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* From the Critical Care Medicine Service, Department of Anesthesiology and Critical Care Medicine (Drs. Dulu, Pastores, and Halpern), Thoracic Surgical Service, Department of Surgery (Drs. Park and Rusch), and Department of Epidemiology and Biostatistics (Ms. Riedel), Memorial Sloan-Kettering Cancer Center, New York, NY.
Correspondence to: Stephen M. Pastores, MD, Associate Attending, Critical Care Medicine Service, Department of Anesthesiology and Critical Care Medicine. Memorial Sloan-Kettering Cancer Center, 1275 York Ave M-210, New York, NY 10021; e-mail: pastores{at}mskcc.org
Abstract
Study objectives: To describe the frequency and outcome of patients with acute lung injury (ALI) and ARDS who require mechanical ventilation (MV) after lung resection, and to analyze preoperative and perioperative variables associated with mortality.
Methods: We retrospectively reviewed the case records of all patients who underwent lung resection and acquired ALI and/or ARDS and required invasive MV and ICU admission at a tertiary-care cancer center from January 1, 2002, to December 31, 2004. Preoperative and perioperative information including ICU-specific variables and outcome data were analyzed. Data are presented as median (range).
Results: During the study period, 2,039 patients underwent a total of 2,192 lung resections. ALI/ARDS developed in 50 patients (2.45%). The prevalence of ALI/ARDS by procedure was as follows: pneumonectomy, 7.9% (10 cases in 126 procedures); lobectomy/bilobectomy, 2.96% (31 cases in 1,047 procedures); and sublobar resection, 0.88% (9 cases in 1,019 procedures). There were 28 men (56%) and 22 women (44%). Median age was 68.5 years (range, 44 to 88 days). Median time of presentation to the ICU with ALI/ARDS following surgery was 4 days (range, 1 to 22 days). Median ICU length of stay was 10 days (range, 2 to 43 days), and median hospital LOS was 26.5 days (range, 6 to 93 days). During hospitalization, 20 of the 50 patients (40%) died: 16 in the ICU and 4 after ICU discharge. The mortality rate was highest after pneumonectomy (50%), followed by lobectomy (42%) and sublobar resections (22%). Although increased age was associated with a higher ICU mortality, none of the preoperative and perioperative variables were significantly associated with hospital mortality. There was a marginally significant association between mortality and time of presentation to the ICU after surgery (p = 0.06).
Conclusions: Our results confirm that ALI/ARDS after lung resection is associated with a high mortality in patients who require invasive MV and ICU care.
Key Words: acute lung injury • ARDS • ICU • lung resection • mechanical ventilation • mortality • thoracic surgery
Non-small cell lung carcinoma remains the leading cause of cancer-related mortality for both men and women in the United States.1 Surgical resection, with or without adjuvant chemotherapy and radiotherapy, is currently the treatment of choice for early stage non-small cell lung carcinoma.2 Major advances in thoracic surgery, intraoperative anesthetic management, and perioperative care over the past 30 years have led to a significant reduction in the postoperative complications of patients undergoing lung resection.3
Respiratory complications remain the major cause of morbidity and mortality following lung resection. Acute lung injury (ALI) and ARDS are responsible for the vast majority of respiratory-related deaths. Both ALI and ARDS are thought to be part of a spectrum of the same disease that is characterized by the acute onset of hypoxemia (ALI: PaO2/fraction of inspired oxygen [FIO2] 
300; ARDS: PaO2/FIO2 200), with radiographic infiltrates consistent with pulmonary edema that occur in the absence of evidence of other identifiable causes.4 Several preoperative risk factors for ALI/ARDS have been identified, including age > 60 years, male gender, chronic suppurative lung disease, reduced diffusion capacity of the lung for carbon monoxide, predicted postoperative lung perfusion of < 55% of total lung perfusion, prior radiation or chemotherapy, and concurrent cardiac disease.3567891011121314151617181920 Perioperative risk factors include type and extent of lung resection, increased blood loss, blood transfusions, excessive volume of perioperative fluids, and reoperation.3891011121314151617
Studies910 that used the American-European consensus conference definitions for ALI/ARDS have reported an overall prevalence rate of 2.2 to 4.2% in patients who have undergone lung resection. The mortality rate from ALI/ARDS in these patients ranged from 52 to 65%.910 Historically, the type of resection influences the mortality associated with ALI/ARDS; lower mortality rates are observed in patients undergoing lobar or sublobar resections, and higher rates are seen following pneumonectomy.3567814151617
The purpose of our study was to describe the frequency and mortality associated with ALI/ARDS after lung resection in patients who required invasive mechanical ventilation (MV) and admission to the ICU at a tertiary-care cancer center. Additionally, we analyzed preoperative and perioperative factors that we hypothesized were associated with increased mortality in this subset of patients.
Materials and Methods
We assessed all patients with ALI/ARDS developing after lung resection who required MV and admission to the ICU from January 1, 2002, to December 31, 2004, at Memorial Sloan-Kettering Cancer Center, a 425-bed academic, tertiary-care referral cancer center in New York City. ALI and ARDS were defined as per the American-European consensus conference.4
All patients were evaluated by the same thoracic surgical team, and all preoperative studies were standardized. In addition to a history and physical examination, preoperative evaluation included chest radiography, pulmonary function testing, and ECG. Quantitative ventilation/perfusion scanning, echocardiography, and radionuclide stress testing were performed when appropriate. CT scans of the chest and upper abdomen, position emission tomography, and brain imaging were performed for extent of disease evaluation.
Operative Procedures and Anesthesia Management
All lung resections (pneumonectomy, lobectomy, and sublobar resections) were performed through a standard posterolateral thoracotomy. Perioperative antimicrobial prophylaxis with cefazolin was administered routinely. After induction of anesthesia, a double-lumen endotracheal tube was inserted for single-lung ventilation. Patients were extubated at the end of the operation or shortly after arrival in the postanesthesia care unit, and were transferred to the surgical ward on the first postoperative day. Postoperative pain control was achieved with continuous IV or epidural patient-controlled analgesia. Patients participated in an active program of physiotherapy including deep-breathing exercises and incentive spirometry during the perioperative period. If respiratory failure requiring MV occurred, the patients were transferred to the ICU, where arterial blood gas analysis, ECG, and chest radiography were performed on admission and daily thereafter. Additionally, chest CT and bronchoscopy were performed for pulmonary toilet and in any case of clinical deterioration.
All patients were ventilated with low-tidal-volume ventilation (6 to 8 mL per measured body weight), and positive end-expiratory pressure levels ranged from 5 to 18 cm H2O (median, 7.5 cm H2O). Broad-spectrum antimicrobials were utilized in all patients with suspected or proven infection. The diagnosis of pneumonia was made by the treating physicians on the basis of clinical and radiologic criteria including the presence of purulent tracheobronchial secretions, radiographic evidence of lobar or multilobar infiltrates, and microbiologic evidence of infection on Gram stain or culture of a tracheal aspirate or bronchial washing.21 Corticosteroids were empirically administered to selected patients in moderate doses (methylprednisolone, 160 to 240 mg/d or equivalent) by the thoracic surgical team based on their clinical suspicion of ALI/ARDS. Corticosteroids were continued in the ICU after intubation and tapered and discontinued as clinically indicated.
We analyzed general demographic data for all patients who underwent lung resections. These included age, gender, smoking history, cardiovascular comorbidities (hypertension, coronary artery disease, heart failure, arrhythmia, or stroke), and indication for lung resection. For patients receiving MV who acquired ALI/ARDS and were admitted to the ICU, we additionally collected preoperative pulmonary function test results, history of chemotherapy or radiotherapy, operative data (type of surgery and laterality), ICU and hospital outcomes (length of stay [LOS] and mortality), and ICU-specific variables. These included timing of postoperative day to ICU admission, glucose and arterial lactate levels (as surrogate markers of severity of critical illness) and PaO2/FIO2 ratio on ICU admission, use of corticosteroids during ICU admission, and complications. The study was granted a limited waiver of authorization and was approved by our Institutional Review Board.
Statistical Analysis
Data are presented as median (range), absolute numbers, or percentages. Univariate associations between ICU or hospital discharge status and each of the preoperative and perioperative variables were examined using Fisher exact test for categorical variables and logistic regression for continuous variables. All statistical analyses were performed using statistical software (SPSS 11.0; SPSS; Chicago, IL; and SAS 9.0; SAS Institute; Cary, NC).
Results
Over the course of 3 years (January 1, 2002, to December 31, 2004), 2,039 patients underwent 2,192 lung resections at our institution (pneumonectomies, n = 126 [5.7%]; lobectomies, n = 1,047 [47.8%]; and sublobar [wedge or segmentectomy] resections, n = 1,019 [46.5%]). Fifty patients (2.45%) acquired ALI and/or ARDS requiring invasive MV and ICU admission. Except for a higher incidence of cardiovascular comorbidities in the ALI/ARDS patients, there were no significant differences in age, gender, and smoking history between the two groups (Table 1 ).
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Of the 50 patients, 20 patients (40%) died during hospitalization: 16 in the ICU and 4 in the surgical ward after ICU discharge. The mortality rate with ALI/ARDS was highest after pneumonectomy (50%), followed by lobectomy (42%) and sublobar resections (22%) [Table 2 ]. Older age was significantly associated with ICU mortality (74.5 years vs 66 years, p = 0.04) but not with overall hospital mortality. There were also no statistically significant differences in hospital mortality based on gender, preoperative lung function, cardiovascular comorbidities, smoking history, use of neoadjuvant chemotherapy and/or radiotherapy and corticosteroids, and glucose, lactate level, and PaO2/FIO2 ratio on ICU admission (Table 3 ). There was, however, a trend toward a higher hospital mortality in patients with a longer median presentation time to the ICU with ALI/ARDS after surgery that was marginally significant (p = 0.06).
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Our prevalence rate of 2.45% is comparable to two studies910 of patients undergoing lung resection who acquired ALI/ARDS (as defined by the American-European consensus conference definitions) and required MV. However, our mortality rate of 40% was lower than the > 50% mortality rate reported in these studies.910 We ascribe our lower mortality rate, in part, to our use of low-tidal-volume ventilation as a ventilatory management strategy. This approach was not yet implemented between 1991 and 1999, when the two prior studies2223 were performed. Our mortality rate of 40%, however, was similar to the mortality rate of 38.5% recently reported in a large prospective study24 of medical-surgical patients with ALI/ARDS. Further decreases in ALI/ARDS mortality may not occur without dramatic improvements in diagnosis and care.
In our study, increased age was significantly associated with a higher ICU mortality (p = 0.04) but not for hospital mortality (p = 0.14). These findings are similar to earlier studies678910111213141516171925 that have demonstrated an inconsistent relationship of age and mortality in patients with ALI/ARDS after lung resection for cancer. We also observed a trend toward a lower mortality when patients were admitted to the ICU earlier rather than later (median postoperative day to ICU admission, 4 days vs 5 days; p = 0.06). Perhaps further study will show an outcome benefit for postthoracotomy patients with ALI/ARDS if the syndrome is recognized earlier to allow for timely ICU admission and intervention.
Similar to previous reports,910111314151617 the mortality from ALI/ARDS in this series was highest in patients who underwent a pneumonectomy as compared to those who underwent lesser resections. It has been hypothesized that the larger volume of resected lung and greater reduction in lymph drainage may account for the higher mortality of ALI/ARDS after pneumonectomy.9
The use of corticosteroids in the treatment of ALI/ARDS after lung resection remains controversial.2627 In our study, 78% of the patients were treated at some point in their postoperative course with corticosteroids. The use of corticosteroids, however, was not associated with a significant difference in mortality. To our knowledge, there has only been one recent, nonrandomized, small, observational study27 that demonstrated a possible benefit of using low-dose corticosteroids in patients with ARDS after thoracotomy. Randomized controlled studies are needed to determine whether or not corticosteroids are beneficial in the treatment of post-lung resection-associated ALI/ARDS.
There are conflicting reports of the role of neoadjuvant chemotherapy and/or radiotherapy on the development of ALI/ARDS after lung resection.317182829303132 Retrospective studies1828 have reported increased postoperative complications including ALI/ARDS after preoperative adjuvant chemotherapy in patients undergoing lung resection. More recent studies32329303132 have found no difference in morbidity and mortality. In our study, the use of preoperative adjuvant chemotherapy or chemoradiation was not associated with increased mortality, although the number of patients (n = 10) in this analysis is relatively small.
Our study has several limitations. First, this was a retrospective study performed in a single center. Thus, the findings may not be applicable to other centers. Second, the relatively small size of our study population precludes a more thorough analysis of predictors of outcome. Variables that were not significantly different among nonsurvivors and survivors may have had an important effect that we were unable to detect. Third, it is possible that we may have underestimated the true incidence of ALI/ARDS in our postthoracotomy population. We studied only patients with ALI/ARDS who required invasive MV and were admitted to the ICU. We did not include patients who may have had ALI/ARDS but did not require invasive MV and were not admitted to the ICU.
In conclusion, the mortality from ALI and ARDS after lung resection remains high in patients who require intubation and ICU admission. We were unable to identify any preoperative or perioperative variables associated with high mortality. Earlier rather than later, ICU admission of this subgroup of patients may lead to a more favorable outcome. Further reduction in mortality of patients with postthoracotomy ALI/ARDS is unlikely to occur without enhancements or paradigm shifts in preoperative screening, postoperative diagnosis, and treatment of ALI/ARDS.
Acknowledgements
We thank Hao Zhang, Research Assistant, Department of Anesthesiology and Critical Care Medicine, for assistance with the data collection and analysis.
Footnotes
Abbreviations: ALI = acute lung injury; FIO2 = fraction of inspired oxygen; LOS = length of stay; MV = mechanical ventilation
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication November 3, 2005. Accepted for publication February 24, 2006.
References
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  A. L. Lagan, G. J. Quinlan, S. Mumby, D. D. Melley, P. Goldstraw, G. J. Bellingan, M. R. Hill, D. Briggs, P. Pantelidis, R. M. du Bois, et al. Variation in Iron Homeostasis Genes Between Patients With ARDS and Healthy Control Subjects Chest, June 1, 2008; 133(6): 1302 - 1311. [Abstract] [Full Text] [PDF]
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M. Licker, J.-M. Tschopp, J. Robert, J.-G. Frey, J. Diaper, and C. Ellenberger Aerosolized Salbutamol Accelerates the Resolution of Pulmonary Edema After Lung Resection Chest, April 1, 2008; 133(4): 845 - 852. [Abstract] [Full Text] [PDF]
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