After the landmark Acute Respiratory Distress Syndrome Network study in 2000, the idea of low tidal volume (VT) ventilation spread through the critical care and anesthesiology communities.1 Studies have shown that positive-pressure ventilation contributes to lung inflammation and might predispose general surgery and intensive care unit (ICU) patients to a higher risk of ventilator-associated lung injury at high VT.2 Whereas acceptance of low VT has been nearly universal for management of patients with acute respiratory distress syndrome (ARDS), its application in the operating room has been varied.3 The effects of VT on pulmonary complications in general surgery patients undergoing two-lung ventilation were described in an extensive systematic review of studies published over a four-decade period and written by investigators with expertise in this field.3 The authors did not find a temporal change in clinical outcomes despite decreases in VT during this period. Although the use of low VT in the operating room was adapted from the ICU literature to both two- and one-lung ventilation, we will focus on patients requiring one-lung ventilation here.
In large-animal experimental studies, one-lung ventilation was found to be injurious in and of itself, particularly with large tidal volumes and no positive end-expiratory pressure (PEEP).4,5 The use of high fluid infusion rates in one of these studies may confound their observations.4 Increased lung edema was noted, as well as evidence of cyclic recruitment injury, which may increase mechanical stress from repeated expansion and collapse.4,5 Compared with the ICU, the duration of mechanical ventilation in the operating room is on the order of hours, rather than days. Specific to thoracic surgery and one-lung ventilation, the chest may be open and exposed to atmospheric pressure or subjected to varying amounts of insufflation pressure during minimally invasive surgery. Moreover, the patient may be in the lateral decubitus position, which can lead to nonhomogenous distribution of aeration and atelectasis in the dependent and ventilated lung.
The application of low VT strategies to one-lung ventilation during thoracic surgery has also gained widespread acceptance. Low VT ventilation may reduce the risk of ventilator-associated lung injury and clinically important postoperative pulmonary complications. Conversely, it might contribute to atelectasis and dead space ventilation with hypercarbia. The most salient strategies for protective lung ventilation are manipulation of VT, PEEP, and driving pressure, but fraction of inspired oxygen (Fio2), fluid management, and choice of anesthetic agents must be considered. We presume that patients undergoing lung resection and one-lung ventilation are at risk of developing varying degrees of acute lung injury after surgery, similar to patients without ARDS (i.e., with healthy lungs) who require mechanical ventilation. In this review, we highlight recent evidence from prospective studies on the use of low VT ventilation and varying levels of PEEP in patients with ARDS and ICU patients without ARDS. We then compare this with evidence from studies of intraoperative one-lung ventilation during lung resection and clinical outcomes.
Randomized Controlled Trials of Patients with ARDS
The most influential ventilation management strategy for patients with ARDS comes from the Acute Respiratory Distress Syndrome Network trial.1 In this study, the control group was treated at a VT of 12 ml/kg predicted body weight, and the experimental group was treated at a VT of 6 ml/kg predicted body weight. Mortality was 8.8% lower in the low VT group. Low VT ventilation was associated with more ventilator-free days and fewer organ-failure days. There was no difference in the incidence of barotrauma between groups. With the finding that low VT is associated with lower mortality, enthusiasm mounted to optimize oxygenation and improve rates of atelectasis.
Three aspects of low VT ventilation were postulated to have contributed to the lower mortality observed in the Acute Respiratory Distress Syndrome Network trial: coincident lower peak inspiratory airway pressure, plateau pressure, and driving pressure.1 Limiting driving pressure to less than 15 cm H2O (in addition to the use of low VT) was analyzed in two meta-analyses that demonstrated a significant benefit on mortality.6,7 Subsequent studies of higher PEEP or titration of PEEP to other physiologic parameters have not demonstrated a further benefit.
A strategy featuring higher PEEP, compared with that in the initial Acute Respiratory Distress Syndrome Network stepladder, while maintaining low VT was associated with a higher initial partial pressure of oxygen to fraction of inspired oxygen ratio (Pao2:Fio2); however, survival and ventilator-free days were similar between groups.8 The findings of a small study suggested that the use of a PEEP recruitment maneuver could improve rates of hypoxemia and reduce the need for respiratory rescue therapies.9 Subsequently, a strategy to optimize PEEP—by performing recruitment maneuvers (PEEP of up to 45 cm H2O) and then titrating PEEP to the optimal static compliance—was tested.10 In this study, 1,013 patients were randomized to either standard PEEP or the recruitment maneuver plus titrated PEEP. Early oxygenation was better in patients managed with the recruitment maneuver. Unfortunately, rates of barotrauma and mortality were also higher in these patients, which instigated an early end to the trial.
It was hypothesized that titration of PEEP by optimizing pleural pressures could lead to better outcomes. To investigate this, PEEP was adjusted with esophageal manometry to achieve transpulmonary pressures of 0 to 6 cm H2O. Pao2:Fio2 ratio and lung compliance within the first 3 days and 28-day survival were significantly better with this approach.11 Unfortunately, advantages in 180-day survival, rates of kidney injury, and use of rescue ventilation procedures were not statistically significant. Further investigation revealed no benefits on mortality or ventilator-free days.12
Randomized Controlled Trials of ICU Patients without ARDS
With the substantially better outcomes among patients with ARDS managed with low VT ventilation, the eagerness to examine lower VT extended to ventilation of all ICU patients, particularly those at risk of developing ARDS. Although low VT ventilation has been associated with a lower risk of ventilator-associated lung injury, it might contribute to ventilator dyssynchrony, delirium, atelectasis, and pulmonary dead space ventilation with hypercarbia. The findings of retrospective13–19 and prospective20–25 studies of ventilation of ICU patients without ARDS (i.e., with healthy lungs) are summarized in table 1. Our discussion of ICU patients without ARDS is limited to contemporary prospective trials.
While the Acute Respiratory Distress Syndrome Network trial was underway, the results of a counterpart study of patients without ARDS emerged.22 Patients who were at risk of developing ARDS were assigned a moderate versus high goal VT. Patients were randomized, and VT ranged from 6.8 to 7.2 ml/kg predicted body weight in the low VT group and from 10.1 to 10.7 ml/kg predicted body weight in the high VT group. In-hospital mortality was approximately 50% in both groups. The low VT group had a higher partial pressure of carbon dioxide and more frequently required paralytics and hemodialysis than the high VT group. One possible explanation for the lack of a benefit on mortality from this intervention might involve subsequent evolution in ICU practice. A relatively small trial of patients randomized to a VT of either 6.4 ml/kg predicted body weight or 10 ml/kg predicted body weight was stopped at the interim analysis because of the finding of a higher incidence of “lung injury” in the high VT group.23 Lung injury in this study was identified as a change on chest radiography with a corresponding clinical decline in respiratory status. Neither barotrauma nor pneumothorax was identified. PEEP and Fio2 were adjusted as in the Acute Respiratory Distress Syndrome Network trial.1 Also correlated with lung injury were the number of blood transfusions, PEEP level, and interleukin-6 (IL-6) level. Mortality at 28 days and ventilator-free days were similar between the two groups.23
In the largest randomized trial of patients expected to require mechanical ventilation for more than 24 h, six institutions in the Netherlands managed intubated patients without ARDS with a low versus high VT target.24 The low VT group was managed with 5.9 to 7.4 ml/kg predicted body weight, whereas the high VT group was managed with 9.1 to 9.3 ml/kg predicted body weight. None of the studied outcomes—28-day ventilator-free days, ICU length of stay, and 28- or 90-day mortality—differed significantly between the groups. There was no obvious downside to either strategy, because the incidence of atelectasis, ARDS, delirium, pneumonia, and pneumothorax and the need for tracheostomy were similar between the groups.
Whereas low to moderate VT is recommended by experts for patients without ARDS, the optimal PEEP is less clear. Current trends in mechanical ventilation practice suggest that many critical care physicians are targeting a PEEP of 8 cm H2O, instead of the traditional 5 cm H2O. The uncertainty regarding optimal PEEP was addressed in a recent large trial of intubated patients without ARDS who were randomized to a PEEP of either less than 5 cm H2O or 8 cm H2O. Although the study was not blinded, the study groups were well balanced, and the target PEEP levels were achieved. There were no significant differences in survival or freedom from mechanical ventilation.25 With lower PEEP, there was a significantly lower Pao2:Fio2 ratio and higher driving pressure. Of note, the difference in PEEP level between groups (3 to 5 cm H2O) might have been inadequate to determine the superiority of either approach.
Mechanical ventilation can be lifesaving; however, high VT and high driving pressure can contribute to lung inflammation. Results from earlier retrospective studies demonstrating improved outcomes with lower VT in patients with healthy lungs are inconsistent with results from more recent large prospective randomized trials (table 1). As this area of investigation evolves, current expert recommendations are that intubated patients without ARDS should be managed with a limited VT of less than 10 ml/kg predicted body weight, and potentially 7 to 8 ml/kg predicted body weight, and a driving pressure of less than 15 cm H2O. Management of hypoxemia and atelectasis can be further guided by use of the Acute Respiratory Distress Syndrome Network PEEP protocol.26
Retrospective Studies of One-Lung Ventilation
We identified 10 studies of varying sizes that retrospectively examined patients who underwent one-lung ventilation during lung resection (table 2). Licker et al.27 published three studies, the first of which identified the following risk factors for development of acute lung injury: high intraoperative ventilatory pressure index (a product of peak inspiratory pressure and duration of one-lung ventilation), pneumonectomy, chronic alcohol use, and high volume of intravenously administrated fluids during the first 24 h after surgery. Large intraoperative fluid intake was also found to be a risk factor for postoperative pulmonary complications and/or death by three other studies.28–30 In 2006, the authors expanded their original study to include patients treated from 1990 to 2004.31 Preoperative forced expiratory volume in 1 s less than 60 (% of predicted) was identified as a strong predictor of respiratory complications and death at 30 days. The authors did not specifically comment on whether any ventilation variables were associated with outcomes.31 In 2009, the same group compared an historical cohort with a retrospective cohort who had undergone protective lung ventilation and found that protective lung ventilation was associated with lower rates of postoperative respiratory complications, specifically acute lung injury, atelectasis, and shorter length of ICU stay.32 In a large study of patients who underwent lung resection for cancer, preoperative chemotherapy and lower diffusion capacity of the lung for carbon monoxide were identified as independent predictors of postoperative pulmonary complications.33 Pulmonary complications included atelectasis, pneumonia, pulmonary embolism, respiratory failure, and need for supplemental oxygen at hospital discharge. In this study, the inspiratory pressure was maintained at less than 35 cm H2O, and VT was 6 to 8 ml/kg actual body weight during one-lung ventilation. In two studies of patients undergoing pneumonectomy, low VT was found to be a protective factor.28,30 Conversely, in another study of patients undergoing pneumonectomy, ventilation variables were not associated with respiratory complications, although intraoperative administration of blood was.34 Blank et al.35 subsequently expanded their study to include all patients undergoing thoracic procedures that required one-lung ventilation. This is the only study identified to show higher rates of respiratory complications with low VT during one-lung ventilation. Despite this finding, the authors did not conclude that the use of low VT is injurious, but rather that it might not be protective in the absence of sufficient PEEP, underscoring the difficulty of interpreting data from studies in which more than one parameter differs between the control and intervention groups. Colquhoun et al.36 recently reported on the largest, five-center observational study of patients undergoing lung resection, comparing the use of a protective lung ventilation strategy (defined as VT less than or equal to 5 ml/kg with PEEP greater than or equal to 5 cm H2O during one-lung ventilation) with no protective lung ventilation. In the propensity score–matched analysis of 381 pairs, 30-day postoperative pulmonary complications were not significantly different between the groups. In addition, ventilation with higher modified airway driving or peak inspiratory pressures was not found to be associated with adverse pulmonary outcomes.
Prospective Observational Studies of One-Lung Ventilation
A small number of prospective observational studies of one-lung ventilation have been published (table 2). Amar et al.37 prospectively collected data on a large cohort of patients, of whom 608 underwent pneumonectomy and lobectomy and 472 underwent wedge resection. In this study, the ventilation parameters during one-lung ventilation were left to the discretion of the anesthesiologist but, in general, consisted of limiting peak airway pressure to less than 30 cm H2O coupled with intentional crystalloid restriction. Propensity score–matched analyses were performed for each surgical subgroup using a cutoff VT of less than 8 ml/kg predicted body weight or less than 6 ml/kg predicted body weight. The primary outcome was incidence of acute lung injury, ARDS, and/or pneumonia; radiologically observed atelectasis was considered a secondary outcome. Overall, the total number of complications was small, and the primary and secondary outcomes were not significantly different by VT cutoff. Okahara et al.38 prospectively studied patients managed with one-lung ventilation, of whom most underwent lung resection for cancer. The primary outcome was the composite incidence of postoperative pulmonary complications within 7 days of thoracotomy, including pneumonia, pleural effusion, atelectasis, prolonged air leak, pulmonary embolism, and respiratory failure. The authors reported that higher oxygen concentration was associated with a higher rate of overall complications, which consisted mostly of atelectasis and prolonged air leak, and they did not observe a difference in ventilation parameters between patients who developed postoperative pulmonary complications and patients who did not. Finally, the Individualized Perioperative Open-lung Ventilatory Strategy trial (iPROVE Belda) investigators studied patients who underwent lung resection with PEEP titration as part of a protective lung ventilation protocol during one-lung ventilation that consisted of a VT of 5 to 6 ml/kg predicted body weight, recruitment maneuvers, and plateau pressure of less than 25 cm H2O.39 The authors observed an overall low rate of postoperative pulmonary complications and an association between the use of this technique and increased lung compliance, which led them to conclude that future randomized controlled trials should examine whether this strategy is associated with better outcomes.
Randomized Controlled Trials of One-Lung Ventilation
We identified eight randomized controlled trials (one of which is ongoing) that examined aspects of protective lung ventilation in patients undergoing one-lung ventilation during lung resection (table 3). The studies by Schilling et al.43 and Ahn et al.44 included relatively small numbers of patients and focused on inflammatory markers. The largest of the randomized studies40 included patients undergoing lobectomy or pneumonectomy. Rates of major postoperative complications were significantly lower in the protective lung ventilation group (22.2%) than in the control group (13.4%). Of note, this study had an important limitation in design, with substantial differences between the control group (VT of 10 ml/kg predicted body weight without PEEP) and the intervention group (VT of 5 ml/kg predicted body weight plus PEEP of 5 to 8 cm H2O). This illustrates the difficulty determining which variable from the protective lung ventilation bundle was significant—namely, low VT or use of PEEP and whether the PEEP used in the protective lung ventilation arm was optimal. Further criticism could be raised that the composite outcome used included nonpulmonary outcomes, such as shock secondary to sepsis, which could be unrelated to the patient’s lung pathology and the ventilation strategy used. In a much smaller cohort, Yang et al.41 compared a VT of 10 ml/kg predicted body weight, no PEEP, and volume-controlled ventilation versus a VT of 6 ml/kg predicted body weight, PEEP of 5 cm H2O, and pressure-controlled ventilation. This study had the greatest divergence in approaches between the control and intervention groups, because the Fio2 and ventilation modes used also differed between the cohorts. The authors reported a lower rate of postoperative pulmonary complications in the protective lung ventilation group (22% vs. 4%), which they defined as the presence of Pao2:Fio2 ratio less than 300 mmHg, lung infiltration, or atelectasis within 72 h. It can be argued that, although atelectasis or infiltrates on chest radiography might be associated with poor outcomes, they might also signify mild findings that do not meaningfully affect the patient’s clinical course. In another small trial, Unzueta et al.42 showed that the use of a recruitment maneuver, before and after one-lung ventilation, with a VT of 6 ml/kg predicted body weight and PEEP of 8 cm H2O was associated with lower rates of dead space and higher Pao2. Nevertheless, recruitment maneuvers were not associated with clinically better outcomes and might simply be a useful strategy to treat transient hypoxemia intraoperatively.43,44 The very small study by Maslow et al.45 showed no differences in outcomes between high and low VT groups, and neither trial arm had a single patient who developed the primary outcome of acute lung injury or ARDS. Park et al.46 performed a randomized study comparing conventional protective ventilation with an approach that included individualized titration of PEEP to achieve the lowest driving pressure. They found lower rates of postoperative pulmonary complications with the limitation of driving pressure to 15 cm H2O or less. Overall, the number of complications in this study was small, and patients underwent widely different surgeries—for example, wedge resections versus esophagectomies. Furthermore, the statistical methods used to analyze the primary outcome were criticized.47
Of interest, Peel et al.48,49 conducted two meta-analyses combining retrospective and prospective studies. The first concluded that the use of PEEP and recruitment maneuvers during one-lung ventilation was not associated with significantly lower rates of postoperative pulmonary complications.48 The second study concluded that lower VT during one-lung ventilation was associated with lower rates of postoperative pulmonary complications.49 The ongoing Protective Ventilation With High Versus Low PEEP During One-lung Ventilation for Thoracic Surgery study is more optimally designed to answer the question of whether high or low PEEP (10 vs. 5 cm H2O) during one-lung ventilation is superior; the study aims to recruit a large group of patients undergoing pneumonectomy, lobectomy, or wedge resection.50
Recent and perhaps more relevant evidence derived from prospective randomized controlled trials on the ventilation of ICU patients without ARDS suggests that clinically important outcomes do not differ between patients who are ventilated with a low or higher VT or with low versus higher PEEP. Although it can be hypothesized that protective lung ventilation during one-lung ventilation is a prudent strategy to reduce postoperative pulmonary complications, there is limited evidence to support this, and data from both observational and randomized studies are conflicting. Certainly, none of the trials showed that a strategy of high VT ventilation was superior. Determination of the optimal VT level during one-lung ventilation requires further study, because the identified VT levels ranged from 4 to 8 ml/kg predicted body weight (which may not be low, per se, but reflect the physiologic level) and the effects of low versus higher PEEP are unclear. The importance of proven risk factors for postoperative pulmonary complications after lung resection, such as decrements in forced expiratory volume in 1 s or diffusion capacity of the lung for carbon monoxide and greater fluid administration during surgery, should also be emphasized and considered when interpreting observational data or in the design of future randomized controlled trials to examine the impact of protective lung ventilation during one-lung ventilation. Of these known risk factors, fluid restriction and ventilatory settings can be modified by anesthesiologists, as can less proven factors that may impact inflammatory responses, such as choice of inhalational or intravenous anesthetic agents, Fio2, and hypercapnia.51
The authors thank David B. Sewell, M.A., M.F.A. (Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York) for his help with preparation of the manuscript.
Support was provided, in part, by the Slomo and Cindy Silvian Foundation (Melville, New York; to Dr. Amar) and by grant No. P30 CA008748 from the National Institutes of Health/National Cancer Institute (Bethesda, Maryland; to Dr. Amar).
The authors declare no competing interests.