ORIGINAL ARTICLE Lung Inhomogeneity in Patients with Acute Respiratory Distress Syndrome Massimo Cressoni1, Paolo Cadringher1, Chiara Chiurazzi1, Martina Amini1, Elisabetta Gallazzi1, Antonella Marino1, Matteo Brioni1, Eleonora Carlesso1, Davide Chiumello2, Michael Quintel3, Guillermo Bugedo4, and Luciano Gattinoni1,2 1
Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Milan, Italy; 2Dipartimento di Anestesia, Rianimazione e Terapia del Dolore, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy; 3Department of Anesthesiology, Emergency and Intensive Care Medicine, GeorgAugust University of Gottingen, ¨ Gottingen, ¨ Germany; and 4Departimentos de Anestesiologia y Medicina Intensiva, Facultad de Medicina, Pontificia Universitad Catolica de Chile, Santiago, Chile
Abstract 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).
Ventilator-induced lung injury (VILI) is a well-recognized side effect of mechanical ventilation when applied to patients with acute respiratory distress syndrome (ARDS) (1, 2), chronic obstructive pulmonary disease exacerbation (3), and even to patients with healthy lungs during surgical
Measurements and Main Results: The extent of lung inhomogeneities increased with the severity of ARDS (14 6 5, 18 6 8, and 23 6 10% of lung volume in mild, moderate, and severe ARDS; P , 0.001) and correlated with the physiologic dead space (r2 = 0.34; P , 0.0001). The application of positive end-expiratory pressure reduced the extent of lung inhomogeneities from 18 6 8 to 12 6 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 6 9 vs. 17 6 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. Keywords: mechanical ventilation; acute respiratory distress
syndrome; ventilator-induced lung injury
procedures (4–6). The primary cause of VILI is an unphysiologic strain and stress applied to the extracellular lung matrix, which may be considered as the “lung skeleton” (7, 8). However, to damage the healthy lung with mechanical ventilation, in experimental settings it is necessary to
apply tidal volumes as high as 30–70 ml/kg (9–11), whereas only 12 ml/kg are known to induce harm in ARDS lung (12, 13). Several hypothesis can be made to explain this discrepancy. First, in injured lung further damage develops at lower stress and strain (second hit hypothesis) (14). Second,
( Received in original form August 30, 2013; accepted in final form November 19, 2013 ) Supported in part by an Italian grant provided by Fondazione Fiera di Milano for Translational and Competitive Research (2007 to L.G.) and by the ESICM Bernhard Drager ¨ Award for Advanced Treatment of Acute Respiratory Failure. Author Contributions: Conception and design, L.G., P.C., and M.C. Acquisition of data, D.C., C.C., M.C., E.G., A.M., M.B., G.B., and M.Q. Analysis and interpretation of data, L.G., M.C., C.C., M.A., A.M., M.B., and E.C. Drafting of the manuscript, L.G., M.C., C.C., M.A., and A.M. Critical revision of the manuscript for important intellectual content, all authors. Statistical analysis, L.G., M.C., C.C., M.A., A.M., and E.C. Correspondence and requests for reprints should be addressed to Luciano Gattinoni, M.D., Dipartimento di Anestesia, Rianimazione (Intensiva e Subintensiva) e Terapia del Dolore, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy. E-mail: [email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 189, Iss 2, pp 149–158, Jan 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201308-1567OC on November 21, 2013 Internet address: www.atsjournals.org
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At a Glance Commentary Scientific Knowledge on the Subject:
Ventilator-induced lung injury (VILI) is a well-known side effect of mechanical ventilation. Pressures and volumes needed to induce VILI in healthy animals are far greater than pressure and volumes applied in clinical practice. A possible explanation may be the presence of local pressure multipliers (stress raisers). What This Study Adds to the Field:
Lung inhomogeneities were quantified and correlated with all the variables describing acute respiratory distress syndrome severity and outcome. Lung inhomogeneities may act regionally as stress raisers by multiplying the applied pressures by near 2. Increasing airway pressure decreased but did not abolish the lung inhomogeneities determined by CT scan.
the “baby lung” is so small that even low tidal volumes lead to overdistension of the ventilatable lung parenchyma (15). Third, in an injured inhomogeneous lung parenchyma the stress and strain are unevenly distributed with localized increase of stress, as described on a theoretical background by Mead and coworkers (16). According to this, the regional inhomogeneity may act as “stress raisers.” If so, a transpulmonary pressure that is safe in a homogeneous lung, if multiplied sufficiently by regional stress raisers, may locally reach harmful levels for the lung structure. On this background, we aimed to quantify the lung inhomogeneity of patients with ARDS by computed tomography (CT). To do so we analyzed whole-lung parenchyma by comparing a given lung region (approximately acinar dimension) with its neighboring regions: if the gas fraction (a surrogate of strain) was the same in the region studied and its neighbors, their ratio would have been equal to 1 (perfect homogeneity), whereas if the gas fraction was greater in the neighboring regions (ratio .1) we assumed that these regions were more strained and the region in study could act on its neighbors as a stress raiser. In this paper we describe
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Figure 1. Two-dimensional representation of the algorithm used for the lung inhomogeneity computation. The grid represents the individual voxels seen from above and below. Circle radii and voxels are represented in scale (each voxel is 0.73 3 0.73 mm). The central voxel is represented in black and the two radii determining the spherical crust are indicated. All the voxels included, even partially, in the spherical crust were included in the analysis. The stress raiser was computed as the maximum of the vector of ratios between the gas fraction of the voxels included in the spherical crust and the gas fraction of the central voxel.
the quantitative distribution of the lung inhomogeneities and their relationship with ARDS severity (17) and with the main relevant physiologic variables and outcome in a population of 148 patients with ARDS. Some of the results of these studies have been previously reported in the form of an abstract (18).
Methods We retrospectively analyzed a database of 148 patients previously enrolled in four clinical trials (see online supplement for detailed information) who underwent a whole-lung CT scan at different pressure levels. Patients were classified as mild, moderate, and severe ARDS according the Berlin definition (17). A control group of 100 spontaneous breathing subjects without ARDS who underwent lung CT scan at end inspiration (19) was studied for comparison. CT Scan Analysis
Lung profiles were manually drawn in each CT section, and images were analyzed with dedicated software (Soft-EFilm; www.elekton.it, Milan, Italy). Lung parenchyma was classified according to its gas/tissue ratio into not-inflated, poorly inflated, well-inflated, and overinflated
tissue (20). Lung recruitability was defined as the fraction of lung tissue that is not inflated at 5 cm H2O positive endexpiratory pressure (PEEP) and regains inflation at 45 cm H2O airway pressure. Assessment of Stress Raisers
A homogeneous lung would have the same gas/tissue ratio in all its regions. If a lung region expands less than the neighboring regions, the neighboring regions are more strained to compensate for the nonexpanding or less-expanding region. Therefore, the less expanded and nonexpanded regions act as stress raisers and are characterized by an increased local pressure/stress. Accordingly, the presence of neighboring regions with different inflation through the lung parenchyma indicates the presence of stress raisers. We measured the lung inhomogeneities by computing, voxel by voxel, the ratio between the gas fraction of each voxel (weighted by the surrounding voxels using a Gaussian filter with the size of one acinus, 2.41 mm) and a spherical crust starting at 2.41 mm (radius of an acinus at FRC) and ending at 3.675 mm (equal to the radius of an acinus at FRC 3 0.5) (7). If the inflation is the same (homogeneity) the ratio is equal to 1; if the inflation of the surrounding regions is greater than the region of interest (i.e., more strained) the ratio between
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ORIGINAL ARTICLE the two is greater than 1 and was taken as a measure of stress raiser (see Figure 1). However, our assessment of inhomogeneity is always relative (between two neighboring units) because we lack an absolute reference standard. See the online supplement for details. A representative false-color map of lung inhomogeneities in healthy subjects and patients is shown in Figure 2. We considered as pathologic lung inhomogeneities the regions showing
a value greater than the 95th percentile of the control group (1.61). We defined as “extent” of the lung inhomogeneities the fraction of lung volume including pathologic lung inhomogeneities and as “intensity” the average value of the lung inhomogeneities included in that fraction. Statistical Methods
Physiologic and CT scan data between mild, moderate, and severe ARDS according to the Berlin definition (17) were compared
with one-way analysis of variance or Kruskal-Wallis test, as appropriate. Multiple comparisons were performed with the Bonferroni correction. Relationships between physiologic and CT scan variables and lung inhomogeneities were assessed with linear regression. The relationship between lung inhomogeneities and outcome was studied with multivariate logistic regression. The R software was used for statistical analysis (21).
Figure 2. False-color images of the lung inhomogeneities superimposed to computed tomography (CT) scan images of representative subjects. Light blue = stress raisers , 1.61, orange = stress raisers between 1.61 and 3, red = stress raisers . 3. (A) Representative image of a control subject taken at end-inspiration. (B–D) Representative images of patients with mild, moderate, and severe acute respiratory distress syndrome (ARDS) taken a 5 cm H2O positive end-expiratory pressure (PEEP). (B) Representative CT slice of the lung obtained at the level of lung hilum at 5 cm H2O PEEP. ARDS developed in the patient after an episode of necrotizing fasciitis (PaO2/FIO2 240; PaCO2 38.1 mm Hg; lung recruitability 11.4%; VD/VT 44%; lung inhomogeneity extent 18.3% at 5 cm H2O PEEP). (C) Representative CT slice of the lung obtained at the level of lung hilum at 5 cm H2O PEEP. ARDS was caused by pneumonia in a bone marrow transplant recipient (PaO2/FIO2 137; PaCO2 51 mm Hg; lung recruitability 10%; VD/VT 60%; lung inhomogeneity extent 32% at 5 cm H2O PEEP). (D) Representative CT slice of the lung obtained at the level of lung hilum at 5 cm H2O PEEP. ARDS was caused by viral pneumonia (PaO2/FIO2 66; PaCO2 47.8 mm Hg; lung recruitability 10%; VD/VT 66%; stress raisers extent 32% at 5 cm H2O PEEP). Differences of light blue intensity are caused by the overlapping between the underlying CT scanning images and the false-color map of lung inhomogeneities.
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ORIGINAL ARTICLE Results Lung Inhomogeneities in Healthy Patients and Patients with ARDS
Figure 3 shows the frequency distribution of lung inhomogeneities in patients with ARDS and control subjects. As shown, lung inhomogeneities greater than the 95th percentile of the control group (1.61) that we arbitrary considered abnormal were 5 6 2% in the control patients and 18 6 8% in the patients with ARDS. Moreover, lung inhomogeneities in healthy subjects seem to be primarily located at the pleural surface and at the interface with bronchi and vessels, whereas in patients with ARDS they are distributed through the lung parenchyma primarily at the interface between “healthy” and “diseased” lung regions, of different densities (Figure 2). Lung Inhomogeneities in Mild, Moderate, and Severe ARDS
Table 1 shows the characteristics of the study population, divided into mild, moderate, and severe ARDS using the PaO2/FIO2 threshold defined in Berlin, where PaO2/FIO2 (17) was measured at standard PEEP of 5 cm H2O. As shown there was a progressive deterioration of
Figure 3. Frequency distribution of lung inhomogeneities in patients with acute respiratory distress syndrome (ARDS) and healthy control subjects. White bars represent healthy control subjects; black bars represent patients with ARDS. Statistical analysis was performed with two-way analysis of variance on ranked data using as classification factors the lung inhomogeneity class (0–1.61, 1.61–2, 2–2.5, .2.5) and the healthy/ARDS status of the subject; both the classification factors and the interaction were highly significant (P , 0.0001); we performed post hoc tests comparing healthy control subjects with patients with ARDS within each lung inhomogeneity class using the Bonferroni correction. *P , 0.05 healthy subjects versus patients with ARDS. Only 2 6 1% of the lung volumes in patients with ARDS and 0.0008 6 0.00052% of healthy subjects had lung inhomogeneities below 1.
gas exchange from mild to severe ARDS, whereas the anthropometric characteristic, the causes leading to ARDS, and respiratory
mechanics were similar in the three subgroups. In Table 2 we report the main CT scan variables measured at 5 cm H2O
Table 1: Baseline Characteristics of the Study Population
Age, yr Female sex, no. (%) Body mass index, kg/m2 SAPS II Tidal volume, ml/kg Plateau pressure, cm H2O Respiratory system compliance, cm H2O Minute ventilation, L/min PaO2/FIO2 Fraction of inspired oxygen, % PaCO2, mm Hg Arterial pH Cause of lung ARDS, no. (%) Pneumonia Sepsis Aspiration Trauma Other
Mild ARDS (33 Patients)
Moderate ARDS (94 Patients)
Severe ARDS (21 Patients)
56.8 6 16.4 11 (33) 26.3 6 4.7 39.2 6 12.2 8.6 6 1.6 18.5 6 3.1 45 6 14 9.3 6 2.6 247 6 38*† 40 6 7*† 39.9 6 6.2*† 7.402 6 0.075
60.0 6 16.5 30 (32) 25.6 6 4.8 42.5 6 15.6 8.4 6 1.5 18.9 6 3.8 43 6 15 9.0 6 2.3 146 6 28* 50 6 11* 43.9 6 8.5* 7.388 6 0.076
59.3 6 16.8 8 (38) 28.0 6 9.2 45.2 6 13.3 8.2 6 1.6 19.6 6 4.3 40 6 18 10.1 6 2.4 73 6 14 80 6 15 49.4 6 8.6 7.362 6 0.073
8 14 2 3 6
(5) (9) (1) (2) (4)
42 25 8 7 12
(28) (17) (5) (5) (8)
14 3 1 0 3
P Value 0.64 0.85 0.19 0.32 0.59 0.61 0.53 0.12 ,0.0001 ,0.0001 ,0.001 0.17 0.14
(9) (2) (1) (0) (2)
Definition of abbreviations: ARDS = acute respiratory distress syndrome; SAPS = Simplified Acute Physiology Score. Plus–minus values are means 6 SD. Because of rounding, percentages may not total 100. The body mass index is the weight in kilograms divided by the square of the height in meters. P values were obtained by analysis of variance, Kruskal-Wallis test, or Fisher exact test, as appropriate; the Bonferroni correction was used for multiple comparisons. SAPS II was used to assess the severity of systemic illness at study entry. Scores can range from 0 to 163, with higher scores indicating more severe illness. Respiratory system compliance was calculated as the ratio of the tidal volume to the difference between inspiratory plateau pressure and positive end-expiratory pressure. *P , 0.05 versus severe ARDS. † P , 0.05 versus moderate ARDS.
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ORIGINAL ARTICLE Table 2: Computed Tomography Scan Variables Mild ARDS Total lung tissue, g Total gas, ml Lung recruitability, % Not inflated tissue, % Poorly inflated tissue, % Well-inflated tissue, % Overinflated tissue, %
1,255 1,355 8 31 31 38 0
6 6 6 6 6 6 6
Moderate ARDS
263* 505 7*† 13*† 11 11*† 0
1,446 1,241 14 40 32 27 0
6 6 6 6 6 6 6
479* 681 10* 15* 12 13* 1
Severe ARDS 1,957 1,087 20 49 32 18 0
6 6 6 6 6 6 6
P Value ,0.0001 0.35 ,0.0001 ,0.0001 0.87 ,0.0001 0.66
604 769 13 17 13 14 2
Definition of abbreviation: ARDS = acute respiratory distress syndrome. Plus–minus values are means 6 SD. Because of rounding, percentages may not total 100. P values were obtained by analysis of variance, Kruskal-Wallis test, or Fisher exact test, as appropriate; the Bonferroni correction was used for multiple comparisons. Lung recruitability was available in 141 patients (31 mild ARDS, 89 moderate ARDS, and 21 severe ARDS). *P , 0.05 versus severe ARDS. † P , 0.05 versus moderate ARDS.
PEEP in mild, moderate, and severe ARDS. As shown, from mild to severe ARDS there is a progressive decrease in well-aerated tissue (the baby lung) (22) associated with a significant increase of noninflated tissue, whereas the amount of overinflated and poorly inflated tissue were similar in the two groups. In Table 3 we report the average values of the lung inhomogeneities in mild, moderate, and severe ARDS; their extent; and their intensity. As shown, the mean values of lung inhomogeneities significantly increased from mild to severe ARDS. Interestingly, however, the intensity of the lung inhomogeneities was similar in mild, moderate, and severe ARDS. What significantly changed was the extent of the
lung inhomogeneities, which significantly increased from mild to severe ARDS, from 14 to 23%. Therefore, we may estimate that abnormal lung inhomogeneities represent 14–23% of the lung volume and it is possible to speculate that in these fractions of lung volume the stress may be almost double the transpulmonary pressure applied to the whole lung (multiplication factor z1.88 6 0.09). Spatial Distribution of Lung Inhomogeneities
Figure 4 shows the distribution of the abnormal lung inhomogeneities (with values .1.61) along the sternum–vertebral axis; as shown, the greater concentration of the lung inhomogeneities in mild and
moderate ARDS is in the most dependent lung regions, whereas it shifts to the middle lung in severe ARDS. This regional distribution should correspond to regional distribution of the VILI. The distribution of the lung inhomogeneities along the apicocaudal axis, in contrast, was similar in the mild, moderate, and severe ARDS, although quantitatively increasing from mild to severe ARDS (data not shown). Lung Inhomogeneities and Physiologic and CT Scan Variables
We found several correlations between the extent of lung inhomogeneities and physiologic variables as PaO2/FIO2 (PaO2/FIO2 = 208 2 279 3 lung inhomogeneity extent; P , 0.0001; r2 = 0.13), physiologic shunt (shunt fraction = 0.26 1 0.68 3 lung inhomogeneity extent; P , 0.0001; r2 = 0.15; shunt fraction was available in 140 patients), and plateau pressure (plateau pressure [cm H2O] = 15 1 22 3 lung inhomogeneity extent; P , 0.0001; r2 = 0.21). The most striking correlation, however, was with the dead space fraction (Figure 5) (lung inhomogeneity extent = 0.41 1 0.93 3 VD/VT; r2 = 0.34; P , 0.0001; physiologic dead space fraction was available in 124 patients). The lung inhomogeneity extent was associated with several CT scan variables: we found a positive correlation with lung weight (lung inhomogeneity extent = 0.088 1 6.26 3 1025 3 lung weight [g];
Table 3: Average and Extent of Lung Inhomogeneities PEEP (cm H2O) Average lung inhomogeneities Extent of lung inhomogeneities Intensity of lung inhomogeneities
5 15 45 5 15 45 5 15 45
Healthy Subjects
1.15 6 0.05 0.05 6 0.02 2.26 6 0.24
Mild ARDS 1.34 1.31 1.27 0.14 0.12 0.10 2.62 2.76 2.88
6 6 6 6 6 6 6 6 6
0.09* 0.10 0.09* 0.05*† 0.04 0.04 0.22 0.26 0.26
Moderate ARDS 1.38 1.36 1.31 0.18 0.16 0.12 2.57 2.63 2.77
6 6 6 6 6 6 6 6 6
0.12 0.14 0.13* 0.08* 0.08 0.07 0.18 0.25 0.22
Severe ARDS 1.45 1.42 1.40 0.23 0.20 0.18 2.53 2.60 2.71
6 6 6 6 6 6 6 6 6
0.16 0.16 0.14 0.10 0.09 0.08 0.21 0.27 0.32
P Value 0.01 0.09 ,0.001 ,0.001 0.01 ,0.0001 0.22 0.08 0.04
Definition of abbreviations: ARDS = acute respiratory distress syndrome; PEEP = positive end-expiratory pressure. Plus–minus values are means 6 SD. Because of rounding, percentages may not total 100. P values were obtained by analysis of variance; the Bonferroni correction was used for multiple comparisons. “Extent of lung inhomogeneities” refers to the fraction of lung volume that presented a lung inhomogeneity greater than 1.61 (95th percentile of healthy subjects). “Intensity of lung inhomogeneities” refers to the average stress raiser of the voxels presenting a lung inhomogeneity greater than 1.61 (95th percentile of healthy subjects). Data at PEEP 15 cm H2O were available in 89 patients (24 mild, 55 moderate, and 10 severe ARDS). Data at PEEP 45 cm H2O were available in 141 patients (31 mild, 89 moderate, and 21 severe ARDS). Data from comparisons population were added in the row relative to 45 cm H2O pressure because computed tomography scan images were taken at end-inspiration. Data from healthy patients were not included in the statistics. *P , 0.05 versus severe ARDS. † P , 0.05 versus moderate ARDS.
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ORIGINAL ARTICLE P , 0.0001) (Figure 6A). A positive correlation, however, was found between the lung inhomogeneities and the poorly aerated tissue (lung inhomogeneity extent = 0.06 1 0.39 3 poorly inflated tissue [fraction]; r2 = 0.35; P , 0.0001), as shown in Figure 6B. Lung Inhomogeneities at Different Airway Pressures
Figure 4. Distribution of lung inhomogeneities (with values . 1.61) along the sternum–vertebral axis. Bar height represents the median of the lung inhomogeneity extent along 10 sternum–vertebral segments; error bars represent the third quartile of lung inhomogeneity extent. The first bar (light gray) represents control subjects, whereas the black, dark gray, and white bars represent mild, moderate, and severe patients with acute respiratory distress syndrome (ARDS). To compare the distribution between mild, moderate, and severe ARDS we fit a Gaussian function along the median points [f = y0 1 a 3 exp(20.5 3 [(x 2 x0)/b]2)]; no statistics were performed on control subjects that do not exhibit a particular sternum–vertebral pattern. Function peak value was at sternum–vertebral level 6.31 (standard error 0.18) for severe ARDS, 7.98 (standard error 0.13) for moderate ARDS, and 8.84 (standard error 0.08) for mild ARDS. The three Gaussian distributions computed on medians were compared with one-way analysis of variance (P = 0.0007) and post hoc test was performed with the Bonferroni correction. The position of the peak of mild ARDS was significantly different from severe ARDS (P = 0.008), whereas moderate and severe ARDS peaks (P = 0.05) and moderate and mild ARDS (P = 1) were not different.
r2 = 0.16; P , 0.0001) (see Figure E7 in the online supplement) and a weak but significant correlation with noninflated tissue (lung inhomogeneity extent = 0.14 1 0.092 3 fraction of not inflated tissue; r2 =
0.03; P = 0.02) (see Figure E8), whereas we measured a negative correlation with the fraction of well-inflated tissue (lung inhomogeneity extent = 0.29 – 0.39 3 well-inflated tissue [fraction]; r2 = 0.47;
Figure 5. Relationship between lung inhomogeneity extent and physiologic dead space measured at positive end-expiratory pressure (PEEP) 5 cm H2O. Physiologic dead space (%) = 0.41 1 0.93 3 lung inhomogeneity extent; r2 = 0.34; P , 0.0001. Physiologic dead space was available in 124 patients.
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The lung inhomogeneity pattern at airway pressure of 5, 15, and 45 cm H2O is summarized in Table 3. As shown, the average values of the lung inhomogeneities slightly but significantly decreased. Moreover, their extent significantly decreased by 18 6 18% increasing PEEP from 5 to 15 cm H2O and by 30 6 22% increasing the airway pressure from 5 cm H2O to a plateau pressure of 45 cm H2O airway pressure, suggesting a more homogeneous lung at higher airway pressures. The lung inhomogeneity extent at PEEP 15 cm H2O and at 45 cm H2O airway pressure was highly correlated with the lung inhomogeneities extent at PEEP 5 cm H 2 O (lung inhomogeneity extent PEEP 15 cm H2 O = 20.0035 1 0.85 3 lung inhomogeneity extent PEEP 5 cm H 2 O; r2 = 0.83; P , 0.0001; Figure 7A) (lung inhomogeneity extent 45 cm H 2 O airway pressure = 0.0073 1 0.65 3 lung inhomogeneity extent PEEP 5 cm H 2 O; r2 = 0.59; P , 0.0001; Figure 7B). Interestingly, 15 patients (17%) increased instead of decreased their lung inhomogeneity extent while increasing PEEP from 5 to 15 cm H2O and 11 patients (8%) going from 5 to 45 cm H2O endinspiratory pressure. This was primarily related to the behavior of the poorly aerated tissue: in the 11 patients in whom the lung inhomogeneities unexpectedly increased increasing the pressure from 5 to 45 cm H2O the poorly aerated tissue also increased by 12 6 8%. In contrast, in the remaining 130 patients where the lung inhomogeneities decreased increasing pressure, the poorly aerated tissue also decreased by 7 6 10%. The changes of the lung inhomogeneity extent and the poorly aerated fraction changes with PEEP were significantly correlated over the range of pressures we explored (D lung inhomogeneity extent [5 – 45 cm H2O] = 20.045 1 0.21 3 D fraction of poorly inflated tissue [5 – 45 cm H2O]; r2 = 0.21; P , 0.0001) (see Figure E9).
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ORIGINAL ARTICLE extent). We added in the logistic regression the fractions of poorly inflated and noninflated tissues, not significantly different between survivors and nonsurvivors, which were considered markers of overall severity. Among the CT-derived variables entered in the regression the only one independently associated with outcome was the extent of the abnormal lung inhomogeneities (P = 0.65 by the Hosmer-Lemeshow goodness-of-fit statistics; C = 0.62). The odds ratio for each percent point increase of the lung inhomogeneity extent was 1.062 (95% confidence interval, 1.015–1.11).
Discussion
Figure 6. (A) Relationship between lung inhomogeneity extent and the fraction of well-inflated tissue (computed tomography [CT] value between 2500 and 2900 HU) measured at positive end-expiratory pressure (PEEP) 5 cm H2O. Well-inflated tissue (fraction) = 0.51- 1.25 3 lung inhomogeneity extent; r2 = 0.47; P , 0.0001. (B) Relationship between lung inhomogeneity extent and the fraction of poorly inflated tissue (CT value between 2100 and 2500 HU) measured at PEEP 5 cm H2O. Poorly inflated tissue (fraction) = 0.15 1 0.91 3 lung inhomogeneity extent; r2 = 0.35; P , 0.0001.
Lung Inhomogeneities and Lung Recruitability
We found that the recruitability, measured between 5 and 45 cm H2O, was not significantly related with the extent decrease of lung inhomogeneities from 5 to 45 cm H2O (P = 0.09) (see Figure E10). However, if we consider that the relationship between recruitability and lung inhomogeneities changes only in the patients in whom the poorly aerated tissue decreased (104 patients out of 141) we found that the relationship becomes significant (D lung inhomogeneity extent = 0.031 1 0.36 3 lung recruitability; r2 = 0.39; P , 0.0001) (see Figure E11). In contrast, no correlation between
recruitability and the lung inhomogeneity extent was observed in the patients (37 patients) in which the poorly aerated tissue increased while increasing pressure (P = 0.30) (see Figure E12). Lung Inhomogeneities and Outcome
The lung inhomogeneity extent was significantly higher in the 51 patients who died compared with the 97 patients who survived (20 6 9 vs. 17 6 7%; P = 0.01). We performed a multivariate backward logistic regression model to study the association between CT scan variables that were different between survivors and nonsurvivors (lung recruitability, well-inflated tissue, lung inhomogeneity
Cressoni, Cadringher, Chiurazzi, et al.: Lung Inhomogeneity in ARDS
In this study we attempted to quantify the inhomogeneities of the lung parenchyma whose prevention and correction represents the theoretical basis of the open lung strategy as modeled by Mead and coworkers (16) and proposed by Lachmann (23). Briefly, when a force is applied to a theoretical homogeneous lung, it is evenly distributed through the lung skeleton (the extracellular matrix), so that each fiber bears the same load (8). If the lung is not homogenous (e.g., because of the presence of local atelectasis or consolidation), the fibers neighbor to the unexpanded lung region must carry the additional load of the nonexpanding fibers, therefore locally increasing their stress and strain. Mead and coworkers (16) estimated that the ratio between the volume of two neighboring regions, one totally expanded and the other totally collapsed, is 10:1 at 30 cm H2O transpulmonary pressure, and the local pressure (stress) is 30 3 (V1/V0)2/3 = 30 3 (10/1)2/3 = z140 cm H2O being the two-third power the scale factor to pass from volumes to areas. In this study, as measure of the strain (i.e., distention) we used the gas/tissue ratio computed from CT scan density (24); if a lung region does not expand or expands less, the neighboring regions carrying their load are more strained (and stressed) and present a higher gas/tissue ratio. Unfortunately, although the stress caused by material inhomogeneity may be quantified in the engineering field, it is impossible to measure it directly in the lung (8). In particular alveolar level information cannot be obtained from CT scan 155
ORIGINAL ARTICLE
Figure 7. (A) Relationship between the lung inhomogeneity extent determined at positive endexpiratory pressure (PEEP) 5 cm H2O and at PEEP 15 cm H2O. Lung inhomogeneity extent at PEEP 15 cm H2O = 20.0035 1 0.85 3 lung inhomogeneity extent PEEP 5 cm H2O; r2 = 0.83; P , 0.0001. (B) Relationship between the lung inhomogeneity extent measured at 5 cm H2O and at 45 cm H2O end inspiration. Lung inhomogeneity extent at 45 cm H2O end inspiration = 0.0073 1 0.65 3 lung inhomogeneity extent PEEP 5 cm H2O; r2 = 0.59; P , 0.0001.
measurements. Therefore, it is possible that the association we found between our measurements and the overall ARDS severity are simply explained by the presence of more or less edema in different lung regions independently on local pressure multiplication. It is worth remembering, however, that the theory on which the lung protective strategy is based is the presence of stress raisers. Indeed, with these limitations in mind, we proceed in our discussion assuming that the underlying disease generates lung inhomogeneities, which, in turn, act as a stress raiser, further disrupting lung parenchyma. Because the normal lung parenchyma is inhomogeneous due to airways, vessels, 156
and the visceral pleura, we used 100 subjects as control group (19) to define the control inhomogeneity. In these control subjects we found that the average 95th percentile of inhomogeneity was 1.61. Accordingly, we defined as abnormal lung inhomogeneities the regions with value greater than 1.61 (intensity) and we computed the fraction of lung volume represented by these regions (extent). We found that the lung inhomogeneities increased with ARDS severity, were positively associated with dead space fraction and poorly aerated tissue, decreased when PEEP was increased, and were independently associated with outcome. As shown in Table 3, the average values of the lung inhomogeneity intensity
were similar in mild, moderate, and severe ARDS and did not change significantly increasing pressure from 5 to 45 cm H2O. In its theoretical model Mead and coworkers (16) computed the multiplication factor between open and closed regions as high as (10/1)2/3 = 4.64. In this study we found that this average multiplication factor was (2.62)2/3 = 1.9; this suggests that at the interfaces of interest the applied transpulmonary pressure should induce a stress almost double. Although the intensity of the lung inhomogeneities was similar in mild, moderate, and severe ARDS what actually changed was their extent. In normal animals the applied transpulmonary pressure becomes lethal when it approaches the total lung capacity (9); by inference, one may speculate that in humans an “innocent” applied transpulmonary pressure of 12 cm H2O may locally result in a harmful stress of 12 3 1.9 (intensity) = 22.8 cm H2O, which is in the range of total lung capacity of humans (25), and that this stress occurs in fractions of lung volume that sharply increase with ARDS severity. That the intensity of lung inhomogeneities was similar in mild, moderate, and severe ARDS may appear surprising. However, if we consider, for analogy, a pulmonary unit collapsed or consolidated the PO2 of the blood leaving this unit (the intensity of local hypoxemia) is obviously equal to the venous PO2 in mild, moderate, and severe ARDS. What determines the severity of the total hypoxemia is the number of units (extent), which generate different total shunt. Analogously, the stress raisers may be considered as local points that multiply the pressure at similar level (intensity), whereas the overall severity depends on the number of such points (extent). The physiologic dead space is likely the strongest predictor of the ARDS outcome because it is related, more than oxygenation, to the structural changes of the lung (26, 27). Of note, the only CT scan–derived variable significantly associated with dead space fraction was the lung inhomogeneity extent. This relationship has a sound anatomic and physiologic rationale because the inhomogeneity, and the dead space, is likely related to structural abnormalities of the ventilated lung fraction as capillary and alveolar wall destruction, presence of bullae or blebs, and fibrotic reactions.
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ORIGINAL ARTICLE These structural abnormalities may determine either the dead space fraction or the gas/tissue ratio inhomogeneities. Not surprisingly we found an inverse relationship between lung inhomogeneity extent and the well-aerated tissue that appears homogeneously inflated. In contrast, the fraction of the poorly aerated tissue is well associated with the extent of inhomogeneity ratio. This is quite interesting because, as far as we know, the pathophysiologic meaning of the poorly aerated tissue has never been fully understood in ARDS (but the obvious fact that this tissue is associated with less aeration). It is possible, however, that the poorly aerated tissue may be relevant in the development of VILI. Other factors, however, should be considered because the CT scan simply models the lung as “blood flow less” organ. The lung microcirculation, as an example, is prone to rupture depending on the interplay between trans-pulmonary pressure and hemodynamic conditions (28–30); this interaction is most marked in the most dependent lung regions initially and thereafter at the interphase between aerated and nonaerated lung tissue where lung inhomogeneities are prevalent. These findings, however, are not in contrast with the hypothesis that lung inhomogeneity may lead to pressure multiplication because the introduction of unphysiologic strain may lead to capillary lesions. The potential benefit of PEEP in the framework of lung protective strategy is to maintain open, at end-expiration, the lung parenchyma that has been recruited during inspiration phase, thus decreasing the lung inhomogeneity and the VILI (15, 16, 23). Actually, we found that
the lung inhomogeneities decreased increasing PEEP and, in addition, were significantly but weakly related with lung recruitability. In individual patients, however, recruitability, PEEP, and lung inhomogeneity pattern were not associated. A possible explanation is the behavior of the poorly aerated tissue. In fact, increasing pressure may lead to an absolute decrease of the poorly aerated tissue, a powerful source of inhomogeneity, or may lead to its increase, depending on the characteristics of the lung. If we consider only the patients in whom the poorly aerated tissue decreased with pressures, greater was the recruitability, greater was the decrease of the lung inhomogeneities when airway pressure was increased (see online supplement). These results suggest that, in the individual patient, PEEP may increase, not modify, or decrease the lung inhomogeneities, although in most patients, its favorable effects prevail. Mechanical ventilation is the common therapy of ARDS and over the decades huge efforts have been devoted to decrease its potential harms. Within the possible risk factors as FIO2 (31–33), respiratory rate (34), tidal volume (12), and PEEP (35–37), in the last years the greatest attention had been paid to the last two variables. The accepted view is that low tidal volume and higher PEEP may protect the lung by decreasing the stress and strain of the parenchyma: the low tidal volume by lowering the lung stress and strain and the higher PEEP by decreasing the lung inhomogeneity. In this paper we found that a consistent fraction of the lung, depending on ARDS severity, may be exposed to a stress twofold the transpulmonary pressure applied. We do not know the
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Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Milan, Italy; 2Dipartimento di Anestesia, Rianimazione e Terapia del Dolore, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy; 3Department of Anesthesiology, Emergency and Intensive Care Medicine, GeorgAugust University of Gottingen, ¨ Gottingen, ¨ Germany; and 4Departimentos de Anestesiologia y Medicina Intensiva, Facultad de Medicina, Pontificia Universitad Catolica de Chile, Santiago, Chile
Abstract 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).
Ventilator-induced lung injury (VILI) is a well-recognized side effect of mechanical ventilation when applied to patients with acute respiratory distress syndrome (ARDS) (1, 2), chronic obstructive pulmonary disease exacerbation (3), and even to patients with healthy lungs during surgical
Measurements and Main Results: The extent of lung inhomogeneities increased with the severity of ARDS (14 6 5, 18 6 8, and 23 6 10% of lung volume in mild, moderate, and severe ARDS; P , 0.001) and correlated with the physiologic dead space (r2 = 0.34; P , 0.0001). The application of positive end-expiratory pressure reduced the extent of lung inhomogeneities from 18 6 8 to 12 6 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 6 9 vs. 17 6 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. Keywords: mechanical ventilation; acute respiratory distress
syndrome; ventilator-induced lung injury
procedures (4–6). The primary cause of VILI is an unphysiologic strain and stress applied to the extracellular lung matrix, which may be considered as the “lung skeleton” (7, 8). However, to damage the healthy lung with mechanical ventilation, in experimental settings it is necessary to
apply tidal volumes as high as 30–70 ml/kg (9–11), whereas only 12 ml/kg are known to induce harm in ARDS lung (12, 13). Several hypothesis can be made to explain this discrepancy. First, in injured lung further damage develops at lower stress and strain (second hit hypothesis) (14). Second,
( Received in original form August 30, 2013; accepted in final form November 19, 2013 ) Supported in part by an Italian grant provided by Fondazione Fiera di Milano for Translational and Competitive Research (2007 to L.G.) and by the ESICM Bernhard Drager ¨ Award for Advanced Treatment of Acute Respiratory Failure. Author Contributions: Conception and design, L.G., P.C., and M.C. Acquisition of data, D.C., C.C., M.C., E.G., A.M., M.B., G.B., and M.Q. Analysis and interpretation of data, L.G., M.C., C.C., M.A., A.M., M.B., and E.C. Drafting of the manuscript, L.G., M.C., C.C., M.A., and A.M. Critical revision of the manuscript for important intellectual content, all authors. Statistical analysis, L.G., M.C., C.C., M.A., A.M., and E.C. Correspondence and requests for reprints should be addressed to Luciano Gattinoni, M.D., Dipartimento di Anestesia, Rianimazione (Intensiva e Subintensiva) e Terapia del Dolore, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy. E-mail: [email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 189, Iss 2, pp 149–158, Jan 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201308-1567OC on November 21, 2013 Internet address: www.atsjournals.org
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ORIGINAL ARTICLE
At a Glance Commentary Scientific Knowledge on the Subject:
Ventilator-induced lung injury (VILI) is a well-known side effect of mechanical ventilation. Pressures and volumes needed to induce VILI in healthy animals are far greater than pressure and volumes applied in clinical practice. A possible explanation may be the presence of local pressure multipliers (stress raisers). What This Study Adds to the Field:
Lung inhomogeneities were quantified and correlated with all the variables describing acute respiratory distress syndrome severity and outcome. Lung inhomogeneities may act regionally as stress raisers by multiplying the applied pressures by near 2. Increasing airway pressure decreased but did not abolish the lung inhomogeneities determined by CT scan.
the “baby lung” is so small that even low tidal volumes lead to overdistension of the ventilatable lung parenchyma (15). Third, in an injured inhomogeneous lung parenchyma the stress and strain are unevenly distributed with localized increase of stress, as described on a theoretical background by Mead and coworkers (16). According to this, the regional inhomogeneity may act as “stress raisers.” If so, a transpulmonary pressure that is safe in a homogeneous lung, if multiplied sufficiently by regional stress raisers, may locally reach harmful levels for the lung structure. On this background, we aimed to quantify the lung inhomogeneity of patients with ARDS by computed tomography (CT). To do so we analyzed whole-lung parenchyma by comparing a given lung region (approximately acinar dimension) with its neighboring regions: if the gas fraction (a surrogate of strain) was the same in the region studied and its neighbors, their ratio would have been equal to 1 (perfect homogeneity), whereas if the gas fraction was greater in the neighboring regions (ratio .1) we assumed that these regions were more strained and the region in study could act on its neighbors as a stress raiser. In this paper we describe
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Figure 1. Two-dimensional representation of the algorithm used for the lung inhomogeneity computation. The grid represents the individual voxels seen from above and below. Circle radii and voxels are represented in scale (each voxel is 0.73 3 0.73 mm). The central voxel is represented in black and the two radii determining the spherical crust are indicated. All the voxels included, even partially, in the spherical crust were included in the analysis. The stress raiser was computed as the maximum of the vector of ratios between the gas fraction of the voxels included in the spherical crust and the gas fraction of the central voxel.
the quantitative distribution of the lung inhomogeneities and their relationship with ARDS severity (17) and with the main relevant physiologic variables and outcome in a population of 148 patients with ARDS. Some of the results of these studies have been previously reported in the form of an abstract (18).
Methods We retrospectively analyzed a database of 148 patients previously enrolled in four clinical trials (see online supplement for detailed information) who underwent a whole-lung CT scan at different pressure levels. Patients were classified as mild, moderate, and severe ARDS according the Berlin definition (17). A control group of 100 spontaneous breathing subjects without ARDS who underwent lung CT scan at end inspiration (19) was studied for comparison. CT Scan Analysis
Lung profiles were manually drawn in each CT section, and images were analyzed with dedicated software (Soft-EFilm; www.elekton.it, Milan, Italy). Lung parenchyma was classified according to its gas/tissue ratio into not-inflated, poorly inflated, well-inflated, and overinflated
tissue (20). Lung recruitability was defined as the fraction of lung tissue that is not inflated at 5 cm H2O positive endexpiratory pressure (PEEP) and regains inflation at 45 cm H2O airway pressure. Assessment of Stress Raisers
A homogeneous lung would have the same gas/tissue ratio in all its regions. If a lung region expands less than the neighboring regions, the neighboring regions are more strained to compensate for the nonexpanding or less-expanding region. Therefore, the less expanded and nonexpanded regions act as stress raisers and are characterized by an increased local pressure/stress. Accordingly, the presence of neighboring regions with different inflation through the lung parenchyma indicates the presence of stress raisers. We measured the lung inhomogeneities by computing, voxel by voxel, the ratio between the gas fraction of each voxel (weighted by the surrounding voxels using a Gaussian filter with the size of one acinus, 2.41 mm) and a spherical crust starting at 2.41 mm (radius of an acinus at FRC) and ending at 3.675 mm (equal to the radius of an acinus at FRC 3 0.5) (7). If the inflation is the same (homogeneity) the ratio is equal to 1; if the inflation of the surrounding regions is greater than the region of interest (i.e., more strained) the ratio between
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 2 | January 15 2014
ORIGINAL ARTICLE the two is greater than 1 and was taken as a measure of stress raiser (see Figure 1). However, our assessment of inhomogeneity is always relative (between two neighboring units) because we lack an absolute reference standard. See the online supplement for details. A representative false-color map of lung inhomogeneities in healthy subjects and patients is shown in Figure 2. We considered as pathologic lung inhomogeneities the regions showing
a value greater than the 95th percentile of the control group (1.61). We defined as “extent” of the lung inhomogeneities the fraction of lung volume including pathologic lung inhomogeneities and as “intensity” the average value of the lung inhomogeneities included in that fraction. Statistical Methods
Physiologic and CT scan data between mild, moderate, and severe ARDS according to the Berlin definition (17) were compared
with one-way analysis of variance or Kruskal-Wallis test, as appropriate. Multiple comparisons were performed with the Bonferroni correction. Relationships between physiologic and CT scan variables and lung inhomogeneities were assessed with linear regression. The relationship between lung inhomogeneities and outcome was studied with multivariate logistic regression. The R software was used for statistical analysis (21).
Figure 2. False-color images of the lung inhomogeneities superimposed to computed tomography (CT) scan images of representative subjects. Light blue = stress raisers , 1.61, orange = stress raisers between 1.61 and 3, red = stress raisers . 3. (A) Representative image of a control subject taken at end-inspiration. (B–D) Representative images of patients with mild, moderate, and severe acute respiratory distress syndrome (ARDS) taken a 5 cm H2O positive end-expiratory pressure (PEEP). (B) Representative CT slice of the lung obtained at the level of lung hilum at 5 cm H2O PEEP. ARDS developed in the patient after an episode of necrotizing fasciitis (PaO2/FIO2 240; PaCO2 38.1 mm Hg; lung recruitability 11.4%; VD/VT 44%; lung inhomogeneity extent 18.3% at 5 cm H2O PEEP). (C) Representative CT slice of the lung obtained at the level of lung hilum at 5 cm H2O PEEP. ARDS was caused by pneumonia in a bone marrow transplant recipient (PaO2/FIO2 137; PaCO2 51 mm Hg; lung recruitability 10%; VD/VT 60%; lung inhomogeneity extent 32% at 5 cm H2O PEEP). (D) Representative CT slice of the lung obtained at the level of lung hilum at 5 cm H2O PEEP. ARDS was caused by viral pneumonia (PaO2/FIO2 66; PaCO2 47.8 mm Hg; lung recruitability 10%; VD/VT 66%; stress raisers extent 32% at 5 cm H2O PEEP). Differences of light blue intensity are caused by the overlapping between the underlying CT scanning images and the false-color map of lung inhomogeneities.
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ORIGINAL ARTICLE Results Lung Inhomogeneities in Healthy Patients and Patients with ARDS
Figure 3 shows the frequency distribution of lung inhomogeneities in patients with ARDS and control subjects. As shown, lung inhomogeneities greater than the 95th percentile of the control group (1.61) that we arbitrary considered abnormal were 5 6 2% in the control patients and 18 6 8% in the patients with ARDS. Moreover, lung inhomogeneities in healthy subjects seem to be primarily located at the pleural surface and at the interface with bronchi and vessels, whereas in patients with ARDS they are distributed through the lung parenchyma primarily at the interface between “healthy” and “diseased” lung regions, of different densities (Figure 2). Lung Inhomogeneities in Mild, Moderate, and Severe ARDS
Table 1 shows the characteristics of the study population, divided into mild, moderate, and severe ARDS using the PaO2/FIO2 threshold defined in Berlin, where PaO2/FIO2 (17) was measured at standard PEEP of 5 cm H2O. As shown there was a progressive deterioration of
Figure 3. Frequency distribution of lung inhomogeneities in patients with acute respiratory distress syndrome (ARDS) and healthy control subjects. White bars represent healthy control subjects; black bars represent patients with ARDS. Statistical analysis was performed with two-way analysis of variance on ranked data using as classification factors the lung inhomogeneity class (0–1.61, 1.61–2, 2–2.5, .2.5) and the healthy/ARDS status of the subject; both the classification factors and the interaction were highly significant (P , 0.0001); we performed post hoc tests comparing healthy control subjects with patients with ARDS within each lung inhomogeneity class using the Bonferroni correction. *P , 0.05 healthy subjects versus patients with ARDS. Only 2 6 1% of the lung volumes in patients with ARDS and 0.0008 6 0.00052% of healthy subjects had lung inhomogeneities below 1.
gas exchange from mild to severe ARDS, whereas the anthropometric characteristic, the causes leading to ARDS, and respiratory
mechanics were similar in the three subgroups. In Table 2 we report the main CT scan variables measured at 5 cm H2O
Table 1: Baseline Characteristics of the Study Population
Age, yr Female sex, no. (%) Body mass index, kg/m2 SAPS II Tidal volume, ml/kg Plateau pressure, cm H2O Respiratory system compliance, cm H2O Minute ventilation, L/min PaO2/FIO2 Fraction of inspired oxygen, % PaCO2, mm Hg Arterial pH Cause of lung ARDS, no. (%) Pneumonia Sepsis Aspiration Trauma Other
Mild ARDS (33 Patients)
Moderate ARDS (94 Patients)
Severe ARDS (21 Patients)
56.8 6 16.4 11 (33) 26.3 6 4.7 39.2 6 12.2 8.6 6 1.6 18.5 6 3.1 45 6 14 9.3 6 2.6 247 6 38*† 40 6 7*† 39.9 6 6.2*† 7.402 6 0.075
60.0 6 16.5 30 (32) 25.6 6 4.8 42.5 6 15.6 8.4 6 1.5 18.9 6 3.8 43 6 15 9.0 6 2.3 146 6 28* 50 6 11* 43.9 6 8.5* 7.388 6 0.076
59.3 6 16.8 8 (38) 28.0 6 9.2 45.2 6 13.3 8.2 6 1.6 19.6 6 4.3 40 6 18 10.1 6 2.4 73 6 14 80 6 15 49.4 6 8.6 7.362 6 0.073
8 14 2 3 6
(5) (9) (1) (2) (4)
42 25 8 7 12
(28) (17) (5) (5) (8)
14 3 1 0 3
P Value 0.64 0.85 0.19 0.32 0.59 0.61 0.53 0.12 ,0.0001 ,0.0001 ,0.001 0.17 0.14
(9) (2) (1) (0) (2)
Definition of abbreviations: ARDS = acute respiratory distress syndrome; SAPS = Simplified Acute Physiology Score. Plus–minus values are means 6 SD. Because of rounding, percentages may not total 100. The body mass index is the weight in kilograms divided by the square of the height in meters. P values were obtained by analysis of variance, Kruskal-Wallis test, or Fisher exact test, as appropriate; the Bonferroni correction was used for multiple comparisons. SAPS II was used to assess the severity of systemic illness at study entry. Scores can range from 0 to 163, with higher scores indicating more severe illness. Respiratory system compliance was calculated as the ratio of the tidal volume to the difference between inspiratory plateau pressure and positive end-expiratory pressure. *P , 0.05 versus severe ARDS. † P , 0.05 versus moderate ARDS.
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ORIGINAL ARTICLE Table 2: Computed Tomography Scan Variables Mild ARDS Total lung tissue, g Total gas, ml Lung recruitability, % Not inflated tissue, % Poorly inflated tissue, % Well-inflated tissue, % Overinflated tissue, %
1,255 1,355 8 31 31 38 0
6 6 6 6 6 6 6
Moderate ARDS
263* 505 7*† 13*† 11 11*† 0
1,446 1,241 14 40 32 27 0
6 6 6 6 6 6 6
479* 681 10* 15* 12 13* 1
Severe ARDS 1,957 1,087 20 49 32 18 0
6 6 6 6 6 6 6
P Value ,0.0001 0.35 ,0.0001 ,0.0001 0.87 ,0.0001 0.66
604 769 13 17 13 14 2
Definition of abbreviation: ARDS = acute respiratory distress syndrome. Plus–minus values are means 6 SD. Because of rounding, percentages may not total 100. P values were obtained by analysis of variance, Kruskal-Wallis test, or Fisher exact test, as appropriate; the Bonferroni correction was used for multiple comparisons. Lung recruitability was available in 141 patients (31 mild ARDS, 89 moderate ARDS, and 21 severe ARDS). *P , 0.05 versus severe ARDS. † P , 0.05 versus moderate ARDS.
PEEP in mild, moderate, and severe ARDS. As shown, from mild to severe ARDS there is a progressive decrease in well-aerated tissue (the baby lung) (22) associated with a significant increase of noninflated tissue, whereas the amount of overinflated and poorly inflated tissue were similar in the two groups. In Table 3 we report the average values of the lung inhomogeneities in mild, moderate, and severe ARDS; their extent; and their intensity. As shown, the mean values of lung inhomogeneities significantly increased from mild to severe ARDS. Interestingly, however, the intensity of the lung inhomogeneities was similar in mild, moderate, and severe ARDS. What significantly changed was the extent of the
lung inhomogeneities, which significantly increased from mild to severe ARDS, from 14 to 23%. Therefore, we may estimate that abnormal lung inhomogeneities represent 14–23% of the lung volume and it is possible to speculate that in these fractions of lung volume the stress may be almost double the transpulmonary pressure applied to the whole lung (multiplication factor z1.88 6 0.09). Spatial Distribution of Lung Inhomogeneities
Figure 4 shows the distribution of the abnormal lung inhomogeneities (with values .1.61) along the sternum–vertebral axis; as shown, the greater concentration of the lung inhomogeneities in mild and
moderate ARDS is in the most dependent lung regions, whereas it shifts to the middle lung in severe ARDS. This regional distribution should correspond to regional distribution of the VILI. The distribution of the lung inhomogeneities along the apicocaudal axis, in contrast, was similar in the mild, moderate, and severe ARDS, although quantitatively increasing from mild to severe ARDS (data not shown). Lung Inhomogeneities and Physiologic and CT Scan Variables
We found several correlations between the extent of lung inhomogeneities and physiologic variables as PaO2/FIO2 (PaO2/FIO2 = 208 2 279 3 lung inhomogeneity extent; P , 0.0001; r2 = 0.13), physiologic shunt (shunt fraction = 0.26 1 0.68 3 lung inhomogeneity extent; P , 0.0001; r2 = 0.15; shunt fraction was available in 140 patients), and plateau pressure (plateau pressure [cm H2O] = 15 1 22 3 lung inhomogeneity extent; P , 0.0001; r2 = 0.21). The most striking correlation, however, was with the dead space fraction (Figure 5) (lung inhomogeneity extent = 0.41 1 0.93 3 VD/VT; r2 = 0.34; P , 0.0001; physiologic dead space fraction was available in 124 patients). The lung inhomogeneity extent was associated with several CT scan variables: we found a positive correlation with lung weight (lung inhomogeneity extent = 0.088 1 6.26 3 1025 3 lung weight [g];
Table 3: Average and Extent of Lung Inhomogeneities PEEP (cm H2O) Average lung inhomogeneities Extent of lung inhomogeneities Intensity of lung inhomogeneities
5 15 45 5 15 45 5 15 45
Healthy Subjects
1.15 6 0.05 0.05 6 0.02 2.26 6 0.24
Mild ARDS 1.34 1.31 1.27 0.14 0.12 0.10 2.62 2.76 2.88
6 6 6 6 6 6 6 6 6
0.09* 0.10 0.09* 0.05*† 0.04 0.04 0.22 0.26 0.26
Moderate ARDS 1.38 1.36 1.31 0.18 0.16 0.12 2.57 2.63 2.77
6 6 6 6 6 6 6 6 6
0.12 0.14 0.13* 0.08* 0.08 0.07 0.18 0.25 0.22
Severe ARDS 1.45 1.42 1.40 0.23 0.20 0.18 2.53 2.60 2.71
6 6 6 6 6 6 6 6 6
0.16 0.16 0.14 0.10 0.09 0.08 0.21 0.27 0.32
P Value 0.01 0.09 ,0.001 ,0.001 0.01 ,0.0001 0.22 0.08 0.04
Definition of abbreviations: ARDS = acute respiratory distress syndrome; PEEP = positive end-expiratory pressure. Plus–minus values are means 6 SD. Because of rounding, percentages may not total 100. P values were obtained by analysis of variance; the Bonferroni correction was used for multiple comparisons. “Extent of lung inhomogeneities” refers to the fraction of lung volume that presented a lung inhomogeneity greater than 1.61 (95th percentile of healthy subjects). “Intensity of lung inhomogeneities” refers to the average stress raiser of the voxels presenting a lung inhomogeneity greater than 1.61 (95th percentile of healthy subjects). Data at PEEP 15 cm H2O were available in 89 patients (24 mild, 55 moderate, and 10 severe ARDS). Data at PEEP 45 cm H2O were available in 141 patients (31 mild, 89 moderate, and 21 severe ARDS). Data from comparisons population were added in the row relative to 45 cm H2O pressure because computed tomography scan images were taken at end-inspiration. Data from healthy patients were not included in the statistics. *P , 0.05 versus severe ARDS. † P , 0.05 versus moderate ARDS.
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ORIGINAL ARTICLE P , 0.0001) (Figure 6A). A positive correlation, however, was found between the lung inhomogeneities and the poorly aerated tissue (lung inhomogeneity extent = 0.06 1 0.39 3 poorly inflated tissue [fraction]; r2 = 0.35; P , 0.0001), as shown in Figure 6B. Lung Inhomogeneities at Different Airway Pressures
Figure 4. Distribution of lung inhomogeneities (with values . 1.61) along the sternum–vertebral axis. Bar height represents the median of the lung inhomogeneity extent along 10 sternum–vertebral segments; error bars represent the third quartile of lung inhomogeneity extent. The first bar (light gray) represents control subjects, whereas the black, dark gray, and white bars represent mild, moderate, and severe patients with acute respiratory distress syndrome (ARDS). To compare the distribution between mild, moderate, and severe ARDS we fit a Gaussian function along the median points [f = y0 1 a 3 exp(20.5 3 [(x 2 x0)/b]2)]; no statistics were performed on control subjects that do not exhibit a particular sternum–vertebral pattern. Function peak value was at sternum–vertebral level 6.31 (standard error 0.18) for severe ARDS, 7.98 (standard error 0.13) for moderate ARDS, and 8.84 (standard error 0.08) for mild ARDS. The three Gaussian distributions computed on medians were compared with one-way analysis of variance (P = 0.0007) and post hoc test was performed with the Bonferroni correction. The position of the peak of mild ARDS was significantly different from severe ARDS (P = 0.008), whereas moderate and severe ARDS peaks (P = 0.05) and moderate and mild ARDS (P = 1) were not different.
r2 = 0.16; P , 0.0001) (see Figure E7 in the online supplement) and a weak but significant correlation with noninflated tissue (lung inhomogeneity extent = 0.14 1 0.092 3 fraction of not inflated tissue; r2 =
0.03; P = 0.02) (see Figure E8), whereas we measured a negative correlation with the fraction of well-inflated tissue (lung inhomogeneity extent = 0.29 – 0.39 3 well-inflated tissue [fraction]; r2 = 0.47;
Figure 5. Relationship between lung inhomogeneity extent and physiologic dead space measured at positive end-expiratory pressure (PEEP) 5 cm H2O. Physiologic dead space (%) = 0.41 1 0.93 3 lung inhomogeneity extent; r2 = 0.34; P , 0.0001. Physiologic dead space was available in 124 patients.
154
The lung inhomogeneity pattern at airway pressure of 5, 15, and 45 cm H2O is summarized in Table 3. As shown, the average values of the lung inhomogeneities slightly but significantly decreased. Moreover, their extent significantly decreased by 18 6 18% increasing PEEP from 5 to 15 cm H2O and by 30 6 22% increasing the airway pressure from 5 cm H2O to a plateau pressure of 45 cm H2O airway pressure, suggesting a more homogeneous lung at higher airway pressures. The lung inhomogeneity extent at PEEP 15 cm H2O and at 45 cm H2O airway pressure was highly correlated with the lung inhomogeneities extent at PEEP 5 cm H 2 O (lung inhomogeneity extent PEEP 15 cm H2 O = 20.0035 1 0.85 3 lung inhomogeneity extent PEEP 5 cm H 2 O; r2 = 0.83; P , 0.0001; Figure 7A) (lung inhomogeneity extent 45 cm H 2 O airway pressure = 0.0073 1 0.65 3 lung inhomogeneity extent PEEP 5 cm H 2 O; r2 = 0.59; P , 0.0001; Figure 7B). Interestingly, 15 patients (17%) increased instead of decreased their lung inhomogeneity extent while increasing PEEP from 5 to 15 cm H2O and 11 patients (8%) going from 5 to 45 cm H2O endinspiratory pressure. This was primarily related to the behavior of the poorly aerated tissue: in the 11 patients in whom the lung inhomogeneities unexpectedly increased increasing the pressure from 5 to 45 cm H2O the poorly aerated tissue also increased by 12 6 8%. In contrast, in the remaining 130 patients where the lung inhomogeneities decreased increasing pressure, the poorly aerated tissue also decreased by 7 6 10%. The changes of the lung inhomogeneity extent and the poorly aerated fraction changes with PEEP were significantly correlated over the range of pressures we explored (D lung inhomogeneity extent [5 – 45 cm H2O] = 20.045 1 0.21 3 D fraction of poorly inflated tissue [5 – 45 cm H2O]; r2 = 0.21; P , 0.0001) (see Figure E9).
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 2 | January 15 2014
ORIGINAL ARTICLE extent). We added in the logistic regression the fractions of poorly inflated and noninflated tissues, not significantly different between survivors and nonsurvivors, which were considered markers of overall severity. Among the CT-derived variables entered in the regression the only one independently associated with outcome was the extent of the abnormal lung inhomogeneities (P = 0.65 by the Hosmer-Lemeshow goodness-of-fit statistics; C = 0.62). The odds ratio for each percent point increase of the lung inhomogeneity extent was 1.062 (95% confidence interval, 1.015–1.11).
Discussion
Figure 6. (A) Relationship between lung inhomogeneity extent and the fraction of well-inflated tissue (computed tomography [CT] value between 2500 and 2900 HU) measured at positive end-expiratory pressure (PEEP) 5 cm H2O. Well-inflated tissue (fraction) = 0.51- 1.25 3 lung inhomogeneity extent; r2 = 0.47; P , 0.0001. (B) Relationship between lung inhomogeneity extent and the fraction of poorly inflated tissue (CT value between 2100 and 2500 HU) measured at PEEP 5 cm H2O. Poorly inflated tissue (fraction) = 0.15 1 0.91 3 lung inhomogeneity extent; r2 = 0.35; P , 0.0001.
Lung Inhomogeneities and Lung Recruitability
We found that the recruitability, measured between 5 and 45 cm H2O, was not significantly related with the extent decrease of lung inhomogeneities from 5 to 45 cm H2O (P = 0.09) (see Figure E10). However, if we consider that the relationship between recruitability and lung inhomogeneities changes only in the patients in whom the poorly aerated tissue decreased (104 patients out of 141) we found that the relationship becomes significant (D lung inhomogeneity extent = 0.031 1 0.36 3 lung recruitability; r2 = 0.39; P , 0.0001) (see Figure E11). In contrast, no correlation between
recruitability and the lung inhomogeneity extent was observed in the patients (37 patients) in which the poorly aerated tissue increased while increasing pressure (P = 0.30) (see Figure E12). Lung Inhomogeneities and Outcome
The lung inhomogeneity extent was significantly higher in the 51 patients who died compared with the 97 patients who survived (20 6 9 vs. 17 6 7%; P = 0.01). We performed a multivariate backward logistic regression model to study the association between CT scan variables that were different between survivors and nonsurvivors (lung recruitability, well-inflated tissue, lung inhomogeneity
Cressoni, Cadringher, Chiurazzi, et al.: Lung Inhomogeneity in ARDS
In this study we attempted to quantify the inhomogeneities of the lung parenchyma whose prevention and correction represents the theoretical basis of the open lung strategy as modeled by Mead and coworkers (16) and proposed by Lachmann (23). Briefly, when a force is applied to a theoretical homogeneous lung, it is evenly distributed through the lung skeleton (the extracellular matrix), so that each fiber bears the same load (8). If the lung is not homogenous (e.g., because of the presence of local atelectasis or consolidation), the fibers neighbor to the unexpanded lung region must carry the additional load of the nonexpanding fibers, therefore locally increasing their stress and strain. Mead and coworkers (16) estimated that the ratio between the volume of two neighboring regions, one totally expanded and the other totally collapsed, is 10:1 at 30 cm H2O transpulmonary pressure, and the local pressure (stress) is 30 3 (V1/V0)2/3 = 30 3 (10/1)2/3 = z140 cm H2O being the two-third power the scale factor to pass from volumes to areas. In this study, as measure of the strain (i.e., distention) we used the gas/tissue ratio computed from CT scan density (24); if a lung region does not expand or expands less, the neighboring regions carrying their load are more strained (and stressed) and present a higher gas/tissue ratio. Unfortunately, although the stress caused by material inhomogeneity may be quantified in the engineering field, it is impossible to measure it directly in the lung (8). In particular alveolar level information cannot be obtained from CT scan 155
ORIGINAL ARTICLE
Figure 7. (A) Relationship between the lung inhomogeneity extent determined at positive endexpiratory pressure (PEEP) 5 cm H2O and at PEEP 15 cm H2O. Lung inhomogeneity extent at PEEP 15 cm H2O = 20.0035 1 0.85 3 lung inhomogeneity extent PEEP 5 cm H2O; r2 = 0.83; P , 0.0001. (B) Relationship between the lung inhomogeneity extent measured at 5 cm H2O and at 45 cm H2O end inspiration. Lung inhomogeneity extent at 45 cm H2O end inspiration = 0.0073 1 0.65 3 lung inhomogeneity extent PEEP 5 cm H2O; r2 = 0.59; P , 0.0001.
measurements. Therefore, it is possible that the association we found between our measurements and the overall ARDS severity are simply explained by the presence of more or less edema in different lung regions independently on local pressure multiplication. It is worth remembering, however, that the theory on which the lung protective strategy is based is the presence of stress raisers. Indeed, with these limitations in mind, we proceed in our discussion assuming that the underlying disease generates lung inhomogeneities, which, in turn, act as a stress raiser, further disrupting lung parenchyma. Because the normal lung parenchyma is inhomogeneous due to airways, vessels, 156
and the visceral pleura, we used 100 subjects as control group (19) to define the control inhomogeneity. In these control subjects we found that the average 95th percentile of inhomogeneity was 1.61. Accordingly, we defined as abnormal lung inhomogeneities the regions with value greater than 1.61 (intensity) and we computed the fraction of lung volume represented by these regions (extent). We found that the lung inhomogeneities increased with ARDS severity, were positively associated with dead space fraction and poorly aerated tissue, decreased when PEEP was increased, and were independently associated with outcome. As shown in Table 3, the average values of the lung inhomogeneity intensity
were similar in mild, moderate, and severe ARDS and did not change significantly increasing pressure from 5 to 45 cm H2O. In its theoretical model Mead and coworkers (16) computed the multiplication factor between open and closed regions as high as (10/1)2/3 = 4.64. In this study we found that this average multiplication factor was (2.62)2/3 = 1.9; this suggests that at the interfaces of interest the applied transpulmonary pressure should induce a stress almost double. Although the intensity of the lung inhomogeneities was similar in mild, moderate, and severe ARDS what actually changed was their extent. In normal animals the applied transpulmonary pressure becomes lethal when it approaches the total lung capacity (9); by inference, one may speculate that in humans an “innocent” applied transpulmonary pressure of 12 cm H2O may locally result in a harmful stress of 12 3 1.9 (intensity) = 22.8 cm H2O, which is in the range of total lung capacity of humans (25), and that this stress occurs in fractions of lung volume that sharply increase with ARDS severity. That the intensity of lung inhomogeneities was similar in mild, moderate, and severe ARDS may appear surprising. However, if we consider, for analogy, a pulmonary unit collapsed or consolidated the PO2 of the blood leaving this unit (the intensity of local hypoxemia) is obviously equal to the venous PO2 in mild, moderate, and severe ARDS. What determines the severity of the total hypoxemia is the number of units (extent), which generate different total shunt. Analogously, the stress raisers may be considered as local points that multiply the pressure at similar level (intensity), whereas the overall severity depends on the number of such points (extent). The physiologic dead space is likely the strongest predictor of the ARDS outcome because it is related, more than oxygenation, to the structural changes of the lung (26, 27). Of note, the only CT scan–derived variable significantly associated with dead space fraction was the lung inhomogeneity extent. This relationship has a sound anatomic and physiologic rationale because the inhomogeneity, and the dead space, is likely related to structural abnormalities of the ventilated lung fraction as capillary and alveolar wall destruction, presence of bullae or blebs, and fibrotic reactions.
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 2 | January 15 2014
ORIGINAL ARTICLE These structural abnormalities may determine either the dead space fraction or the gas/tissue ratio inhomogeneities. Not surprisingly we found an inverse relationship between lung inhomogeneity extent and the well-aerated tissue that appears homogeneously inflated. In contrast, the fraction of the poorly aerated tissue is well associated with the extent of inhomogeneity ratio. This is quite interesting because, as far as we know, the pathophysiologic meaning of the poorly aerated tissue has never been fully understood in ARDS (but the obvious fact that this tissue is associated with less aeration). It is possible, however, that the poorly aerated tissue may be relevant in the development of VILI. Other factors, however, should be considered because the CT scan simply models the lung as “blood flow less” organ. The lung microcirculation, as an example, is prone to rupture depending on the interplay between trans-pulmonary pressure and hemodynamic conditions (28–30); this interaction is most marked in the most dependent lung regions initially and thereafter at the interphase between aerated and nonaerated lung tissue where lung inhomogeneities are prevalent. These findings, however, are not in contrast with the hypothesis that lung inhomogeneity may lead to pressure multiplication because the introduction of unphysiologic strain may lead to capillary lesions. The potential benefit of PEEP in the framework of lung protective strategy is to maintain open, at end-expiration, the lung parenchyma that has been recruited during inspiration phase, thus decreasing the lung inhomogeneity and the VILI (15, 16, 23). Actually, we found that
the lung inhomogeneities decreased increasing PEEP and, in addition, were significantly but weakly related with lung recruitability. In individual patients, however, recruitability, PEEP, and lung inhomogeneity pattern were not associated. A possible explanation is the behavior of the poorly aerated tissue. In fact, increasing pressure may lead to an absolute decrease of the poorly aerated tissue, a powerful source of inhomogeneity, or may lead to its increase, depending on the characteristics of the lung. If we consider only the patients in whom the poorly aerated tissue decreased with pressures, greater was the recruitability, greater was the decrease of the lung inhomogeneities when airway pressure was increased (see online supplement). These results suggest that, in the individual patient, PEEP may increase, not modify, or decrease the lung inhomogeneities, although in most patients, its favorable effects prevail. Mechanical ventilation is the common therapy of ARDS and over the decades huge efforts have been devoted to decrease its potential harms. Within the possible risk factors as FIO2 (31–33), respiratory rate (34), tidal volume (12), and PEEP (35–37), in the last years the greatest attention had been paid to the last two variables. The accepted view is that low tidal volume and higher PEEP may protect the lung by decreasing the stress and strain of the parenchyma: the low tidal volume by lowering the lung stress and strain and the higher PEEP by decreasing the lung inhomogeneity. In this paper we found that a consistent fraction of the lung, depending on ARDS severity, may be exposed to a stress twofold the transpulmonary pressure applied. We do not know the
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American Journal of Respiratory and Critical Care Medicine Volume 189 Number 2 | January 15 2014
