Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening conditions that affect critically ill patients. Despite recent advances in intensive care medicine, ALI and ARDS present a major health problem. More than 150 000 patients are affected annually in the United States and the lethality of the condition is 40-50% . This syndrome is characterized by an acute onset of hypoxaemia with bilateral pulmonary infiltrates seen in the chest radiograph consistent with pulmonary oedema that cannot be explained by left heart failure (Table 1) . Diffuse damage to the alveolar-capillary membrane leads to high-permeability pulmonary oedema characterized by extravasation of plasma proteins, surfactant dysfunction and impairment of alveolar fluid clearance . The development of ALI/ARDS is commonly preceded by various pulmonary (pneumonia, aspiration of gastric contents, inhalation injury, pulmonary contusion, near drowning) and extrapulmonary (sepsis, shock, transfusion, trauma) conditions .
Since ARDS was first described by Ashbaugh and colleagues in 1967 , numerous clinical investigations have been conducted testing various, predominantly antiinflammatory treatment strategies . The results were uniformly disappointing until first observational studies  and later randomized trials [6,7] reported improved outcomes with the use of protective mechanical ventilation. This suggested a pivotal role of ventilator-induced lung injury (VILI) in the progression of ALI/ARDS.
In the following sections we will review the mechanisms of VILI, the evidence from recent clinical studies on the efficacy of different ventilator strategies, and the suggested approach to mechanical ventilation in patients with ALI/ARDS.
Mechanisms of VILI
The vast majority of patients with ALI/ARDS require respiratory life support in the form of mechanical ventilation. VILI is best understood as a spectrum of lung injuries caused by mechanical ventilation. Overt barotrauma, including pneumothorax, pneumomediastinum and interstitial emphysema, has long been recognized as a complication of mechanical ventilation. Animal experiments revealed more subtle forms of VILI that were clinically and pathologically indistinguishable from ALI/ARDS [8-11]. Overdistension injury induced by high-tidal-volume (Vt) ventilation (‘volutrauma') has been identified as the single most important determinant of VILI [9,11] (Fig. 1). In addition, ventilation at low lung volumes in the absence of positive end-expiratory pressure (PEEP) may lead to lung injury caused by repetitive collapse and re-opening of the alveolar units (‘atelectrauma', see Fig. 1) . Other important determinants of VILI include body position, respiratory rate, inspiratory flow, hypercapnic acidosis, temperature and vascular pressures [13-21].
Inflammatory mediators (cytokines, chemokines) and microorganisms may pass into the systemic circulation secondary to the increased alveolar-capillary permeability and contribute to the development of multiple organ dysfunction (‘biotrauma') [22-24]. While conventional mechanical ventilation has been associated with the increased levels of inflammatory mediators in the systemic circulation in patients with ALI/ARDS [6,25], short-term studies in patients ventilated during surgery yielded inconsistent results [26,27].
Better understanding of the pathophysiology of ALI/ARDS and the role of VILI prompted the use of smaller Vt with lower inspiratory pressures and a moderate amount of PEEP to prevent expiratory collapse (‘open lung') (Fig. 1). This type of approach has also been termed a lung-protective ventilation strategy.
Low-tidal-volume mechanical ventilation strategies in patients with ALI/ARDS
For many years, ventilation with high Vt (12-15 mL kg−1 predicted body weight (PBW), see Fig. 2) was considered a standard of care for patients with ALI/ARDS. Large-Vt ventilation was largely adopted from an anaesthesia setting where it was used to counteract atelectasis and hypoxaemia . Ventilation with large Vt enables easier control of CO2 clearance when dead space is increased and may also help recruit small bronchioles and alveoli, reducing shunt fraction and temporary improving oxygenation.
With the advancement in the understanding of VILI, some clinicians began to use lower-Vt ventilation, allowing above normal concentrations of arterial CO2 (permissive hypercapnia). During the early 1990s first observational studies reported significantly improved outcome in patients ventilated with low Vt . Subsequently, six randomized controlled clinical trials (Table 2) evaluated lung-protective ventilation compared with conventional approaches, using different volume and pressure-limited strategies. In the largest of these trials, the multicentre ARDS-Net study, lung-protective mechanical ventilation was associated with substantial reduction in mortality (31% vs. 40%) and shorter duration of mechanical ventilation. The study randomized 861 patients to either a low tidal volume (6 mL kg−1 PBW, inspiratory plateau pressure, Ppl < 30 cmH2O) or a conventional mechanical ventilation (12 mL kg−1 PBW and Ppl <50 cmH2O) . Amato and colleagues  assessed the effects of a lung-protective ventilation strategy that combined volume and pressure-limited and open-lung approaches. Patients randomized to the conventional study group received Vt of approximately 12 mL kg−1 of measured body weight and PEEP of approximately 8 cmH2O during the first 7 days of mechanical ventilation. Patients randomized to the lung-protective ventilation group received initial tidal volumes of approximately 6 mL kg−1 of measured body weight and PEEP of approximately 15 cmH2O. The incidence of clinical barotrauma (7% vs. 42%), and 28-day mortality (38% vs. 71%) were all significantly decreased in the protective ventilation group . Recently, Villar and colleagues  compared a protective mechanical ventilation strategy defined as the use of low Vt (5-8 mL kg−1 PBW) and the PEEP level set above the lower inflection point of the pressure-volume curve (8.2 ± 3 cmH2O) with a conventional ventilatory protocol, Vt (9-11 mL kg−1 PBW) and PEEP level ≥5 cmH2O . Patients randomized to protective mechanical ventilation had a lower ICU mortality rate and a higher number of ventilator-free days.
However, in the remaining three clinical trials, the volume- and pressure-limited approach was not associated with improved clinical outcomes [29-31]. The differences between Vt settings, plateau pressures and mortality, in both positive and negative trials, are presented in Table 2. The reasons for the apparent discrepancy in the results are not entirely clear but may be related to the absolute differences in Vt and Ppl, the sample size, underlying patient characteristics, the presence of external and intrinsic PEEP and the management of acidosis . It is important to emphasize that ARDS-Net investigators adjusted Vt according to the predicted rather than the actual body weight (ABW) (Fig. 2). Ideally, Vt should be adjusted according to the size of a ‘baby lung' (i.e. functional residual capacity, FRC) . However, routine FRC measurements are not available in clinical practice. PBW is known to correlate better with lung size than the ABW. Adjusting Vt according to ABW may place women and shorter patients at higher risk of VILI .
A recent systematic review of the above-mentioned clinical trials identified the threshold for Vt of <7.7 mL kg−1 PBW and Ppl <30 mmHg to be associated with improved outcomes . These results were confirmed in a recent European multicentre observational study where patients with ALI/ARDS who were ventilated with Vt above those recommended by ARDS-Net trial experienced worse outcome .
Challenges to implementation of low-tidal-volume ventilation in clinical practice
Although there is general agreement about the beneficial effects of low-Vt ventilation, the implementation of this strategy into clinical practice has been delayed. Failure to recognize ALI/ARDS by physicians treating patients on mechanical ventilation is a common problem . Additional barriers include the fear of haemodynamic consequences of hypercapnia and respiratory acidosis, patient-ventilator asynchrony and the fear of an increased need for sedation and neuromuscular blockade. Clinical series have shown that controlled subacute elevation of CO2 is tolerated well and that this technique is relatively benign (‘permissive hypercapnia') [5,38]. The exceptions are patients with increased intracranial pressure who may need increased Vt if adjustment in respiratory rate fails to prevent hypercapnia . In a recent study, permissive hypercapnia was independently associated with improved outcome in patients with ALI/ARDS who were treated with higher Vt (12 mL kg−1 PBW) . This effect however was not present in patients ventilated with low Vt (6 mL kg−1 PBW) .
Cheng and colleagues  examined the effects of Vt selection on supportive therapy in a retrospective analysis of data from the ARDS-Net trial. Compared with 12 mL kg−1 PBW, treatment with a Vt of 6 mL kg−1 PBW had no adverse effect on the need for haemodynamic support. Moreover, there was no difference in the need for sedation or neuromuscular blockade between the two groups. Figure 3 outlines the strategies to improve patient-ventilator synchrony in the setting of low-Vt ventilation .
In a recent study, feedback and education have been shown to improve adherence to lung-protective ventilation strategies .
PEEP and recruitment manoeuvres
PEEP is an essential component of care of many critically ill patients who require ventilatory support. The use of PEEP in patients with ALI/ARDS can help achieve adequate oxygenation and decrease the requirement for high fractions of inspired oxygen. Three mechanisms have been proposed to explain the improvement in gas exchange with PEEP:
- Alveolar recruitment with increased functional residual capacity
- Redistribution of extravascular lung water
- Improved ventilation-perfusion matching.
Moreover, the addition of PEEP has been shown to reduce VILI even in animals ventilated at both high  and low Vt . Computed tomography studies demonstrated PEEP induced recruitment of previously collapsed alveoli and that lung regions recruited with PEEP may not completely collapse at end-expiration . This in turn leads to more even distribution of airway pressures within the lung parenchyma. High PEEP settings (15-20 mmHg) preceded by vital capacity manoeuvres (recruitment manoeuvres: brief periods of increase in end-expiratory pressure to ∼40 mmHg with the intent to recruit collapsed alveolar units) have been recommended as an attractive ventilatory strategy both in patients with ALI/ARDS and in those undergoing general anaesthesia (‘open-lung approach') . In contrast to atelectasis that is a predominant finding in patients undergoing general anaesthesia, patients with ALI/ARDS have heterogeneous changes consisting of oedema and consolidation rather than atelectasis. In these patients, the effects of recruitment manoeuvres may therefore be less beneficial. In fact, ARDS-Net investigators abandoned the use of recruitment manoeuvres after a randomized cross-over study failed to demonstrate more than a short-lived improvement in oxygenation. Not uncommonly, recruitment manoeuvres were complicated by haemodynamic compromise .
While moderate levels of PEEP (8-10 mmHg) have been used by most clinicians and investigators, the benefit from higher levels of PEEP could not be demonstrated in a prospective clinical trial by ARDS-Net investigators . This study was stopped early, due to futility, after enrollment of 549 of 750 patients. Clinical outcomes were similar whether the lower (8 mmHg) or higher (14 mmHg) PEEP levels were used. Of note, the patients randomized to the high PEEP group were significantly older and had lower PaO2/FiO2 ratios. While future clinical trials will inform the practice about optimal PEEP for different patient groups, in clinical practice the settings of PEEP should aim for optimal recruitment and the maintenance of adequate oxygenation, while avoiding alveolar overdistention and haemodynamic compromise.
Pressure-controlled and inverse-ratio ventilation
Pressure-controlled ventilation (PCV) with or without prolonged inspiratory time (inverse-ratio ventilation, IRV) has been commonly used in patients with ALI/ARDS (Fig. 1). PCV is generally perceived to enhance patient ventilator synchrony and lead to more homogeneous distribution of Vt and airway pressure in the injured lungs. However, in a recent study PCV failed to reduce work of breathing in patients with ALI/ARDS . Moreover, during the PCV mode Vt was frequently elevated above the limits of protective ventilatory strategy (6-8 mL kg−1 PBW) .
Since the oxygenation predominantly depends on mean airway pressure (MAP), the increase in MAP by IRV may be an attractive option for improving oxygenation without a dangerous increase in plateau airway pressure. During IRV higher MAP is achieved by prolonging the inspiratory time (I : E, inspiratory-to-expiratory ratio). However, in the absence of significant intrinsic PEEP (‘auto PEEP') inverse IRV does not improve oxygenation, although it may increase CO2 elimination .
While lung-protective ventilation can be provided by both volume- and pressure-preset modes of ventilation, in pressure preset modes the control of Vt is more difficult .
Spontaneous breathing during mechanical ventilation
Ventilatory modes that allow spontaneous breathing (airway pressure release ventilation (APRV) and bi-level ventilation) have been extensively used in some European countries. During APRV, the patient is allowed to breathe spontaneously in between set limits of upper and lower airway pressures. In clinical studies, APRV has been associated with improved patient-ventilator synchrony, improved haemodynamics and better ventilation-perfusion matching (by recruitment of alveolar units above the diaphragm) . The main disadvantage of APRV is the inability to control Vt, potentially allowing for dangerously high elevations of transpulmonary pressure . No large study has compared APRV to lung-protective ventilation.
Some patients with ARDS are unable to achieve adequate oxygenation using conventional lung-protective ventilation, and the mortality rate remains unacceptably high. While high-frequency ventilation (HFV) has been extensively used in neonates with respiratory distress syndrome, its use in adults until recently has been very limited. During HFV, very rapid inspiratory rate (3-10 Hz) may allow for improved gas exchange without applying excessive peak inspiratory pressures, therefore minimizing VILI . High-frequency oscillatory ventilation has been studied in two multicentre randomized trials [52,53]. Derdak and colleagues  randomized 148 patients with ARDS to HFV or to conventional PCV (Vt ∼ 10 mL kg−1 PBW). The use of HFV was associated with a significant improvement in the PaO2/FiO2 ratio with HFV for the first 24 h and a trend towards decreased 30-day mortality (37% for HFV vs. 52% for conventional ventilation, P = 0.102). This finding must be interpreted with caution because the patients in the control group were not ventilated with the current standard of volume and pressure-limited lung-protective ventilation. Bollen and colleagues  conducted a small multicentre randomized controlled trial of HFV vs. conventional ventilation in adults with ARDS. There were no significant differences in efficacy or safety between HFV and conventional ventilation, as early treatment strategies in ARDS.
Observational studies reported reasonable success rates when HFV was used as a rescue measure in patients who failed conventional lung-protective ventilation . Mehta and colleagues  found that, when instituted early, HFV has beneficial effects on oxygenation and ventilation and may be a safe and effective rescue therapy for patients with severe oxygenation failure.
Both animal and human studies have shown that mechanical ventilation in the prone position significantly improves gas exchange. Potential benefits of prone position include improved ventilation-perfusion matching, decreasing shunt flow and more uniform distribution of transpulmonary pressure gradients. Animals ventilated in the prone position demonstrated a lower degree of VILI . Although generally considered to be safe, potential concerns include difficult nursing, pressure sores and the loss of airway or a central venous access during the turn. An early multicentre study in ALI patients demonstrated no overall effect on mortality, although a post hoc analysis suggested benefit in a subgroup of patients with more severe oxygenation impairment . The second large-scale trial  again failed to demonstrate significant mortality benefit. Patients randomized to prone position had a lower incidence of ventilator-associated pneumonia but more frequent airway problems and pressure sores.
Extracorporeal membrane oxygenation
Extracorporeal membrane oxygenation (ECMO), a modification of cardiopulmonary bypass used to eliminate CO2, has been sometimes used as a rescue treatment in infants, children and less commonly adults with severe acute respiratory failure. During the 1970s, a multicentre clinical trial did not demonstrate a benefit of ECMO in adult patients with ARDS . However, over the years, complications associated with the use of ECMO have decreased and several investigators reported reasonable success rates in patients with severe ARDS who failed conventional therapies .
Non-invasive ventilation (NIV) therapy has become an increasingly popular alternative to invasive mechanical ventilation in various forms of acute respiratory failure. While NIV has become a standard of care in patients with exacerbation of chronic obstructive pulmonary disease and cardiogenic pulmonary oedema, its use in patients with ALI/ARDS has been limited. Small studies suggested a benefit in selected patients with underlying immunosuppression, in whom the use of NIV was associated with avoidance of endotracheal intubation and associated infectious complications . A recent observational study reported high failure rate of NIV in patients with ALI/ARDS . In particular, ALI/ARDS patients with shock, metabolic acidosis and severe hypoxaemia are unlikely to benefit from NIV . The use of NIV in patients with ALI/ARDS must therefore be limited to haemodynamically stable patients, who can be closely monitored in an environment where endotracheal intubation is promptly available.
In conclusion, in patients with ALI/ARDS lung-protective ventilation strategies yield better clinical outcomes compared to traditional approaches in which more generous tidal volumes are used. Limiting Vt to ≤6-8 mL kg−1 PBW, with further reductions of Vt if the Ppl is high (>30 cmH2O) has been shown to improve outcomes  and should be considered as a standard of care for the majority of patients with ALI/ARDS. Feedback and education are essential to improve recognition of ALI/ARDS and the adherence to lung-protective ventilation strategies.
This work was supported in part by NHLBI K23 HL78743-01A1 and by Akdeniz University Medical Research Unit, Antalya, Turkey.
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