Protective lung ventilation during general anesthesia: is there any evidence?

Postoperative pulmonary complications remain a significant problem after surgery. They occur in 5-10 % of all surgical patients and 9-40 % of those undergoing abdominal surgery experience postoperative pulmonary complications [19], which increase morbidity and mortality [19], [20]. Among the postoperative pulmonary complications, lung atelectasis is one of the principle mechanisms for the development of VILI, pneumonia and postoperative respiratory failure.

In this context, Wrigge and colleagues investigated in two studies the effect of different ventilatory strategies on the release of inflammatory mediators in patients undergoing elective surgery [21], [22]. In the first study, 39 patients scheduled for extra-thoracic surgery (abdominal, vascular, bone and other) were randomized to one of three mechanical ventilation strategies: 1) V_T of 15 ml/kg ideal body weight without PEEP; 2) V_T of 6 ml/ kg without PEEP; and 3) V_T of 6 ml/kg with PEEP 10 cmH₂O. Plasma levels of interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α were measured after one hour of mechanical ventilation [21]. In the second study, 64 patients undergoing general anesthesia were randomized to receive mechanical ventilation with a V_T of 1215 ml/kg ideal body weight without PEEP, or with V_T of 6 ml/kg and PEEP levels of 10 cmH₂O. Local and systemic inflammatory biomarkers, including IL-8, IL-1, IL-6, IL-10, TNF-α and IL-12, were determined after 3 hours of mechanical ventilation [22]. Both studies were unable to find any significant differences in terms of inflammatory mediators and the authors concluded that, in contrast to patients with acute lung injury in whom there is a systemic inflammatory reaction during major surgery, in uninjured normal lungs short term mechanical ventilation alone with high V_T levels did not increase pulmonary or systemic inflammation related to surgery [21], [22]. No differences in biomarkers of lung epithelial injury were observed after 5 hours in a later study, which compared ventilation with V_T 12 ml/kg ideal body weight without PEEP versus V_T 6 ml/kg and PEEP 10 cmH₂O [23].

To explore the effect of a high compared to a low V_T for similar PEEP levels, Treschan et al. randomized patients to receive a V_T of 12 ml/kg body weight versus 6 ml/kg with a PEEP of 5 cmH₂O [24]. Except for the intraoperative oxygenation, which was higher in the high V_T group, there was no significant difference in forced vital capacity and forced expiratory volume in one second between groups, for up to five days after the surgery.

Different from the previous studies, Weingarten et al. evaluated an open lung strategy in which low V_T ventilation was associated with PEEP plus a recruitment maneuver in order to minimize atelectasis and shear stress in the lung parenchyma [25]. This open lung strategy, consisting of a V_T of 6 ml/kg predicted body weight with PEEP 12 cmH₂O and recruitment maneuvers, significantly improved only intraoperative oxygenation with no difference in the inflammatory response or length of hospital stay compared to a V_T of 10 ml/kg without PEEP [25]. These first studies seem to suggest that a protective ventilator strategy does not have any role in patients without lung injury [21‐25]. However, these studies demonstrated that this mode of ventilation is feasible in open abdominal surgery with no adverse effects [23], [25]. In contrast to the previous studies, Severgnini et al., comparing a lung protective mechanical ventilation consisting of a V_T of 7 ml/kg ideal body weight with PEEP levels of 10 cmH₂O and recruitment maneuvers versus a V_T of 9 ml/kg without PEEP, showed beneficial effects of the lung-protective strategy during general anesthesia lasting more than 2 hours [26]. The lung-protective strategy improved postoperative respiratory function in terms of dynamic spirometry, oxygenation, and pulmonary complications for up to 5 days after surgery, without increasing the incidence of intraoperative complications. Although there was no significant difference in the hospital length of stay between groups, 20 % of the patients in the lung-protective group, compared with 40 % in the control group, were still in hospital on postoperative day 14 [26].

A recent multicenter randomized clinical trial in which lung-protective ventilation with a V_T of 6-8 ml/kg predicted body weight, PEEP 6-8 cmH₂O and recruitment maneuvers repeated every 30 minutes was compared with non-protective ventilation with V_T 1012 ml/kg without PEEP, found that the lung-protective ventilation significantly reduced major pulmonary and extrapulmonary complications from 27.5 % to 10.5 % [27]. The lung-protective strategy also significantly reduced the proportion of patients who required postoperative ventilator assistance from 17 % to 5 % and the hospital length of stay.

Compared to the earlier studies [22‐25], these two recent trials found a beneficial effect of a lung-protective strategy probably because of the large number of enrolled patients, the homogeneity of the selected population of patients undergoing open abdominal surgery with an expected duration of at least 2 hours, the standardization of fluid management, and the clinically relevant outcomes explored (not only lung inflammatory mediators) in the postoperative period.

These results demonstrate that in patients undergoing abdominal surgery a multifaceted open lung protective strategy can prevent the intraoperative alveolar opening and closing and overdistension of lung areas that lead to VILI and pulmonary complications. Currently, we are waiting for the results of the PROVHILO study, a worldwide multicenter RCT in which patients scheduled for abdominal surgery are being enrolled. In this study, all patients are ventilated with protective tidal volumes (in both groups, V_T < 8 ml/kg predicted body weight) and randomly assigned to a lung-protective strategy with use of recruitment maneuvers and PEEP levels of 12 cmH₂O or a conventional strategy without recruitment maneuvers and PEEP between 0 and 2 cmH₂O [28]. If the results of this study confirm those of the last two trials [27], [26], lung-protective strategies will be more widely applied in patients undergoing abdominal surgery [28].

During thoracic surgery, one-lung ventilation is an established procedure that could increase the risk of promoting VILI compared to double lung ventilation, because of greater reduction in lung volume and greater degree of alveolar collapse in dependent lung regions. Two retrospective studies of patients who had undergone elective pneumonectomy found that larger intraoperative V_T and higher inspiratory airway pressure were associated with the development of pulmonary edema and respiratory failure [29], [30]. Despite this, conventional mechanical ventilation in these patients consists of V_T between 8-12 ml/kg to prevent lung atelectasis with zero or low levels of PEEP to avoid shunt aggravation by redistribution of blood flow to non-ventilated regions [31], [32]. However this approach is not an evidence-based guideline.

Schilling et al., in a randomized study in patients scheduled for open thoracic surgery undergoing one-lung ventilation, showed that mechanical ventilation with V_T of 5 ml/kg ideal body weight compared to 10 ml/kg significantly decreased the pulmonary inflammatory response up to 2 hours postoperatively [33]. Subsequently, Licker et al. retrospectively evaluated the implementation of a lung-protective ventilation strategy in lung cancer resection combining a low V_T (< 8 ml/kg) with PEEP 4-10 cmH₂O and recruitment maneuvers versus a conventional V_T target ventilation of 9-12 ml/kg during two-lung ventilation and 8-10 ml/kg during one-lung ventilation without recruitment maneuvers and PEEP applied at the discretion of the anesthetist [34]. The lung-protective strategy significantly reduced the incidence of atelectasis (from 8.8 % to 5 %), postoperative acute lung injury (from 3.7 % to 0.9 %), ICU admission (from 9.4 % to 2.5 %) and length of hospital stay (from 14.5 ± 3.3 to 11.8 ± 4.1 days). These data were confirmed in a randomized study during elective lobectomy in which patients were ventilated with a high V_T of 10 ml/kg without PEEP compared to a low V_T of 6 ml/kg with 5 cmH₂O of PEEP and pressure controlled ventilation [35]. The lung-protective ventilation was associated with a lower incidence of lung infiltration or atelectasis (2 versus 10) and of cases of hypoxemia (1 versus 8).

During esophagectomy, a procedure requiring a prolonged period of one-lung ventilation, Michelet et al. demonstrated in an RCT that lung-protective ventilation (V_T 9 ml/kg during two-lung ventilation, reduced to 5 ml/ kg during one-lung ventilation and PEEP 5 cmH₂O throughout the operative time) could prevent alterations in lung function and reduce the inflammatory response in patients without previous lung disease compared to conventional ventilation strategy (V_T 9 ml/kg during two- and one-lung ventilation without PEEP) [36].

The majority of studies so far have demonstrated that, during thoracic surgery, traditional intraoperative ventilatory settings seem to be harmful. An intraoperative open lung approach based on small V_T, moderate-high PEEP and recruitment maneuvers may be beneficial but further randomized clinical trials are necessary to generate clinical evidence.

In cardiac surgery, use of cardiopulmonary bypass (CPB), contact of the blood with artificial surfaces and ischemia/ reperfusion of the heart and lungs are associated with a pulmonary and systemic inflammatory response, with activation of elements of the complement cascade, neutrophils and pro-inflammatory cytokines [37‐39]. This systemic inflammatory response syndrome can be mild to severe in 10 to 35 % of cases and may induce an acute lung injury, which generally resolves within 24 hours. This clinical event contributes to increased morbidity and mortality [40]. In this context, injurious mechanical ventilation could aggravate the primary inflammatory response described above (first hit), representing a second hit. Moreover, during CPB, the lungs are not ventilated and either rest at low values of continuous positive pressure [41] or are completely disconnected from the ventilator [42‐44]. Traditionally, ventilator settings in cardiac surgery patients included large V_T (10-15 ml/kg) in order to minimize atelectasis and minimal levels of PEEP to reduce hemodynamic consequences. Following the results of clinical trials in ARDS patients [45], [46], there has been increased interest in protective lung ventilatory strategies during cardiac anesthesia and several trials have tried to demonstrate the role of protective lung ventilation in this context.

Koner et al. found no differences in plasma levels of IL-6 and TNF-α 2 hours after the end of CBP among patients randomized to receive protective ventilation (V_T 6 ml/kg ideal body weight, PEEP 5 cmH₂O) or conventional V_T ventilation (V_T 10 ml/kg) with and without PEEP levels at 5 cmH₂O [42]. There were no differences among groups in the explored clinical outcomes, including total intraoperative fluid balance, intubation time and hospital length of stay [42].

Wrigge et al. measured pulmonary and plasma levels of different cytokines and chemokines (IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α and interferon-γ) in patients ventilated with high or with low tidal volumes (V_T 12 ml/kg versus V_T 6 ml/kg ideal body weight). They observed higher values of TNF-α after 6 hours of ventilation with high V_T, with no differences in other inflammatory mediators [41].

However, a significantly reduced inflammatory response, in terms of pulmonary and systemic mediator levels (IL-6 and IL-8) was observed when applying a moderate PEEP level strategy (V_T 8 ml/kg with PEEP 10 cmH₂O) compared to a low PEEP and high V_T strategy (10-12 ml/kg with PEEP 2-3 cmH₂O) [44]. In comparison to previous studies [41], [42], this study evaluated a greater difference in PEEP levels and a longer duration of mechanical ventilation [44].

Reis et al. investigated the effect of open lung ventilation, consisting of low V_T (4-6 ml/kg) with moderate-high PEEP levels (10 cmH₂O) and recruitment maneuvers, on inflammatory mediators. In this study, they compared an early (immediately after intubation) and a late (at the end of CPB) application of the same open lung strategy, with conventional ventilation (V_T 6-8 ml/kg, PEEP 5 cmH₂O). Both the open lung approaches significantly decreased IL-8 and IL-10 levels after CPB [47]. Subsequently, the same authors showed that the early open lung approach significantly attenuated the reduction in postoperative FRC, for up to 5 days after surgery, and reduced the incidence of hypoxemic events during the first 3 days after extubation [48]. Ventilation and weaning times were similar among groups. This positive effect on postoperative FRC could be related to the prevention of additional lung injury caused by mechanical ventilation. Chaney et al. similarly reported better dynamic and static lung compliance and less shunt in patients ventilated with low compared to high V_T (6 versus 12 ml/kg) [49].

Recently Sundar and colleagues observed that a larger number of patients were extubated after 8 hours (53 % versus 31 %) when ventilated with a low V_T of 6 ml/kg ideal body weight compared to V_T 10 ml/kg with similar PEEP levels. Furthermore, a lower postoperative reintubation rate was observed. However, global time to extubation was similar between groups, as were ICU length of stay and 28-day mortality [43].

There is, therefore, a small amount of evidence from small studies in support of lung-protective ventilation in cardiac surgery patients [50]. However, the presence of several confounding factors, not related to mechanical ventilation, which could contribute to the development of a systemic inflammatory response and postoperative pulmonary complications, may have influenced the main outcome results. Hence, further studies with larger cohorts of patients are needed to confirm the still weak evidence in favor of lung-protective ventilation in cardiac anesthesia.