64 Acute respiratory failure and acute respiratory distress syndrome

Respiratory failure is present whenever the respiratory system fails in the gas exchange function. It is classified as ‘hypoxaemic’ when oxygen tension values are lower than normal, or ‘ventilatory’ when the elimination of CO2 is insufficient. The acute hypoxaemic respiratory failure arising from widespread diffuse injury to the alveolar-capillary membrane is termed acute respiratory distress syndrome (ARDS). ARDS is the clinical and radiographic manifestation of acute pulmonary inflammatory states. The cause may be of either pulmonary or extrapulmonary origin. The generalized inflammatory response process begins with the local production of cytokines by inflammatory cells, epithelial cells, and fibroblasts which increases the alveolar-capillary barrier permeability. The progression of the lung injury has been divided into three phases: exudative, proliferative, and fibrotic. Up to 2011 the definition routinely used to recruit ARDS patients included the sudden onset of acute hypoxaemic respiratory failure (PaO₂/FiO₂ ratio <300), presence of diffuse pulmonary infiltrates that are not caused by hydrostatic pulmonary oedema, and absence of left atrial hypertension. In 2011 a panel of experts developed the so-called “Berlin definition of ARDS”. The new definition specifies an acute time frame of the pathology, removed the term ALI introducing three mutually exclusive subgroups of ARDS according to severity. Moreover, a minimal PEEP/CPAP level has been added, chest radiograph criteria have been clarified and CT scan has been included, the pulmonary artery wedge pressure criterion removed and risk factors have been added. The knowledge of ARDS pathology and mechanisms has been greatly improved by the use of CT analysis, which makes it possible to delineate the ARDS lung appearance, oedema distribution, and superimposed pressure computation, and characterize lung severity and potential for lung recruitment. The primary treatment for ARDS patients is mechanical ventilation, used to buy time while awaiting the resolution of the underlying pathology. Several randomized clinical trials have been conducted to investigate many aspects of the treatment such as the use of the prone position, the setting of ventilation parameters, and fluid resuscitation.

Respiratory failure is defined as an acute or chronic impairment of the function of the respiratory system to maintain normal O₂ and CO₂ values when breathing room air. ‘Oxygenation failure’ occurs when the PaO₂ value is lower than the normal predicted values for age and altitude and may be due to ventillation perfusion mismatch (V/Q) mismatch or low O₂ concentration in the inspired air. In contrast, ‘ventilatory failure’ primarily involves CO₂ elimination, with PaCO₂ >45 mmHg. The most common causes are chronic obstructive pulmonary disease (COPD) exacerbation, asthma, and neuromuscular fatigue, leading to dyspnoea, tachypnoea, tachycardia, the use of the accessory muscles of respiration, and an altered consciousness. History and arterial blood gas (ABG) analysis are the easiest way to assess the nature of acute respiratory failure, and treatment should resolve the baseline pathology. In severe cases, mechanical ventilation is necessary as a ‘buying time’ therapy. The acute hypoxaemic respiratory failure arising from widespread diffuse injury to the alveolar–capillary membrane is termed acute respiratory distress syndrome (ARDS), which is the clinical and radiographic manifestation of acute pulmonary inflammatory states.

A summary of the pathology, causes, mechanisms, and intervention is shown in Table 64.1.

Alveolar hypoxia is characterized by a reduced fraction of O₂ on the alveolar side of the pulmonary units. A low alveolar O₂ concentration may be caused by breathing at a reduced barometric pressure or inhalation of gas mixture with an FiO₂ of <21%. However the most clinically relevant mechanism is a V/Q mismatch. Briefly, perfusion removes a given amount of O₂ per unit of time from the alveolar units, which is granted by alveolar ventilation. This mechanism works properly when the V/Q ratio is near 1. The O₂ provided by ventilation may be computed as:

(where FeO₂ is the expired O₂ concentration, Vo₂ the amount of required O₂, and Va the alveolar ventilation)

The above equation shows that, if ventilation decreases, at a constant O₂ subtraction, the difference between the inspired and expired O₂ fractions must increase by the same percentage. If the FiO₂ is not varied, the Feo₂ decreases, and the alveolar O₂ concentration also decreases. Alveolar hypoxia, however, is simply corrected by increasing the FiO₂

The worst V/Q alteration is called a ‘shunt’, which is defined as the fraction of cardiac output perfusing non-ventilated regions (V/Q = 0) where no gas exchange occurs. A shunt may be either intracardiac or intrapulmonary. An interesting lung model, developed by Riley [1], divides the lung into three ideal compartments, according to the V/Q ratio: (1) ventilated and perfused, (2) perfused, but not ventilated (shunt), and (3) ventilated, but not perfused (dead space). Hypoxaemia due to a shunt can only be partially corrected by supplemental O₂ administration, as it will increase the alveolar PO₂, without affecting the non-ventilated regions. With shunt fractions as high as 30–35%, the PaO₂ will not exceed 100 mmHg, even with an FiO₂ of up to 100%. Correction of hypoxaemia due to a shunt requires either pulmonary blood flow diversion or anatomical modification of the shunt regions. It has been shown that the same collapsed lung fraction corresponds to different hypoxaemia levels in different patients, according to hypoxic vasoconstriction. This means that, at the same PaO₂/FiO₂ ratio, the lung parenchyma may be differently involved in the pathology.

Hypercapnic respiratory failure or ventilatory failure is defined as the inability of the respiratory system to maintain normal levels of PaCO₂ (i.e. PaCO₂ <45 mmHg), due to an impaired excretion of CO_2.. In steady state, the rate of CO₂ production (Vco₂) equals the CO₂ excretion. Moreover:

(where FACO₂ is the alveolar fraction of CO₂, PACO₂ the alveolar PCO₂, BP the barometric pressure, and PH₂O the saturated water vapour pressure).

According to gas laws, it follows that VCO₂ equals:

This simple formula highlights that increased FACO₂, usually associated to decreased alveolar O₂ concentration, is the hallmark of ventilatory failure. In fact, if VA decreases, to maintain a constant CO₂ excretion, FACO₂, i.e. PACO₂ and PaCO₂, must increase by the same proportion.

Minute ventilation (VT) is equal to the sum of VA and dead space ventilation (VD), so by rearranging the previous equation, it follows that:

Therefore, an elevated FACO₂ (and PaCO₂) may result from a combination of the alteration of any of the three variables, i.e. an increased CO₂ production, a decreased tidal ventilation, and an increased dead space.

The PaO₂ and PaCO₂ values obtained by blood gas analysis give immediate information for the diagnosis and determination of the ‘nature’ (oxygenation or ventilatory) of respiratory failure. A challenge test with two different levels of FiO₂ may be useful to assess the primary mechanism of oxygenation failure. In fact, if hypoxaemia is partially corrected by increasing the FiO₂, the origin is alveolar hypoxia; otherwise, if hypoxaemia is only partially corrected, the most likely primary cause is a shunt.

In most clinical cases, pulse oximetry is an adequate surrogate for arterial PaO₂ [2, 3], while end-tidal CO₂ may reflect PaCO₂ [4]. In steady state, arterial PCO₂ is well correlated with venous PCO₂, being 4–5 cmH₂O higher [5]. Consequently, PvCO₂ of >50 mmHg may indicate ventilatory failure [6]. On the other hand, PvO₂ is poorly correlated with PaO₂ and cannot be used a surrogate [5]. This derives from the fact that central venous O₂ saturation (SvO₂), despite being very sensitive, is not specific, as it depends not only on arterial O₂ saturation (changes in respiratory function, SaO₂), but also on a series of variables such as VO₂ (metabolism), cardiac output (CO), oxygen-carrying capacity (haemoglobin concentration, Hb):

A summary of the diagnosis corresponding to different PO₂/PCO₂ combinations is shown in Table 64.2.

Portable chest X-ray (CXR) is one of the simplest examinations used to assess the cardiopulmonary status of patients. Its great advantage is a low exposure to radiation and the possibility to perform the examination at the bedside. CXRs are useful to assess device positions [7], and to detect pulmonary infiltrates, pneumothorax, and pleural effusions. Although the daily CXR has been abandoned [8–11], in critically ill patients, it remains a valid preliminary examination for suspected respiratory failure.

The use of computed tomography (CT) scans allows a complete examination of the lung parenchyma, and quantitative analysis makes it possible to determine the degree of aeration of each lung region [12]. This has led clinicians to recognize clinical problems, such as localized pneumothorax, pleural effusions, and bronchial and tracheal alterations, not shown on X-rays. Moreover, X-rays are not specific for distinguishing generalized inflammatory oedema, while quantitative analysis on CT scans is a much better indicator of it.

Positron emission tomography (PET) has been used in experimental models and in patients to study the pathophysiology and regional lung function of ARDS and ventilator-induced lung injury (VILI). Depending on the technique and on the tracers used, PET can quantify regional perfusion, ventilation, aeration, lung vascular permeability, edema, inflammatory cell and enzyme activity and pulmonary gene expression [142].

Lung ultrasound has been suggested as a bedside tool to assess the state of aeration and ventilation of the lung, the presence of heterogeneity, and the temporal evolution of pathologies. It can be a valid alternative to CXRs, as it is cheap, free from radiation, and, after appropriate training, accurate and repeatable. Moreover, assessing multiple images from different perspectives allows a 3D reconstruction, filling the gap between X-rays and CT scans, without the disadvantage of patient transport [13].

Electric impedance tomography (EIT) technique does not provide morphological information but images representing regions changing cyclically lung impedance. This technique has been studied to evaluate regional lung ventilation [140] as the lung impedance is closely related to the degree of parenchymal inflation. In ARDS patients, EIT monitors lung heterogeneities, the effects of ventilatory maneuvers and the physiological effects of PEEP and tidal volume.

A comprehensive review of the imaging techniques may be found elsewhere [139].

The haemodynamic status of the patient has to be carefully assessed to understand the nature of respiratory failure. Cardiac output and pulmonary wedge pressure may provide important information for the diagnosis (e.g. PE, cardiac failure, etc.). Pulmonary pressure measurement is useful in patients with chronic respiratory failure to evaluate possible cardiogenic components of the pathology.

Pulmonary artery catheters (PACs) or central venous catheters (CVCs) allow precise monitoring of the volaemic status, cardiac function, and the haemodynamic effects of mechanical ventilation. Central venous saturation (SvO₂) is an optimal index of the adequacy of O₂ transport [14, 15]. Normal SvO₂ values are between 68 and 77% [16]; values <65% indicate possible cardiovascular problems, while values <50% are associated with metabolic acidosis [17]. It should be remembered that PACs and CVCs give slightly different values of O₂ saturation, due to the different positioning [18]. Moreover, abnormally low saturation values should be checked, as they may possibly be due to sources of error.

Bedside echocardiography has become useful for the management of critically ill patients and as a non-invasive diagnostic and monitoring tool for circulatory and respiratory failure. First described by Edler et al. in 1954, it has been introduced in the 80s in the ICUs for haemodynamic evaluations and visualization. Trans thoracic echocardiogram (TTE) is usually applied as a basic tool to perform a quick assessment of the heart status, while transoesophageal echocardiography (TOE) is an advanced semi-invasive procedure applied in mechanically ventilated patients with ARDS or septic shock [19]. The use of TOE has also been validated in ARDS patients in the prone position [20]. Echocardiography allows the assessment of fluid responsiveness, with parameters indicating the heart–lung interaction and the haemodynamic management in septic shock. Moreover, it is a useful tool for adapting the ventilatory parameters to the RV function to reduce overload [21].

The treatment of respiratory failure includes therapies, with three different targets, namely:

The three kinds of therapy are not mutually exclusive, but they should be delivered together to obtain the best result. Particular attention should be paid to the treatments devoted to correct symptoms, as they allow the buying of time, while awaiting resolution of the underlying pathology. The choice of the appropriate treatment should evaluate the mechanism causing the symptoms. A summary of the treatments is shown in Table 64.1. For example, hypoxaemia due to alveolar hypoxia may be corrected by a moderate increase in the FiO_2.. On the other hand, the resolution of hypoxaemia due to a shunt implies a series of considerations, including: the individual potential for lung recruitment, the optimum level of positive end expiratory pressure (PEEP), and the best way to ventilate the patient. These aspects will be discussed in detail in the next section on the treatment of ARDS.

The original description of ARDS was published in 1967 by Ashbaugh and colleagues in a cornerstone paper in The Lancet [22]. The authors outlined the characteristics and clinical course of 12 patients treated for respiratory failure who did not respond to usual therapeutic modalities. ‘The clinical pattern… includes severe dyspnoea, tachypnoea, cyanosis that is refractory to oxygen therapy, loss of lung compliance, and a diffuse alveolar infiltrate seen on chest X-ray’. Seven patients died, and, at autopsy, the authors found that ‘At necropsy in seven patients, gross inspection showed heavy and deep reddish-purple lungs… the appearance resembled liver tissue’. In 1971, after a conference at the National Academy of Sciences in the US, the same authors coined the name ‘adult respiratory distress syndrome’ [23].

Over the years, there have been several revisions of the ARDS criteria in order to define an operative definition. In 1982, Pepe et al. introduced the non-cardiogenic origin of pulmonary oedema in the definition [24]. Up till 1988, no major revision was introduced, and the only variations to the ARDS definition revolved around a combination of the presence of hypoxaemia (PaO₂, FiO₂), radiographic infiltrates, low compliance, and wedge pressure [25–27]. In 1988, Murray [28] proposed an approach based on the ‘lung injury score’ (LIS) to quantify the lung damage. The score system takes into account the different components and the different degrees of their abnormality:

Three levels in severity of lung injury were defined: (1) the absence of lung injury (LIS = 0); (2) mild to moderate lung injury (LIS = 0.1–2.5); and (3) severe lung injury (ARDS) (LIS >2.5).

In 1994, the American European Consensus Conference (AEEC) developed a definition which has been routinely used for years in the enrolment of ARDS patients into clinical and epidemiological studies [29] and which has been revised only recently. According to this definition, ARDS is characterized by the sudden onset of acute hypoxaemic respiratory failure, diffuse pulmonary infiltrates that are not caused by hydrostatic pulmonary oedema, and the absence of LA hypertension (when measured, the pulmonary artery wedge pressure must be <18 mmHg). The definition is also based on the degree of hypoxaemia, defined by a PaO₂/FiO₂ ratio cut-point of 300; a ratio between 200 and 300 indicates ALI, while a ratio lower than 300 indicates ARDS. The AEEC conference recommended that the syndrome be called ‘acute’, rather than ‘adult’, respiratory distress syndrome. Although this definition provided a standard way of selecting patients, it is not without its limitations, such as the high variability of CXR interpretation [30], the problematic exclusion of the cardiogenic origin of pulmonary oedema [31], and the alteration of oxygenation by PEEP manipulation. Studies showed that over half of patients initially classified as ARDS did not meet the criteria after 30 min of ventilation with a standardized PEEP [32]. Even at autopsy, the AEEC definition demonstrated a low accuracy [32]. Gattinoni et al., in a study on 68 ALI/ARDS patients enrolled according to the AEEC definition, found that lung collapse, the amount of lung oedema, and the potential for lung recruitment (defined as the percentage of tissue regaining aeration from 5 cmH₂O PEEP to 45 cmH₂O end-inspiratory plateau pressure) have wide distributions [33]. Moreover the authors found that the higher the alveolar collapse is, the higher the potential for lung recruitment, with a distribution from nearly 0 to 65% of the lung weight. Furthermore, the results showed that higher percentage of recruitment indicated higher severity, severe hypoxaemia, and higher amount of oedema. The results highlight that the ARDS definition should consider the amount of lung tissue involved in the pathology, as indicated by the amount of pulmonary oedema. Moreover, ARDS should be diagnosed in those patients with extended pulmonary oedema, high potential for lung recruitment, a positive response to PEEP, or in pronation. Unfortunately, at the moment, the only technique available to estimate lung recruitment is the quantitative analysis of CT scan images of the lung. After 18 years, in 2011, a panel of experts, under the initiative of the European Society of Intensive Care Medicine, endorsed by the American Thoracic Society and Society of Critical Care Medicine, convened to develop what has been called the ‘Berlin definition’ [34, 35]. The panel highlighted the issues that emerged on the AECC definition criteria. The new definition specifies an acute time frame of the pathology. To eliminate the mispresentation of PaO₂/FiO₂ limits and the confusion between ALI and ARDS, three mutually exclusive subgroups of ARDS, according to the severity from the PaO₂/FiO₂ ratio, were defined, and the ALI term was removed. The three subgroups are: mild (200 < PaO₂/FiO₂ ≤ 300 mmHg, with PEEP or CPAP ≥5 cmH₂O), moderate (100 <PaO₂/FiO₂ ≤ 200 mmHg, with PEEP ≥5 cmH₂O), and severe (PaO₂/FiO₂ ≤100, with PEEP ≥5 cmH₂O). A minimal PEEP/continuous positive airway pressure (CPAP) level has been added across the subgroups to correct for the sensitivity of PaO₂/FiO₂ to different ventilator settings. Moreover, chest radiograph criteria have been clarified, and the CT scan has been included. The pulmonary artery wedge pressure criterion has been removed, and risk factors have been added. The final definition is shown in Table 64.3.

Many heterogeneous diseases, either direct or indirect lung injuries, have been reported as potential risk factors for ARDS (see Table 64.4).

The major incidence of ARDS is linked to pneumonia, aspiration, sepsis, and trauma. However, a series of biological variables emerged as potential risk factors for mortality, such as age, African-American ethnicity, and male gender. Sepsis and trauma are linked to a greater mortality, and the number of non-pulmonary organ failures, increased illness severity, shock, and hepatic failure are independent risk factors for mortality, while the degree of hypoxaemia is not [36].

ARDS has always been considered a rare pathology. It is quite difficult to identify a specific incidence of the phenomenon, which is related to geography and the definition used. The first epidemiological report, published in 1972 by the National Heart and Lung Institute Task Force on Respiratory Diseases [37], estimated an incidence of 150 000 cases per year (75 cases/100 000 population per year) in the US. Other studies, however, published in the 80s and 90s, reported an incidence of between 1.5 and 8.3 case/100 000 population [27, 38–41]. Further studies reported an incidence of 17.9 cases/100 000 population in Scandinavia [42], 34 in Australia [43], and 78.9 in the US [44]. The last report from Rubenfeld et al. reported a considerably higher incidence, at least in the US. The reliability of these data, however, is granted by the rigorous method of patient selection and by the particular geographical configuration of King County, which suggests that the majority of the inhabitants in need of care were treated at the study hospital. Villar et al reported that, on the basis of the literature published in 2014-5, the incidence and overall hospital mortality of ARDS has not changed substantially in the last decade. Moreover, the reported incidence of ARDS is an order of magnitude lower in Europe than in the USA, independently of the definition used for the diagnosis (Villar J, 2016). Bellani et al. evaluated incidence and outcome of ARDS in ICU in a large international cohort from 50 countries. ARDS represented 10.4% (95% CI, 10.0%-10.7%) of total ICU admissions and 23.4% (95% CI, 21.7%-25.2%) of all patients requiring mechanical ventilation and constituted 0.42 cases/ICU bed over 4 weeks. There was some geographic variation, with Europe having an incidence of 0.48 cases/ICU bed over 4 weeks; North America, 0.46; South America, 0.31; Asia, 0.27; Africa, 0.32; and Oceania, 0.57 cases/ICU bed per 4 weeks. ARDS was underdiagnosed, with 60.2% of all patients with ARDS being clinician-recognized. Clinician recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) for mild ARDS to 78.5% (95% CI, 74.8%-81.8%) for severe ARDS. Clinician recognition of ARDS at the time of fulfillment of ARDS criteria was 34.0% (95% CI, 32.0-36.0), suggesting that diagnosis of ARDS was frequently delayed (Bellani, 2016).

According to mortality data, it is important to remember that, in the initial description, seven of 12 patients died [22]. Despite nearly three decades of progress, the mortality rates reported in the 80s and 90s were similar, ranging between 40% and 70% [27, 38, 39, 41]. Recent studies and a meta-analysis, however, reported a decline in the mortality rate (29–40%) [44–46]. Li et al. [47] observed a reduction of mortality from 2001 to 2009 and a reduced incidence in patients with hospital-acquired ARDS, because the incidence of ARDS on hospital admission remained stable over the study period. An explanation for these results may be that there is better general care for critically ill patients as well as improved mechanical ventilation [45, 47]. Cortes et al., however, pointed out that the mortality reduction is a controversial result, as it is partially influenced by randomized clinical trials, in which only selected patients are included [48], and a review from Phua et al. [49] reported that mortality has remained stable since the AECC definition, at 44% from observational studies and 34.2% from randomized trials. Villar et al reported that current hospital mortality of combined moderate and severe ARDS reported in observational studies is greater than 40% (Villar J, 2016). Bellani et al reported that unadjusted ICU and hospital mortality from ARDS were 35.3% and 40%, respectively [142].

Most patients appear to die with acute lung injury (ALI) or from complications of their underlying risk factor, as opposed to dying from unsupportable hypoxaemic respiratory failure [43]. In follow-up studies of ARDS survivors, long-term mortality has been reported to range between 11 and 60%, not dependent on the severity of ARDS but mainly on age and comorbidities (Chiumello, 2017). The combination of declining short-term mortality, associated with the incidence, suggests that caring of ALI survivors will be an increasingly important problem in the future. In fact, although patients who survived ARDS show mild radiological pulmonary abnormalities and a recovery of pulmonary function, data suggest that there is a significant increase of long-term exercise limitations, neuromuscular, cognitive, and neurophysiological dysfunction in survivors of ALI/ARDS [50, 51], leading to possible post-traumatic stress disorders [52].

ARDS is the clinical and radiographic manifestation of acute pulmonary inflammatory states. The noxious stimulus, either of pulmonary or extrapulmonary origin, causes a generalized inflammatory response involving the whole lung. The process begins with the local production of cytokines by inflammatory cells, epithelial cells, and fibroblasts, which increases the alveolar–capillary barrier permeability. The progression of the lung injury has been divided into three phases: (1) exudative, (2) proliferative, and (3) fibrotic. The exudative phase of the pathology consists of the progression of injury to the interstitium and alveolar spaces, to which inflammatory cells and proteins migrate. Protein-rich fluid enters the alveolar spaces, with the formation of hyaline membranes. The generalized inflammation of lung parenchyma leads to pulmonary oedema formation of non-cardiogenic origin, which causes alveolar collapse. This phase can rapidly resolve, or it can last as long as 5–7 days up to fibrosis development. The proliferative or regenerative phase is characterized by a gradual reduction of the inflammatory process and the proliferation of type II pneumocytes in the reparative process. In this phase, the interstitium remains oedematous, and inflammatory cells are still present. The third phase (fibrotic) is characterized by dense deposition of collagen in the interstitial spaces and in the alveolar spaces of collapsed alveoli.

The CT scan images of the lung during the early phase of ARDS are characterized by three vertically distributed compartments: the non-dependent regions, which are usually normally aerated; the middle lung, characterized by ground glass opacification, and the almost consolidated dependent regions [12]. According to the descriptors proposed by the Fleischner Society Nomenclature Committee [53], ‘ground glass opacification’ means an ‘increase in lung attenuation, with preservation of bronchial and vascular margins’, while ‘consolidation’ means a ‘homogeneous increase in lung attenuation that obscures bronchovascular margins in which an air bronchogram may be present’. Ground glass opacification reflects an active inflammatory process, involving the interstitium, filling of the alveolar space, and oedema, which corresponds to poorly aerated tissue. Consolidation refers to the lung parenchyma being completely, or almost completely, airless, due to either a complete filling of the alveolar spaces or the total collapse of potentially recruitable pulmonary units (atelectasis). On quantitative analysis, it corresponds to the non-aerated tissue. The late phase of ARDS is characterized by decreased densities and the presence of fibrosis, with distortion of bronchovascular markings, subpleural cysts, or bullae. Patients surviving ARDS present, at follow-up, a reticular pattern, principally in the non-dependent lung regions [12].

The quantitative assessment of CT scan images [12, 54] demonstrates that the amount of normally aerated tissue of the ARDS lung has the same order of magnitude as that of a 5- or 6-year-old child. This amount has been found to correlate with the respiratory system compliance, indicating that the ARDS lung is small and not stiff (the ‘baby lung’ concept) [55, 56]. The ‘baby lung’, however, is not an anatomical entity located in the non-dependent regions; in fact, on turning the patient into a prone position, the densities were redistributed in the dependent lung regions [57]. On regional analysis, by dividing the lung into ten levels, along the sternovertebral axis, it has been found that, at each level, the mass is almost doubled, compared to the normal values, suggesting an even distribution of lung oedema throughout the lung parenchyma [58]. The non-gravitational distribution of lung oedema apparently contrasts with the gravitational distribution of densities. However, the increased weight, due to oedema accumulation, raises the hydrostatic pressure transmitted throughout the lung, reducing the TPP (i.e. the distending force of the lung) and squeezing out the gas from the lung parenchyma. Hence, the loss of alveolar gas results from compressive gravitational forces, including the weight of the heart, and is not as a result of an increase in the amount of oedema [12]. This phenomenon accounts for the mechanism of PEEP; a PEEP level higher than the superimposed pressure is necessary to keep open the most dependent lung regions. These findings led to the development of the ARDS model: the sponge model [59]. Accordingly, the ALI/ARDS lung increases its own permeability in each region, with an even distribution of oedema, and the increased lung mass causes lung collapse under its own weight. However, there are also both craniocaudal and sternovertebral gradients, which account for the weight of the heart and the abdominal pressure.

The amount of non-aerated tissue, measured on CT scan analysis, correlates well with hypoxaemia and shunt fraction, indicating that hypoxaemia in the case of ARDS is primarily due to shunt. Although the relationship between non-aerated tissue and hypoxaemia is straightforward, the relationship between hypoxaemia and poorly aerated tissue (ground glass opacification) is still not known. Taken together, the amount of poorly aerated and non-aerated tissue relates to hypoxaemia, while that of poorly aerated tissue alone does not [12]. The CT scan, in fact, does not provide information on the degree of perfusion or on ventilation (as it is a fixed image of the ventilatory status), so it is not known at which degree the compartment is capable of oxygenating blood. The same also holds true for the normally aerated tissue. In fact, if these regions are overdistended, they exchange O₂ well but do not exchange CO₂. Despite these limitations, the re-expansion of non-aerated regions is usually associated with increased oxygenation [60].

The quantitative analysis of CT scan images provides several other pieces of information, which are important in understanding the ARDS pathophysiology [33]. As an example, the severity of the overall lung injury may be expressed as the ratio of non-aerated lung tissue weight to total lung weight at end-expiration (5 cmH₂O PEEP). This index includes both consolidation and collapsed tissue which can regain aeration. Another important index is the potential for lung recruitment, which is, as described previously, the ratio of the amount of lung tissue which regains aeration from 5 cmH₂O PEEP to 45 cmH₂O airway plateau pressure at end-inspiration to the total lung weight at 5 cmH₂O PEEP (see Figure 64.1). In a population of 68 ALI/ARDS patients, Gattinoni et al. found that both the amount of non-aerated tissue and the potential for lung recruitment are highly variable in ALI/ARDS patients, ranging from 5% to 70% and from nearly 0 to >50%, respectively [33]. The PEEP response to lung recruitment depends on the amount of potential for lung recruitment: the higher the potential for lung recruitment, the higher the lung portion that remains aerated, increasing the PEEP level from 5 to 15 cmH₂O. It has also been found that increasing PEEP from 5 to 15 cmH₂O keeps open a portion of lung tissue nearly equal to 50% of the maximal potential for lung recruitment [33]. Up till recent years, patients with a high percentage of recruitable lung were considered less severe than those that, for the same degree of lung damage, had a lower percentage of lung recruitment. In fact, Gattinoni et al. found that patients with higher percentages of potential for lung recruitment had a worse gas exchange, respiratory mechanics, and a higher mortality rate [33]. A high potential for lung recruitment, in fact, is correlated with the initial lung damage, defined as non-aerated tissue. This is easily understandable, considering that less severe patients have a nearly completely aerated lung and a minimal percentage of potential recruitment; on the other hand, patients with higher amounts of lung oedema have higher percentages of potential recruitment. As previously described, non-aerated lung tissue includes both consolidated tissue (non-recruitable) and lung collapse (recruitable). The former represents the initial nucleus of the pathology, while the latter represents the inflammatory response in the adjacent lung tissue and oedema. Lung collapse is due to gravity effects, i.e. the lung weight. In the study by Gattinoni et al., lung consolidation was nearly constant in all patients, amounting to 25% of the total lung weight. Patients with a higher potential for lung recruitment have, however, higher amounts of collapsed tissue. These results give an explanation also for the PEEP effect on the cyclic opening and closing during tidal ventilation. Patients with less potential for lung recruitment have less benefit from high PEEP levels, or even more damage due to overdistension. On the other hand, the application of high PEEP levels in patients with high potential for lung recruitment should recruit the collapsed tissue at end-expiration, avoiding cycling opening and closing. Caironi et al. estimated the alveolar strain and cyclic opening and closing in 68 ALI/ARDS patients and found that, in patients with a higher percentage of potentially recruitable lung, the opening and closing of lung tissue was reduced by increased PEEP, whereas no differences were observed in patients with a lower percentage of potentially recruitable lung. Moreover, opening and closing lung tissue appeared to be an independent risk factor for death. In contrast, alveolar strain—defined as the ratio of end-inspiratory lung volume variation above the estimated volume at 0 cmH₂O airway pressure (due to both Vt and PEEP application) to the lung resting volume at 0 cmH₂O airway pressure (FRC)—similarly increased in the two groups [61]. Cressoni et al. reported data on opening pressure necessary for lung opening. Accordingly, in moderate and mild ARDS, the recruitment is almost nearly completely accomplished at plateau pressure of 30 cmH₂O while, in severe ARDS, at the same pressure almost 30% of the recruitable lung remains closed. Most interestingly, Cressoni found that at 15 cmH₂O PEEP, a consistent fraction of lung still underwent opening and closing phenomenon [138].

To date, CT scan analysis is the only reliable method to measure the potential for lung recruitment at the bedside. Different combinations of physiological variables have been tested. The best results have been obtained on combining PaO₂/FiO₂ <150 mmHg (at 5 cmH₂O PEEP), increase of lung compliance, and decrease of dead space from 5 to 15 cmH₂O PEEP (sensitivity 79%, specificity 81%). It is worth reminding that respiratory variables measure the functional recruitment of lung tissue (i.e. the lung compartments participating in gas exchange), while CT scan data represent the anatomical recruitment.

CT scan analysis allows the regional measurement of lung strain. Strain is defined as the deformation of lung tissue (tidal volume to functional residual capacity (FRC) ratio) due to the application of transpulmonary pressure. The reactive force rising in the tissue is called stress. Lung homogeneity is evaluated by the measurement of strain difference between contiguous structures. In a homogeneous material, an applied force should cause the same strain in each one of its part. In contrast, if the strain is different in different voxels, we may infer that the forces acting locally, and the resulting local stress, are also proportionally different. Cressoni et al. found, with the CT scan, that locally the stress may be near twofold the applied pressure [138]. The ammount of voxels in which this phenomenon may occur (called “stress risers”) increases with ARDS severity, while higher PEEP levels may decrease this phenomenon.

Mechanical ventilation is an important ‘buying time’ manoeuvre in the treatment of ALI/ARDS patients. Over the years, modalities and techniques have been sensibly modified to provide ventilatory support, thus improving oxygenation, while avoiding augmentation of the existing lung damage. In the 70s, ALI/ARDS patients were ventilated with high V_T and low PEEP levels [62]. Lung damages due to mechanical ventilation were not known at that time, and the only concerns were high inspiratory O₂ concentrations and haemodynamics. Clinical and experimental studies led to the development of barotrauma [63–66], i.e. lung damages due to excessive strain, and even rupture, caused by high ventilating pressures. Suter et al. [67] published in 1975 the first study combining PEEP, respiratory mechanics, gas exchange, and haemodynamics. In the following years, the concept of volutrauma, which is overdistension due to high V_T, was developed from the work of Dreyfuss and colleagues [68–70]. As previously discussed, in the 80s, the use of CT scan in the management of ALI/ARDS patients was a cornerstone in understanding new aspects of the pathophysiology of the syndrome [71, 72], leading to the baby lung concept and its evolutions [55, 56]. The next step in the ALI/ARDS history was the use of extracorporeal CO₂ removal to prevent damages caused by mechanical ventilation in lungs with extremely small aerated compartments [73, 74]. The goal of mechanical ventilation progressively shifted to the improvement of gas exchange to avoid lung damage. Stemming from the mechanical ventilation strategy in patients with status asthmaticus [75], the concept of permissive hypercapnia was applied to ARDS by Hickling et al. [76]. Accordingly, it consists of ventilating the lung open to ventilation with a small V_T, even at the cost of an increased PaCO₂. Several other studies have been conducted on this topic. Another mechanism that could potentially damage the lung is the cycling opening and closing of the alveoli (termed atelectrauma). Moreover, alveolar overdistension may give rise to a systemic inflammatory response (biotrauma) [66]. Recently the concept of ergotrauma has been introduced [146]. In a series of experiments on healthy pigs, Cressoni et al found that a strain considered lethal (i.e. greater than 2) was only fatal when delivered at 15 breaths per minute, not at rates of 3 to 6 bpm. In addition, the tidal strain was more related to injury than the static strain [138]). Given these data, it can be concluded that the cause of VILI could be described as a single physical entity which combines volume, pressures, flow and respiratory rate, the mechanical power.

Noninvasive support is considered for mild ARDS patients, however, it can be extended to selected moderate ARDS patients (i.e. in cognizant younger patients, patients with a Simplified Acute Physiology Score (SAPS II) < 34, patients with ARDS not caused by pneumonia). Patients undergoing noninvasive support should be closely monitored and invasive mechanical ventilation should be started immediately if gas exchange and respiratory rate do not improve within a few hours. Suggested markers for intubation are excessive transpulmonary pressure swings, a rapid shallow breathing index higher than 105 breaths/min/L, monitored tidal volumes persistently > 9.5 ml/kg predicted body weight. Delayed intubation is associated with increased mortality in patients with acute respiratory failure [152].

Continuous positive airway pressure (CPAP) delivered by facial mask has been associated with an early improvement of oxygenation but it was not associated with the reduction of intubation need or improved outcome. In a recent trial, the intubation rate was significantly lower with high flow nasal cannula (HFNC) oxygen compared to standard oxygen or NIV among patients with PaO₂/FiO₂ ≤ 200 mmHg at enrollment. In the overall population, (patients with PaO₂/FiO₂ ≤ 300 mmHg), patients managed with HFNC had improved survival. No differences in outcomes between NIV and standard oxygen (Frat JP, 2015). HFNC can generate low levels of PEEP in the upper airways, decrease work of breathing and reduce dead space. It is an attractive technique as a first-line therapy to avoid intubation but the results need confirmation (Mauri T, 2017).

The setting of ventilator parameters involves the respiratory rate, V_T, I:E ratio, and pressure.

Concerning the I:E ratio, there is no evidence that ratios other than 1 may be useful in ALI/ARDS patients. Inverse ratio ventilation was advocated in the past as a tool to improve mechanical ventilation effects in ARDS [77–80]. Studies showed an improved arterial oxygenation at the cost of an increased mean airway pressure, intrinsic PEEP, and a decreased cardiac output [81]. In ALI/ARDS, extreme forms of manipulating the I:E ratio are not recommended; values between 0.5 and 1.5 are acceptable.

Modern ventilators provide a wide range of respiratory frequencies, from nearly 0 to 2000–3000 breaths/min. Each of the respiratory cycles may be considered as a ‘stress cycle’. Increasing the number of stress cycles may increase lung damage. Animal studies on isolated lung demonstrated that low rates reduce oedema formation [82]. On the other hand, during spontaneous breathing, high respiratory rates increase oedema formation [83]. Protti et al. ventilated 20 pigs for 54 hours at a global strain of 2.5, either entirely dynamic, partly dynamic and partly static, or mainly static. They found that all animals ventilated with an entirely dynamic strain developed pulmonary oedema, whereas none of those ventilated with mainly static strain did. Animals ventilated with intermediate combinations finally had normal or largely increased lung weights [84].

The HFOV has been proposed as an alternative technique to provide mechanical ventilation, using low V_T and very high mean airway pressure, thus improving oxygenation and minimizing inspiratory overdistension and end-expiratory lung collapse [85]. However, experimental models did not find gas exchange and lung mechanic differences, using 15, 120, and 1000 breaths/min [86]. A meta-analysis on six RCTs, comparing HFOV to mechanical ventilation, suggested a survival benefit at 30 days [87]. Two recent trials the OSCILLATE and OSCAR trials did not show survival benefits. The OSCILLATE trial was stopped due to increased in-hospital mortality and found that, in adults with moderate to severe ARDS, early application of HFOV, compared with a ventilation strategy of low V_T and high PEEP, does not reduce, and may increase, in-hospital mortality [88]. The OSCAR trial concluded that the use of HFOV had no significant effect on 30-day mortality in patients undergoing mechanical ventilation for ARDS [89]. The accompanying editorial of the two trials suggests that ‘for now clinicians should be cautious about applying HFOV routinely in patients with ARDS’ [90]. A recent meta-analysis suggested that HFOV may be of potential advantage in very severe ARDS patients (PaO₂/FiO₂ < 70 mmHg) (Meade, 2017).

V_T and inspiratory pressure need particular attention, as, in recent years, they have been extensively studied. The scientific community agrees on the use of a low V_T, as it provides less injury to the lung; the debate is still open, however, on an adequate PEEP setting.

In clinical practice, V_T is normalized on the patient’s predicted body weight (PBW) from the patient’s height (V_T/PBW) to avoid excessive strain on the lung parenchyma. Several clinical studies analyzed the effects of lower vs higher values of V_T/PBW. The ARDS Network tested 6 mL/kg PBW vs 12 mL/kg PBW, finding a significant mortality reduction in the low V_T group (31% vs 40%) [91]. On the other hand, other studies did not find any significant mortality reduction [92–94]. These studies, however, tested intermediate V_T values in the 6–12 mL/kg range. Amato and colleagues [95] tested two different ventilator strategies, one characterized by low V_T/PBW (<6 mL/kg) and high PEEP level, and the other with high V_T/PBW (12 mL/kg) and low PEEP. The authors found a significant mortality reduction in the low V_T/high PEEP group (38% vs 71%). In this study, however, it was not possible to differentiate the effect of V_T from the effect of PEEP, and the mortality value in the high V_T/low PEEP group was unusually high. As previously mentioned, low V_T ventilation has been widely accepted by the scientific community. However, we have to say that normalizing V_T to the PBW is not a precise surrogate for the strain to which the lung parenchyma is subjected. In fact, we have to remember that, according to the severity, the percentage of the lung open to ventilation in ALI/ARDS patients is highly variable, so the same V_T can be either safe or dangerous. The most correct way to normalize V_T is with respect to the end-expiratory lung volume (FRC) [96].

Therefore, it was recently suggested that tidal volume should be scaled to compliance using the driving pressure (∆P = Pplat – PEEP). Indeed driving pressure is the ratio of tidal volume to compliance, the latter indicating the “functional” size of the lung (Amato, 2015. Driving pressure predicts outcomes better than any other ventilatory parameters in patients with ARDS, with values exceeding 15 cmH₂O of particular concern (Chiumello, 2016).

Driving pressure is just one of the causes of VILI which are included in the computation mechanical power. As previously told, the cause of VILI could be described as a single physical entity (i.e., the mechanical power), which combines volume, pressures, flow and respiratory rate [153].

The maximal value for airway pressure (P_AW) proposed is 30 cmH₂O [97]. This value has been successively modified in a post hoc analysis by the ARDS Network, as even lower values may cause lung damage [98]. Even airway pressure, as described for V_T /PBW, is not a good surrogate for lung stress, as the real distending force of the lung is the transpulmonary pressure (P_L). The same P_AW, in fact, is associated with a wide range of P_L, due to different ratios of the lung elastance (E_L) to the respiratory system elastance (E_RS):

where E_L is the P_L variation associated with a volume variation of 1 L, as determined by:

and E_RS is the P_AW variation associated with a volume variation of 1 L, as determined by:

It is still not clear what the best way is to set an adequate PEEP level. Several methods have been proposed, according to lung mechanics, pressure–volume curve, and hysteresis. The ARDS Network randomized trial in an unselected ALI/ARDS population did not find a significant mortality reduction, and it has been stopped for futility [93]. Three other recent trials (LOV [99], ExPress study [100], and the study by Ranieri et al. [101]) tested low vs high PEEP levels in unselected ALI/ARDS population and did not find mortality differences. On the other hand, Villar et al. [102] found a significant mortality difference in a severe ARDS population. The authors enrolled only patients who still had severe ARDS criteria after 24 hours. Even the previously described study of Amato et al. [95] found improved survival in the high PEEP group, but, as for V_T/PBW, it is not possible to discriminate the PEEP effect. The analysis conducted by Gattinoni et al. [103], discussed in the editorial accompanying the LOV and ExPress publications, evaluated the number of severe patients included in the trials. In the LOV trials, the most severe patients were characterized by a PaO₂ <60 mmHg and an FiO₂ of 100%; in the ExPress trial, severe patients were defined according to a PaO₂ <55 mmHg, an SaO₂ <88%, and an FiO₂ >80% for at least 1 hour. Taken together, the severe patients enrolled in the two studies were 94 (10.9%) in the high PEEP group, and 184 (20.7%) in the low PEEP group. As the overall mortality was not different (60.6% vs 58.2%, respectively), the different percentages of severe patients suggests that the mortality rate in the high PEEP group is lower than that in the low PEEP group (6.6% vs 12%, respectively). It sounds reasonable that high PEEP is effective in the most severe patients, characterized by smaller baby lung and a high percentage of potential for lung recruitment. In the other patients, high PEEP levels may not only be ineffective, but can also overstretch the lung parenchyma. This can also explain the results of the clinical trials; the positive effects on the most severe patients may be cancelled by the nil or negative effects on the less severe ones. In fact, two meta-analyses seem to confirm this hypothesis. The meta-analysis by Phoenix et al. [104] showed a trend towards an improved survival in the high PEEP group, with no evidence of an increase in barotrauma. The other meta-analysis by Briel et al. [105] on the largest three trials reported no treatment effect on hospital survival between higher and lower PEEP groups, while a significantly improved survival was found in patients with ARDS defined as PaO₂/FiO₂ of ≤200. In contrast, in patients with mild and moderate ARDS, higher PEEP seemed harmful. This suggests that correct patient characterization is needed before tailoring mechanical ventilation [103]. PEEP selection criteria may include lung recruitability, end-expiratory transpulmonary pressure, respiratory system compliance and driving pressure. The open lung approach performed by aggressive recruitment maneuvers followed by PEEP selection according to the compliance changes measured during the deflation has been recently tested in a large randomized trial (Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, 2017). To surprise of many, the mortality rate was significantly lower in the control where the PEEP was selected according to NIH table than in the patients treated according to the open lung approach. These results cast serious doubts on the application of high PEEP level. Moreover, they may contribute to explain the HFOV trial failure, where the PEEP applied was closed to the pressure needed to reach total lung capacity (i.e. higher than 30 cmH₂O).

The prone position is suggested for ALI/ARDS patients, in whom mechanical ventilation has potentially injurious effects. Since its first description in 1976 [106], the beneficial effect on oxygenation provided by the prone position has been proven, and other physiological mechanisms have been postulated: the improvement of V/Q mismatch, the recruitment of the most dependent areas, shunt reduction, and less lung compression by the heart. Moreover, extensive laboratory work [107, 108] has proven that prone positioning is able to prevent or delay the development of ventilator-induced lung injury, probably because of a more homogeneous distribution of lung stress and strain. Mancebo et al. [109], in a study in which the prone position was prolonged for 20 hours, found a significant trend towards increased survival. The authors concluded that: ’Prone ventilation is feasible and safe, and may reduce mortality in patients with severe ARDS when it is initiated early and applied for most of the day’. A subgroup analysis of the Italian randomized trial suggested that the prone position may have beneficial effects in the most severe patients [110]. In a meta-analysis, the subgroup analysis on the most severe ALI/ARDS patients (PaO₂/FiO₂ <100 mmHg) showed a significant reduction in mortality in the prone group, but not in patients with PaO₂/FiO₂ >100 mmHg [111]. Similar results were obtained in a pooled analysis of the four largest databases on the prone position, in which a 10% reduction of mortality was found in the most severe ARDS patients. On the other hand, the prone position in patients with moderate ARDS may be useless or even harmful. This suggests that the prone position is beneficial in the most severe patients, while the lack of benefit in moderately hypoxaemic patients makes unacceptable the risk of complications that result from the long-term use of prone positioning. A recent clinical RCT by Guerin et al. tested the effects of prone positioning on mortality in patients with severe and persistent ARDS [112]. The criteria for the enrolment included PaO₂/FiO₂ <150, FiO₂ ≥60%, PEEP ≥5 cmH₂O, and the prone position was applied for at least 16 hours/day. The study showed a survival benefit in patients treated with the prone position, with a reduction in mortality of nearly 50% [113]. Therefore, the prone position has its definite role in the treatment of severe ARDS patients.

Contraindications to prone positioning include the presence of an open abdominal wound, unstable pelvic fracture, spinal lesions and instability, and brain injury without monitoring of intracranial pressure. In addition, well-trained staff are required for its safe implementation.

Extracorporeal support of ARDS was first applied in 1972 [114, 151]. It is a temporary artificial support of the respiratory and/or cardiac system, used for the treatment of cardiopulmonary failure refractory to conventional therapies, which includes several techniques with different aims. The technique to be applied is chosen on the basis of the patient’s status and on the clinician’s preference. If the aim is to treat life-threatening hypoxaemia, the indication is high-flow veno-venous ECMO if the patient does not present with severe cardiac failure. In this case, veno-arterial ECMO must be used. The CESAR trial indicated that treatment with extracorporeal support may increase the survival rate in a selected population of severely hypoxaemic ARDS patients treated in an expert high case volume centre, when compared to non-specialized hospitals [115, 144, 145]. The study was obviously criticized, as it tested the difference in outcome between a specialized centre with high-volume activity and single centres with low-volume activity. It must be noted, however, that a randomized clinical trial testing for 10% mortality reduction would require such a high number of patients presenting with ECMO criteria that it would be unfeasible. Another study was published in 2009 by Noah et al., comparing the hospital mortality of patients with influenza A virus subtype H1N1-related ARDS, referred, accepted, and transferred for ECMO, with matched patients who were not referred for ECMO [116, 147, 146]. The authors concluded that, for patients with H1N1-related ARDS, referral and transfer to an ECMO centre was associated with lower hospital mortality, compared with matched non-ECMO-referred patients. The H1N1 flu pandemics, however, caused the rebirth of the technique, and an impressive number of centres worldwide started to use ECMO in severely hypoxaemic patients unresponsive to conventional treatments, with a survival rate ranging between 56% and 79% [117–123]. The question is different when severe hypoxaemia is still manageable with more conventional approaches, and the possible benefits of ECMO have to be balanced against lethal complications, i.e. intracranial haemorrhage. Few data are available that indicate the incidence of the phenomenon. According to the Italian ECMOnet experience, intracranial haemorrhage occurred in one patient out of 49 [124, 140]; Noah et al. reported eight cases of intracranial haemorrhage from 80 ECMO patients [116]. In patients treatable with more conventional treatments, the possible benefits of extra corporeal membrane oxygenation (ECMO) have to be balanced against lethal complications.

Extracorporeal CO₂ removal (ECCO₂R) is indicated when the target is complete lung rest. The arteriovenous bypass allows the removal of CO₂ using low extracorporeal blood flow, with negligible O₂ transfer, as the inflowing blood is highly saturated [125]. In ARDS patients, however, in whom the lung function may be impaired, it would be better to use devices that allow blood flow as high as 2–2.5 L/min to maintain oxygenation. Dead space and respiratory system compliance have been suggested as a guide to select patients for clinical trials of ECCO₂R more efficiently than other indices of severity (e.g. oxygenation) [145, 155, 154].

In summary, the extracorporeal support, which is now increasingly employed in intensive care, is still a controversial issue. The need of randomized trial to test its effectiveness is still debated, as recently discussed in details [156, 157, 158].

ALI/ARDS patients are subjected to a number of risk factors. Prophylaxis for PE and venous thrombosis should be applied in all patients, unless contraindicated [126]. Enteral nutrition is also important to prevent gastro intestinal (GI) bleeding and to maintain the normal barrier function of the mucosa [126–128, 143]. Tight glycaemic control has been proven to reduce the number of multiple organ failure in a population of post-operative patients treated with intensive insulin, thus also improving ICU and hospital outcome [129, 130]. The same results were not translated into a general medical ICU population, but the authors found a survival improvement in patients who remained in the ICU for >3 days [130]. An important goal of treatment is the prevention of nosocomial or secondary infections and ventilator associated pneumonia (VAP), which are responsible for the high mortality rate of ALI/ARDS patients [131, 132, 148, 149]. Several ways have been proposed to improve oxygenation, while reducing the FiO₂ [133]. Most of these techniques, including the prone position, sighs, recruitment manoeuvres, and vasodilators are subject to accurate evaluations. Lung recruitment, for example, is the gain of aeration of previously non-aerated lung tissue. However, for the lung to be opened, it is necessary that part of it should be collapsed, before the application of positive airway pressure. Therefore, we may expect that recruitment manoeuvres are very effective when the lung recruitability is high, and less effective, or even nil and dangerous, when the lung recruitability is low [33]. Concerning the use of inhaled nitric oxide (NO), we have to say that it improves oxygenation. Two randomized clinical trials, however, failed to demonstrate a survival improvement associated with inhaled NO, compared to placebo administration [134, 135, 150].

Finally, the use of corticosteroids in ALI/ARDS patients has been tested by the ARDS Network [136]. The authors conducted a randomized placebo-controlled trial, using corticosteroids in ALI/ARDS patients that needed mechanical ventilation for not less than 7, and no more than 28, days. They did not find benefits in terms of survival, duration of mechanical ventilation, and ICU stay. On the other hand, in the steroid group, more patients had to return to mechanical ventilation, and, in the subgroups of patients with ARDS for >14 days, the rate of mortality was higher. The authors concluded that the routine use of corticosteroids is not recommended in patients with persistent ARDS.