Francisco Taboada

Absence or Inhibition of Matrix Metalloproteinase–8 Decreases Ventilator-Induced Lung Injury

Mechanical ventilation is a life-saving therapy that can also damage the lungs. Ventilator-induced lung injury (VILI) promotes inflammation and up-regulates matrix metalloproteinases (MMPs). Among these enzymes, MMP-8 is involved in the onset of inflammation by processing different immune mediators. To clarify the role of MMP-8 in a model of VILI and their relevance as a therapeutic target, we ventilated wild-type and MMP-8-deficient mice with low or high pressures for 2 hours. There were no significant differences after low-pressure ventilation between wild-type and knockout animals. However, lack of MMP-8 results in better gas exchange, decreased lung edema and permeability, and diminished histological injury after high-pressure ventilation. Mmp8(-/-) mice had a different immune response to injurious ventilation, with decreased neutrophilic infiltration, lower levels of IFN-γ and chemokines (LPS-induced CXC chemokine, macrophage inflammatory protein-2), and significant increases in anti-inflammatory cytokines (IL-4, IL-10) in lung tissue and bronchoalveolar lavage fluid. There were no differences in MMP-2, MMP-9, or tissue inhibitor of metalloproteinase-1 between wild-type and knockout mice. These results were confirmed by showing a similar protective effect in wild-type mice treated with a selective MMP-8 inhibitor. We conclude that MMP-8 promotes acute inflammation after ventilation with high pressures, and its short-term inhibition could be a therapeutic goal to limit VILI.

Inflammation and matrix remodeling during repair of ventilator-induced lung injury

High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

Matrix metalloproteinase-9 (MMP-9) is released by neutrophils at the sites of acute inflammation. This enzyme modulates matrix turnover and inflammatory response, and its activity has been found to be increased after ventilator-induced lung injury. To clarify the role of MMP-9, mice lacking this enzyme and their wild-type counterparts were ventilated for 2 h with high- or low-peak inspiratory pressures (25 and 15 cmH2O, respectively). Lung injury was evaluated by gas exchange, respiratory mechanics, wet-to-dry weight ratio, and histological analysis. The activity of MMP-9 and levels of IL-1beta, IL-4, and macrophage inflammatory protein (MIP-2) were measured in lung tissue and bronchoalveolar lavage fluid (BALF). Cell count and myeloperoxidase activity were measured in BALF. There were no differences between wild-type and Mmp9-/- animals after low-pressure ventilation. After high-pressure ventilation, wild-type mice exhibited an increase in MMP-9 in tissue and BALF. Mice lacking MMP-9 developed more severe lung injury than wild-type mice, in terms of impaired oxygenation and lung mechanics, and higher damage in the histological study. These effects correlated with an increase in both cell count and myeloperoxidase activity in the BALF, suggesting an increased neutrophilic influx in response to ventilation. An increase in IL-1beta and IL-4 in the BALF only in knockout mice could be responsible for the differences. There were no differences between genotypes in MMP-2, MMP-8, or tissue inhibitors of metalloproteinases. These results show that MMP-9 protects against ventilator-induced lung injury by decreasing alveolar neutrophilic infiltration, probably by modulation of the cytokine response in the air spaces.

Application of continuous positive airway pressure to trace static pressure-volume curves of the respiratory system

ObjectiveTo evaluate a new technique for pressure-volume curve tracing. DesignProspective experimental study. SettingAnimal research laboratory. SubjectsSix anesthetized rats. InterventionsTwo pressure-volume curves were obtained by means of the super-syringe method (gold standard) and the continuous positive airway pressure (CPAP) method. For the CPAP method, the ventilator was switched to CPAP and the pressure level was raised from 0 to 50 cm H2O in 5 cm H2O steps and then decreased, while we measured lung volume using respiratory inductive plethysmography. Thereafter, lung injury was induced using very high-volume ventilation. Following injury, two further pressure-volume curves were traced. Pressure-volume pairs were fitted to a mathematical model. Measurements and Main ResultsPressure-volume curves were equivalent for each method, with intraclass correlation coefficients being higher than .75 for each pressure level measured. Bias and precision for volume values were 0.46 ± 0.875 mL in basal measurements and 0.31 ± 0.67 mL in postinjury conditions. Lower and upper inflection points on the inspiratory limb and maximum curvature point on the deflation limb obtained using both methods and measured by regression analysis also were correlated, with intraclass correlation coefficients (95% confidence interval) being .97 (.58, .99), .85 (.55, .95), and .94 (.81, .98) (p < .001 for each one). When inflection points were estimated by observers, the correlation coefficient between methods was .90 (.67, .98) for lower inflection points (p < .001). However, estimations for upper inflection points and maximum curvature point were significantly different. ConclusionsThe CPAP method for tracing pressure-volume curves is equivalent to the super-syringe method. It is easily applicable at the bedside, avoids disconnection from the ventilator, and can be used to obtain both the inspiratory and the deflation limbs of the pressure-volume curve. Use of regression techniques improves determination of inflection points.

Effects of melatonin in an experimental model of ventilator-induced lung injury

Melatonin is a free radical scavenger and a broad-spectrum antioxidant and has well-documented immunomodulatory effects. We studied the effects of this hormone on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Swiss mice (n = 48). Animals were randomized into three experimental groups: control (not ventilated); low-pressure ventilation [peak inspiratory pressure 15 cmH(2)O, positive end-expiratory pressure (PEEP) 2 cmH(2)O], and high-pressure ventilation (peak inspiratory pressure 25 cmH(2)O, PEEP 0 cmH(2)O). Each group was divided into two subgroups: eight animals were treated with melatonin (10 mg/kg ip, 30 min before the onset of ventilation) and the remaining eight with vehicle. After 2 h of ventilation, lung injury was evaluated by gas exchange, wet-to-dry weight ratio, and histological analysis. Levels of malondialdehyde, glutathione peroxidase, interleukins IL-1beta, IL-6, TNF-alpha, and IL-10, and matrix metalloproteinases 2 and 9 in lung tissue were measured as indicators of oxidation status, pro-/anti-inflammatory cytokines, and matrix turnover, respectively. Ventilation with high pressures induced severe lung damage and release of TNF-alpha, IL-6, and matrix metalloproteinase-9. Treatment with melatonin improved oxygenation and decreased histological lung injury but significantly increased oxidative stress quantified by malondialdehyde levels. There were no differences in TNF-alpha, IL-1beta, IL-6, or matrix metalloproteinases caused by melatonin treatment, but IL-10 levels were significantly higher in treated animals. These results suggest that melatonin decreases VILI by increasing the anti-inflammatory response despite an unexpected increase in oxidative stress.

Comparative study of four sigmoid models of pressure-volume curve in acute lung injury

BackgroundThe pressure-volume curve of the respiratory system is a tool to monitor and set mechanical ventilation in acute lung injury. Mathematical models of the static pressure-volume curve of the respiratory system have been proposed to overcome the inter- and intra-observer variability derived from eye-fitting. However, different models have not been compared.MethodsThe goodness-of-fit and the values of derived parameters (upper asymptote, maximum compliance and points of maximum curvature) in four sigmoid models were compared, using pressure-volume data from 30 mechanically ventilated patients during the early phase of acute lung injury.ResultsAll models showed an excellent goodness-of-fit (R2 always above 0.92). There were significant differences between the models in the parameters derived from the inspiratory limb, but not in those derived from the expiratory limb of the curve. The within-case standard deviations of the pressures at the points of maximum curvature ranged from 2.33 to 6.08 cmH2O.ConclusionThere are substantial variabilities in relevant parameters obtained from the four different models of the static pressure-volume curve of the respiratory system.

Predicting the probability of survival in intensive care unit patients from a small number of variables and training examples

OBJECTIVE Survival probability predictions in critically ill patients are mainly used to measure the efficacy of intensive care unit (ICU) treatment. The available models are functions induced from data on thousands of patients. Eventually, some of the variables used for these purposes are not part of the clinical routine, and may not be registered in some patients. In this paper, we propose a new method to build scoring functions able to make reliable predictions, though functions whose induction only requires records from a small set of patients described by a few variables. METHODS We present a learning method based on the use of support vector machines (SVM), and a detailed study of its prediction performance, in different contexts, of groups of variables defined according to the source of information: monitoring devices, laboratory findings, and demographic and diagnostic features. RESULTS We employed a data set collected in general ICUs at 10 units of hospitals in Spain, 6 of which include coronary patients, while the other 4 do not treat coronary diseases. The total number of patients considered in our study was 2501, 19.83% of whom did not survive. Using these data, we report a comparison between the SVM method proposed here with other approaches based on logistic regression (LR), including a second-level recalibration of release III of the acute physiology and chronic health evaluation (APACHE, a scoring system commonly used in ICUs) induced from the available data. The SVM method significantly outperforms them all from a statistical point of view. Comparison with the commercial version of APACHE III shows that the SVM scores are slightly better when working with data sets of more than 500 patients. CONCLUSIONS From a practical point of view, the implications of the research reported here may be helpful to address the construction of cheap and reliable prediction systems in accordance with the peculiarities of ICUs and kinds of patients.

Respuesta inflamatoria y apoptosis en la lesión pulmonar aguda

One of the principal mechanisms of pulmonary injury in acute respiratory distress is due to the effects of the precipitated inflammatory response. The damage produced to the alveolar epithelium and underlying endothelium depends on the sequestration and activation of inflammatory cells, which in turn exert their actions through mediators. On the other hand, apoptosis is a mechanism responsible for epithelial damage and regulation of inflammation. Response of the lung tissue subjected to mechanical ventilation stimulus is added to the previous mechanisms. All these processes flow into a series of common pathways of cellular activation. Knowledge of these mechanisms could serve to identify which patients would benefit from a specific treatment before applying therapies that act indiscriminately in the inflammatory response.

Diagnóstico de muerte encefálica mediante tomografia computarizada multicorte : angio-TC y perfusión cérébral

BD was diagnosed by clinical examination, electroencephalogram (EEG), Transcranial Doppler (TCD) and multislice CT of 64 detectors. Initially, a brain perfusion study was performed. This was followed by supra-aortic trunk and brain artery angiography with acquisition of images using 0.5 mm slices, from the origin of the aortic root to the vertex. In all the patients, BD diagnosis was verified by clinical examination, EEG and TCD. Brain perfusion never detected brain blood flow. The angioCT through internal carotid arteries and vertebral arteries demonstrated complete absence of intracranial circulation, observing circulation of the external carotid artery branches. Sensitivity and specificity of the method compared with clinical examination was 100%. These findings demonstrate that the study of brain perfusion and brain angiography by multislice CT scan is a rapid and minimally invasive technique, that is easily available and that shows the absence of brain blood flow through the four vascular trunks. This technique makes it possible to made the diagnosis of BD with high diagnostic safety. Its use has special interest in patients with clinical diagnostic difficulty due to treatment with sedative drugs and serious metabolic alterations.BD was diagnosed by clinical examination, electroencephalogram (EEG), Transcranial Doppler (TCD) and multislice CT of 64 detectors. Initially, a brain perfusion study was performed. This was followed by supra-aortic trunk and brain artery angiography with acquisition of images using 0.5 mm slices, from the origin of the aortic root to the vertex. In all the patients, BD diagnosis was verified by clinical examination, EEG and TCD. Brain perfusion never detected brain blood flow. The angioCT through internal carotid arteries and vertebral arteries demonstrated complete absence of intracranial circulation, observing circulation of the external carotid artery branches. Sensitivity and specificity of the method compared with clinical examination was 100%. These findings demonstrate that the study of brain perfusion and brain angiography by multislice CT scan is a rapid and minimally invasive technique, that is easily available and that shows the absence of brain blood flow through the four vascular trunks. This technique makes it possible to made the diagnosis of BD with high diagnostic safety. Its use has special interest in patients with clinical diagnostic difficulty due to treatment with sedative drugs and serious metabolic alterations.

Tratamiento endovascular y trombólisis intraarterial en el ictus isquémico agudo

OBJECTIVE Analysis of the safety and efficacy of intra-arterial thrombolysis therapy and endovascular treatment in acute ischemic stroke. DESIGN AND AREA: An observational prospective study in the Intensive Care Unit. PATIENTS AND METHODS 16 patients had endovascular treatment. Epidemiological data, arterial occlusion site, time between stroke onset and treatment, treatment indication, NIHSS scale at admission and discharge from hospital, complications and functional outcome measured by modified Rankin scale (obtained by telephone survey) were collected. RESULTS Ten male patients with a mean age of 59 years (29-74) were included. The mean stay in the ICU was 6 days (1-33). Seven patients required mechanical ventilation. Treatment indications were: intravenous thrombolysis failure in 4 patients, major vessel occlusion in 5, outside of the therapeutic window in 2, posterior circulation occlusion in 3, outside of the therapeutic window plus major vessel occlusion in 1 and intravenous thrombolysis contraindication in 1. The occlusion site was on posterior circulation in 3 and on carotid territories and branches in 13. Thrombolytic treatment used was Urokinase at a dose of 100,000-600,000IU. Four patients required mechanical embolectomy and 10 stent implantation. Complete recanalization was observed in 11 (69%) and partial in 4 (25%). Three evolved to brain death. Six patients (46%) had a favorable outcome (modified Rankin scale score ≤ 2). Technical complication was 1 femoral artery pseudoaneurysm. CONCLUSIONS With the intra-arterial treatment, high rates of recanalization and favorable outcome are obtained with few complications. It could be indicated in patients with severe neurological injury (NIHSS ≥ 10), evolution time between 3-6h, intravenous thrombolysis contraindication and proximal arterial occlusion.