Perioperative medicine training resources: U3M2: Prehabilitation programs

Abstract
Background: Poor functional capacity has been identified as an important modifiable risk factor for postoperative complications. Cardiopulmonary exercise testing (CPET) provides objective parameters of functional capacity (e.g., oxygen consumption at peak exercise, peak VO2), with significant prognostication for postoperative complications. However, sex-specific thresholds for functional capacity to predict surgical risk are yet to be established. Therefore, we performed a post hoc analysis of the international, multicentre, prospective observational METS (Measurement of Exercise Tolerance before Surgery) study to evaluate if sex-specific thresholds of peak VO2 improve risk prediction of postoperative complications.

Methods: We undertook a post hoc analysis (HREC/71824/PMCC) of the METS study, which was performed between March 2013 and March 2016. We investigated whether sex-specific differences exist for CPET-derived parameters and associated thresholds for predicting postoperative complications in this large cohort of patients that had major non-cardiac surgery (n = 1266). Logistic regression models were analyzed for the association of low peak VO2 with moderate-to-severe in-hospital postoperative complications. Optimal sex-specific peak VO2 thresholds were obtained by maximizing the Youden index of receiver operating characteristic (ROC) curves. Finally, multivariable logistic regression models tested the resulting sex-specific thresholds against the established non-sex-specific peak VO2 threshold (14 mL kg-1 min-1) adjusted for clinically relevant features such as comorbidities and surgical complexity. Models were evaluated by bootstrapping optimism-corrected area under the ROC curve and the net reclassification improvement index (NRI).

Findings: Female patients (n = 480) had a lower mean (SD) peak VO2 than males (16.7 (4.9) mL kg-1 min-1 versus 21.2 (6.5) mL kg-1 min-1, p < 0.001) and a lower postoperative complication rate (10.4% versus 15.3%; p = 0.018) than males (n = 786). The optimal peak VO2 threshold for predicting postoperative complications was 12.4 mL kg-1 min-1 for females and 22.3 mL kg-1 min-1 for males, respectively. In the multivariable regression model, low non-sex-specific peak VO2 did not independently predict postoperative complications. In contrast, low sex-specific peak VO2 was an independent predictor of postoperative complications (OR 2.29; 95% CI: 1.60, 3.30; p < 0.001). The optimism-corrected AUC-ROC of the sex-specific model was higher compared with the non-sex-specific model (0.73 versus 0.7; DeLong's test: p = 0.021). The sex-specific model classified 39% of the patients more correctly than the baseline model (NRI = 0.39; 95% CI: 0.24, 0.55). In contrast, the non-sex-specific model only classified 9% of the patients more correctly when compared against the baseline model (NRI = 0.09; 95% CI: -0.04, 0.22).

Interpretation: Our data report sex-specific differences in preoperative CPET-derived functional capacity parameters. Sex-specific peak VO2 thresholds identify patients at increased risk for postoperative complications with a higher discriminatory ability than a sex-unspecific threshold. As such, sex-specific threshold values should be considered in preoperative CPET to potentially improve risk stratification and to guide surgical decision-making, including eligibility for surgery, preoperative optimization strategies (prehabilitation) or seeking non-surgical options.

Funding: There was no funding for the present study. The original METS study was funded by Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.

Abstract
Background: After cancer surgery, complications, and disability prevent some patients from receiving subsequent treatments. Given that an inability to complete all intended cancer therapies might negate the oncologic benefits of surgical therapy, strategies to improve return to intended oncologic treatment (RIOT), including minimally invasive surgery (MIS), are being investigated.

Methods: This project was designed to evaluate liver tumor patients to determine the RIOT rate, risk factors for inability to RIOT, and its impact on survivals. Outcomes for a homogenous cohort of 223 patients who underwent open-approach surgery for metachronous colorectal liver metastases and a group of 27 liver tumor patients treated with MIS hepatectomy were examined.

Results: Of the 223 open-approach patients, 167 were offered postoperative therapy, yielding a RIOT rate of 75%. The remaining 56 (25%) patients were unable to receive further treatment due to surgical complications (n = 29 pts) or poor performance status (n = 27 pts). Risk factors associated with inability to RIOT were hypertension (OR 2.2, P = 0.025), multiple preoperative chemotherapy regimens (OR 5.9, P = 0.039), and postoperative complications (OR 2.0, P = 0.039). Inability to RIOT correlated with shorter disease-free and overall survivals (P < 0.001, HR = 2.16; and P = 0.005, HR = 2.07, respectively). In contrast to the open surgery group, 100% of MIS patients who were intended to initiate postoperative therapy did so (P = 0.038) within a shorter median time interval (MIS: 15 days vs. open: 42 days; P < 0.001).

Conclusions: The relationship between RIOT and long-term oncologic outcomes suggests that RIOT rates for both open- and MIS-approach cancer surgery should routinely be reported as a quality indicator.

Abstract
Importance: The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear.

Objective: To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity.

Design, setting, and participants: We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years.

Exposures: Leisure time moderate- to vigorous-intensity physical activity.

Main outcomes and measures: The upper limit of mortality benefit from high levels of leisure time physical activity.

Results: Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer.

Conclusions and relevance: Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.

Abstract
Objective: The aim of this study was to assess the impact of personalized prehabilitation on postoperative complications in high-risk patients undergoing elective major abdominal surgery.

Summary background data: Prehabilitation, including endurance exercise training and promotion of physical activity, in patients undergoing major abdominal surgery has been postulated as an effective preventive intervention to reduce postoperative complications. However, the existing studies provide controversial results and show a clear bias toward low-risk patients.

Methods: This was a randomized blinded controlled trial. Eligible candidates accepting to participate were blindly randomized (1:1 ratio) to control (standard care) or intervention (standard care + prehabilitation) groups. Inclusion criteria were: i) age >70 years; and/or, ii) American Society of Anesthesiologists score III/IV. Prehabilitation covered 3 actions: i) motivational interview; ii) high-intensity endurance training; and promotion of physical activity. The main study outcome was the proportion of patients suffering postoperative complications. Secondary outcomes included the endurance time (ET) during cycle-ergometer exercise.

Results: We randomized 71 patients to the control arm and 73 to intervention. After excluding 19 patients because of changes in the surgical plan, 63 controls and 62 intervention patients were included in the intention-to-treat analysis. The intervention group enhanced aerobic capacity [ΔET 135 (218) %; P < 0.001), reduced the number of patients with postoperative complications by 51% (relative risk 0.5; 95% confidence interval, 0.3-0.8; P = 0.001) and the rate of complications [1.4 (1.6) and 0.5 (1.0) (P = 0.001)] as compared with controls.

Conclusion: Prehabilitation enhanced postoperative clinical outcomes in high-risk candidates for elective major abdominal surgery, which can be explained by the increased aerobic capacity.

Abstract
Background: Perioperative infection and sepsis are of fundamental concern to perioperative clinicians. However, standardised endpoints are either poorly defined or not routinely implemented. The Standardised Endpoints in Perioperative Medicine (StEP) initiative was established to derive a set of standardised endpoints for use in perioperative clinical trials.

Methods: We undertook a systematic review to identify measures of infection and sepsis used in the perioperative literature. A multi-round Delphi consensus process that included more than 60 clinician researchers was then used to refine a recommended list of outcome measures.

Results: A literature search yielded 1857 titles of which 255 met inclusion criteria for endpoint extraction. A long list of endpoints, with definitions and timescales, was generated and those potentially relevant to infection and sepsis circulated to the theme subgroup and then the wider StEP-COMPAC working group, undergoing a three-stage Delphi process. The response rates for Delphi rounds 1, 3, and 3 were 89% (n=8), 67% (n=62), and 80% (n=8), respectively. A set of 13 endpoints including fever, surgical site, and organ-specific infections as defined by the US Centres for Disease Control and Sepsis-3 are proposed for future use.

Conclusions: We defined a consensus list of standardised endpoints related to infection and sepsis for perioperative trials using an established and rigorous approach. Each endpoint was evaluated with respect to validity, reliability, feasibility, and patient centredness. One or more of these should be considered for inclusion in future perioperative clinical trials assessing infection, sepsis, or both, thereby permitting synthesis and comparison of future results.

Abstract
Background: Preoperative risk stratification is used to derive an optimal treatment plan for patients requiring cancer surgery. Patients with reversible risk factors are candidates for prehabilitation programmes. This pilot study explores the impact of preoperative covariates of comorbid disease (Charlson Co-morbidity Index), preoperative serum biomarkers, and traditional cardiopulmonary exercise testing (CPET)-derived parameters of functional capacity on postoperative outcomes after major colorectal cancer surgery.

Methods: Consecutive patients who underwent CPET prior to colorectal cancer surgery over a 2-year period were identified and a minimum of 2-year postoperative follow-up was performed. Postoperative assessment included: Clavien-Dindo complication score, Comprehensive Complication Index, Days at Home within 90 days (DAH-90) after surgery, and overall survival.

Results: The Charlson Co-morbidity Index did not discriminate postoperative complications, or overall survival. In contrast, low preoperative haemoglobin, low albumin, or high neutrophil count were associated with postoperative complications and reduced overall survival. CPET-derived parameters predictive of postoperative complications, DAH-90, and reduced overall survival included measures of VCO2 kinetics at anaerobic threshold (AT), peakVO2 (corrected to body surface area), and VO2 kinetics during the post-exercise recovery phase. Inflammatory parameters and CO2 kinetics added significant predictive value to peakVO2 within bi-variable models for postoperative complications and overall survival (P < 0.0001).

Conclusion: Consideration of modifiable 'triple low' preoperative risk (anaemia, malnutrition, deconditioning) factors and inflammation will improve surgical risk prediction and guide prehabilitation. Gas exchange parameters that focus on VCO2 kinetics at AT and correcting peakVO2 to body surface area (rather than absolute weight) may improve CPET-derived preoperative risk assessment.

Keywords: CPET; Cardiopulmonary exercise testing; Colorectal cancer surgery; Functional capacity; Prehabilitation.

Abstract
Background: Outcome selection underpins clinical trial interpretation. Inconsistency in outcome selection and reporting hinders comparison of different trials' results, reducing the utility of research findings.

Methods: We conducted an iterative consensus process to develop a set of Core Outcome Measures for Perioperative and Anaesthetic Care (COMPAC), following the established Core Outcome Measures for Effectiveness Trials (COMET) methodology. First, we undertook a systematic review of RCTs in high-impact journals to describe current outcome reporting trends. We then surveyed patients, carers, researchers, and perioperative clinicians about important outcomes after surgery. Finally, a purposive stakeholder sample participated in a modified Delphi process to develop a core outcome set for perioperative and anaesthesia trials.

Results: Our systematic review revealed widespread inconsistency in outcome reporting, with variable or absent definitions, levels of detail, and temporal criteria. In the survey, almost all patients, carers, and clinicians rated clinical outcome measures critically important, but clinicians rated patient-centred outcomes less highly than patients and carers. The final core outcome set was: (i) mortality/survival (postoperative mortality, long-term survival); (ii) perioperative complications (major postoperative complications/adverse events; complications/adverse events causing permanent harm); (iii) resource use (length of hospital stay, unplanned readmission within 30 days); (iv) short-term recovery (discharge destination, level of dependence, or both); and (v) longer-term recovery (overall health-related quality of life).

Conclusions: This core set, incorporating important outcomes for both clinicians and patients, should guide outcome selection in future perioperative medicine or anaesthesia trials. Mapping these alongside standardised endpoint definitions will yield a comprehensive perioperative outcome framework.

Keywords: anaesthesia; core outcome; patient-centred outcome; perioperative medicine; standardised endpoints; surgery.

Byberg L, Melhus H, Gedeborg R, et al. Total mortality after changes in leisure time physical activity in 50 year old men: 35 year follow-up of population based cohort. BMJ. 2009;338:b688.

Abstract
A lack of physical activity is a generally accepted risk factor for colorectal cancer. However, research on the effect of preoperative physical activity on postoperative and long-term outcomes is limited, especially in patients with stage IV colorectal cancer who underwent palliative surgery. Patients who underwent bowel resection for stage IV primary colorectal cancer between January 1995 and December 2016 were retrospectively enrolled. A total of 2185 patients were divided into two groups according to preoperative leisure-time weekly physical activity as assessed by metabolic equivalent of task (MET) values: MET < 12 (n = 1845) and MET ≥ 12 (n = 340). Inverse probability of treatment weighting (IPTW) was used to reduce imbalance and selection biases between the two groups. After the IPTW process, the MET < 12 group showed a higher postoperative morbidity rate (18.7% vs. 10.6%; p < 0.001) and mortality rate (2.4% vs. 0.6%; p < 0.001) than the MET ≥ 12 group. No significant difference was found in overall survival. Weekly preoperative leisure-time physical activity with MET ≥ 12 was associated with reduced short-term postoperative morbidity and mortality in patients undergoing palliative resection for metastatic colorectal cancer. However, no difference was detected in long-term survival.

Keywords: colorectal cancer; inverse probability of treatment weighting; long-term survival; metabolic equivalent of task; physical activity; short-term morbidity.

Abstract
A simple, rapid, reproducible method for quantification of lower extremity muscle strength was standardized. The time needed to stand 10 times from a standard chair was recorded in 139 healthy subjects, aged 20 to 85 years (77 men, 62 women). Reproducibility was 6.8 percent (+/- 3.4 percent). Neither height nor weight was related to time in either sex. Weight was related to time (p less than 0.05) after adjusting for age, but this effect was slight compared with the effect of age alone. A highly significant (p less than 0.0001) relationship between time and age was found in both sexes. Younger men performed better than younger women, although this difference was lost in the older age groups. The results of this simple test correlated well with published data on the strength of knee flexor and extensor muscles in groups of men and women of various ages. This method was used to evaluate serially six consecutive patients with classic polymyositis or dermatomyositis. Improvement after treatment with prednisone used alone or in combination with azathioprine or methotrexate was found in all cases.

Abstract
In this review we discuss current findings in the human skeletal muscle literature describing the acute influence of nutrients (leucine-enriched essential amino acids in particular) and resistance exercise on muscle protein synthesis and mammalian target of rapamycin complex 1 (mTORC1) signaling. We show that essential amino acids and an acute bout of resistance exercise independently stimulate human skeletal muscle protein synthesis. It also appears that ingestion of essential amino acids following resistance exercise leads to an even larger increase in the rate of muscle protein synthesis compared with the independent effects of nutrients or muscle contraction. Until recently the cellular mechanisms responsible for controlling the rate of muscle protein synthesis in humans were unknown. In this review, we highlight new studies in humans that have clearly shown the mTORC1 signaling pathway is playing an important regulatory role in controlling muscle protein synthesis in response to nutrients and/or muscle contraction. We propose that essential amino acid ingestion shortly following a bout of resistance exercise is beneficial in promoting skeletal muscle growth and may be useful in counteracting muscle wasting in a variety of conditions such as aging, cancer cachexia, physical inactivity, and perhaps during rehabilitation following trauma or surgery.

Abstract
Purpose: For patients with breast cancer (BC), the optimal time to initiation of adjuvant chemotherapy (TTC) after definitive surgery is unknown. We evaluated the association between TTC and survival according to breast cancer subtype and stage at diagnosis.

Patients and methods: Women diagnosed with BC stages I to III between 1997 and 2011 who received adjuvant chemotherapy at our institution were included. Patients were categorized into three groups according to TTC: ≤ 30, 31 to 60, and ≥ 61 days. Survival outcomes were estimated and compared according to TTC and by BC subtype.

Results: Among the 6,827 patients included, the 5-year overall survival (OS), relapse-free survival (RFS), and distant RFS (DRFS) estimates were similar for the different TTC categories. Initiation of chemotherapy ≥ 61 days after surgery was associated with adverse outcomes among patients with stage II (DRFS: hazard ratio [HR], 1.20; 95% CI, 1.02 to 1.43) and stage III (OS: HR, 1.76; 95% CI, 1.26 to 2.46; RFS: HR, 1.34; 95% CI, 1.01 to 1.76; and DRFS: HR, 1.36; 95% CI, 1.02 to 1.80) BC. Patients with triple-negative BC (TNBC) tumors and those with human epidermal growth factor receptor 2 (HER2) -positive tumors treated with trastuzumab who started chemotherapy ≥ 61 days after surgery had worse survival (HR, 1.54; 95% CI, 1.09 to 2.18 and HR, 3.09; 95% CI, 1.49 to 6.39, respectively) compared with those who initiated treatment in the first 30 days after surgery.

Conclusion: TTC influenced survival outcomes in the overall study cohort. This finding was particularly meaningful for patients with stage III BC, TNBC, and trastuzumab-treated HER2-positive tumors who experienced worse outcomes when chemotherapy was delayed. Our findings suggest that early initiation of chemotherapy should be granted for patients in these high-risk groups.

Abstract
Background: In creating the Merit-Based Incentive Payment System, Congress has mandated pay-for-performance (P4P) for all physicians, including anesthesiologists. There are currently no National Quality Forum-endorsed risk-adjusted outcome metrics for anesthesiologists to use as the basis for P4P.

Methods: Using clinical data from the New York State Cardiac Surgery Reporting System, we conducted a retrospective observational study of 55,436 patients undergoing cardiac surgery between 2009 and 2012. Hierarchical logistic regression modeling was used to examine the variation in in-hospital mortality or major complications (Q-wave myocardial infarction, renal failure, stroke, and respiratory failure) among anesthesiologists, controlling for patient demographics, severity of disease, comorbidities, and hospital quality.

Results: Although the variation in performance among anesthesiologists was statistically significant (P = 0.025), none of the anesthesiologists in the sample was classified as a high- or low-performance outliers. The contribution of anesthesiologists to outcomes represented 0.51% of the overall variability in patient outcomes (intraclass correlation coefficient [ICC] = 0.0051; 95% confidence interval [CI], 0.002-0.014), whereas the contribution of hospitals to patient outcomes was 2.90% (ICC = 0.029; 95% CI, 0.017-0.050). The anesthesiologist median odds ratio (MOR) was 1.13 (95% CI, 1.08-1.24), suggesting that the variation between anesthesiologist was modest, whereas the hospital MOR was 1.35 (95% CI, 1.25-1.48). In a separate analysis, the contribution of surgeons to overall outcomes represented 1.76% of the overall variability in patient outcomes (ICC = 0.018, 95% CI, 0.010-0.031), and the surgeon MOR was 1.26 (95% CI, 1.19-1.37). Twelve of the surgeons were identified as performance outliers.

Conclusions: The impact of anesthesiologists on the total variability in cardiac surgical outcomes was probably about one-fourth as large as the surgeons' contribution. None of the anesthesiologists caring for cardiac surgical patients in New York State over a 3+ year period were identified as performance outliers. The use of a performance metric based on death or major complications for P4P may not be feasible for cardiac anesthesiologists.

Abstract
The case for radical pathway re-design before surgery is in part driven by healthcare system pressures which are in turn the result of continuously rising demand in the face of tightly constrained resources. Such circumstances tend to drive revolutionary, rather than incremental, change. The current approach to preoperative assessment, that typically occurs in the weeks leading up to surgery, but is all too often only a few days before surgery, results in a lost opportunity for perioperative physicians to improve patient care. Re-engineering this process based on a patient-focused, pathway-driven vision of perioperative medicine offers a means of exploiting this opportunity. This review explores drivers for change, the opportunity offered by pathway re-design, and suggests a variety of strategies to add value in the preoperative pathway, each of which is facilitated by early engagement between perioperative physician and patient: collaborative decision-making, collaborative behavioural change, targeted comorbidity management as well as expectation management and psychological preparation for surgery including surgery schools.

Abstract
Purpose: To determine if cardiopulmonary exercise testing (CPET) was useful in predicting response to exercise in cancer patients preoperatively. A secondary aim was to explore if exercise was associated with improved postoperative outcomes.

Methods: A retrospective cohort study was performed on consecutive cancer patients from 2012 to 2014, referred for exercise prehabilitation and had two CPET preoperatively.

Results: Twenty-six patients were analysed. There was a significant overall increase in oxygen uptake at anaerobic threshold (AT) from 10.4 to 11.6 ml kg(-1) min(-1) (ΔAT = 1.2 ± 3.0 ml kg(-1) min(-1) [9 %]; p = 0.046); peak oxygen uptake (pVO2) from 16.0 to 17.7 ml kg(-1) min(-1) (ΔpVO2 = 1.7 ± 2.4 ml kg(-1) min(-1) [9 %]; p = 0.002); and pVO2/BSA from 658 to 726 ml min(-1) m(-2); (ΔpVO2/BSA = 68 ± 112.3 mL min(-1) m(2) [10 %]; p = 0.004). Fifty percent of patients were responders to exercise, defined as having >10 % increase in AT. Responders had a median increase in AT of 26 % [IQR 7 %, 45 %] with an absolute increase in AT of 2.5 ml kg(-1) min(-1) [IQR 1.1, 3.9] (p = 0.002) and a median increase in pVO2 of 22 % [IQR 11.5, 32.5 %] with an absolute increase in pVO2 of 3.8 ml.kg(-1).min(-1) [IQR 2.0, 5.7] (p < 0.001). Responders were more likely to have a lower baseline AT (9.1 ml kg(-1) min(-1); p = 0.002).

Conclusions: Exercise improved cardiorespiratory fitness prior to major cancer surgery. Not all patients responded the same, with only 50 % of the study cohort being responders to exercise. A low AT, pVO2 and ratio of AT/pVO2 at baseline were good predictors of response to exercise, with a tendency for responders to suffer fewer major postoperative complications.

Abstract
Background: Exercise capacity is inversely related to mortality risk in healthy individuals and those with cardiovascular diseases. This evidence is based largely on white populations, with little information available for blacks.

Methods and results: We assessed the association between exercise capacity and mortality in black (n=6749; age, 58+/-11 years) and white (n=8911; age, 60+/-11 years) male veterans with and without cardiovascular disease who successfully completed a treadmill exercise test at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, Calif. Fitness categories were based on peak metabolic equivalents (METs) achieved. Subjects were followed up for all-cause mortality for 7.5+/-5.3 years. Among clinical and exercise test variables, exercise capacity was the strongest predictor of risk for mortality. The adjusted risk was reduced by 13% for every 1-MET increase in exercise capacity (hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.88; P<0.001). Compared with those who achieved <5 METs, the mortality risk was approximately 50% lower for those with an exercise capacity of 7.1 to 10 METs (hazard ratio, 0.51; 95% confidence interval, 0.47 to 0.56; P<0.001) and 70% lower for those achieving >10 METs (hazard ratio, 0.31; 95% confidence interval, 0.26 to 0.36; P<0.001). The findings were similar for those with and without cardiovascular disease and for both races.

Conclusions: Exercise capacity is a strong predictor of all-cause mortality in blacks and whites. The relationship was inverse and graded, with a similar impact on mortality outcomes for both blacks and whites.

Keywords: Duke Activity Status Index; METS study; cardiopulmonary exercise testing; cardiovascular risk; functional capacity; preoperative screening; risk assessment.

Abstract
Background: Due to the lack of evidence and inconsistency of sex differences in Heart failure (HF) in the Chinese population, this study aimed to compare sex differences in functional capacity and quality of life (QoL) between women and men after standard HF medications therapies, and analyze whether sex differences were associated with the composite endpoints of all-cause mortality or HF-related hospitalization and cardiac event-free survival rate in Chinese patients with HF.

Methods: This was a 1-year longitudinal study. Participants included patients with HF from March 2017 to December 2018. At baseline and followed up at 1, 6, and 12 months later, functional capacity was assessed by 6-minute walk testing (6MWT), QoL was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQoL five dimensions (EQ-5D). The Cox proportional hazards model and Kaplan-Meier curves were used to determine sex differences in subsequent outcomes. The Cox proportional hazards model was used to identify the risk factors for composite endpoints. Kaplan-Meier curves were used to compare survival.

Results: All patients were assigned to either men group (n = 94) or women group (n = 60). Longitudinal follow-ups showed a continuously increasing in 6MWT, Kansas City Cardiomyopathy Questionnaire overall score, EQ-5D visual analogue scale, and EQ-5D Index score in both groups (all P < 0.001); however, women reported a lower level of all parameters at the 1, 6, and 12 months follow-ups (all P < 0.05). In addition, women had a higher risk of all-cause mortality or HF-related hospitalization and a lower cardiac event-free survival rate than men (log-rank test, P = 0.027).

Conclusion: Women reported worse functional capacity, QoL, and prognosis than men in a sample of Chinese patients with HF. Our findings highlight the importance of paying attention to sex differences in HF.

Abstract
Importance: Colorectal surgery is associated with substantial morbidity rates and a lowered functional capacity. Optimization of the patient's condition in the weeks prior to surgery may attenuate these unfavorable sequelae.

Objective: To determine whether multimodal prehabilitation before colorectal cancer surgery can reduce postoperative complications and enhance functional recovery.

Design, setting, and participants: The PREHAB randomized clinical trial was an international, multicenter trial conducted in teaching hospitals with implemented enhanced recovery after surgery programs. Adult patients with nonmetastasized colorectal cancer were assessed for eligibility and randomized to either prehabilitation or standard care. Both arms received standard perioperative care. Patients were enrolled from June 2017 to December 2020, and follow-up was completed in December 2021. However, this trial was prematurely stopped due to the COVID-19 pandemic.

Interventions: The 4-week in-hospital supervised multimodal prehabilitation program consisted of a high-intensity exercise program 3 times per week, a nutritional intervention, psychological support, and a smoking cessation program when needed.

Main outcomes and measures: Comprehensive Complication Index (CCI) score, number of patients with CCI score more than 20, and improved walking capacity expressed as the 6-minute walking distance 4 weeks postoperatively.

Results: In the intention-to-treat population of 251 participants (median [IQR] age, 69 [60-76] years; 138 [55%] male), 206 (82%) had tumors located in the colon and 234 (93%) underwent laparoscopic- or robotic-assisted surgery. The number of severe complications (CCI score >20) was significantly lower favoring prehabilitation compared with standard care (21 of 123 [17.1%] vs 38 of 128 [29.7%]; odds ratio, 0.47 [95% CI, 0.26-0.87]; P = .02). Participants in prehabilitation encountered fewer medical complications (eg, respiratory) compared with participants receiving standard care (19 of 123 [15.4%] vs 35 of 128 [27.3%]; odds ratio, 0.48 [95% CI, 0.26-0.89]; P = .02). Four weeks after surgery, 6-minute walking distance did not differ significantly between groups when compared with baseline (mean difference prehabilitation vs standard care 15.6 m [95% CI, -1.4 to 32.6]; P = .07). Secondary parameters of functional capacity in the postoperative period generally favored prehabilitation compared with standard care.

Conclusions and relevance: This PREHAB trial demonstrates the benefit of a multimodal prehabilitation program before colorectal cancer surgery as reflected by fewer severe and medical complications postoperatively and an optimized postoperative recovery compared with standard care.

Trial registration: trialregister.nl Identifier: NTR5947.

Abstract
Patients undergoing major cancer interventions such as major surgical resection, chemotherapy, radiotherapy, and immunotherapy are prone to the adverse effects of their cancer, as well as to the side effects of the treatments designed to cure them. The Prehabilitation process supports cancer patients in preparing for the physiological challenges of their cancer treatments, whilst aiming to shorten recovery time, reduce peri-operative complications and improve compliance with non-surgical treatments. Prehabilitation will be most useful in older patients. Greater Manchester Integrated Care system is the first regional system in the UK to introduce delivery of system-wide, large scale physical activity supported multi-modal prehabilitation and recovery programme, Prehab4Cancer as a standard of care for cancer patients. It builds upon the successful implementation of Enhanced Recovery After Surgery + programme to improve surgical care in Greater Manchester. During this review we describe the journey to develop a system wide prehabilitation model for patients with cancer. Prehab4Cancer to date has focused on robust co-design, development, and implementation of an effective service model with attention paid to stakeholder engagement. This has led to receipt of high numbers of referrals from across Greater Manchester for the all the cancer groups involved. The successful implementation of the P4C pathway in GM presents a best practice model that might be adopted by other local and combined authority areas nationally.

Abstract
Objective: We evaluated the usefulness of analyzing expired gas during exercise testing for the prediction of postoperative cardiopulmonary complications in patients with esophageal carcinoma.

Background data: Radical esophagectomy with 3-field lymphadenectomy is performed in patients with thoracic esophageal carcinoma but has a high risk of postoperative complications. To reduce the surgical risk, we performed preoperative risk analysis using 8 factors. Although hospital mortality was decreased when this risk analysis was used, severe cardiopulmonary complications still occurred.

Methods: The study group consisted of 91 patients who had undergone curative esophagectomy with 3-field lymphadenectomy. The maximum oxygen uptake, anaerobic threshold, vital capacity, percent vital capacity, forced expiratory volume in 1 second, percent forced expiratory volume, V.(25)/HT, forced expired flow at 75% of forced vital capacity to height ratio (FEF(75%)/HT), forced expired flow at 50% to 75% of forced vital capacity ratio (FEF(50%)/FEF(75%)), percent diffusion capacity for carbon monoxide, and arterial oxygen tension were measured. Patients were divided into 2 groups on the basis of the presence or absence of postoperative cardiopulmonary complications.

Results: Only the maximum oxygen uptake was significantly different between the 2 groups. All patients were grouped according to the value of the maximum oxygen uptake, and the occurrence of postoperative cardiopulmonary complications was calculated for each group. A cardiopulmonary complication rate of 86% was found for patients with a maximum oxygen uptake of less than 699 mL. min(-1). m(-2); for those with a value of 700 to 799 mL. min(-1). m(-2), the complication rate was 44%.

Conclusions: The maximum oxygen uptake obtained by expired gas analysis during exercise testing correlates with the postoperative cardiopulmonary complication rate. On the basis of these results, esophagectomy with 3-field lymphadenectomy can be safely performed in patients with a maximum oxygen uptake of at least 800 mL. min(-1). m(-2).

Abstract
Background: Accurate assessment of functional capacity, a predictor of postoperative morbidity and mortality, is essential to improving surgical planning and outcomes. We assessed if all 12 items of the Duke Activity Status Index (DASI) were equally important in reflecting exercise capacity.

Methods: In this secondary cross-sectional analysis of the international, multicentre Measurement of Exercise Tolerance before Surgery (METS) study, we assessed cardiopulmonary exercise testing and DASI data from 1455 participants. Multivariable regression analyses were used to revise the DASI model in predicting an anaerobic threshold (AT) >11 ml kg-1 min-1 and peak oxygen consumption (VO2 peak) >16 ml kg-1 min-1, cut-points that represent a reduced risk of postoperative complications.

Abstract
Background: Preoperative spirometry and cardiopulmonary exercise testing (CPET) may stratify risk for respiratory complications. This secondary analysis of the Measurement of Exercise Tolerance before Surgery (METS) study examined whether CPET performance (i.e., cardiopulmonary fitness) confounds associations of spirometry with outcomes.

Methods: The analysis included 1200 participants having major non-cardiac surgery at 25 hospitals in Canada, Australia, New Zealand and UK. Forced expiratory volume in 1 s (FEV1), and ratio of FEV1 to forced vital capacity (FVC) were measured during preoperative spirometry, and peak oxygen consumption and ventilatory efficiency during preoperative CPET. Outcomes were respiratory morbidity (Postoperative Morbidity Survey) and pulmonary complications (pneumonia or respiratory failure). We used multivariable logistic regression models to estimate associations of FEV1 with outcomes after adjustment for risk factors and either peak oxygen consumption or ventilatory efficiency.

Findings: 128 participants (11%) developed respiratory morbidity, and 48 (4%) developed pulmonary complications. There was no strong evidence that FEV1 predicted respiratory morbidity after adjustment for peak oxygen consumption (p = 0·80) or ventilatory efficiency (p = 0·76), or FEV1 predicted pulmonary complications after adjustment for ventilatory efficiency (p = 0·37). Peak oxygen consumption (odds ratio 0·66 per 5 mL/kg/min increase; 95% CI, 0·54-0·82) was associated with respiratory morbidity. Ventilatory efficiency was associated with respiratory morbidity (p = 0·04) and pulmonary complications (p = 0·02). Peak oxygen consumption also confounded the association between FEV1 and respiratory morbidity.

Interpretation: After accounting for fitness and clinical factors, FEV1 was not strongly predictive of respiratory complications. Prior associations between FEV1 and respiratory morbidity may be explained by confounding by peak oxygen consumption.

Funding: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.

Abstract
The field of cancer survivorship has significantly advanced person-centered care throughout the cancer continuum. Within cancer survivorship, the last decade has seen remarkable growth in the investigation of prehabilitation comprising pre-treatment interventions to prevent or attenuate the burden of oncologic therapies. While the majority of evidence remains in the surgical setting, prehabilitation is being adapted to target modifiable risk factors that predict poor treatment outcomes in patients receiving other systemic and localized anti-tumor treatments. Here, we propose a multiphasic approach for prehabilitation across the cancer continuum, as a conceptual framework, to encompass the variability in cancer treatment experiences while adopting the most inclusive definition of the cancer survivor.

Abstract
Shared decision making (SDM) is a method of care that is suitable for the care of patients with cancer. It involves a collaborative conversation seeking to respond sensibly to the problematic situation of the patient, cocreating a plan of care that makes sense intellectually, practically, and emotionally. Genetic testing to identify whether a patient has a hereditary cancer syndrome represents a prime example of the importance for SDM in oncology. SDM is important for genetic testing because not only results affect current cancer treatment, cancer surveillance, and care of relatives but also these tests generate both complex results and psychological concerns. SDM conversations should take place without interruptions, disruptions, or hurry and be supported, where available, by tools that assist in conveying the relevant evidence and in supporting plan development. Examples of these tools include treatment SDM encounter aids and the Genetics Adviser. Patients are expected to play a key role in making decisions and implementing plans of care, but several evolving challenges related to the unfettered access to information and expertise of varying trustworthiness and complexity in between interactions with clinicians can both support and complicate this role. SDM should result in a plan of care that is maximally responsive to the biology and biography of each patient, maximally supportive of each patient's goals and priorities, and minimally disruptive of their lives and loves.

Abstract
This study reviews the predictive value of maximum oxygen consumption (VO2max) and anaerobic threshold, obtained through cardiopulmonary exercise testing, in calculating peri-operative morbidity and mortality in non-cardiopulmonary thoraco-abdominal surgery. A literature review provided nine studies that investigated either one or both of these two variables across a wide range of surgical procedures. Six of the seven studies that reported sufficiently detailed results on peak oxygen consumption and four of the six studies that reported sufficiently detailed results on anaerobic threshold found them to be significant predictors. We conclude that peak oxygen consumption and possibly anaerobic threshold are valid predictors of peri-operative morbidity and mortality in non-cardiopulmonary thoraco-abdominal surgery. These indicators could potentially provide a means of allocating increased care to high-risk patients.

Abstract
Backgrounds: There is mixed evidence on the value of preoperative cardiorespiratory exercise test (CPET) to predict postoperative outcomes in patients undergoing a cancer surgical procedure. The purpose of this review was to investigate the association between preoperative CPET variables and postoperative complications, length of hospital stay, and quality of life in patients undergoing cancer surgery.

Methods: A search was conducted on MEDLINE, Embase, AMED, and Web of science from inception to April 2020. Cohort studies investigating the association between preoperative CPET variables, including peak oxygen uptake (peak VO2), anaerobic threshold (AT), or ventilatory equivalent for carbon dioxide (VE/VCO2), and postoperative outcomes (complications, length of stay, and quality of life) were included. Risk of bias was assessed using the QUIPS tool. A random-effect model meta-analysis was performed whenever possible.

Results: Fifty-two unique studies, including 10,030 patients were included. Overall, most studies were rated as having low risk of bias. Higher preoperative peak VO2 was associated with absence of postoperative complications (mean difference [MD]: 2.28; 95% confidence interval [CI]: 1.26-3.29) and no pulmonary complication (MD: 1.47; 95% CI: 0.49-2.45). Preoperative AT and VE/VCO2 also demonstrated some positive trends. None of the included studies reported a negative trend.

Conclusions: This systematic review and meta-analysis demonstrated a significant association between superior preoperative CPET values, especially peak VO2, and better postoperative outcomes. The assessment of preoperative functional capacity in patients undergoing cancer surgery has the potential to facilitate treatment decision making.

Abstract
Introduction: Cardiopulmonary exercise testing (CPET) is widely used within the United Kingdom for preoperative risk stratification. Despite this, CPET's performance in predicting adverse events has not been systematically evaluated within the framework of classifier performance.

Methods: After prospective registration on PROSPERO (CRD42018095508) we systematically identified studies where CPET was used to aid in the prognostication of mortality, cardiorespiratory complications, and unplanned intensive care unit (ICU) admission in individuals undergoing non-cardiopulmonary surgery. For all included studies we extracted or calculated measures of predictive performance whilst identifying and critiquing predictive models encompassing CPET derived variables.

Results: We identified 36 studies for qualitative review, from 27 of which measures of classifier performance could be calculated. We found studies to be highly heterogeneous in methodology and quality with high potential for bias and confounding. We found seven studies that presented risk prediction models for outcomes of interest. Of these, only four studies outlined a clear process of model development; assessment of discrimination and calibration were performed in only two and only one study undertook internal validation. No scores were externally validated. Systematically identified and calculated measures of test performance for CPET demonstrated mixed performance. Data was most complete for anaerobic threshold (AT) based predictions: calculated sensitivities ranged from 20-100% when used for predicting risk of mortality with high negative predictive values (96-100%). In contrast, positive predictive value (PPV) was poor (2.9-42.1%). PPV appeared to be generally higher for cardiorespiratory complications, with similar sensitivities. Similar patterns were seen for the association of Peak VO2 (sensitivity 85.7-100%, PPV 2.7-5.9%) and VE/VCO2 (Sensitivity 27.8%-100%, PPV 3.4-7.1%) with mortality.

Conclusions: In general CPET's 'rule-out' capability appears better than its ability to 'rule-in' complications. Poor PPV may reflect the frequency of complications in studied populations. Our calculated estimates of classifier performance suggest the need for a balanced interpretation of the pros and cons of CPET guided pre-operative risk stratification.

Abstract
Background: Prehabilitation services assist patients in preparing for surgery, yet access to these services are often limited by geographical factors. Enabling rural and regional patients to access specialist surgical prehabilitation support with the use of telehealth technology has the potential to overcome health inequities and improve post-operative outcomes.

Aim: To evaluate the current and likely future impact of a telehealth preoperative education package for patients preparing for major abdominal cancer surgery.

Methods: A telehealth alternative to a hospital based pre-operative education session was developed and implemented at a dedicated cancer hospital. Adult patients (≥18 years) scheduled for elective major cancer surgery were offered this telehealth alternative. Impact evaluation was conducted using the RE-AIM framework.

Results: To date, 35 participants have consented to participate in the study. Thirty-one participants attended the intervention; 24 (69%) residing in rural or regional areas. Twenty-four (77%) reported that if given a choice they would prefer the online session as opposed to attending the hospital in person. The majority (97%) reported they would recommend the intervention to others preparing for surgery. Session information was recalled by all 26 participants and 77% of participants reported acting on recommendations 2 weeks after the session. Lessons learnt and recommendations for providers implementing similar programs are reported.

Conclusion: Telehealth alternatives to hospital based pre-operative education are well received by patients preparing for major cancer surgery. We make seven recommendations to improve implementation. Further evaluation of implementation strategies alongside clinical effectiveness in future studies is essential.

Abstract
Purpose: Prehabilitation programs are effective in optimising patient's functional reserve prior to surgery and increasingly associated with reduced postoperative complications. However, acceptability of programs among patients is largely unknown. This study set out to explore the acceptability of prehabilitation from the perspective of patients awaiting major cancer surgery.

Methods: Adult patients awaiting major gastrointestinal and urological cancer surgeries were surveyed. Patients were excluded if they were unable to complete the survey due to language, intellectual impairment and/or visual/hearing deficit. The survey was designed to explore categories related to patient demographics, level of physical activity and perceived enablers and barriers to prehabilitation.

Results: One hundred and three participants presenting to a pre-anaesthesia clinic completed the survey over a 5-month period, with 83% response rate. Approximately, half of the respondents were female (55%) and were currently physically active (53%). Fewer than one third (30%) felt they completed 'enough exercise'. The majority of participants (83%) were unfamiliar with the concept of prehabilitation but two thirds (68%) were interested in such a program after explanation. The majority of participants (72%) indicated a strong preference to exercise in a home-based environment. Medical recommendation increased willingness to participate (p < 0.001), while program costs (p = 0.01) were potential barriers to participation.

Conclusion: Patients are willing to participate in prehabilitation prior to major cancer surgery but practical barriers and facilitators should be considered when designing prehabilitation programs to maximise patient commitment to facilitate improved postoperative outcomes.

Abstract
Objectives: This systematic review set out to identify, evaluate and synthesise the evidence examining the effect of prehabilitation including exercise on postoperative outcomes following abdominal cancer surgery. Methods: Five electronic databases (MEDLINE 1946-2020, EMBASE 1947-2020, CINAHL 1937-2020, PEDro 1999-2020, and Cochrane Central Registry of Controlled Trials 1991-2020) were systematically searched (until August 2020) for randomised controlled trials (RCTs) that investigated the effects of prehabilitation interventions in patients undergoing abdominal cancer surgery. This review included any form of prehabilitation either unimodal or multimodal that included whole body and/or respiratory exercises as a stand-alone intervention or in addition to other prehabilitation interventions (such as nutrition and psychology) compared to standard care. Results: Twenty-two studies were included in the systematic review and 21 studies in the meta-analysis. There was moderate quality of evidence that multimodal prehabilitation improves pre-operative functional capacity as measured by 6 min walk distance (Mean difference [MD] 33.09 metres, 95% CI 17.69-48.50; p = <0.01) but improvement in cardiorespiratory fitness such as preoperative oxygen consumption at peak exercise (VO2 peak; MD 1.74 mL/kg/min, 95% CI -0.03-3.50; p = 0.05) and anaerobic threshold (AT; MD 1.21 mL/kg/min, 95% CI -0.34-2.76; p = 0.13) were not significant. A reduction in hospital length of stay (MD 3.68 days, 95% CI 0.92-6.44; p = 0.009) was observed but no effect was observed for postoperative complications (Odds Ratio [OR] 0.81, 95% CI 0.55-1.18; p = 0.27), pulmonary complications (OR 0.53, 95% CI 0.28-1.01; p = 0.05), hospital re-admission (OR 1.07, 95% CI 0.61-1.90; p = 0.81) or postoperative mortality (OR 0.95, 95% CI 0.43-2.09, p = 0.90). Conclusion: Multimodal prehabilitation improves preoperative functional capacity with reduction in hospital length of stay. This supports the need for ongoing research on innovative cost-effective prehabilitation approaches, research within large multicentre studies to verify this effect and to explore implementation strategies within clinical practise.

Abstract
Background: Patients requiring surgery for locally advanced rectal cancer often additionally undergo neoadjuvant chemoradiotherapy (NACRT), of which the effects on physical fitness are unknown. The aim of this feasibility and pilot study was to investigate the effects of NACRT and a 6 week structured responsive exercise training programme (SRETP) on oxygen uptake [Formula: see text] at lactate threshold ([Formula: see text]) in such patients.

Methods: We prospectively studied 39 consecutive subjects (27 males) with T3-4/N+ resection margin threatened rectal cancer who completed standardized NACRT. Subjects underwent cardiopulmonary exercise testing at baseline (pre-NACRT), at week 0 (post-NACRT), and week 6 (post-SRETP). Twenty-two subjects undertook a 6 week SRETP on a training bike (three sessions per week) between week 0 and week 6 (exercise group). These were compared with 17 contemporaneous non-randomized subjects (control group). Changes in [Formula: see text] at [Formula: see text] over time and between the groups were compared using a compound symmetry covariance linear mixed model.

Results: Of 39 recruited subjects, 22 out of 22 (exercise) and 13 out of 17 (control) completed the study. There were differences between the exercise and control groups at baseline [age, ASA score physical status, World Health Organisation performance status, and Colorectal Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity (CR-POSSUM) predicted mortality]. In all subjects, [Formula: see text] at [Formula: see text] significantly reduced between baseline and week 0 [-1.9 ml kg(-1) min(-1); 95% confidence interval (CI) -1.3, -2.6; P<0.0001]. In the exercise group, [Formula: see text] at [Formula: see text] significantly improved between week 0 and week 6 (+2.1 ml kg(-1) min(-1); 95% CI +1.3, +2.9; P<0.0001), whereas the control group values were unchanged (-0.7 ml kg(-1) min(-1); 95% CI -1.66, +0.37; P=0.204).

Conclusions: NACRT before rectal cancer surgery reduces physical fitness. A structured exercise intervention is feasible post-NACRT and returns fitness to baseline levels within 6 weeks.

Clinical trial registration nct: 01325909.

Trial registration: ClinicalTrials.gov NCT01325909.

Keywords: anaerobic threshold; cardiopulmonary exercise test; exercise; prehabilitation; rectal cancer; surgery.

Abstract
Background: Functional capacity is an important component of risk assessment for major surgery. Doctors' clinical subjective assessment of patients' functional capacity has uncertain accuracy. We did a study to compare preoperative subjective assessment with alternative markers of fitness (cardiopulmonary exercise testing [CPET], scores on the Duke Activity Status Index [DASI] questionnaire, and serum N-terminal pro-B-type natriuretic peptide [NT pro-BNP] concentrations) for predicting death or complications after major elective non-cardiac surgery.

Methods: We did a multicentre, international, prospective cohort study at 25 hospitals: five in Canada, seven in the UK, ten in Australia, and three in New Zealand. We recruited adults aged at least 40 years who were scheduled for major non-cardiac surgery and deemed to have one or more risk factors for cardiac complications (eg, a history of heart failure, stroke, or diabetes) or coronary artery disease. Functional capacity was subjectively assessed in units of metabolic equivalents of tasks by the responsible anaesthesiologists in the preoperative assessment clinic, graded as poor (<4), moderate (4-10), or good (>10). All participants also completed the DASI questionnaire, underwent CPET to measure peak oxygen consumption, and had blood tests for measurement of NT pro-BNP concentrations. After surgery, patients had daily electrocardiograms and blood tests to measure troponin and creatinine concentrations until the third postoperative day or hospital discharge. The primary outcome was death or myocardial infarction within 30 days after surgery, assessed in all participants who underwent both CPET and surgery. Prognostic accuracy was assessed using logistic regression, receiver-operating-characteristic curves, and net risk reclassification.