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Keywords:

  • outcome;
  • risk assessment;
  • morbidity;
  • anaerobic threshold

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest
  9. References

Objective

  • To determine the relationship of preoperatively measured cardiorespiratory function, to the development of postoperative complications and length of hospital stay (LOS) in a cohort of patients undergoing radical cystectomy (RC), as RC and conduit formation is curative but is associated with significant postoperative morbidity and mortality.

Patients and Methods

  • Consecutive patients planned to have RC underwent cardiopulmonary exercise testing (CPET) to a standardised protocol.
  • The results of the CPET were ‘blinded’ from the clinicians involved in the care of the patients.
  • Patients were prospectively monitored for the primary outcome of postoperative complications, as defined by a validated classification (Clavien-Dindo).
  • Secondary outcome included LOS and mortality.

Results

  • In all, 82 patients underwent CPET before RC. Eight patients did not subsequently undergo RC and a further five did not exercise sufficiently to allow for appropriate determination of the cardiopulmonary variables of interest.
  • There was a significant difference in LOS between those patients who had a major perioperative complication (Clavien score > 3) and those that did not (16 vs 30 days; P < 0.001; hazard ratio [HR] 3.6, 95% confidence interval [CI] 2.1–6.3).
  • The anaerobic threshold (AT) remained as the only significant independent predictor variable for the presence or absence of major postoperative complications (odds ratio 0.74, 95% CI 0.57–0.97; P = 0.03).
  • When the optimal predictive value of AT of 12 mL/min/kg was used as a fitness marker, there was a significant relationship between fitness and LOS (median LOS: ‘unfit’ 22 days vs ‘fit’ 16 days; HR 0.47, 95% CI 0.28–0.80; P = 0.006)

Conclusion

  • Impaired preoperative cardiopulmonary reserve was related to major morbidity, prolonged LOS and increased use of critical care resource after RC.
  • This has important health and economic implications for risk assessment, rationalisation of postoperative resource and the potential for therapeutic preoperative intervention with exercise therapy.

Abbreviations
AT

anaerobic threshold

CPET

cardiopulmonary exercise test

CRF

cardiorespiratory function

HR

hazard ratio

LOS

length of hospital stay

OR

odds ratio

RC

radical cystectomy

ROC

receiver operating characteristic

VCO2

carbon dioxide production

VE

minute ventilation

VO2

oxygen consumption

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest
  9. References

TCC of the bladder is a common cancer worldwide, with about 20–30% of patients having muscle-invasive disease at the time of presentation and diagnosis [1]. Radical cystectomy (RC) with pelvic lymph node dissection and ileal conduit or orthotopic bladder reconstruction remains the ‘gold standard’ surgical treatment for muscle-invasive bladder cancer [2]. However, RC is associated with high rates of morbidity (19–64%) [3-9] and mortality (6–11%) [10-14], although there is considerable variability between published series.

As oncological therapy appears comparable in the short term to open surgery, preoperative recognition of patients at high risk of postoperative morbidity is important in defining both the necessity for operation and subsequent postoperative care requirements. Advancing age per se is not a discriminatory factor for RC [2, 15, 16]. However, the combination of major surgery, in an elderly patient group with significant preoperative co-morbidities, constitutes an important risk consideration for postoperative morbidity after RC [3-9, 17].

Current preoperative risk assessment techniques lack the appropriate specificity and sensitivity to predict postoperative complications after RC [3, 10-14, 18]. More specific preoperative investigations, e.g. resting or stress echocardiography, are designed solely to investigate risk of specific complications [19, 20] rather than predict overall postoperative morbidity.

Cardiopulmonary exercise testing (CPET) is a safe, reproducible and non-invasive method of assessing cardiorespiratory function (CRF) [2, 21]. Variables derived from CPET have shown predictive value for morbidity and mortality after major surgical procedures [3-9, 22-28].

The present study aimed to define the relationship between preoperative CRF and morbidity (defined by the Clavien-Dindo system [6, 10-14]) and length of hospital stay (LOS) in a cohort of patients undergoing open RC and conduit formation.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest
  9. References

Over a 3-year period an unselected cohort of patients being considered for RC at a single specialist centre performed a preoperative cardiopulmonary exercise test (CPET). After the provision of informed consent, a CPET was used to screen for undiagnosed heart disease and provide information about cardiorespiratory fitness. The study was performed with full institutional approval from Newcastle upon Tyne Research and Development Department and Regional Ethics Committee Support as a service evaluation protocol. If the CPET proved positive for cardiac complications (e.g. myocardial ischaemia) the patients were to be referred to an appropriate cardiologist for further investigations and management. Patients were excluded from the analysis if a major surgical procedure was not performed due to extensive malignancy or preoperative co-morbidity or if patients did not exercise sufficiently to reach an objective measure (anaerobic threshold, AT) of cardiorespiratory fitness at CPET (i.e. the test was not informative). All patients had standard surgical and anaesthetic management intraoperatively. Patients received a fentanyl, propofol and atracurium induction. Isoflurane was used for maintenance intraoperatively and oesophageal Doppler monitoring was available for fluid management in all cases. Epidural analgesia was undertaken for all patients unless contraindicated.

Those involved in clinical management were ‘blinded’ to the results of the CPET and cardiorespiratory fitness was not used to determine fitness for surgery or perioperative management of patients.

All patients were discharged from the theatre complex to the ward unless the anaesthetist requested a critical care bed on the basis of the patient's co-morbidities with no reference to the CPET. If the patient was admitted to the critical care area they were discharged to the ward when pre-defined physiological parameters were met and were discharged from hospital when deemed appropriate by the surgical team both with no reference to the CPET test result.

Cardiopulmonary Exercise Testing

Patients underwent a maximal progressive exercise test on an electronically braked ergometer (Lode, Groningen, the Netherlands). During the test, expired gases were collected and analysed offline for minute ventilation (VE), oxygen consumption (VO2), carbon dioxide production (VCO2) (Scott Medical, Plumsteadville, USA) and cardiac function measured by 12-lead electrocardiogram (Welch Allan, New York, USA). Flow and gas calibration were performed manually before each test. The increment in work rate was predetermined using equations for an estimate of expected work capacity, to aim for test duration of 6–10 min. The test was stopped upon voluntary termination (fatigue, pain, light-headedness), failure to maintain >40 revolutions/min for >30 s despite encouragement or presentation of clinical indications. Cardiopulmonary reserve was calculated by the V-slope AT method [15, 16, 29] and peak oxygen consumption as the highest VO2 during the final 30 s of exercise.

Data Collection/Risk Assessment

Patient demographics (age, height, weight) were collected along with the results of the CPET. Postoperative morbidity data was collected and defined by the Clavien Index [6, 17]. The surgical team, in charge of the care of the patient, recorded this. LOS, critical care usage and in-hospital mortality were also recorded.

Table 1. Demographics of patients with no, minor and major complications.
VariableNo complicationsClavien 1–2Clavien ≥3
  1. BMI, body mass index; HR, heart rate; OUES, oxygen uptake efficiency slope.

Demographic   
n302613
Mean (sd)   
Age, years68.7 (6.3)70.2 (7.4)70.6 (5.3)
Sex (M/F), n18/1219/711/2
Weight, kg75.7 (17.2)76.7 (18.3)83.0 (23.9)
BMI, kg/m226.8 (4.9)26.1 (5.2)28.6 (6.2)
CPET   
AT, mL/min/kg12.8 (3.5)13.7 (3.7)10.9 (1.8)
VO2/HR9.4 (3.3)10.9 (3.8)12.0 (6.6)
OUES, mL/min/logVE1506 (466)1625 (449)1573 (126)
VE/VCO236.0 (5.1)36.3 (6.5)36.0 (6.2)
Peak VO2, mL/min/kg16.3 (4.9)16.8 (4.6)15.0 (3.0)

Statistical Methods

The relationship between the development of postoperative complications (as defined by the Clavien Classification) and LOS was determined by Kaplan–Meier analysis. Calculated statistics investigated differences between complication groups categorised as ‘No complications’, ‘Clavien-Dindo score < 3 (minor)’ and ‘Clavien-Dindo score ≥ 3 (major)’.

The relationship of preoperative gaseous exchange variables, derived from CPET, with the development of postoperative complications, were analysed by logistic regression analysis. A multivariate regression approach was used to explore the independent significance of relevant variables. The dependent variables used were: (i) ‘No complications’ vs ‘All complications’ and (ii) ‘Minor or no complications (Clavien-Dindo complication score 0 to <3)’ vs ‘Major complications (Clavien-Dindo ≥ 3)’. Odds ratios (ORs) and their corresponding 95% CIs were estimated from the maximum likelihood logistic regression models.

Where appropriate, receiver operating characteristic (ROC) curve analysis was used to further investigate independent variables as predictors of postoperative complications. An optimal threshold level taken as the uppermost left point on the ROC curve was used to define high- and low-risk groups in a Kaplan–Meier analysis for LOS.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest
  9. References

In all, 82 unselected patients attended the pre-assessment clinic at the Freeman Hospital and underwent preoperative CPET. Five patients were unable to attain the AT or perform the test and were censored from survival analysis and defined as missing data in the logistic regression analysis results. Eight patients did not undergo a RC due to clinician determined fitness, advanced malignancy or refusal of the planned operation. Overall, 69 patients both completed CPET and underwent RC. No patients had ST-segment changes during the CPET and therefore no patients were referred to cardiology services.

Morbidity and Mortality

Minor or major complications (defined by Clavien score) occurred in 39 (56%) patients. Of these, 26 (67%) were classified as minor (Clavien < 3) and 13 (33%) major (Clavien ≥ 3) (Table 1). The overall mortality rate was 2.9% (two patients).

Morbidity and LOS

The median LOS for the whole group was 17.5 days. Patients who had any postoperative complication had a significantly increased LOS (median) compared with those patients who had no complication (21 vs 15 days; P < 0.001; hazard ratio [HR] 3.66, 95% CI 1.98–6.76). There was a significant difference in LOS between Clavien complication groups (chi squared 26.5, d.f. 2; P < 0.001; Fig. 1). The median values for LOS in the Clavien groups no complications, Clavien < 3 and Clavien ≥ 3, were 15 (95% CI 13.8–16.2), 19 (95% CI 13.0–23.0) and 30 (95% CI 28.9–31.1) days, respectively.

figure

Figure 1. Kaplan–Meier survival curves for LOS by Clavien complication groups [No complications, Clavien 1 and 2 (Minor) and Clavien ≥ 3 (Major)]. Chi squared 26.5, d.f. 2; P < 0.001. The median values for LOS in the Clavien groups no complications, Clavien < 3 and Clavien ≥ 3, were 15 (95% CI 13.8–16.2), 19 (95% CI 13.0–23.0) and 30 (95% CI 28.9–31.1) days, respectively.

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Cardiopulmonary Variables and Postoperative Complications

Multivariate logistic regression showed that the AT was the only significant independent predictor for postoperative major morbidity (Clavien ≥ 3) when compared with those with no or minor Clavien (<3) complications (OR 0.74, 95% CI 0.57–0.97; P = 0.03) (Table  2). No other variables were significant in either univariate or multivariate regression analysis. ROC curve analysis of the AT to major complication development showed good accuracy, with an area under the curve of 0.72 (95% CI 0.60–0.82; P = 0.002).

Table 2. Demographics of patients with Clavien score <3 vs Clavien score ≥3.
VariableClavien <3Clavien ≥3P
  1. BMI, body mass index; HR, heart rate; OUES, oxygen uptake efficiency slope.

Baseline   
N5613 
Age, years69.4 (6.8)70.6 (5.3)0.55
Sex (M/F), n37/1911/20.19
BMI, kg/m226.5 (5.0)28.6 (6.2)0.19
Weight, kg76.2 (17.6)83.0 (23.9)0.24
CPET   
AT, mL/min/kg13.2 (3.6)10.8 (1.8)0.03
VO2/HR10.1 (3.6)10.3 (2.8)0.81
VE/VCO236.1 (5.7)36.0 (6.2)0.90
OUES, mL/min/logVE1561 (459)1573 (454)0.93
Peak VO2, mL/min/kg16.5 (4.7)15.0 (3.0)0.26

The optimal AT level to predict major complications was 12.0 mL/min/kg (sensitivity 77%, specificity 63%). No CPET parameters were predictive of the development of complications when compared with ‘no complications. When the optimal value of AT of 12 mL/min/kg, derived from the ROC curve analysis, was used as a threshold to define patients at risk of major complications, there was a significant relationship between cardiorespiratory fitness groups and LOS, at a median LOS of ‘unfit’ 22 days vs ‘fit’ 16 days (HR 0.47, 95% CI 0.28–0.80; P = 0.006; Fig. 2).

figure

Figure 2. Kaplan–Meier survival curves for LOS by fitness groups (AT ≥ 12 mL/min/kg and <12 mL/min/kg). The median LOS: ‘unfit’ 22 days vs ‘fit’ 16 days (HR 0.47, 95% CI 0.28–0.80; P = 0.006.

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There were 13 patients admitted to the critical care unit electively and five unplanned admissions. Using the 12 mL/min/kg as the AT value, 40% of this high-risk group were admitted electively to critical care. However, most returned to a general surgical ward postoperatively. A further 10% of this high-risk group were admitted to the critical care unit as unplanned admissions. The two patients that died, did so on the critical care unit of multi-organ failure, secondary to sepsis and both were classified as ‘unfit’, with an AT of <12 mL/min/kg (8.4 and 9.8 mL/min/kg, respectively). Both patients had not been admitted to the critical care unit electively. The rate of critical care usage for those with an AT of >12 mL/min/kg was extremely low. Only one patient was admitted electively and two patients were unplanned admissions. These three patients stayed for <48 h.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest
  9. References

Preoperative risk prediction before major surgery is important in preventing postoperative morbidity. The present study shows that an objective measure of cardiorespiratory reserve, determined by preoperative CPET, is independently related to a validated surgical complication classification system (Clavien-Dindo) and to the LOS after RC.

Morbidity after major urological surgery, including sepsis, respiratory failure and bowel dysfunction has been variably reported with a wide range of incidence of between 19 and 64% [3, 4, 6, 18]. RC with ileal conduit formation is also associated with significant postoperative morbidity [6, 9, 19, 20, 30]. Much of the variability in this estimate can be attributed to the use of multiple reporting systems for describing postoperative complications [31]. The Clavien classification was devised in a general surgical population [32, 33], but since the influential publication by Shabsigh et al. [6], it has been developed into the standard format for reporting major complications after urological surgery. The present study therefore used the Clavien-Dindo system as the primary outcome measure of morbidity after RC. The morbidity rates in the present study, including a rate of 15% for major complications, are consistent with the Clavien-Dindo validation study in urological surgery [6].

Development of any complication after major surgery has significant impact on short- and long-term mortality [34]. A recent study of 6577 patients undergoing RC, showed that even one postoperative complication can double the odds of postoperative death, with postoperative respiratory tract infections and systemic infection having the most significant influence [35]. However, the relationship between postoperative complications and mortality is complex. The concept of ‘failure to rescue’ has been developed, whereby it is the early recognition and effective treatment of a complication that has more impact on mortality, than the development of the complication per se [36]. Recognition of preoperative factors related to the development of complications, is important in this regard. The present study, implicating a recognised objective measure of CRF, i.e. AT, in the development of postoperative morbidity after RC, provides evidence to support the importance of the preoperative fitness to postoperative outcome.

Major surgery provides a potent stimulus for increased postoperative oxygen consumption requirements. The AT is a recognised marker of cardiorespiratory fitness [37-39]. In the face of increasing oxygen consumption, the AT may be described as the oxygen consumption level at which energy requirements provided by aerobic metabolism need to be supplemented by anaerobic metabolism. The ability of patients with reduced AT (poor cardiorespiratory reserve) to maintain aerobic metabolism is limited and leads to the development of tissue hypoxia and lactate acidosis, the basis for multiple organ failure and postoperative mortality. Specifically, in the present study, the AT was significantly related to the development of major postoperative complications (Clavien Class ≥ 3). Preoperative recognition of patients with a reduced preoperative AT, would firstly warn clinicians of the need to be vigilant in a high-risk population. Secondly, it would improve rationalisation of limited critical care resources and allow the institution appropriate postoperative care pathways to promote expedient recognition and treatment of complications when they occur, conforming to the ‘failure to rescue’ principle.

The optimal threshold value for the prediction of complications by AT (12 mL/min/kg) in the present cohort of patients was significantly higher than that of a previously reported study from our institution. In major abdominal surgical patients, an AT level of 10 mL/min/kg predicted those at risk of perioperative complications [22]. However, all these patients returned to a critical care environment in the immediate postoperative period. This early supportive therapy may be seen as an important component of being able to withstand the inflammatory insult caused by major surgery. In contrast, most patients undergoing RC in our institution are returned to ward-based care.

The management and follow-up of bladder cancer has been reported to be the most expensive malignancy in terms of healthcare costs over a patient's lifetime [35]. In the perioperative phase, this is in part due to postoperative surgical morbidity impacting on LOS. In a recent survey involving 6577 patients undergoing RC, the presence of even one complication (seen in 28% of patients) increased the median LOS by 2 days, in addition to increasing readmission rates [35]. Furthermore, NHS Hospital Episode Statistics data collated whilst promoting urological enhanced recovery programmes, show that the LOS after urological surgery is amongst the highest in any patients undergoing abdominal procedures [40, 41]. However, postoperative morbidity is only one component of LOS, as there are multiple reasons to delay discharge after surgery. For this reason, the use of LOS as a simple surrogate indicator of complicated outcome is often unjustified. However, this study in the present cohort of patients undergoing RC, lends support to the surrogate hypothesis, as complications were significantly related to LOS. More importantly, we have shown that a preoperative measure of cardiorespiratory fitness is independently related both to the development of postoperative complications and to the LOS. The implication is that poor preoperative cardiorespiratory reserve, predicts delayed postoperative recovery after RC, thereby increasing the burden on hospital resource, which is directly related to the development of postoperative complications. In support of this, the present study has shown that those patients deemed ‘high risk’ by virtue of poor AT values, received more postoperative critical care support and had a significantly greater LOS than the low-risk patients. Although a detailed economic analysis was not performed in the present study, based on daily bed occupancy rates at our institution, it is estimated that patients in the high-risk group cost on average £5052 more per operation. This figure does not take into account extra medication and investigation costs that may have been necessary.

Prevention of postoperative complications occurring in the first place is a more radical but ultimately more appealing option than early recognition and treatment of complications when they occur. Previous attempts at preventing complications have focused on therapeutic management, e.g. drug therapy (increase or decrease β-blockers or statins) or nutritional intervention. However, recognition that CRF is related to outcome in patients undergoing RC has considerably more importance to preoperative intervention. Even short-term exercise training consistently improves CRF in healthy and unhealthy patient groups [42, 43]. The direct preoperative modification of CRF, by the implementation of preoperative exercise training programmes, in major urological surgery candidates, has major potential to improve surgical outcome and requires further investigation.

We appreciate there are several limitations to this present study. Single centre experiences must be tested in other centres before extrapolation of the findings is appropriate. This is true for the use of CPET before RC. Furthermore, despite best efforts some unidentified patients did not undergo CPET due to failure to attend the pre-assessment clinic at the Freeman Hospital or due to capacity issues at the time of assessment. Although the patient group is not consecutive, the cohort was unselected. CPET does have an associated ‘failure’ rate. In the present study, we only included patients in whom we were able to identify an AT. There will be some patients who achieved a peak VO2 of >12 mL/min/kg but did not reach their AT. This does not necessarily indicate reduced functional reserve.

In summary, the present study shows in a cohort of patients undergoing RC, that CPET holds significant clinical value in its ability to define preoperative cardiorespiratory fitness, which is related to postoperative morbidity and LOS. This is important, firstly, to direct early recognition and treatment of complications through rationalised postoperative clinical management and secondly, to allow targeting of preventive preoperative interventions including exercise therapy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest
  9. References

The research leading to these results has received funding from The Medical Research Council Newcastle Centre for Brain Ageing and Vitality; The UK National Institute for Health Research Biomedical Research Centre on Ageing and Age Related Diseases. M.T. was supported by a Senior Research Fellowship from the UK National Institutes for Health Research.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest
  9. References