Respiratory failure is a leading cause of postoperative morbidity and mortality in patients undergoing pneumonectomy. The authors hypothesized that intraoperative mechanical ventilation with large tidal volumes (VTs) would be associated with increased risk of postpneumonectomy respiratory failure.


Patients undergoing elective pneumonectomy at the authors' institution from January 1999 to January 2003 were studied. The authors collected data on demographics, relevant comorbidities, neoadjuvant therapy, pulmonary function tests, site and type of operation, duration of surgery, intraoperative ventilator settings, and intraoperative fluid administration. The primary outcome measure was postoperative respiratory failure, defined as the need for continuation of mechanical ventilation for greater than 48 h postoperatively or the need for reinstitution of mechanical ventilation after extubation.


Of 170 pneumonectomy patients who met inclusion criteria, 30 (18%) developed postoperative respiratory failure. Causes of postoperative respiratory failure were acute lung injury in 50% (n = 15), cardiogenic pulmonary edema in 17% (n = 5), pneumonia in 23% (n = 7), bronchopleural fistula in 7% (n = 2), and pulmonary thromboembolism in 3% (n = 1). Patients who developed respiratory failure were ventilated with larger intraoperative VT than those who did not (median, 8.3 vs. 6.7 ml/kg predicted body weight; P < 0.001). In a multivariate regression analysis, larger intraoperative VT (odds ratio, 1.56 for each ml/kg increase; 95% confidence interval, 1.12-2.23) was associated with development of postoperative respiratory failure. The interaction between larger VT and fluid administration was also statistically significant (odds ratio, 1.36; 95% confidence interval, 1.05-1.97).


Mechanical ventilation with large intraoperative VT is associated with increased risk of postpneumonectomy respiratory failure.

PNEUMONECTOMY is a high-risk surgical procedure that predisposes patients to postoperative respiratory failure and other pulmonary complications.1–7Several intraoperative risk factors for respiratory failure have been identified, including excessive perioperative fluid administration,8duration of operation,9extent of lung resection,5,9right-sided pneumonectomy,10and high intraoperative airway pressures.11,12 

Mechanical ventilation of patients undergoing pneumonectomy is often accompanied by high intraoperative airway pressures. Potential causes of high airway pressures include a decrease in pulmonary compliance (e.g. , due to a decrease in the number of recruitable alveoli), an increase in pulmonary or airway resistance (e.g. , due to bronchospasm), and the use of large tidal volume (VT). Alveolar overdistension associated with the use of large VTmay lead to alveolar stretch injury and the development of permeability pulmonary edema (ventilator-induced lung injury [VILI]).11–19Several recent reports have suggested that VILI can not only worsen preexisting acute lung injury (ALI) but can also initiate such injury in a previously normal lung.15,17,20–23Surgery that otherwise may be well tolerated can culminate in inflammatory injury when paired with another noxious influence such as VILI (multiple hit hypothesis).

Although mechanical ventilation with large VTis the main risk factor for VILI,21,24no study has evaluated intraoperative VTas a potential risk factor for postoperative complications. In this study, we sought to determine the incidence of and risk factors associated with postoperative respiratory failure in a cohort of patients undergoing pneumonectomy. We hypothesized that mechanical ventilation with large VTduring anesthesia would be associated with an increased incidence of postpneumonectomy respiratory failure.

The study was approved by the Mayo Clinic Institutional Review Board (Rochester, Minnesota). Only medical record data with patient written consent of research authorization was used in the study. From the institutional surgical database, we identified and reviewed the charts of consecutive patients who had undergone elective pneumonectomy at the Mayo Clinic in Rochester, Minnesota, between January 1, 1999, and January 1, 2003. Patients who had previously denied research authorization, those who were mechanically ventilated (invasively or noninvasively) in the preoperative period, and those who had undergone urgent or posttraumatic pneumonectomy were excluded from the study.

The primary endpoint of the study was development of postoperative respiratory failure, defined as the need for continuation of mechanical ventilation for greater than 48 h after surgery25,26or reinstitution of mechanical ventilation (invasive or noninvasive) at any time during the postoperative period. Patients requiring reintubation or mechanical ventilation for reoperation, elective procedures, or any complication other than respiratory failure due to a primary pulmonary process were excluded.

Secondary outcomes included postoperative pulmonary complications occurring within 60 days of thoracotomy, including ALI,27pneumonia,28pulmonary thromboembolism confirmed by contrast-enhanced chest computed tomography, cardiogenic pulmonary edema (distinct from ALI because of clinical evidence of left atrial hypertension), and bronchopleural fistula.4 

The following data were abstracted from the medical records: age, sex, height, weight, body mass index, smoking and alcohol history, preoperative comorbidities (diabetes mellitus, hypertension, renal insufficiency, coronary artery disease, congestive heart failure), preoperative pulmonary function tests, the American Society of Anesthesiologists class, and the presence of neoadjuvant treatment (chemotherapy and/or radiation). Intraoperatively, side (left vs.  right) and duration of surgery, total fluid infusion, and the largest VTdocumented during anesthesia were recorded. Adjusted VTwas calculated according to lung size based on the predicted body weight24and forced vital capacity.

To minimize potential bias, one abstractor reviewed the primary outcome measure and the exposure to intraoperative variables in two separately occasions and collected the information in different secured databases. The investigators involved in the data analysis were blind to the intraoperative data until the completion of the study. To assess the reliability for the screening procedure for ascertainment of postoperative respiratory failure, we randomly selected 20 patients among those without respiratory failure and verified whether postoperative respiratory failure criteria were present in the body of the record. None of them had any respiratory failure mentioned in the body of the record.

Statistical Analysis

To compare patients who did and did not develop postoperative respiratory failure, we used the Wilcoxon or Student t  test for continuous variables and chi-square or Fisher exact for categorical variables. To determine independently associated risk factors, we created a stepwise multivariate logistic regression model with postoperative respiratory failure as the dependent variable. Risk factors for postoperative respiratory failure were considered for the multivariable logistic regression model if they (1) were statistically significant in the bivariate analyses (P < 0.05), (2) had high odds ratios (≥ 1.5) for categorical variables or for the range of continuous variables, (3) were biologically plausible, and (4) had 20% or less missing data. For variables that were significant, two-way interactions were considered. When interactions were included in the model, the main effects from the interaction were included as covariates. The variables were treated as continuous or categorical according to their data distribution, the goodness of fit of the overall model, and the presence or absence of a clinically meaningful threshold value. All statistical tests were two sided. JMP statistical software (JMP, version 5.1; SAS Institute Inc., Cary, NC) was used for data analyses.

From a total of 176 patients who had undergone elective pneumonectomy, 6 patients were excluded (4 subjects did not authorize the use of their medical record for research, and 2 patients were mechanically ventilated before surgery).

Therefore, there were 170 eligible study patients who underwent pneumonectomy, and 30 (18%) developed postoperative respiratory failure. After the operation, 25 patients were reintubated, 3 patients required continuation of mechanical ventilation for more than 48 h postoperatively, and 2 patients were treated with noninvasive positive-pressure ventilation. Causes of postoperative respiratory failure were ALI in 50% (n = 15), cardiogenic pulmonary edema in 17% (n = 5), pneumonia in 23% (n = 7), bronchopleural fistula in 7% (n = 2), and pulmonary thromboembolism in 3% (n = 1). Table 1demonstrates the clinical characteristics of patients who did and did not develop postoperative respiratory failure after pneumonectomy. There were no significant differences in age, sex, comorbid conditions (coronary artery disease, diabetes, hypertension, congestive heart failure), creatinine, baseline pulmonary function tests, smoking and alcohol history, American Society of Anesthesiologists class, the presence of neoadjuvant treatment, side of pneumonectomy, and duration of anesthesia between patients who did and did not develop respiratory failure. However, patients who developed respiratory failure were ventilated with larger intraoperative VTthan those who did not (median, 8.3 vs.  6.7 ml/kg predicted body weight; P < 0.001; fig. 1) and received larger intraoperative fluid volumes (median, 2.2 vs.  1.3 l, respectively; P = 0.001). In a multivariate logistic regression analysis, larger intraoperative VTwas associated with the development of postoperative respiratory failure (table 2). The interaction between larger VTand fluid administration was also statistically significant (table 2). Patients who developed postoperative respiratory failure had a higher 60-day mortality (23% vs.  4%; P = 0.02) and longer hospital durations of stay (median, 22 vs.  6 days; P = 0.001). Six of the 15 patients developing postoperative ALI died (40%), compared with only 1 of the 15 patients with non-ALI postoperative respiratory failure (6.6%). No significant differences were observed in the hospital duration of stay between patients who developed ALI and those with other causes of postoperative respiratory failure (median, 27 vs.  16 days; P = 0.204).

In this historical cohort study of patients undergoing pneumonectomy at a teaching institution, intraoperative large VTand larger amount of fluid administration were associated with the development of postoperative respiratory failure. Patients who developed postoperative respiratory failure had a longer hospital duration of stay and higher mortality.

Our data suggest that mechanical ventilation with large intraoperative VTis an important risk factor for development of postoperative respiratory failure in patients undergoing pneumonectomy. The adverse effects of mechanical ventilation with large VTand high airway pressure are well described in patients with ALI who are mechanically ventilated in the intensive care unit.24In this group of patients, low VTventilation is associated with a more rapid attenuation of the inflammatory response.29Similarly, in a recent prospective randomized study, the use of smaller VTin patients undergoing thoracic surgery resulted in a significant decrease of alveolar inflammatory cytokines.30 

Our study suggests that even brief exposure to adverse ventilator settings during surgery may result in clinically significant VILI and adverse postoperative outcome. This may come as no surprise given the experimental evidence that even brief periods of mechanical ventilation with large VTmay result in VILI. VILI can be demonstrated after only 20 min of large VTventilation in small animals21and after 2 h of large VTventilation in larger mammals.31,32Two previous studies demonstrated that high intraoperative airway pressures were associated with development of ALI after lung resection.11,12Van der Werf et al.  12studied 190 patients who underwent lung resection and found that peak inspiratory pressures in excess of 40 cm H2O were associated with the development of postpneumonectomy pulmonary edema (relative risk, 3.0; 95% confidence interval, 1.2–7.3). In a recent cohort study of 879 patients undergoing pneumonectomy for lung cancer, the “ventilatory hyperpressure index” (product of duration of one-lung ventilation and inspiratory plateau pressure exceeding 10 cm H2O) was associated with the development of ALI in the postoperative period (odds ratio, 3.53; 95% confidence interval, 1.71–8.45).11 

The incidence rate of postoperative respiratory failure from this study is in the range of those published from single-institution retrospective series.1,2,7,33Also, the 60-day postoperative mortality rate was similar to those previously reported.2,4,34 

Although some investigators have not shown an association between larger intraoperative fluid administration and respiratory failure,35the current study is in agreement with other reports suggesting that excessive intraoperative fluid administration may be a contributing factor in the development of postpneumonectomy respiratory failure.8,11Recent studies in nonthoracic surgery patients also support these findings.36,37The significant interaction between large VTand fluid administration is perhaps the most interesting finding in our study. Two mechanisms may explain this association. First, greater fluid administration may have been the consequence of large VTventilation. Large VTs predispose to air trapping and to paradoxic pulse in the operating room and may also increase the right ventricular afterload. Therefore, the resulting hypotension forces the anesthesiologist to administer fluids. Moreover, the interaction between VTand lung hemodynamics can also affect the clinical manifestations of VILI.38 

There are several limitations of our study design. The observational nature of the study does not allow estimation of the cause-and-effect relation between the risk factors and outcome because unmeasured confounding factors may not have been accounted for. For example, larger intraoperative VTs and higher airway pressures may be a marker for lung disease and hypoxemia and not causative of lung injury and/or postoperative respiratory failure. However, the current practice of setting the ventilator at 10 ml/kg per actual body weight may create a setting for “natural experiment” where women, shorter and obese patients, and those with preexisting restrictive lung disease are exposed to much higher VTper lung size. Indeed, women in our study were ventilated with higher intraoperative VT(ml/kg of predicted body weight) than men (8.3 vs.  6.3; P = 0.001) and tended to develop postoperative respiratory failure more often (16 [25%]vs.  14 [13%] of total cases of pneumonectomies; P = 0.062).

Importantly, our analysis was based on a single largest VTcharted during anesthesia. We were unable to precisely determine the VTs and airway pressures (positive end-inspiratory pressure, peak and plateau airway pressure) used during the period of one-lung ventilation because of incomplete or missing data in the medical records (> 20% missing data). Although a positive end-inspiratory pressure level of zero was used as a default setting during anesthesia at our institution during the study period, the changes in positive end-inspiratory pressure as a response to intraoperative hypoxemia were not consistently charted at the time of the study. Therefore, we were not able to evaluate the cumulative exposure to potentially harmful ventilator settings.

In conclusion, the association between large VTand larger fluid administration with the development of postoperative respiratory failure is the most interesting finding of this study. It raises important implications with regard to the etiology of postoperative respiratory failure and ALI, and possible prevention strategies. Randomized clinical trials are needed to determine optimal intraoperative ventilator settings and fluid management in patients undergoing high-risk operations such as pneumonectomy. While awaiting the results of such studies, anesthesiologists should be aware of the potential risks associated with large VTventilation.

Miller DL, Deschamps C, Jenkins GD, Bernard A, Allen MS, Pairolero PC: Completion pneumonectomy: Factors affecting operative mortality and cardiopulmonary morbidity. Ann Thorac Surg 2002; 74:876–83
Joo JB, DeBord JR, Montgomery CE, Munns JR, Marshall JS, Paulsen JK, Anderson RC, Meyer LE, Estes NC: Perioperative factors as predictors of operative mortality and morbidity in pneumonectomy. Am Surg 2001; 67:318–21
Ruffini E, Parola A, Papalia E, Filosso PL, Mancuso M, Oliaro A, Actis-Dato G, Maggi G: Frequency and mortality of acute lung injury and acute respiratory distress syndrome after pulmonary resection for bronchogenic carcinoma. Eur J Cardiothorac Surg 2001; 20:30–6
Stephan F, Boucheseiche S, Hollande J, Flahault A, Cheffi A, Bazelly B, Bonnet F: Pulmonary complications following lung resection: A comprehensive analysis of incidence and possible risk factors. Chest 2000; 118:1263–70
Kutlu CA, Williams EA, Evans TW, Pastorino U, Goldstraw P: Acute lung injury and acute respiratory distress syndrome after pulmonary resection. Ann Thorac Surg 2000; 69:376–80
Busch E, Verazin G, Antkowiak JG, Driscoll D, Takita H: Pulmonary complications in patients undergoing thoracotomy for lung carcinoma. Chest 1994; 105:760–6
Hirschler-Schulte CJ, Hylkema BS, Meyer RW: Mechanical ventilation for acute postoperative respiratory failure after surgery for bronchial carcinoma. Thorax 1985; 40:387–90
Parquin F, Marchal M, Mehiri S, Herve P, Lescot B: Post-pneumonectomy pulmonary edema: Analysis and risk factors. Eur J Cardiothorac Surg 1996; 10:929–32
Deslauriers J, Aucoin A, Gregoire J: Postpneumonectomy pulmonary edema. Chest Surg Clin N Am 1998; 8:611–31
Alvarez JM, Bairstow BM, Tang C, Newman MA: Post-lung resection pulmonary edema: A case for aggressive management. J Cardiothorac Vasc Anesth 1998; 12:199–205
Licker M, de Perrot M, Spiliopoulos A, Robert J, Diaper J, Chevalley C, Tschopp JM: Risk factors for acute lung injury after thoracic surgery for lung cancer. Anesth Analg 2003; 97:1558–65
van der Werff YD, van der Houwen HK, Heijmans PJ, Duurkens VA, Leusink HA, van Heesewijk HP, de Boer A: Postpneumonectomy pulmonary edema: A retrospective analysis of incidence and possible risk factors. Chest 1997; 111:1278–84
Szegedi LL, Bardoczky GI, Engelman EE, d’Hollander AA: Airway pressure changes during one-lung ventilation. Anesth Analg 1997; 84:1034–7
Larsson A, Malmkvist G, Werner O: Variations in lung volume and compliance during pulmonary surgery. Br J Anaesth 1987; 59:585–91
Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Lymp JF, Afessa B, Hubmayr RD: Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 2004; 32:1817–24
Wrigge H, Uhlig U, Zinserling J, Behrends-Callsen E, Ottersbach G, Fischer M, Uhlig S, Putensen C: The effects of different ventilatory settings on pulmonary and systemic inflammatory responses during major surgery. Anesth Analg 2004; 98:775–81
Gajic O, Lee J, Doerr CH, Berrios JC, Myers JL, Hubmayr RD: Ventilator-induced cell wounding and repair in the intact lung. Am J Respir Crit Care Med 2003; 167:1057–63
Craig SR, Leaver HA, Yap PL, Pugh GC, Walker WS: Acute phase responses following minimal access and conventional thoracic surgery. Eur J Cardiothorac Surg 2001; 20:455–63
Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS: Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 1997; 99:944–52
International Consensus Conferences in Intensive Care Medicine: Ventilator-associated lung injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societe de Reanimation de Langue Francaise, and was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 1999;160: 2118–24
International Consensus Conferences in Intensive Care Medicine
Dreyfuss D, Basset G, Soler P, Saumon G: Intermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary microvascular injury in rats. Am Rev Respir Dis 1985; 132:880–4
Zupancich E, Paparella D, Turani F, Munch C, Rossi A, Massaccesi S, Ranieri VM: Mechanical ventilation affects inflammatory mediators in patients undergoing cardiopulmonary bypass for cardiac surgery: A randomized clinical trial. J Thorac Cardiovasc Surg 2005; 130:378–83
Gajic O, Frutos-Vivar F, Esteban A, Hubmayr RD, Anzueto A: Ventilator settings as a risk factor for acute respiratory distress syndrome in mechanically ventilated patients. Intensive Care Med 2005; 31:922–6
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301–8
Arozullah AM, Daley J, Henderson WG, Khuri SF: Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. The National Veterans Administration Surgical Quality Improvement Program. Ann Surg 2000; 232:242–53
Svensson LG, Hess KR, Coselli JS, Safi HJ, Crawford ES: A prospective study of respiratory failure after high-risk surgery on the thoracoabdominal aorta. J Vasc Surg 1991; 14:271–82
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; 149:818–24
Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM: CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:128–40
Parsons PE, Eisner MD, Thompson BT, Matthay MA, Ancukiewicz M, Bernard GR, Wheeler AP: Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005; 33:1–6
Schilling T, Kozian A, Huth C, Buhling F, Kretzschmar M, Welte T, Hachenberg T: The pulmonary immune effects of mechanical ventilation in patients undergoing thoracic surgery. Anesth Analg 2005; 101:957–65
Tsuno K, Prato P, Kolobow T: Acute lung injury from mechanical ventilation at moderately high airway pressures. J Appl Physiol 1990; 69:956–61
Mandava S, Kolobow T, Vitale G, Foti G, Aprigliano M, Jones M, Muller E: Lethal systemic capillary leak syndrome associated with severe ventilator-induced lung injury: An experimental study. Crit Care Med 2003; 31:885–92
Licker M, Spiliopoulos A, Frey JG, Robert J, Hohn L, de Perrot M, Tschopp JM: Risk factors for early mortality and major complications following pneumonectomy for non-small cell carcinoma of the lung. Chest 2002; 121:1890–7
Alexiou C, Beggs D, Rogers ML, Beggs L, Asopa S, Salama FD: Pneumonectomy for non-small cell lung cancer: Predictors of operative mortality and survival. Eur J Cardiothorac Surg 2001; 20:476–80
Turnage WS, Lunn JJ: Postpneumonectomy pulmonary edema: A retrospective analysis of associated variables. Chest 1993; 103:1646–50
Brandstrup B, Tonnesen H, Beier-Holgersen R, Hjortso E, Ording H, Lindorff-Larsen K, Rasmussen MS, Lanng C, Wallin L, Iversen LH, Gramkow CS, Okholm M, Blemmer T, Svendsen PE, Rottensten HH, Thage B, Riis J, Jeppesen IS, Teilum D, Christensen AM, Graungaard B, Pott F: Effects of intravenous fluid restriction on postoperative complications: Comparison of two perioperative fluid regimens. A randomized assessor-blinded multicenter trial. Ann Surg 2003; 238:641–8
Christopherson R, Beattie C, Frank SM, Norris EJ, Meinert CL, Gottlieb SO, Yates H, Rock P, Parker SD, Perler BA, Williams GM, Perioperative Ischemia Randomized Anesthesia Trial Study Group: Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery. Anesthesiology 1993; 79:422–34
Perioperative Ischemia Randomized Anesthesia Trial Study Group
Broccard AF, Hotchkiss JR, Kuwayama N, Olson DA, Jamal S, Wangensteen DO, Marini JJ: Consequences of vascular flow on lung injury induced by mechanical ventilation. Am J Respir Crit Care Med 1998; 157:1935–42