Risk of postoperative complications in chronic

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Apr 7, 2016 - Jaume Sauledaa,c and Borja G. Cosíoa,c,* ... ing capacity for carbon monoxide of 10 ml/kg/min were .... 0.403. DLCO%. 41.8 ± 9.5. 53.8 ± 18.8. 0.031. KCO%. 46.5 ± 9.7.
ORIGINAL ARTICLE

European Journal of Cardio-Thoracic Surgery 50 (2016) 772–779 doi:10.1093/ejcts/ezw104 Advance Access publication 7 April 2016

Cite this article as: Shafiek H, Valera JL, Togores B, Torrecilla JA, Sauleda J, Cosío BG. Risk of postoperative complications in chronic obstructive lung diseases patients considered fit for lung cancer surgery: beyond oxygen consumption. Eur J Cardiothorac Surg 2016;50:772–9.

Risk of postoperative complications in chronic obstructive lung diseases patients considered fit for lung cancer surgery: beyond oxygen consumption Hanaa Shafieka,b, Jose Luis Valeraa,c, Bernat Togoresa,c, Juan Antonio Torrecillad, Jaume Sauledaa,c and Borja G. Cosíoa,c,* a b c d

Department of Respiratory Medicine, Hospital Universitario Son Espases-IdISPa, Palma de Mallorca, Spain Chest Diseases Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt Ciber de Enfermedades Respiratorias (Ciberes), Madrid, Spain Department of Thoracic Surgery, Hospital Universitario Son Espases, Palma de Mallorca, Spain

* Corresponding author. Department of Respiratory Medicine, Hospital Universitario Son Espases, Ctra de Valldemossa 79, 07010 Palma de Mallorca, Spain. Tel: +871-205419/871-205050; e-mail: [email protected] (B.G. Cosío). Received 11 November 2015; received in revised form 17 February 2016; accepted 22 February 2016

Abstract OBJECTIVES: Patients with poor lung function usually undergo cardiopulmonary exercise testing (CPET) and those with a predicted postoperative maximal oxygen consumption (VO2 max) of >10 ml/kg/min undergo lung resection surgery and still some complications are observed. We aimed to determine other parameters beyond VO2 able to predict postoperative complications in patients undergoing lung resection surgery. METHODS: This is an observational study with longitudinal follow-up. Patients with forced expiratory volume in 1 second (FEV1) or diffusing capacity for carbon monoxide of 10 ml/kg/min were considered fit for surgery. Patients were followed up prospectively for 12 months and postoperative complications and survival were recorded. Physiological parameters obtained during CPET and pulmonary function tests were analysed. RESULTS: Eighty-three chronic obstructive pulmonary disease (COPD) patients were evaluated for surgery between 2010 and 2015. Twenty-four patients were considered unfit for surgery and received an alternative therapy. Fifty-five patients had a VO2 max of >10 ml/kg/min and underwent lung surgery. Among them, 4% died and 41% developed complications postoperatively. Baseline minute ventilation to carbon dioxide output (VE/VCO2) slope was significantly higher among those who developed postoperative complications or died (P = 0.047). Furthermore, VE/VCO2 slope of >35 (at maximal exercise) was the single parameter most strongly associated with the probability of mortality and postoperative complications (hazard ratio 5.14) with a survival probability of 40% after 1 year of follow-up. In a multivariable model, VO2, VE/VCO2 slope of >35 and work load were independently associated with the probability of having an event. CONCLUSIONS: VO2 is not the unique parameter to consider when CPET is performed to evaluate the postoperative risk of lung cancer surgery in COPD patients. The signs of ventilatory inefficiency such as VE/VCO2 slope predict complications better than VO2 does. Keywords: Oxygen consumption • Minute ventilation • Lung cancer • Operability • Postoperative complications

INTRODUCTION Chronic obstructive pulmonary disease (COPD) patients frequently suffer from lung cancer, with resection surgery being the best therapeutic option. However, surgery is a challenge in these patients because they are at risk of postoperative complications and mortality [1] and a precise selection of fit for surgery patients is required. These postoperative complications include pneumonia, acute and chronic respiratory failure, mechanical ventilation of more than 48 h, pulmonary embolism, acute pulmonary oedema, acute myocardial infarction, lobar atelectasis requiring

bronchoscopy as well as arrhythmias [2]. The preoperative physiological assessment of patients undergoing lung resection surgery should begin with cardiovascular evaluation and lung function assessment that includes spirometry to measure the FEV1 and the diffusing capacity for carbon monoxide (DLCO). Predicted postoperative (PPO) lung function should be calculated [3]. According to the current recommendations, if the % PPO FEV1 and % PPO DLCO values are both >60%, the patient is considered at low risk of anatomical lung resection [1], and no further tests are indicated. In general practice, it has been proposed that the shuttle walking test could be useful since it identifies patients with higher oxygen

© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

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METHODS Study design and ethics This is a observational cross-sectional study with longitudinal follow-up that enrolled patients undergoing preoperative evaluation before surgical lung resection for lung cancer treatment according to the current guidelines [3] between 2010 and 2015 in a tertiary hospital. The study protocol was approved by the Ethics Committee of the participating hospital and the written informed consent was obtained from all subjects.

Study population The study enrolled 83 patients of whom 79 patients were analysed. COPD was diagnosed according to GOLD criteria [9] based on pulmonary function tests. All patients were discussed in a multidisciplinary lung cancer expert board that includes chest physicians, oncologists, radiologists and thoracic surgeons. All patients with FEV1 or carbon monoxide diffusion capacity (DLCO) predicted postoperative 10 ml/kg/min were considered as fit and underwent surgical treatment. Thoracotomy was the commonly used surgical approach for management. All the patients underwent postoperative respiratory rehabilitation according to the institutional protocol, including early mobilization and incentive spirometry with pain control and inhalation of bronchodilators and/or mucolytics. Postoperative cardiopulmonary complications and mortality were recorded during the 12 months after surgery (Fig. 1). We analysed the postoperative pulmonary complications— including bronchopleural fistula defined as persistent chest tube leak of >7 days, empyema, atelectasis, pneumonia, acute respiratory

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failure requiring >48 h ventilation, adult respiratory distress syndrome, haemothorax, chylothorax, subcutaneous emphysema, pulmonary oedema, pulmonary embolism, lobar torsion, cardiac hernia, oesophago-pleural fistula and new requirement for chronic oxygen therapy—and cardiac complications namely cardiac arrhythmias, acute myocardial infarction and acute coronary syndrome. Moreover, local tumour recurrence during the 12 months following the surgery was recorded.

Characterization of participants All patients underwent clinical history (including age, gender, associated cardiac comorbidities, smoking history) and pulmonary function testing [including forced spirometry, DLCO and its correction to alveolar volume (KCO) and static lung volumes] that was performed according to the international guidelines.

Cardiopulmonary exercise testing All patients underwent CPET using an electromagnetically braked cycle ergometer (Ergocard, Medi-soft S.A., Belgium) according to the international guidelines [10]. Reference values were taken from Jones et al. [11]. Serial blood gases analyses were taken every 2 min throughout the test for lactate measurement. All the parameters of the test were recorded at baseline, anaerobic threshold (AT) and maximal work load.

Statistical analysis All the data were expressed as mean ± standard deviation unless otherwise stated. Categorized variables were expressed as numbers and percentages. Comparisons between different groups were performed using the χ 2 or unpaired t-test as appropriate. Univariable and multivariable cox regression hazard analysis was applied to study the survival dependency of different CPET parameters. Stepwise selection was used for multivariable model building. The choice of covariables was verified by hands-on modelling, where terms are added or removed in a logical order based on heavily clinically related covariables in combination with a review of the literature rather than solely according to the statistical significance to identify predictors for multivariable analyses. Multiple

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consumption (VO2) [4]. A cardiopulmonary exercise testing (CPET) is indicated when the PPO FEV1 and/or PPO DLCO are 35 was the parameter most strongly associated with the probability of mortality or postoperative complications in patients with VO2/kg higher than 10 ml/kg/min (hazard ratio 5.14), and was also associated with a survival probability of 30% after 1-year follow-up (Fig. 2). Furthermore, VE/VCO2 slope of >35 was still significant in the multivariable analysis (P = 0.017; Table 4); similarly, work load

H. Shafiek et al. / European Journal of Cardio-Thoracic Surgery

DISCUSSION We have shown that COPD patients undergoing lung resection surgery for lung cancer are still at risk of complications and death despite preoperatively selecting the fitter patients. By analysing the functional parameters obtained during preoperative CPET, we have found that, even in those with VO2 max higher than

Figure 2: Kaplan–Meier survival analysis for VE/VCO2 slope of >35. VE/VCO2: ventilation to carbon dioxide output.

10 ml/kg/min, parameters of ventilator inefficiency, especially a VE/VCO2 slope of more than 35, are the strongest predictors of complications and death 1 year after surgery.

Previous studies and interpretation of the findings We found that 41% developed postoperative cardiopulmonary complications, whereas 4% died despite being at an acceptable risk according to CPET. In accordance with our finding, Stanzani et al. [12] reported 31.6% morbidity and 4.3% mortality in their population subjected to CPET that correlated significantly with COPD. We observed that decreased diffusion capacity was related to postoperative complications and mortality. Similarly, Ferguson et al. [13] found that diminished diffusion capacity was associated with both mortality and pulmonary morbidity. We also observed that VO2/kg (ml/kg/min) at maximal exercise was not independently related to postoperative complications. Similarly, Campione et al. [14] did not find that measured VO2 max correlated with postoperative complications. In our population of COPD patients with VO2 max of >10 ml/kg/min, other factors may play an important role in the preoperative evaluation that are important to predict postoperative complications. In this study, we found that the baseline VE/VCO2 slope was significantly higher among the patients who developed complications or died postoperatively with a hazard ratio of 2.6. Ventilatory inefficiency is one of the most important parameters that gained high acceptance in the evaluation of different groups of patients with problems such as COPD, interstitial lung diseases, pulmonary hypertension and congestive heart failure (CHF) [15]. Moreover, we found that VE% predicted at submaximal exercise (AT) and VE % predicted at maximal exercise were good predictors of all postoperative events as well as maximum VO2/kg (%) in the univariable analysis (Table 3) and VO2 (l/min) in the multivariable analysis (Table 4). This could be explained by the associated dynamic hyperinflation, an important pathophysiological characteristic of COPD, that increases during exercise and greatly compromises maximal exercise capacity reflected by lower VO2 max, VCO2 max and VE max [16]. Additionally, we found that higher RQ (reflecting combined VO2 and VCO2 changes) was another predictor of all postoperative events. It is accepted that VE is closely linked to both VO2 and VCO2 and more affected with the changes in VCO2 in a linear relationship and expressed as VE/VCO2. Furthermore, we observed that VE/VCO2 slope of >35 was associated with all postoperative events in COPD patients. It has been previously demonstrated that VE/VCO2 slope of ≥34 was associated with less survival in CHF [17] and pulmonary hypertension [18] and with higher sensitivity rather than VO2 max. Torchio THORACIC

(watts) and VO2 (l/min) at maximal exercise have a statistical significance in the multivariable analysis. Moreover, VO2 (l/min) was a significant protector factor (P = 0.036; Table 4) that was not present in the univariable analysis (P = 0.132; Table 3). Kaplan– Meier survival analysis for the presence of complications in the multivariable model was 40% for all covariates after 1-year followup (Fig. 3). However, 1-year survival of the high-risk surgical patients (i.e. those with VE/VCO2 slope of >35) did not significantly differ from those who underwent non-surgical treatment for their lung cancer (P = 0.148; Fig. 4). Among the patients who underwent lung resection, 37% (19 patients) had poor 1-year survival secondary to their cancer stage, whereas 45% (23 patients) had poor 1-year survival due to poor pulmonary function and high VE/ VCO2 slope of >35.

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Table 4: Multivariable Cox proportional hazards regression model regarding the overall events Covariate (maximum exercise)

Work load VO2 (l) VE/VCO2 >35 Overall model

B

0.774 −0.728 1.667

SE

0.380 0.347 0.698

CI: confidence interval; VO2: oxygen consumption; VCO2: carbon dioxide output.

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Sig.

0.042 0.036 0.017 0.012

Hazard ratio

2.169 0.483 5.296

95% CI for hazard ratio Lower

Upper

1.029 0.244 1.348

4.570 0.954 20.813

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H. Shafiek et al. / European Journal of Cardio-Thoracic Surgery

(Supplementary Table S4) or secondary to abnormal control of blood pressure [10]. Associated cardiovascular comorbidity was not found to be a risk factor of postoperative complications in our population, probably reflecting a selection of fitter patients; however, it is well known as a risk factor for perioperative complications and preoperative cardiac evaluation have been incorporated recently [21] in the assessment of the patients with lung cancer planned for surgical resection. Similarly, neither age nor the extent of pulmonary resection was associated with postoperative complications in our population, as has been previously suggested by some authors [1].

Clinical implications

Figure 3: Kaplan–Meier survival analysis for the mean of multiple covariates at maximal exercise.

The present study showed first that ventilator efficiency as expressed by VE% predicted, VE/VCO2 slope and VO2 (l/min) is an important predictor of the overall postoperative event including complications and mortality. We suggest that these parameters are more reliable in the patient stratification especially among those with COPD and should not be ignored in the preoperative evaluation. Secondly, we assumed that COPD patients with lung cancer and VE/VCO2 slope of >35 could benefit from optimal pharmacological treatment and pulmonary rehabilitation programme preoperatively with risk reduction of postoperative complications. Recent studies showed that COPD with lung cancer undergoing surgical treatment got benefit from preoperative pulmonary rehabilitation and VO2 max improved significantly [22]. Furthermore, therapeutic hyperoxia in resting normoxic COPD could change perioperative risk stratification as it was associated with significant improvement in VO2 max and decreased VE/VCO2 slope [23].

Study limitations

Figure 4: Kaplan–Meier survival analysis comparing those who underwent nonsurgical treatment of their lung cancer and the high-risk surgical patients (i.e. those with VE/VCO2 slope of >35).

et al. [19] found that high VE/VCO2 slope of ≥34 is an independent predictor of postoperative mortality after lung resection for lung cancer. More recently, Brunelli et al. [20] found that VE/VCO2 slope of >35 was associated with higher rate of early (30 days) postoperative respiratory complications among COPD patients rather than VO2 max and they recommended its incorporation in the clinical practice for preoperative evaluation for lung resection. Our results are in keeping with those observations and extend the risk of cardiopulmonary complications during the year after surgery. Furthermore, we found that high VE/VCO2 slope of >35 denoting ventilatory inefficiency is a more relevant cause of poor survival in COPD patients eligible for lung resection than cancer-related mortality. We also observed that systolic blood pressure at maximal exercise was significantly higher among those who died postoperatively. This could be due to their higher resting hypertension despite not being statistically significant

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The current study has some limitations. First, we could not analyse the different CPET parameters in relation to mortality separately due to the limited number of postoperative mortality (only 2 patients) and we used the overall postoperative events for the identification of dependent risk factors. However, we provided a comparison between postoperative complications and mortality including both baseline characteristics and different CPET parameters. Secondly, we did not take into consideration the estimated PPO (VO2 max) in the comparison between the development of postoperative complications and its absence and we used only the measured VO2 max. Bolliger et al. [24] found that calculated PPO (VO2 max) was a reliable factor for predicting postoperative pulmonary complications. However, a meta-analysis of 14 studies confirmed the strong relationship between measured VO2 max during CPET and the occurrence of postoperative complications and it was accepted in the last updated guidelines for the physiological evaluation of lung cancer patient [3]. Lastly, the number of events analysed in the current study was low. However, this low number (23 events, 45%) did not affect the power of a survival analysis as at least 10 events are needed to be observed for each covariate considered that is not related to the number of participants [25].

CONCLUSIONS Forty-five percent of COPD patients undergoing lung resection surgery had some form of complications during the following year

despite an appropriate risk stratification using CPET. VO2 max failed to be a good predictor of events by itself, and markers of ventilator inefficiency, especially a VE/VCO2 slope higher than 35, and work load as well as baseline VE/VCO2 slope are independently associated with an increased risk of postoperative complications or mortality.

SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online.

ACKNOWLEDGEMENTS Authors are grateful to all the Lung Function Unit team for their contribution to the logistics of the study.

Funding This study was funded by Direcció General d’Investigació i desenvolupament tecnològic de la Conselleria d’Innovació, Interior i Justícia de la Comunitat Autònoma de les Illes Balears and Fondos FEDER [Grupos competitivos (PRE-R-22528-2011)]. Conflict of interest: Hanaa Shafiek was granted by the University of Alexandria and Ministry of Higher Education of Egypt as member of ParOwn (the Partnership and Ownership initiative).

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