Eleonora Carlesso

Lung Stress and Strain during Mechanical Ventilation for Acute Respiratory Distress Syndrome

RATIONALE Lung injury caused by a ventilator results from nonphysiologic lung stress (transpulmonary pressure) and strain (inflated volume to functional residual capacity ratio). OBJECTIVES To determine whether plateau pressure and tidal volume are adequate surrogates for stress and strain, and to quantify the stress to strain relationship in patients and control subjects. METHODS Nineteen postsurgical healthy patients (group 1), 11 patients with medical diseases (group 2), 26 patients with acute lung injury (group 3), and 24 patients with acute respiratory distress syndrome (group 4) underwent a positive end-expiratory pressure (PEEP) trial (5 and 15 cm H2O) with 6, 8, 10, and 12 ml/kg tidal volume. MEASUREMENTS AND MAIN RESULTS Plateau airway pressure, lung and chest wall elastances, and lung stress and strain significantly increased from groups 1 to 4 and with increasing PEEP and tidal volume. Within each group, a given applied airway pressure produced largely variable stress due to the variability of the lung elastance to respiratory system elastance ratio (range, 0.33-0.95). Analogously, for the same applied tidal volume, the strain variability within subgroups was remarkable, due to the functional residual capacity variability. Therefore, low or high tidal volume, such as 6 and 12 ml/kg, respectively, could produce similar stress and strain in a remarkable fraction of patients in each subgroup. In contrast, the stress to strain ratio-that is, specific lung elastance-was similar throughout the subgroups (13.4 +/- 3.4, 12.6 +/- 3.0, 14.4 +/- 3.6, and 13.5 +/- 4.1 cm H2O for groups 1 through 4, respectively; P = 0.58) and did not change with PEEP and tidal volume. CONCLUSIONS Plateau pressure and tidal volume are inadequate surrogates for lung stress and strain. Clinical trial registered with www.clinicaltrials.gov (NCT 00143468).

Lung Opening and Closing during Ventilation of Acute Respiratory Distress Syndrome

RATIONALE The effects of high positive end-expiratory pressure (PEEP) strictly depend on lung recruitability, which varies widely during acute respiratory distress syndrome (ARDS). Unfortunately, increasing PEEP may lead to opposing effects on two main factors potentially worsening the lung injury, that is, alveolar strain and intratidal opening and closing, being detrimental (increasing the former) or beneficial (decreasing the latter). OBJECTIVES To investigate how lung recruitability influences alveolar strain and intratidal opening and closing after the application of high PEEP. METHODS We analyzed data from a database of 68 patients with acute lung injury or ARDS who underwent whole-lung computed tomography at 5, 15, and 45 cm H(2)O airway pressure. MEASUREMENTS AND MAIN RESULTS End-inspiratory nonaerated lung tissue was estimated from computed tomography pressure-volume curves. Alveolar strain and opening and closing lung tissue were computed at 5 and 15 cm H(2)O PEEP. In patients with a higher percentage of potentially recruitable lung, the increase in PEEP markedly reduced opening and closing lung tissue (P < 0.001), whereas no differences were observed in patients with a lower percentage of potentially recruitable lung. In contrast, alveolar strain similarly increased in the two groups (P = 0.89). Opening and closing lung tissue was distributed mainly in the dependent and hilar lung regions, and it appeared to be an independent risk factor for death (odds ratio, 1.10 for each 10-g increase). CONCLUSIONS In ARDS, especially in patients with higher lung recruitability, the beneficial impact of reducing intratidal alveolar opening and closing by increasing PEEP prevails over the effects of increasing alveolar strain.

Physical and biological triggers of ventilator-induced lung injury and its prevention.

Ventilator-induced lung injury is a side-effect of mechanical ventilation. Its prevention or attenuation implies knowledge of the sequence of events that lead from mechanical stress to lung inflammation and stress at rupture. A literature review was undertaken which focused on the link between the mechanical forces in the diseased lung and the resulting inflammation/rupture. The distending force of the lung is the transpulmonary pressure. This applied force, in a homogeneous lung, is shared equally by each fibre of the lungs fibrous skeleton. In a nonhomogeneous lung, the collapsed or consolidated regions do not strain, whereas the neighbouring fibres experience excessive strain. Indeed, if the global applied force is excessive, or the fibres near the diseased regions experience excessive stress/strain, biological activation and/or mechanical rupture are observed. Excessive strain activates macrophages and epithelial cells to produce interleukin‐8. This cytokine recruits neutrophils, with consequent full-blown inflammation. In order to prevent initiation of ventilator-induced lung injury, transpulmonary pressure must be kept within the physiological range. The prone position may attenuate ventilator-induced lung injury by increasing the homogeneity of transpulmonary pressure distribution. Positive end-expiratory pressure may prevent ventilator-induced lung injury by keeping open the lung, thus reducing the regional stress/strain maldistribution. If the transpulmonary pressure rather than the tidal volume per kilogram of body weight is taken into account, the contradictory results of the randomised trials dealing with different strategies of mechanical ventilation may be better understood.

Decrease in PaCO2 with prone position is predictive of improved outcome in acute respiratory distress syndrome.

ObjectiveTo determine whether gas exchange improvement in response to the prone position is associated with an improved outcome in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). DesignRetrospective analysis of patients in the pronation arm of a controlled randomized trial on prone positioning and patients enrolled in a previous pilot study of the prone position. SettingTwenty-eight Italian and two Swiss intensive care units. PatientsWe studied 225 patients meeting the criteria for ALI or ARDS. InterventionsPatients were in prone position for 10 days for 6 hrs/day if they met ALI/ARDS criteria when assessed each morning. Respiratory variables were recorded before and after 6 hrs of pronation with unchanged ventilatory settings. Measurements and Main ResultsWe measured arterial blood gas alterations to the first pronation and the 28-day mortality rate. The independent risk factors for death in the general population were the Pao2/Fio2 ratio (odds ratio, 0.992; confidence interval, 0.986–0.998), the minute ventilation/Paco2 ratio (odds ratio, 1.003; confidence interval, 1.000–1.006), and the concentration of plasma creatinine (odds ratio, 1.385; confidence interval, 1.116–1.720). Pao2 responders (defined as the patients who increased their Pao2/Fio2 by ≥20 mm Hg, 150 patients, mean increase of 100.6 ± 61.6 mm Hg [13.4 ± 8.2 kPa]) had an outcome similar to the nonresponders (59 patients, mean decrease −6.3 ± 23.7 mm Hg [−0.8 ± 3.2 kPa]; mortality rate 44% and 46%, respectively; relative risk, 1.04; confidence interval, 0.74–1.45, p = .65). The Paco2 responders (defined as patients whose Paco2 decreased by ≥1 mm Hg, 94 patients, mean decrease −6.0 ± 6 mm Hg [−0.8 ± 0.8 kPa]) had an improved survival when compared with nonresponders (115 patients, mean increase 6 ± 6 mm Hg [0.8 ± 0.8 kPa]; mortality rate 35.1% and 52.2%, respectively; relative risk, 1.48; confidence interval, 1.07–2.05, p = .01). ConclusionALI/ARDS patients who respond to prone positioning with reduction of their Paco2 show an increased survival at 28 days. Improved efficiency of alveolar ventilation (decreased physiologic deadspace ratio) is an important marker of patients who will survive acute respiratory failure.

Ventilator-induced lung injury: the anatomical and physiological framework.

Since its introduction into the management of the acute respiratory distress syndrome, mechanical ventilation has been so strongly interwoven with its side effects that it came to be considered as invariably dangerous. Over the decades, attention has shifted from gross barotrauma to volutrauma and, more recently, to atelectrauma and biotrauma. In this article, we describe the anatomical and physiologic framework in which ventilator-induced lung injury may occur. We address the concept of lung stress/strain as applied to the whole lung or specific pulmonary regions. We challenge some common beliefs, such as separately studying the dangerous effects of different tidal volumes (end inspiration) and end-expiratory positive pressures. Based on available data, we suggest that stress at rupture is only rarely reached and that high tidal volume induces ventilator-induced lung injury by augmenting the pressure heterogeneity at the interface between open and constantly closed units. We believe that ventilator-induced lung injury occurs only when a given threshold is exceeded; below this limit, mechanical ventilation is likely to be safe.

Lung Inhomogeneity in Patients with Acute Respiratory Distress Syndrome

RATIONALE Pressures and volumes needed to induce ventilator-induced lung injury in healthy lungs are far greater than those applied in diseased lungs. A possible explanation may be the presence of local inhomogeneities acting as pressure multipliers (stress raisers). OBJECTIVES To quantify lung inhomogeneities in patients with acute respiratory distress syndrome (ARDS). METHODS Retrospective quantitative analysis of CT scan images of 148 patients with ARDS and 100 control subjects. An ideally homogeneous lung would have the same expansion in all regions; lung expansion was measured by CT scan as gas/tissue ratio and lung inhomogeneities were measured as lung regions with lower gas/tissue ratio than their neighboring lung regions. We defined as the extent of lung inhomogeneities the fraction of the lung showing an inflation ratio greater than 95th percentile of the control group (1.61). MEASUREMENTS AND MAIN RESULTS The extent of lung inhomogeneities increased with the severity of ARDS (14 ± 5, 18 ± 8, and 23 ± 10% of lung volume in mild, moderate, and severe ARDS; P < 0.001) and correlated with the physiologic dead space (r(2) = 0.34; P < 0.0001). The application of positive end-expiratory pressure reduced the extent of lung inhomogeneities from 18 ± 8 to 12 ± 7% (P < 0.0001) going from 5 to 45 cm H2O airway pressure. Lung inhomogeneities were greater in nonsurvivor patients than in survivor patients (20 ± 9 vs. 17 ± 7% of lung volume; P = 0.01) and were the only CT scan variable independently associated with mortality at backward logistic regression. CONCLUSIONS Lung inhomogeneities are associated with overall disease severity and mortality. Increasing the airway pressures decreased but did not abolish the extent of lung inhomogeneities.

Positive end-expiratory pressure.

Purpose of review In the last 2 years, several reports have dealt with recruitment/positive end-expiratory pressure (PEEP) selection. Most of them confirm previous results and few add new information. Recent findings It has been definitely confirmed that opening pressures are different throughout the acute respiratory distress syndrome lung parenchyma, ranging from 5–10 up to 30–40 cmH2O. The highest opening pressures are required to open the most dependent lung regions. It has been found that in 2 s, most of the recruitable lung regions may be open when a proper pressure is applied. The best way to assess recruitment is computed tomography scanning, whereas lung mechanics are a reasonable bedside surrogate. Impedance tomography has been increasingly tested, whereas gas exchange is the less reliable indicator of recruitment. A large outcome study showed that higher PEEP might provide survival benefit in a subgroup of more severe patients as compared with lower PEEP. To set PEEP in each individual patient, the use of the expiratory limb of the pressure–volume curve has been suggested. Setting PEEP according to transpulmonary pressure has a robust physiological background, although it requires confirmatory study. Summary Indiscriminate application of recruitment maneuver in unselected acute respiratory distress syndrome population does not provide benefits. However, in the most severe patients, recruitment maneuver has to be considered and higher PEEP applied. To individualize PEEP, the expiratory phase has to be considered, and the esophageal pressure measurement to compute the transpulmonary pressure should be progressively introduced in clinical practice.

Prone position delays the progression of ventilator-induced lung injury in rats : Does lung strain distribution play a role?

Objective:To investigate if prone position delays the progression of experimental ventilator-induced lung injury, possibly due to a more homogeneous distribution of strain within lung parenchyma. Design:Prospective, randomized, controlled trial. Setting:Animal laboratory of a university hospital. Subjects:Thirty-five Sprague Dawley male rats (weight 257 ± 45 g). Interventions:Mechanical ventilation in either supine or prone position and computed tomography scan analysis. Measurements:Animals were ventilated in supine (n = 15) or prone (n = 15) position until a similar ventilator-induced lung injury was reached. To do so, experiments were interrupted when respiratory system elastance was 150% of baseline. Ventilator-induced lung injury was assessed as lung wet-to-dry ratio and histology. Time to reach lung injury was considered as a main outcome measure. In five additional animals, computed tomography scans (GE Light Speed QX/I, thickness 1.25 mm, interval 0.6 mm, 100 MA, 100 Kv) were randomly taken at end-expiration and end-inspiration in both positions, and quantitative analysis was performed. Data are shown as mean ± sd. Measurements and Main Results:Similar ventilator-induced lung injury was reached (respiratory system elastance, wet-to-dry ratio, and histology). The time taken to achieve the target ventilator-induced lung injury was longer with prone position (73 ± 37 mins vs. 112 ± 42, supine vs. prone, p = .011). Computed tomography scan analysis performed before lung injury revealed that at end-expiration, the lung was wider in prone position (p = .004) and somewhat shorter (p = .09), despite similar lung volumes (p = .455). Lung density along the vertical axis increased significantly only in supine position (p = .002). Lung strain was greater in supine as opposed to prone position (width strain, 7.8 ± 1.8% vs. 5.6 ± 0.9, supine vs. prone, p = .029). Conclusions:Prone position delays the progression of ventilator-induced lung injury. Computed tomography scan analysis suggests that a more homogeneous distribution of strain may be implicated in the protective role of prone position against ventilator-induced lung injury.

Prone Position in Acute Respiratory Distress Syndrome. Rationale, Indications, and Limits

In the prone position, computed tomography scan densities redistribute from dorsal to ventral as the dorsal region tends to reexpand while the ventral zone tends to collapse. Although gravitational influence is similar in both positions, dorsal recruitment usually prevails over ventral derecruitment, because of the need for the lung and its confining chest wall to conform to the same volume. The final result of proning is that the overall lung inflation is more homogeneous from dorsal to ventral than in the supine position, with more homogeneously distributed stress and strain. As the distribution of perfusion remains nearly constant in both postures, proning usually improves oxygenation. Animal experiments clearly show that prone positioning delays or prevents ventilation-induced lung injury, likely due in large part to more homogeneously distributed stress and strain. Over the last 15 years, five major trials have been conducted to compare the prone and supine positions in acute respiratory distress syndrome, regarding survival advantage. The sequence of trials enrolled patients who were progressively more hypoxemic; exposure to the prone position was extended from 8 to 17 hours/day, and lung-protective ventilation was more rigorously applied. Single-patient and meta-analyses drawing from the four major trials showed significant survival benefit in patients with PaO2/FiO2 lower than 100. The latest PROSEVA (Proning Severe ARDS Patients) trial confirmed these benefits in a formal randomized study. The bulk of data indicates that in severe acute respiratory distress syndrome, carefully performed prone positioning offers an absolute survival advantage of 10-17%, making this intervention highly recommended in this specific population subset.

Bedside selection of positive end-expiratory pressure in mild, moderate, and severe acute respiratory distress syndrome.

Objective:Positive end-expiratory pressure exerts its effects keeping open at end-expiration previously collapsed areas of the lung; consequently, higher positive end-expiratory pressure should be limited to patients with high recruitability. We aimed to determine which bedside method would provide positive end-expiratory pressure better related to lung recruitability. Design:Prospective study performed between 2008 and 2011. Setting:Two university hospitals (Italy and Germany). Patients:Fifty-one patients with acute respiratory distress syndrome. Interventions:Whole lung CT scans were taken in static conditions at 5 and 45 cm H2O during an end-expiratory/end-inspiratory pause to measure lung recruitability. To select individual positive end-expiratory pressure, we applied bedside methods based on lung mechanics (ExPress, stress index), esophageal pressure, and oxygenation (higher positive end-expiratory pressure table of lung open ventilation study). Measurements and Main Results:Patients were classified in mild, moderate and severe acute respiratory distress syndrome. Positive end-expiratory pressure levels selected by the ExPress, stress index, and absolute esophageal pressures methods were unrelated with lung recruitability, whereas positive end-expiratory pressure levels selected by the lung open ventilation method showed a weak relationship with lung recruitability (r2 = 0.29; p < 0.0001). When patients were classified according to the acute respiratory distress syndrome Berlin definition, the lung open ventilation method was the only one which gave lower positive end-expiratory pressure levels in mild and moderate acute respiratory distress syndrome compared with severe acute respiratory distress syndrome (8 ± 2 and 11 ± 3 cm H2O vs 15 ± 3 cm H2O; p < 0.05), whereas ExPress, stress index, and esophageal pressure methods gave similar positive end-expiratory pressure values in mild, moderate, and severe acute respiratory distress syndrome. The positive end-expiratory pressure selected by the different methods were unrelated to each other with the exception of the two methods based on lung mechanics (ExPress and stress index). Conclusions:Bedside positive end-expiratory pressure selection methods based on lung mechanics or absolute esophageal pressures provide positive end-expiratory pressure levels unrelated to lung recruitability and similar in mild, moderate, and severe acute respiratory distress syndrome, whereas the oxygenation-based method provided positive end-expiratory pressure levels related with lung recruitability progressively increasing from mild to moderate and severe acute respiratory distress syndrome.