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ABSTRACT |
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Mechanical ventilation-induced air-space enlargement was investigated in a porcine model of multifocal pneumonia. Following the intrabronchial inoculation of Escherichia coli, 9 piglets (22 ± 2 kg) were ventilated with a tidal volume (VT) of 15 ml/kg for 43 ± 15 h. Five noninoculated piglets ventilated for 60 h with the same VT served as control animals. Following death, the lungs were fixed and lung morphometry was assessed. In inoculated animals, unventilated infected and normally ventilated noninfected pulmonary lobules coexisted. In normally ventilated lung regions (1) emphysema-like lesions were present, (2) mean alveolar area and mean linear intercept were significantly greater in inoculated than in control animals, and (3) the degree of alveolar distension correlated with the decrease in respiratory compliance. In unventilated lung areas (1) pseudocysts were frequent, (2) alveolar edema was rare, (3) bronchiolectasis was frequent, (4) mean bronchiolar area was greater in inoculated than in control animals, and (5) the degree of bronchiolar distension correlated with the increase in inspiratory plateau pressure. In conclusion, in piglets with severe bronchopneumonia, air-space enlargement rather than pulmonary edema was the major feature of mechanical ventilation-induced lung barotrauma and resembled lesions previously reported in critically ill patients ventilated using high inspiratory pressures.
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Air-space enlargement
emphysema-like lesions, bronchectasis, and pseudocystsis a characteristic feature of lung baro-trauma in patients with severe acute respiratory distress syndrome (ARDS) (1). Mechanical ventilation could be a causative factor, particularly if high peak inspiratory pressures and
large tidal volumes are delivered to the lungs (1). Air-space
enlargement may be the result of a nonhomogeneous distribution of the loss of aeration characterizing ARDS. Most acute
pulmonary diseases are characterized by alveolar lesions that
are unevenly distributed within the lung parenchyma and,
therefore, unventilated lung areas are frequently coexisting
with fully expanded lung regions. CT scan studies performed in patients with ARDS have confirmed that normally ventilated pulmonary regions are often present despite the massive
loss of aeration characterizing the major part of the lung, thereby
inducing marked disparities in regional lung compliances (7,
8). In addition, lung superinfection, which predominates in
dependent lung segments (9), tends to aggravate the uneven
distribution of the loss of aeration within the lungs. As a consequence, the tidal volume coming from the ventilator is predominantly directed to the compliant normally ventilated lung
regions that are at risk of overdistension. Previous morphometric studies, performed in experimental models of diffuse
alveolar damage such as paraquat- or saline lavage-induced lung
injury, did not reveal any histological sign of air-space enlargement (10). However, these models appear to be of limited
relevance in studying ventilator-induced air-space enlargement in humans because the loss of aeration resulting from the experimental lung injury is homogeneously distributed
within the lung parenchyma.
In the present study, a more clinically relevant model of multifocal bronchopneumonia was set up in anesthetized piglets to study mechanical ventilation-induced air-space enlargement. Multilobar bronchopneumonia was obtained by fiberoptic intrabronchial inoculation of Escherichia coli. After 3 d of mechanical ventilation delivering a constant tidal volume of 15 ml/kg, lung morphometry was assessed by measuring the mean alveolar area, the mean bronchiolar area, and the mean linear intercept on multiple lung histological sections obtained from the lungs of inoculated and control animals.
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The Experimental Intensive Care Unit
In 1997, an Experimental Intensive Care Unit (ICU) was initiated by a group at La Pitié-Salpétrière hospital (J. J. Rouby) and set up in Lille in collaboration with the Department of Pneumology of Lille (C.-H. Marquette). Two operating tables were fully equipped with cardiovascular monitors (Hewlett-Packard, Palo Alto, CA), ventilators (Taema, Antony, France), and electrical infusors. A medical team composed of two physicians was on call on a 24-h period shift. Two technicians were present daily from 9:00 A.M. to 5:00 P.M. Despite the cost and the difficulties of such a project, the existence of an experimental ICU allowing the prolonged mechanical ventilation of large animals was considered as mandatory for reproducing clinical conditions that are encountered in ICUs.
Animal Preparation
Fourteen healthy bred domestic Largewhite-Landrace piglets, aged 3- 4 mo and weighing 23 ± 2 kg, were anesthesized using propofol 3 mg/kg and orotracheally intubated in the supine position with a 7.0 Hi-Lo Jet Mallinckrodt tube (Mallinckrodt Inc., Argyle, NY). Anesthesia was maintained with a continuous infusion of midazolam 0.3 mg/kg/h, pancuronium 0.3 mg/kg/h, and fentanyl 5 µg/kg/h. A catheter was inserted in the right femoral vein for continuous infusion of 10% dextrose (1.5 ml/kg/h) and Ringer's lactate (3 ml/kg/h) with an infusion pump and the femoral artery was cannulated with a 3F polyethylene catheter (Plastimed, St Leu la forêt, France) for pressure monitoring and blood sampling. An 8F suprapubic urinary catheter (Vesicoset; Angiomed, Karlsruhe, Germany) was placed in the bladder transabdominally. All animals were treated according to the guidelines of the Department of Experimental Research of the Lille University and the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 93-23, revised 1985).
Respiratory Measurements
After anesthesia and technical preparation, the piglets were placed in the prone position. They were mechanically ventilated in a volume-controlled mode with a Cesar type 1 ventilator (Taema). The initial ventilatory parameters consisted of a tidal volume (VT) of 15 ml/kg, a respiratory rate (RR) of 15 breaths per minute, an I/E ratio of 0.5, and zero end-expiratory pressure (ZEEP). Inspired gases were humidified using a conventional humidifier (MR290; Fisher Paykel, Auckland, New Zealand) and an initial fraction of inspired oxygen (FIO2) of 0.21 was used. Airway pressure was measured at the distal tip of the Hi-Lo Jet endotracheal tube. Pressure-volume (P-V) curves were performed on the Cesar ventilator after a 3-s end-expiratory pause. According to a previously validated technique (13), a low constant flow of 9 L/min was delivered for 9.6 s and the P-V curve was displayed on the screen of the ventilator. Respiratory compliance was determined as the slope of the linear portion of the P-V curve. Blood gases were analyzed at 98.6° F with an ABL120 blood gas analyzer (Radiometer Coppenhagen, Denmark). All data were recorded on a strip-chart recorder (Gould ES1000; Gould Instruments, Cleveland, OH).
Bronchial Inoculation and Mechanical Ventilation
After measurements of baseline respiratory parameters at steady state, nine piglets were inoculated with a suspension of Escherichia coli (biotype 54465543420-API 32 E, Department of Bacteriology, Lille). The initial suspension was diluted to different concentrations ranging from 105 to 109 colony-forming units (cfu) to obtain bronchopneumonic lesions of increasing severity. Three animals were instilled with 105-106 cfu/ml, two with 107 cfu/ml, and 4 with 108-109 cfu/ml. The suspension was selectively inoculated using bronchoscopy in the prone position. A volume of 50 ml was instilled in both lower lobes, 40 ml in the lingula and the right middle lobe and 10 ml in both upper lobes. A control group of five anesthetized animals was ventilated with the same respiratory settings but without intrabronchial inoculation. The piglets were ventilated for a maximum of 3 d with a fixed tidal volume of 15 ml/kg. Hemodynamic parameters, airway pressures, respiratory compliance, and blood gases were determined every 6 h. Throughout the protocol, FIO2 was increased to maintain PaO2 above 80 mm Hg. PaCO2 was kept between 35 and 45 mm Hg by increasing the respiratory frequency to the maximum level preceding the appearance of auto-PEEP. Above this limit, hypercapnia was tolerated. Septic shock, defined as a 30% decrease of a mean arterial pressure persisting despite a rapid 500 ml intravenous fluid loading, was treated by norepinephrine infusion. In case of a sudden rise in airway pressures or hemodynamic failure, pneumothorax was suspected and drained promptly. Sacrifice was performed at Day 3 if death had not occurred earlier.
Fixation of the Lungs
Following death and the intravenous injection of heparin (5,000 U), a sternotomy was performed while maintaining mechanical ventilation and the piglets were exsanguinated by cardiac puncture. Following sections of the main bronchi and pulmonary vessels, the left lung was removed, weighed, and fixed by intrabronchial instillation of a solution composed of 10% formalin, 10% 70° C ethanol, 30% polyethylene glycol, and 50% water. The lung was filled to reach a pulmonary volume closed to the functional residual capacity. The instillation was stopped when the lung placed in the thorax exactly fit the rib cage volume. The filling procedure was 40 cm H2O pressure limited, determined by the elevation of the reservoir containing the fixative. The purpose of this fixation technique was to avoid artifactual overexpansion of normally ventilated lung areas. After fixation, the lung was sagittally sectioned in the middle. The macroscopic aspect was carefully examined and manually drawn. The blocks used for histological analysis were sampled according to the following protocol: juxtaposed blocks 0.5 inch thick were cut in a sagittal plane parallel to the main section of the lung, involving both subpleural and parahilar regions. Blocks were taken from dependent and nondependent sides of each lobe, and the distance between each block and the pulmonary apex was measured. This was done to obtain samples representative of all lung areas. The blocks were processed for routine histological preparation and embedded in paraffin. Sections 4 µm thick were cut and stained with hematoxylin-eosin.
Histomorphometrical Analysis of the Lungs
An image analyzer computer system (Leïca Qwin, Cambridge, UK) was connected through a high-resolution color camera (JVC KYF 3ccD, Yokohama, Japan) to an optical microscope. Alveolar dimensions were measured in lung areas remaining fully ventilated. According to the extension of lung consolidation, 5 to 15 noncoincident ventilated fields observed at a magnification of ×5 were analyzed on each histological section. Mean alveolar area (MAA) was determined as the average area of the alveoli present on all examined fields. Between 9 × 103 and 26 × 103 ventilated alveoli were analyzed in each piglet. Mean linear intercept (MLI) was defined as the mean distance between alveolar walls on 10 parallel transverse lines drawn in each examined field (14). As for bronchiole size determination, both ventilated and nonaerated areas were analyzed and considered separately. Mean bronchiolar area (MBA) was defined as the mean area of the transverse section of noncartilaginous bronchioles present on a given histological section. Between 220 and 270 inflated bronchioles were analyzed in each piglet. Bronchioles cut along a longitudinal axis were not included in the analysis.
Histological Analysis of Alveolar Edema and Bronchopneumonia
Each section was divided in 50 fields of 1 mm2 and observed at a magnification of ×5. Each field was qualitatively assessed as to the presence of edema and/or bronchopneumonia. Alveolar edema was defined as a pink staining fluid flooding at least half of the area of the considered field. Bronchopneumonic lesions were defined as an intense accumulation of polymorphonuclear neutrophils within bronchiolar lumen and adjacent alveoli involving one or several pulmonary lobules (9).
Statistical Analysis
Baseline hemodynamic and respiratory parameters were compared between the two groups by a Wilcoxon test, whereas changes according to time were compared using a two-way analysis of variance for repeated measures. Histomorphometric data between inoculated and control animals were compared by an unpaired Student's t test. Cephalocaudal and anteroposterior distribution of the histomorphometric parameters were studied using a two-way analysis of variance for repeated measures. The proportions of edema and bronchopneumonia among the different histological fields were compared between inoculated and control animals and between dependent and nondependent lung regions using a Chi-square test. The correlation between histomorphometric parameters and cardiorespiratory data was tested by linear regression analysis. The statistical analysis was performed using Statview 5.0 (SAS Institute Inc., Cary, NC). All data are expressed as mean ± standard deviation (SD) unless otherwise specified. The significance level was fixed at 0.05.
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Changes in Respiratory Parameters During the Experiment
Table 1 shows the respiratory data at baseline (after anesthesia) and before death. Baseline values were not significantly different between the two groups. The mean duration of ventilation for inoculated animals was 43 ± 15 h whereas control animals were sacrificed 60 h after anesthesia. Inoculated animals experienced a progressive and significant deterioration of gas exchange and respiratory mechanics, whereas control animals had similar changes but of smaller importance (positive interaction between the two groups). A significant correlation was found between the lung weight at the end of the experiment and the decrease in respiratory compliance (R = 0.73). Deterioration of respiratory status as assessed by the decrease in PaO2/FIO2 ratio and respiratory compliance and the increase in airway pressure and lung weight were found to be inoculum dependent (data not shown).
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Gross Findings and Lung Weight at Autopsy
At autopsy, the lungs of control animals appeared pink and well ventilated except some small areas of focal consolidation. There was no pleural effusion or blebs. The lungs of inoculated animals showed massive consolidation that involved more than 75% of lung volume and that predominated in dependant regions. There were numerous pleural blebs, predominating in upper lobes and nondependent regions. On the sagittal section, the lungs of inoculated animals showed a focal distribution of ventilated and unventilated areas organized at the level of the secondary pulmonary lobule and delineated by interlobular septa (Figures 1A and 1B). There were fewer ventilated pulmonary lobules in dependent areas. As shown in Figure 2, intraparenchymal pseudocysts were numerous and predominantly found in consolidated lung areas. The exsanguinated lungs were heavier in inoculated animals than in control animals (Table 1).
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Mechanical Ventilation-induced Alveolar Overdistension
All inoculated animals had evident air-space enlargement in the ventilated lung regions, which is typical of emphysema-like lesions made of alveolar overdistension and alveolar wall ruptures (Figures 1D and 1E). Intraparenchymal pseudocysts were frequently observed (Figure 2) but not taken into account for the measurement of MAA and MLI. As shown in Figure 3, both MAA and MLI were increased in inoculated piglets compared with control animals. MAA and MLI were similar in dependent and nondependent lung regions and in cephalic and juxtadiaphragmatic lung regions (Figure 4). As shown in Figure 5, MAA correlated with the weight of exsanguinated lung and the decrease in respiratory compliance (area under the curve of the respiratory compliance during the experiment), suggesting that the degree of air-space enlargement was dependent on the extension of alveolar damage.
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Mechanical Ventilation-induced Bronchiolar Overdistension
Severe damage to terminal bronchioles characterized by bronchiolar dilatation and mucosal necrosis was observed in all inoculated animals (Figure 1F). MBA was determined distinctively in ventilated and unventilated lung regions, present both in inoculated and control animals. In both groups, bronchioles were more distended in unventilated than in ventilated lung regions (Figure 6). MBA was greater in inoculated than in control animals in unventilated regions only. No significant anteroposterior or cephalocaudal gradient for MBA was found in unventilated lung areas (data not shown). As shown in Figure 7, bronchiolar distension was significantly correlated with the decrease in respiratory compliance and the increase in inspiratory plateau pressure measured at the end of the experiment.
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Alveolar Edema and Bronchopneumonia
Approximately 50 fields were quoted for the presence of alveolar edema and/or bronchopneumonic lesions on each pulmonary section. Among the 750 histological fields analyzed in each piglet, the frequency of edema was low: 11% of the fields in inoculated animals and 8% of the fields in control animals (NS). In inoculated animals, alveolar edema was more frequently associated with bronchopneumonia than isolated: 7% versus 4% (p < 0.01). These proportions were similar in dependent and nondependent lung regions.
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Histological lesions characteristic of mechanical ventilation-induced air-space enlargement observed in humans with ARDS such as emphysema-like lesions, intraparenchymal pseudocysts, bronchiolar distension, and pleural blebs could be reproduced in a porcine model of focal bronchopneumonia. In the lung regions remaining ventilated, two morphometric indices of alveolar distension, the mean alveolar area and the mean linear intercept, were found significantly increased. In unventilated bronchopneumonic lung areas, bronchioles appeared severely overdistended. The degree of alveolar and bronchiolar overdistension was correlated with two indices reflecting the extension and the severity of lung damage, the increase in lung weight and the decrease in respiratory compliance. Alveolar edema was rarely observed and was mainly associated with bronchopneumonic lesions.
Description of the Model and Methodological Limitations
A porcine model of experimental bronchopneumonia requiring prolonged mechanical ventilation was set up to study ventilator-induced air-space enlargement. After the fiberoptic bronchial inoculation of various inoculi of Escherichia coli according to a previously described technique (15, 16), piglets were mechanically ventilated in the prone position for 2 to 3 d. Because tidal volume was kept constant at 15 ml/kg, airway pressures increased progressively according to the progression of lung infection and the reduction of lung aeration. Basically, this experimental protocol was aimed at producing a multifocal lung injury with bronchopneumonic lung areas coexisting with normally ventilated lung regions. Macroscopically, lung infection resulted in areas of massive consolidation predominating in dependent and caudal lung regions. As observed in humans with ARDS (7, 17) and ventilator-associated pneumonia (9, 18), the lower lobes and the dependent parts of the lung appeared as essentially unventilated, whereas some nondependent pulmonary regions remained normally ventilated. Microscopically, lung infection was focally distributed. Foci of bronchopneumonia involving one or several secondary pulmonary lobules were adjacent to normally ventilated pulmonary lobules resulting in a patchy distribution of alveolar consolidation and lung aeration. This model of focal lung injury is radically different from models of diffuse alveolar damage resulting from lung lavage or the intravenous administration of different toxins (11, 19) where the loss of aeration is uniformly distributed. It appears more relevant to humans with ARDS where the loss of aeration frequently has a lobar or a patchy distribution (7, 17, 18, 20).
Great attention was paid to avoiding artifactual distension during the postmortem preparation of the lungs. The instillation of formalin was stopped when the lung volume perfectly fit the rib cage volume. The intrabronchial infusion of the fixative solution was performed at a pressure of 40 cm H2O, even though the peak and the plateau inspiratory pressures were frequently above 40 cm H2O during the period of mechanical ventilation. Therefore, it can be assumed that the morphometric analysis was performed at a lung volume close to the functional residual capacity, giving a realistic approach of alveolar and bronchiolar distension present at end expiration.
Alveolar Distension
In the present study, alveolar distension was very similar to the air-space enlargement reported in humans ventilated for ARDS (1, 3, 21) and in animals ventilated at high peak airway pressure (22). In noninflammatory lung areas, distension of alveoli together with alveolar wall ruptures resulted in a typical aspect of emphysema, which could be quantified by measuring mean alveolar area and mean linear intercept. In highly inflammatory lung areas, large pseudocysts were very frequently observed. The external limits of these structures were made of alveolar walls, suggesting that they were the consequence of the confluence of ruptured alveoli, resulting themselves from mechanical ventilation-induced overdistension. However, causes of alveolar emphysema can be multifactorial, involving destruction of lung tissue related to infection or ischemia (23), oxygen toxicity (24), prolonged exposure to nitric oxide, nitrogen dioxide, and ozone (25, 26), denutrition (27), chronic endotoxinemia (28), and, very likely, positive pressure mechanical ventilation (1). The lack of alveolar distension in inflammatory and unventilated lung areas strongly suggests that positive pressure mechanical ventilation is required to induce emphysema-like lesions. The definitive evidence that mechanical ventilation per se can create such lesions would require a morphometric study showing the absence of alveolar distension in spontaneously breathing inoculated animals.
Interestingly, the degree of alveolar distension was positively correlated with the lung weight at the end of the experiment and negatively correlated with the area under the curve of the respiratory compliance during the experiment, both indices of the extension of lung injury. As lung infection was extending, the fixed VT was distributed in a smaller ventilated lung. As a consequence, distension of alveolar spaces likely increased with time, causing the formation of emphysema-like lesions in ventilated lung regions and pseudocysts in unventilated lung regions. Quite logically, the correlation between alveolar overdistension and the decrease in respiratory compliance was found only if time was taken into account. Lung overdistension was not associated with an increase in respiratory compliance, because nonventilated lung regions were much more extended than normally ventilated lung regions. In fact, alveolar overdistension reflected the extension of lung consolidation and therefore correlated with the decrease in respiratory compliance.
No gradient of alveolar distension was observed although ventrodorsal and cephalocaudal gradients of aeration were reported in normal dogs (29) caused by a gradient of transpulmonary pressure (30). In the present model, massive inoculations of Escherichia coli were administered to each pulmonary lobe and the regional distribution of aeration, consolidation, and inflammation depended exclusively on the distribution of the inoculum in the different bronchial segments, thereby eliminating the physiological gradients of transpulmonary pressure.
Bronchiolar Distension
Bronchiolectasis was very frequently found in bronchopneumonic lung areas. Pathological evidence of bronchiolar distension following a prolonged period of mechanical ventilation has been previously reported (1, 4). Slavin and coworkers (4) showed in a series of patients who died from ARDS that the existence of bronchiolectasis at autopsy was associated with a high alveolar dead space during the period of mechanical ventilation, suggesting that bronchiolar distension was present in lung areas that were not participating in gas exchange. Recently, two studies gave CT scan evidence of dilated bronchi within lung areas of a ground glass pattern in patients with late stage ARDS (5, 6). The present study confirms that distended bronchioles are frequently surrounded by unventilated consolidated alveoli. Such findings can be explained from the data obtained in the present study. In the few lung areas remaining normally ventilated, the alveoli remain the most compliant lung structures. As a consequence, overdistension predominantly involves the alveolar space resulting in emphysema-like lesions. In the majority of lung areas where normal aeration is replaced by consolidation, conducting airways become the most compliant lung structures and high pressures are predominantly transmitted to bronchioles resulting in bronchiolectasis. The significant correlation found between the premortem inspiratory plateau pressure, the respiratory compliance, and the degree of bronchiolar distension is a strong argument supporting this hypothesis. Positive end-expiratory pressure has been incriminated as a cause of bronchiolectasis (4, 31). In the present study, bronchiolar distension was observed in the absence of positive end-expiratory pressure.
Alveolar Edema
According to gross findings, in each animal consolidation involved at least 75% of the lung volume. As a consequence, the VT of 15 ml/kg administered to the rare lung areas remaining ventilated was likely equivalent to a VT of 40-50 ml/kg administered to a normally ventilated non-consolidated lung. According to previous experimental studies (10, 32), alveolar edema resulting from hyperventilation-induced pulmonary microvascular injury (32) should have been found in nonbronchopneumonic lung regions. Surprisingly, the overall incidence of histological fields with alveolar edema was very low. When present, alveolar edema appeared to be significantly associated with bronchopneumonic lesions. The reasons for the absence of pulmonary edema despite a respiratory condition predisposing to lung volutrauma are unknown and remain to be elucidated.
In conclusion, the administration of a tidal volume fixed at 15 ml/kg for 43 h to anesthetized piglets with multifocal bronchopneumonia induced emphysema-like lesions in lung areas remaining ventilated and pseudocysts and bronchiolectasis in bronchopneumonic lung regions. The degree of alveolar and bronchiolar distension was positively correlated with lung weight and inspiratory plateau pressure and negatively correlated with respiratory compliance, suggesting a correlation between mechanical ventilation-induced air-space enlargment and the extension of acute alveolar damage. The lesions of distension were very similar to those reported in patients with ARDS submitted to prolonged mechanical ventilation. When lung infection is the direct cause of acute lung injury, mechanical ventilation-induced lung barotrauma in piglets is expressed more as air-space enlargement than as high permeability type alveolar edema.
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Correspondence and requests for reprints should be addressed to J.-J. Rouby, Surgical Intensive Care Unit, Department of Anesthesiology, La Pitié-Salpêtrière Hospital, 47-83 boulevard de l'Hôpital, 75013 Paris, France. E-mail: jjrouby.pitie{at}invivo.edu
(Received in original form June 15, 2000 and in revised form September 28, 2000).
Members of the Experimental ICU Study Group: The following members of the Experimental ICU Study Group participated in this study: F. Wallet, Department of Bacteriology, Lille, France; L. Puybasset, C. Vezinet, Pierre Coriat, Réanimation Chirurgicale Pierre Viars, Pitié-Salpêtrière Hospital, Paris, France; Jack Richecoeur, Réanimation Medicale de Pontoise, France; Pablo Gusman, Department of Anesthesiology, Santa Casa de Misericordia, Juiz de Fora, M.G., Brazil; L. Malbouisson, Department of Anesthesiology, Hospital Das Clinicas, Sao Paulo, Brazil; Y. Lecharpentier, Department of Pathology, Pitié-Salpêtrière Hospital, Paris, France.| |
References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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