INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

In acute respiratory failure mechanical ventilation can cause lung damage that adds to the damage produced by the underlying disease or trauma. Overdistension and repeated opening and closing of alveolar units might be mechanisms that lead to additional lung damage (1, 2). Pressure-controlled ventilation (PCV) with a short expiratory phase has been proposed as a ventilatory pattern to keep the lung open and to avoid barotrauma/volotrauma (3). This is conceptually similar to airway pressure release ventilation (APRV), which in addition allows unrestricted spontaneous breathing (4). APRV has been used in clinical trials for the treatment of patients with acute respiratory failure (5), but the pressure levels and time intervals for the inspiratory and expiratory phases have only been determined empirically. In order to optimize APRV and PCV it would be desirable to know how fast end-expiratory lung collapse occurs, so that a time interval for expiration can be chosen that minimizes lung collapse and still allows the lung to expire. Furthermore, the dynamics of recruitment might serve as a basis for selecting the inspiratory time interval long enough to ensure reopening of lung tissue and as short as possible to minimize mechanical trauma to the lung. The dynamics of lung collapse and recruitment might be modified by different PEEP levels as well as different inspiratory pressure levels.

Therefore, we investigated the influence of different airway pressures on the dynamics of lung collapse and recruitment in oleic-acid-induced lung injury in pigs in order to find a rationale for setting the inspiratory and expiratory time intervals and pressure levels during ventilation with pressure-controlled modes.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Study Protocol

After approval of the local animal ethics committee, 14 healthy pigs, mixed breed of Hampshire, Yorkshire, and Swedish country breed weighing 31.3 ± 3.3 kg, were anesthetized and mechanically ventilated. Baseline values were obtained after a 30-min stabilization period, then lung injury was induced with oleic acid (0.1 ml/kg) injected via a central venous catheter. Hemodynamic and ventilatory parameters were measured 120 min after induction of lung injury. Then, PEEP = 10 cm H₂O was applied in order to ensure an acceptable gas exchange, and hemodynamic and ventilatory measurements were made again 45 min later. The pigs were transferred to the radiology department and repeated CT scans were taken in the same transverse plane of the chest during expiratory and inspiratory hold procedures with four different pressure levels (see below). This resulted in a total study period of approximately 6.5 h (Figure 1).

View larger version (39K): [in this window] [in a new window]   Figure 1.   Study protocol. In all animals, measurements include hemodynamics, extravascular lung water, mixed venous and arterial blood gas samples, and ventilatory parameters. In addition, the ventilation-perfusion distribution was studied in nine animals with the MIGET-technique. Repetitive CT scans were obtained during expiration with PEEP of 10, 15, 20, and 25 cm H2O, as well as during inspiration with a pressure of 15 cm H2O above PEEP. For further details, see METHODS.

The investigation was performed in the experimental laboratories of the Department of Clinical Physiology and in the Department of Diagnostic Radiology at the University Hospital of Uppsala.

Anesthesia

Forty milligrams of azaperonum (Stresnil; Janssen, Belgium) were given intramuscularly as premedication before transport from the farm. General anesthesia was induced with atropine (0.04 mg/kg), tiletamin/ zolazepam (Zoletil; Reading, Carros, France) (6 mg/kg) and xylazin (Rompun; Bayer, Leverkusen, Germany) (2.2 mg/kg) given intramuscularly, followed by a constant infusion of 400 mg/h clomethiazole (Heminevrin; Astra, Södertälje, Sweden), 150 µg/h fentanyl, and 2.5 mg/h pancuronium bromide for muscle relaxation. Additional fentanyl and pancuronium bromide were given when needed. The animals were tracheotomized and ventilated through a cuffed endotracheal tube.

Ringer-acetate (1,000 ml) (Pharmacia AB, Stockholm, Sweden) at body temperature was infused prior to baseline measurements, thereafter, fluid replacement aimed at a constant hemoglobin value and a stable systemic arterial blood pressure. This resulted in an average infusion rate of 30 ml/kg/h after induction of lung injury.

Ventilation

Mechanical ventilation was initiated in volume-controlled mode (Servo 900 C; Siemens Elema, Lund, Sweden) with a constant flow, a rate of 20 breaths/min, an inspiratory:expiratory ratio (I:E) of 1:2, PEEP = 0 cm H₂O, FI_O2 = 1.0, and a tidal volume (VT) of 15 ml/kg. VT was then adjusted to maintain normocapnia (Pa_CO2, 35 to 45 mm Hg) guided by end-tidal CO₂ monitoring (Capnomac Ultima; Datex Instrumentation Corp., Helsinki, Finland) and intermittently taken arterial blood samples. If hypercapnia developed, minute ventilation was increased as long as VT was below 15 ml/kg. If VT was above 15 ml/kg, a Pa_CO2 of 60 mm Hg was tolerated before VT was increased further. After induction of lung injury and the following stabilization period, PEEP was increased to 10 cm H₂O. For transportation to the radiology department and during CT scanning, a Servo 300 ventilator (Siemens Elema) was used. The breathholding procedures (see below) were performed during PCV.

Ventilatory Parameters

Tidal volume and minute ventilation (E) were recorded by the flow sensors in the ventilator. Airway pressure (Paw) and flow were measured in the ventilator on the inspiratory side and recorded on a personal computer for on-line signal processing, taking gas compression within the ventilatory circuit into account (software: LabVIEW 3.1, C-O Sjöberg Engineering, 32983 B 70; National Instruments, Austin, TX). Resistance (Rrs) and static compliance (Crs) of the total respiratory system (lung and chestwall) were determined during an inspiratory hold maneuver (about 4 s). Rrs was calculated according to Kochi and coworkers (8) by rapid airway occlusion. Crs was calculated as VT divided by the difference of inspiratory plateau pressure minus end-expiratory airway pressure [Crs = VT/(Paw_plateau  Paw_{end-expiration})]. The mean of two inspiratory hold maneuvers was used for statistical evaluation.

Hemodynamics

For pressure measurement and arterial blood sampling, an 18-gauge catheter was inserted into the left carotid artery, together with a thermistor-tipped fiberoptic catheter (Pulsiocath 4F FT PV 2024; Pulsion Medical System, Munich, Germany) that was advanced into the descending aorta for measurements of cardiac output (CO) and extravascular lung water (EVLW). A Swan Ganz catheter and an 18-gauge catheter were introduced into the right external jugular vein. Exact position of catheters was confirmed by pressure tracing as well as radiologically during CT scanning.

Systemic, pulmonary arterial and central venous pressure were displayed on a bedside monitor together with the oxyhemoglobin saturation (Series 7010; Tram, Marquette Electronics Inc., Milwaukee, WI) and recorded with reference-to-atmospheric pressure at midthoracic level at end-expiration. CO and EVLW were determined randomly within the respiratory cycle by injection of 8 to 10 ml of a double indicator bolus consisting of 1 mg/ml indocyanine green (ICG-Pulsion; Pulsion Medical System) mixed in sterile water (temperature about 5 to 7° C). The thermistor-tipped fiberoptic catheter in the descending aorta detects the dye and temperature dilution curves, and CO and EVLW are automatically calculated by a connected computer (Pulsion COLD Z-021; Pulsion Medical System). The mean of triplicate measurements was calculated and used for statistical evaluation. Oxygen delivery (O₂), oxygen consumption (O₂), systemic vascular resistance (SVR), and pulmonary vascular resistance (PVR) were calculated with standard equations.

Gas Exchange and Ventilation-Perfusion Relationship

Arterial and mixed venous blood gas samples were analyzed with ABL 300 and OSM 3 Hemoximeters (Radiometer, Copenhagen, Denmark).

Determination of the ventilation/perfusion distribution (A/) was done with the multiple inertgas elimination technique (MIGET) (9) in nine animals. This method is based on the constant infusion of six inert gases with different solubility in blood and their steady-state elimination from the lung. The inert gases are dissolved in isotonic saline and infused into a peripheral vein. Arterial and mixed venous blood samples are tonometered with gas and analyzed together with an expired gas sample by gas chromatography (5890, series II; Hewlett-Packard, Avondale, PA). These data enable the construction of a virtually continuous distribution of A/ ratios against blood flow or ventilation, with separation of shunt (A/ < 0.005) from regions with low A/ ratios (0.005 < A/ < 0.1, poorly ventilated lung units in relation to their perfusion), as well as the calculation of dead space (A/ > 100). The standard deviation of the logarithmic distribution of perfusion (LogSDQ) was calculated as a measure of the dispersion (mismatch) of the blood flow distribution.

Lung Injury

Oleic acid (Apoteksbolaget, Göterborg, Sweden) 0.1 ml/kg suspended in 20 ml isotonic saline was slowly (over 20 min) injected via the central venous catheter. During injection blood pressure was stabilized with titrated doses of adrenaline.

CT Scans at End-Expiration

After 4 s of expiratory breathholding with PEEP = 10 cm H₂O and PEEP = 0 cm H₂O, respectively, frontal topograms and helical CT of the chest were performed with a Somatom Plus 4 (Siemens, Erlangen, Germany) using a 512 × 512 matrix, 140 kV, 200 mA, scanning time of 0.75 s, pitch of 1.0, and collimation of 8 mm. Images were reconstructed with an increment of 8 mm (Figure 4) in order to define the scanning level that resulted in the largest transverse lung area. This level was chosen and kept constant during all succeeding experiments.

View larger version (77K): [in this window] [in a new window]   Figure 4.   CT scans of oleic-acid-induced lung injury. CT scans of the chest were performed at end-expiration (left panel ) with PEEP = 10 cm H2O and at end-inspiration with Paw = 25 cm H2O. The transverse cuts were always obtained between the top of the diaphragm and the base of the heart. However, a small portion of the heart and anterior mediastinum was usually seen below the sternum, whereas the aorta and vena cava inferior were located posterior in front of the spine.

Dynamic CT Scanning

The ventilatory mode was changed to PCV with a pressure rise time of 0.5% of the inspiratory cycle for a nearly rectangular pressure increase. In order to achieve a stable inspiratory plateau pressure during a 4 s inspiratory period, the respiratory rate was reduced to 12 breaths/min with an I:E ratio = 4:1. After approximately 4 s of inspiratory hold a dynamic Serio CT was performed of the same slice with a scanning time of 0.5 s, and a time interval of 0.3 s between scans (total cycle time, 0.8 s), at 140 kV and 111 mA. Immediately after the first scan, Paw was decreased to a predefined PEEP level (10, 15, 20, or 25 cm H₂O) and immediately after the sixth scan, Paw was increased by 15 cm H₂O and five more CT scans were obtained. PEEP levels were set at random order. Between PEEP level changes, the pigs were ventilated for 10 min in volume-controlled mode with PEEP = 10 cm H₂O.

With computed tomography lung density is averaged over the whole scanning time. The first scan obtained after end-expiration or end-inspiration showed, therefore, changes corresponding to a time interval of approximately 0.6 s (0.3-s pause + one-half scanning time), rather than 0.8 s).

In order to check the timing of Paw changes in relation to CT scanning, Paw was measured continuously during the whole maneuver with a differential pressure transducer (MPX 2010 DP; Motorola, Solna, Sweden) at the proximal end of the endotracheal tube. The CT scanner triggered pulses via a fiberoptic receiving module (TORX 173; Toshiba, Tokyo, Japan) with each scan, which were recorded together with Paw. In four animals the flow signal of the ventilator and the CT signal were recorded together in order to relate density changes measured with CT scanning to the expired and inspired volume.

Image Analysis

Images were analyzed with the computer program Sienet-Magic View, Version VA30A (Siemens). All transverse CT scans were analyzed by two different approaches.

1. The entire left and right lungs were chosen as region of interest (ROI) by drawing the boundaries of the lungs at the inside of the ribs and along the mediastinal organs. The total area of both lungs and its mean density was determined by including all pixels with density values between 1,000 and +100 Hounsfield units (HU) in the evaluation. Selecting a wider range between 1,000 and +1,000 HU resulted in an increase of the total area < 1%. Thereafter, using the same ROI, the area of pixels with HU in the range of 100 to +100 representing atelectasis or lung parenchyma with a maximum of 10% gas (10, 11) was measured.
2. In order to analyze differences in regional aeration four circular ROIs, averaging 1.8 ± 0.4 cm², were drawn in the uppermost, upper middle, lower middle, and dorsal parts of the right lung (inset of Figure 7). The position of the ROIs were kept constant for each animal in order to evaluate approximately the same area each time. No adjustments were made for the changes of size and shape of the transverse scans that occurred with changing lung volumes. The mean density of each ROI was determined including pixels within the range of 1,000 to +100 HU.

View larger version (20K): [in this window] [in a new window]   Figure 7.   Regional lung densities. Data are given as mean ± SEM. The x-axis shows the time and the y-axis gives the density measured in Hounsfield units (HU). On the left side prolonged breaths with PEEP = 10 cm H2O are shown, and on the right side PEEP was set to 25 cm H2O. The ROI positions are shown in the inset. The vertical distance of the ROIs from the ventral border of the lung parenchyma was: 1 (uppermost ROI) = 1.0 ± 0.2 cm; 2 (upper middle ROI) = 3.8 ± 0.2 cm; 3 (lower middle ROI) = 7.5 ± 0.3 cm; 4 (dorsal ROI) = 10.5 ± 0.8 cm. In the horizontal plane, ROI 1 and ROI 4 were positioned in the midline of the right lung. The horizontal distance to the pleural space was: ROI 2 = 0.8 ± 0.2 cm and ROI 3 = 0.7 ± 0.3 cm. In the uppermost ROI clear density changes between inspiration and expiration are no longer visible with PEEP = 25 cm H2O. In the dorsal ROI, density decreased throughout inspiration when inspiration was started from PEEP = 25 cm H2O.

Calculation of Time Constants

In order to compare the dynamics of atelectasis-, lung volume-, or lung density changes, data were fitted to exponential rise functions. Time constants were calculated as: Y = Y₀(1  e^Time/), where Y₀ is the difference of lung density or lung volume between the beginning of expiration and infinity, and  is the time constant measured in seconds (12).

Computed tomography averages lung density and atelectasis over the whole scanning time, which leads to a nonexponential change of density and atelectasis between the first two data points. In addition, Paw was changed after the first scan was completed. Therefore, the first image does not really correspond to time zero of the exponential rise function, and it was excluded from the analysis. Fitted curves were accepted if correlation coefficients exceeded 0.85.

Statistics

All data are presented as mean ± standard deviation, if not stated otherwise; p < 0.05 was chosen as the level of significance. Parameters were tested with Friedman's ANOVA, followed by Wilcoxon's signed rank test if significant differences were detected. Regression analyses and exponential curve-fitting were done with the least squares method. Calculations were performed with the software package Statistica on a personal computer.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Lung Injury

Induction of lung injury resulted in significant effects on hemodynamics and respiratory mechanics, as shown in Table 1. Although VT was raised by almost 20% as compared with baseline, normoventilation was no longer achieved after induction of lung injury. In nine animals that were examined with the MIGET technique, shunt increased dramatically (baseline, 5.7 ± 1.9%; lung injury, 43.8 ± 13.7%; p < 0.01; n = 9) and perfusion of regions with low A/ ratios appeared (lung injury, 4.9 ± 4.3% of total perfusion; p = 0.011) from having been absent during baseline measurements. The dispersion of the blood flow distribution (LogSDQ) increased from 0.63 ± 0.06 at baseline to 1.45 ± 0.47 (p < 0.01) after injection of oleic acid.

PEEP of 10 cm H₂O affected gas exchange slightly. Shunt tended to decrease to 34.8 ± 21.2% (NS), but LogSDQ increased even further, to 1.58 ± 0.76 (NS). Respiratory mechanics improved, although EVLW increased after the application of PEEP (Table 1).

Lung Density and Lung Volume Changes

Lung density changes (_Density) measured between end-expiration and end-inspiration were linearly correlated to the expired or inspired volume (_Volume): _Density = 0.21 · _Volume + 3.84, r = 0.93, p < 10⁶ (Figure 2). During ventilation, density changes followed volume changes with a short delay (Figure 3), which was partially caused by the data-averaging during CT scanning (see METHODS). The time constants for lung density changes, however, which were corrected for this delay by excluding the first data point, were longer (_Density: 0.23 to 3.91 s) than time constants for lung volume changes (_Volume: 0.21 to 1.78 s), and _Density and _Volume were related according to the equation: _Volume = 0.29 · _Density + 0.39, r = 0.71, p < 10⁴. Thus, density changes did not exclusively reflect changes of aeration.

View larger version (11K): [in this window] [in a new window]   Figure 2.   Static lung volume versus lung density changes. The x-axis shows the expired or inspired volume of the whole lung, and the y-axis gives the corresponding changes of the mean lung density at end-expiration and end-inspiration in one transverse scan, which was located between the diaphragm and the base of the heart. Measurements were performed in four animals. There was a highly significant correlation between lung volume and lung density changes (p < 106).

View larger version (27K): [in this window] [in a new window]   Figure 3.   Dynamic lung volume versus lung density changes. The x-axis shows the time measured in seconds, the left y-axis gives the volume changes of the whole lung (ml) and the right y-axis gives the changes of the mean lung density (HU) in one transverse scan, which was located between the diaphragm and the base of the heart. Data are shown as mean ± SEM and were obtained in four animals during expiration to PEEP = 10 and 20 cm H2O. The left and right y-axis were scaled in order to allow a comparison between volume and density changes. Note that density curves follow volume curves with a short delay, which is partially due to data averaging during CT scanning (see METHODS).

Statics of Lung Collapse and Recruitment

Representative CT scans obtained at end-expiration and end-inspiration with Paw = 10 and 25 cm H₂O, respectively, are shown in Figure 4. Lung density decreased nearly linearly with increasing airway pressure, but density values were higher (p < 0.001) when an identical Paw = 25 cm H₂O was reached at end-inspiration compared with end-expiration (Figure 5). Atelectasis developed mainly in dependent lung areas, and the amount of atelectasis decreased with increasing Paw between 10 and 40 cm H₂O. However, even with an end-inspiratory Paw of 40 cm H₂O, atelectasis did not completely resolve (Figure 5). Significantly more atelectasis was present at an end- inspiratory Paw of 25 and 30 cm H₂O, than at an end-expiratory Paw of 25 cm H₂O (p = 0.0012).

View larger version (15K): [in this window] [in a new window]   Figure 5.   Lung density and atelectasis versus airway pressure. Data are shown as mean ± SEM. (Left panel ) The y-axis gives the mean lung density measured in Hounsfield units (HU), the x-axis shows the end-expiratory (closed diamonds) and end-inspiratory (closed squares) airway pressure. There is a highly significant correlation between Paw and lung density (r = 0.98, p < 0.001). (Right panel ) The y-axis shows the atelectatic area in percent of total lung area, and the x-axis gives the end-expiratory (closed diamonds) and end-inspiratory (closed squares) airway pressure. With an identical Paw = 25 cm H2O, lung density was lower and atelectasis was smaller at end-expiration as compared with end-inspiration. Correlation coefficient between Paw and atelectasis: r = 0.89, p = 0.0029.

Dynamics of Lung Collapse and Recruitment

During the beginning of expiration and inspiration lung density changed rapidly and almost without delay if the interval between the first two data points was corrected to 0.6 s (Figure 6). Time constants averaged 0.74 ± 0.62 s for density changes during expiration but only 0.49 ± 0.20 s during inspiration (p = 0.001 for difference between expiration and inspiration). PEEP levels had no significant influence on .

View larger version (24K): [in this window] [in a new window]   Figure 6.   Dynamics of density and atelectasis changes. Data are shown as mean ± SEM. (Left panel ) The y-axis shows the lung density measured in Hounsfield units (HU), the x-axis shows the time period of expiration and inspiration hold. The time interval after the beginning of expiration and inspiration is adjusted to 0.6 s. (Right panel ) The formation and resolution of atelectasis, measured as percentage of lung area, is shown versus time. The arrows mark the beginning of the expiration or inspiration. CT scans were obtained every 0.8 s, and expiration was initiated immediately after the first scan. After the sixth CT scan, inspiration was initiated with Paw 15 cm H2O higher as PEEP. Note the time delay before atelectasis started to increase with PEEP = 10 or 15 cm H2O.

Atelectasis, in contrast, started to increase rapidly after an initial delay period of 0.6 s during expiration with PEEP = 10 and 15 cm H₂O (Figure 6). Time constants for atelectasis formation averaged 0.86 ± 0.67 s, and expiration to the different PEEP levels had no significant influence on . However, with PEEP = 25 cm H₂O the total increase of atelectasis was minimal (5.8 ± 6.3 cm²) and it was moderate with PEEP = 20 cm H₂O (10.7 ± 8.3 cm²).

During inspiration time constants averaged 0.69 ± 0.54 s so that recruitment was 85% complete within 1.4 s. In contrast to expiration, no delay period occurred before atelectasis started to change rapidly in size. Thus, expiratory and inspiratory changes of atelectasis were not symmetrical.

Regional Aeration

Density increased down the lung from the ventral (sternum) to the dorsal border at all pressure levels (Figure 7). The uppermost ROI (Position 1 in the inset of Figure 7) was generally well aerated and showed the smallest density changes during an inspiration or an expiration. Time constants (Table 2) tended to be shorter in the ventrally located ROIs, but  could be calculated only in 60% (271 of 448) of all analyses with a correlation coefficient exceeding 0.85. PEEP had no significant influence on time constants in individual ROIs. The distribution of tidal volumes within the lung changed when inspiration started from different PEEP levels. Thus, with rising PEEP, ventilation was redistributed from upper to lower lung areas (Figure 8).

View larger version (31K): [in this window] [in a new window]   Figure 8.   Inspiratory density changes of separate lung regions. Each bar shows the mean ± SEM of the density decrease during inspiration with 15 cm H2O starting from different PEEP levels. The positions of the ROIs are shown in the inset of Figure 7. With increasing PEEP levels, tidal volumes are redistributed towards more dependent lung regions.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Oleic-acid-injured lungs collapsed rapidly after a short delay period if a PEEP level of  15 cm H₂O was applied during expiration, whereas a PEEP of  20 cm H₂O nearly stabilized the lung during almost 4 s of expiration. During inspiration with a pressure increase of 15 cm H₂O above PEEP, recruitment reached a plateau within the first 1.4 s, but atelectasis did not resolve completely with airway pressures as great as 40 cm H₂O. In this experimental setting an inspiratory plateau pressure  40 cm H₂O in combination with PEEP  20 cm H₂O, or if PEEP was less than 15 cm H₂O, an inspiratory plateau pressure  40 cm H₂O in combination with an expiration time  0.6 s is therefore necessary, in order to effectively "open up the lung and keep the lung open" (3). Thus, the time window that allows the lungs to expire but prevents expiratory lung collapse without extrinsic PEEP is short.

Oleic-acid-induced lung injury shares many similarities with the early phase of an acute respiratory distress syndrome (ARDS) (13) and has therefore been extensively used to investigate different strategies of mechanical ventilatory support. In the present study, oleic-acid injection induced a severe lung injury as indicated by the increase of shunt, EVLWI, and the deterioration of compliance and resistance. Most animals fulfilled, therefore, the strict criteria for an ARDS (14).

Methodologic Aspects

CT-scans were obtained at a constant scanning level relative to the spine. However, the position of the diaphragm changes with respiration. Thus, lung parenchyma, scanned during the course of prolonged breathing, was not identical. An uneven craniocaudal distribution of the lung damage could therefore influence our results, but we found lung density to be almost uniformly distributed in a craniocaudal direction (average increase of +4 HU/1 cm movement towards the diaphragm). A systematic influence on our results by scanning different lung tissue during breathing seems therefore to be unlikely. However, the oleic-acid-induced damage caused a patchy edema distribution at a regional level, which may have contributed to the difficulties to fit exponential functions to the density changes during inspiration or expiration in individual ROIs.

Intrathoracic blood volume decreases with increasing mean airway pressure (15). Because the filling of pulmonary blood vessels affects the lung density measured by CT scanning, an increase of Paw decreases lung density because of better aeration and to some extent by a decrease of the pulmonary blood volume. This may explain why time constants were slightly longer for density changes compared with volume changes. In addition, changes of atelectasis may have been overestimated in our study if vascular filling increased density to above 100 HU during expiration, and reduced density to below 100 HU during inspiration.

At end-expiration with PEEP = 10 cm H₂O the lung area in the transverse scans was 4.2 ± 2.8 cm² (2.6 ± 1.5%) smaller compared with end-inspiration with 40 cm H₂O. Thus, the influence of changing lung area on the determination of atelectasis, expressed as a percentage of total lung area, is small and has been neglected.

Ventilation with FI_O2 = 1.0 has been shown to facilitate atelectasis formation (16), but it was necessary in order to avoid severe hypoxia after induction of lung injury.

Implications of Static CT Scanning

At end-inspiration and end-expiration, density increased down the lung (Figure 7). Except for the uppermost ROI, which was well aerated at all pressure levels, end-expiratory aeration was improved more by PEEP in the upper (more ventrally located) than in the lower lung areas. However, increasing PEEP levels caused a redistribution of inspiratory tidal volumes from upper to lower lung regions, so that a more homogenous distribution over the lung of tidal volumes was achieved (Figure 8). Similar findings have previously been obtained in patients with ARDS (17).

Lung density was significantly higher and atelectasis significantly larger when the same Paw of 25 cm H₂O was reached at end-inspiration compared to end-expiration as previously shown in lavage-induced lung injury of pigs (18). Consequently, the airway pressure that was necessary to open up the lung exceeded the airway pressure at which lung collapse occurred during expiration. This may promote successive collapse of lung tissue during mechanical ventilation if recruitment is incomplete during inspiration and end-expiratory lung collapse can not be completely prevented. Atelectasis decreased in size, but resolved only incompletely with increasing inspiratory airway pressures as great as 40 cm H₂O (Figure 5). An end-inspiratory airway pressure of 35 to 45 cm H₂O during each tidal cycle, which is recommended in order to avoid barotrauma (19), might therefore fail to open up the lung effectively and thus might fail to restore adequate oxygenation, as seen in this animal model.

Implications of Dynamic CT Scanning

Lung collapse and recruitment occurred mainly during the first 1 to 2 s (time interval of 2 to 3 scans) of expiration and inspiration with the ventilatory pattern studied (Figure 6).

At all PEEP levels atelectasis had increased already to some extent in the first CT scan obtained after the beginning of expiration (within 0.6 s, if the time interval is corrected). This increase, however, was rather small. Mainly, atelectasis formation occurred after the first expiratory scan was obtained. Such a delay was neither apparent during the resolution of atelectasis nor for the changes of lung density (Figure 6) and is not an artifact of CT scanning. It should therefore be possible to prevent lung collapse during expiration without high PEEP if expiration is short enough. In our experimental setting, an appropriate expiratory time interval that avoids end-expiratory lung collapse would be  0.6 s. Such a ventilatory pattern, however, will certainly lead to a high intrinsic PEEP and a high mean airway pressure (20), so it is questionable if it offers any advantages over a ventilatory pattern that applies extrinsic PEEP for stabilizing the lung during expiration.

During inspiration recruitment occurred rapidly within the time interval of 2 scans (approximately 1.4 s). Even with a respiratory rate of 20 breaths/min such a time interval would be achieved already with an I:E-ratio of 1:1. Therefore, reopening of collapsed lung tissue seems to be no argument supporting inverse ratio ventilation (IRV), and IRV has not consistently improved oxygenation in clinical and laboratory investigations (for reviews see References 22 and 23). Atelectasis in lung areas with a high resistance might not be recruited within 1.4 s, but considering the exponential dynamics of lung reopening, the potential benefit of increasingly longer inspiration times is most likely small.

However, we studied only the immediate effects of changing Paw on lung collapse and recruitment, thus we cannot speculate on effects that might occur slowly over longer time periods.

Conclusion

To avoid cyclic alveolar collapse during mechanical ventilation in oleic-acid-induced lung injury in pigs, a PEEP level > 20 cm H₂O or an expiration time < 0.6 s is required. Thus, the time window to prevent end-expiratory lung collapse without extrinsic PEEP is extremely short, and an expiration time < 0.6 s might not be feasible during mechanical ventilation of many patients with ARDS. Recruitment occurred mainly within the first 1.4 s of inspiration using an inspiratory pressure of 15 cm H₂O above PEEP, but it was incomplete even with a inspiratory airway pressure of 40 cm H₂O. Longer inspiration times seem to offer no advantage over conventional ventilatory settings.