Does the introduction of pre‐operative cardiopulmonary exercise testing in radical cystectomy delay or alter surgical care?

Abstract Objectives To assess if the introduction of routine pre‐operative cardiopulmonary exercise testing (CPET) in radical cystectomy has delayed surgical intervention. Materials and Methods A prospective database of patients undergoing radical cystectomy in our local health network was maintained. A retrospective analysis of two years (2018–2020) included 38 patients. Of these, 15 patients had CPET pre‐operatively, and a direct comparison was performed. Results The mean time from diagnosis to cystectomy was 95 days in patients who did not have CPET compared to 110 days for those who did (p = 0.32), with comparable rates of neoadjuvant chemotherapy (NAC) (62.5% and 64.29%). Average length of stay was 18.6 days compared with 13.87 (p = 0.16), favouring the CPET group. The CPET group also had a lower readmission rate within 30 days (13.33% compared with 21.05%, p = 0.35). Cause‐specific mortality within 90 days was 10.2% and within the study timeframe was 36.84% (estimated 5‐year mortality rate 43–65%). Within the CPET group, eight had an anaerobic threshold (AT) of <11 ml/kg/min (range 6.3–10.5): Of these, 50% had Clavien‐Dindo complications of grade 2 or higher and the 90‐day mortality rate was 37.5% (cf. 0% in those with AT > 11 ml/kg/min in this series). Conclusion CPET is a valuable risk evaluation tool. This study suggested that CPET contributed to a minor non‐significant delay to surgery, however was associated with reduced length of stay and readmission rates, and was a valuable risk evaluation tool. We found that CPET AT <11 ml/kg/min is associated with higher rates of patient morbidity and perioperative mortality.


| INTRODUCTION
Radical cystectomies are performed for muscle invasive and high risk or recurrent non-muscle invasive bladder cancer, a major operation with significant morbidity (significant complications in $30%, overall complications up to 64%) and a perioperative 90 day mortality rate of 5-8%. 1,2 When adjusted for comorbidity and smoking status, age itself is not deemed a risk factor for post-operative morbidity/ mortality, rather cardiorespiratory fitness status. [1][2][3][4] CPET is a non-invasive and reproducible method of assessing cardiorespiratory function and reserve through a closely monitored exercise test. Its focus is measuring oxygen uptake (VO 2 ) (and calculating ventilatory equivalent for carbon dioxide [VE/VCO 2 ]) during exercise and the point at which aerobic respiration is supplemented by anaerobic respiration to produce energy (the anaerobic threshold [AT]), which appears to correlate with peri-operative outcomes. 2,5 CPET is being adopted increasingly into the pre-operative workup and optimisation of patients prior to major elective non-cardiac surgeries. 6 It has played a role in Early Recovery After Surgery (ERAS) protocols for abdominal surgery and surgical p/rehabilitation. 4,7,8 CPET can help risk assessment for perioperative morbidity and mortality (therefore guide perioperative care and anaesthetic practice), inform multidisciplinary decision-making, assess optimisation of comorbidities, identify underlying pathology, and evaluate the effect of neoadjuvant therapies. 8 This is particularly important in non-cardiothoracic surgery such as cystectomy where there are increased cardiovascular demands without the expected cardiorespiratory improvement from the intervention itself. 9 However, there is paucity of studies in the literature assessing the realistic impact of introducing CPET-driven pre-operative co-morbid optimisation, or any service-delivery related learning curve, on time to surgery.
Studies have suggested poor CPET scores pre-operatively are correlated with a longer and more morbid length of stay. 2,5,10 For radical cystectomy, post-operative functional performance has also been found to correlate with overall survival. 3,11 Patients with a low AT of ≤11-12 ml/kg/min and VE/VCO 2 ≥ 33 appear to be at higher risk of complications and mortality. 2,5 However, the literature is still relatively sparse for CPET in radical cystectomy (either laparoscopic/ robotic or open) compared with other major abdominal surgery, and results have been to some degree divided. The best variables to predict outcome risks are still being clarified and validated. 2,8,12 This pilot study aims to identify whether the introduction of CPET prior to radical cystectomy resulted in delay to surgical intervention. The secondary outcomes assessed included comparison of length of stay, readmission within 90 days, post-operative morbidity and mortality rates.

| RESULTS
Thirty-eight patients were included over the two-year retrospective study period. Overall, the mean age at diagnosis was 64 years and patients waited an average of 100.8 days from diagnosis to cystectomy. Twenty-three patients had neoadjuvant chemotherapy (60.5%), and an additional seven had adjuvant chemotherapy. The mean albumin pre-operatively was 35.94 g/L, and mean drop in haemoglobin from pre-operatively to immediately post-operatively was 23.84 g/L. The mean hospital length of stay was 16.05 days, whilst average ICU length of stay was 0.14 days. The readmission rate within 30 days was 21.05%. The overall cause-specific mortality within the study timeframe was 36.84%, and the 90 day mortality rate was 10.2% (four patients).
These patients were divided into Group 1 (no CPET assessment, n = 23) and Group 2 (CPET assessment, n = 15) for comparative analysis (  [16][17][18] Anaerobic threshold is considered the optimal predictor of outcome in intra-abdominal surgery, with <10-11 ml/kg/min considered high risk. 2,5,19 We certainly found this to be consistent CPET is a valuable risk evaluation tool. This study suggested that CPET contributed to a clinically non-significant delay to surgery and may result in reduced length of stay and readmission rates. We found CPET AT <11 ml/kg/min is associated with higher rates of patient morbidity and perioperative mortality.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
This research study was conducted retrospectively from data obtained for clinical purposes. It was registered and approved (identifier 2020/STE01913) with the research ethics and governance information system (REGIS).

AUTHOR CONTRIBUTIONS
KL and AB conceived the study. KL researched the literature, developed the protocol, and obtained ethics approval with RC. KL drafted the manuscript and performed data analysis. AT and AB supervised the study, and AB edited and approved the final manuscript. All authors have read and approved the manuscript.

DATA AVAILABILITY STATEMENT
The data analyses generated are available within the presented study but specific datasets are kept confidential due to their nature of including clinical and radiological details. Further information regarding dataset analysis may be available from the corresponding author upon request.