The cardiopulmonary exercise test (CPET) has been

Transcription

1 Minute Ventilation-to-Carbon Dioxide Output (V E/V CO2 ) Slope Is the Strongest Predictor of Respiratory Complications and Death After Pulmonary Resection Alessandro Brunelli, MD, Romualdo Belardinelli, MD, Cecilia Pompili, MD, Francesco Xiumé, MD, Majed Refai, MD, Michele Salati, MD, and Armando Sabbatini, MD Divisions of Thoracic Surgery and Cardiology, Ospedali Riuniti, Ancona, Italy Background. This study assessed whether the minute ventilation-to-carbon dioxide output (V E/V CO2 ) slope, a measure of ventilatory efficiency routinely measured during cardiopulmonary exercise testing (CPET), is an independent predictor of respiratory complications after major lung resections. Methods. Prospective observational analysis was performed on 225 consecutive candidates after lobectomy (197 patients) or pneumonectomy (28 patients) from 2008 to Inoperability criteria were peak oxygen consumption (V O2 ) of less than 10 ml/kg/min in association with predicted postoperative forced expiratory volume in 1 second of less than 30% and diffusion capacity of the lung for carbon monoxide of less than 30%. All patients performed a symptom-limited CPET on cycle ergometer. Respiratory complications (30 days or in-hospital) were prospectively recorded: pneumonia, atelectasis requiring bronchoscopy, respiratory failure on mechanical ventilation exceeding 48 hours, adult respiratory distress syndrome, pulmonary edema, and pulmonary embolism. Univariable and multivariable regression analyses were used to identify independent predictors of respiratory complications. Results. Cardiopulmonary morbidity and mortality rates were 23% (51 patients) and 2.2% (5 patients). The 25 patients with respiratory complications had a significantly higher V E/V CO2 slope than those without complications (34.8 vs 30.9, p 0.001). Peak V O2 was not associated with respiratory complications. Logistic regression and bootstrap analyses showed that, after adjusting for other baseline and perioperative variables, the strongest predictor of respiratory complications was V E/ V CO2 slope (regression coefficient, 0.09; bootstrap frequency, 89%; p 0.004). Patients with a V E/V CO2 slope exceeding 35 had a higher incidence of respiratory complications (22% vs 7.6%, p 0.004) and mortality (7.2% vs. 0.6%, p 0.01). Conclusions. V E/V CO2 slope is a better predictor of respiratory complications than peak V O2. This inexpensive and operator-independent variable should be considered in the clinical practice to refine operability selection criteria. (Ann Thorac Surg 2012;93:1802 6) 2012 by The Society of Thoracic Surgeons The cardiopulmonary exercise test (CPET) has been recommended as a pivotal step in the preoperative evaluation of lung resection candidates [1]. Although peak oxygen consumption (V o 2 peak) is the most used variable for patient selection, several other direct or derived indicators can be used for risk stratification and for determining and possibly correcting deficits in the oxygen transport system. Among ventilatory variables, the ratio of minute ventilation (V e) to carbon dioxide output (V co 2 ), defined as ventilatory efficiency (V e/v co 2 Accepted for publication March 5, Presented at the Poster Session of the Forty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 Feb 1, An- Address correspondence to Dr Brunelli, Via S. Margherita 23, cona, Italy; brunellialex@gmail.com. slope), has been used with increasing frequency to classify functional limitations in patients with heart disease and to stratify clinical outcome in heart failure patients [2 6] and, most recently, in thoracic surgical patients [7]. The objective of this investigation was to verify the role of the V e/v co 2 slope in predicting respiratory complications (RCs) after major lung resections. Patients and Methods This was a prospective observational study of 225 consecutive candidates for lobectomy (197 patients) or pneumonectomy (28 patients) at our institution from 2008 to The study was approved by the local Institutional Review Board, and all patients gave their consent to 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg BRUNELLI ET AL 2012;93: V e/v co 2 SLOPE AND LUNG RESECTION participate in the institutional prospective database and use of their data for research and clinical purposes. Patients were operated on by board-certified thoracic surgeons through a muscle-sparing, nerve-sparing lateral thoracotomy [8]. Perioperative management followed standardized pathways of care. Patients were usually extubated in the operating room and transferred to a dedicated thoracic ward. Functional inoperability criteria were: peak V O 2 of less than 10 ml/kg/min in association with a predicted postoperative (ppo) forced expiratory volume in 1 second (FEV 1 ) of less than 30% and ppo diffusion capacity of the lung for carbon monoxide (Dlco) of less than 30% according to published guidelines [1, 9]. Postoperative treatment focused on early as possible mobilization, chest physiotherapy, and physical rehabilitation administered by a specialized physiotherapist. Thoracotomy chest pain was controlled by a continuous systemic infusion of nonopioid drugs or paravertebral analgesia with local analgesics to maintain the numeric pain score below 4 in a scale ranging from 0 (no pain) to 10 (excruciating pain). Pulmonary Assessment All patients performed a preoperative (within 1 week before their operation) symptom-limited CPET on an electronically braked cycle ergometer using a ramppattern increase in work rate to reach exhaustion between 8 and 12 min. Expired gases and volumes were analyzed, breath-by-breath, with a metabolic cart. CPET was stopped when one or more of the following criteria were present: fatigue, dyspnea, excessive systemic blood pressure increase (ie, 230/130 mm Hg), a 2-mm or more ST depression in at least 2 adjacent leads, or angina. The following RCs occurring within 30 days of the operation or during hospitalization were defined a priori and prospectively recorded: pneumonia (chest roentgenogram infiltrates/consolidation, leukocytosis, fever), atelectasis requiring bronchoscopy, respiratory failure needing mechanical ventilation for longer than 48 hours, adult respiratory distress syndrome (defined according to the American-European consensus conference [10]), pulmonary edema, or pulmonary embolism (confirmed by V/Q scan or computed tomography scan). In addition to the 225 patients considered for the analysis, another 20 patients underwent major pulmonary anatomic resections during the same period but were excluded because they were unable to perform a CPET because of logistic or severe incapacitating comorbidities. Statistical Analysis The Shapiro-Wilk normality test was used to assess normal distribution of numeric variables. Univariable analysis was initially used to screen variables associated with RCs. The univariable comparisons of outcomes were performed with the unpaired Student t test for numeric variables with normal distribution and by using the Mann-Whitney U test for numeric variables without a normal distribution. Categoric variables were compared using the 2 test or the Fisher exact test, whenever appropriate. The following variables were tested for a possible association with postoperative RCs: age, sex, body mass index, FEV 1 %, Dlco%, ppofev 1 %, ppodlco%, moderate to severe chronic COPD status (defined as FEV 1 80% FEV1/FVC ratio 0.7), peak V o 2 (ml/kg/min), V e/v co 2 slope, induction chemotherapy, pack-years of smoking, and type of operation. Variables with p of less than 0.1 at univariable analysis were used as independent predictors in a stepwise logistic regression analysis, with presence of RCs as the dependent variable. All data were at least 95% complete. Sporadic missing data were imputed by averaging the nonmissing values (numeric variables) or taking the most frequent response category (categoric variables). To avoid multicollinearity, only one variable in a set of variables with a correlation coefficient greater than 0.5 was selected (by bootstrap procedure) and used in the regression model. For the purpose of this investigation, V e/v co 2 slope was analyzed with peak V o 2. The two variables were not correlated (r 0.1). A value of p 0.05 was selected for retention of variables in the final model. The multivariable procedure was validated by bootstrap analysis with 1,000 samples [11 13]. In the bootstrap procedure, repeated samples of the same number of observations as the original database were selected with replacement from the original set observations. For each sample, stepwise logistic regression was performed entering the variables with p less than 0.1 at univariable analysis. The stability of the final model was assessed by identifying the variables that entered most frequently in the repeated bootstrap models and comparing those variables with the variables in the final stepwise model. If the final model variables occurred in 50% of the bootstrap models, the original final stepwise regression model was judged to be stable. A further analysis was performed using the V e/v co 2 cutoff of more than 35, which has been shown to be associated with worse prognosis in patients with heart disease [14]. All statistical tests were two-tailed and a significance level of 0.05 was accepted. The analysis was performed on Stata 10 software (Stata Corp, College Station, TX). Results 1803 The characteristics of the study patients are reported in Table 1. The overall cardiopulmonary morbidity and mortality rates were 23% (51 cases) and 2.2% (5 cases). RCs were present in 25 patients (11%) and had a significantly higher V e/v co 2 slope compared with those without complications (34.8 vs 30.9, p 0.001). The 5 patients who died had a higher value of V e/v co 2 slope than survivors (36.3 vs 31.2, p 0.07). Unlike patients with RCs, patients with cardiac complications (mainly atrial fibrillation) did not have a significantly higher value of V e/v co 2 slope compared with those without cardiac complications (31.8 vs 31.2, p 0.6). In addition to V e/v co 2, the following variables were also associated with RC at univariable analysis: FEV 1 % (75.6% vs 82.3%, GENERAL THORACIC

3 1804 BRUNELLI ET AL Ann Thorac Surg V e/v co 2 SLOPE AND LUNG RESECTION 2012;93: Table 1. Characteristics of the Study Patients Variables a Outcome Age, years 67.2 (9.8) Male sex, No. (%) 183 (81) Body mass index, kg/m (4.7) FEV 1 % 81.6 (18.1) Dlco% 76.4 (19.8) Predicted postoperative FEV 1,% 63.7 (14.9) Dlco, % 60 (16.7) COPD, No. (%) b 70 (31) Pack-years 47.5 (34) Peak V o 2, ml/kg/min 16.1 (3.7) Peak V o 2 % 63.1 (16.5) V e/v co 2 slope 31.3 (6.1) a Results are expressed as means (standard deviation) unless otherwise indicated. b Assessed as moderate to severe. COPD chronic obstructive pulmonary disease; Dlco diffusion capacity of the lung for carbon monoxide; FEV 1 forced expiratory volume in 1 second; V e/v co 2 expired volume to carbon dioxide output; V o 2 volume of oxygen consumption. p 0.07), ppofev 1 % (58.6% vs 64.3%, p 0.07), presence of moderate to severe COPD (17% vs 8%, p 0.06). PeakV o 2 (ml/kg/min or percentage of predicted value) was not associated with RCs or mortality in this series (Table 2). Stepwise logistic regression and bootstrap analyses showed that the only predictor reliably associated with RCs remained the V e/v co 2 slope (regression coefficient, 0.09; standard error, 0.03; bootstrap frequency, 89%; p 0.004). Compared with patients with a lower V e/v co 2 slope value, those with a V e/v co 2 slope exceeding 35 had a threefold higher rate of RCs (22% vs 7.6%, p 0.004) and 12-fold higher rate of mortality (7.2% vs 0.6%, p 0.01). Figure 1 plots the V e/v co 2 slope values against the RC rate. There is a direct relationship between the V e/v co 2 slope values and the incidence of RC with a linear increase of morbidity, which is particularly high with values above 35. The interaction between V e/v co 2 and RCs occurred in patients without (complicated 34.4 vs noncomplicated 31.1, p 0.02) and with COPD (complicated 35.2 vs noncomplicated 30.3, p 0.03; Fig 2). The difference between values of V e/v co 2 slope in patients with and without RCs was more pronounced in the patients with peak V o 2 exceeding 15 ml/kg/min (complicated 35.2 vs noncomplicated 29.8, p 0.004) compared with those with lower peak V o 2 (complicated 34.3 vs noncomplicated 32.3, p 0.2). Nevertheless, compared with patients with lower V e/v co 2 slope values, the incidence of RCs in patients with V e/v co 2 exceeding 35 was more than double in both groups (peak V o 2 15: 21% vs 9%, p 0.15; peak V o 2 15: 27% vs 7%, p 0.02), and the relationship between V e/v co 2 slope and respiratory complications was similar (Fig 3). Finally, we plotted the values of V e/v co 2 slope against the postoperative length of stay, showing a linear direct relationship between them. Higher V e/v co 2 slope values correspond to a longer hospital stay, reflecting a more complicated and difficult postoperative course (Fig 4). Comment The CPET is increasingly used for stratifying the risk of lung resection candidates. A peak V o 2 below 10 ml/kg/ min or 35% predicted value has been indicated as a prohibitive threshold for major anatomic resection [1]. Table 2. Results of the Univariable Comparison Between Patients With and Without Respiratory Complications With RCs Without RCs Variables a (n 25) (n 200) p Value Age, years 68.8 (8.4) 67 (9.9) 0.4 b Body mass index, kg/m (4.8) 26.9 (4.6) 0.2 b FEV 1 % 75.6 (16.8) 82.3 (18.2) 0.07 Dlco% 74.3 (18) 76.6 (20) 0.6 Predicted postoperative FEV1 % 58.6 (12.8) 64.3 (15.1) 0.07 Dlco% 59.3 (13) 60 (17.1) 0.8 Pneumonectomy, No. (%) c 3 (12) 25 (13) 0.9 Induction chemotherapy, No (%) d 4 (16) 32 (16).99 COPD, e No. (%) 12 (48) 58 (28) 0.06 Peak V o 2, ml/kg/min 15.6 (3.4) 16.1 (3.8) 0.5 b Peak V o 2,% 63 (14.5) 63.1 (13.5) 0.8 b V e/v Co2 slope 34.8 (5.5) 30.9 (6.1) b a Continuous variables are expressed as means (standard deviation) and categoric variables as indicated. b Mann-Whitney test. c Percentage of pneumonectomy patients with or without respiratory complications. d Percentage of patients with or without respiratory complications who underwent induction chemotherapy. e Percentage of patients with moderate to severe COPD with or without respiratory complications. COPD chronic obstructive pulmonary disease; Dlco diffusion capacity of the lung for carbon monoxide; FEV 1 forced expiratory volume in 1 second; RCs respiratory complications; V e/v co 2 expired volume to carbon dioxide output; V o 2 volume of oxygen consumption.

4 Ann Thorac Surg BRUNELLI ET AL 2012;93: V e/v co 2 SLOPE AND LUNG RESECTION 1805 GENERAL THORACIC Fig 1. Relationship between the level of the minute ventilation-tocarbon complications. Although peakv o 2 is certainly the most widely used variable, CPET provides several other direct or indirect indicators that change in response to incremental workloads. This not only allows assessment of over-all cardiopulmonary reserves, but also, in case of a limitation of exercise capacity, the detection of its cause, such as pulmonary, cardiovascular, or musculoskeletal limitations [15]. Among the ventilatory expired gas variables, an abnormally high relationship between minute ventilation (V e) and carbon dioxide output (V co 2 ), expressed as the V e/v co 2 slope, has been recently associated with poor outcome in patients with chronic heart failure [4]. A high V e/v co 2 reflects a combination of factors that underlie ventilatory inefficiency. Although many reports have demonstrated the independent prognostic role of V e/ V co 2 in patients with heart disease, scant information is available about its utility in those with normal heart efficiency. In particular, only one report investigated the role of V e/v co 2 slope in COPD candidates for lung Fig 3. Relationship between the level of the minute ventilation-tocarbon complications in patients with peak oxygen consumption (V o 2 ) greater (solid line) or lower (dashed line) than 15 ml/kg/min. resection [7]. These authors found that a higher V e/v co 2 slope was associated with an increased mortality rate but did not find a significant association of this parameter with cardiopulmonary morbidity. The objective of this study was to verify the role of V e/v co 2 slope value in predicting RCs after major pulmonary resections. We found that the V e/v co 2 slope remained the only significant factor associated with RCs after controlling the effect of other confounders in a stepwise logistic regression analysis. In particular, by using the cutoff value of more than 35, found by other authors to be predictive of adverse outcome in patients with chronic heart failure [14, 16], we found that patients with V e/v co 2 slope exceeding 35 had an incidence of RCs and mortality that were threefold and 12-fold higher than those with a lower V e/v co 2 slope, respectively. The association of ventilatory efficiency with the risk of RCs occurred both in patients with and without moderate Fig 2. Relationship between the level of the minute ventilation-tocarbon complications in patients with (dotted line) and without (solid line) chronic obstructive pulmonary disease (COPD). Fig 4. Relationship between the level of the minute ventilation-tocarbon dioxide output (V e/v co 2 ) slope and postoperative length of stay.

5 1806 BRUNELLI ET AL Ann Thorac Surg V e/v co 2 SLOPE AND LUNG RESECTION 2012;93: to severe COPD. This expands the findings of Torchio and colleagues [7], who found this factor was associated with death only in patients with COPD. The V e/v co 2 slope appears to be a useful marker of some underlying ventilatory alterations that become more evident during exercise, irrespective of the baseline pulmonary function. Another interesting finding of our study was that the association between a high V e/v co 2 slope and the risk of RCs was present not only for patients with reduced aerobic capacity but even, and perhaps in a more pronounced way, at higher levels of peakv o 2 ( 15 ml/kg/ min). This confirmed previous studies in patients with heart failure, suggesting a differential interpretation of these two ergometric variables [4].V o 2 level is influenced by the combined contribution of the heart, lungs, the oxygen transport system, and skeletal muscles to external work. In this regard, it is a more global variable than V e/v co 2 slope alone, which is specifically the expression of ventilatory efficiency. In this regard, the V e/v co 2 slope may represent a useful indicator to refine risk-stratification independent of the peak V o 2 level. The main limitation of this study is its retrospective nature, which may have introduced inherent selection biases. However, the V e/v co 2 slope value was not used in any way to select patients for operation, minimizing the risk of an influence on the results. Furthermore, the RCs were defined a priori and recorded prospectively in an electronic database. In conclusion, we found that V e/v co 2 slope is a better predictor of RCs and death than peak V o 2. This variable is routinely calculated during CPETs and may be used, along with peak V o 2, to refine operability selection criteria. References 1. Brunelli A, Charloux A, Bolliger CT, et al; European Respiratory Society and European Society of Thoracic Surgeons joint task force on fitness for radical therapy. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). Eur Respir J 2009;34: Arena R, Myers J, Williams MA, et al. Assessment of functional capacity in clinical and research settings. A scientific statement from the American heart association committee on exercise, rehabilitation, and prevention of the council on clinical cardiology and the council on cardiovascular nursing. Circulation 2007;116: Myers J. Applications of cardiopulmonary exercise testing in the management of cardiovascular and pulmonary disease. Int J Sports Med 2005;26(Suppl 1):S Corra U, Mezzani A, Bosimini E, Giannuzzi P. Cardiopulmonary exercise testing and prognosis in chronic heart failure: a prognosticating algorithm for the individual patient. Chest 2004;126: Arena R, Myers J, Aslam SS, Varughese EB, Peberdy MA. Peak VO2 and VE/VCO 2 slope in patients with heart failure: a prognostic comparison. Am Heart J 2004;147: Tumminello G, Guazzi M, Lancellotti P, Pie=rard LA. Exercise ventilation inefficiency in heart failure: pathophysiological and clinical significance. Eur Heart J 2007;28: Torchio R, Guglielmo M, Giardino R, et al. Exercise ventilatory inefficiency and mortality in patients with chronic obstructive pulmonary disease undergoing surgery for non small cell lung cancer. Eur J Cardiothorac Surg 2010;38: Cerfolio RJ, Bryant AS, Maniscalco LM. A non divided intercostal muscle flap further reduces pain of thoracotomy: a prospective randomized trial. Ann Thorac Surg 2008;85: Brunelli A, Salati M. Preoperative evaluation of lung cancer: predicting the impact of surgery on physiology and quality of life. Curr Opin Pulm Med 2008;14: Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149: Blackstone EH. Breaking down barriers: helpful breakthrough statistical methods you need to understand better. J Thorac Cardiovasc Surg 2001;122: Grunkemeier GL, Wu YX. Bootstrap resampling method: something for nothing? Ann Thorac Surg 2004;77: Brunelli A, Rocco G. Internal validation of risk models in lung resection surgery: bootstrap versus training and test sampling. J Thorac Cardiovasc Surg 2006;131: Corrà U, Mezzani A, Bosimini E, Scapellato F, Imparato A, Giannuzzi P. Ventilatory response to exercise improves risk stratification in patients with chronic heart failure and intermediate functional capacity. Am Heart J 2002;143: Ferguson MK, Lehman AG, Bolliger CT, Brunelli A. The role of diffusing capacity and exercise tests. Thorac Surg Clin 2008;18: Chua TP, Ponikowski P, Harrington D, et al. Clinical correlates and prognostic significance of the ventilatory response to exercise in CHF. J Am Coll Cardiol 1997;29: