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Anesthesiology:
doi: 10.1097/01.anes.0000264748.86145.ac
Laboratory Investigations

Regional Gas Exchange and Cellular Metabolic Activity in Ventilator-induced Lung Injury

Musch, Guido M.D.*; Venegas, Jose G. Ph.D.†; Bellani, Giacomo M.D.‡; Winkler, Tilo Ph.D.§; Schroeder, Tobias M.Eng.∥; Petersen, Bodil M.D.∥; Harris, R Scott M.D.#; Vidal Melo, Marcos F. M.D., Ph.D.*

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Abstract

Background: Alveolar overdistension and repetitive derecruitment–recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident.
Methods: The authors assessed cellular metabolic activity with [18F]fluorodeoxyglucose and regional gas exchange with [13N]nitrogen. In 12 sheep, the left (“test”) lung was overdistended with end-inspiratory pressure of 50 cm H2O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of −10 cm H2O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H2O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right (“control”) lung was protected from VILI.
Results: Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [18F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [18F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone.
Conclusion: The authors could detect regional neutrophil activation in VILI even when end-expiratory derecruitment was prevented and impairment of gas exchange was not evident. Concomitant end-expiratory derecruitment converted this activation into profound inflammation with decreased aeration and regional shunting.
VENTILATOR-INDUCED lung injury (VILI) can contribute to the morbidity and mortality of patients with acute lung injury (ALI).1 Overdistension, repetitive alveolar derecruitment and recruitment, and large tidal excursion are three physical determinants of VILI.2–10 Because the pulmonary inflammatory process triggered by these physical stimuli is an important pathogenic event of VILI, a method to assess activation of inflammatory cells in the lung noninvasively and in vivo could be valuable, especially if it provided topographical information allowing identification of lung regions most affected by the inflammatory process of VILI.
Among the inflammatory cells involved in VILI, neutrophils have been shown to be sensitive to the pattern of mechanical ventilation.11–13 Furthermore, neutrophil depletion attenuated,14 whereas neutrophil stimulation worsened,15 the pulmonary injury associated with mechanical ventilation. These observations point to a prominent role of neutrophils in VILI.16 Metabolic activity of neutrophils can be assessed in vivo and noninvasively by imaging, with positron emission tomography (PET), the regional uptake of 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG).17–24 The topographic association between neutrophil activity and impairment of gas exchange can be investigated by imaging both [18F]FDG and [13N]nitrogen (13N2) infused intravenously in saline solution.
In this study, we used PET imaging of the pulmonary kinetics of [18F]FDG and 13N2 to measure regional metabolic activity of neutrophils and gas exchange in a sheep model of unilateral VILI. To induce unilateral VILI,25 we used separate ventilation: The left (“test”) lung was injuriously ventilated, while the right (“control”) lung was protected from VILI. In one group of animals, the test lung was injured with both end-inspiratory overdistension and end-expiratory derecruitment to assess whether [18F]FDG uptake was increased in a lung with VILI compared with an uninjured lung. In a second group, the test lung was also dynamically overdistended, but positive end-expiratory pressure (PEEP) was applied to prevent end-expiratory derecruitment and delay VILI induced by the same level of end-inspiratory pressure as in the first group.26 In this second group, we assessed whether metabolic activation could be detected early during pure overdistension, when other manifestations of VILI, such as impairment of gas exchange, decreased respiratory compliance, and histopathologic changes,2–4 had not yet occurred.
By imposing marked pressure changes on a uniform healthy lung, we aimed at achieving controlled levels of mechanical stress that could be comparable to those that develop regionally in the heterogeneously inflated acutely injured lung.27 Therefore, this experimental study aimed at assessing the direct contribution of mechanical stress associated with overdistension and repetitive derecruitment to inflammatory cell activation and regional gas exchange impairment, not at evaluating viable clinical ventilatory strategies or at reproducing multiple nonmechanical factors that can modulate VILI in patients with ALI, such as preexisting blood-borne injury to the lung,28,29 surfactant dysfunction,30 or infection.31
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Materials and Methods

Experimental Preparation
The experimental procedures were approved by the Subcommittee on Research Animal Care of the Massachusetts General Hospital (Boston, Massachusetts). Twelve sheep, weighing 25.7 ± 2.9 kg (mean ± SD) (range, 20.5–30 kg) were fasted overnight and premedicated with intramuscular midazolam (2 mg/kg) and ketamine (4 mg/kg) in the morning. After intravenous induction of anesthesia with thiopental (30 mg/kg) and fentanyl (12.5–25 μg/kg), a cuffed endotracheal tube (HiLo Tube; Mallinckrodt Medical Inc., St. Louis, MO) was inserted through a tracheotomy. Anesthesia was maintained with a continuous infusion of thiopental (15–25 mg · kg−1 · h−1) and fentanyl (10 - 30 μg · kg−1 · h−1). After induction of anesthesia, paralysis was established with intravenous pancuronium (0.2 mg · kg−1 · h−1), and the animals were ventilated in volume control mode with tidal volume of 11 ml/kg (end-inspiratory pressure, 16.2 ± 4.0 cm H2O), respiratory rate of 18 breaths/min, inspiratory-to-expiratory time ratio of 1:1.5, and fraction of inspired oxygen of 1. Using aseptic surgical technique, an arterial and a Swan-Ganz catheter (model 831HF75; Edwards Lifesciences, Irvine, CA) were inserted through the femoral vessels, and a jugular venous catheter was placed for infusion of 13N2 in saline solution and [18F]FDG.
After surgical instrumentation of the animal was completed, the endotracheal tube was replaced with a 35-French left-sided double-lumen endobronchial tube to deliver injurious ventilation only to the left lung during the period of injury.32,33 The double-lumen tube had been modified to accommodate sheep lung anatomy. The bronchial tip had been trimmed back approximately 3 mm to ensure ventilation of both left lobes, and the tracheal cuff had been moved 2 cm proximally to allow trimming of the distal tracheal opening of the double lumen tube and ensure adequate aeration of the right upper lobe. Proper position of the double lumen tube was confirmed by fiberoptic bronchoscopy. After airway instrumentation was completed, the animals were anticoagulated with intravenous heparin (200-U/kg bolus followed by an infusion at 50 U · kg−1 · h−1) to prevent blood clotting in the intravascular catheters.
The animals were then suspended prone in a cylindrical tube34 and kept prone with unsupported abdomen for the remainder of the experiment. The rationale for the use of the suspended prone position was to favor homogeneous lung expansion and minimize baseline intraregional mechanical heterogeneity so that the whole lung could be regarded as an approximately uniform region.
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Experimental Protocol
Fig. 1
Fig. 1
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The protocol schema is shown in figure 1. After transport from the surgical preparation suite to the PET suite, the animals were placed prone in the PET scanner with the caudal end of the field of view just superior to the dome of the diaphragm. During transport (approximately 2 min), bilateral ventilation was provided with an Ambu bag. In the PET suite, the animals were connected to the mechanical ventilator used for 13N2 scanning35,36 and, after a recruitment maneuver (airway pressure of 40 cm H2O for 30 s), combined bilateral mechanical ventilation with baseline settings was resumed. Starting at 15 min after the recruitment maneuver, a 10-min PET transmission scan was acquired to measure regional aeration, and a complete set of baseline physiologic data was collected during the last 2 min of the transmission scan. After the transmission scan, a 4-min 13N2–saline bolus infusion scan was acquired to measure regional perfusion and shunt. When baseline scans were completed, the animals were assigned to one of two groups of unilateral injurious ventilation. In both groups, injurious ventilation was delivered for 90 min only to the left (test) lung, while the right (control) lung was maintained at continuous positive airway pressure of 10 cm H2O with a bias flow of 100% oxygen. Injurious ventilation was performed with a volume-cycled ventilator that delivered a half-sinusoidal inspiratory flow waveform (Harvard Apparatus, Millis, MA). Accordingly, during injury, end-inspiratory flow in the test lung approached zero and end-inspiratory airway pressure approximated plateau pressure. In both groups, tidal volume to the test lung was set to achieve end-inspiratory airway pressure of 50 cm H2O. In one group (n = 6), negative end-expiratory pressure (NEEP) of −10 cm H2O was applied to the test lung to promote end-expiratory alveolar derecruitment,30,37 whereas in the other group (n = 6), PEEP of 10 cm H2O was used to prevent derecruitment. NEEP was obtained by connecting the expiratory port of the Harvard ventilator to a Y tube that was open to atmosphere through an adjustable resistor on one arm and was connected to a vacuum source through the other arm. PEEP was obtained by connecting the expiratory port of the Harvard ventilator to a positive pressure valve. Respiratory rate of the test lung was set at 22 breaths/min, inspiratory-to-expiratory time ratio was set at 1:1, and fraction of inspired oxygen was left at 1. To prevent a possible injurious effect of hypocapnia from hyperventilation in the NEEP group,38 an adjustable dead space volume was inserted proximally to the left bronchial port of the double-lumen tube, and respiratory rate could be varied by up to 2 breaths/min to keep arterial carbon dioxide tension (Paco2) at or above 30 mmHg (arterial blood gases were measured intermittently throughout the period of injurious ventilation).
After 90 min of unilateral injurious ventilation, the Harvard ventilator was substituted with the ventilator system suitable for 13N2 PET scanning and, after a recruitment maneuver, bilateral combined mechanical ventilation was resumed at baseline settings. Fifteen minutes later, transmission and 13N2 PET scans were acquired, and a complete set of physiologic data was collected. After completion of the postinjury 13N2 scan and clearance of 13N2 radioactivity, [18F]FDG was infused to measure metabolic activity.
At the end of the protocol, the animals were given additional anesthetics (30 mg/kg thiopental and 25 μg/kg fentanyl) and killed by intravenous potassium (40 mmol).
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Physiologic Data
Airway and systemic and pulmonary arterial pressures were measured using a strip chart recorder (Hewlett Packard Inc., Palo Alto, CA). During the period of unilateral injurious ventilation, pressure at the airway opening was measured separately in the test and control lungs to ensure adequate lung separation and maintenance of the set ventilatory parameters. Cardiac output was measured by thermodilution (model COM-1; Edwards Laboratory, Santa Ana, CA). Blood gases were measured using a blood gas analyzer (model ABL5/BPH5; Radiometer Medical, Copenhagen, Denmark). Oxygen saturation was estimated from the oxyhemoglobin dissociation curve for hemoglobin B in sheep.39 Global shunt fraction was calculated from blood oxygen content with the Berggren equation.40 Tidal volume was measured by integration of the flow signal. Before and after injury, quasi-static respiratory chord compliance was calculated with a 0.5-s end-inspiratory pause, according to standard formulas.41
Table 1
Table 1
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Table 2
Table 2
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For physiologic variables that were measured during injury, values recorded halfway through the period of unilateral injurious ventilation are reported (table 1). A complete set of physiologic data was collected before and after injury, when the animals were ventilated with bilateral combined mechanical ventilation (table 2).
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Positron Emission Tomography Imaging
A PET scanner that imaged 15 contiguous, 6.5-mm-thick slices of thorax at a spatial resolution of 6-mm full width at half maximum was used (PC-4096; Scanditronix AB, Uppsala, Sweden). We previously estimated, in sheep of similar weight, that this field of view encompassed approximately 70% of the lung.42 Emission scans were reconstructed with a filtered back projection algorithm and low-pass filtered to an effective in-plane spatial resolution of 13 × 13 mm. Therefore, the size of the final resolution element was 13 × 13 × 6.5 mm. Three types of PET scans were acquired:
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Transmission (Density) Scan.
Equation (Uncited)
Equation (Uncited)
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Ten-minute transmission scans were acquired at baseline, halfway through the period of unilateral injury, and after injury. They were used to demarcate the lung field (see below) and to calculate gas fraction from the linear relation between tissue attenuation and lung density.43,44 Gas fraction was measured for each voxel of lung. The fraction of the voxel’s volume occupied by parenchyma, blood, inflammatory infiltrate, or edema was calculated as
Because the transmission scan cannot differentiate tissue components with similar density, tissue fraction, in the lung, represents the fractional content of all components with unit density and therefore includes not only the contribution of parenchyma but also of blood, inflammatory infiltrate, and edema.
Gas fraction of each lung was computed by averaging the corresponding voxel values. Lung volume was calculated as the product of the number of voxels within each lung field by the voxel’s volume.
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13N2–Saline Bolus Infusion (Perfusion) Scan.
Fig. 2
Fig. 2
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13N2 (19 ± 6 mCi) dissolved in saline solution (38 ± 2 ml) was infused through the jugular catheter as a bolus over the initial 3 s of a 60-s apnea. Apnea was performed at an airway pressure corresponding to the mean airway pressure measured during the preceding period of bilateral combined ventilation.36 Simultaneously with the start of the 13N2–saline infusion, the acquisition of a series of sequential PET frames (8 × 2.5 s, 10 × 10 s, 4 × 30 s) was initiated to measure the pulmonary kinetics of 13N2. Because of the low solubility of nitrogen in blood and tissues (partition coefficient water-to-air is 0.015 at 37°C), the pulmonary kinetics of infused 13N2 (fig. 2) differ between regions that are perfused and aerated and regions containing alveolar units which, being perfused but not aerated, do not exchange gas (i.e., shunting units). In perfused and aerated regions, virtually all 13N2 diffuses into the alveolar airspace at first pass, where it accumulates in proportion to regional perfusion for the remainder of the apnea.43,45 In regions that contain shunting alveolar units, 13N2 kinetics during apnea show a peak of tracer concentration in the early PET frames, corresponding to arrival of the bolus of tracer with pulmonary blood flow, followed by an exponential decrease toward a plateau. This decrease of activity reflects lack of retention of 13N2 in nonaerated units, and its magnitude is therefore related to regional shunt.36,42 Perfusion and shunt fraction of the test and control lungs were calculated with a tracer kinetics model.46,47
Equation (Uncited)
Equation (Uncited)
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Perfusion was normalized to tissue volume of each lung, measured from the corresponding transmission scan and defined as
Normalized perfusion was expressed in ml blood · min−1 · ml tissue−1.
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[18F]FDG (Metabolic Activity) Scan.
After 13N2 clearance, [18F]FDG (5–10 mCi) was infused through the jugular catheter over 60 s and, starting at the beginning of [18F]FDG infusion, sequential PET frames (6 × 30 s, 7 × 60 s, 15 × 120 s, 1 × 300 s, 3 × 600 s) were acquired over 75 min while pulmonary arterial blood was sampled at the following intervals: 15 s × 3 min, 30 s × 2 min, 60 s × 5 min, 300 s × 55 min, followed by a last sample at 75 min. Blood samples (1 ml) were spun down, and the activity of plasma was measured in a gamma counter cross-calibrated with the PET scanner. [18F]FDG PET scans were acquired only after injury because of the 110-min half-life of [18F]fluoride.
Fig. 3
Fig. 3
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Fig. 4
Fig. 4
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Equation (Uncited)
Equation (Uncited)
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After being transported into the cell by the same mechanism as glucose, [18F]FDG is phosphorylated by hexokinase to [18F]FDG-6-phosphate, which accumulates in proportion to the metabolic rate of the cell. [18F]FDG net uptake rate, a measure of cellular metabolic activity, was calculated with the graphical method of Patlak et al.48,49 by plotting lung activity normalized to plasma activity versus the integral of plasma activity normalized to plasma activity. At steady state of tracer transfer between plasma and intracellular compartments, the plot becomes a straight line (in the lung, usually 8–10 min after injection of [18F]FDG), the slope of which corresponds to the [18F]FDG uptake rate (fig. 3). [18F]FDG uptake rate was calculated for each voxel in the lung field and displayed as a parametric image of metabolic activity (fig. 4). To account for the effect of variations in lung density on local [18F]FDG uptake, we normalized the uptake rate by tissue fraction and defined specific metabolic activity (i.e., [18F]FDG uptake rate per unit of tissue) as
The normalized rate is expected to account for differences in lung inflation or volume of inflammatory infiltrate and exudate.19 [18F]FDG uptake of each lung was obtained by averaging the corresponding voxel values.
To ascertain the contribution of neutrophils to the [18F]FDG signal, two additional sheep were submitted to the NEEP injury protocol after either moderate (4-day treatment) or severe (8-day treatment) systemic neutrophil depletion with intravenous hydroxyurea (200 mg · kg−1 · day−1). In these two sheep, and in the sheep studied last in the NEEP group, blood neutrophils were counted on the day of the experiment to investigate the relation between [18F]FDG uptake rate and circulating neutrophil count.
To assess the effect of NEEP per se (i.e., in the absence of end-inspiratory overdistension and large tidal volume) on [18F]FDG uptake, two sheep underwent 90 min of separate ventilation with the test lung ventilated at NEEP of –10 cm H2O, end-inspiratory pressure of 15 cm H2O (tidal volume, 6.0 and 6.6 ml/kg), respiratory rate of 22 breaths/min, and inspiratory-to-expiratory time ratio of 1:1. To prevent hypercapnia, the control lung was also ventilated in these two sheep, with end-inspiratory pressure of 15 cm H2O (tidal volume, 4.4 and 3.8 ml/kg), respiratory rate of 15 breaths/min, inspiratory-to-expiratory time ratio of 1:1.5, and no PEEP. With these settings, Paco2 was 31 and 35 mmHg in the two animals halfway through the period of separate ventilation. Fraction of inspired oxygen was left at 1.
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Demarcation of the Lung Field.
Aerated lung regions were identified by applying a threshold to the transmission scan.43,44 Perfused regions were identified by applying a threshold to the early frames of the 13N2–saline bolus infusion scan.34,36 A lung field mask was created, for each lung of each animal, from the union of aerated regions and of perfused regions, and was refined by hand to exclude main bronchi and large pulmonary vessels.
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Histologic Analysis
At the end of the study protocol, lung histologic analysis was performed in all animals of the PEEP group and in three animals of the NEEP group. The lungs were excised and suspended, and the trachea was connected to a reservoir containing Trump fixative (4% formaldehyde and 1% glutaraldehyde in phosphate-buffered saline). The lungs were filled with fixative to a pressure of 25 cm H2O, the trachea was clamped, and the lungs were submersed in a container filled with fixative and stored for 7 days at 4°C. After fixing, the lungs were cut in 1-cm-thick slices along the sagittal plane, and the second most lateral slice of each lung was selected for further histologic analysis (the most lateral slice was fully covered with pleura on its lateral aspect, which would have made it harder for the embedding resin to penetrate, whereas more medial slices contained large vessels and airways). Using a stratified random sampling technique, a 1-cm3 block of lung tissue was selected from each of the ventral, middle, and dorsal regions of the slice. The tissue block was embedded in Technovit 7100 resin (Heraeus Kulzer, Wehrheim, Germany), and 2-μm-thick sections were cut, mounted, and stained with 0.01% toluidine blue for light microscopy.50 Extravascular lung neutrophils were counted in 240 randomly selected high-power (40×) fields (0.033 mm2/field) per lung by a pathologist-trained physician who was blinded to the group assignment and to whether the lung was a test or a control lung.
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Statistical Analysis
Statistical analysis was performed with nonparametric statistical tests (SPSS 13.0; SPSS Inc., Chicago, IL) to reduce the effect of single data values on small sample statistics. Differences within group, either between before and after injury or between the test and control lungs, were tested with Wilcoxon signed ranks test for matched pairs, because measurements were performed on the same animal. Differences between the two groups were tested with Mann–Whitney U test. Associations between variables were measured both with Pearson (parametric) correlation coefficient and with Spearman (nonparametric) rank coefficient.
Fig. 5
Fig. 5
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Fig. 6
Fig. 6
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Fig. 7
Fig. 7
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Fig. 8
Fig. 8
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For global physiologic variables (table 2), groups were compared at baseline, and the effect of injury was assessed within group by testing the difference between before and after injury. For PET-derived regional variables (figs. 5–7), differences between lungs were tested separately at baseline and after injury, because [18F]FDG uptake could be measured only after injury (fig. 8).
Statistical significance was set at P < 0.05. Data are mean ± SD.
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Results

Physiologic Variables during Unilateral Injurious Ventilation
As expected from the experimental protocol, tidal volume and mean inspiratory flow of the test (i.e., injuriously ventilated) lung were higher in the NEEP than in the PEEP group (table 1). End-inspiratory airway pressure was similar in the test lung of the two groups. End-expiratory and mean airway pressures of the test lung were lower in the NEEP than in the PEEP group. The control lung was held at 10 cm H2O of continuous positive airway pressure in both groups.
Consistent with the airway pressure data, the transmission scan acquired halfway through the period of unilateral injurious ventilation showed a lower gas fraction in the test lung of the NEEP group than in that of the PEEP group (0.59 ± 0.07 vs. 0.83 ± 0.10; P < 0.05) and no significant difference in gas fraction of the control lungs (0.66 ± 0.08 and 0.70 ± 0.15, respectively).
During the period of unilateral injurious ventilation, Paco2 was higher in the PEEP than in the NEEP group, but pH was not significantly different between groups, probably because base excess was higher in the PEEP group. Arterial oxygen tension (Pao2) and hemodynamics were not significantly different between groups (table 1).
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Changes in Global Physiologic Variables between before and after Injury
At baseline, global physiologic variables were not significantly different between groups except pH and arterial base excess, which were higher in the PEEP group (table 2). Paco2 tended to be lower, although not significantly, in the PEEP than in the NEEP group despite similar tidal volume (11.0 ± 0.6 and 10.7 ± 1.2 ml/kg, respectively) and respiratory rate (18.0 ± 0.4 and 17.7 ± 1.9 breaths/min). Respiratory system compliance, global shunt fraction, hemodynamics, and body temperature were not significantly different between groups at baseline.
Physiologic measurements performed after the end of unilateral injurious ventilation and resumption of bilateral combined ventilation at baseline settings showed that compliance had decreased with injury only in the NEEP group (table 2). In this group, Pao2 tended to decrease and global shunt fraction tended to increase after injury, but these changes did not reach statistical significance. In the PEEP group, neither global gas exchange nor compliance was affected by the 90-min period of unilateral overdistension. Except for a decrease of heart rate in the NEEP group, changes in hemodynamics were not significant in either group.
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Regional Aeration, Shunt Fraction, and Perfusion at Baseline and after Injury
Before injury, gas fraction (fig. 5), shunt fraction (fig. 6), and perfusion (fig. 7) were similar in the test and control lungs of both groups.
After the period of unilateral injurious ventilation, gas fraction of the test lung in the NEEP group became lower than that of the control lung (fig. 5). In the PEEP group, gas fraction of the test lung became higher than that of its control lung and of the test lung of the NEEP group. In the NEEP group, shunt fraction of the test lung became higher than that of the control lung (fig. 6), and the difference in shunt fraction between the test and control lungs (i.e., the increase in regional shunt fraction attributable to localized VILI) was significantly greater than the increase in global shunt fraction (0.22 ± 0.17 vs. 0.05 ± 0.10; P < 0.05). In the PEEP group, shunt fraction remained similarly low in the test and control lungs. Accordingly, shunt fraction of the test lung became higher in the NEEP than in the PEEP group. Normalized perfusion was not significantly different between the test and control lungs, although five of six animals in both groups showed lower perfusion to the test than to the control lung after injury (fig. 7).
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Regional Metabolic Activity
After unilateral injury, the [18F]FDG uptake rate of the test lung in the NEEP group was higher than that of its control lung and of the test lung in the PEEP group (fig. 8A). The [18F]FDG uptake rate was similar, on average, in the test and control lungs of the PEEP group, with three animals in this group showing higher [18F]FDG uptake in the test than in the control lung and three animals showing higher uptake in the control lung. Interestingly, this inconsistent behavior among animals of the PEEP group was no longer present when local [18F]FDG uptake rate was normalized by tissue fraction, as normalized [18F]FDG uptake rate was higher in the test than in the control lung of all animals in the PEEP group (fig. 8B). Uptake of [18F]FDG remained higher in the test than in the control lung of the NEEP group also after normalization. Uptake of [18F]FDG was remarkably similar in the control lungs of the two groups.
In the two additional animals in which the test lung was ventilated at NEEP of −10 cm H2O without end-inspiratory overdistension, the [18F]FDG uptake rate of the control lung (0.00318 and 0.00315 min−1) was virtually identical to that of the test lung (0.00337 min−1 for both animals).
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Relation between [18F]FDG Uptake and Neutrophil Count
Fig. 9
Fig. 9
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Lung neutrophil count was significantly higher in the test lung of the NEEP group than in that of the PEEP group (1,046 ± 623 vs. 29 ± 59; P < 0.05), whereas it was similar in the control lung of the two groups (2 ± 3 and 2 ± 5). The difference in [18F]FDG uptake rate between the test and control lungs was positively correlated (Pearson coefficient, 0.72; Spearman coefficient, 0.93; P < 0.05 for both) with the difference in neutrophil count (fig. 9).
Fig. 10
Fig. 10
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To further ascertain the contribution of neutrophils to the [18F]FDG signal in this VILI model, two additional sheep were submitted to the NEEP injury protocol after moderate or severe systemic neutrophil depletion. [18F]FDG uptake of the test lung decreased markedly with decreasing blood neutrophil count, whereas the reduction of [18F]FDG uptake was negligible in the control lung (fig. 10). Even in the sheep with severe neutrophil depletion, however, the [18F]FDG uptake rate of the test lung remained higher than that of the control lung.
Fig. 11
Fig. 11
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Observation of tissue sections revealed histopathologic signs of VILI such as heterogeneous distension of alveoli, neutrophil infiltration, and intraalveolar proteinaceous material (light blue tinted with toluidine blue stain) in the test lung of the NEEP group, whereas alveoli were well distended with scant intraalveolar neutrophils in the test lung of the PEEP group (fig. 11).
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Discussion

The main findings of this study were as follows: (1) PET with [18F]FDG and 13N2 could quantify, noninvasively and in vivo, the regional pulmonary neutrophil activation and impairment of gas exchange caused by injurious mechanical ventilation; and (2) pulmonary metabolic activation could be detected within 90 min of dynamic overdistension without repetitive end-expiratory derecruitment, even though regional and global gas exchange and respiratory compliance were still preserved and histopathologic changes were not yet evident.
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Interpretation of [18F]FDG Uptake
Using microautoradiography of tissue sections after intravenous administration of [3H]deoxyglucose, Jones et al.17,18 demonstrated that deoxyglucose uptake by inflammatory cells is virtually confined to neutrophils during both acute and chronic lung inflammation. In this study, the contribution of neutrophils to the [18F]FDG signal was confirmed by two observations. First, there was a positive correlation between [18F]FDG uptake and lung neutrophil count. Second, [18F]FDG uptake decreased markedly in the test lung with progressive systemic neutrophil depletion.
Because hyperinflation of the test lung of the PEEP group persisted after injury, we normalized the [18F]FDG uptake rate to tissue fraction. Whereas the unnormalized rate depends both on density and metabolic activity of lung tissue,19 the normalized rate should reflect only the mean level of cellular metabolic activity in the tissue compartment, after accounting for differences in lung inflation or in the volume of inflammatory infiltrate. Consequently, we used the normalized rate to measure the effect of injurious ventilation on the metabolic rate of a unit of tissue (i.e., specific metabolic activity) and determine whether pure overdistension induced cell activation in the PEEP test lung, after accounting for the increased aeration of this lung.
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Rationale of the Experimental Model
We used the suspended prone position to minimize baseline intraregional mechanical and functional heterogeneity34 so that the source of mechanical lung stress would be largely under the control of external ventilatory pressure. The potential relevance of this approach lies in the argument that levels of mechanical stress comparable to those used in this study can develop regionally in the heterogeneously inflated acutely injured lung even when transpulmonary pressure is within narrower limits than those used in this study.27
Three observations argue against the possibility that the reduction in gas fraction with increase in shunt and the increase in [18F]FDG uptake of the test lung of the NEEP group were due exclusively to transient atelectasis or negative pressure edema rather than to VILI. First, the recruitment maneuver performed after injury should have reversed transient atelectasis. Second, [18F]FDG uptake remained higher in the test than in the control lung of the NEEP group even after normalization by tissue fraction. Because nonspecific leakage of [18F]FDG into edema fluid does not significantly increase the [18F]FDG uptake rate21 whereas edema reduces gas fraction, edema in the absence of cell activation would be expected to lead to a reduction, not an increase, of normalized [18F]FDG uptake rate compared with the nonedematous control lung, similarly to the normalization by the initial volume of distribution of [18F]FDG.51 Nor should atelectasis in the absence of cell activation increase the normalized [18F]FDG uptake rate compared with the nonatelectatic control lung, because normalization by tissue fraction is expected to compensate for differences in lung inflation. Although use of 100% oxygen may have favored formation of resorption atelectasis,52 it should have also minimized the injurious effect of atelectasis by attenuating hypoxia in atelectatic regions.53 Consistent with the concept that NEEP per se did not result in increased [18F]FDG uptake, there was no rise in [18F]FDG uptake in the two lungs ventilated at NEEP without end-inspiratory overdistension. Third, histologic analysis revealed marked neutrophil infiltration and other signs of VILI in the test lung of the NEEP group. Furthermore, ventilation with repetitive end-expiratory derecruitment and recruitment has been shown to induce a cytokine response in the isolated lung.54 These considerations do not imply absence of atelectasis or edema in our model, both of which are expected from impaired surfactant function and increased alveolocapillary permeability due to large tidal excursion5,6,9,10,33,55 and repeated alveolar collapse and expansion,30,37,56 but suggest that the functional, metabolic, and histologic changes observed were not due simply to transient atelectasis or edema but to VILI.
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Effect of Injurious Ventilation on Regional Gas Exchange and Cellular Metabolic Activity
Neutrophils play a crucial role in the pathogenesis of VILI.14,57,58 When overdistension was accompanied by repetitive end-expiratory derecruitment and recruitment, we could detect increased [18F]FDG uptake, neutrophil infiltration, decreased aeration, and increased shunt fraction within 90 min of the start of injurious ventilation. This time interval is much shorter than that required to observe VILI in large,2–4 as opposed to small,5–7 animals exposed to overdistension without end-expiratory derecruitment. The mechanisms by which derecruitment may contribute to VILI include concentration of stress in the parenchyma around an atelectatic region27 and dynamic shear stress on airway and alveolar epithelium when recruitment ensues.59,60 Interestingly, cell activation occurred also after 90 min of overdistension without end-expiratory derecruitment, as shown by increased specific metabolic activity of the test lung in the PEEP group. In this lung, however, shunt fraction was not increased and neutrophil count was lower than in the NEEP group, in line with previous studies showing that 24–48 h was necessary to observe gas exchange impairment and histopathologic changes in response to overdistension alone in sheep.2,3 Taken together, these findings suggest that a brief period of dynamic overdistension induced cell activation irrespective of the presence or absence of end-expiratory derecruitment, but concomitant repetitive derecruitment and recruitment, with larger tidal excursion, rapidly converted this activation into a profound inflammatory response with impairment in gas exchange.
The finding that a brief period of pure overdistension was sufficient to induce cell activation in a large animal with pulmonary physiology similar to the human and in the absence of other signs of VILI is potentially clinically relevant because regional overdistension could occur even at moderate transpulmonary pressure in a structurally abnormal lung,27 and hyperinflation, which can be associated with overdistension, has been shown in mechanically ventilated patients with ALI.61 Overdistension, albeit of a lesser degree but possibly longer duration than in this study, could also occur in patients on single lung ventilation during thoracic surgery, if tidal volume is not reduced.62
An additional factor that could have delayed VILI in the test lung of the PEEP group was hypercapnia during the period of injury,63–65 although pH, which is thought to mediate the protective effect of carbon dioxide in VILI,66 was not significantly different between groups during injury.
The finding that specific metabolic activity was increased in the test lung of both groups can be reconciled with the significantly higher neutrophil count in the test lung of the NEEP group on two considerations. First, normalization of [18F]FDG uptake rate by lung density is expected to account, at least in part, for the greater infiltration of activated neutrophils in the NEEP than in the PEEP test lung. Second, injurious ventilation could promote metabolic activation of other cell types such as vascular endothelial cells,67 which are activated by tidal overdistension and can promote leukocyte recruitment,68 and pneumocytes, which can act as a mechanosensor in response to cyclic stretch.69 The fact that [18F]FDG uptake remained higher in the test than in the control lung after virtually complete neutrophil depletion suggests that, even with neutrophils as the main contributors to the [18F]FDG signal, other cells were activated by the injurious ventilation, similarly to what has been reported for endotoxin-induced ALI in mice.70
The finding that [18F]FDG uptake of the control lung was remarkably similar between groups despite higher neutrophil count and unnormalized [18F]FDG uptake of the test lung in the NEEP than in the PEEP group suggests that the neutrophilic inflammation induced in the test lung did not propagate systemically to the control lung. In addition, the fact that [18F]FDG uptake of the control lung in the NEEP injury protocol was virtually independent of circulating neutrophil count (i.e., the slope of the dotted line in fig. 10 is close to zero) would argue against the hypothesis that systemic neutrophil activation induced by localized VILI mediated significant inflammation of the contralateral lung. Remote inflammation in this VILI model, however, could occur in organs other than the lung, involve pathways not assessable by [18F]FDG or require longer to manifest.
In the NEEP group, the increase in global shunt fraction underestimated the increase in regional shunt fraction attributable to localized injury. This underestimation was due to two factors. First, shunt fraction remained low in the control lung. Second, perfusion redistributed away from the test lung in five of the six animals. The importance of perfusion redistribution in modulating the impact of regional shunt fraction on global shunt fraction is apparent from the behavior of the two animals of the NEEP group with the highest shunt fraction in the test lung (fig. 6). After injury, the animal corresponding to the filled circle did not redistribute perfusion from the shunting lung to the control lung (fig. 7). Accordingly, this animal had a high global shunt fraction (0.29). In contrast, the animal corresponding to the filled triangle, which had a similarly elevated shunt fraction in the test lung, redistributed perfusion away from this lung, thus maintaining a low global shunt fraction (0.06). In both animals, global shunt fraction equaled the perfusion-weighted average of the shunt fractions calculated with 13N2 for the test and control lungs. Therefore, despite similarly severe gas exchange impairment in the injured lung, in one of these animals global shunt fraction markedly underestimated the severity of regional dysfunction because of perfusion redistribution away from the shunting lung, possibly due to strong hypoxic pulmonary vasoconstriction. This case exemplifies the potential limitation of relying on global shunt fraction, and for that matter Pao2, to infer the severity of a pulmonary process that is spatially heterogenous, like ALI. When the loss of aeration is heterogeneous, perfusion redistribution from poorly aerated shunting regions to well-aerated regions will affect the degree of hypoxemia.36,71
In summary, PET can measure the pulmonary metabolic activation of neutrophils during VILI. This technique had sufficient sensitivity to show that activation occurred in response to a brief period of pure overdistension, even in the absence of deterioration in regional or global gas exchange. Concomitant repetitive derecruitment and recruitment, with larger tidal excursion, rapidly converted this activation into a profound localized inflammatory cell response with regional impairment of gas exchange.
The authors thank Steven B. Weise (Senior Research Technician, Division of Nuclear Medicine, Massachusetts General Hospital, Boston, Massachusetts) and Sandra A. Barrow (Certified Nuclear Medicine Technician, Division of Nuclear Medicine, Massachusetts General Hospital) for image acquisition and processing; Peter A. Rice, B.S., R.Ph., and Stephen C. Dragotakes, R.Ph. (Certified Nuclear Pharmacists, Department of Radiology, Massachusetts General Hospital), John A. Correia, Ph.D. (Associate Professor of Radiology, Harvard Medical School, Boston, Massachusetts), William M. Buceliewicz and David F. Lee, B.S. (Senior Cyclotron Engineers, Department of Radiology, Massachusetts General Hospital), for preparation of the radioisotopes; Olga Syrkina, M.D. (Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital), for animal preparation; and Rosemary C. Jones, Ph.D. (Associate Professor of Pathology, Harvard Medical School), and Diane E. Capen, B.A. (Senior Research Technician, Department of Anesthesia and Critical Care, Massachusetts General Hospital), for assistance with histologic analysis.
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