24) will receive dietary counselling and individualised (based on body weight) plans to meet their energy and protein requirements. At baseline, the participants will be instructed to complete a 3-day food diary. This diary is then analysed to estimate their intake of macronutrients, such as carbohydrates, proteins and fats. The estimation process will involve using food exchange lists and composition tables, which are tools that help in quantifying the nutritional content of different foods based on their standard serving sizes and nutrient profiles. Patients with renal insufficiency or diabetes will be referred to the nutrition outpatient clinic, where a dietitian will develop an individualised nutritional intervention plan. To facilitate the achievement of these goals, oral nutritional supplements will be prescribed for patients unable to meet their protein and energy requirements through dietary intake alone. Patients are advised to take the supplements within 1 hour after their exercise to maximise muscle protein synthesis.
Cognitive prehabilitation and brain protection
PREERAS programme will focus on the following five key areas for perioperative brain function protection: sleep management, multiple medications, pain control, psychological support and multidisciplinary management for patients with a high risk for delirium.27
Strategies to improve adherence
The PREERAS programme also includes certain techniques to enhance adherence and compliance with these interventions. First, all materials will be provided to patients on the day of enrolment. The materials provided to patients of intervention group include video-lesson, education booklet (see online supplemental appendix 3), tools for exercise (an elastic band, a grip power ball and a towel). Second, during the first session, patients are educated on how to record their dietary and exercise status in the booklet. Each patient will receive weekly phone calls from the physical therapist to record adherence, as a motivational strategy. The calls will also be used to discuss any barriers to adhering to the programme and to advance the exercises and nutritional optimisation if possible. Third, the adherence in the malnourished group will be checked by performing 24 hours dietary recall 3 days after baseline visit. If necessary, oral nutritional supplementation will be prescribed. Successful completion of the exercise programme is defined as adherence to 60% of prescribed. Fourth, we will offer patients easy access to consultative services to obtain timely feedback.
Supplemental material
Data collection and management
Baseline assessment of the patients will be done within 1 week after the preoperative assessment visit. Preoperative baseline data include demographic characteristics, educational status, smoking status, drinking status, primary diagnosis, duration of symptoms (based on self-reported duration of symptoms prior to surgical intervention), medication use, Charlson comorbidity index, geriatric assessment results, levels of pain (Visual Analogue Scale (VAS, from 0 to 10 points)) and Oswestry disability index (ODI, from 0 to 100 points) for lumbar surgery and Neck Disability Index (NDI, from 0 to 100 points) for cervical surgery).29 Physical function will be assessed using walking speed (time in seconds to walk 6 m at usual pace expressed as m/s) and hand grip strength. Grip strength will be measured in both hands. The best performance, regardless of hand dominance, will be recorded. Preoperative smoking status was classified as ‘never smoking’, ‘former smoking (stopping smoking for more than 1 year)’ and ‘current smoking’. Smoking status was classified into three groups: never drinking, quit drinking (more than 1 year) and current drinking. Surgery-related variables will also be reviewed and collected. Preoperative geriatric assessment consists of frailty (Fried frailty phenotype),30 MNA31 and Montreal cognitive assessment.32 The criteria for the Frailty Phenotype will be adapted from Wu’s research, which specifically investigates frailty within the context of the Chinese population.33 Physical function pain level and geriatric assessment will be performed at the time of enrollment, admission and follow-up visit.
The data collected, which include paper pencil records, functional test results and questionnaire responses, are manually transferred to an electronic database using Microsoft Excel, which is part of the Microsoft Office Professional Plus 2019 suite. Access to the data is restricted to employees who are directly involved in the study, ensuring that sensitive information remains secure. The personal data of participants will be stored securely and will be accessible only to trial staff and authorised individuals. All study documentation will be provided on request for monitoring and auditing by the sponsor or the research ethics committee.
Outcome measures
Primary outcome
The primary outcome is the Comprehensive Complication Index (CCI; scores range from 0 to 100, with a score of 100 being death as a result of complications) which integrates all complications with their respective severities on a continuous scale ranging from 0 (no burden due to complications) to 100 (death as a result of complications).34 The CCI is based on the complication grading by the Clavien-Dindo Classification and captures every complication that occurred after an intervention.35 36 Postoperative complications were recorded 90 days after surgery and scored by severity using the Clavien-Dindo classification (online supplemental appendix 4). The Clavien-Dindo Classification is a standardised system of grading postoperative complications, ranging from grade I (minor events) to grade V (death). The therapy used to treat a specific complication is the basis of this classification in order to classify a complication in an objective and reproducible manner.35 36 The CCI is computed using these scores and an online calculator found at this link: http://www.assessurgery.com. Previous studies have validated the CCI as a measure of postoperative morbidity, suggesting that it offers a more comprehensive and sensitive endpoint for surgical research compared with traditional morbidity measures, such as the overall rate of complications or the rate of severe complications.34
Supplemental material
Secondary outcomes
Pain levels and pain-related function and activity limitation will be measured by VAS and ODI/NDI. Health- related quality of life will be evaluated by EuroQol Five Dimensions Questionnaire (0=worst health and 100=best health). Physical function will be assessed using 6 m walking speed and hand grip strength. Patient satisfaction will be measured using the North American Spine Society (NASS) satisfaction scale, measured on a scale of 1–4, with 1 indicating most satisfied and 4 indicating least satisfied.37 Answers on the satisfaction scale are as follows: The treatment met my expectations (score 1); I don’t not improve as much as I had hoped, but I would undergo the same treatment for the same outcome (score 2); I don’t improve as much as I had hoped and I would not undergo the same treatment for the same outcome (score 3); I am the same or worse than before treatment (score 4). Data regarding primary and total length of stay (LOS), non-home discharge, readmissions and unplanned readmission within 90 days after surgery will be followed up. The criteria for patient discharge were established as (1) a complete or significant reduction in preoperative symptoms, or the treatment has achieved the patient’s satisfaction; (2) absence of surgical complications or successful management of any postoperative issues and (3) no necessity for additional therapy.
Sample size determination and recruitment
Before patient enrolment, a sample-size calculation was performed using the Pwr package (R Project for Statistical Computing V.4.3.2, Base Package). The determination of the sample size for this trial was based on past data and assumptions. The significance of a 10-point difference in the Clavien-Dindo classification, which is deemed clinically meaningful, lies in its representation of the impact of a single grade 1 complication. Specifically, this difference correlates with the increased burden associated with a complication. Drawing from a prior investigation, the mean (SD) CCI for elderly patients who had spine surgery was found to be 14.0 (16.6).38 Therefore, a minimum of 118 participants is required. This is based on a 95% (α=0.05) confidence level and a 90% statistical power.
Estimations of sample size calculations were also performed for the secondary outcome. Based on a minimally clinical important difference of 10% on the ODI, an estimated SD for the ODI=20, a significance level of p=0.05, a power of 90%, an estimated 78 patients were required in each of the intervention groups.39 Considering a 5% attrition rate, the study was designed to enrol 164 patients. Our analysis led us to set a target of 78 patients per group. This is an exploratory study. The sample sizes were determined based on past research, as there is limited information available on elderly patients in the ERAS population. Recruitment for the study begins in May 2024, and the study is anticipated to be complete by December 2025.
Feasibility analysis
During the planning phase of the study, we evaluated the feasibility of the research, including aspects such as participant recruitment, the design of RCT, the follow-up plan and the schedule of progress. All three centres included in this study are large, tertiary teaching hospitals with a significant annual caseload of older patients (≥75 years old) requiring spinal fusion surgery, approximately 120 cases per year. This high volume of potential patients ensures a sufficient and consistent supply of candidates for the trial. The trial focuses on a specific disease area, which allows for a well-defined and accessible patient population. We will leverage this by collaborating with local healthcare providers and leveraging social media platforms to reach potential participants effectively. Recruitment progress will be closely monitored, and strategies will be adjusted as needed to overcome any challenges that may arise, ensuring the trial stays on track to meet its recruitment targets.
In the current protocol, the multidisciplinary team will play a crucial role in the study design phase, ensuring that the intervention is feasible and tailored to the specific needs of our patient population. During the conduct of the study, the intervention will be primarily guided by geriatricians and dietitians. Patients with severe malnutrition (MNA score <17) will be recommended for referral to specialised outpatient clinics. This study will be initiated by the National Clinical Research Center for Geriatric Diseases. Our multidisciplinary team has successfully collaborated in these previous studies,40–42 demonstrating our ability to manage complex interventions and collect high-quality data.
Statistical analysis plan
Data collected at different time points will be analysed according to the intention-to-treat principle. If patients decide after inclusion that they do not want surgery after all, the last testing will be done before the originally scheduled surgery date. Baseline characteristics will be compared between groups with the use of independent-samples t-test or Mann-Whitney U test for continuous variables, and data are presented as the mean (SD) or the median (IQR, 25–75) according to the distribution. χ2 test or Fisher’s exact test will be used for categorical variables, and data are presented as the number (percentage). Comparison of the primary outcome (90-day CCI) between groups will be performed using linear regression. Recruitment site (fixed-effect), age, body mass index (BMI), American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index, cervical/lumbar surgery and Fried score will be included in linear regression model as adjustment variables. Comparison of ODI/NDI and NASS scores between groups will be also performed using linear regression. Recruitment site (fixed-effect), age, BMI, American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index, cervical/lumbar surgery, baseline ODI/NDI and Fried score will be included in linear regression model as adjustment variables. The rates of postoperative complications, non-home discharge and 90-day unplanned readmission between groups will be compared using χ2 test or Fisher’s exact test. Comparison of primary/total LOS between groups will be performed using linear regression. Recruitment site (fixed-effect), insurance status, age, BMI, ASA score, Charlson Comorbidity Index, cervical/lumbar surgery, baseline ODI/NDI and Fried score will be included in linear regression model as adjustment variables. Because we had a single prespecified confirmatory outcome, we did not adjust for multiple comparisons. All tests were two sided, and the level of significance is p=0.05. Data analysis will be conducted by using Stata, V.14 (Stata).
Adverse event reporting and harms
Data on adverse events and serious adverse events will be collected and monitored by the research team to ensure the ongoing safety of participants. All adverse events will be recorded, and serious adverse events will be reported to the research ethics committees. In addition, the participants can also contact the staff via the hotline. The project team may discontinue any participant’s participation, for example, due to an adverse event and safety concerns.
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. As mentioned in the individual consent form, participants may obtain access to the final results of the study through the principal investigator.
Ethics and dissemination
Ethical approval has been provided by the independent Regional Committee of Ethics on 10th April 2024 (2024-088-001). Informed consent will be obtained by each participant prior to study enrolment. The findings of the current study will be shared with the scientific community through peer-reviewed publications and presentations at academic conferences. On the completion of the study, the aggregate results will be communicated to the participants and their families during an educational symposium. This symposium will provide an opportunity for participants to learn about the study outcomes and contribute to the broader understanding of the research findings.
Ethics statements
Patient consent for publication
Acknowledgments
We thank the multidisciplinary team consisting of geriatrician, spine surgeons, nurses, rehabilitation specialists, anaesthesiologists, neurologists, nutritionist and social workers. We thank all the participants involved in this study.
References
Footnotes
Contributors S-KW: concept, design, recruitment and first draft and review/editing of final manuscript. SL and PW: concept, design, recruitment and review/editing of final manuscript. SL and WW: review/editing of final manuscript. SL acted as guarantor.
Funding This study was funded by Capital’s Funds for Health Improvement and Research (No. 2024-1-2012) and Post-subsidy funds for National Clinical Research Center, Ministry of Science and Technology of China (No. XM2020_026283_000012_00414779_XMCG-JH001-XM001).
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.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.