Open access Protocol Multimodal prehabilitation as strategy for reduction of postoperative complications after cardiac surgery: a randomised controlled trial protocol Miquel Coca-­Martinez,1 Antonio Lopez-­Hernandez ‍ ‍,1 Mar Montane-­Muntane,1 Maria Jose Arguis,1,2 Elena Gimeno-­Santos,2,3 Ricard Navarro-­Ripoll,1 Juan Perdomo,1 Manuel Lopez-­Baamonde,1 Jose Rios,2,4 Jorge Moises,5 Maria Sanz de la Garza,6 Elena Sandoval,7 Barbara Romano,8 Raquel Sebio,3 Fernando Dana,3 Graciela Martinez-­Palli1,2 To cite: Coca-­Martinez M, ABSTRACT Lopez-­Hernandez A, Montane-­ Strengths and limitations of this study Introduction Prehabilitation programmes that Muntane M, et al. Multimodal combine exercise training, nutritional support and prehabilitation as strategy for ►► Scarce evidence of the benefits of multimodal pre- emotional reinforcement (multimodal prehabilitation) reduction of postoperative habilitation in cardiac surgery population. have demonstrated efficacy reducing postoperative complications after cardiac ►► First multimodal prehabilitation randomised con- surgery: a randomised controlled complications in the context of abdominal surgery. trolled trial assessing postoperative complications trial protocol. BMJ Open However, such programmes have seldom been studied as primary outcome in high-­risk cardiac surgery 2020;10:e039885. doi:10.1136/ in cardiac surgery, one of the surgeries associated with patients. bmjopen-2020-039885 higher postoperative morbidity and mortality. This trial will ►► A decrease in postoperative complications could assess the feasibility and efficacy in terms of reduction of ►► Prepublication history for have a big impact in clinical practice, contributing to postoperative complications and cost-­effectiveness of a this paper is available online. decrease length of stay and associated costs. To view these files, please visit multimodal prehabilitation programme comparing to the ►► Unmasked single-­ centre study. Nevertheless, as- the journal online (http://​dx.​doi.​ standard of care in cardiac surgical patients. sessments and postoperative complications will be org/​10.​1136/​bmjopen-​2020-​ Methods and analysis This is a single-­centre, collected by an independent blinded evaluator. 039885). randomised, open-­label, controlled trial with a 1:1 ►► Limited sample size of 160 patients to detect a re- ratio. Consecutive 160 elective valve replacement and/ Received 04 May 2020 duction of postoperative complications of 20%. or coronary revascularisation surgical patients will be Revised 02 November 2020 randomised to either standard of care or 4–6 weeks of Accepted 20 November 2020 multimodal prehabilitation that will consist in (1) two times/week supervised endurance and strength exercise the magnitude of the surgical stress and by the training sessions, (2) promotion of physical activity and patient’s functional status, which is frequently healthy lifestyle, (3) respiratory physiotherapy, (4) nutrition conditioned by the presence of comorbidities.2 counselling and supplementation if needed, and (5) weekly Despite the great advances that cardiac surgery mindfulness sessions. Baseline, preoperative and 3-­month and postoperative care have accomplished in postoperative data will be collected by an independent the last decades, perioperative morbidity and blinded evaluator. The primary outcome of this study will mortality continue to be significant; mainly due be the incidence of postoperative complications. to the increase of surgical indications in high-­ Ethics and dissemination This study has been approved by the Ethics Committee of Clinical investigation of risk populations, older patients and patients Hospital Clinic de Barcelona (HCB/2017/0708). The results with multiple comorbidities. The proportion of will be disseminated in a peer-­reviewed journal. patients referred to cardiac surgery aged more Trial registration number NCT03466606. than 75 years has risen from 16% in 1990 to 25%, © Author(s) (or their as shown in recent studies.3 Postsurgical compli- employer(s)) 2020. Re-­use cations have undeniable impact in quality of permitted under CC BY-­NC. No commercial re-­use. See rights INTRODUCTION life, short-­term and middle-­term survival and and permissions. Published by Background and rationale economical cost.4 5 Many studies have demon- BMJ. Patients undergoing cardiac surgery are the strated the association between frailty and For numbered affiliations see most likely to have complications (more than morbidity, mortality and hospital length of stay.6 end of article. 20%) and to die within the perioperative period Frailty is defined as a state of major vulnerability Correspondence to (5.5% perioperative mortality in Spain).1 The to stressors which usually goes with sarcopenia, Dr Graciela Martinez-­Palli; occurrence of postoperative complications and reduced strength, resistance and level of phys- ​GMARTIN@​clinic.​cat the risk of death are mainly conditioned by ical activity.7 It is estimated that 25%–50% of the Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 1 Open access candidates to cardiac surgery are frail. Frailty has been asso- behaviours, potentially beneficious preoperatively and ciated with a twofold to threefold increased risk of mortality postoperatively. and major morbidity after cardiac surgery and increased Although there is robust evidence regarding the effec- healthcare costs.7 8 tiveness of prehabilitation in patients undergoing abdom- Patients referred to cardiac surgery usually present a inal oncological surgery,18 24–26 the role of prehabilitation significant reduction in their functional capacity, which programmes on reducing undesirable perioperative is multifactorial. The cardiovascular disease itself and events has been assessed to a smaller extent in patients its associated symptoms such as dyspnoea or angina undergoing cardiac surgery. Arthur et al27 showed the pectoris, respiratory comorbidities, anaemia, malnour- efficacy of a multidimensional intervention in terms of ishment, muscle mass loss, depression or anxiety can be intensive care unit (ICU) and hospital length of stay found among the factors causing a decline in functional after coronary artery bypass grafting (CABG). However, capacity.9–12 All of the aforementioned factors induce a this study was carried out in a group of low-­risk patients tendency to physical inactivity which further deterio- and it did neither describe the preoperative intervention rates functional capacity. This deconditioning places nor its impact on functional capacity. Even though the the patients at a higher risk of postoperative morbidity existing evidence hints at a beneficial effect of prehabili- and mortality, complicating the recovery phase as well. A tation in cardiac surgery, the available literature is limited recent study in patients referred to oncological abdominal to low-­risk patients and presents high heterogeneity on surgery showed that the preservation of physical activity the intervention performed.28–30 This is a barrier to large-­ was the only factor independently associated to lower scale implementation of prehabilitation programmes in postoperative morbidity and mortality, showing a higher candidates to cardiac surgery. predictive value than age and the presence of comorbid- ities.13 This is concordant with numerous studies that Objectives relate physical activity and functional capacity with post- The general aim of this study is to investigate whether multi- operative complications and postoperative recovery after modal prehabilitation is effective in reducing postoperative major surgery.8 14 15 During the waiting period especially complications in patients undergoing elective coronary for surgery, physical inactivity is frequently more marked revascularisation and/or valve replacement surgery. due to the fear that physical activity may exacerbate Secondary outcomes will include: severity of postoper- symptoms and also due to surgical anticipatory anxiety. ative complications, impact of prehabilitation on func- Consequently, during this time span, there is a progres- tional capacity, anxiety and depression, physical activity, sive deterioration in functional capacity which is not only hospital length of stay, ICU stay and readmission rate and reflected by a significant mortality rate among patients a cost-­effectiveness analysis. who are on the wait list but also by a prolongation of the patients’ recovery.16 This prolonged postoperative period Trial design causes an increase in hospital length of stay, medication The trial protocol was written following the Standard administration and delays patients’ return to daily activi- Protocol Items: Recommendations for Interventional ties. Therefore, it has an impact on patients’ quality of life Trials guidelines.31 This is a prospective, randomised, and also on healthcare costs.4 5 open-­ label, controlled trial with allocation ratio 1:1 The aim of preoperative identification of the high-­ comparing standard of care versus 4–6 weeks of a multi- risk candidates to cardiac surgery is the development of modal prehabilitation programme. The recruitment strategies to optimise their health status and functional period is scheduled from March 2018 to January 2021. capacity prior to surgery.17 Prehabilitation emerges as a Both primary end-­point and baseline data will be blindly promising preventive intervention18 19 carried out during assessed. Intention-­to-­treat criteria will be used in order the presurgical period, while the patient is on the waiting to define the analysis population; all randomised patients list. It integrates a programme of supervised physical exer- will be included in the analysis according to assigned cise training, nutritional counselling and supplementa- group. The study protocol and informed consent have tion, and psychological support.20 21 The goal of physical been evaluated and accepted by the Medical Research exercise training is to increase the patient’s functional Ethics Committee at Hospital Clinic de Barcelona capacity in order to increase their physiological resistance (2017/0708). The trial will be conducted according to to surgical stress. Nutritional counselling is an essential the rules of Good Clinical Practice. complement to physical exercise training in as much as it guides patients in losing weight if needed, promotes anabolism and it ensures adequate protein intake to counteract the catabolism induced by exercise training.22 METHODS AND ANALYSIS Psychological support is a useful tool to reduce periop- Setting erative anxiety and depression, which in turn increases This trial will be conducted in a single academic tertiary patient engagement to physical exercise.23 Then, preha- hospital in Barcelona, Spain (Hospital Clinic de Barcelona). bilitation would provide an approach, through risk Assessments and study interventions will be performed at reduction therapies and promotion of heart healthy the outpatient ambulatory infrastructure of Hospital Clinic 2 Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 Open access de Barcelona. Surgery and postoperative hospitalisation will patient could tolerate on the incremental CPET (Ergo- take place in the aforementioned hospital. line 900, Ergoline, Bitz, Germany and Ergocard Profes- sional, Medisoft, Sorinnes, Belgium). It will detect the Eligibility criteria responsiveness of interventions in terms of improved Inclusion criteria exercise capacity. Participants will also undergo hand Patients older than 18 years old scheduled for CABG and/ grip strength test (Jamar Hydraulic Hand Dynamometer; or valve surgery, with an expected waiting time before Sammons Preston, Bolingbrook, Illinois, USA), 6 min surgery of 6 weeks or more and that accept to participate walk test (6MWT)35 and sit-­ stand (STS) test.36 The to-­ in this clinical trial. 6MWT will assess functional capacity in relation to activ- ities of daily living. Constant work rate exercise test and Exclusion criteria 6MWT are complementary in the comprehensive evalua- Functional or anatomical physical impairment that tion of these patients. Nutritional status will be assessed makes it impossible to complete the assessments and the by a registered dietitian using the Patient Generated prehabilitation programme, determined by an experi- Subjective Global Assessment, weight, body mass index, enced physiotherapist in cardiopulmonary rehabilitation; prealbumin and glycosylated hemoglobin (HbA1c). cognitive impairment that would impede understanding American Society of Anesthesiologists status, Charlson of study procedures, informed consent or study question- Comorbidity Index37 and Euroscore II38 data will be naires; cardiac instability; dynamic left ventricle outflow recorded. Physical activity will be measured by the Yale tract obstruction, proven exercise induced arrhythmias; Physical Activity Survey (YPAS),39 functional capacity by other comorbidities that imply clinical instability; patient Dukes Activity Status Index questionnaire40 and Anxiety refusal to participate in the study or impossibility to and depression measured using the Hospital and Anxiety attend supervised training sessions. Specifically, we will Scale (HADS).41 All patients will be reassessed using the not exclude patients with severe pulmonary hypertension same tests before undergoing cardiac surgery (T7) and at or severe valvular stenosis. 3 months postoperatively (T9). Study outline Participant screening, recruitment, randomisation and informed Procedures consent (T-1) Standard of care (T1–T6) Participant selection will begin after surgery is proposed by Participants in the control group will follow the standard the cardiac surgeon and a referral for preoperative evalu- preoperative protocol at Hospital Clinic de Barcelona ation is done. Within 1 week of the referral patient will be that includes physical activity recommendation, nutri- seen by an anaesthesiologist who will screen for eligibility tional and smoking cessation advice. Moreover, patients criteria and will explore the willing of participating in a suffering from iron-­deficiency anaemia will receive intra- study related with cardiopulmonary reserve and postop- venous iron infusion.42 erative outcome. If eligibility criteria are met, patient will be approached by a research medical staff involved in the Multimodal Prehabilitation programme (PreHab) (T1–T6) trial. The research medical staff in charge of obtaining Participants in the intervention group will undergo, informed consent will randomise prior to meeting with in addition to the standard of care aforementioned, the patient and proposing study participation. a 4–6 week personalised multimodal prehabilitation Participants will be randomised with 1:1 ratio by a programme. The interventions included will be patient-­ computer-­generated sequence using Macro-­SCReN soft- centred aiming to optimise patients’ preoperative health ware V.4.8.1.8302 (2018 Elsevier). status while enhancing their empowerment and engage- ment. The main components of the programme will Baseline assessment (T0) consist in: After signing the informed consent all participants will 1. Supervised exercise training programme: 1-­hour ses- undergo a full blinded baseline medical, functional, sion, two sessions per week at the hospital outpatient nutritional and psychological assessment. Allocation to gym facility conducted by a physiotherapist. Heart rate, study group will be revealed to the part of the research blood pressure, oxygen saturation and perceived exer- team that will carry out the intervention once baseline tion rate using the modified Borg scale43 will be moni- assessment is completed. The functional capacity assess- tored throughout the training session. ment will be conducted by a physiotherapist on different i. Endurance training will be performed on station- days to avoid fatigue related to it, and will consist in a ary bicycle (Bike Forma; Technogym; Cesena, standard incremental cardiopulmonary exercise testing Italy) and will be tailored to the participants ac- on cycloergometer (CPET), where physiological variables cording to their PWR (baseline CPET). Each in response to exercise and workload in watts (W) will be session includes 5 min of warm-­up and 5 min of measured at the anaerobic threshold and at VO2 peak.32–34 cool-­down pedalling at 30%–40% of their PWR. Endurance time (ET)33 in seconds will be measured by An interval training consists in at least 5 bouts a cycling constant work-­rate exercise test performed at a combining 2 min of moderate to high-­intensity ex- load equivalent of 80% of the peak workload (PWR) the ercise (starting at 70% of PWR and progressing to Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 3 Open access 90%–100% of PWR throughout the programme) the prehabilitation period will be recorded and will be interspersed with 3 min recovery periods at lower reported immediately to the principal investigator. intensity (40%–50% of the PWR). Progression during the sessions will be tailored on individual Preoperative (T7) and 3-month postoperative functional basis to maximise the training effect. assessment (T9) ii. Strength training will consist in 2–3 upper (pecto- All participants’ functional capacity will be reassessed rals and latissimus dorsi) and lower (quadriceps) before surgery and 3 months postoperative using ET, limb exercises based on 2–3 sets of 8–12 repeti- hand grip strength test, 6MWT and STS test. Anxiety and tions avoiding valsalva’s manoeuvres. The train- depression and physical activity questionnaires will be ing is performed in a modular training station also recorded at these time points. using external load (Plurima Multistation Wall, Technogym; Cesena, Italy). At the first session, the Surgery and hospital admission (T8) physiotherapist obtains for each muscle group, Surgery will take place in the habitual waiting timeframe the tolerated weight for the eight-­repetition max- and will be performed by the regular cardiac surgery imum test, to establish the initial weight for the teams present in Hospital Clinic de Barcelona. Perioper- strength training. The weight and/or the number ative clinical protocols will be followed in a usual fashion of repetitions will increase every week to ensure independently of the group allocation or study partici- strength progression and maximise the training pation. Hospital staff, anesthesiologists, surgeons, nurses effect. The strength training is performed 2 days and other people involved in patient care will be blinded per week (in combination with the endurance to the study arm. Intraoperative complications or events training). as well as the need blood product transfusion or any devi- 2. Promotion of physical activity and healthy lifestyle: ation from normal course will be recorded in the intraop- a physiotherapist adequately trained in behavioural erative case report form (CRF). strategies will use motivational interviewing techniques Summary of flow chart is given in figure 1. to promote physical activity and healthy lifestyle. The The primary outcome of this study is the incidence motivational interview will focus on empathy, reflective of postoperative complications before patient discharge listening and affirmation, and will address the patients’ from the hospital. The type of complications included barriers and limitations related to physical activity, to will be classified following the standards of the European get a change in behaviour. Society of Anesthesiology and the European Society of 3. Respiratory physiotherapy: patients will be instructed Intensive Care medicine46: Acute kidney injury, acute on daily breathing exercises (chest expansions, dia- respiratory distress syndrome, arrhythmia, cardiac arrest, phragmatic respirations and deep inspirations) with a cardiogenic pulmonary oedema, deep vein throm- volumetric incentive spirometer (Coach 2; Smith Med- bosis, delirium, gastrointestinal bleed, infection, source ical; London, UK), at least twice per day, 1–2 sets of uncertain, laboratory confirmed bloodstream infection, 10–15 breathings for each exercise. myocardial infarction, pneumonia, paralytic ileus, post- 4. Nutrition counselling and supplementation: partic- operative haemorrhage, pulmonary embolism, stroke, ipants will meet with a registered dietitian that will surgical site infection and urinary tract infection. assess their nutritional status and their diet based on The severity of complications will be also recorded, as a self-­reported 3-­day food diary. Nutritional teaching a secondary outcome measure, following the Clavien-­ and a Mediterranean, well-­balanced cardioprotective Dindo classification.47 To ensure accuracy of the primary diet will be instructed. An adequate protein intake of endpoint, the data will be collected by a physician member 1.2–1.5 g/kg/day will be aimed to meet the European of the team, every day according to standard clinical care, Society for Clinical Nutrition and Metabolism recom- and then reviewed by another researcher. Both of them mendations.44 45 If patient does not reach the recom- will be blinded to the study group to avoid bias. Patient-­ mended daily protein intake with diet, protein supple- chargeable costs (ie, pharmacy and blood bank); tariff-­ mentation with whey protein (Fresubin Protein pow- chargeable costs (ie, medical care, diagnostic techniques, der, Fresenius Kabi España) will be provided to reach laboratories, interconsultations); other healthcare the aforementioned daily protein intake. resources use (ie, ICU stay, total hospitalisation length of 5. Weekly mindfulness sessions: Patients will be invited to stay, readmissions, emergency room visits) and survival attend 1 weekly hourly session of Mindfulness-­Based will be also assessed at 3 months and 1 year postcardiac Stress Reduction conducted by a registered psychol- surgery by chart review. ogist. It will be strongly recommended to those who reported high rates of anxiety and depression on the Data collection management and monitoring baseline HADS. All participant’s de-­identified data collected at different Compliance to the prehabilitation programme will be time points (table 1) will be entered by research staff calculated counting the number of supervised sessions members into Research Electronic Data Capture attended out of the total intended sessions. The occur- (REDCap) CRF via a secure webpage interface. Online rence of any exercise-­ related adverse events during data will be stored in a safe server located the Hospital 4 Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 Open access Data monitoring Previous experiences in prehabilitation studies show a clear absence of safety problems related to the experimental procedure. In addition, it is an unmasked trial, which is easier and faster to detect a problem and take appropriate measures. The investigators of the present study are responsible for ensuring that the study meets the proposed milestones and deadlines. They will also be responsible for all aspects of the study design, management, ethical conduct, anal- ysis and dissemination of results. Safety data, including new hospitalisation, worsening angina or heart failure and arrhythmias, will be captured and all adverse events will be reported. They are respon- sible to periodically evaluate the study data for participant safety and study conduct, in addition to making modifi- cations and/or termination of the trial after communica- tion to the Ethics Committee of Clinical investigation of Hospital Clinic de Barcelona. Outcomes Clinical outcomes The primary outcome variable of the study is the inci- dence of postoperative complications classified following the standards of the European Society of Anaesthesiology and European Society of intensive Care Medicine.46 Secondary outcome variables will be: (1) severity of postoperative complications using Dindo-­Clavien classifi- cation; (2) hospital and ICU days of stay and (3) 3-­month and 1-­year mortality. Other outcome variables include: (1) ET measured by a cycling constant work-­rate exercise testing at 80% of peak oxygen uptake; (2) distance covered in the 6MWT; (3) STS test and hand-­grip strength; (4) physical activity by the YPAS and (5) hospitalisation direct costs and use of healthcare resources into the follow-­up 1-­year period after surgery. Outcomes for feasibility of prehabilitation include inci- dence of adverse events during training, compliance to the supervised training sessions and adherence to the programme. Statistical analyses Sample size for this trial has been calculated based on the primary outcome of the study that is the reduction of incidence of postoperative complications in the preha- bilitation group. Our own data in a similar population of patients indicated that the incidence of postoperative complications was 30%. Accepting a two-­sided alpha-­risk of 0.05 and beta-­risk of 0.20, anticipating 10% of drop-­ outs, indicated the need of including 80 participants per Figure 1 Flow chart. CABG, coronary artery bypass group to detect a reduction of the percentage of patients grafting. with complications in the intervention group compared with the control group 20%. No adjustment for multi- plicity was proposed due to this is a clinical trial with one Clinic facilities. All research team members will receive primary outcome and without needed of interim analyses. training on how to perform all the functional test This trial will use intention-­to-­treat criteria for main included in the trial and how to input data in REDCap analysis; nevertheless, analysis per protocol will also be data manager. performed as supportive analysis. Categorical variables, as Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 5 6 Table 1 Study procedures and timeline Multimodal prehabilitation Screening Baseline 6 weeks T1–T6 Preoperative Surgery and 3 months 12 months Time point visit T(−1) assessment T0 T1 T2 T3 T4 T5 T6 assessment T7 admission T8 postoperative T9 postoperative T10 Open access Medical evaluation X X Screening for trial eligibility X Informed consent X Patient random allocation X Study groups Multimodal Prehab (PreHab) X X X X X X X X X X X Standard of Care (control) X X X X X Study tests and measurements Demographics X Anthropometrics X X Incremental CPET X Constant work-­rate CPET X X X Prealbumin, albumin, Hb, HbA1c X 6MWT X X X Sit to Stand test X X X Grip strength X X X YPAS X X X Compliance to prehab programme X X X X X X HADS X X X Charlson Comorbidity Index X Euroscore II X Intraoperative complications X ICU stay X Length of stay X Postoperative complications X Reinterventions X Readmissions X X Emergency room visits X X Survival X X CPET, cardiopulmonary exercise testing; HADS, Hospital and Anxiety Scale; ICU, intensive care unit; 6MWT, 6 min walk test; YPAS, Yale Physical Activity Survey. Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 Open access well primary outcome, will be analysed with Fisher’s exact All the explorations and tests in this trial are consid- test. Continuous variables will be compared with Student's ered minimally invasive and are performed in pres- t-­test for independent groups and Mann-­Whitney U test ence of a physician under strict monitoring. The according to each variable distribution. Ordinal variables non-­pharmacological characteristics of the intervention will be analysed by Mann-­Whitney U test. exclude the need for additional trial insurances. Secondary outcomes looking at the difference between groups for the change in functional capacity over the Informed consent different time points (repeated measures) will be anal- To avoid contamination among groups, there will be two ysed using generalised estimating equations models and informed consents: all participants allocated in the control will be shown as estimated effect and their 95% CI. For group will be proposed to participate in a study to inves- these analyses, we will apply unstructured matrix in order tigate the relationship between cardiopulmonary reserve to assess intra-­subject correlation, for cases with no adjust- and postoperative outcomes and will sign the informed ments we will apply an autoregressive model (AR) (1) consent for the control group. All participants allocated type matrix. in the intervention group will be proposed to participate A cost-­effectiveness study will be carried out from the in a study that investigates the effects of a multimodal perspective of the hospital, taking into account the costs prehabilitation programme on postoperative outcomes. of the intervention and the expenses related to the disease Patients in the intervention group will sign the interven- during the follow-­ up (30 days). For costs, the mean or tion group informed consent, where the intervention is median and their 95% CI of difference in per-­patient costs defined. All potential participants will be given time to between the two groups will be computed (control-­group read the informed consent form, consider participation costs minus prehabilitation-­ group costs), so that positive and ask doubts or questions regarding the study partici- values will be interpreted as savings of the prehabilitation pation. If patient agrees to participate, he or she will be programme. Considering previous experience with preha- asked to provide written consent in the informed consent bilitation cost analysis,19 a highly skewed distribution will document. Participants will be free to withdraw their probably be present. Right-­sided asymmetric distribution consent and opt out from the trial at any time without appears when some patients incur in high costs, mainly needing to explain the reason why. Withdrawal from the because of major medical complications. To deal with this, trial will not carry any prejudice in the participant care. a non-­parametric approach (bootstrapping) will be used. Bootstrap analysis yields more robust when dealing with Author affiliations 1 Anaesthesiology and Intensive Care, Hospital Clinic de Barcelona, Barcelona, skewed cost data compared with non-­parametric tests. Catalunya, Spain 2 August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Catalunya, Patient and public involvement Spain Patient and public involvement was taken into consideration 3 Prehabilitation Unit, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain 4 for the development of this protocol. A satisfaction question- Biostatistics Unit, Universitat Autonoma de Barcelona Facultat de Medicina, naire was given to a sample of patients who had undergone a Bellaterra, Catalunya, Spain 5 Respiratory Medicine, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain prehabilitation programme as part of their clinical pathway 6 Department of Cardiology, Cardiovascular Institute, Hospital Clinic de Barcelona, before an abdominal surgery. They gave feedback about Barcelona, Catalunya, Spain both the assessments and interventions included in this trial. 7 Department of Cardiac Surgery, Cardiovascular Institute, Hospital Clinic de As a result of their feedback we proceeded to reduce the Barcelona, Barcelona, Catalunya, Spain 8 number of questionnaires given during the assessments, as Nutrition and Clinical Dietetics, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain well as an assessment and intervention redesign, resulting in a more flexible schedule for the participants. Contributors MC-­M, EG-­S, AL-­H, MSdlG, RN-­R, MJA and GM-­P contributed to trial design and conception. MJA, GM-­P colead investigators, obtained ethics approval. MC-­M, MM-­M, AL-­H, MJA, JR and GM-­P contributed to manuscript conception and ETHICS AND DISSEMINATION drafting. EG-­S, MSdlG, ES, BR, RN-­R, FD, JM, RS, JP contributed to manuscript revision and edition. MC-­M, MM-­M, AL-­H, EG-­S, MSdlG, ES, BR, RN-­R, FD, JM, RS, Ethics approval for this trial has been obtained by the Ethics JP, ML-­B, MJA and GM-­P approved the final version of the manuscript. Committee of Clinical investigation of Hospital Clinic de Funding Funding for the trial was provided by a grant from the Spanish Public Barcelona (HCB/2017/0708). This trial will be conducted Government Fondos de Investigación en Salud (FIS) Instituto Carlos III (PI17/00852), according to the principles emanating from the Helsinki after a peer-­reviewed process. The grant was awarded as a mean for the Declaration, with compliance to the Good Clinical Prac- implementation of multimodal prehabilitation in cardiac surgery and the present trial is the main receiver of its funds along with a subproject of prehabilitation tice and the International Council for Harmonisation of for cardiac transplant candidates. Protein supplementation with Fresubin Protein Technical Requirements for Pharmaceuticals for Human powder was provided and supported by Fresenius Kabi España. Use (ICH) guidelines. Confidentiality for participants and Disclaimer The funding sources had no role in the design of this study and will not their data will be guaranteed according to the Spanish have any role during its execution, analyses or interpretation of the data. data protection law ‘Ley Orgánica de Protección de Datos Competing interests All researchers and authors of this protocol declare that they de Carácter Personal’ (15/1999, 13 diciembre) and the have no conflict of interest. General Data Protection Regulation from the European Patient and public involvement Patients and/or the public were not involved in Union (EU 2016/679). the design, or conduct, or reporting, or dissemination plans of this research. Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 7 Open access Patient consent for publication Not required. 21 van Rooijen SJ, Molenaar CJL, Schep G, et al. Making patients fit for surgery: introducing a four Pillar multimodal prehabilitation program Provenance and peer review Not commissioned; externally peer reviewed. in colorectal cancer. Am J Phys Med Rehabil 2019;98:888–96. Open access This is an open access article distributed in accordance with the 22 Gillis C, Carli F. Promoting perioperative metabolic and nutritional Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which care. Anesthesiology 2015;123:1455–72. 23 Miró J, Raich RM. Preoperative preparation for surgery: an analysis permits others to distribute, remix, adapt, build upon this work non-­commercially, of the effects of relaxation and information provision. Clin Psychol and license their derivative works on different terms, provided the original work is Psychother 1999;6:202–9. properly cited, appropriate credit is given, any changes made indicated, and the use 24 Trépanier M, Minnella EM, Paradis T, et al. Improved disease-­free is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. survival after prehabilitation for colorectal cancer surgery. Ann Surg 2019;270:493–501. ORCID iD 25 Minnella EM, Awasthi R, Loiselle S-­E, et al. Effect of exercise and Antonio Lopez-­Hernandez http://​orcid.​org/​0000-​0002-​5310-​030X nutrition prehabilitation on functional capacity in esophagogastric cancer surgery: a randomized clinical trial. JAMA Surg 2018;153:1081–9. 26 Minnella EM, Bousquet-­Dion G, Awasthi R, et al. Multimodal prehabilitation improves functional capacity before and after colorectal surgery for cancer: a five-­year research experience. Acta REFERENCES Oncol 2017;56:295–300. 1 Polo López L, Centella Hernández T, López Menéndez J, et al. 27 Arthur HM, Daniels C, McKelvie R, et al. Effect of a preoperative Cirugía cardiovascular en España en El año 2015. Registro de intervention on preoperative and postoperative outcomes in low-­risk intervenciones de la Sociedad Española de Cirugía Torácica-­ patients awaiting elective coronary artery bypass graft surgery. A Cardiovascular. Cir cardiov 2016;23:289–305. randomized, controlled trial. Ann Intern Med 2000;133:253–62. 2 Moonesinghe SR, Mythen MG, Grocott MPW. High-­risk surgery: 28 Hulzebos EHJ, Helders PJM, Favié NJ, et al. Preoperative intensive epidemiology and outcomes. Anesth Analg 2011;112:891–901. inspiratory muscle training to prevent postoperative pulmonary 3 Afilalo J, Mottillo S, Eisenberg MJ, et al. Addition of frailty and complications in high-­risk patients undergoing CABG surgery: a disability to cardiac surgery risk scores identifies elderly patients randomized clinical trial. JAMA 2006;296:1851–7. at high risk of mortality or major morbidity. Circ Cardiovasc Qual 29 Waite I, Deshpande R, Baghai M, et al. Home-­based preoperative Outcomes 2012;5:222–8. rehabilitation (prehab) to improve physical function and reduce 4 Vonlanthen R, Slankamenac K, Breitenstein S, et al. The impact of hospital length of stay for frail patients undergoing coronary artery complications on costs of major surgical procedures: a cost analysis bypass graft and valve surgery. J Cardiothorac Surg 2017;12:91. of 1200 patients. Ann Surg 2011;254:907–13. 30 Sawatzky J-­AV, Kehler DS, Ready AE, et al. Prehabilitation program 5 Lee L, Tran T, Mayo NE, et al. What does it really mean to “recover” from an operation? Surgery 2014;155:211–6. for elective coronary artery bypass graft surgery patients: a pilot 6 Lee DH, Buth KJ, Martin B-­J, et al. Frail patients are at increased risk randomized controlled study. Clin Rehabil 2014;28:648–57. for mortality and prolonged institutional care after cardiac surgery. 31 Chan A-­W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: Circulation 2010;121:973–8. defining standard protocol items for clinical trials. Ann Intern Med 7 Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of 2013;158:200–7. disability, frailty, and comorbidity: implications for improved targeting 32 West MA, Asher R, Browning M, et al. Validation of preoperative and care. J Gerontol A Biol Sci Med Sci 2004;59:M255–63. cardiopulmonary exercise testing-­derived variables to predict 8 Afilalo J, Eisenberg MJ, Morin J-­F, et al. Gait speed as an incremental in-­hospital morbidity after major colorectal surgery. Br J Surg predictor of mortality and major morbidity in elderly patients 2016;103:744–52. undergoing cardiac surgery. J Am Coll Cardiol 2010;56:1668–76. 33 American Thoracic Society, American College of Chest Physicians. 9 Foster C, Haviland J, Winter J, et al. Pre-­Surgery depression and ATS/ACCP statement on cardiopulmonary exercise testing. Am J confidence to manage problems predict recovery trajectories of Respir Crit Care Med 2003;167:211–77. health and wellbeing in the first two years following colorectal cancer: 34 Levett DZH, Jack S, Swart M, et al. Perioperative cardiopulmonary results from the crew cohort study. PLoS One 2016;11:e0155434. exercise testing (CPET): consensus clinical guidelines on indications, 10 Wilson RJT, Davies S, Yates D, et al. Impaired functional capacity organization, conduct, and physiological interpretation. Br J Anaesth is associated with all-­cause mortality after major elective intra-­ 2018;120:484–500. abdominal surgery. Br J Anaesth 2010;105:297–303. 35 ATS Committee on Proficiency Standards for Clinical Pulmonary 11 Wolfe RR. The underappreciated role of muscle in health and Function Laboratories. ATS statement: guidelines for the six-­minute disease. Am J Clin Nutr 2006;84:475–82. walk test. Am J Respir Crit Care Med 2002;166:111–7. 12 Chermesh I, Hajos J, Mashiach T, et al. Malnutrition in cardiac 36 Jones CJ, Rikli RE, Beam WC. A 30-­S chair-­stand test as a measure surgery: food for thought. Eur J Prev Cardiol 2014;21:475–83. of lower body strength in community-­residing older adults. Res Q 13 Dronkers JJ, Chorus AMJ, van Meeteren NLU, et al. The association Exerc Sport 1999;70:113–9. of pre-­operative physical fitness and physical activity with 37 Charlson ME, Pompei P, Ales KL, et al. A new method of classifying outcome after scheduled major abdominal surgery. Anaesthesia prognostic comorbidity in longitudinal studies: development and 2013;68:67–73. validation. J Chronic Dis 1987;40:373–83. 14 Snowden CP, Prentis J, Jacques B, et al. Cardiorespiratory fitness 38 Nashef SAM, Roques F, Sharples LD, et al. EuroSCORE II. Eur J predicts mortality and hospital length of stay after major elective Cardiothorac Surg 2012;41:734–45. surgery in older people. Ann Surg 2013;257:999–1004. 39 Donaire-­Gonzalez D, Gimeno-­Santos E, Serra I, et al. [Validation of 15 Shulman MA, Cuthbertson BH, Wijeysundera DN, et al. Using the the Yale Physical Activity Survey in chronic obstructive pulmonary 6-­minute walk test to predict disability-­free survival after major disease patients]. Arch Bronconeumol 2011;47:552–60. surgery. Br J Anaesth 2019;122:111–9. 40 Struthers R, Erasmus P, Holmes K, et al. Assessing fitness for 16 Sobolev BG, Levy AR, Kuramoto L, et al. The risk of death surgery: a comparison of questionnaire, incremental shuttle walk, associated with delayed coronary artery bypass surgery. BMC Health and cardiopulmonary exercise testing in general surgical patients. Br Serv Res 2006;6:85. J Anaesth 2008;101:774–80. 17 Carli F, Minnella EM. Preoperative functional assessment and 41 Snaith RP. The hospital anxiety and depression scale. Health Qual optimization in surgical patient: changing the paradigm. Minerva Life Outcomes 2003;1:29. Anestesiol 2017;83:214–8. 42 Munting KE, Klein AA. Optimisation of pre-­operative anaemia in 18 Barberan-­Garcia A, Ubré M, Roca J, et al. Personalised patients before elective major surgery - why, who, when and how? prehabilitation in high-­risk patients undergoing elective major Anaesthesia 2019;74 Suppl 1:49–57. abdominal surgery: a randomized blinded controlled trial. Ann Surg 43 Borg G. Psychophysical scaling with applications in physical work 2018;267:50–6. and the perception of exertion. Scand J Work Environ Health 1990;16 19 Barberan-­Garcia A, Ubre M, Pascual-­Argente N, et al. Post-­discharge Suppl 1:55–8. impact and cost-­consequence analysis of prehabilitation in high-­risk 44 Weimann A, Braga M, Carli F, et al. ESPEN guideline: clinical nutrition patients undergoing major abdominal surgery: secondary results in surgery. Clin Nutr 2017;36:623–50. from a randomised controlled trial. Br J Anaesth 2019;123:450–6. 45 Gillis C, Loiselle S-­E, Fiore JF, et al. Prehabilitation with whey protein 20 Bousquet-­Dion G, Awasthi R, Loiselle Sarah-Ève, et al. Evaluation of supplementation on perioperative functional exercise capacity in supervised multimodal prehabilitation programme in cancer patients patients undergoing colorectal resection for cancer: a pilot double-­ undergoing colorectal resection: a randomized control trial. Acta blinded randomized placebo-­controlled trial. J Acad Nutr Diet Oncol 2018;57:849–59. 2016;116:802–12. 8 Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 Open access 46 Jammer I, Wickboldt N, Sander M, et al. Standards for definitions Taskforce on perioperative outcome measures. Eur J Anaesthesiol and use of outcome measures for clinical effectiveness research in 2015;32:88–105. perioperative medicine: European perioperative clinical outcome 47 Dindo D, Demartines N, Clavien P-­A. Classification of surgical (EPCO) definitions: a statement from the ESA-­ESICM joint complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. Coca-­Martinez M, et al. BMJ Open 2020;10:e039885. doi:10.1136/bmjopen-2020-039885 9