Tomographic Study of the Inflection Points of the PressureVolume Curve in Acute Lung Injury

Guillermo M. Albaiceta, Francisco Taboada, Diego Parra, Luis H. Luyando, Juan Calvo, Rafael Menendez, and Jesu s Otero
Departments of Intensive Medicine and Radiology, Hospital Universitario Central de Asturias, Oviedo, Spain

The inflection points of the pressurevolume curve have been used for setting mechanical ventilation in patients with acute lung injury. However, the lung status at these points has never been specifically addressed. In 12 patients with early lung injury we traced both limbs of the pressurevolume curve by means of a stepwise change in airway pressure, and a computed tomography (CT) scan slice was obtained for every pressure level. Although aeration (increase in normally aerated lung) and recruitment (decrease in nonaerated lung) were parallel and continuous along the pressure axis during inflation, loss of aeration and derecruitment were only significant at pressures below the point of maximum curvature on the deflation limb of the pressurevolume curve. This point was related to a higher amount of normally aerated tissue and a lower amount of nonaerated tissue when compared with the lower inflection point on both limbs of the curve. Aeration at the inflection points was similar in lung injury from pulmonary or extrapulmonary origin. There were no significant changes in hyperinflated lung tissue. These results support the use of the deflation limb of the pressure volume curve for positive end-expiratory pressure setting in patients with acute lung injury. Keywords: acute lung injury; alveolar recruitment; computed tomography; mechanical ventilation; positive end-expiratory pressure

The use of computed tomography (CT) in ARDS has yielded a wide knowledge of the underlying physiopathology of the disease (14, 15). Several studies have focused on alveolar recruitment at different pressure levels (1618), but human data are scarce, particularly regarding the deation limb of the pressure volume curve. As far as we know, assessment of lung status at the different inection points has been limited to the LIP and slope of the inspiratory limb of the pressurevolume curve. The objective of this study is to assess (using CT scan) the changes in lung parenchyma at the different inection points of both limbs of the pressurevolume curve. This could help to identify the relationships between recruitment, aeration, and these inection points. Some of the results of these studies have been previously reported in the form of an abstract (19, 20).

METHODS
A detailed description of these methods can be found in the online supplement. Study protocol was approved by the in-hospital Ethics committee. Informed consent was obtained from each patients next of kin. All patients who met the American-European Consensus Conference criteria for ARDS (21) were included. Exclusion criteria were: age greater than 18 years, more than 3 days from ARDS diagnosis or 5 days of mechanical ventilation, presence of air leaks, brain injury, severe hemodynamic impairment, or chronic lung or chest wall pathology. Patients were classied as having ARDS from pulmonary or extrapulmonary origin according to diagnosis and clinical and microbiological data. Patients were transferred to the CT scanner and kept sedated, analgesiated, and relaxed throughout the procedure. Blood pressure, electrocardiogram, pulse-oxymetry, esophageal pressure, and airway pressure and ow were monitored. Volume was calculated by the integration of ow.

The only ventilatory strategy that has shown a decrease in acute respiratory distress syndrome (ARDS) mortality in randomized studies is the use of low tidal volume ventilation (1, 2). However, it is known that low tidal volumes lead to progressive lung derecruitment (3) that can be detrimental (4), and recently the safety of low-pressure ventilation has been challenged (5). Lung protective ventilatory strategies (6) advocate the use of high levels of positive end-expiratory pressure (PEEP) to avoid these adverse effects of low tidal volumes. Among different criteria for PEEP settings in ARDS (7), inection points of the static pressurevolume curve of the respiratory system (which are in fact points of maximum curvature) have been proposed. However, the most common use of the lower inection point (LIP) of the inspiratory limb has been challenged on theoretical (8), experimental (9, 10), and clinical (11) grounds. Some authors have suggested the use of the deation limb of the pressurevolume curve, because PEEP is an expiratory phenomenon that could be correlated with derecruitment (12). However, this approach has shown no benet over the use of LIP in an animal model (13).

PressureVolume Curve Maneuver

Static pressurevolume curves were constructed using the continuous positive airway pressure technique (Figure 1) (22). After volume history standardization (with three breaths of 10 ml/kg), the ventilator was switched to continuous positive airway pressure mode, and airway pressure was raised from 0 to 35 cm H2O in 5-cm-H2O steps. Ventilation was restored for 5 minutes, and then the maneuver was repeated, this time decreasing pressure from 35 to 0 cm H2O. At each step, airway, esophageal, and transpulmonary pressures (calculated as airway pressure minus esophageal pressure) and volume were recorded, and a single CT scan slice was acquired at a xed position. At the end of the procedure, chord compliances of the respiratory system, chest wall, and lung were calculated.

(Received in original form December 2, 2003; accepted in final form August 17, 2004) Supported by grants from Fondo de Investigacio n Sanitaria (PI03/0833) and Red GIRA (G03/063). Correspondence and requests for reprints should be addressed to Guillermo M. Albaiceta, Intensive Care Unit, Hospital Universitario Central de Asturias, Celestino Villamil s/n, 33006 Oviedo, Spain. E-mail: guillermo.muniz@sespa.princast.es This article has an online data supplement, which is accessible from this issues table of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 170. pp 10661072, 2004 Originally Published in Press as DOI: 10.1164/rccm.200312-1644OC on August 18, 2004 Internet address: www.atsjournals.org

CT Scan Image Analysis

The absolute volume of hyperinated (1,000 to 900 Hounseld units), normally aerated (899 to 500 units), poorly aerated (499 to 100 units), and nonaerated (99 to 100 units) lung tissue was calculated in each slice. For inection points, these percentages were interpolated between those corresponding to the two closest transpulmonary pressures.

PressureVolume Curves
Data pairs of transpulmonary pressure and volume were tted to a sigmoid model modied from that proposed by Venegas and coworkers

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Figure 1. Representation of the procedure in a patient. Airway pressure (Paw) and volume are plotted against time. At each pressure level a CT scan slice is acquired.

(23). Using this model, we calculated the lower (LIP) and upper inection points (UIP) on the inspiratory limb, and the point of maximum curvature (PMC) on the expiratory limb. We dened LIPe as the point on the expiratory limb with the same transpulmonary pressure as LIP. Aeration was dened as the volume increase of normally aerated lung tissue. Recruitment was dened as the volume decrease of nonaerated lung tissue. Both were expressed in microliters. Pressureaeration and pressurerecruitment curves were traced by plotting aeration and recruitment against transpulmonary pressure, tting them to the same model. Volume, aeration, and recruitment corresponding to transpulmonary pressures from 0 to 30 cm H2O in 5-cm-H2O steps were calculated.

patients were studied in their rst 3 days from ARDS diagnosis. There were differences in age (67.4 5.9 vs. 49.4 14.6 years for pulmonary and extrapulmonary groups respectively, p 0.05), but not in APACHE-II (26.1 5.4 vs. 20.4 9.1, n.s.), lung injury score (3.07 0.2 vs. 3.05 0.3, n.s.), or PaO2 to FiO2 ratio (155 21 vs. 162 56 mm Hg, n.s.). No patient showed any kind of deterioration during the study.
PressureVolume Curves

Statistical Analysis
All data are expressed as mean SD. Clinical variables were compared using a t test, whereas data regarding different pressure levels were compared using an ANOVA, with a within-group factor (pressure level) and a between-group factor (ARDS origin), and Bonferronis post hoc tests. A p 0.05 was considered signicant.

RESULTS
Patients

Seven patients with pulmonary ARDS and ve patients with extrapulmonary ARDS were included (Table 1). By design, all

All curves were tted to the model, being R2 0.98 0.02, 0.97 0.02, and 0.95 0.05 for pressurevolume, pressureaeration, and pressurerecruitment curves, respectively (pooling data from inspiratory and expiratory limbs). Transpulmonary pressure at the LIP (10.1 4.6 cm H2O) was always lower than that at the PMC (15.7 5.7 cm H2O), which was always below pressures at the UIP (21 6.1 cm H2O, p 0.05 in the twoway ANOVA and all post hoc tests). All inection points of the transpulmonary pressurevolume curve were placed at higher pressures in patients with pulmonary ARDS (Table 2). When airway pressures corresponding to these transpulmonary pressures were compared, the differences between LIP, PMC, and UIP persisted (15.1 3.6, 25.3 4.7, and 31.9 4.1 cm H2O,

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 170 2004 TABLE 1. PATIENT CHARACTERISTICS
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 Mean SD Diagnosis Pneumonia Esophageal cancer Cervical spine surgery Status epilepticus Hydatidosis Subphrenic abscess Bladder cancer Valproic acid overdose Syncope Acute cholecystitis Cholangitis Kidney transplantation Cause of ARDS Pneumonia Septic Shock Nosocomial pneumonia Nosocomial pneumonia Aspirative pneumonia Septic shock Septic shock Catheter-related sepsis Aspirative pneumonia Nosocomial pneumonia Septic shock Aspergillus pneumonia Age (yr) 73 60 67 69 56 48 68 36 66 74 35 67 59.9 13.5 Sex F F M M F M M M M F F F A-II 29 12 25 28 23 11 31 20 20 36 28 22 23.8 7.4 PaO2/FiO2 127 198 176 148 140 200 87 182 185 168 122 144 158 37 LIS 3 2.75 3 3 3 3.25 3.25 3.25 3.25 2.75 2.75 3.5 3.1 0.2 Origin P E P P P E E E P P E P Outcome S S D D S S S S S S S D

Definition of abbreviations: A-II APACHE II score; D dead; E extrapulmonary; LIS lung injury score; P pulmonary; S survivor.

respectively, p 0.05), but there were no differences between pulmonary and extrapulmonary groups (p 0.77, Table 2). Patients with ARDS from pulmonary origin, when compared with the extrapulmonary group, had a lower lung compliance (59.6 22.9 vs. 84.6 14.5 ml/cm H2O, p 0.05) and higher chest wall compliance (170.8 47.6 vs. 83.6 11.1 ml/cm H2O, p 0.05), with no difference in respiratory system compliance (43 14.1 ml/cm H2O vs. 41.6 4.1 ml/cm H2O, p 0.83).
Aeration, Recruitment, and Hyperinflation

Inflection Points

Aeration and recruitment were continuous along the pressure axis (Figure 2). Whereas volume of normally and poorly aerated tissue started to change from 0 cm H2O, recruitment (i.e., the decrease of nonaerated lung volume) started at pressures above the LIP and continued up to an airway pressure of 35 cm H2O. During deation, loss of aeration and derecruitment were only signicant at pressures below the PMC. There were no signicant changes in volume of poorly aerated lung. Hyperination increased continuously from 0 cm H2O to the maximum pressure level, and decreased in a similar fashion when pressure was decreased, although these changes did not reach statistical signicance (p 0.07 and p 0.21 for the inspiratory and expiratory limbs, respectively). There were no signicant differences in these mechanisms of aeration, recruitment, and hyperination between pulmonary and extrapulmonary ARDS (Figure 3).

When the volume of the different lung compartments at LIP, UIP, PMC, and LIPe was compared (Figure 4), the UIP and the PMC were similar in terms of aeration and recruitment. In contrast, the LIP is the point with the highest amount of nonaerated lung volume and with the lowest volume of normally aerated parenchyma, and both change signicantly when this point is translated onto the expiratory limb. When UIP was translated onto the expiratory limb, there were no differences when compared with the PMC in any of the measured volumes (data not shown). We did not nd differences in the volume of hyperinated nor poorly aerated lung between all the studied points (p 0.1 and p 0.09, respectively). These results were similar when pulmonary and extrapulmonary groups were studied separately (data not shown).

DISCUSSION
The main nding of our study is that the PMC in the deation limb of the pressurevolume curve is characterized by a higher aeration and recruitment than the LIP, and similar to the UIP in the ination limb. Moreover, the decrease in lung aeration from an airway pressure of 35 cm H2O to PMC is not signicant. Taken together, these ndings support the use of PMC as a level of PEEP that achieves the two objectives of the lung protective ventilation (6): the highest amount of normally aerated tissue for ventilation and the lowest derecruitment during end-expiration. However, it must be noted that these afrmations should be validated in a study aimed to directly compare two ventilatory strategies with different PEEP levels, one being the PMC.
Changes in Lung Aeration

TABLE 2. LOWER AND UPPER INFLECTION POINTS AND POINT OF MAXIMUM CURVATURE OF PRESSUREVOLUME CURVES OF THE RESPIRATORY SYSTEM AND THE LUNG IN PULMONARY AND EXTRAPULMONARY GROUPS
Pulmonary ARDS Airway pressurevolume curve LIP UIP PMC Transpulmonary pressurevolume curve LIP UIP PMC 15.2 4.3 32.1 5.1 25.7 4.7 12 5.1 24.2 5.8 18.4 5.3 Extrapulmonary ARDS 14.9 2.6 31.6 2.5 24.7 5 7.4 2.3* 16.6 2.9* 11.8 3.9*

Definition of abbreviations: ARDS acute respiratory distress syndrome; LIP lower inflection point; PMC maximum curvature of pressurevolume curves; UIP upper inflection point. * p 0.05 for the difference between pulmonary and extrapulmonary groups.

Our technique for pressurevolume curve tracing allows us to study changes in lung parenchyma in a stepwise manner. As previously described (9, 11), aeration and recruitment were continuous along the pressure axis. We have described a different aeration pattern for poorly aerated and nonaerated lung tissue, with a higher pressure of re-aeration in the latter. Some CT scan studies on ARDS have described this relationship between LIP and the start of recruitment of nonaerated tissue (11). However, the change in poorly aerated tissue volume was only signicant between 0 cm H2O and the LIP. This lack of signicance at higher pressures could be explained by a continuous model in which nonaerated lung changes into poorly aerated and then, if enough pressure is applied, into normally aerated tissue, so that

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Figure 2. Pressurevolume (filled dots), pressureaeration (squares, right y-axis), and pressurerecruitment (triangles, right y-axis) curves during inflation (A ) and deflation (B ).

variations in poorly aerated tissue can be masked by recruitment. We cannot discard the hypothesis that poorly aerated and nonaerated zones have different aeration pressures and similar pressures of aeration loss. This may be in line with the different classes of atelectasis proposed by Pelosi and coworkers (24).

Our results clearly show that the deation limb of the pressurevolume curve presents a higher aeration and recruitment than the ination limb. The total amount of nonaerated and poorly aerated tissue decreases signicantly when the LIP is translated onto the expiratory limb of the pressurevolume curve

Figure 3. Changes in hyperinflated, normally aerated, poorly aerated, and nonaerated lung tissue along the inspiratory (upper row) and expiratory (lower row) limbs of the pressurevolume curves. Inflection points are used as markers in the pressure axis. Continuous line: pooled data from all patients. Dashed line: data from pulmonary (triangles) and extrapulmonary (squares) groups. * p 0.05 in post hoc tests for pooled data. LIP lower inflection point; LIPe lower inflection point projected onto the expiratory limb; Maxe maximum transpulmonary pressure achieved during deflation; Maxi maximum transpulmonary pressure achieved during inflation; PMC point of maximum curvature; UIP upper inflection point.

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Figure 4. Volume of the different compartments of the lung at each inflection point.

(LIPe), although aeration and recruitment at this point were lower than that at PMC. We do not know whether ventilation can be boosted to this limb using recruitment maneuvers, as suggested by animal models (25), or only with time and PEEP above LIP (26, 27). A recruited lung could be less prone to ventilator-induced lung injury due to a higher normally aerated lung to which the bulk of ventilation could be diverted (28) and a lower heterogeneity (26), which is associated with a decrease in shear forces between healthy and injured zones. However, PEEP-induced overination of other lung regions could counteract these benets.
Pulmonary and Extrapulmonary ARDS

The main difference between pulmonary and extrapulmonary ARDS that we have found is the shift to the right of the inection points in the former group, in line with previously published data regarding pressurevolume curves (29). Although some differences between these two groups were described using CT (30), this was done using a morphologic approach. As other authors, we did not nd any differences in aeration and recruitment at these points between these two groups (16, 31). Puybasset and coworkers previously reported that density histograms of the lower lobes (as is our case) are similar in different ARDS radiologic patterns (32).
Implications for PEEP Setting

The evidence that expiratory loss of aeration of alveoli previously aerated during inspiration can cause or exacerbate lung injury (33) has led to the use of high levels of PEEP in the socalled lung protective ventilatory strategies (6). Due to the classic optimal PEEP concept (34) based on maximal compliance, a PEEP level slightly above the LIP has been proposed and tested in clinical trials (1, 35). However, PEEP is an expiratory phenomenon whose objective is to avoid the loss of recruitment achieved during inspiration (which depends on the peak inspiratory pressure [11]). Some studies have demonstrated that pressure levels well above this LIP cannot keep the achieved recruitment (26, 31, 36). Even if ventilation occurs over the deation limb of the pressurevolume curve (27, 37), a pressure level equal to the LIP (i.e., LIPe in our study) is unable to avoid some loss of aeration. Our study shows that the PMC on the deation limb of the pressurevolume curve is a good marker of the start of derecruitment and loss of aeration. Moreover, the PMC was related to the maximal amount of normally aerated lung tissue

and the lowest nonaerated volume when the different inection points were compared, without a signicant increase of hyperination. The PMC also reects the optimal mean airway pressure during high frequency oscillatory ventilation (27, 38), which is somewhat similar to our decreasing pressure maneuver. In addition, the pressure range for this point in our study (2025 cm H2O) is in agreement with PEEP levels required to avoid derecruitment in other clinical studies (36, 39). On the other side, high pressure levels can result in overstretching and ventilator-induced lung injury, and the decrease in recruitment and aeration between the PMC and the LIPe seen in our study is, although statistically signicant, small in magnitude, so its clinical relevance could be low. Moreover, the only ventilatory strategy that has proven to be benecial in terms of mortality reduction is one that favors both low tidal volumes and low levels of PEEP (even lower than the LIP [2]), and high PEEP levels can be an independent risk factor for the development of barotrauma (40). The benets of high PEEP levels, avoidance of derecruitment or the use of pressurevolume curves for ventilator setting are to be shown. In addition, the use of PMC as PEEP level in a saline-lavage animal model was not better than the use of LIP in terms of oxygenation and lung injury (13). There should be noted, however, that the salinelavage model is highly reclutable at low pressures and very different from the real ARDS (9, 11, 41). As discussed, high PEEP levels could have their benets and drawbacks. Our study cannot help to clarify the optimal PEEP level, because we only made static measurements of the respiratory system. It could be possible that the pressure level required to keep the lung as aerated as possible, which in our study is the pressure at the PMC, would not be the same when tidal ventilation is in course.
Hyperinflated Tissue

The volume of hyperinated tissue in this study is low even using slices of only 1 mm that can avoid partial volume artifacts, and differences did not reach statistical signicance. This is in agreement with previously published data (11, 28). However there is a strong tendency to an increase of hyperination along the pressure axis (more accentuated in the pulmonary group), and other authors have found higher amounts of hyperinated lung tissue when the whole lung was scanned (26, 42) and different types of lung morphology were taken into account (17). It is remarkable the presence of hyperinated tissue at 0 cmH2O in static conditions, which could be related to voxels corresponding

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Acknowledgment : The authors thank all the nursing and technician personnel at the Intensive care Unit and CT scanner of the Hospital Universitario Central de Asturias for their help. They also thank Lluis Blanch for his suggestions about the manuscript.

to the lumen of distal bronchioles (100% gas without tissue). These results raise concerns about the accuracy of single-slice CT scanning for detecting overstretching in ARDS lungs, as this is different from hyperination.
Limitations of the Study

References
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The methodology used in our study is subjected to three limitations: 1. Small number of patients: This study includes only a small amount of patients, so it may be underpowered to detect small differences between pulmonary and extrapulmonary groups. 2. Pressurevolume curves: The deation limb of the pressure volume curve is prone to artifacts due to oxygen consumption and changes in temperature and humidity of inspired gas (43, 44). The continuous positive airway pressure technique for pressurevolume curve tracing avoids these limitations by using a short maneuver ( 50 seconds for tracing each limb) without disconnecting the patient from the ventilator. Due to the fact that peak inspiratory airway pressure was 35 cm H2O in all the cases, transpulmonary pressure was different in each patient and inection points and lung aeration might change with peak pressure changes, as in animal models (45). To minimize these causes of possible artifacts, we used regression techniques for inection point measurements (46), and the volume history of the lungs was stardardized using three volume-controlled (without a preelected pressure limit) sighs. However, we cannot discard that a curve maneuver guided by transpulmonary instead of airway pressures would have yielded different results. 3. CT scan measurements: Quantication of recruitment using only one slice is the main limitation of our study because of regional differences in recruitment, distension and hyperination in ARDS lungs (15, 16, 32, 4749). Moreover, the lung level studied at each pressure level is not exactly the same, as the lung moves with ination. We cannot discard that a CT scan study including more slices or a whole lung scan per pressure level would have yielded different results. However, this would lead to an increase of the radiation dose and duration of the maneuver (which can cause artifacts in the pressurevolume curves [43,44]) and may increase the risk of adverse events for the patient. As recently discussed (14), the number of slices per study is a compromise between the different congurations studied and the radiation dose, and morphologic studies (16, 32, 49) cannot be compared with physiologic protocols like this and others (11, 27, 28).
Conclusion

We can conclude that, whereas aeration and recruitment are parallel phenomena along ination, loss of aeration and derecruitment have a threshold at the point of maximum curvature on the deation limb, regardless of the origin of the ARDS. The application of this point as the PEEP level required to keep the lung open remains to be determined.
Conflict of Interest Statement : G.M.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; F.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.H.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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