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DOI: 10.1148/radiol.2392042177
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(Radiology 2006;239:398-405.)
© RSNA, 2006

Experimental Studies

Dynamic CT Measurement of Pulmonary Enhancement in Piglets with Experimental Acute Respiratory Distress Syndrome1

Claudia Schueller-Weidekamm, MD, Esther Wassermann, MD, Heinz Redl, PhD, Mathias Prokop, MD, Michael Zimpfer, MD, MBA, Christian Herold, MD, Peter Germann, MD and Roman Ullrich, MD

1 From the Departments of Radiology (C.S., M.P., C.H.) and Anesthesia and General Intensive Care (M.Z., P.G., R.U.), Medical University of Vienna, Vienna General Hospital, 18-20 Waehringer Guertel, 1090 Vienna, Austria; and the Ludwig Boltzmann Institute of Experimental and Clinical Traumatology, Vienna, Austria (E.W., H.R.). From the 2002 RSNA Annual Meeting. Received December 22, 2004; revision requested February 23, 2005; revision received April 11; accepted May 9; final version accepted July 18. Address correspondence to R.U. (e-mail: roman.ullrich{at}meduniwien.ac.at).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Purpose: To investigate whether analysis of a washout curve of contrast material obtained with serial computed tomography (CT) enables differentiation between hydrostatic pulmonary edema and pulmonary edema caused by increased capillary permeability.

Materials and Methods: The institutional committee on animal experiments approved this study, which was performed in accordance with designated guidelines. Chest CT was performed in 12 piglets after induction of anesthesia and start of mechanical ventilation. Dynamic CT was performed before and after induction of hydrostatic edema (n = 5) or oleic acid–induced increased vascular permeability edema (n = 7). Scans were obtained over 240 seconds during inspiratory breath holding at a single representative subcarinal level in the lungs. This anatomic level was kept constant and included areas of normal ventilation before and after induction of pulmonary edema and areas of ground-glass opacity and consolidation after induction of pulmonary edema. Measured lung attenuation in the regions of interest was normalized to that before contrast material injection and plotted as a function of time. Statistical analysis was performed by using two-way analysis of variance with repeated measures.

Results: In general, before induction of pulmonary edema, attenuation of normally aerated lung areas did not increase after the initial peak of enhancement during the first pass of contrast material. In animals with hydrostatic edema, no attenuation changes in areas of ground-glass opacity were observed after the initial peak. Conversely, lung attenuation increased continuously in animals with oleic acid–induced high-permeability pulmonary edema (P = .002). After induction of lung edema, pulmonary enhancement measured in lung regions with normal ventilation or consolidation did not change in either group. Pulmonary fluid accumulation 90 minutes after induction of edema did not significantly differ between groups.

Conclusion: Dynamic contrast–material enhanced CT can help differentiate between permeability and hydrostatic lung edema in an animal model.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Acute respiratory distress syndrome (ARDS) presents a substantial challenge in the care of critically ill patients, with mortality rates of 40%–80% (1,2). Currently, we lack a specific test for diagnosing ARDS, and patients with respiratory distress are mainly identified on the basis of clinical parameters and findings of chest radiography (3). Pathophysiologically, ARDS is an underlying specific inflammatory response to a variety of direct and indirect injuries to the lungs and has different and distinct stages (1). It is well established that diffuse alveolar damage is present in early ARDS. This damage is mediated by the accumulation of inflammatory cells and the release of cytokines. ARDS is characterized by an increase in pulmonary capillary permeability, which thereby causes a profound, noncardiogenic lung edema.

From one helical computed tomographic (CT) scan of the lungs, we can gain important information about the presence of alveolar edema or pleural effusions and the extent and distribution of parenchymal alterations (4,5). To our knowledge, only a few investigators have evaluated the pathognomonic CT findings of hydrostatic and permeability pulmonary edema. Scillia et al (6) investigated the distribution of hydrostatic and oleic acid–induced pulmonary edema in a canine model. They showed that hydrostatic edema is characterized by a gravitational gradient, whereas oleic acid–induced pulmonary edema is characterized by a nearly homogeneous distribution (6). Although this analysis is helpful in the detection of morphologic distribution patterns, it may not be specific enough for assessing the presence or absence of increased capillary permeability because gravitational gradients are often present in subjects receiving ventilation, both experimentally and clinically (7).

On the basis of a study by Rouby et al (8), we hypothesized that, compared with contrast material in subjects with healthy lungs without capillary leakage (which remains intravascular), contrast material in patients with ARDS penetrates the extravascular lung parenchyma because of alterations in the alveolar-capillary barrier and is not rapidly eliminated in the urine. Thus, the purpose of our study was to investigate whether analysis of a washout curve of contrast material obtained with serial CT enables differentiation between hydrostatic pulmonary edema and that caused by increased capillary permeability.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study Population
Our institutional committee on animal experiments approved the experimental protocol, and all experiments were performed in accordance with the guidelines described in the "Guide for the Care and Use of Laboratory Animals" of the Institute of Laboratory Animal Research (http://www.nap.edu/books/0309053773/html/index.html).

We studied 12 piglets aged 2–5 months (seven female and five male piglets) and weighing 30–35 kg. The 12 piglets were assigned to one of two groups by chance (flip of a coin). This resulted in an uneven distribution between groups. In the first group (n = 7; female-to-male ratio, 4:3; mean weight ± standard deviation, 33 kg ± 1.5), we induced increased permeability edema within the lungs by means of continuous infusion of 0.15 mL of oleic acid per kilogram of body weight directly into the right atrium through a central venous catheter (R.U. and E.W.). The administration of oleic acid induces, within 15–90 minutes, severe pulmonary edema characterized by marked capillary leakage, which leads to the accumulation of fluid and proteins in the alveolar space (9–11). In the second group (n = 5; female-to-male ratio, 3:2; mean weight, 31 kg ± 0.5), we induced hydrostatic pulmonary edema by inflating a balloon, which had been positioned surgically in the left atrium, to approximately 36 mm Hg over 90 minutes (R.U. and E.W.). This procedure leads to an increase in extravascular pulmonary fluid, which is driven purely by hydrostatic forces (normal left atrial pressure, 5–10 mm Hg) (12).

Experimental Preparation
All procedures in the piglets were performed by three authors (R.U., E.W., and H.R.). Animals were anesthetized with an intravenous injection of azaperone (7 mg/kg) and alloferin (0.2 mg/kg). Their tracheas were intubated and mechanical ventilation was started at a tidal volume of 10 mL/kg, a respiratory rate of 15 breaths per minutes, and a positive end-expiratory pressure level of 12 cm H2O. Respirator settings were adjusted to maintain blood gas values within the physiologic range and were kept constant thereafter. Anesthesia was maintained with a continuous intravenous infusion of midazolam (10 mg/h) and sufentanil (0.1 mg/h). Alloferin (0.2 µg · kg–1 · min–1) was added to produce muscle relaxation. Polyethylene catheters were placed in the right carotid artery and right femoral vein. A 7.5-F Swan-Ganz flow-directed thermodilution tip catheter (REF-1; Baxter Healthcare, Irvine, Calif) was positioned in the proximal pulmonary artery via the right jugular vein. A 14-F silastic catheter was inserted suprapubically into the bladder. All catheters were placed by means of direct cutdown, and the wounds were closed surgically. An electrocardiogram was obtained with six-lead needle electrodes, and body temperature was recorded with a rectal thermistor. All catheters were flushed with saline containing heparin to prevent clotting.

Measurements of Hemodynamics and Lung Mechanics
Mean arterial blood pressure, mean pulmonary artery pressure, central venous pressure, and peak airway pressure were continuously monitored by using biomedical amplifiers. The heart rate was derived from the electrocardiogram. The expiratory tidal volume (VTexp) was measured with a flowmeter, and static lung compliance was calculated with the following equation: Pplateau-PPEEP/VTexp, where PPEEP is the positive end-expiratory pressure period. The length of the inspiratory plateau pressure (Pplateau) was 5 seconds. All measured signals were transferred to an analog-to-digital converter, displayed on a computer screen, and recorded with a data acquisition system. All monitoring equipment was calibrated before each experiment. Cardiac output was determined with a thermodilution technique. The average of three measurements taken at end expiration was accepted as the value for each period.

CT Protocol
CT scans were obtained with a bedside unit (Tomoscan M; Philips, Eindhoven, the Netherlands). First, the examination range included the entire chest from the lung apices to the diaphragm to evaluate additional lung abnormalities and help choose the representative subcarinal level for the subsequent transverse baseline dynamic CT examination. CT was performed during an inspiratory breath hold at total lung capacity. In addition, transverse dynamic scans were obtained before and 90 minutes after the induction of lung edema at the same anatomic subcarinal level that contained lung regions with different lung attenuations, the main pulmonary artery, and the aortic arch (Fig 1) (13,14). The appropriate anatomic level was chosen by a radiologist (C.S.) by using images obtained during the first CT examination that included the entire chest. For serial CT after the induction of lung edema, we moved the CT table to the same table position used to perform baseline serial CT. Piglets were not moved during the entire experiment; however, because total lung capacity and, consequently, lung volume were reduced after the induction of lung edema, we adjusted the table position to exactly the same anatomic level as that used for the first serial CT examination.


Figure 1
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  		Figure 1: Representative unenhanced transverse CT scan obtained at the subcarinal level 90 minutes after the start of oleic acid administration. Three different ROIs are identified, as follows: ROI a shows normally ventilated areas, ROI b shows ground-glass opacities, and ROI c shows consolidation areas. Note the patchy and uneven distribution of ground-glass opacities within the lungs. Analysis of dynamic CT scans concentrated on ground-glass opacities because, in this experimental setting, they are representative of alveolar edema and/or inflammatory processes in the lungs.

 
Scans were obtained every 7 seconds at the total lung capacity level for a period of 240 seconds starting at least 7 seconds before contrast material injection (Fig 2). These dynamic CT examinations were performed in each animal twice—before and after the induction of lung edema. Nonionic contrast material (iobitridol, 300 mg/mL [Xenetix; Guerbet, Roissy, France]) was injected at a concentration of 1 mL/kg as a tight bolus (flow rate of more than 8 mL/sec). This was immediately followed by a 50-mL saline flush. Before contrast material enhancement was evident in the main pulmonary artery, we started examining the chosen subcarinal anatomic level to obtain unenhanced CT scans at the beginning of the serial CT examinations. Before and after the induction of hydrostatic or permeability lung edema, CT scans were obtained with 3-mm collimation for a single section to reduce partial volume effects but maintain noise at an acceptable level. The examination time was 2 seconds per transverse image with a delay of 5 seconds between each acquisition. Exposure parameters were 100 kVp and 30 mAs to guarantee sufficient image quality.


Figure 2
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  		Figure 2: Diagram shows experimental setup for the ventilation protocol. CT was performed during the same inspiratory phase after reaching the plateau of a pressure-controlled ventilation mode to ensure constant intrathoracic pressure. Contrast material (CM) was administered after the first CT scan was obtained. Thereafter, serial CT scans were obtained at the identical anatomic level for 240 seconds.

 
CT Ventilation Protocol
To ensure that every CT scan in the dynamic sequence during contrast material application was obtained in an identical phase of the respiratory cycle, the following mechanical ventilation protocol was applied during the examination. We used an airway pressure release ventilatory mode (BIPAP; Draeger, Luebeck, Germany) at a fraction of inspired oxygen of 1.0 with an upper pressure level of 35 cm H2O and a lower pressure level of 12 cm H2O. The inspiration and expiration times were set to 5 and 2 seconds, respectively, to guarantee images were obtained within the inspiration phase (Fig 2). Synchronization between the CT scan and ventilator during CT was assessed by a study coordinator (R.U.). The start of the CT examination, indicated by an acoustic signal, always occurred after the start of inspiration, as monitored on the pressure curve display on the mechanical ventilator. In addition, synchronization was demonstrated by the fact that we did not observe any change in anatomic structures (ie, the carina) on the serial CT sections obtained without table feed at the total lung capacity level for each individual animal. Thus, we ensured that CT was performed with a constant lung volume and at an identical level.

Image Analysis
Two chest radiologists (M.P. and C.S., with 17 and 4 years of experience, respectively) performed consensus interpretation of the transverse CT scans at a conventional lung window setting (level, –500 HU; width, 1500 HU). CT scans were interpreted for the distribution of ground-glass opacification and the depiction of the representative regions of interest (ROIs), including aerated, opacified, and consolidated areas of lung parenchyma. The first unenhanced scan of each dynamic CT series, obtained at an anatomic level just below the carina and main pulmonary artery, was analyzed for the presence of areas of different lung attenuations representing normal aerated areas, ground-glass opacities, and consolidated areas. ROIs were set in each of the representative areas and copied to the corresponding transverse scan from the dynamic series, obtained at the identical anatomic level and during the inspiratory phase. The mean size of the ROIs was 2.0 cm2 (range, 1.0–2.4 cm2). Larger ROIs would not enable us to exclude the presence of bronchovascular structures, and, therefore, a homogeneous lung parenchyma would not be obtained for measurements. Quantitative analysis of the transverse CT scans was performed in different ROIs of areas of the three representative lung attenuations by measuring CT numbers in at least one ROI.

The lung attenuation of each voxel (voxel size, 0.32 x 0.32 x 3.0 mm; matrix, 512 x 512; section thickness, 3 mm) was defined by using CT numbers and measured on a dimensionless arbitrary scale in Hounsfield units. By convention, CT numbers range from a maximum of +1000 HU, which represents bone attenuation, to a minimum of –1000 HU, which represents air. Consolidation of lung parenchyma was defined as homogeneous opacification of the parenchyma with obscuration of the underlying bronchovascular structures. Ground-glass opacities were defined as hazy areas of increased opacity or attenuation without obscuration of the underlying bronchovascular structures (15–17). Normal aerated areas did not show any lung parenchyma abnormalities and ranged from –1000 HU to –750 HU (15).

CT numbers measured during dynamic CT were divided by those obtained before contrast material enhancement to normalize the values of the dynamic CT scans. Normalization of the CT numbers helps delineate the change in the CT numbers and eliminates any differences in baseline CT opacity between animals. The normalized CT numbers were plotted against time to yield an attenuation-over-time curve.

Extravascular Lung Water Measurements
Extravascular lung water was measured with the indocyanine double-indicator dilution technique, as described previously (18,19). After the completion of imaging, animals were sacrificed with an intravenous injection of a bolus of pentobarbital (300 mg/kg) followed by an intravenous injection of 10-mL potassium chloride. The postmortem wet-to-dry ratio of both lungs was calculated to obtain a second measure of fluid accumulation within the lung parenchyma. For this procedure, at the end of the experimental study, the animals were exsanguinated and the lungs removed and processed for gravimetric determination of extravascular lung water and dry weight according to previous studies (20). The difference between the wet and dry weight is indicative of the extravascular fluid accumulation.

Statistical Analysis
Normalization of the data for the single time points was performed by dividing the averaged CT number measured in an ROI after contrast material enhancement at the different time points by the CT number measured in the ROI before contrast material administration. Individual normalized plots of changes in CT attenuation yielded a typical curve characterized by an initial peak of increased CT attenuation that returned to the baseline level within a few seconds. The following course of the CT attenuation curve was analyzed separately for each group by using one-way analysis of variance with repeated measures. Statistical significance was indicated by a P value of less than .05. A P value of less than .05 was indicative of a significant difference in the CT attenuation, where the curve is indicative of pulmonary accumulation of the marker. Differences in the mean curve values of each group were tested with a two-way analysis of variance with repeated measures with two independent variables. One factor was assignment to either the high-permeability edema group (n = 7) or the left atrial hypertension group (n = 6); the second factor was the repeated CT measurements at the respective time points. This analysis also tested the variance between the groups. Measurements of hemodynamics and lung mechanics were tested for normal distribution (Lilliefors test for normality), and differences between groups were determined by using the Student t test (SPSS, version 11.5, SPSS, Chicago, Ill; Statistica for Windows, StatSoft, Tulsa, Okla). All data are expressed as means ± standard errors of the mean.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Gas Exchange and Hemodynamics
Gas exchange and hemodynamic parameters before and 90 minutes after the induction of edema are shown in Tables 1 and 2. Oleic acid injection increased the alveolar-to-arterial partial pressure difference from 151 mm Hg ± 31 to 418 mm Hg ± 58 and decreased the PaO2 from 515 mm Hg ± 32 to 196 mm Hg ± 58 (P < .001 for both). Similarly, the induction of hydrostatic edema by means of left atrial hypertension increased the alveolar-to-arterial partial pressure difference from 69 mm Hg ± 16 to 349 mm Hg ± 115 and decreased the PaO2 from 612 mm Hg ± 20 to 281 mm Hg ± 93 (P < .001 for both).


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  		Table 1. Hemodynamic Parameters

 

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  		Table 2. Summary of Oxygenation and Respiratory Parameters

 
In both groups, there was no statistically significant difference between the pulmonary arterial pressure, cardiac output, and systemic vascular resistance index obtained at the start of the examination and that obtained after the induction of edema. Conversely, the pulmonary vascular resistance index more than tripled 90 minutes after oleic acid injection, from 147 dyne · sec · cm–5 · m–2 ± 21 to 440 dyne · sec · cm–5 · m–2 ± 104 (P < .001). There was no statistically significant difference between the pulmonary vascular resistance index before and after the induction of hydrostatic edema.

Subjective Assessment of Ground-Glass Opacification
In piglets with high-permeability edema, we observed a patchy, nearly homogeneous distribution of areas of ground-glass opacity throughout the lungs and atelectasis of dorsally dependent lung areas and regions of normal ventilation, most of which were localized ventrally.

In lungs with hydrostatic edema, however, we observed a gravitational attenuation gradient with atelectasis located in the dependent lung areas dorsally.

Pulmonary Enhancement in Vascular Permeability Edema versus Hydrostatic Edema
Approximately 7 seconds after contrast material administration, there was an initial increase in CT numbers measured in the main pulmonary artery and aortic arch before and after induction of pulmonary edema. An initial increase in pulmonary enhancement was also observed in normally ventilated areas before the induction of lung edema and in areas of ground-glass opacity and consolidation after the induction of hydrostatic or high-permeability lung edema. This initial increase in CT numbers in the lung parenchyma started 7–14 seconds after contrast material administration and lasted for 35 seconds (Fig 3). It is notable that this initial peak returned to the baseline level in all animals in both groups, regardless of the presence or absence of edema, and was interpreted as being indicative of the first pass of the contrast material in the circulation (21). Thus, this initial peak of contrast material was omitted from further analysis.


Figure 3
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  		Figure 3: Graph shows changes in lung attenuation at dynamic CT performed at an identical anatomic level 90 minutes after oleic acid–induced vascular permeability pulmonary edema and hydrostatic pulmonary edema induced by means of left atrial hypertension. CT numbers were plotted over time for lung attenuation observed in ground-glass opacities. Values of lung attenuation in ground-glass opacities at the respective time points (GGt) were normalized to CT numbers obtained before the administration of contrast material (GG0). The first initial peak was omitted from further analysis because it represented early vascular filling of intrapulmonary vessels. We included time points from 90 seconds after the first scan in the analysis. The statistical difference between the two curves was tested with a two-way analysis of variance with repeated measures (P < .001, oleic acid–induced pulmonary edema vs hydrostatic pulmonary edema).

 
Ninety minutes after the administration of oleic acid, we observed a continuous increase in CT numbers in areas of ground-glass opacity in animals with high-permeability edema. This accumulation of contrast material occurred approximately 90 seconds after the start of contrast material administration and lasted for 150 seconds. The CT numbers subsequently decreased to values measured before contrast material administration (P = .016).

Conversely, 90 minutes after the start of left atrial hypertension, no changes in CT numbers in ground-glass opacities were observed in animals with hydrostatic edema (P = .132).

The increase in CT numbers 90 minutes after the induction of edema was significantly higher in animals with permeability pulmonary edema than in those with hydrostatic edema (P = .002, Fig 3).

Furthermore, in both groups, there was no increase in CT numbers in normally ventilated or consolidated lung areas, either before or 90 minutes after the induction of edema (data not shown).

Extravascular lung water increased markedly in both groups after the induction of lung edema. There was no significant difference between the extravascular lung water in hydrostatic and permeability edema 90 minutes after the induction of edema, thereby demonstrating a comparable degree of fluid accumulation within the lungs (9.9 mL/kg ± 0.9 vs 11.9 mL/kg ± 1.3 for high-permeability edema and hydrostatic edema, respectively; P = .25; Fig 4).


Figure 4
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  		Figure 4: Chart shows changes in the extravascular lung water index (EVLWI) (left y-axis) before (Baseline) and 90 minutes after induction of oleic acid–induced high-permeability edema or hydrostatic edema induced by means of left atrial hypertension. Note the similar increase in the extravascular lung water index in both forms of experimental pulmonary edema (P < .05 compared with baseline). The right y-axis shows the postmortem lung wet-to-dry ratios in animals with oleic acid–induced high-permeability edema and hydrostatic edema. There is no difference in the accumulation of fluid between the forms of experimental edema.

 
Wet-to-dry lung weights were measured immediately after the imaging experiments. Oleic acid and left atrial hypertension induced a progressive increase in extravascular lung water that corresponded to the hemodynamic changes shown in Table 2. Pulmonary fluid accumulation did not differ significantly between vascular permeability edema and hydrostatic edema, as expressed with the wet-to-dry ratio (wet-to-dry ratio, 8.9 ± 0.7 vs 8.8 ± 1.4 for vascular permeability and hydrostatic edema, respectively; P = .723; Fig 4).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
To our knowledge, no investigators have previously compared the dynamic enhancement of lung parenchyma after contrast material administration in conditions with increased vascular permeability to that in conditions with intact vascular integrity. In our experimental setup, we used an infusion of oleic acid to induce acute high-permeability pulmonary edema by causing diffuse capillary damage, which leads to a marked increase in pulmonary capillary permeability to small and large molecules (22,23). We observed a patchy distribution of ground-glass opacities throughout the lungs on CT scans obtained 90 minutes after oleic acid administration together with atelectasis of dorsally dependent lung areas. We also observed lung regions with preserved normal ventilation, and these were mainly localized to the ventral lung areas. These radiologic changes are similar to CT findings in patients with ARDS and to CT findings in experimental studies (3,8,24–26). Some investigators have stated that, because of the characteristic distribution of the ground-glass opacities, CT can be used to differentiate between hydrostatic edema, which has a gravitational gradient distribution, and increased vascular permeability lung edema, which is characterized by a more homogeneous distribution (6). This distribution, however, may be present in different conditions with and without increased vascular permeability and does not enable reliable differentiation between pulmonary edema caused by increased capillary permeability and lung edema induced by pressure overload. For example, subjects who are anesthetized while in the supine position rapidly develop basal atelectasis as measured with CT, therefore providing a confounding variable to the analysis of gravitational gradients because they may be present even in the absence of lung edema (7).

In our study, we used serial CT to analyze the washout curve of a single bolus of contrast material in areas of ground-glass opacity, consolidated areas, and normally aerated areas. We observed that there was an initial increase in overall lung attenuation, including the major intrathoracic vessels of the representative level, which is indicative of the first pass effect of the contrast material. Lung attenuation returned to baseline levels within 80 seconds in all animals under all conditions. This behavior of the contrast material bolus is similar to the first pass observed with radioactive tracers used to evaluate microvascular permeability (21,23,27). Because we were interested in the diffusive behavior of the bolus of contrast material, we omitted this peak of activity from further analysis. As expected, there was no further increase in lung attenuation after the initial peak before oleic acid–induced lung edema. In areas with a ground-glass appearance, however, a marked and steady increase in lung attenuation was observed 90 minutes after oleic acid administration. Lung attenuation can only be reliably measured when the lung volume is kept constant (25), which is ensured by keeping the total lung capacity level constant during CT. The increase in CT numbers did not occur in normally ventilated or atelectatic lung regions.

To exclude the possibility that the pulmonary enhancement observed in areas of ground-glass opacity after high-permeability edema was a nonspecific sign of increased interstitial fluid accumulation, we performed additional experiments in which we induced pure hydrostatic edema by means of left atrial hypertension. In hydrostatic pulmonary edema, ground-glass opacities were depicted on CT scans as soon as the effective pulmonary capillary pressure equaled the critical pulmonary capillary pressure (2).

Several investigators using radionuclide methods have shown that the distribution of intravascular markers is not affected in pulmonary edema caused by left atrial hypertension, whereas there is accumulation of intravascular radioactive markers within the interstitium in animals with high-permeability edema (12,27–29). Similar results were observed in clinical studies in which pulmonary capillary permeability to radionuclide tracers in patients with ARDS was compared with that in patients with pulmonary edema due to cardiac failure (30–33). In contrast to the pulmonary enhancement observed at dynamic CT in animals with high-permeability edema, we did not find an increase in CT numbers in ground-glass opacities in animals with hydrostatic edema. These differences in appearance at dynamic CT cannot be explained by different amounts of pulmonary edema because extravascular lung water measured immediately after CT, together with postmortem wet-to-dry lung weight, did not differ between groups. Together, these results strongly suggest that pulmonary enhancement of areas of ground-glass opacity on dynamic CT scans is specific for the presence of increased vascular permeability.

In a recent clinical study by Bouhemad et al (34), there was a significant increase in lung attenuation 15 minutes after the administration of a bolus of contrast material in patients with ARDS. This suggests that increased pulmonary vascular permeability leads to an accumulation of contrast material in the interstitial space after a single bolus, which can be depicted on serial CT scans as pulmonary enhancement of areas of ground-glass opacity. Experimental studies demonstrated an increase in vascular permeability and the consecutive presence of homogeneously distributed ground-glass opacities after the administration of oleic acid, simulating experimental ARDS (6). On the basis of our results, we believe that the alteration in the pulmonary capillary integrity induced by means of oleic acid administration facilitated the spread of contrast material into the interstitial space and backward distribution, thereby shifting the balance in favor of the interstitial space. Because capillary integrity is unchanged in hydrostatic edema, there is no increased path for contrast material into the interstitium and, thus, no accumulation can be observed (35). This view follows a two-compartment model for fluid equilibrium within the pulmonary parenchyma that has been recently proposed to explain the flux of small and large molecules between the intra- and extravascular space within the lungs (36).

Overall, several limitations to the interpretation of our studies must be considered. First, it should be noted that our studies do not enable quantification of the degree or the extent of the increase in pulmonary capillary permeability. Second, because measurements of CT attenuation are less sensitive than scintigraphic methods with radionuclide markers, we cannot rule out that a part of the increased lung attenuation following oleic acid administration might be caused by increased filtration of contrast material caused by altered transpulmonary pressures. Conversely, it is true that the methodologic approach is not capable of depicting any possible small alteration in capillary integrity that might be caused by increased filtration pressure owing to left atrial hypertension. It must be noted, however, that in a controlled experimental setup, pulmonary enhancement on dynamic CT scans enabled differentiation between the presence and absence of highly increased pulmonary capillary permeability. Last, differences in pulmonary blood volume have the potential to interfere severely with the distribution of intravascular markers (36). It is unlikely, however, that meaningful changes in pulmonary blood volume occurred during our studies because the cardiac output between the time before and after dynamic CT did not differ. Another concern is that the high cardiac rhythm of piglets causes motion artifacts that might interfere with the measurements of ROIs within the lung parenchyma. In our study, we avoided placing ROIs close to the heart. In addition, ventilation was held constant within animals and between groups; therefore, the same changes in intrathoracic pressures occurred during CT.

In summary, the results of our study suggest that dynamic contrast-enhanced CT can help differentiate between permeability and hydrostatic lung edema in an animal model. This is shown by pulmonary enhancement of areas of ground-glass opacity on dynamic CT scans obtained at an identical anatomic level in animals with oleic acid–induced high permeability pulmonary edema. This pulmonary enhancement was not observed in animals with hydrostatic pulmonary edema presumed to have intact capillary integrity.

Practical application: Contrast material–enhanced dynamic CT scans might prove helpful for selecting patients in acute stages of ARDS and would benefit the stratification of patients to clinical trials as well as to novel therapies. Moreover, this technique would increase our insight into the efficacy of therapeutic strategies with regard to the different stages of ARDS. Further studies are required to demonstrate the feasibility of this approach in a clinical setting.


   FOOTNOTES
 

Abbreviations: ARDS = acute respiratory distress syndrome • ROI = region of interest

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, C.S., C.H., R.U.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, C.S., P.G., R.U.; experimental studies, C.S., E.W., H.R., P.G., R.U.; statistical analysis, C.S.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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