Mechanical Ventilation in Acute Respiratory Distress Syndrome

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Mechanical Ventilation in Acute Respiratory Distress Syndrome

Luciano Gattinoni, Eleonora Carlesso and Pietro Caironi

Chapter Outline

Since the first description of acute respiratory distress syndrome (ARDS) in 1967,¹ mechanical ventilation has been the primary “buying time” treatment for acute lung injury (ALI). Mechanical ventilation is not a “gas exchanger,” but instead replaces, totally or partially, the force normally generated by the respiratory muscles to promote ventilation, providing muscle rest. The effects of mechanical ventilation on gas exchange are indirect and include (1) better clearance of carbon dioxide (CO₂) by the power of the mechanical ventilator to expand the diseased and collapsed lung; (2) improvement in oxygenation by preventing alveolar hypoxia caused by hypoventilation; (3) improvement in oxygenation by increasing inspiratory oxygen fraction, which affects alveolar partial pressure of oxygen (PAO₂); (4) improvement in oxygenation by opening lung regions otherwise collapsed (alveolar recruitment); and (5) improving oxygenation by maintaining positive end-expiratory pressure (PEEP), preventing the collapse of the lung regions previously recruited during the inspiratory phase.

The negative effects of mechanical ventilation are interwoven with its positive effects. First, the driving force applied by the ventilator, if excessive, may alter, in different ways, the lung parenchyma and produce ventilator-induced lung injury (VILI). Second, the positive-pressure ventilation unavoidably turns the physiologically negative intrathoracic pressures into positive pressures. In consideration of this, the guiding principle of mechanical ventilation of ARDS patients should be that, whenever one manipulates the ventilator settings, one should refer to one polar star: The new setting is less harmful to the lung structure than the previous one.

History

Extensive reviews on the history of mechanical ventilation of ARDS can be found elsewhere.2,3 In the 1970s, mechanical ventilation was recommended and performed with low PEEP and high tidal volume: “. . . larger tidal volumes (10 to 15 per kilogram) are preferable, having been used in several thousand ventilated patients with no evidence of development of pulmonary damage.”⁴ Today, this advice seems inconceivable. At that time, the main concerns were the putative harm of high inspiratory oxygen fraction and the hemodynamic impairment. It was later recognized in experimental and clinical settings^5–7 that high-volume/high-pressure mechanical ventilation could severely damage the lung parenchyma. Such lesions, primarily attributed to the excessive airway pressure, were collectively classified as barotrauma. In the same period, Suter and colleagues⁸ published a report that, for the first time, systematically described the interaction between PEEP, lung mechanics, gas exchange, and hemodynamics.

In the 1980s, based on the work of Dreyfuss,9,10 the focus progressively shifted from the potential harm of pressure to the harm of volume (overdistention), a concept that was popularized as volutrauma.¹¹ In the mid-1980s, the application of computed tomography (CT)^12,13 and the quantitative approach to CT analysis¹⁴ led to the concept of baby lung,^15,16 which accounted for most of the previous observations on respiratory mechanics, gas exchange functionality, and potential harm of mechanical ventilation. The premise of this line of thought is that high pressure or excessive distention applied to a small fraction of the lung parenchyma (with a size similar to the lung of a baby) unavoidably leads to structural lesions of the lung regions open to ventilation. Total lung rest was achievable with the use of extracorporeal CO₂ removal, targeted to prevent the damages of high-pressure/high-volume ventilation.^17–19 The target of mechanical ventilation shifted toward lung protection, rather than normal gas exchange functionality. Hickling and associates²⁰ proposed the “permissive hypercapnia” strategy for ARDS, providing “gentle treatment” of the portion of the lung that remains open to ventilation (the baby lung) through less aggressive mechanical ventilation, at the acceptable price of an abnormally higher arterial partial pressure of carbon dioxide (PaCO₂).

A large amount of experimental and clinical data over the years has supported the approach of a lung protective strategy.21–25 Low tidal volume prevents the excessive global stress and strain of the baby lung, whereas higher PEEP prevents the regional excessive stress and strain by avoiding alveolar collapse and reopening during mechanical ventilation.²⁶ These mechanical events are associated with an inflammatory reaction of the epithelial and endothelial lung cells (biotrauma/atelectrauma) as shown by the seminal study of Tremblay and colleagues²⁷ (see also work of Dreyfuss and Saumon¹¹ and Tremblay and Slutsky²⁸). The literature to date supports the thought that the harm of mechanical ventilation is due to excessive global or regional stress and strain.²⁹ This situation leads to two results—a physical rupture of the lung and a mechanically induced inflammation of the lung parenchyma, constituting VILI. The best “mechanical ventilation” would provide adequate gas exchange with the lowest amount of VILI.

Physiologic Basis of Mechanical Ventilation

Driving Force

To ventilate the respiratory system, force is required. The driving force for ventilation under normal circumstances is provided by the respiratory muscles. During spontaneous breathing, the thoracic cage expands. This causes a decrease in intrathoracic pressure (pleural pressure, Ppl) relative to the atmosphere (in normal conditions approximately 2 mm Hg of ΔPpl is sufficient to expand the thoracic cage by 0.5 L). Because the lungs are connected in series with the thoracic cage, their volume is expanded to a near equal extent (not considering the blood shift ³⁰). The force that distends the lung is the pressure difference between the alveoli and the pleural cavity (the transpulmonary pressure, PL). As the lung expands, the alveolar pressure becomes subatmospheric, and gas flow is generated (inspiration). When the respiratory muscles relax, the potential energy accumulated in the respiratory system (lung and chest wall) returns the chest wall and the lung parenchyma to the resting position (expiration). In spontaneously breathing subjects, the driving force (muscular pressure, ΔPmusc) is spent partly to expand the chest wall (ΔPpl), partly to expand the lung (ΔPL), and partly to overcome the resistances to the gas flow. In quasi-static conditions, in which the resistances to gas flow are negligible:

During positive-pressure mechanical ventilation, the rules are exactly the same, with the exception that ΔPmusc is substituted by the force provided by the ventilator, and the force is applied to the lung parenchyma and not to the chest wall. The driving pressure, which coincides with the airway pressure at plateau during an end-inspiratory pause (in quasi-static conditions), is spent first to expand the lung and second to expand the chest wall:

In spontaneous breathing and during positive-pressure mechanical ventilation, the distending force of the lung is the transpulmonary pressure. During spontaneous breathing, pleural pressure is negative (facilitating venous return), whereas during mechanical ventilation it is positive (impairing venous return). What matters from the pulmonary perspective is the distending force (i.e., the transpulmonary pressure [ΔPL]), whereas what matters from the hemodynamic perspective is the pleural pressure (ΔPpl).

Transpulmonary Pressure

At the same driving force applied to the whole respiratory system (lung and chest wall), the resulting transpulmonary pressure, ΔPL, may be extremely variable. If the lung is relatively “stiff,” and the chest wall is relatively “soft” (e.g., during pulmonary fibrosis or ARDS of pulmonary origin), a greater fraction of the driving pressure is spent to distend the lung (high transpulmonary pressure). In contrast, if the lung is relatively soft, but the chest wall is relatively stiff (e.g., in the presence of an abdominal disease or severe obesity), most of the driving force is spent to move the chest wall (high pleural pressure).

To express this phenomenon quantitatively, it is convenient to consider the concept of elastance. The elastance of the whole respiratory system is the driving force (ΔPaw) required to increase the lung and the chest wall 1 L above their resting position (Etot = ΔPaw/1 L). Part of this driving force is spent to increase the lung volume of 1 L (EL = ΔPL/1L), and part is spent to increase the chest wall by the same amount (Ecw = ΔPpl/1 L). Transpulmonary pressure (ΔPL) can be expressed as the driving force times the ratio between lung elastance and total elastance of the respiratory system:

The transpulmonary pressure for a given driving pressure uniquely depends on the ratio of lung elastance to respiratory system elastance. In normal subjects EL/Etot is approximately 0.5, whereas in patients with ARDS it may range from 0.2 (e.g., in obese patients or in patients with high intra-abdominal pressure) to 0.8 (e.g., in patients with a very small baby lung and a normal chest wall elastance). This variability implies that for the same driving force applied and read on the ventilator display (e.g., 30 cm H₂O), the resulting transpulmonary pressure may range from 6 to 24 cm H₂O (Fig. 11.1).

Figure 11.1 Two examples of EL/Etot variability in patients with acute lung injury/acute respiratory distress syndrome. A, EL/Etot = 0.2. B, EL/Etot = 0.8. This variability implies that for the same airway pressure applied (e.g., 30 cm H₂O), the resulting transpulmonary pressure (PL) may range from 6 to 24 cm H₂O.

Force-Bearing Structure of Lung Parenchyma

The transpulmonary pressure is applied to the force-bearing structure of lung parenchyma, the extracellular matrix, which constitutes the lung skeleton.³¹ The lung skeleton is a complex and metabolically active structure that includes a network of several components—elastin, collagen, and proteoglycans. All these molecules are involved in determining the mechanical characteristics of the respiratory system. The elastin may be considered as an elastic spring, whereas the unextensible collagen, which is folded at end expiration and completely unfolded at a lung volume equal to total lung capacity, acts as a stop-length fiber.^32,33 The proteoglycans stabilize the collagen-elastin network, contributing to lung elasticity and alveolar stability at low and medium lung volumes.³⁴

The matrix of elastin, collagen, and proteoglycans is arranged in two main fiber systems: (1) the axial system, which originates from the pulmonary hilum and runs deeply into the lung parenchyma down to the alveolar level, where it joins (2) the peripheral system, which originates from the visceral pleura and runs centripetally within the lung parenchyma.³¹ The lung skeleton may be considered as a continuous elastic structure that reaches its extension limits at total lung capacity, a lung volume equal to about threefold the lung resting volume. At this level of alveolar distention, the collagen is completely unfolded, and further expansion is prevented. The epithelial and endothelial cells do not directly bear the applied forces because they are anchored to the extracellular matrix by a series of structural proteins (integrins), which are connected to the cytoskeleton. During lung expansion, the epithelial and the endothelial cells modify their shape.

It is well documented that mechanically induced cellular deformation activates a series of mechanosensors with the production of several inflammatory mediators, such as cytokines (interleukin 6, tumor necrosis factor-α, and interferon-γ),27,35 metalloproteinases (enzymes involved in the remodeling of the matrix),³⁶ leukotrienes,³⁷ and interleukin 8,^38–40 the most powerful attractor of neutrophils.⁴¹ Gross barotrauma (e.g., pneumothorax) is due to the stress at rupture of the lung skeleton, whereas intrapulmonary inflammation is primarily due to the excessive strain of the epithelial and endothelial cells.

Concept of Stress and Strain

Stress is the applied force, and strain is the linear deformation of material. In the whole lung, the rough approximation of stress is the transpulmonary pressure, whereas the approximation of the average strain is the change in volume relative to the lung resting volume. The ratio between alveolar stress and strain is defined as lung-specific elastance (Espec), which is mathematically defined as:

where ΔV is the volume variation applied to the lung (i.e., the tidal volume), and V₀ is the lung resting volume (i.e., the functional residual capacity at atmospheric pressure [without any application of PEEP]). The lung-specific elastance is the transpulmonary pressure required to double the lung resting volume (i.e., the ΔPL when ΔV/V₀ is equal to 1). In ARDS, lung-specific elastance is similar to normal,^16,42 reinforcing the concept of the baby lung (lung is small and not stiff), and questions the use of normalizing the tidal volume to the ideal body weight. The same tidal volume per kilogram may result in completely different strain according to the size of the baby lung (the V₀ of the previous equation). For example, a 70-kg man with ARDS may have, according to the severity of the lung injury, a residual baby lung equal to 60%, 40%, or 20% of his normal lung size. If the ventilator is set to deliver 10 mL/kg, the actual delivered tidal volume would generate an alveolar strain, which would result from the application, in normal lung, of a tidal volume equal to 17 mL/kg, 25 mL/kg, and 50 mL/kg, values associated with a significant lung injury in laboratory studies.^11,29

Recently we attempted to quantify the relationship between stress-strain and VILI in healthy animals. We found that edema formation was a threshold phenomenon, induced by mechanical ventilation when the global strain reaches a critical value of about 2.⁴³ This threshold roughly corresponds to the point where the stress-strain curve loses its linearity and starts an exponential growth, indicating that some lung regions reach their own total capacity and cannot expand any further. At this level of strain, in a period of 24 to 48 hours the mechanical ventilation is lethal and the increased lung weight (two to three times the baseline) is associated with a striking impairment of respiratory mechanics, gas exchange, hemodynamics, inflammation, distal organs damage, and 100% mortality rate. This lethal strain, and associated stress, however, is rarely applied in clinical practice. To explain VILI in a diseased lung, therefore, alternative phenomena must be taken into account as the lung dishomogeneity and the presence of stress rise, which will be discussed later.

Patient Characterization

Using the least harmful mechanical ventilation setting requires a preliminary knowledge of the main pathophysiologic characteristics of the patient. The most relevant characteristics are the kind and amount of the lung injury, the chest wall elastance, and the lung recruitability.

Gas Exchange

Oxygen

PaO₂, PaO₂-to-fraction of inspired oxygen ratio (PaO₂/FIO₂), and Riley’s shunt fraction ⁴⁴ are the most commonly used variables to assess the severity of lung injury. In particular, the PaO₂/FIO₂ thresholds of 300 and 200 were used to define ALI (300) and ARDS (200) according to the American-European Consensus Conference on ARDS.⁴⁵ Consequently, the PaO₂/FIO₂ ratio is perceived as a key variable by most intensive care unit (ICU) physicians: The lower the PaO₂/FIO₂ ratio, the greater the lung injury. This equivalence is highly questionable. First, in most large studies on ARDS, no association was found between hypoxemia and outcome.⁴⁶ In the large study showing a better outcome with low tidal volume compared with higher tidal volume, the PaO₂/FIO₂ ratio was significantly lower in the low tidal volume group despite ending with better outcome.²⁵ Finally, the PaO₂/FIO₂ ratio was not different in patients with early, intermediate, and late ARDS, suggesting that oxygenation was not dependent on the structural changes of lung parenchyma occurring with time.⁴⁷ In a study⁴⁸ in which the lung severity was assessed by CT scan (and defined as a fraction of the gasless tissue), we did not find significant changes of PaO₂/FIO₂ ratio over a wide range of nonaerated tissue (Fig. 11.2), and PaO₂/FIO₂ ratio was not associated with outcome.

Figure 11.2 Frequency distribution of nonaerated lung tissue, expressed as a proportion of the total lung weight, recorded at 5 cm H₂O positive end-expiratory pressure in 68 patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Green columns represent patients with PaO₂/FIO₂ less than 300 (ALI without ARDS), whereas purple columns represent patients with PaO₂/FIO₂ less than 200 (ARDS). The nonaerated lung tissue was defined as the lung tissue having a physical density at computed tomography scan image analysis between +100 Hounsfield units (HU) and –100 HU, representing the portion of lung parenchyma that is consolidated or collapsed or both (i.e., the lung injury severity). (With permission from Gattinoni L, Caironi P, Cressoni M, et al: Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006;354:1775-1786.)

Most data suggest that PaO₂/FIO₂ ratio is a weak indicator of the overall lung severity, with compensatory rearrangement of perfusion during ARDS limiting the deterioration of oxygenation. The same limits apply when PaO₂/FIO₂ ratio changes are used to assess lung recruitment. Because this maneuver is unavoidably associated with changes of perfusion (global or regional), the increase of PaO₂/FIO₂ ratio may be partly due to decrease of perfusion, as shown in the 1980s.49–51 Most data suggest that the use of oxygenation variables alone to assess lung severity is misleading.

Carbon Dioxide

Although less considered, the variables derived from CO₂, as the total or alveolar deadspace, seem to be of greater value in assessing lung severity. It has been shown in ALI/ARDS patients that deadspace at entry is a strong predictor of outcome,⁵² and that PaCO₂ for the same total ventilation steadily increases from early to intermediate and to late ARDS, reflecting the lung structural changes.⁴⁷ The PCO₂ response to prone position (in contrast to PO₂ response) is a strong prognostic index of mortality.⁵³ Most data suggest that CO₂-related variables (deadspace), more than PaO₂/FIO₂ ratio, reflect the severity of lung injury (and associated mortality rate) at the time of presentation and the structural changes of lung parenchyma occurring with time (fibrosis, Pneumocystis, and possibly perfusion defects).

Respiratory Mechanics, Chest Wall Elastance, and Lung Volume

In the original description of ARDS,¹ the low compliance (i.e., high elastance) of the respiratory system was a landmark of the syndrome. The respiratory system compliance is not considered in the current definition of ARDS, however.⁴⁵ For years, the low compliance was attributed uniquely to the lung component (lung stiffness and lack of surfactant). Quantitative CT shows, however, that the respiratory system compliance primarily reflects the size of lung open to gases (the baby lung^14,16), suggesting that the intrinsic functioning lung elasticity in ARDS is close to normal (the lung is “small” rather than “stiff”). More than gas exchange, the respiratory system compliance indirectly assesses the lung injury severity (the smaller baby lung, the greater lung injury),⁵⁴ as confirmed in animal experiments.⁵⁵ Another variable also must be taken into account—the elastance of the chest wall. It has been shown in a significant portion of ALI/ARDS patients that the chest wall elastance is greater than normal because of increased intra-abdominal pressure, obesity, or severe edema.⁵⁶ In patients with extrapulmonary ARDS⁵⁷ and in obese patients,⁵⁸ the high elastance of the respiratory system may be due to the chest wall and to the lung derangement. Measurement of intra-abdominal pressure should be considered when selecting mechanical ventilator settings.

Severity of Lung Injury and Lung Recruitability

CT can be used to assess the severity of lung injury by measuring the fraction of nonaerated lung tissue at end expiration (end expiration pause at 5 cm H₂O). This fraction includes the lung tissue that is “consolidated” (i.e., not openable at 45 cm H₂O airway pressure) and the tissue that is collapsed but openable at 45 cm H₂O. These values were chosen to produce a minimal risk during the maneuver and because this is the most frequently used in the literature for recruitment maneuver.⁵⁹ In patients with elevated chest wall elastance, the resulting transpulmonary pressure could be insufficient, however, to overcome the opening pressure of some pulmonary units.

The total fractions of nonaerated lung tissue (consolidated plus recruitable) and the recruitable tissue alone (tissue that regains aeration at 45 cm H₂O airway pressure) are strongly associated with mortality rate. The data of Figure 11.2 show the inadequacy of the term ALI/ARDS, as currently defined, to describe the lung injury.⁴⁸ The data refer to a population of ALI/ARDS patients, classified according to the American-European Consensus Conference on ARDS,⁴⁵ in which a CT-based quantitative analysis of the whole lung parenchyma at 5 cm H₂O PEEP was performed. As shown in Figure 11.3, the fraction of the nonaerated lung tissue (consolidated or collapsed or both) may range from 5% to 70% of the entire lung parenchyma. Patients meeting ALI/ARDS criteria may have a baby lung size very close to that of normal subjects, or a baby lung that is just a small fraction of the expected normal lung. When the distending force is applied to the lungs by the mechanical ventilator, previously collapsed lung regions may open. Lung recruitability may be expressed as the amount of lung tissue regaining aeration when increasing the applied driving force from 5 to 45 cm H₂O. As shown in Figure 11.3, in some patients, lung recruitability was almost negligible, whereas in others it was equal to 25% to 35% of the entire lung parenchyma. Lung recruitability was strongly associated with the fraction of nonaerated tissue, suggesting that the greater the inflammatory edema, the greater the lung collapse. It seems that the best way to assess the overall lung severity and the related lung recruitability, both strongly associated with mortality rate, is the CT scan analysis. Physiologic variables are poor indicators of the severity of the lung injury. This relationship is shown in Figure 11.4—for a large variation of lung injury, ranging from 20% to 60% of the lung parenchyma, the values of PaO₂/FIO₂ ratio, lung compliance, and PaCO₂ greatly overlap.

Figure 11.3 Frequency distribution of 68 patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) according to the percentage of potentially recruitable lung, expressed as the percentage of total lung weight. ALI without ARDS was defined by a PaO₂/FIO₂ ratio less than 300, but not less than 200; ARDS was defined by a PaO₂/FIO₂ ratio less than 200. The percentage of potentially recruitable lung was defined as the proportion of lung tissue in which aeration was restored at airway pressures between 5 and 45 cm H₂O. (With permission from Gattinoni L, Caironi P, Cressoni M, et al: Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006;354:1775-1786.)

Figure 11.4 Mean ± standard deviation values of respiratory variables of a population of 68 patients with acute lung injury/acute respiratory distress syndrome. Blue columns represent PaO₂/FIO₂ ratio at positive end-expiratory pressure (PEEP) 5 cm H₂O (mm Hg), red columns represent respiratory system compliance at PEEP 5 cm H₂O (mL/cm H₂O), green columns represent deadspace fraction (%), and gold columns represent alveolar deadspace fraction (%). *P < 0.05 versus patients with a fraction of nonaerated tissue recorded at 5 cm H₂O PEEP less than 0.2. ^†P < 0.05 versus patients with a fraction of nonaerated tissue recorded at 5 cm H₂O PEEP ranging from 0.2 to 0.4. The continuous purple line represents the likelihood of death predicted by the fraction of nonaerated lung tissue recorded at 5 cm H₂O PEEP (P = 0.015). Weight is a poor surrogate of strain because ARDS patients with similar body weights may have completely different lung sizes and consequently different levels of strain at equal tidal volumes. This is confirmed by the plateau pressures measured in these different studies (see Fig. 11.5). As shown for the same tidal volume per ideal body weight, the plateau pressures are widely distributed with huge overlap between the studies. This reflects a wide distribution of the respiratory system compliance and consequently of the lung size.

Ards Classification

Although, in our opinion, the definition of ARDS should include a quantitative estimate of the lung edema, because this is not feasible in most of the ICU, alternative ways for defining ARDS have been sought. ARDS was first defined by Ashbaugh and coworkers in 1967.¹ Several other definitions have been introduced afterward, up to the American-European Consensus Conference (AECC) in 1994.⁴⁵ This conference defined ARDS as the acute onset of hypoxemia (PaO₂/FIO₂ ≤ 200) with bilateral infiltrates seen at x-ray study and no evidence of left atrial hypertension, and these parameters were largely used for the enrollment of patients in clinical trials. In 2011, a panel of experts, under the initiative of the European Society of Intensive Care Medicine endorsed from the American Thoracic Society and Society of Critical Care Medicine, convened to develop what has been called the “Berlin definition.”⁶⁰ The final Berlin definition is reported in Table 11.1. Stages of mild, moderate, and severe ARDS were related to increased mortality rates and increased median duration of mechanical ventilation in survivors.

Table 11.1

The Berlin Definition of ARDS

Defining Features	Criteria
Timing	Within 1 week of a known clinical insult or new/worsening respiratory symptoms
Chest imaging*	Bilateral opacities, not fully explained by effusions, lobar/lung collapse, or nodules
Origin of edema	Respiratory failure not fully explained by cardiac failure or fluid overload Need for objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor is present
Oxygenation^†
Mild	200 < PaO₂/FIO₂ ≤ 300 with PEEP or CPAP ≥ 5 cm H₂O^‡
Moderate	100 < PaO₂/FIO₂ ≤ 200 with PEEP ≥ 5 cm H₂O
Severe	PaO₂/FIO₂ ≤ 100 with PEEP ≥ 5 cm H₂O

ARDS, acute respiratory distress syndrome; PaO₂, partial pressure of arterial oxygen; FIO₂, fraction of inspired oxygen; PEEP, positive end-expiratory pressure; CPAP, continuous positive airway pressure.

^*Chest x-ray study or computed tomography scan.

^†If altitude is higher than 1000 m, the following correction factor should be used: PaO₂/FIO₂ × (barometric pressure/760).

^‡This may be delivered noninvasively in the “Mild” group.

From The ARDS Definition Task Force. Acute Respiratory Distress Syndrome—The Berlin definition. JAMA 2012;307(23):2526-2533.

Mechanical Ventilation in Acute Respiratory Distress Syndrome: Available Evidence

Setting Tidal Volume

The main results of several outcome studies specifically designed to compare different tidal volumes are summarized in Table 11.2. A survival benefit was found in the study comparing 6 mL/kg tidal volume versus 12 mL/kg, the highest tidal volume range tested,²⁵ whereas no survival differences were found in the other studies, which compared intermediate values of tidal volumes.^21,23,24 As previously discussed, the tidal volume per ideal body weight is a poor surrogate of strain because ARDS patients with similar body weight may have completely different lung sizes and consequently different strain at equal tidal volume. This is confirmed by the plateau pressures measured in these different studies (Fig. 11.5). As shown for the same tidal volume per ideal body weight, the plateau pressures are widely distributed with huge overlap between the studies. This reflects a wide distribution of the respiratory system compliance and consequently of the lung size.

Table 11.2

Different Tidal Volumes per Ideal Weight and Airway Plateau Pressures Investigated in Other Studies

Studies cited in this table can be found in the complete list of references for the chapter, available online at www.expertconsult.com.

^*Mean ± standard error values of tidal volume (mL/kg) were not provided in the report by Amato and colleagues. The value set by the physician and the mean ± standard error values of tidal volume in mL (over the first 36 hours) have been provided.

Figure 11.5 Distribution of tidal volume (VT) per ideal body weight (mL/kg) (left column) and of plateau pressure (right column) (red line = treated group; blue line = control group) in five randomized trials (computed from the reported mean ± standard deviation assuming a Gaussian distribution). Data taken from the following studies: A and B, Acute Respiratory Distress Syndrome Network;²⁵ C and D, The Multicenter Trial Group on Tidal Volume Reduction in ARDS;²³ E and F, Pressure- and Volume-Limited Ventilation Strategy Group;²¹ G and H, Brower and associates;²⁴ I, Amato and associates.²² (With permission from Gattinoni L, Carlesso E, Cadringher P, et al: Physical and biological triggers of ventilator-induced lung injury and its prevention. Eur Respir J Suppl 2003;47:15s-25s.)

Despite the lack of information about stress and strain in each individual patient, most available data strongly suggest that a gentle ventilation is safer than the application of high volumes and pressures. This evidence does not mean that 6 mL/kg ideal body weight represents the ideal tidal volume. In a patient with a very small baby lung, it still may be harmful, inducing excessive strain, whereas if applied to a lung characterized by a large ventilatable area, it may be low. There is little doubt, however, that 12 mL/kg ideal body weight is excessively high and unnecessary. It is evident that low tidal volume ventilation, decreasing the global alveolar stress and strain, is advantageous compared with high tidal volume ventilation in different patients.

It has been suggested that a plateau pressure of 30 cm H₂O represents the safe limit for plateau pressure.⁶¹ In a retrospective analysis, such a safe limit has been challenged, however.⁶² This is understandable if we consider that the airway plateau pressure is a poor surrogate of stress owing to the high variability of the chest wall compliance. The same plateau pressure, 30 cm H₂O, may result in completely different stress values in different patients.

Setting Positive End-Expiratory Pressure

The available evidence on the effects of higher versus lower levels of PEEP in ALI/ARDS patients is summarized in Table 11.3. As shown, despite the fact that the experimental data provide striking evidence that PEEP may reduce the damages of mechanical ventilation, the largest studies comparing higher versus lower PEEP levels in unselected ALI/ARDS patients were unable to find any difference in outcome.^63–66 It has been suggested that PEEP should be of benefit in patients with higher lung recruitability and useless or harmful in patients with low lung recruitability.⁶⁷ Actually two meta-analyses seem to confirm this hypothesis. The meta-analysis by Phoenix and associates⁶⁸ showed a trend toward improved survival in the high PEEP group with no evidence of increase in barotrauma. The other meta-analysis by Briel and colleagues⁶⁹ on the largest three trials reported no treatment effect on hospital survival between higher and lower PEEP groups while a significant improved survival rate was found in patients in presence of ARDS defined as PaO₂/FIO₂ ratio equal or less than 200. In contrast, in patients with mild and moderate ARDS, higher PEEP seemed harmful. These results roughly account for what we know about the ARDS pathophysiology. In fact, the putative beneficial effect of PEEP on survival should be related to the prevention of excessive regional stress and strain by keeping open lung regions that would otherwise collapse.^26,70 When we studied lung recruitability in an unselected ALI/ARDS population, we found that it varied from 0% to more than 50% of the whole lung.⁵⁹ We found that severity of lung injury was associated with higher lung recruitability and more severe hypoxemia, greater deadspace, and lower compliance of the respiratory system. By arbitrarily dividing the study population into patients with higher or lower lung recruitability, we first observed that in the latter, the amount of recruitable lung was almost negligible, amounting to about 50 g of tissue weight. The response to the application of higher levels of PEEP was minimal and much lower than that observed in patients with higher lung recruitability.

Table 11.3

Summary of Available Evidence on the Effects of Higher PEEP in Patients with ALI/ARDS

ALI/ARDS, acute lung injury/acute respiratory distress syndrome; NS, not significant; PEEP, positive end-expiratory pressure; P flex, lower inflection point of the pressure-volume curve of the respiratory system.

Studies cited in this table can be found in the complete list of references for the chapter, available online at www.expertconsult.com.

Setting Respiratory Rate

Although extensive work has been devoted to understanding better how to set tidal volume and PEEP in ARDS, the potential importance of respiratory rate in the development of VILI has been scarcely investigated. Technology allows the use of respiratory rate from near zero breaths per minute using extracorporeal techniques to remove CO₂ to 2000 to 3000 breaths per minute, by employing high-frequency oscillation. Each tidal volume delivered may be considered as a stress cycle. Increasing the number of stress cycles may increase the lung damage. In experimental ARDS models, it has been observed that decreasing the respiratory rate decreases edema formation in isolated rabbit lung,⁷¹ whereas an increase in respiratory rate, during spontaneous breathing, leads to an increase in edema formation.⁷² It is conceivable that the respiratory rate may play a role in the pathogenesis of VILI when associated with a harmful tidal volume or inadequate PEEP. A different issue is the use of high-frequency oscillatory ventilation (HFOV), a technique that uses very high respiratory frequencies in association with very low tidal volumes and very high mean airway pressure, minimizing inspiratory overdistention and end-expiratory lung collapse.⁷³ Most patients treated with HFOV improved PaO₂/FIO₂ ratio and reduced oxygenation index over time. Clinical trials were not able to prove a survival benefit, however, a recent meta-analysis on six randomized controlled trials comparing HFOV to conventional ventilation suggested a survival benefit at 30 days.⁷⁴ Two clinical trials are currently ongoing with the aim of comparing HFOV with lung protective mechanical ventilation (OSCAR trial in the United Kingdom [ISRCTN10416500] and OSCILLATE trial in Canada [ISRCTN87124254]). In the absence of definitive evidence HFOV remains investigational for routine management of ARDS and should be reserved for patients unresponsive to conventional ventilator strategies.

Setting Inspiratory-to-Expiratory Ratio

Mechanical ventilators provide a wide range of inspiratory-to-expiratory (I:E) ratios. Setting an adequate I:E ratio may be of great importance when ventilating patients with structural alterations of lung parenchyma, such as chronic obstructive pulmonary disease and emphysema, and during asthmatic exacerbation. In these conditions characterized by a time constant of the respiratory system greater than normal, a longer expiratory time must be provided to allow deflation of gas from the lungs before the next respiratory cycle, avoiding dynamic hyperinflation and intrinsic PEEP.⁷⁵ During ALI/ARDS, no convincing evidence has been provided for the advantages of setting an I:E ratio different from 1:1.

In the past, inverse ratio ventilation ⁷⁶ was advocated as a tool to improve the effects of mechanical ventilation in ARDS.^77–79 Studies primarily showed an improvement of arterial oxygenation. Increased mean airway pressure, intrinsic PEEP, and a decrease in cardiac output were problematic.⁸⁰ Extreme forms of manipulating I:E ratio are not recommended; an I:E ratio in ALI/ARDS of 0.5 to 1.5 is appropriate.

Individualizing Mechanical Ventilation in Patients with Acute Respiratory Distress Syndrome

General principles underlying the application of mechanical ventilation in ALI/ARDS patients have been discussed. We now present the sequence of interventions that we believe are most appropriate for tailoring mechanical ventilation in an individual patient.⁸¹

The first intervention after admission to the ICU is to determine whether the patient has the criteria for ARDS diagnosis, keeping in mind that this syndrome consists of diffuse inflammatory lung edema. Patient history (research for possible etiologic factors leading to ARDS) and clinical observation (cyanosis, higher respiratory rate, use of accessory respiratory muscles, inspiratory crackles at lung auscultation mainly in the dependent lung regions) may suggest a possible lung inflammatory edema. Blood gas analysis and chest x-ray studies may confirm the initial diagnosis of the syndrome. The choice between an attempt of noninvasive respiratory support (facemask continuous positive airway pressure or noninvasive ventilation) or endotracheal intubation should be made on a clinical basis, according to the severity of illness, and whether the patient is stable or deteriorating. We pay particular attention to the improvement of PaO₂ after oxygen administration and to PaCO₂. The lack of remarkable response in oxygenation to increased FIO₂ indicates a remarkable fraction of right-to-left intrapulmonary shunt, which is typical of ARDS. Low PaCO₂ suggests that the respiratory muscles of the patient are still able to deal with the decreased compliance of the respiratory system (i.e., sustaining the increased respiratory effort), whereas normal or high levels of PaCO₂ suggest a near exhaustion of the respiratory muscles and need of immediate ventilatory support.

Clinicians should be aware of the immediate possible consequences of intubation and initiation of mechanical ventilation. Sedation, either by itself or in association with muscle paralysis, produces a loss of respiratory muscle tone and a cranial shift of the diaphragm, promoting further lung collapse with immediate consequences in gas exchange. Mechanical ventilation produces an increase in intrathoracic pressure and decreased venous return. The intravascular volume status of the patient should be assessed before intubation, and hypovolemia should be corrected. The rate and the amount of fluid replacement should be decided for each individual patient. Inadequate fluid replacement may lead to a severe hemodynamic impairment immediately after beginning positive-pressure ventilation. An excessive fluid replacement in an inflamed lung with leaking capillaries may result in a dramatic increase of pulmonary edema with devastating consequences on gas exchange. Wiedemann and coworkers,⁸² in a study published in the New England Journal of Medicine, compared a conservative and a liberal strategy of fluid management in 1000 patients with ALI. Although the primary end point (60-day mortality) was not significantly different, patients treated with the conservative strategy had better lung function and shorter duration of mechanical ventilation and intensive care without increasing nonpulmonary organ failures. For these reasons, we prefer to tailor fluid replacement according to the results of a fluid challenge test. Echocardiography also may be helpful in assessing the volumetric status.⁸³ After endotracheal intubation, the initial ventilatory setting employed is blind because the pathophysiologic characteristics of the patient have not yet been assessed. We usually set the ventilator (volume controlled) with a tidal volume equal to 6 to 8 mL/kg ideal body weight, FIO₂ equal to 0.7, and a respiratory rate of 15 breaths per minute, with an I:E ratio of 1:1. As soon as hemodynamic stability is obtained, a PEEP trial (preceded by a recruitment maneuver) is performed by applying in a random sequence of 5 to 15 cm H₂O PEEP with the patient under sedation and, sometimes, muscle paralysis. At each level of PEEP, we maintain tidal volume, respiratory rate, FIO₂, and I:E ratio constant for about 20 minutes, after which we measure (1) arterial oxygenation, (2) respiratory system compliance, and (3) alveolar deadspace. Patients who, after the application of higher PEEP, improve at least two of these three parameters have a greater likelihood of having a higher lung recruitability. Alternatively, it is possible to target a specific saturation on the basis of pulse oximetry, if available, aiming at a hemoglobin oxygen saturation of 90%.

The improvement in arterial oxygenation alone, although commonly employed, may be misleading for the assessment of lung recruitment because it may be the result of a slight decrease in cardiac output or a modification of regional distribution of pulmonary blood flow or both. It has been shown that improvement in respiratory physiologic variables from a PEEP trial has low sensitivity (71%) and specificity (59%) in assessing lung recruitability;⁵⁹ we prefer to obtain whole-lung CT scanning. In the CT scan facility, while maintaining the baseline ventilator setting, whole-lung CT scanning is performed at 5 cm H₂O PEEP at end expiration and 45 cm H₂O at end inspiration. The subsequent quantitative analysis of the CT scans allows us to obtain a precise assessment of lung recruitability. In patients with higher recruitability we apply PEEP greater than 15 cm H₂O, up to 20 cm H₂O and exceptionally greater than 20 but not exceeding 25 cm H₂O, whereas in patients with lower lung recruitability we apply a PEEP level not greater than 10 cm H₂O.

If CT scan is unavailable, and only the PEEP trial has been performed, we assign to the high-recruitment group patients with either a baseline PaO₂/FIO₂ ratio less than 150 when measured at 5 cm H₂O PEEP or patients who respond to 15 cm H₂O PEEP compared with 5 cm H₂O with a positive response of two of the following three variables: increased PaO₂, decreased alveolar deadspace, or increased compliance of the respiratory system.

We attempt to keep the plateau pressure less than 30 cm H₂O by modifying tidal volume and respiratory rate. As discussed earlier, however, tidal volume and plateau pressure are inadequate surrogates for alveolar stress and strain. We now measure, in each severe ARDS patient, the transpulmonary pressure by helium dilution technique, by employing an esophageal balloon (lung resting volume of 0 cm H₂O or 5 cm H₂O PEEP). With mechanical ventilation, a global pulmonary strain greater than about 1.5 (strain is dimensionless because it is the ratio of two volumes), or an end-inspiratory transpulmonary pressure greater than 20 cm H₂O, may cause VILI, with irreversible respiratory failure to follow.11,29 These values of alveolar stress and strain are the ones at which the residual ventilatable lung reaches its near total lung capacity, with a full extension of the collagen fibers of the lung skeleton.

In some patients, we have observed that a tidal volume of 8 to 10 mL/kg ideal body weight determines a lung strain value less than 1 and a transpulmonary pressure value less than 14 cm H₂O. In these patients, we employ a tidal volume greater than 6 mL/kg ideal body weight, avoiding excessive hypercapnia or need for sedation. In contrast, in the most severe patients, in which the baby lung is extremely small, even a ventilation with 6 mL/kg ideal body weight may result in values of alveolar stress and strain higher than those required to reach total lung capacity. Evidence from the literature and physiologic reasoning strongly indicate that for these patients a safe form of mechanical ventilation does not exist.84,85 We reserve to them the use of extracorporeal support. We acknowledge that measuring alveolar stress and strain may seem to be a physiologic curiosity or a research tool. Nonetheless, we have introduced them in our clinical practice as the most logical approach for VILI prevention.

Some authors advocate the use of other forms of mechanical ventilation in patients with ARDS.86,87 The rationale of pressure support ventilation in ARDS relies on the possibility of decreasing the need for sedation, while preserving the contribution of spontaneous breathing, and with possible advantages on gas and flow pulmonary distribution.⁸⁸ During the full-blown phase of the illness, we prefer to keep the patient well sedated. This approach may help to reduce energy requirement and oxygen consumption and CO₂ production.

The onset of recovery is characterized by the control or reversal, or both, of the cause of ARDS. An increase of systemic oxygenation and respiratory system compliance follows. When a PaO₂ value greater than 80 mm Hg is obtained at FIO₂ of 0.4, we start the weaning from PEEP application, decreasing the PEEP level no more than 1 cm H₂O every 4 to 6 hours, and suspending the process if the oxygenation consistently deteriorates. Subsequently, after an appropriate adjustment of sedation, we shift from pressure-controlled or volume-controlled to pressure-support ventilation, initially setting the support at the same inspiratory pressure used during controlled ventilation. According to the patient’s response, pressure-support level is progressively decreased, and the final phase of weaning is initiated at pressure support of 5 to 10 cm H₂O, FIO₂ lower than 0.4, and PEEP level equal to 5 cm H₂O.

Possible Adjuncts to Mechanical Ventilation

Prone Position

Prone positioning, first proposed in 1974 ⁸⁹ and first applied in ARDS patients in 1976,⁹⁰ results in improved arterial oxygenation in most patients. After the introduction of CT scanning, showing lung consolidation located in the dependent lung regions and the aerated baby lung in the nondependent lung regions,^12,16 we integrated prone positioning as standard practice in clinical treatment of ARDS patients to improve systemic oxygenation.⁹¹ The initial hypothesis was that better perfusion of the baby lung, located in the dependent lung regions after prone positioning, would provide advantages in gas exchange. The picture observed was quite different, however. We did observe an improvement in arterial oxygenation, but the mechanism was likely different because CT scans taken in the prone position showed a density redistribution toward the dependent lung areas.⁹²

This observation led to our introduction of the “sponge model” as our pathophysiologic understanding of ARDS.⁹³ Whatever the position of the patient, the increased weight of the nondependent lung tissue squeezes the gas out of the dependent regions of the lung.⁴² The mechanisms of improved gas exchange were different from that first hypothesized. It is not the aim of this chapter to discuss the possible physiologic mechanisms of prone positioning, which may be found elsewhere.^94–98 Taken together, all of the studies, including small and large series of patients, consistently showed that in 70% of the patients systemic oxygenation improves in prone compared with supine positioning,^98,99 without any change in the applied airway pressure. There is no doubt that in life-threatening severe hypoxemia a trial in the prone position is indicated.

A different issue is the effectiveness of the prone position in improving ARDS outcome. Is mechanical ventilation in ARDS less harmful in the prone compared with the supine position? Does mechanical ventilation induce less alveolar stress and strain in the prone position? There is a consistent physiologic rationale to believe that this is the case. In experimental settings 100–103 and in normal subjects and patients affected by ARDS, CT scan shows a more homogeneous distribution of gas throughout the lung parenchyma in the prone compared with the supine position.⁹⁸ This observation strongly suggests that the distribution of alveolar stress and strain is more homogeneous in the prone position. In experimental models of ARDS, there is evidence that prone positioning prevents or significantly delays the development of VILI.^103,104 Two large randomized studies on prone positioning were unable to show a significant benefit on outcome;^97,105 however, prone positioning was applied for only about a quarter of the day, and mechanical ventilation was not controlled. In a more recent trial,¹⁰⁶ in which prone positioning was applied for 20 hours per day and mechanical ventilation was strictly controlled, a positive benefit was found for the patients treated with prone positioning. On these bases the Prone-Supine II study¹⁰⁷ was organized to detect potential survival benefit of prone positioning avoiding the limitations of previous trials. Although, the study was not able to show a significant survival benefit in the general population, a favorable trend was detected in the subgroup of patients with severe ARDS. In a meta-analysis including 10 clinical trials on adults and children Sud and associates¹⁰⁸ found that prone ventilation reduced mortality rate in severely hypoxemic patients (PaO₂/FIO₂ ≤ 100, p = 0.01) but not in patients with PaO₂/FIO₂ greater than 100 (p = 0.36). The authors’ suggestion was that prone position may provide benefits in severely hypoxemic patients, but it should not be routinely used in all patients affected by acute hypoxemic respiratory failure. In a pooled analysis¹⁰⁷ of the four largest databases^99,105–107 of trials on prone position, the absolute mortality rate reduction in severe ARDS patients treated in prone position was approximately 10% (log-rank = 0.03). On the contrary, in patients with moderate ARDS prolonged prone position may be useless or possibly harmful.

Extracorporeal Support

Extracorporeal support of ARDS was first applied in 1972.¹⁰⁹ The first randomized trial ever performed in ALI/ARDS showed that patients treated with extracorporeal support or with conventional ventilation had similar mortality rates, equal to about 90%.¹¹⁰ In the 1980s, our center introduced extracorporeal CO₂ removal in ARDS, aiming at lung rest with a suggestion of benefit.^111,112 A randomized study performed in 1994 did not show any survival benefit with extracorporeal CO₂ removal support.¹¹³ The results of this trial may have been significantly influenced by bleeding complications in patients undergoing extracorporeal CO₂ removal. Despite the discouraging results, in Europe few centers continued to use veno-venous extracorporeal support as a last resource in selected series of patients.¹¹⁴ In the United States, Bartlett and colleagues^115,116 continued to provide extracorporeal support associated with mechanical ventilation with less strict entry criteria and with encouraging results. The interest on extracorporeal membrane oxygenation (ECMO) renewed after the publication of CESAR trial in 2009,¹¹⁷ which showed clear benefits on outcome when severely hypoxemic patients were treated with extracorporeal support in an expert high case volume center when compared to nonspecialized hospitals. The rebirth of the technique, however, occurred with its use as a rescue therapy during H1N1 flu epidemics in Australia and New Zealand in severely hypoxemic patients untreatable with conventional methods.¹¹⁸ The approach was veno-venous with high blood flows. This report showed a survival rate higher than 70%, and an impressive number of centers in Europe, United States, South America, Canada, and Asia started to use ECMO in severely hypoxemic patients who do not receive benefits from maximal mechanical ventilation.^119–124 Survival rate ranged between 56% and 79%.

The impressive diffusion of ECMO led to the great improvement of this technology, and there are increasing numbers of reports describing simple forms of extracorporeal support, primarily aiming at CO₂ removal.¹²⁵ The actual indications for ECMO depend on the patient’s need and the physician’s request. The choice of the technique may vary from low-flow bypass with CO₂ removal to high-flow ECMO with total oxygenation support. If the aim is the treatment of life-threatening hypoxemia, the clear-cut indication is high-flow veno-venous ECMO. If the patient, however, presents with severe cardiac failure, veno-arterial ECMO must be used.

A simplified schema of the possible intervention is reported in Figure 11.6, which underlines the recent ARDS Berlin definition, which may be helpful in dictating the sequence of possible intervention when ARDS severity is increasing.

Key Points