Prehabilitation Prior to Major Cancer Surgery

Prehabilitation Prior to Major Cancer Surgery: Training for Surgery to Optimize Physiologic Reserve to Reduce Postoperative Complications Hilmy Ismail, Prue Cormie, Kate Burbury, Jamie Waterland, Linda Denehy & Bernhard Riedel Current Anesthesiology Reports e-ISSN 2167-6275 Curr Anesthesiol Rep DOI 10.1007/s40140-018-0300-7

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Author's personal copy Current Anesthesiology Reports https://doi.org/10.1007/s40140-018-0300-7

CANCER ANESTHESIA (B RIEDEL AND V GOTTUMUKKALA, SECTION EDITORS)

Prehabilitation Prior to Major Cancer Surgery: Training for Surgery to Optimize Physiologic Reserve to Reduce Postoperative Complications Hilmy Ismail 1,2 & Prue Cormie 3 & Kate Burbury 4 & Jamie Waterland 1,5,6 & Linda Denehy 5,6 & Bernhard Riedel 1,2

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract Purpose of Review The aging, sedentary global population and associated increasing incidence of cancer calls for increasingly complex surgery. These patients are at particular risk of postoperative complications. This review will explore the redesign of the perioperative care pathway, with emphasis on preoperative risk stratification to identify modifiable risk, to implement risk mitigation strategies (e.g., prehabilitation), and to partner with patients to enhance recovery after surgery. Recent Findings In the last decade, there has been a growing body of literature surrounding prehabilitation. A number of these studies report a staggering halving of postoperative complications. This body of literature requires perioperative medicine clinicians to appraise and build on the robustness of the data and to consider pragmatic strategies toward implementation of what appears to be a cost-effective intervention. Summary A redesign of perioperative care pathways with early risk stratification and implementing risk mitigation strategies is essential to delivering on the value proposition of healthcare. Challenges include a redesign of funding models to deliver such services, engaging patients with relatively remote access to such services, and the cultural trends of sedentary lifestyles and perceived urgency to have immediate surgery at all costs. Keywords Cancer surgery . Prehabilitation . Exercise . Nutrition . Hematinics . Postoperative complications

Introduction

This article is part of the Topical Collection on Cancer Anesthesia * Hilmy Ismail [email protected] 1

Department of Anaesthesia, Perioperative and Pain Medicine, Peter MacCallum Cancer Centre, Grattan St, Parkville, VIC 3005, Australia

2

Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia

3

Exercise Physiology, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia

4

Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Australia

5

Physiotherapy, Melbourne School of Health Sciences, Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia

6

Department of Allied Health, Peter MacCallum Cancer Centre, Melbourne, Australia

At a time when healthcare is under increasing pressure to provide patient-centered value-based care, prehabilitation provides a potentially cost-effective opportunity to mitigate modifiable risk, to reduce complications after surgery and significantly reduce healthcare expenditure. This article provides an overview of the current evidence for prehabilitation with particular emphasis on cancer surgery and explores the impact and value proposition of prehabilitation and the barriers to implementation. Prehabilitation is a process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment (e.g., surgery). Prehabilitation includes assessments of baseline functional level of patients, identification of modifiable risk factors, provision of targeted interventions to mitigate risk and reduce the incidence and the severity of current and future impairments [1]. Over the last decade or so, this definition has widened to include respiratory [2••] and aerobic exercise programs [3••] to include hematinic [4], nutritional [5], and psychological [6, 7] interventions.

Author's personal copy Curr Anesthesiol Rep

Complications after Surgery Complications after major surgery are common. In the analysis of a large database of over 100,000 patients, major complications occurred in up to 19.3% of patients, including pneumonia in up to 28.7% of patients following colectomy [8]. The cost of severe complications can exceed non-complicated surgery by several fold [9]. Independent of preoperative patient risk, the occurrence of a complication within 30 days of surgery also associates with reduced intermediate term survival by 69% [8]. This is further supported by more recent studies reporting that postoperative myocardial injury and postoperative pulmonary complications are associated with decreased intermediate term survival [2••, 10]. In patients having cancer surgery, this association between complications and decreased long-term survival may be partly explained by a delay in return to Intended Oncological Therapies (RIOT; postoperative adjuvant therapy) with poor oncological outcomes [11]. Why do patients suffer postoperative complications? Patients presenting for cancer surgery are often significantly deconditioned due to frailty, multiple comorbidities, and neoadjuvant treatments for cancer. These patients have been typically described to be subject to “multiple hits” [12]. Frequently, underpinning these “multiple hits” is a sedentary lifestyle, reflected in poor functional capacity. The inability to increase oxygen delivery (DO2) and reduce oxygen debt at times of “stress” has been putatively proposed as one of the key underlying mechanisms for developing postoperative complications [13, 14].

Quantifying Surgical Risk Predicting patients’ risk for postoperative complications is vital if perioperative clinicians are to attempt to optimize the patient’s status prior to surgery [15]. The wide variation in risk scores and definitions of postoperative morbidity and surgical outcomes in the current literature adds complexity to establishing strategies for risk mitigation. Various organ-specific and system-specific risk-estimates for perioperative complications exist and are commonly used. These include the Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score [16], and the Melbourne Group Score, [2••, 17, 18] for respiratory complications. Also, the Revised Cardiac Risk Index (RCRI), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentrations and the Duke Activity Status Index (DASI) for cardiac complications [19]. These biomarkers and risk indices are commonly researched and reported in isolation from each other [2••, 19]. This in turn results in optimization strategies being implemented in siloes with unimodal interventions. Global risk scoring systems include the ASA-PS (American Society of Anesthesia Physical Status) scores, the American College of Surgeons National Surgical Quality Improvement

Program (NSQIP) risk score [20], POSSUM (physiological and operative severity score for the enumeration of mortality and morbidity) [21], SORT (Surgical Outcome Risk Tool) [22], etc. These scores are clinician-estimated and may incorporate elements of functional capacity. The NSQIP score allows the clinician to use functional capacity or frailty to add a subjective risk-weightage and also considers the complexity of the surgical procedure. Similarly, the subjective functional status can be incorporated to the ASA score and has been successfully used to predict postoperative morbidity [23]. The limitation of this approach, though, is the risk of introducing inter-observer variability into the risk assessment. Objective, individualized measures of predicting global risk of postoperative complications have focused on assessing functional capacity to identify the “unfit” patient, which is modifiable [24]. Cardiopulmonary Exercise Testing (CPET), unlike other objectively measured functional tests of exercise capacity like the Incremental Shuttle Walk Test (ISWT), or 6-Min Walk Test (6MWT), has been shown to be predictive of postoperative complications in a meta-analysis of 1418 patients with colorectal cancer [25], gastro-esophageal cancer [26], hepatic and pancreatic resection [27], and lung surgery [28], albeit predominantly in single-center studies. With regard to postoperative morbidity, West et al. [29] reported that CPET-derived parameters had good predictive capacity (AUC = 0.83, 95%CI 0.79– 0.87) in a validation study of 703 patients having major colorectal cancer surgery from 6 UK centers. With regard to mortality, Wilson et al. reported in a retrospective analysis of a cohort of 847 patients that a clinical history of ischemic heart disease (RR 3.1, 95% CI 1.3–7.7), respiratory inefficiency during exercise (Ve/VCO2 > 34: RR 4.6, 95% CI 1.4–14.8), and impaired oxygen consumption at anaerobic threshold (VO2 at AT < 10.9 mL/kg/min; RR 6.8, 95% CI 1.6–29.5) were significant predictors of all-cause in-hospital and 90-day mortality following major abdominal cancer surgery [30]. In the largest (N = 1401) prospective cohort study to date of CPET-based assessment of functional capacity before major non-cardiac surgery, the METS (Measurement of Exercise Tolerance Before Surgery) investigators were not able to demonstrate that CPET-derived metrics of exercise tolerance (anaerobic threshold and peak VO2) were predictive of myocardial infarction or mortality at 30 days following the index surgical procedure. The Duke Activity Status Index (DASI) score was predictive of the primary outcome (adjusted odds ratio 0.91, 95% CI 0·83–0·99; p = 0·03; AUC = 0.71) [19]. However, notwithstanding the shortcomings of this trial of low-risk patients (66% ASA classification 1 or 2; 90% classified as class 1 or 2 RCRI) having low risk surgery (only 37% of participants undergoing major surgery), the study did show that CPET-derived peak VO2 (< 15 mL/kg/min) was predictive of moderate or severe postoperative non-cardiac complications (adjusted odds ratio 0·86, 95% CI 0·78–0·97; p = 0· 007; AUC = 0.74), including wound infection, anastomotic


leak, and pulmonary complications [21]. Although the anaerobic threshold was not shown to be predictive of this outcome (adjusted odds ratio 0.87, CI 0.74–1.02; p = 0.08; AUC = 0.69), the point prevalence estimate suggests that a meaningful effect may have been present had a more conventional CPET cohort been able to be recruited. Combining objective assessment of functional capacity (CPET-derived peak VO2) with other global scores (ASA, DASI, NSQIP) and with organ-specific scores or biomarkers (ARISCAT [respiratory], albumin [nutritional status], NT-proBNP [cardiac], etc.) into a composite index as alluded to in an editorial accompanying the description of a multivariate risk model [15, 31] may be a promising avenue of future research in the quest for the “holy grail” of risk prediction. Importantly, this also allows prehabilitation to be tailored to each patient for preoperative optimization prior to surgery (prehabilitation) (Fig. 1).

Prehabilitation: Therapeutic Strategies for Risk Mitigation Exercise as Therapy A large body of epidemiological evidence indicates a consistent signal of improved cancer-free survival and reduction in allcause mortality in patients with superior exercise behaviors. Fig. 1 Conceptual framework for developing a global, composite risk assessment tool to direct targeted prehabilitation strategies in patients presenting for major surgery. (MST—Malnutrition Screening Tool, VTE—Venous Thromboembolism, MOCA—Montreal Cognitive Assessment Test Form. CPET [1] and CPET [2••] refer to references [88]) and [19], respectively)

This is particularly so for patients with breast, prostate, and colorectal cancer [32, 33]. Physical activity levels of 360+ min per week are inversely related to cancer-specific mortality in cancer survivors (HR = 0.30, 95% CI 0.13–0.7 compared with patients who reported no physical activity) [34]. Additionally, an extensive body of clinical evidence indicates that exercise is an effective intervention to ameliorate the adverse physical and psychosocial side effects of cancer and cancer-related treatments [33, 35]. Specifically, considerable evidence has established the therapeutic effects of exercise in minimizing the physical decline, fatigue, psychological distress, and compromised quality of life caused by cancer and its treatment. This compelling level of evidence has prompted the Clinical Oncology Society of Australia to recommend that exercise be embedded as a part of standard practice, taking on the role of an adjuvant therapy in cancer care pathways [35]. However, researching the evidence for application prior to surgery is an evolving field of perioperative medicine that may require a more nuanced approach. Can We Get Patients Fit for Surgery? Unlike most chronic medical conditions, poor exercise capacity and functional capacity (deconditioning) in sedentary individuals are potentially modifiable [36]. Consequently, if a subject was able to partake in a prescribed exercise program such that their exercise capacity improves, the improvement in


functional capacity and reduction in postoperative morbidity would provide a rationale in support of routine application of prehabilitation in the management of patients undergoing surgery [37]. This concept has been challenged by the notion that the individual’s genetic and innate psychological, social, and physiologic capacity limits the response capacity to such exercise, and the often limited amount of time available between cancer diagnosis and surgery [38]. Moreover, the challenges in study design of exercise intervention fidelity (finding the optimum dosage, timing, modality and patient adherence to exercise, evaluation metrics, and the difficulty in blinding participants) are well documented and compound the difficulty in researching exercise as an intervention in clinical trials. That said, a meta-analysis of pooled data from six randomized control trials (RCTs) indicated that exercise training resulted in statistically significant increase in peak VO2 (WMD, 2.90 mL/kg/min; 95% CI 1.16–4.64) in patients with hematologic, breast, prostate, and colon cancer, with minimal adverse events from the training program [39]. Subsequent prospective cohort studies have also demonstrated improved functional capacity as measured by 6-min walk tests [40, 41], aerobic exercise capacity (VO2) [42•], and peak inspiratory pressures [43] following a combination of multimodal or single modality interventions. Importantly, West et al. were able to demonstrate effectiveness of prehabilitation in preventing the loss of functional capacity related to neoadjuvant chemoradiotherapy prior to major rectal cancer surgery [44, 45]. Similarly, in a recent RCT of 51 patients having esophagogastric cancer surgery, Minnella et al. demonstrated the effectiveness of a prehabilitation (exercise and nutrition) program in improving functional capacity (6 MWT) before surgery and importantly sustaining functional capacity 4–8 weeks after surgery, while the control group had significant decline in postoperative functional capacity [41]. These results reinforce that at worst, exercise prior to surgery is not harmful and at best has the potential to be applicable to every patient presenting for major surgery [46]. However, the scalability for effective prehabilitation programs is a major challenge and reflected in the study by Minella et al. [41] where only 31% of screened patients were recruited into the study. In addition, a retrospective study of prehabilitation in patients presenting for major cancer surgery reported that close to one third of the patients were classified as “non-responders” to exercise [47]. The underlying cause of non-response may be inherent to the patient (e.g., motivation, compliance, access to programs in the community, or home-based setting) or disease-related (e.g., inflammatory states) factors, and this requires further research. This concept of “non-response” may explain the mixed results of earlier prehabilitation studies that failed to show improvements in exercise capacity prior to surgery [48].

Nutrition Malnutrition is detected in up to 50% of patients with cancer, and there is an abundance of evidence that perioperative malnutrition is a predictor of poor postoperative outcome [49, 50]. Recent prospective observational data indicate that undernourished patients are twice as likely to be re-admitted to hospital within 30 days after elective colorectal surgery [51]. The majority of perioperative nutritional studies are small, single-center studies of unimodal nutritional prehabilitation, and these have yielded mixed results. For example, a 20% reduction in postoperative morbidity achieved in patients with poor nutritional states having gastrointestinal surgery [52]. In patients having esophageal surgery (n = 55), a 5-day nutritional intervention was able to demonstrate reductions in infective complications, length of hospital stay, and mortality [53]. Kabata et al., using a non-immune modulating protein based drink (20 g/day) for 2 weeks prior to surgery, demonstrated a significant reduction in 30-day postoperative complications after gastrointestinal cancer surgery. Although this trial was terminated prematurely due to the higher incidence in wound infection and anastomotic leak in the control group, it appears to be limited by being an unblinded study [54]. Multimodal interventions incorporating nutritional interventions have also been published, with mixed results. Gillis et al. in 2018, combining the results of 2 RCTs (n = 139) demonstrated that multimodal prehabilitation, including nutritional interventions, attenuated postoperative loss of lean body mass better than those randomized to postoperative rehabilitation) [55]. Although it seems clear that nutritional interventions could be envisaged to have an additive effect in combination with exercise-based interventions to reduce postoperative complications, robust data supporting its use as a component of multimodal prehabilitation is lacking and requires urgent research. The American Society for Enhanced Recovery and Perioperative Quality Initiative’s Joint Consensus Statement on nutritional interventions within ERAS pathways provides a useful summary of the current literature for clinicians and researchers [56]. Hematinic Optimization Perioperative anemia is common, occurring in up to 76% of patients with cancer, and moreover, is associated with decreased aerobic capacity [57–59], increased likelihood of receiving allogeneic blood transfusion and adverse outcomes following major surgery [25]. A Cochrane review identified three prospective RCTs evaluating preoperative iron therapy to correct anemia (two in colorectal and one in gynecological surgery, n = 114 patients). A meta-analysis of two of these trials reported a reduction in blood transfusions with the administration of iron therapy, but the reduction was not statistically significant (RR = 0.56, 95% CI 0.27–1.18). In the same


study, intravenous iron increased hemoglobin at the end of treatment prior to surgery (MD 1.90 g/dL, 95% CI 1.16 to 2.64; participants = 56), but the results were at high risk of bias [60]. Correcting anemia has also been shown to improve exercise capacity [61, 62]. When considered together, these observations suggest that targeted preoperative elevation of hemoglobin mass may improve aerobic capacity both directly and indirectly (augmenting the ability to exercise) and may thus improve postoperative outcomes [4]. However, studies have yet to demonstrate benefits of iron transfusion alone on aerobic capacity in the cancer population. The use of erythropoietic agents in cancer remains controversial, demonstrating benefits to quality of life and decreased need for blood transfusions however being associated with an increase of thromboembolic complications, hypertension, and decreased survival [63]. Psychological Interventions (Stress Reduction, Motivation) A systematic review (n = 356) of unimodal psychological intervention in patients with breast, gynecological, and colorectal cancer did not affect traditional surgical outcomes (e.g., length of hospital stay, complications, analgesia use, or mortality) but was shown to improve patients’ immunologic function [6]. Other studies have successfully used psychological interventions as part of a multimodal package of interventions [64–66]. Prehabilitation, especially with exercise, requires considerable motivation on the part of both clinicians and patients. Behavioral interventions such as psychological counseling are important to facilitate successful implementation of any change in behavior. As such, motivational strategies, including support by family or peer group and patient and support group education through initiatives such as preoperative surgery school [67] for patients will play an important role in the success of prehabilitation as a therapeutic strategy.

Does Prehabilitation Improve Postoperative Outcomes? Exercise is protective in terms of health outcomes. For example, in deconditioned patients, with low levels of fitness, 4 weeks of prehabilitation will improve cardiovascular fitness and therefore the ability to increase heart rate, peak power output, and oxygen uptake during submaximal exercise [68]. These hemodynamic changes in turn contribute to increased physiological reserves and improved oxygen delivery by influencing the oxygen cascade, which may be protective in the perioperative period [38, 69, 70]. A combined analysis of patients having trimodal prehabilitation with exercise, nutritional, and psychological interventions compared with patients having only rehabilitation found that patients on the prehabilitation program maintained their lean body mass

better compared to patients having postoperative rehabilitation only [55]. Exercise mitigates the rapid decline in muscle and physiological reserves that occurs even after 1 week of bed rest [71], and this may explain the observation that prehabilitation is superior to rehabilitation. Furthermore, the timing of education and interventions before surgery may facilitate earlier initiation of exercise, resumption of activities, and nutritional intake after surgery thus reversing the effects of anesthesia and surgical insult more effectively [2••]. Specific to cancer patients, prehabilitation with exercise may also modulate postsurgical inflammatory response, a factor relevant in cancer-promoting pathways [72], and modulate the adverse effects of chemotherapy, e.g., reduce anthracycline-induced myocardial toxicity by lessening oxidative stress, apoptosis, and myocardial protein turnover [73]. Based on the data presented, it is evident that functional capacity can be preserved and even enhanced prior to surgery with exercise programs, but is not clear if this strategy reduces postoperative complications. The evidence is limited by heterogeneity in patient groups, interventions, controls, and outcomes across these studies. The findings of these studies are summarized in the systematic reviews with meta-analyses summarized in Table 1. The preponderance of evidence suggests that exercisebased prehabilitation improves functional capacity and reduces postoperative complications following lung resection surgery while studies of most other major cancer surgeries only support the ability of prehabilitation (multi and unimodal strategies) to improve functional capacity and physical fitness [76]. Exceptions to this body of evidence are two recently published high-quality randomized controlled studies in cancer and one in major abdominal vascular surgery that are not reviewed in any systematic review or meta-analysis to date: &

LIPPSMAck-POP (2018) was a randomized controlled trial testing the hypothesis that preoperative physiotherapy education and training prevents postoperative pulmonary complications following abdominal surgery. The intervention group was administered a 30-min educational and instructional treatment. In contrast, the control group received an educational brochure only. The incidence of postoperative pulmonary complications within 14 postoperative hospital days was halved (adjusted hazard ratio 0.48, 95% CI, 0.30–0.75, P = 0.001) in the intervention compared with the control group, with an absolute risk reduction of 15% (95% CI, 7–22%) and a number needed to treat (NNT) of 7 (95% CI 5–14). In spite of randomization, several pre- and intra-operative factors differed between groups. These variables were controlled for as covariates in analyses (baseline age, previous respiratory disease, and hepatobiliary/upper gastrointestinal surgery) [2••].

Study characteristics

Quality of studies

Patient population

Steffens et al. (2018) [75]

Lung resection, All trials had high RCTs; lung n = 5 studies; risk of esophageal, esophageal resection, liver, and oral cancer performance n = 2; colon surgery, bias (blinding) surgery; 2010–2017 n = 1; liver surgery, (CRBT). Overall n=1 “low”, “very low” quality (GRADE)

Jones et al. (2011) [39] Non-randomized study “Low” risk of bias Adult cancer for all studies. (breast, colon, interventions lymphoma) (NRSI); 2002–2009. Major abdominal Quality of studies Moran et al. (2016) [38] Randomized cancer surgery “low” due to controlled performance bias trials (RCTs); (Cochrane Risk 2008–2014. of Bias Tool) (CRBT) Serbio Garcia et al. RCTs and NRSIs; Lung cancer surgery Pedro score = 5 (2016) [74] lung cancer surgery; (2–8), 2005–2014 “moderate” risk of bias

Author (year) (reference)

I2 = 0% (lung surgery)

X2 = 19.89, df = 7 (P = 0.006); I2 = 65% [All complications]

Inspiratory muscle Reduced postoperative complications training, aerobic (OR 0.59; 95%CI 0.38–0.91; training and P = 0.03). resistance training

8 (801) Inspiratory muscle Reduced postoperative complications (RR = 0.45; training, aerobic 95% CI 0.28,0.74) Reduced training and hospital stay (− 4.83, resistance training %CI − 5.9, 3.76) Improved pulmonary function (FVC, FEV1) (SMD = 0.38,95% CI 0.14–0.63 and SMD = 0.27, 95% CI 0.11,0.42, respectively] 7 (432) Aerobic training and Reduced postoperative complications breathing (RR 0.52, 95% CI 0.36 to 0.74) exercises Reduced hospital stay for lung cancer, (MD − 2.86 days, breathing exercise 95% CI − 5.40 to − 0.33) only for (lung surgery) esophageal cancer, 1–4 weeks duration

X2 = 39.25, df = 5 (P < 0.00001); I2 = 87%

Heterogeneity

X2 = 12.3, df = 7 (P = 0.09); I2 = 43%

Improved fitness peak VO2 MD 2.90 (1.16–4.61).

Number of studies (patients) 6 (571)

9 (435)

Aerobic training, 8–24 weeks duration

Exercise intervention Effect of the intervention on outcome

Summary of findings of four meta-analyses of trials of prehabilitation prior to cancer surgery

Systematic reviews with meta-analyses: trials of prehabilitation in cancer surgery

Table 1



&

&

Comparing the results of this study to a similar study with contrasting results (Brasher 2003) needs to take into account the different type of surgery, baseline incidence of pulmonary complications, and the varying definitions for postoperative pulmonary complications [77]. Notably, an accompanying sub-study of LIPPSMAck investigated the treatment receipt, differentiation, and enactment (of mobility) indicating high fidelity of this intervention [78]. This is useful information for future implementation research for demonstration of adaptability to the clinical care context. Baberan-Garcia et al. (2018) assessed the impact of a personalized 6-week prehabilitation program on postoperative complications in high-risk patients undergoing elective major abdominal surgery using a blinded randomized controlled trial design. Elderly (> 70 years), high-risk (ASA 3 and 4) patients were randomized to multimodal prehabilitation consisting of a motivational interview, increased activity and supervised, structured, responsive aerobic exercise training vs. standard care in the control group. This intervention enhanced aerobic capacity by 135% [ΔET 135% (218); p < 0.001), reduced the number of patients with postoperative complications by 51% (RR 0.5; 95%CI, 0.3–0.8; p = 0.001) and the rate of all complications by 64% [1.4% (1.6) and 0.5% (1.0) events per patient (SD); p = 0.001)] compared with controls. The intervention also showed a lower mean number of cardiovascular complications per patient (RR 0.1, 95% CI, 0.1– 1.0; p = 0.033). There was also a significant reduction in the number of days in intensive care in the intervention group admitted to ICU compared to the control group [(n = 44) 3 (2) vs 12 [20]; p = 0.046). The authors claim this is the first randomized blinded controlled trial assessing the impact of a prehabilitation intervention on perioperative complications in high-risk patients undergoing major abdominal surgery. Encouragingly, these authors have a larger trial underway investigating this intervention across a wider cohort of patients [79••]. Barakat et al. (2016) reported on an RCT of non-cancer patients presenting for abdominal aortic aneurysm repair who were randomized to a 6-week structured supervised exercise prehabilitation program vs. standard care. Results were remarkably similar to the previously cited studies: the primary endpoint of postoperative cardiac, pulmonary, and/or renal complications was significantly reduced by 50% in the exercise group (22.6% cf. 41.9% [control group]; p = 0.021). RRR was 46.1% and the NNT was 5 (95% CI, 3–35). Also, patients in the exercise group had a shorter hospital stay (median 7.0, [IQR] 5.0–9.0 days vs. 8.0, [IQR] 6.0–12.3 days; p = 0.025). In the subgroup of patients having CPET measurements before and after the study intervention, there were significant improvements in AT and peak VO2 in the intervention group [80••].

This strong signal in favor of prehabilitation from these RCTs strengthens the evidence base for implementing multimodal prehabilitation into the perioperative pathway for patients having major surgery. By incorporating prehabilitation into ERAS programs, there is true potential for adding to the value proposition of perioperative medicine by improving patient outcomes and reducing healthcare expenditure, with prehabilitation being a cost-effective strategy that can be delivered in the community setting and outside of hospitals [1].

Implementation Science: Bringing Clinical Value to Research It has been stated that it takes on average up to 17 years for the findings of clinical research to enter clinical practice [81]. One of the reasons for this is that most research focuses on the effectiveness and efficacy of interventions and not on the methods of uptake and sustained implementation of such interventions. The challenge of Implementation Science (IS) is to identify barriers and strategies for early and sustained uptake [81]. Implementation strategies are defined as methods designed to incentivize users to adopt targeted interventions. Implementing effective treatments can be considered in the context of “will it work”? This asks if the treatment will be effective in real-life contexts, settings, and cultures/populations that might adopt the intervention as practice. Typically, methods used in IS studies include qualitative data to understand the perspectives of different stakeholders. Qualitative research methods offer useful tools for understanding both institutional (health service) and community cultures. The increased use of feasibility studies measuring metrics such as acceptability, demand, practicality, adaptation, and integration will increase the likelihood of implementing evidence such as described in this review and scaling interventions across health services [82]. Unfortunately, to our knowledge, no studies exist that investigated implementation of multimodal prehabilitation in the perioperative context. The study by Boden et al. [78] focused on the fidelity of the intervention (lung exercises) and included a qualitative evaluation of the acceptability of the intervention. Moor et al. [67] and Cassidy et al. [83] reported on the use of PDSA cycles to achieve favorable results from implementing a respiratory bundle as a prehabilitation program. A study in the UK [84] surveying colorectal surgeons produced a consensus opinion on exercise prehabilitation in elderly colorectal surgical patients indicating broad support for the concept. The National Institute of Academic Anesthesia/James Lind Alliance Research Priority Setting Partnership in the UK used a Delphi survey that included anesthesiologists, patients, and public to identify research priorities in anesthesia and perioperative care, and prehabilitation was considered a top ten research priority [85]. Currently, we await the outcomes of two large RCTs in the UK and Spain to provide us with further evidence on the efficacy, effectiveness, and ability to implement prehabilitation


interventions. These studies include [1] The Implementation of Collaborative Self-Management Services to Promote Physical Activity (NEXTCARE-PA; NCT02976064; n = 2300) [86]. This is an implementation study looking at cost effectiveness of increasing physical activity in a range of cohorts including high-risk patients presenting for abdominal surgery, and [2] The Wessex Fit-4-Cancer Surgery Trial (WesFit:www. ClinicalTrials.gov Identifier: NCT03509428; n = 1500) is an efficacy trial looking at the effect of a Structured Responsive Exercise Training Program (SREPT) and psychological intervention on postoperative outcomes [87].

Conclusion There is an increasing body of literature showing the feasibility, safety, and efficacy of prehabilitation programs prior to major surgery, especially surgical oncology. This review has identified recent RCTs affirming this view. Future research needs to explore optimal risk stratification methods, optimal prehabilitation strategies (dose, duration, and modalities), optimal outcomes (and their definitions) that should be measured, and implementation strategies for effective delivery of prehabilitation strategies to impact change in healthcare systems. In the meantime, incorporating a multimodal prehabilitation program into existing hospital pathways (such as ERAS) would be a pragmatic approach to improving quality of care and adding value to current practice.

Compliance with Ethical Standards Conflict of Interest Hilmy Ismail declares that he has no conflict of interest. Prue Cormie is a Director of Fit-4-Surgery Pty Ltd. Kate Burbury declares that she has no conflict of interest. Jamie Waterland declares that she has no conflict of interest. Linda Denehy declares that she has no conflict of interest. Bernhard Riedel declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors..

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Silver JK, Baima J. Cancer prehabilitation: an opportunity to decrease treatment-related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes. Am J Phys Med Rehabil. 2013;92(8):715–27.

2.•• Boden I, Skinner EH, Browning L, Reeve J, Anderson L, Hill C, et al. Preoperative physiotherapy for the prevention of respiratory complications after upper abdominal surgery: pragmatic, double blinded, multicentre randomised controlled trial. BMJ. 2018;360: j5916 Randomised Controlled Trial demonstrating how a package of respiratory prehabilitation including education and instructions can reduce postoperative pulmonary complications by almost 50% in patients presenting for major abdominal surgery. 3.•• Carli F, Silver JK, Feldman LS, McKee A, Gilman S, Gillis C, et al. Surgical prehabilitation in patients with Cancer: state-of-the-science and recommendations for future research from a panel of subject matter experts. Phys Med Rehabil Clin N Am. 2017;28(1):49–64 Excellent narative review of the current research and clinical utility of prehabilitation by a group of reserachers who are among the leaders in this field internationally. 4. Plumb JO, Otto JM, Grocott MP. ‘Blood doping’ from Armstrong to prehabilitation: manipulation of blood to improve performance in athletes and physiological reserve in patients. Extrem Physiol Med. 2016;5:5. 5. Gillis C, Loiselle SE, Fiore JF Jr, Awasthi R, Wykes L, Liberman AS, et al. Prehabilitation with whey protein supplementation on perioperative functional exercise capacity in patients undergoing colorectal resection for cancer: a pilot double-blinded randomized placebo-controlled trial. J Acad Nutr Diet. 2016;116(5):802–12. 6. Tsimopoulou I, Pasquali S, Howard R, Desai A, Gourevitch D, Tolosa I, et al. Psychological prehabilitation before cancer surgery: a systematic review. Ann Surg Oncol. 2015;22(13):4117–23. 7. Carli F, Gillis C, Scheede-Bergdahl C. Promoting a culture of prehabilitation for the surgical cancer patient. Acta Oncol. 2017;56(2):128–33. 8. Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ, et al. Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg. 2005;242(3):326–41 discussion 41-3. 9. Govaert JA, Fiocco M, van Dijk WA, Scheffer AC, de Graaf EJ, Tollenaar RA, et al. Costs of complications after colorectal cancer surgery in the Netherlands: building the business case for hospitals. Eur J Surg Oncol. 2015;41(8):1059–67. 10. Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study I, Devereaux PJ, Chan MT, Alonso-Coello P, Walsh M, Berwanger O, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;307(21):2295–304. 11. Aloia TA, Zimmitti G, Conrad C, Gottumukalla V, Kopetz S, Vauthey JN. Return to intended oncologic treatment (RIOT): a novel metric for evaluating the quality of oncosurgical therapy for malignancy. J Surg Oncol. 2014;110(2):107–14. 12. Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol. 2007;50(15):1435–41. 13. Davies SJ, Wilson RJ. Preoperative optimization of the high-risk surgical patient. Br J Anaesth. 2004;93(1):121–8. 14. Moonesinghe SR, Mythen MG, Grocott MP. High-risk surgery: epidemiology and outcomes. Anesth Analg. 2011;112(4):891–901. 15. Ajitsaria P, Eissa SZ, Kerridge RK. Risk assessment. Curr Anesthesiol Rep. 2018;8(1):1–8. 16. Canet J, Gallart L, Gomar C, Paluzie G, Valles J, Castillo J, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113(6): 1338–50. 17. Dronkers JJ, Chorus AM, van Meeteren NL, Hopman-Rock M. The association of pre-operative physical fitness and physical activity with outcome after scheduled major abdominal surgery. Anaesthesia. 2013;68(1):67–73.

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21. 22. 23.

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Kupeli E, Er Dedekarginoglu B, Ulubay G, Oner Eyuboglu F, Haberal M. American Society of Anesthesiologists classification versus ARISCAT risk index: predicting pulmonary complications following renal transplant. Exp Clin Transplant. 2017;15(Suppl 1): 208–13. Wijeysundera DN, Pearse RM, Shulman MA, Abbott TEF, Torres E, Ambosta A, et al. Assessment of functional capacity before major non-cardiac surgery: an international, prospective cohort study. Lancet. 2018;391(10140):2631–40. Bilimoria KY, Liu Y, Paruch JL, Zhou L, Kmiecik TE, Ko CY, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217(5):833–42 e1–3. P-POSSUM [Available from: http://www.riskprediction.org.uk/ index-pp.php. Surgical Outcome Risk Tool [Available from: http://www. sortsurgery.com. Visnjevac O, Davari-Farid S, Lee J, Pourafkari L, Arora P, Dosluoglu HH, et al. The effect of adding functional classification to ASA status for predicting 30-day mortality. Anesth Analg. 2015;121(1):110–6. Shulman MA, Thompson BR. Not fit for a haircut ... how should we assess fitness and stratify risk for surgery? Br J Anaesth. 2014;112(6):955–7. Lee CHA, Kong JC, Ismail H, Riedel B, Heriot A. Systematic review and meta-analysis of objective assessment of physical fitness in patients undergoing colorectal cancer surgery. Dis Colon Rectum. 2018;61(3):400–9. Nagamatsu Y, Shima I, Yamana H, Fujita H, Shirouzu K, Ishitake T. Preoperative evaluation of cardiopulmonary reserve with the use of expired gas analysis during exercise testing in patients with squamous cell carcinoma of the thoracic esophagus. J Thorac Cardiovasc Surg. 2001;121(6):1064–8. Moran J, Wilson F, Guinan E, McCormick P, Hussey J, Moriarty J. Role of cardiopulmonary exercise testing as a risk-assessment method in patients undergoing intra-abdominal surgery: a systematic review. Br J Anaesth. 2016;116(2):177–91. Jones LW, Watson D, Herndon JE 2nd, Eves ND, Haithcock BE, Loewen G, et al. Peak oxygen consumption and long-term all-cause mortality in nonsmall cell lung cancer. Cancer. 2010;116(20):4825–32. West MA, Asher R, Browning M, Minto G, Swart M, Richardson K, et al. Validation of preoperative cardiopulmonary exercise testing-derived variables to predict in-hospital morbidity after major colorectal surgery. Br J Surg. 2016;103(6):744–52. Wilson RJ, Davies S, Yates D, Redman J, Stone M. Impaired functional capacity is associated with all-cause mortality after major elective intra-abdominal surgery. Br J Anaesth. 2010;105(3):297–303. Howell SJ. Predicting survival after surgery: a matter of life and death. Anaesthesia. 2015;70(6):637–40. Van Blarigan EL, Fuchs CS, Niedzwiecki D, Zhang S, Saltz LB, Mayer RJ, et al. Association of survival with adherence to the American Cancer Society nutrition and physical activity guidelines for Cancer survivors after colon cancer diagnosis: the CALGB 89803/Alliance trial. JAMA Oncol. 2018;4(6):783–90. Cormie P, Zopf EM, Zhang X, Schmitz KH. The impact of exercise on cancer mortality, recurrence, and treatment-related adverse effects. Epidemiol Rev. 2017;39(1):71–92. Gunnell AS, Joyce S, Tomlin S, Taaffe DR, Cormie P, Newton RU, et al. Physical activity and survival among long-term cancer survivor and non-cancer cohorts. Front Public Health. 2017;5:19. Cormie P, Atkinson M, Bucci L, Cust A, Eakin E, Hayes S, et al. Clinical Oncology Society of Australia position statement on exercise in cancer care. Med J Aust. 2018;209(4):184–7. Arem H, Pfeiffer RM, Engels EA, Alfano CM, Hollenbeck A, Park Y, et al. Pre- and postdiagnosis physical activity, television viewing, and mortality among patients with colorectal cancer in the National

Institutes of Health-AARP diet and health study. J Clin Oncol. 2015;33(2):180–8. 37. Myers JN, Fonda H. The impact of fitness on surgical outcomes: the case for prehabilitation. Curr Sports Med Rep. 2016;15(4):282–9. 38. Moran J, Guinan E, McCormick P, Larkin J, Mockler D, Hussey J, et al. The ability of prehabilitation to influence postoperative outcome after intra-abdominal operation: a systematic review and meta-analysis. Surgery. 2016;160(5):1189–201. 39. Jones LW, Liang Y, Pituskin EN, Battaglini CL, Scott JM, Hornsby WE, et al. Effect of exercise training on peak oxygen consumption in patients with cancer: a meta-analysis. Oncologist. 2011;16(1): 112–20. 40. Li C, Carli F, Lee L, Charlebois P, Stein B, Liberman AS, et al. Impact of a trimodal prehabilitation program on functional recovery after colorectal cancer surgery: a pilot study. Surg Endosc. 2013;27(4):1072–82. 41. Minnella EM, Awasthi R, Loiselle SE, Agnihotram RV, Ferri LE, Carli F. Effect of exercise and nutrition prehabilitation on functional capacity in esophagogastric cancer surgery: a randomized clinical trial. JAMA Surg. 2018. 42.• West MA, Loughney L, Lythgoe D, Barben CP, Sripadam R, Kemp GJ, et al. Effect of prehabilitation on objectively measured physical fitness after neoadjuvant treatment in preoperative rectal cancer patients: a blinded interventional pilot study. Br J Anaesth. 2015;114(2):244–51 Landmark study demonstrating the feasibilty, safety and eficacy of exercise preahbilitation in the context of colorectal surgery. 43. Valkenet K, Trappenburg JCA, Ruurda JP, Guinan EM, Reynolds JV, Nafteux P, et al. Multicentre randomized clinical trial of inspiratory muscle training versus usual care before surgery for oesophageal cancer. Br J Surg. 2018;105(5):502–11. 44. West MA, Loughney L, Ambler G, Dimitrov BD, Kelly JJ, Mythen MG, et al. The effect of neoadjuvant chemotherapy and chemoradiotherapy on exercise capacity and outcome following upper gastrointestinal cancer surgery: an observational cohort study. BMC Cancer. 2016;16(1):710. 45. West MA, Loughney L, Barben CP, Sripadam R, Kemp GJ, Grocott MP, et al. The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients. Eur J Surg Oncol. 2014;40(11):1421–8. 46. Fry BT, Hallway A, Englesbe MJ. Moving toward every patient training for surgery. JAMA Surg. 2018. 47. Huang GH, Ismail H, Murnane A, Kim P, Riedel B. Structured exercise program prior to major cancer surgery improves cardiopulmonary fitness: a retrospective cohort study. Support Care Cancer. 2016;24(5):2277–85. 48. Carli F, Charlebois P, Stein B, Feldman L, Zavorsky G, Kim DJ, et al. Randomized clinical trial of prehabilitation in colorectal surgery. Br J Surg. 2010;97(8):1187–97. 49. Braga M, Ljungqvist O, Soeters P, Fearon K, Weimann A, Bozzetti F, et al. ESPEN guidelines on parenteral nutrition: surgery. Clin Nutr. 2009;28(4):378–86. 50. Schwegler I, von Holzen A, Gutzwiller JP, Schlumpf R, Muhlebach S, Stanga Z. Nutritional risk is a clinical predictor of postoperative mortality and morbidity in surgery for colorectal cancer. Br J Surg. 2010;97(1):92–7. 51. Gillis C, Nguyen TH, Liberman AS, Carli F. Nutrition adequacy in enhanced recovery after surgery: a single academic center experience. Nutr Clin Pract. 2015;30(3):414–9. 52. Benoist S, Brouquet A. Nutritional assessment and screening for malnutrition. J Visc Surg. 2015;152(Suppl 1):S3–7. 53. Kubota K, Kuroda J, Yoshida M, Okada A, Deguchi T, Kitajima M. Preoperative oral supplementation support in patients with esophageal cancer. J Nutr Health Aging. 2014;18(4):437–40. 54. Kabata P, Jastrzebski T, Kakol M, Krol K, Bobowicz M, Kosowska A, et al. Preoperative nutritional support in cancer patients with no


55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

clinical signs of malnutrition—prospective randomized controlled trial. Support Care Cancer. 2015;23(2):365–70. Gillis C, Fenton TR, Sajobi TT, Minnella EM, Awasthi R, Loiselle SE, et al. Trimodal prehabilitation for colorectal surgery attenuates post-surgical losses in lean body mass: a pooled analysis of randomized controlled trials. Clin Nutr. 2018. Wischmeyer PE, Carli F, Evans DC, Guilbert S, Kozar R, Pryor A, et al. American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on nutrition screening and therapy within a surgical enhanced recovery pathway. Anesth Analg. 2018;126(6):1883–95. Khanbhai M, Shah M, Cantanhede G, Ilyas S, Richards T. The problem of anaemia in patients with colorectal cancer. ISRN Hematol. 2014;2014:547914. Ludwig H, Muldur E, Endler G, Hubl W. Prevalence of iron deficiency across different tumors and its association with poor performance status, disease status and anemia. Ann Oncol. 2013;24(7): 1886–92. Musallam KM, Tamim HM, Richards T, Spahn DR, Rosendaal FR, Habbal A, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet. 2011;378(9800):1396–407. Ng O, Keeler BD, Mishra A, Simpson A, Neal K, Brookes MJ, et al. Iron therapy for pre-operative anaemia. Cochrane Database Syst Rev. 2015;12:CD011588. Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol. 2008;51(2):103–12. Wright SE, Pearce B, Snowden CP, Anderson H, Wallis JP. Cardiopulmonary exercise testing before and after blood transfusion: a prospective clinical study. Br J Anaesth. 2014;113(1):91–6. Tonelli M, Hemmelgarn B, Reiman T, Manns B, Reaume MN, Lloyd A, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis. CMAJ. 2009;180(11):E62–71. Gillis C, Li C, Lee L, Awasthi R, Augustin B, Gamsa A, et al. Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer. Anesthesiology. 2014;121(5):937–47. Chen BP, Awasthi R, Sweet SN, Minnella EM, Bergdahl A, Santa Mina D, et al. Four-week prehabilitation program is sufficient to modify exercise behaviors and improve preoperative functional walking capacity in patients with colorectal cancer. Support Care Cancer. 2017;25(1):33–40. Barberan-Garcia A, Rodriguez DA, Blanco I, Gea J, Torralba Y, Arbillaga-Etxarri A, et al. Non-anaemic iron deficiency impairs response to pulmonary rehabilitation in COPD. Respirology. 2015;20(7):1089–95. Moore JA, Conway DH, Thomas N, Cummings D, Atkinson D. Impact of a peri-operative quality improvement programme on postoperative pulmonary complications. Anaesthesia. 2017;72(3): 317–27. Kim DJ, Mayo NE, Carli F, Montgomery DL, Zavorsky GS. Responsive measures to prehabilitation in patients undergoing bowel resection surgery. Tohoku J Exp Med. 2009;217(2):109–15. Jones LW, Eves ND, Haykowsky M, Freedland SJ, Mackey JR. Exercise intolerance in cancer and the role of exercise therapy to reverse dysfunction. Lancet Oncol. 2009;10(6):598–605. Carli F, Scheede-Bergdahl C. Prehabilitation to enhance perioperative care. Anesthesiol Clin. 2015;33(1):17–33.

71. 72.

73.

74.

75.

76.

77.

78.

79.••

80.••

81. 82.

83.

84.

Mujika I, Padilla S. Muscular characteristics of detraining in humans. Med Sci Sports Exerc. 2001;33(8):1297–303. Murillo R, Albendea C, Penagos I, Marin C, Rivero T, Ruiz B, et al. Inflammatory response modulation by prehabilitation therapy in colonic surgery. Clin Nutr ESPEN. 2016;12:e54. Scott JM, Khakoo A, Mackey JR, Haykowsky MJ, Douglas PS, Jones LW. Modulation of anthracycline-induced cardiotoxicity by aerobic exercise in breast cancer: current evidence and underlying mechanisms. Circulation. 2011;124(5):642–50. Sebio Garcia R, Yanez Brage MI, Gimenez Moolhuyzen E, Granger CL, Denehy L. Functional and postoperative outcomes after preoperative exercise training in patients with lung cancer: a systematic review and meta-analysis. Interact Cardiovasc Thorac Surg. 2016;23(3):486–97. Steffens D, Beckenkamp PR, Hancock M, Solomon M, Young J. Preoperative exercise halves the postoperative complication rate in patients with lung cancer: a systematic review of the effect of exercise on complications, length of stay and quality of life in patients with cancer. Br J Sports Med. 2018;52(5):344. Bolshinsky V, Li MH, Ismail H, Burbury K, Riedel B, Heriot A. Multimodal prehabilitation programs as a bundle of care in gastrointestinal cancer surgery: a systematic review. Dis Colon Rectum. 2018;61(1):124–38. Brasher PA, McClelland KH, Denehy L, Story I. Does removal of deep breathing exercises from a physiotherapy program including pre-operative education and early mobilisation after cardiac surgery alter patient outcomes? Aust J Physiother. 2003;49(3):165–73. Boden I, El-Ansary D, Zalucki N, Robertson IK, Browning L, Skinner EH, et al. Physiotherapy education and training prior to upper abdominal surgery is memorable and has high treatment fidelity: a nested mixed-methods randomised-controlled study. Physiotherapy. 2017. Barberan-Garcia A, Ubre M, Roca J, Lacy AM, Burgos F, Risco R, et al. Personalised prehabilitation in high-risk patients undergoing elective major abdominal surgery: a randomized blinded controlled trial. Ann Surg. 2018;267(1):50–6 Randomized blinded controlled trial assessing the impact of a prehabilitation intervention in high-risk patients undergoing major abdominal surgery, demonstrating a 51% reduction in postoperative complications and significant reduction in cardiac complications and length of ICU stay. Barakat HM, Shahin Y, Khan JA, PT MC, Chetter IC. Preoperative supervised exercise improves outcomes after elective abdominal aortic aneurysm repair: a randomized controlled trial. Ann Surg. 2016;264(1):47–53 Randomized controlled trial assessing the impact of an exercise prehabilitation intervention in high-risk patients undergoing major vascular surgery, demonstrating an improvement in peakVO2, 50% reduction in postoperative complications and significant reduction in hospital stay. Lane-Fall MB, Cobb BT, Cene CW, Beidas RS. Implementation science in perioperative care. Anesthesiol Clin. 2018;36(1):1–15. Bowen DJ, Kreuter M, Spring B, Cofta-Woerpel L, Linnan L, Weiner D, et al. How we design feasibility studies. Am J Prev Med. 2009;36(5):452–7. Cassidy MR, Rosenkranz P, McCabe K, Rosen JE, McAneny D. I COUGH: reducing postoperative pulmonary complications with a multidisciplinary patient care program. JAMA Surg. 2013;148(8): 740–5. Boereboom CL, Williams JP, Leighton P, Lund JN. Exercise prehabilitation in colorectal cancer Delphi study G. forming a consensus opinion on exercise prehabilitation in elderly colorectal cancer patients: a Delphi study. Tech Coloproctol. 2015;19(6):347–54.

Author's personal copy Curr Anesthesiol Rep 85.

86.

Boney O, Bell M, Bell N, Conquest A, Cumbers M, Drake S, et al. Identifying research priorities in anaesthesia and perioperative care: final report of the joint National Institute of academic Anaesthesia/ James Lind Alliance research priority setting partnership. BMJ Open. 2015;5(12):e010006. Barberan-Garcia A, Gimeno-Santos E, Blanco I, Cano I, MartinezPalli G, Burgos F, et al. Protocol for regional implementation of

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collaborative self-management services to promote physical activity. BMC Health Serv Res. 2018;18(1):560. Jack S WM. The Wessex Fit-4-Cancer surgery trial (WesFit). 2018. Guazzi M, Arena R, Halle M, Piepoli MF, Myers J, Lavie CJ. 2016 focused update: clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation. 2016;133(24):e694–711.