Transfusion-related acute lung injury (TRALI) is a serious clinical syndrome associated with the transfusion of plasma-containing blood components. Recently, TRALI has come to be recognized as the leading cause of transfusion-related death in the United States and United Kingdom. This complication typically presents as shortness of breath, hypoxemia, hypotension, fever and noncardiogeneic pulmonary edema, all occurring during or within 6 h after transfusion. Although the mechanism of TRALI has not been fully elucidated, it has been associated with human leukocyte antigen antibodies (class I, class II or neutrophil alloantigens) and with biologically active mediators in stored cellular blood components. Most of the donors implicated in cases of TRALI are multiparous women. Rarely diagnosed, TRALI can be confused with other causes of acute respiratory failure. Greater knowledge regarding TRALI on the part of clinicians could be crucial in preventing and treating this severe complication of blood transfusion.

Keywords: Blood transfusion; Respiratory insufficiency; HLA antigens.

Objective: To evaluate the stability of hemodynamic, respiratory and gas exchange variables in an animal model of oleic acid-induced acute lung injury. Methods: This was an experimental study involving 10 mongrel dogs. The variables were measured at baseline, as well as at 30, 60, 90 and 120 min after the administration of oleic acid. In order to analyze repeated measurements, linear and quadratic effects were tested. Mixed linear models with diversified variance and covariance structures were used, depending on the variable studied. Results: We found that mean arterial blood pressure stabilized at 30 min, as did heart rate, pulmonary arterial pressure and pulmonary capillary pressure at 60 min. Respiratory rate, tidal volume, minute volume and respiratory work stabilized at 30 min. Regarding gas exchange variables, PaO2, PaO2/FiO2 ratio and pulmonary shunt fraction stabilized at 30 min. The remaining variables maintained a continuous rise or fall. Conclusions: This oleic acid-induced acute lung injury model is stable for some of the variables tested, although stabilization occurs at different times. The respiratory and gas exchange variables stabilized at 30 min, whereas the hemodynamic variables stabilized at 60 min.

Keywords: Respiratory distress syndrome, adult; Models, animal; Statistical analysis.

Objetivo: Investigar os efeitos agudos da administração endovenosa de extrato da fumaça do cigarro (EFC) em parâmetros funcionais respiratórios, inflamatórios e histológicos em ratos e comparar esse potencial modelo de lesão pulmonar aguda (LPA) com aquele com o uso de ácido oleico (AO). Métodos: Foram estudados 72 ratos Wistar machos divididos em quatro grupos: tratados somente com soro fisiológico (SF; grupo controle); tratados com EFC e SF (grupo EFC); tratados com SF e AO (grupo AO); e tratados com EFC e AO (grupo EFC/AO). Resultados: As médias de complacência foram significantemente menores nos grupos AO e EFC/AO (2,12 ± 1,13 mL/cmH2O e 1,82 ± 0,77 mL/cmH2O, respectivamente) do que no controle (3,67 ± 1,38 mL/cmH2O). A proporção de neutrófilos e a atividade das metaloproteinases 2 e 9 em lavado broncoalveolar foram significantemente maiores nos grupos AO e EFC/AO que no controle. O acometimento pulmonar avaliado por morfometria foi significantemente maior nos grupos AO e EFC/AO (72,9 ± 13,8% e 77,6 ± 18,0%, respectivamente) do que nos grupos controle e EFC (8,7 ± 4,1% e 32,7 ± 13,1%, respectivamente), e esse acometimento foi significantemente maior no grupo EFC que no grupo controle. Conclusões: A administração endovenosa de EFC, nas doses e tempos deste estudo, associou-se à LPA mínima. O EFC não potencializou a LPA induzida por AO. Estudos adicionais são necessários para esclarecer o papel potencial desse modelo como método de estudo dos mecanismos de agressão pulmonar pelo tabaco.

Keywords: Tabagismo; Lesão pulmonar aguda; Modelos animais.

The ischemia-reperfusion injury is a common pathophysiologic phenomenon in many diseases seen in daily clinical practice. The lung can be affected both directly, as in pulmonary edema after lung transplant or after resolution of pulmonary thromboembolism, and indirectly, as in shock states or after reperfusion injury in distant organs as intestine or lower extremities. The latter situation can occur secondary to aortic occlusion for surgical procedures. Many mediators have been implicated in the ischemia-reperfusion injury: oxygen free radicals, lipid products as thromboxane, adhesion molecules involved in leukocyte-endothelial interaction, tumor necrosis factor, among others. Therapeutic strategies for the reperfusion injury are used only at the experimental level and in very few clinical studies. Antioxidants, inhibitors of lipid mediators and of the leukocyte-endothelial interaction and promoters of blood flow in post-ischemic vessels have been used.

Keywords: Lung. Injury. Reperfusion. Ischemia.

Objective: To establish the incidence of acute lung injury and acute respiratory distress syndrome, as well as related risk factors and mortality in an intensive care unit. To compare patients developing lung injury with at-risk patients not presenting acute lung injury or acute respiratory distress syndrome. Methods: The study was conducted in the intensive care unit of the Ribeirão Preto Hospital das Clínicas Emergency Room. All patients admitted between May 2001 and April 2002 were monitored prospectively. Clinical data, Acute Physiologic and Chronic Health Evaluation II score, complications, length of stay in the intensive care unit and lung injury data were recorded. Results: Of the 524 patients admitted, 175 (33.4%) presented risk factors for acute lung injury and acute respiratory distress syndrome, 33 (6.3%) developed acute respiratory distress syndrome, and 12 (2.3%) developed acute lung injury. The main risk factors were pneumonia (37.7%), shock (32.0%), multiple trauma (24.6%) and sepsis (21.1%). Patients developing acute lung injury had higher Acute Physiologic and Chronic Health Evaluation II scores (p < 0.05), more frequently presented sepsis (p = 0.001), developed more complications (p = 0.001) and presented greater mortality (p = 0.001). The main cause of death was multiple organ failure (38.5%). Conclusion: The incidence of acute lung injury and acute respiratory distress syndrome was 2.3% and 6.3%, respectively.

Keywords: Respiratory distress syndrome, adult/epidemiology; Respiratory distress syndrome, adult/mortality;

Background: It is questionable whether pressure-controlled ventilation (PCV) has advantages over volume-cycled ventilation (VCV). Objectives: To compare PCV to VCV with decelerating flow profile during assisted and controlled modes in an acute lung injury experimental model. Methods: Severe acute lung injury (PaO2/FIO2 < 100 mmHg) was induced by oleic acid IV infusion (0.05 mg/kg) in seven dogs. The animals were submitted to PCV and VCV in a randomized sequence. After 40 minutes in the assisted mode, ventilation was changed to the controlled mode after neuromuscular blockade. The tidal volume and the inspiratory time were kept constant throughout the experiment. Results: There were no differences in gas exchange (PaO2 and PaCO2), cardiac output or oxygen delivery (DO2) between VCV and PCV. The same was observed regarding maximum airway and plateau pressures, and also to the static compliance. Oxygen consumption (VO2) after neuromuscular blockade was 124 ± 48 in VCV versus 143 ± 50 ml/min in PCV, p = 0.42. In the assisted mode, there was a statistical trend of a higher VO2 in PCV (219 ± 72 versus 154 ± 67 ml/min in VCV, p = 0.06), that was associated with a statistical trend of a higher oxygen cost of breathing (OCB) during assisted PCV, although without statistical significance (31 ± 77 in VCV versus 75 ± 96 ml/min in PCV, p = 0.23), and also in a lower PvO2 (34 ± 7 in PCV versus 42 ± 6 ml/min in VCV, p = 0.02). These occurred despite a higher maximum inspiratory flow in the assisted mode in PCV (58 ± 9 versus 48 ± 4 L/min in VCV, p = 0.01). In both VCV and PCV the institution of controlled ventilation reduced cardiac debit and DO2 in as much as 20% relative to the assisted mode. Conclusions: The implementation of controlled ventilation improved the oxygen delivery/consumption relationship in this severe and with high OCB acute lung injury model. The PCV offered no additional benefits to VCV and it was associated with a higher OCB during the assisted mode.

Keywords: Artificial respiration. Pulmonary gas exchange. Tidal volume.

Objective: To compare the effects of early tracheostomy and of late tracheostomy in patients with acute severe brain injury. Methods: A retrospective study involving 28 patients admitted to the ICU of the Federal University of Juiz de Fora University Hospital in Juiz de Fora, Brazil, diagnosed with acute severe brain injury and presenting with a Glasgow coma scale (GCS) score < 8 within the first 48 h of hospitalization. The patients were divided into two groups: early tracheostomy (ET), performed within the first 8 days after admission; and late tracheostomy (LT), performed after postadmission day 8. At admission, we collected demographic data and determined the following scores: Acute Physiology and Chronic Health Evaluation (APACHE) II, GCS and Sequential Organ Failure Assessment (SOFA). Results: There were no significant differences between the groups (ET vs. LT) regarding the demographic data or the scores: APACHE II (26 ± 6 vs. 28 ± 8; p = 0.37), SOFA (6.3 ± 2.7 vs. 7.2 ± 3.0; p = 0.43) and GCS (5.4 ± 1.7 vs. 5.5 ± 1.7; p = 0.87). The 28-day mortality rate was lower in the ET group (9% vs. 47%; p = 0.04). Nosocomial pneumonia occurring within the first 7 days was less common in the ET group, although the difference was not significant (0% vs. 23%; p = 0.13). There were no differences regarding the occurrence of late pneumonia or in the duration of mechanical ventilation between the groups. Conclusions: On the basis of these findings, early tracheostomy should be considered in patients with acute severe brain injury.

Keywords: Tracheostomy; Pulmonary ventilation; Coma.

Although mechanical ventilation is an important therapy, it can result in complications. One major complication is ventilator-induced lung injury, which is caused by alveolar hyperdistension, leading to an inflammatory process, with neutrophilic infiltration, hyaline membrane formation, fibrogenesis and impaired gas exchange. In this process, cellular mechanotransduction of the overstretching stimulus is mediated by means of the cytoskeleton and its cell-cell and cell-extracellular matrix interactions, in such a way that the mechanical stimulus of ventilation is translated into an intracellular biochemical signal, inducing endothelial activation, pulmonary vascular permeability, leukocyte chemotaxis, cytokine production and, possibly, distal organ failure. Clinical studies have shown the relationship between pulmonary distension and mortality in patients with ventilator-induced lung injury. However, although the cytoskeleton plays a fundamental role in the pathogenesis of ventilator-induced lung injury, there have been few in vivo studies of alterations in the cytoskeleton and in cytoskeleton-associated proteins during this pathological process.

Keywords: Respiration, artificial; Cytoskeleton; Cell adhesion molecules; Focal adhesions; Mechanotransduction, cellular

Objective: To investigate the effects of quercetin in a model of bleomycin-induced pulmonary inflammation and fibrosis. Methods: Seventynine adult male hamsters were randomized to receive intratracheal (IT) instillations and intraperitoneal (IP) injections in four configurations: IP vehicle/IT saline (VS group, n = 16); IP quercetin/IT saline (QS group, n = 16); IP vehicle/IT bleomycin (VB group, n = 27); and IP quercetin/ IT bleomycin (QB group, n = 20). Quercetin and bleomycin were administered at 30 mg/kg/day and 10 U/kg, respectively. Quercetin was started/discontinued 3 days before/14 days after the IT instillations. Results: The mortality rate was significantly higher in the VB group than in the other groups (44% vs. VS: 0%; QS: 0%; and QB: 15%). Lung levels of thiobarbituric acid reactive substances (× 10−2 nmol/mg) were significantly higher in the VB group (6.6 ± 1.3 vs. VS: 5.5 ± 0.8; QS: 2.5 ± 0.6; and QB: 5.8 ± 0.6). Lung levels of reduced glutathione (× 10−2 nmol/mg) were significantly lower in the VB/QB groups than in the VS/QS groups (28.9 ± 13.8/28.6 ± 14.8 vs. 43.9 ± 16.0/51.1 ± 20.3), whereas those of hydroxyproline (mg/g) were significantly higher (201.6 ± 37.3/177.6 ± 20.3 vs. 109.6 ± 26.1/117.5 ± 32.0).Mean lung septal thickness (μm) was greatest in the VB group (16.9 ± 3.2 vs. VS: 3.0 ± 0.3; QS: 3.3 ± 0.2; and QB: 5.2 ± 1.1). Conclusions: In a hamster model of lung injury, quercetin exhibited anti-inflammatory effects that are related, at least in part, to its antioxidant properties.

Keywords: Pulmonary fibrosis; Bleomycin; Flavonoids; Lipid peroxidation.

Objective: To evaluate the effects of immunization with a DNA-hsp65 vaccine in an experimental model of pulmonary fibrosis. Methods: A total of 120 male C57BL/6 mice were distributed into four groups: SS, injected with saline (placebo) and then receiving intratracheal (IT) instillation of saline; SB, injected with saline (placebo) and then receiving IT instillation of bleomycin; PB, treated with plasmid only, without bacterial genome, and then receiving IT instillation of bleomycin; and BB, treated with the vaccine and then receiving IT instillation of bleomycin. Bleomycin was instilled 15 days after the last immunization, and the animals were killed six weeks thereafter. The left and right lungs were removed, the former for morphological analysis and the latter for hydroxyproline measurements. Results: The proportion of deaths within the first 48 h after the IT instillation (deaths attributed to the surgical procedure) was higher in the SB group than in the SS group (57.7% vs. 11.1%). The mean area of pulmonary interstitial septa was greater in the SB and PB groups (53.1 ± 8.6% and 53.6 ± 9.3%, respectively) than in the SS and BB groups (32.9 ± 2.7% and 34.3 ± 6.1%, respectively). The mean area of interstitial septa stained by picrosirius was greater in the SB, PB and BB groups than in the SS group (8.2 ± 4.9%, 7.2 ± 4.2% and 6.6 ± 4.1%, respectively, vs. 2.0 ± 1.4%). The total hydroxyproline content in the lung was significantly lower in the SS group (104.9 ± 20.9 pg/lung) than in the other groups (SB: 160.4 ± 47.8 pg/lung; PB: 170.0 ± 72.0 pg/lung; and BB: 162.5 ± 39.7 pg/lung). Conclusions: Immunization with the DNA-hsp65 vaccine reduced the deposition of noncollagen matrix in a model of bleomycin-induced lung lesion.

Keywords: Pulmonary fibrosis; Bleomycin; Collagen.

Objective: To evaluate the effects that administering dexamethasone before the induction of ventilator-induced lung injury (VILI) has on the temporal evolution of that injury. Methods: Wistar rats were allocated to one of three groups: pre-VILI administration of dexamethasone (dexamethasone group); pre-VILI administration of saline (control group); or ventilation only (sham group). The VILI was induced by ventilation at a high tidal volume. Animals in the dexamethasone and control groups were euthanized at 0, 4, 24, and 168 h after VILI induction. We analyzed arterial blood gases, lung edema, cell counts (total and differential) in the BAL fluid, and lung histology. Results: At 0, 4, and 24 h after VILI induction, acute lung injury (ALI) scores were higher in the control group than in the sham group (p < 0.05). Administration of dexamethasone prior to VILI induction decreased the severity of the lung injury. At 4 h and 24 h after induction, the ALI score in the dexamethasone group was not significantly different from that observed for the sham group and was lower than that observed for the control group (p < 0.05). Neutrophil counts in BAL fluid were increased in the control and dexamethasone groups, peaking at 4 h after VILI induction (p < 0.05). However, the neutrophil counts were lower in the dexamethasone group than in the control group at 4 h and 24 h after induction (p < 0.05). Pre-treatment with dexamethasone also prevented the post-induction oxygenation impairment seen in the control group. Conclusions: Administration of dexamethasone prior to VILI induction attenuates the effects of the injury in Wistar rats. The molecular mechanisms of such injury and the possible clinical role of corticosteroids in VILI have yet to be elucidated.

Keywords: Ventilator-induced lung injury; Dexamethasone; Respiratory distress syndrome, adult.

Objectives: Here, we investigated the effects of hyperventilation on acute lung injury (ALI) in spontaneously breathing rats. Methods: Wistar rats were randomized to receive either intraperitoneal lipopolysaccharides (LPS) or saline, and intravenous infusion of NH4Cl (to induce metabolic acidosis and hyperventilation) or saline. Four groups were established: control-control (C-C), control-hyperventilation (C-HV), LPS-control (LPS-C), and LPS-hyperventilation (LPS-HV). Venous blood gases were collected before and after NH4Cl infusion and analyzed to confirm the presence of metabolic acidosis and hyperventilation. After euthanasia, lung injury was assessed using the ALI score, morphometric quantification of perivascular edema, neutrophil counts in the bronchoalveolar lavage, and mRNA expression of biological markers in the lung tissue. Results: Hyperventilation induced inflammatory lung injury in previously healthy lungs and exacerbated injuries previously induced by LPS (ALI score: C-C=0.14 [IQR 0.12; 0.14]; C-HV=0.36 [IQR 0.31; 0.37]; LPS-C=0.51 [IQR 0.50; 0.54]; LPS-HV=0.58 [IQR 0.56; 0.62]; p<0.01). Perivascular edema, neutrophil counts in bronchoalveolar lavage, and amphiregulin mRNA expression were higher in the LPS-HV group compared to the control group. Conclusions: Hyperventilation increased inflammatory injury in rats with ALI during spontaneous ventilation. These results suggest that the impact of vigorous spontaneous breathing efforts on worsening inflammatory lung injury warrants further investigation.

Keywords: acute lung injury, acute respiratory distress syndrome, spontaneous breathing, hyperventilation, lung injury.

Objective: To investigate the effects of N-acetylcysteine (NAC) and pentoxifylline in a model of remote organ injury after hind-limb ischemia/reperfusion (I/R) in rats, the lungs being the remote organ system. Methods: Thirty-five male Wistar rats were assigned to one of five conditions (n = 7/group), as follows: sham operation (control group); hind-limb ischemia, induced by clamping the left femoral artery, for 2 h, followed by 24 h of reperfusion (I/R group); and hind-limb ischemia, as above, followed by intraperitoneal injection (prior to reperfusion) of 150 mg/kg of NAC (I/R+NAC group), 40 mg/kg of pentoxifylline (I/R+PTX group), or both (I/R+NAC+PTX group). At the end of the trial, lung tissues were removed for histological analysis and assessment of oxidative stress. Results: In comparison with the rats in the other groups, those in the I/R group showed lower superoxide dismutase activity and glutathione levels, together with higher malondialdehyde levels and lung injury scores (p < 0.05 for all). Interstitial inflammatory cell infiltration of the lungs was also markedly greater in the I/R group than in the other groups. In addition, I/R group rats showed various signs of interstitial edema and hemorrhage. In the I/R+NAC, I/R+PTX, and I/R+NAC+PTX groups, superoxide dismutase activity, glutathione levels, malondialdehyde levels, and lung injury scores were preserved (p < 0.05 for all). The differences between the administration of NAC or pentoxifylline alone and the administration of the two together were not significant for any of those parameters (p > 0.05 for all). Conclusions: Our results suggest that NAC and pentoxifylline both protect lung tissue from the effects of skeletal muscle I/R. However, their combined use does not appear to increase the level of that protection.

Keywords: Skeletal muscle; Ischemia; Reperfusion injury; Lung injury; Acetylcysteine; Pentoxifylline.

Objective: To determine whether tramadol has a protective effect against lung injury induced by skeletal muscle ischemia-reperfusion. Methods: Twenty Wistar male rats were allocated to one of two groups: ischemia-reperfusion (IR) and ischemia-reperfusion + tramadol (IR+T). The animals were anesthetized with intramuscular injections of ketamine and xylazine (50 mg/kg and 10 mg/kg, respectively). All of the animals underwent 2-h ischemia by occlusion of the femoral artery and 24-h reperfusion. Prior to the occlusion of the femoral artery, 250 IU heparin were administered via the jugular vein in order to prevent clotting. The rats in the IR+T group were treated with tramadol (20 mg/kg i.v.) immediately before reperfusion. After the reperfusion period, the animals were euthanized with pentobarbital (300 mg/kg i.p.), the lungs were carefully removed, and specimens were properly prepared for histopathological and biochemical studies. Results: Myeloperoxidase activity and nitric oxide levels were significantly higher in the IR group than in the IR+T group (p = 0.001 for both). Histological abnormalities, such as intra-alveolar edema, intra-alveolar hemorrhage, and neutrophil infiltration, were significantly more common in the IR group than in the IR+T group. Conclusions: On the basis of our histological and biochemical findings, we conclude that tramadol prevents lung tissue injury after skeletal muscle ischemia-reperfusion.

Keywords: Tramadol; Muscle, skeletal; Ischemic attack, transient; Lung Injury.