| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
| ||||||||||||||
| ||||||||||||||
|
|
|
|
||||||||||||
|
||||||||||||||
*Department of Anaesthesiology, Pharmacology and Surgical Intensive Care and the
Unit of Thoracic Surgery, University Hospital of Geneva, Switzerland; and
Chest Medical Center, Montana
Address correspondence and reprint requests to Marc Licker, MD, Division d’Anesthésiologie, Hopital Universitaire, rue Micheli-Ducrest, CH-1211 Genève 14, Switzerland. Address e-mail to marc-joseph.licker{at}hcuge.ch
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
IMPLICATIONS: In an observational study including all patients undergoing lung surgery, we describe two clinical forms of acute lung injury (ALI): a delayed-onset form triggered by intercurrent complications and an early form associated with preoperative alcohol consumption, pneumonectomy, high intraoperative pressure index, and excessive fluid intake over the first 24 h.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Despite recent advances in surgical techniques and anesthetic management, 30-day mortality now ranges between 3% and 25% for pneumonectomy and 1% and 5% for lobectomy (4). Pulmonary complications are the main causes of postoperative death, including overlapping conditions such as bronchospastic disorders, atelectasis, air leak, bronchopleural fistula, bronchopneumonia, empyema, and acute lung injury (ALI) (5–7).
Previously named postpneumonectomy edema or noncardiogenic pulmonary edema, ALI after lung resection shares similar clinical, radiological, and histopathological characteristics with acute respiratory distress syndrome (ARDS), the most severe form of ALI (8). After thoracic surgery, ALI is a dramatic complication associated with a mortality ranging from 20% up to 100%, reflecting the wide spectrum of lung impairment and associated organ failure (9). Injuries of the alveolar and endothelial barrier involve the activation of neutrophils and macrophages, as well as the release of cytokines and oxygen free radicals (10).
Although the number of reports describing this syndrome increases, identification of postthoracotomy ALI has been obscured by the lack of proper diagnostic criteria and by retrospective analyses of anecdotal cases or small groups that include mixed cases of lung cancer, benign tumors, abscesses, and bullae (11–20). Currently, postoperative ALI/ARDS refers to the occurrence of lung edema and refractory hypoxemia in the absence of other identifiable causes (e.g., cardiac, infectious, or thromboembolic events or gastric inhalation) (21). Use of strict definition criteria, as well as identification of comorbid conditions and intraoperative physiological predictors of ALI, should enhance our understanding of its complex pathogenesis and provide clues for reducing the risk of ALI after thoracic surgery. This study was performed to analyze our population of patients submitted to lung resection for NSCLC over the last 12 yr to 1) determine the incidence and mortality of ALI and 2) identify pre-, intra-, and postoperative risk factors.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study was approved by the local IRB. Preoperative evaluation included a complete history, physical examination, blood cell count, biochemical profile, chest roentgenogram, electrocardiogram (ECG), pulmonary function tests, and computed tomographic scan of the chest and abdomen. Patients with a small forced expiratory volume in 1 s (FEV1; <60% of predicted value) or impaired exercise tolerance underwent a differential lung perfusion scan, a cardiopulmonary exercise test, or both. Surgical candidates were selected to undergo pneumonectomy if the calculated postoperative FEV1 was 
0.8 L (or 40% of the predicted value) and if maximal aerobic capacity was 50%. Further cardiac testing was performed in patients with risk factors for coronary artery disease or cardiac insufficiency.
Before surgery, a thoracic epidural catheter was routinely inserted, except in cases of a patient’s refusal, coagulation disorders, acute neurological problems, local or systemic infection, and technical failure. Prophylactic antibiotics (cefuroxime 1.5 g/8 h for 24 h) were given, and lung resection with systematic lymphnode dissection was performed through a standard posterolateral or an anterolateral muscle-sparing thoracotomy. After anesthesia induction, a left-sided double-lumen tube was inserted, and its correct position was confirmed by fiberoptic bronchoscopy. During one-lung ventilation (OLV), ventilatory settings (respiratory frequency of 10 to 18 breaths/min; tidal volume of 6–10 mL · kg-1 · min-1; inspiratory/expiratory ratio of 1:2 to 1:3; fraction of inspired oxygen [FIO2] of 30%–100%) were adjusted to achieve a PaCO2 of 30–45 mm Hg and oxygen saturation 92% while avoiding increased peak inspiratory pressure (PIP) (>50 cm H2O) and gas trapping at end-expiration (persistent expiratory flow). Anesthesia was maintained with inhaled isoflurane or propofol, and intraoperative analgesia was provided with repeated doses of IV opiate (fentanyl 50–100 µg) or the epidural administration of local anesthetics and opiate (bupivacaine 0.25% and fentanyl 2 µg/mL).
After surgery, all patients were monitored for at least 24 h in the postanesthesia care unit (PACU; n = 782) or the intensive care unit (ICU; n = 97) to provide respiratory care and early mobilization. Oral feeding was resumed within 3 to 10 h after surgery, and total fluid intake was limited to compensate for the volume of blood loss with colloids and to replace insensible loss with glucose 5% in saline at a rate of 1 mL · kg-1 · h-1. The analgesic regimen was continued for 2 to 4 days by using either parenteral morphine (with a patient-controlled analgesia pump) or epidural administration of opiate, local anesthetics, or both. Arterial blood samplings and chest radiograms were routinely performed at arrival in the ICU or PACU, on the first day after surgery, and in any case of clinical deterioration. Chemotherapy was administered to patients with lymphnode involvement, and radiotherapy was initiated after surgery if the resection border showed tumor invasion.
From our local database, we identified all patients who developed postoperative pulmonary edema that fulfilled the revised criteria of ALI established by the American-European Consensus Conference in 1998 (22): 1) sudden onset of respiratory distress; 2) diffuse pulmonary infiltrates on the chest radiograph consistent with alveolar edema; 3) impaired oxygenation with a PaO2/FIO2 ratio of <300 for ALI and <200 for ARDS; and 4) absence of hydrostatic pulmonary edema due to cardiac insufficiency or fluid overload, on the basis of pulmonary arterial catheterization, echocardiogram, laboratory data (CK-MB, troponin), clinical evaluation, or a combination of these. Patients initially presenting with aspiration of gastric contents, major atelectasis, bronchopneumonia, or pulmonary embolism who later developed noncardiogenic pulmonary edema were classified as secondary ALI, whereas primary ALI included the remaining cases (surgery was the main precipitating event).
As detailed in Table 1, several demographic, clinical, surgical, anesthetic, and laboratory items were abstracted from an institutional database, including all patients who underwent thoracic surgery. In addition, nursing charts and medical records, including specialty consultations, anesthesia charts, and results of investigations, as well as hospital discharge letters, were reviewed by two investigators. Histological typing was reported according to the World Health Organization, and staging of the tumor extension was based on the 1997 revised classification (23).
|
70% of predicted value) were used for the diagnosis of chronic obstructive pulmonary disease (25). The five-grade classification of the ASA was used as a composite index of the patient’s general status. During surgery, ventilatory variables (tidal volume, respiratory frequency, inspiratory oxygenation concentration, and arterial oxygen saturation) and the duration of OLV were recorded, and a ventilatory hyperpressure index was determined (product of inspiratory plateau pressure >10 cm H2O and the duration of OLV). After surgery, laboratory data included serial measurements of oxygenation index (PaO2/FIO2), white blood cell counts, and cultures of blood and tracheobronchial secretions. During and after surgery, the use of vasoactive drugs was recorded, as was urine output, chest drainage, and the amount of fluid intake (colloids, crystalloids, homologous blood units, fresh frozen plasma, and beverages).
Mortality was defined as any death occurring during the hospital stay. The cause of death was determined according to autopsy findings and medical files. At the time of ALI diagnosis, organ dysfunctions were estimated with the Sequential Organ Failure Assessment score (26).
Data are presented as mean ± SD, median (range), absolute numbers, or percentages. Potential risk factors for primary ALI were identified by univariate and multivariate logistic regression analysis. To avoid overadjustment by using too many variables in the multivariate model, all variables were subjected to univariate analysis in a first step. Factors with a P value <0.25 were considered as potential risk factors in the forward multivariate model. To avoid multicollinearity, only one variable in a set of variables with a correlation coefficient more than 0.5 was used in the multivariate analysis. Outcome (primary ALI) was the dependent variable, and all clinical, surgical, anesthetic, and pathologic variables were the independent variables. Adjusted odds ratios and their 95% confidence intervals were calculated.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
|
Other (non-ALI) respiratory complications occurred in 14.5% of patients, including atelectasis (7.1%), prolonged chest drainage (5.0%), bronchopneumonia (4.2%), bronchopulmonary fistula (1.8%), pleural effusions (2%), and thromboembolism (0.5%). ICU and hospital stay were significantly prolonged in patients with ALI (7.2 ± 5.8 days and 24.6 ± 9.8 days, respectively) and in those with non-ALI respiratory complications (5.2 ± 3.4 days and 18.3 ± 6.5 days, respectively) compared with patients who did not develop either ALI or other respiratory complications (1.2 ± 1.1 and 10.3 ± 2.4 days, respectively).
Variables associated with the development of primary ALI are shown in Table 2. Preoperative factors included age, history of chronic alcohol consumption, presence of diabetes mellitus, FEV1, and a high-risk ASA status (III and IV). Pneumonectomy, extended resections, duration of surgery and OLV, PIP, barotrauma ventilatory index, amount of fluid infused, and PaO2/FIO2 at arrival in the ICU or PACU were also significantly associated with the development of ALI. Primary ALI occurred more frequently after pneumonectomy (6.8%) than after lobectomy (2.0%) or lesser resections (2.3%) (Table 3). When comparing three consecutive 4-yr periods, we found no significant time-related changes in the incidence of ALI (1991–1994, 4.8%; 1995–1998, 4.1%; 1999–2003, 3.8%). In a forward conditional model of multiple logistic regression analysis, four factors were found to be independent risk factors for primary ALI (Table 4): chronic alcohol abuse, pneumonectomy, intraoperative ventilatory hyperpressure, and cumulative intake of fluids (during surgery and over the first 24 h after surgery).
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Although mortality and major cardiopulmonary complications after lung cancer surgery have decreased steadily over the last two decades, ALI has become a major contributor to respiratory morbidity and mortality, despite improvement in patient preparation and management (10,27,28). In initial reports, imprecise radiological and/or clinical data were used to diagnose noncardiogenic edema (11–20). Recently, the criteria of the American-European Consensus Conference have been adopted to define ALI after thoracic surgery. Kutlu et al. (29) reported a 5.9% incidence of ALI among 625 patients with lung cancer and a mortality rate of 70%. In a larger series of 1221 patients, ALI occurred in 2.2% of cases, with a mortality rate of 52% (30). Using similar diagnostic criteria, we found ALI in 4.2% of cases; these were responsible for almost half of the 3.0% in-hospital mortality rate.
The variable onset of ALI/ARDS, up to 16 days after lung resection, suggests that, besides surgical trauma, postoperative adverse events (e.g., prolonged hypotension, hypoxemia, or infection) could also initiate a systemic inflammatory disorder. In previous studies, the diagnosis of ALI included ALI secondary to nosocomial pneumonia, thromboembolism, and surgical complications such as bleeding, bronchopleural fistula, chylothorax, or recurrent nerve paralysis (11–20,29,30). In our study, identification of intercurrent perioperative complications was helpful to distinguish a delayed form of ALI that was associated with a more frequent rate of multiple organ failure and in-hospital mortality (60% versus 26% after primary ALI). The small number of patients with secondary ALI precluded meaningful analysis of risk factors with sufficient statistical power.
To explain the early occurrence of primary ALI after curative resection for lung cancer, we identified four significant perioperative risk factors: chronic alcohol abuse, pneumonectomy, intraoperative ventilatory barotrauma, and a large fluid intake during the first 24 hours. Chronic alcohol consumption is associated with an increased incidence of postoperative infections, bleeding, cognitive disorders, and cardiopulmonary insufficiency as a result of immunosuppression, hemostatic imbalance, alcohol withdrawal syndrome, and preclinical cardiac, liver, and central nervous system dysfunction (31,32). We observed a twofold increased risk of ALI among surgical candidates who consumed 60 g of ethanol per day. Likewise, Moss et al. (33) found that chronic alcohol consumption increased the risk of ARDS (43% versus 22% in nonalcoholics) and death due to organ failure (65% versus 36% in nonalcoholics) among patients admitted to the ICU. Furthermore, experimental data indicate that ethanol-induced depletion of pulmonary antioxidant glutathione leads to decreased surfactant production, impaired alveolar liquid clearance, and alterations in epithelial cell permeability (34). In chronic alcoholics, increased vulnerability to infectious complications and to ALI could also be explained by impaired immune status (e.g., suppression of the interleukin-6/interleukin-10 ratio), nutritional deficits, and gastric aspiration associated with postoperative alcohol withdrawal syndrome (32–35).
In agreement with previous studies, primary ALI occurred more often after pneumonectomy (6.9%) than after lobar or lesser resections (2.1%). In anesthetized dogs, Zeldin et al. (11) demonstrated that blood flow to the remaining lung increased two- to sixfold as a result of (unilateral) lung amputation, excessive intravascular volume, and surgical stress response; accordingly, hemodynamic shear stress can physically injure capillary endothelium, allowing protein-rich fluid to fill the interstitium and alveolar space. In addition, a restricted capillary volume associated with lung emphysema, as well as impaired lymphatic drainage due to preoperative radiotherapy, surgical dissection, or tumor invasion, can further aggravate postoperative lung edema (20). In our series, ALI was more frequent in patients with excessive intravascular volume, severe chronic obstructive pulmonary disease, and advanced cancer stages, lending indirect support for a critical role of pulmonary vascular reserve volume and lymphatic pump. After multivariate adjustment, cumulative fluid intake within the first 24 hours remained a significant risk factor for ALI.
In the current literature, the effect of perioperative fluid administration has yielded opposing results because of the wide variability in standard practice among clinicians and the poor quality of data related to fluid balance in retrospective reports (36). Nevertheless, an association has been repeatedly demonstrated between postoperative ALI and fluid intake exceeding 3–4 L over the first 24 hours; in contrast, such an association has not been reported in centers where routine fluid management was more restrictive (37). In our study, oral and IV fluid intake were adjusted for the individual patient’s weight and cumulated during the intraoperative and early postoperative periods; patients with ALI received an excess of approximately 1 L of fluid compared with non-ALI patients. These data suggest that large amounts of fluids (>4 L) given within the first 24 hours can contribute to the development of ALI 24–72 hours after surgery.
Regarding potential ventilator-induced injury, we used a barotrauma index taking into account both the duration of OLV and increased inspiratory pressure (Pplateau >10 cm H2O); this index represented the strongest risk factor for ALI (approximately threefold increased risk if PIP 25 cm H2O versus PIP = 15 cm H2O for a similar duration of OLV) and also reflected the severity of the underlying lung disease (e.g., interstitial fibrosis and chronic bronchitis causing low compliance), as well as the difficulty of surgical resection.
Clinical and experimental studies have largely emphasized the importance of different ventilatory strategies (38,39). In a cohort of 190 patients undergoing lung resection, van der Werff et al. (19) reported that patients with intraoperative PIP 40 cm H2O were prone to develop radiological signs of lung edema (35% versus 13% in patients with PIP <40 cm H2O). In ICU patients, overdistension of the lung associated with mechanical ventilation is an important contributory factor to ALI/ARDS and in-hospital mortality; namely, stretch-activated cation channels, oxygen-derived free radicals, activated neutrophils, and upregulation of cytokines in the lung have all been incriminated in the increased microvascular-alveolar permeability (39,40). Conversely, "protective" lung ventilatory strategies aimed at minimizing excessive end-inspiratory stretch and collapse of lung units attenuate the release of cytokines and reduce mortality (20% to 45%) in critically ill patients (40–42). During surgery, pressure-controlled ventilation has been demonstrated to achieve lower airway pressure while improving oxygenation through homogeneous distribution of inspired gas and recruitment of collapsed lung areas (43).
We are aware of several limitations in this observational study. First, over a 12-year period, we collected large amounts of information related to lung cancer surgery in a single center that may not be generalized to other clinical settings and may be biased by time-related changes in medical strategy, including patient screening, preparation, and perioperative care. Nevertheless, the incidence of ALI remained unchanged over three consecutive four-year periods. Second, potential risk factors, such as age and right-sided operation, were excluded, whereas other factors (e.g., preoperative chemo- or radiotherapy, respiratory disease, blood transfusion, poor nutritional status, or smoking) failed to achieve statistical significance because of incomplete data or a small prevalence rate; hence, further studies should explore the effect of underlying lung disease and preoperative treatment. Third, the true incidence of ALI was possibly underestimated because blood gas measurements were limited to the first 24–48 hours after surgery, and interpretation of chest radiographs is known to be highly variable among different observers (44).
Our findings are not unexpected in view of several animal and human studies of the pathogenesis of postoperative ALI/ARDS (10,45,46). Several preoperative patient comorbidities (e.g., chronic alcoholism and respiratory diseases) are associated with increased susceptibility to ALI by reducing lung defense mechanisms, restricting capillary volume, and enhancing the inflammatory response against injurious agents. During and after surgery, the synergistic/additive effects of lung hyperinflation, surgical trauma, and ischemia/reperfusion induce the release of inflammatory mediators and a combination of insults at the alveolar-endothelial barrier, resulting in lung edema and eventual organ dysfunctions. In addition, stretching of capillaries by overzealous fluid administration (or impaired pulmonary venous return) may cause stress failure within microvessels, which further aggravates permeability disturbances.
The corollary of these findings would be to improve preoperative selection criteria and to implement risk-reduction strategies for the occurrence of ALI, particularly in patients undergoing pneumonectomy and in those with underlying lung diseases: 1) withdrawal of alcohol for a safe period of abstinence and correction of nutritional deficits before elective surgery; 2) intraoperative application of pressure-controlled ventilation (or small tidal volume) with air/oxygen mixtures to prevent baro-/volotrauma and oxidative damages; 3) limitation of fluid intake for the first 24–48 hours after surgery while keeping tight control of hemodynamics; and 4) implementation of monitoring tools to assess cardiac preload, intrathoracic blood volume, and pulmonary artery pressure (e.g., stroke volume or pressure variation, transpulmonary thermo-dye dilution technique, and echocardiography) that would allow early detection of pulmonary hypertension and interstitial lung edema and to target treatment with diuretics, inhaled nitric oxide, and/or noninvasive positive pressure ventilatory techniques (47–49).
|
Acknowledgments |
|---|
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  F. T. Lytle and D. R. Brown Appropriate Ventilatory Settings for Thoracic Surgery: Intraoperative and Postoperative Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2008; 12(2): 97 - 108. [Abstract] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 M. Iglesias, E. Martinez, J. R. Badia, and P. Macchiarini Extrapulmonary Ventilation for Unresponsive Severe Acute Respiratory Distress Syndrome After Pulmonary Resection Ann. Thorac. Surg., January 1, 2008; 85(1): 237 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Bapoje, J. F. Whitaker, T. Schulz, E. S. Chu, and R. K. Albert Preoperative Evaluation of the Patient With Pulmonary Disease Chest, November 1, 2007; 132(5): 1637 - 1645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Alam, B. J. Park, A. Wilton, V. E. Seshan, M. S. Bains, R. J. Downey, R. M. Flores, N. Rizk, V. W. Rusch, and D. Amar Incidence and Risk Factors for Lung Injury After Lung Cancer Resection Ann. Thorac. Surg., October 1, 2007; 84(4): 1085 - 1091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Eckle, L. Fullbier, M. Wehrmann, J. Khoury, M. Mittelbronn, J. Ibla, P. Rosenberger, and H. K. Eltzschig Identification of Ectonucleotidases CD39 and CD73 in Innate Protection during Acute Lung Injury J. Immunol., June 15, 2007; 178(12): 8127 - 8137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. Joshi and D. M. Guidot The alcoholic lung: epidemiology, pathophysiology, and potential therapies Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L813 - L823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Slinger Pro: low tidal volume is indicated during one-lung ventilation. Anesth. Analg., August 1, 2006; 103(2): 268 - 270. [Full Text] [PDF]
|
|
|
|
|
|
A. Dulu, S. M. Pastores, B. Park, E. Riedel, V. Rusch, and N. A. Halpern Prevalence and Mortality of Acute Lung Injury and ARDS After Lung Resection. Chest, July 1, 2006; 130(1): 73 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Wiebe, H. Baraki, P. Macchiarini, and A. Haverich Extended pulmonary resections of advanced thoracic malignancies with support of cardiopulmonary bypass Eur. J. Cardiothorac. Surg., April 1, 2006; 29(4): 571 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. de Perrot, E. Fadel, O. Mercier, S. Mussot, A. Chapelier, and P. Dartevelle Long-term results after carinal resection for carcinoma: Does the benefit warrant the risk? J. Thorac. Cardiovasc. Surg., January 1, 2006; 131(1): 81 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. P. Grichnik and T. A. D'Amico Acute Lung Injury and Acute Respiratory Distress Syndrome After Pulmonary Resection Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2004; 8(4): 317 - 334. [Abstract] [PDF]
|
|
|
|
|
|
P. D. Slinger Acute Lung Injury After Pulmonary Resection: More Pieces of the Puzzle Anesth. Analg., December 1, 2003; 97(6): 1555 - 1557. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
