Impact of intraoperative lung-protective interventions in patients undergoing lung cancer surgery

Compared with other surgical procedures, thoracotomy is associated with the highest 30-day mortality rates, ranging from less than 1% for minor resections to up to 12% for pneumonectomies [1–3]. Postoperative onset of acute hypoxemia – unrelated to cardiac failure, pulmonary embolism, atelectasis, sepsis or bronchoaspiration – has attracted much interest as it has become the leading cause of death in patients undergoing lung resection [4, 5]. The guidelines set forth by the American–European Consensus Conference on the acute respiratory distress syndrome have been widely adopted to describe this form of acute lung injury (ALI), previously coined postpneumonectomy pulmonary edema, low-pressure or low-permeability pulmonary edema [6].

Contrasting with other adverse cardiopulmonary events, the incidence of post-thoracotomy ALI has not shown any noticeable decrease although various treatment modalities such as noninvasive ventilation and nitric oxide inhalation have reduced the case-fatality rate [7, 8]. Interestingly, a large tidal volume (V_T) and an elevated inspiratory pressure during one-lung ventilation have been identified as strong predictors of ALI in two retrospective observational studies [9, 10]. The hypothesis of ventilator-induced lung injury during one-lung ventilation has been further supported by the association between tidal volume exceeding 7 to 8 ml/kg predicted body weight (PBW) and the release of systemic and pulmonary inflammatory mediators [11]. Presently, the clinical benefits of lung-protective strategies using lower V_T combined with positive end-expiratory pressure (PEEP) have been clearly demonstrated in randomized controlled trials including only critically ill patients with ALI/acute respiratory distress syndrome [12].

Considering the potential injurious effects of large tidal volume in patients with healthy lungs undergoing short-term one-lung ventilation, we hypothesized that adopting a protective lung ventilation (PLV) protocol as part of a collaborative quality improvement initiative would lead to further reduction in the incidence of post-thoracotomy ALI. In our institutional surgical database, we examined whether protocol-driven changes in ventilatory strategy initiated in 2003 were associated with better clinical outcomes compared with historical controls.

Over a 10-year period, 1,091 patients underwent pulmonary resection for malignancy. Complete data were available in 533 patients from 1 March 1997 to 28 February 2003 and in 558 patients from 1 March 2003 to 28 February 2008.

The cause of death was primarily attributed to ALI in one out of five patients in the PLV group (vs. 6/20 in the historical controls), other causes being related to sepsis (2/5 vs. 4/20, respectively), thromboembolism (1/5 vs. 3/20, respectively) and myocardial infarct (1/5 vs. 1, respectively). Inhospital mortality and the incidence of cardiovascular complications and secondary ALI did not differ between the two groups.

The present observational study is the first to indicate that implementation of an intraoperative ventilatory strategy aimed to limit lung overdistension while maintaining functional residual capacity with external PEEP and recruitment maneuvers leads to significant reduction in the incidence of post-thoracotomy ALI and atelectasis along with fewer admissions to the ICU and a shorter hospital stay.

Importantly, lowering the risk of ALI with PLV by more than 50% was independent of age, severity of underlying lung and cardiovascular diseases as well as other perioperative interventions. Although the present results were obtained by comparison with a historical control group, they strongly suggest that the PLV strategy may also benefit patients undergoing lung cancer resection. Alternatively, the improved respiratory outcome in PLV-treated patients supports the hypothesis that ALI and atelectasis may in part be caused by or be related to intraoperative factors: ventilator-induced lung injury or ventilator-associated injuries and the reduction of functional residual capacity consequent to the effects of surgical insults, anesthesia and muscle paralysis [14, 15]. High shear stress associated with cyclic opening of collapsed areas (atelectotrauma) and deformation of the alveolar epithelium (strain) during one-lung ventilation are thought to generate a proinflammatory state (biotrauma) leading to pulmonary tissue alterations.

By the late 1990s the standard V_T for managing thoracic surgical patients had already been adjusted downwards (from 10 to 12 ml/kg in the 1980s) to 8 to 10 ml/kg, although no specific guidelines existed for one-lung ventilation. Our historical control data were consistent with these values and, after implementation of the PLV protocol, the V_T declined from mean values of 7.1 to 5.3 ml/kg during the one-lung ventilation period. We used predicted rather than actual body weight for calculating the V_T per kilogram of body weight to avoid lung overdistension in obese patients and in women who have smaller lung volumes [16]. Importantly, the ventilatory endpoints (V_T < 8 ml/kg and inspiratory plateau pressure < 35 cmH₂O) were achieved in more than 80% of patients. Compliance with the new ventilatory guidelines was facilitated by the relatively short ventilatory time (< 3 hours), the absence of acute critical illnesses and the commitment of a small number of cardiothoracic anesthesiologists. Interestingly, similar protective ventilatory strategies applied in ICU settings have been associated with a decreased incidence of ALI in high-risk patients, although the target V_T was achieved in only 50% to 60% of cases [17–19].

Thoracic surgical candidates represent a particular group of noncritically ill patients in whom ventilation-induced cytokine upregulation produces a proinflammatory state that renders the host more vulnerable to subsequent hit(s) such as ischemia–reperfusion, hypoxia–reoxygenation and direct tissue trauma [20–22]. Depletion of pulmonary glutathione stores observed in alcoholic patients is expected to further exacerbate oxidative lung injuries [23].

To date, three randomized controlled trials including patients undergoing thoracotomy have compared the application of traditional high V_T with the open lung strategy combining low V_T and PEEP. Although Wrigge and colleagues failed to document any difference in systemic inflammatory markers [24], Schilling and colleagues found reduced alveolar concentrations of TNFα and soluble intercellular adhesion molecules in patients ventilated with small V_T (5 vs. 10 ml/kg) [25]. Confirming these positive results, Michelet and colleagues reported an attenuated systemic proinflammatory response, lower interstitial pulmonary edema and an improved oxygenation index allowing earlier extubation in the protective ventilation group among patients undergoing esophagectomy [26].

In the present study we adopted a PLV including pressure-controlled ventilation, external PEEP and recruitment maneuvers. Actually, delivery of a decelerating gas flow has been reported to achieve more homogeneous flow distribution and lower peak airway pressure [27]. Different lung recruitment strategies have been shown to re-expand the collapsed dependent lung areas that develop in almost all anesthetized patients. During thoracic surgery, application of recruitment maneuvers with moderate PEEP levels to the dependent lung has been shown to improve oxygenation and to reduce both intrinsic PEEP levels and static elastance of the respiratory system without causing significant cardiovascular deterioration [28]. Our data confirm the good hemodynamic tolerance to the PLV protocol since fluid and vasopressor requirements were similar in the two cohorts. Given the difficulties in constructing static pressure–volume curves, we did not titrate the PEEP but we set a fixed moderate level of PEEP that could potentially cause alveolar hyperinflation in healthy or emphysematous areas. This possibility seems unlikely since we observed higher compliance in patients managed with the PLV protocol, which supports the stabilizing effects of PEEP along with effective re-expansion of previously collapsed areas following recruitment maneuvers [29–31].

We acknowledge several limitations in the current study. Although data were collected by clinicians and validated by scientific investigators, we assume variability in initial ventilator settings with the possibility that higher inspiratory pressures and tidal volume were deliberately chosen to correct transient hypoxemia and hypercapnia. The observational design limits the ability to infer causality between the lung-protective protocol and lowering the incidence of ALI. Although statistics were helpful to adjust for some confounding variables, unmeasured factors and other changes in practice or in the patient case mix may have decreased the confidence in observed effects. For instance, potentially beneficial therapies such as preoperative statin and angiotensin-converting enzyme treatment, continuous thoracic epidural anesthesia, goal-directed fluid therapy using transesophageal Doppler monitoring, inhalation of β₂-agonists in high-risk patients, and early postoperative mobilization were popularized during the postintervention period, and thereby could have contributed to the overall reduction in respiratory complications and in hospital length of stay [32]. On the other hand, despite higher prevalence of hypertension in the protocol-treated cohort, mortality and cardiovascular adverse events were unchanged compared with the control cohort. Finally, major limitations also stem from the definition of ALI that may cover different clinical patterns and histological findings, which may explain significant interobserver diagnostic disagreement particularly in postoperative patients [33]. In the present study, we excluded patients with delayed onset of ALI triggered by infection, bronchial aspiration of gastric content and allogenic transfusion. Accordingly, post-thoracotomy ALI probably identified a more homogeneous group of patients predisposed to the injurious effects of mechanical ventilation. The reliability of ALI diagnostic criteria could have been improved by additional measurements of plasma brain natriuretic factor and lung water content with the transpulmonary thermodilution technique [34, 35].

In this observational study, we demonstrated the effectiveness of combining low V_T, PEEP and recruitment maneuvers. This intraoperative open-lung approach was easily implemented in clinical practice and resulted in a reduced incidence of postoperative ALI and atelectasis. Implementation of a bundle of scientifically-based perioperative interventions represents an integral component of clinical quality management. Future clinical trials will determine whether optimization of other ventilator settings (for example, oxygen inspiratory fraction, PEEP level, periodicity of recruitment maneuver) may improve respiratory outcome in specific groups of surgical patients requiring mechanical ventilation.