JOAO BATISTA BORGES SOBRINHO DORINI
Projetos de Pesquisa
Unidades Organizacionais
LIM/09 - Laboratório de Pneumologia, Hospital das Clínicas, Faculdade de Medicina
14 resultados
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article Feasibility of Ga-68-labeled Siglec-9 peptide for the imaging of acute lung inflammation: a pilot study in a porcine model of acute respiratory distress syndrome(2016) RETAMAL, Jaime; SORENSEN, Jens; LUBBERINK, Mark; SUAREZ-SIPMANN, Fernando; BORGES, Joao Batista; FEINSTEIN, Ricardo; JALKANEN, Sirpa; ANTONI, Gunnar; HEDENSTIERNA, Goran; ROIVAINEN, Anne; LARSSON, Anders; VELIKYAN, IrinaThere is an unmet need for noninvasive, specific and quantitative imaging of inherent inflammatory activity. Vascular adhesion protein-1 (VAP-1) translocates to the luminal surface of endothelial cells upon inflammatory challenge. We hypothesized that in a porcine model of acute respiratory distress syndrome (ARDS), positron emission tomography (PET) with sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) based imaging agent targeting VAP-1 would allow quantification of regional pulmonary inflammation. ARDS was induced by lung lavages and injurious mechanical ventilation. Hemodynamics, respiratory system compliance (Crs) and blood gases were monitored. Dynamic examination using [O-15]water PET-CT (10 min) was followed by dynamic (90 min) and whole-body examination using VAP-1 targeting Ga-68-labeled 1,4,7,10-tetraaza cyclododecane-1,4,7-tris-acetic acid-10-ethylene glycol-conjugated Siglec-9 motif peptide ([Ga-68]Ga-DOTA-Siglec-9). The animals received an anti-VAP-1 antibody for post-mortem immunohistochemistry assay of VAP-1 receptors. Tissue samples were collected post-mortem for the radioactivity uptake, histology and immunohistochemistry assessment. Marked reduction of oxygenation and Crs, and higher degree of inflammation were observed in ARDS animals. [Ga-68]Ga-DOTA-Siglec-9 PET showed significant uptake in lungs, kidneys and urinary bladder. Normalization of the net uptake rate (K-i) for the tissue perfusion resulted in 4-fold higher uptake rate of [Ga-68]Ga-DOTA-Siglec-9 in the ARDS lungs. Immunohistochemistry showed positive VAP-1 signal in the injured lungs. Detection of pulmonary inflammation associated with a porcine model of ARDS was possible with [Ga-68]Ga-DOTA-Siglec-9 PET when using kinetic modeling and normalization for tissue perfusion.- Multiple inert gas elimination technique by micropore membrane inlet mass spectrometry-a comparison with reference gas chromatography(2013) KRETZSCHMAR, Moritz; SCHILLING, Thomas; VOGT, Andreas; ROTHEN, Hans Ulrich; BORGES, Joao Batista; HACHENBERG, Thomas; LARSSON, Anders; BAUMGARDNER, James E.; HEDENSTIERNA, GoranThe mismatching of alveolar ventilation and perfusion (V-A/Q) is the major determinant of impaired gas exchange. The gold standard for measuring V-A/Q distributions is based on measurements of the elimination and retention of infused inert gases. Conventional multiple inert gas elimination technique (MIGET) uses gas chromatography (GC) to measure the inert gas partial pressures, which requires tonometry of blood samples with a gas that can then be injected into the chromatograph. The method is laborious and requires meticulous care. A new technique based on micropore membrane inlet mass spectrometry (MMIMS) facilitates the handling of blood and gas samples and provides nearly real-time analysis. In this study we compared MIGET by GC and MMIMS in 10 piglets: 1) 3 with healthy lungs; 2) 4 with oleic acid injury; and 3) 3 with isolated left lower lobe ventilation. The different protocols ensured a large range of normal and abnormal V-A/Q distributions. Eight inert gases (SF6, krypton, ethane, cyclopropane, desflurane, enflurane, diethyl ether, and acetone) were infused; six of these gases were measured with MMIMS, and six were measured with GC. We found close agreement of retention and excretion of the gases and the constructed V-A/Q distributions between GC and MMIMS, and predicted Pa-O2 from both methods compared well with measured Pa-O2. V-A/Q by GC produced more widely dispersed modes than MMIMS, explained in part by differences in the algorithms used to calculate V-A/Q distributions. In conclusion, MMIMS enables faster measurement of V-A/Q, is less demanding than GC, and produces comparable results.
- Dynamic Mechanical Interactions Between Neighboring Airspaces Determine Cyclic Opening and Closure in Injured Lung(2017) BROCHE, Ludovic; PERCHIAZZI, Gaetano; PORRA, Liisa; TANNOIA, Angela; PELLEGRINI, Mariangela; DEROSA, Savino; SINDACO, Alessandra; BORGES, Joao Batista; DEGRUGILLIERS, Loic; LARSSON, Anders; HEDENSTIERNA, Goran; WEXLER, Anthony S.; BRAVIN, Alberto; VERBANCK, Sylvia; SMITH, Bradford J.; BATES, Jason H. T.; BAYAT, SamObjectives: Positive pressure ventilation exposes the lung to mechanical stresses that can exacerbate injury. The exact mechanism of this pathologic process remains elusive. The goal of this study was to describe recruitment/derecruitment at acinar length scales over short-time frames and test the hypothesis that mechanical interdependence between neighboring lung units determines the spatial and temporal distributions of recruitment/derecruitment, using a computational model. Design: Experimental animal study. Setting: International synchrotron radiation laboratory. Subjects: Four anesthetized rabbits, ventilated in pressure controlled mode. Interventions: The lung was consecutively imaged at - 1.5-minute intervals using phase-contrast synchrotron imaging, at positive end expiratory pressures of 12, 9, 6, 3, and 0 cm H2O before and after lavage and mechanical ventilation induced injury. The extent and spatial distribution of recruitment/derecruitment was analyzed by subtracting subsequent images. In a realistic lung structure, we implemented a mechanistic model in which each unit has individual pressures and speeds of opening and closing. Derecruited and recruited lung fractions (F-derecruaed, F-recruited) were computed based on the comparison of the aerated volumes at successive time points. Measurements and Main Results: Alternative recruitment/derecruitment occurred in neighboring alveoli over short-time scales in all tested positive end-expiratory pressure levels and despite stable pressure controlled mode. The computational model reproduced this behavior only when parenchymal interdependence between neighboring acini was accounted for. Simulations closely mimicked the experimental magnitude of F-derecruited and F-recruited when mechanical interdependence was included, while its exclusion gave F-recruited values of zero at positive end -expiratory pressure greater than or equal to 3 cm H2O. Conclusions: These findings give further insight into the microscopic behavior of the injured lung and provide a means of testing protective-ventilation strategies to prevent recruitment/derecruitment and subsequent lung damage. (Crit Care Med 2017; 45:687-694)
- THAM reduces CO2-associated increase in pulmonary vascular resistance - an experimental study in lung-injured piglets(2015) HOSTMAN, Staffan; BORGES, Joao Batista; SUAREZ-SIPMANN, Fernando; AHLGREN, Kerstin M.; ENGSTROM, Joakim; HEDENSTIERNA, Goran; LARSSON, AndersIntroduction: Low tidal volume (VT) ventilation is recommended in patients with acute respiratory distress syndrome (ARDS). This may increase arterial carbon dioxide tension (PaCO2), decrease pH, and augment pulmonary vascular resistance (PVR). We hypothesized that Tris(hydroxymethyl) aminomethane (THAM), a pure proton acceptor, would dampen these effects, preventing the increase in PVR. Methods: A one-hit injury ARDS model was established by repeated lung lavages in 18 piglets. After ventilation with V-T of 6 ml/kg to maintain normocapnia, VT was reduced to 3 ml/kg to induce hypercapnia. Six animals received THAM for 1 h, six for 3 h, and six serving as controls received no THAM. In all, the experiment continued for 6 h. The THAM dosage was calculated to normalize pH and exhibit a lasting effect. Gas exchange, pulmonary, and systemic hemodynamics were tracked. Inflammatory markers were obtained at the end of the experiment. Results: In the controls, the decrease in VT from 6 to 3 ml/kg increased PaCO2 from 6.0 +/- 0.5 to 13.8 +/- 1.5 kPa and lowered pH from 7.40 +/- 0.01 to 7.12 +/- 0.06, whereas base excess (BE) remained stable at 2.7 +/- 2.3 mEq/L to 3.4 +/- 3.2 mEq/L. In the THAM groups, PaCO2 decreased and pH increased above 7.4 during the infusions. After discontinuing the infusions, PaCO2 increased above the corresponding level of the controls (15.2 +/- 1.7 kPa and 22.6 +/- 3.3 kPa for 1-h and 3-h THAM infusions, respectively). Despite a marked increase in BE (13.8 +/- 3.5 and 31.2 +/- 2.2 for 1-h and 3-h THAM infusions, respectively), pH became similar to the corresponding levels of the controls. PVR was lower in the THAM groups (at 6 h, 329 +/- 77 dyn.s/m(5) and 255 +/- 43 dyn.s/m(5) in the 1-h and 3-h groups, respectively, compared with 450 +/- 141 dyn.s/m(5) in the controls), as were pulmonary arterial pressures. Conclusions: The pH in the THAM groups was similar to pH in the controls at 6 h, despite a marked increase in BE. This was due to an increase in PaCO2 after stopping the THAM infusion, possibly by intracellular release of CO2. Pulmonary arterial pressure and PVR were lower in the THAM-treated animals, indicating that THAM may be an option to reduce PVR in acute hypercapnia.
- Does Regional Lung Strain Correlate With Regional Inflammation in Acute Respiratory Distress Syndrome During Nonprotective Ventilation? An Experimental Porcine Study(2018) RETAMAL, Jaime; HURTADO, Daniel; VILLARROEL, Nicolas; BRUHN, Alejandro; BUGEDO, Guillermo; AMATO, Marcelo Britto Passos; COSTA, Eduardo Leite Vieira; HEDENSTIERNA, Goeran; LARSSON, Anders; BORGES, Joao BatistaObjective: It is known that ventilator-induced lung injury causes increased pulmonary inflammation. It has been suggested that one of the underlying mechanisms may be strain. The aim of this study was to investigate whether lung regional strain correlates with regional inflammation in a porcine model of acute respiratory distress syndrome. Design: Retrospective analysis of CT images and positron emission tomography images using [F-18]fluoro-2-deoxy-D-glucose. Setting: University animal research laboratory. Subjects: Seven piglets subjected to experimental acute respiratory distress syndrome and five ventilated controls. Interventions: Acute respiratory distress syndrome was induced by repeated lung lavages, followed by 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressures (mean, 4cm H2O) and high inspiratory pressures (mean plateau pressure, 45cm H2O). All animals were subsequently studied with CT scans acquired at end-expiration and end-inspiration, to obtain maps of volumetric strain (inspiratory volume - expiratory volume)/expiratory volume, and dynamic positron emission tomography imaging. Strain maps and positron emission tomography images were divided into 10 isogravitational horizontal regions-of-interest, from which spatial correlation was calculated for each animal. Measurements and Main Results: The acute respiratory distress syndrome model resulted in a decrease in respiratory system compliance (20.33.4 to 14.0 +/- 4.9mL/cm H2O; p < 0.05) and oxygenation (Pao(2)/Fio(2), 489 +/- 80 to 92 +/- 59; p < 0.05), whereas the control animals did not exhibit changes. In the acute respiratory distress syndrome group, strain maps showed a heterogeneous distribution with a greater concentration in the intermediate gravitational regions, which was similar to the distribution of [F-18]fluoro-2-deoxy-D-glucose uptake observed in the positron emission tomography images, resulting in a positive spatial correlation between both variables (median R-2 = 0.71 [0.02-0.84]; p < 0.05 in five of seven animals), which was not observed in the control animals. Conclusion: In this porcine acute respiratory distress syndrome model, regional lung strain was spatially correlated with regional inflammation, supporting that strain is a relevant and prominent determinant of ventilator-induced lung injury.
conferenceObject A comparison between PEEP titration methods in a porcine ARDS model(2017) PINO, Fabio; BALL, Lorenzo; SCARAMUZZO, Gaetano; RIBAS, Miquel Pinol; PELOSI, Paolo; HEDENSTIERNA, Goran; BORGES, Joao Batista; LARSSON, Anders; GUERIN, Claude; PERCHIAZZI, Gaetano- Open Lung in Lateral Decubitus With Differential Selective Positive End-Expiratory Pressure in an Experimental Model of Early Acute Respiratory Distress Syndrome(2015) BORGES, Joao Batista; SENTURK, Mert; AHLGREN, Oskar; HEDENSTIERNA, Goran; LARSSON, AndersObjective: After lung recruitment, lateral decubitus and differential lung ventilation may enable the titration and application of optimum-selective positive end-expiratory pressure values for the dependent and nondependent lungs. We aimed at compare the effects of optimum-selective positive end-expiratory pressure with optimum global positive end-expiratory pressure on regional collapse and aeration distribution in an experimental model of acute respiratory distress syndrome. Design: Prospective laboratory investigation. Setting: University animal research laboratory. Subjects: Seven piglets. Interventions: A one-hit injury acute respiratory distress syndrome model was established by repeated lung lavages. After replacing the tracheal tube by a double-lumen one, we initiated lateral decubitus and differential ventilation. After maximum-recruitment maneuver, decremental positive end-expiratory pressure titration was performed. The positive end-expiratory pressure corresponding to maximum dynamic compliance was defined globally (optimum global positive end-expiratory pressure) and for each individual lung (optimum-selective positive end-expiratory pressure). After new maximum-recruitment maneuver, two steps were performed in randomized order (15 min each): ventilation applying the optimum global positive end-expiratory pressure and the optimum-selective positive end-expiratory pressure. CT scans were acquired at end expiration and end inspiration. Measurements and Main Results: Aeration homogeneity was evaluated as a nondependent/dependent ratio (percent of total gas content in upper lung/percent of total gas content in lower lung) and tidal recruitment as the difference in the percent mass of nonaerated tissue between expiration and inspiration. At the end of the 15-minute optimum-selective positive end-expiratory pressure, compared with the optimum global positive end-expiratory pressure, resulted in 1) decrease in the percent mass of collapse in the lower lung at expiratory CT (19% 15% vs 4% +/- 5%; p = 0.03); 2) decrease in the nondependent/dependent ratio between the optimum global positive end-expiratory pressure-expiratory-CT and optimum-selective positive end-expiratory pressure-expiratory-CT (3.7 +/- 1.2 vs 0.8 +/- 0.5; p = 0.01); 3) decrease in the nondependent/dependent ratio between the optimum global positive end-expiratory pressure-inspiratory-CT and optimum-selective positive end-expiratory pressure-inspiratory-CT (2.8 +/- 1.1 vs 0.6 +/- 0.3; p = 0.01); and 4) less tidal recruitment (p = 0.049). Conclusions: After maximum lung recruitment, lateral decubitus and differential lung ventilation enabled the titration of optimum-selective positive end-expiratory pressure values for the dependent and the nondependent lungs, made possible the application of an optimized regional open lung approach, promoted better aeration distribution, and minimized lung tissue inhomogeneities.
- Early Inflammation Mainly Affects Normally and Poorly Aerated Lung in Experimental Ventilator-Induced Lung Injury*(2014) BORGES, Joao Batista; COSTA, Eduardo L. V.; SUAREZ-SIPMANN, Fernando; WIDSTROM, Charles; LARSSON, Anders; AMATO, Marcelo; HEDENSTIERNA, GoranObjective: The common denominator in most forms of ventilator-induced lung injury is an intense inflammatory response mediated by neutrophils. PET with [F-18]fluoro-2-deoxy-d-glucose can be used to image cellular metabolism, which, during lung inflammatory processes, mainly reflects neutrophil activity, allowing the study of regional lung inflammation in vivo. The aim of this study was to assess the location and magnitude of lung inflammation using PET imaging of [F-18]fluoro-2-deoxy-d-glucose in a porcine experimental model of early acute respiratory distress syndrome. Design: Prospective laboratory investigation. Setting: A university animal research laboratory. Subjects: Seven piglets submitted to experimental ventilator-induced lung injury and five healthy controls. Interventions: Lung injury was induced by lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. All animals were subsequently studied with dynamic PET imaging of [F-18]fluoro-2-deoxy-d-glucose. CT scans were acquired at end expiration and end inspiration. Measurements and Main Results: [F-18]fluoro-2-deoxy-d-glucose uptake rate was computed for the whole lung, four isogravitational regions, and regions grouping voxels with similar density. Global and intermediate gravitational zones [F-18]fluoro-2-deoxy-d-glucose uptakes were higher in ventilator-induced lung injury piglets compared with controls animals. Uptake of normally and poorly aerated regions was also higher in ventilator-induced lung injury piglets compared with control piglets, whereas regions suffering tidal recruitment or tidal hyperinflation had [F-18]fluoro-2-deoxy-d-glucose uptakes similar to controls. Conclusions: The present findings suggest that normally and poorly aerated regionscorresponding to intermediate gravitational zonesare the primary targets of the inflammatory process accompanying early experimental ventilator-induced lung injury. This may be attributed to the small volume of the aerated lung, which receives most of ventilation.
- Optimal PEEP during one-lung ventilation with capnothorax: An experimental study(2019) REINIUS, Henrik; BORGES, Joao Batista; ENGSTROM, Joakim; AHLGREN, Oskar; LENNMYR, Fredrik; LARSSON, Anders; FREDEN, FilipBackground One-lung ventilation (OLV) with induced capnothorax carries the risk of severely impaired ventilation and circulation. Optimal PEEP may mitigate the physiological perturbations during these conditions. Methods Right-sided OLV with capnothorax (16 cm H2O) on the left side was initiated in eight anesthetized, muscle-relaxed piglets. A recruitment maneuver and a decremental PEEP titration from PEEP 20 cm H2O to zero end-expiratory pressure (ZEEP) was performed. Regional ventilation and perfusion were studied with electrical impedance tomography and computer tomography of the chest was used. End-expiratory lung volume and hemodynamics were recorded and. Results PaO2 peaked at PEEP 12 cm H2O (49 +/- 14 kPa) and decreased to 11 +/- 5 kPa at ZEEP (P < 0.001). PaCO2 was 9.5 +/- 1.3 kPa at 20 cm H2O PEEP and did not change when PEEP step-wise was reduced to 12 cm H2O PaCO2. At lower PEEP, PaCO2 increased markedly. The ventilatory driving pressure was lowest at PEEP 14 cm H2O (19.6 +/- 5.8 cm H2O) and increased to 38.3 +/- 6.1 cm H2O at ZEEP (P < 0.001). When reducing PEEP below 12-14 cm H2O ventilation shifted from the dependent to the nondependent regions of the ventilated lung (P = 0.003), and perfusion shifted from the ventilated to the nonventilated lung (P = 0.02). Conclusion Optimal PEEP was 12-18 cm H2O and probably relates to capnothorax insufflation pressure. With suboptimal PEEP, ventilation/perfusion mismatch in the ventilated lung and redistribution of blood flow to the nonventilated lung occurred.
- Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation(2014) RETAMAL, Jaime; BERGAMINI, Bruno Curty; CARVALHO, Alysson R.; BOZZA, Fernando A.; BORZONE, Gisella; BORGES, Joao Batista; LARSSON, Anders; HEDENSTIERNA, Goeran; BUGEDO, Guillermo; BRUHN, AlejandroIntroduction: When alveoli collapse the traction forces exerted on their walls by adjacent expanded units may increase and concentrate. These forces may promote its re-expansion at the expense of potentially injurious stresses at the interface between the collapsed and the expanded units. We developed an experimental model to test the hypothesis that a local non-lobar atelectasis can act as a stress concentrator, contributing to inflammation and structural alveolar injury in the surrounding healthy lung tissue during mechanical ventilation. Methods: A total of 35 rats were anesthetized, paralyzed and mechanically ventilated. Atelectasis was induced by bronchial blocking: after five minutes of stabilization and pre-oxygenation with FIO2 = 1.0, a silicon cylinder blocker was wedged in the terminal bronchial tree. Afterwards, the animals were randomized between two groups: 1) Tidal volume (V-T) = 10 ml/kg and positive end-expiratory pressure (PEEP) = 3 cmH(2)O (V(T)10/PEEP3); and 2) V-T=20 ml/kg and PEEP = 0 cmH2O (V(T)20/zero end-expiratory pressure (ZEEP)). The animals were then ventilated during 180 minutes. Three series of experiments were performed: histological (n = 12); tissue cytokines (n = 12); and micro-computed tomography (microCT; n = 2). An additional six, non-ventilated, healthy animals were used as controls. Results: Atelectasis was successfully induced in the basal region of the lung of 26 out of 29 animals. The microCT of two animals revealed that the volume of the atelectasis was 0.12 and 0.21 cm(3). There were more alveolar disruption and neutrophilic infiltration in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. Edema was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in the V(T)20/ZEEP than VT10/PEEP3 group. The volume-to-surface ratio was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. We did not find statistical difference in tissue interleukin-1 beta and cytokine-induced neutrophil chemoattractant-1 between regions. Conclusions: The present findings suggest that a local non-lobar atelectasis acts as a stress concentrator, generating structural alveolar injury and inflammation in the surrounding lung tissue.