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Background Gastric contents aspiration is a high-risk condition for acute lung injury (ALI). Consequences range from subclinical pneumonitis to respiratory failure, depending on the volume of aspirate. A large increment in inflammatory cells, an important source of elastase, potentially capable of damaging lung tissue, has been described in experimental models of aspiration. We hypothesized that in early stages of aspiration-induced ALI, there is proteolytic degradation of elastin, preceding collagen deposition. Our aim was to evaluate whether after a single orotracheal instillation of gastric fluid, there is evidence of elastin degradation. Methods Anesthesized Sprague-Dawley rats received a single orotracheal instillation of gastric fluid and were euthanized 4, 12 and 24 h and at day 4 after instillation ( n  = 6/group). We used immunodetection of soluble elastin in lung tissue and BALF and correlated BALF levels of elastin degradation products with markers of ALI. We investigated possible factors involved in elastin degradation and evaluated whether a similar pattern of elastin degradation can be found in BALF samples of patients with interstitial lung diseases known to have aspirated. Non-parametric ANOVA (Kruskall-Wallis) and linear regression analysis were used. Results We found evidence of early proteolytic degradation of lung elastin. Elastin degradation products are detected both in lung tissue and BALF in the first 24 h and are significantly reduced at day 4. They correlate significantly with ALI markers, particularly PMN cell count, are independent of acidity and have a similar molecular weight as those obtained using pancreatic elastase. Evaluation of BALF from patients revealed the presence of elastin degradation products not present in controls that are similar to those found in BALF of rats treated with gastric fluid. Conclusions A single instillation of gastric fluid into the lungs induces early proteolytic degradation of elastin, in relation to the magnitude of alveolar-capillary barrier derangement. PMN-derived proteases released during ALI are mostly responsible for this damage. BALF from patients showed elastin degradation products similar to those found in rats treated with gastric fluid. Long-lasting effects on lung elastic properties could be expected under conditions of repeated instillations of gastric fluid in experimental animals or repeated aspiration events in humans.

Background Gastric contents aspiration in humans has variable consequences depending on the volume of aspirate, ranging from subclinical pneumonitis to respiratory failure with up to 70% mortality. Several experimental approaches have been used to study this condition. In a model of single orotracheal instillation of gastric fluid we have shown that severe acute lung injury evolves from a pattern of diffuse alveolar damage to one of organizing pneumonia (OP), that later resolves leaving normal lung architecture. Little is known about mechanisms of injury resolution after a single aspiration that could be dysregulated with repetitive aspirations. We hypothesized that, in a similar way to cutaneous wound healing, apoptosis may participate in lung injury resolution by reducing the number of myofibroblasts and by affecting the balance between proteases and antiproteases. Our aim was to study activation of apoptosis as well as MMP-2/TIMP-2 balance in the sub-acute phase (4–14 days) of gastric fluid-induced lung injury. Methods Anesthesized Sprague-Dawley rats received a single orotracheal instillation of gastric fluid and were euthanized 4, 7 and 14 days later ( n  = 6/group). In lung tissue we studied caspase-3 activation and its location by double immunofluorescence for cleaved caspase-3 or TUNEL and alpha-SMA. MMP-2/TIMP-2 balance was studied by zymography and Western blot. BALF levels of TGF-β 1 were measured by ELISA. Results An OP pattern with Masson bodies and granulomas was seen at days 4 and 7 that was no longer present at day 14. Cleaved caspase-3 increased at day 7 and was detected by immunofluorescence in Masson body-alpha-SMA-positive and –negative cells. TUNEL-positive cells at days 4 and 7 were located mainly in Masson bodies. Distribution of cleaved caspase-3 and TUNEL-positive cells at day 14 was similar to that in controls. At the peak of apoptosis (day 7), an imbalance between MMP-2 activity and TIMP-2 expression was produced by reduction in TIMP-2 expression. Conclusions Apoptosis is activated in Masson body-alpha-SMA–positive and –negative cells during the sub-acute phase of gastric fluid-induced lung injury. This mechanism likely contributes to OP resolution, by reducing myofibroblast number and new collagen production. In addition, pre-formed collagen degradation is favored by an associated MMP-2/TIMP-2 imbalance.

There is wide variability in mechanical ventilation settings during extracorporeal membrane oxygenation (ECMO) in patients with acute respiratory distress syndrome. Although lung rest is recommended to prevent further injury, there is no evidence to support it. To determine whether near-apneic ventilation decreases lung injury in a pig model of acute respiratory distress syndrome supported with ECMO. Pigs (26-36 kg; n = 24) were anesthetized and connected to mechanical ventilation. In 18 animals lung injury was induced by a double-hit consisting of repeated saline lavages followed by 2 hours of injurious ventilation. Then, animals were connected to high-flow venovenous ECMO, and randomized into three groups: 1) nonprotective (positive end-expiratory pressure [PEEP], 5 cm H O; Vt, 10 ml/kg; respiratory rate, 20 bpm), 2) conventional-protective (PEEP, 10 cm H O; Vt, 6 ml/kg; respiratory rate, 20 bpm), and 3) near-apneic (PEEP, 10 cm H O; driving pressure, 10 cm H O; respiratory rate, 5 bpm). Six other pigs were used as sham. All groups were maintained during the 24-hour study period. Minute ventilation and mechanical power were lower in the near-apneic group, but no differences were observed in oxygenation or compliance. Lung histology revealed less injury in the near-apneic group. Extensive immunohistochemical staining for myofibroblasts and procollagen III was observed in the nonprotective group, with the near-apneic group exhibiting the least alterations. Near-apneic group showed significantly less matrix metalloproteinase-2 and -9 activity. Histologic lung injury and fibroproliferation scores were positively correlated with driving pressure and mechanical power. In an acute respiratory distress syndrome model supported with ECMO, near-apneic ventilation decreased histologic lung injury and matrix metalloproteinase activity, and prevented the expression of myofibroblast markers.

One important variable influencing day-to-day decisions in COVID-19 pandemic has been an impending shortage of mechanical ventilators due to the large number of people that become infected with the virus due to its high contagiousness. We developed a stepwise Markov model (a) to make a short-term prediction of the number of patients on ventilator, and (b) to determine a possible date for a ventilator crisis.Starting with the exponential curve of new cases in the previous 14 days, we calculated a Markov model every 5 days thereafter, resulting in a daily estimate of patients on ventilator for the following 25 days, which we compared with the daily number of devices in use to predict a date for ventilator crisis.During the modeled period, the observed and predicted Markov curves of patients on ventilator were very similar, a finding confirmed by both linear regression (r=0.984; p<0.0001) and the near coincidence with the identity line. Our model estimated ventilator shortage in Chile for June 1st, if the number of devices had remained stable. However, the crisis did not occur due to acquisition of new ventilators by the Ministry of Health.In Chile as in many other countries experiencing several asynchronous local peaks of COVID-19, the stepwise Markov model could become a useful tool for predicting the date of mechanical ventilator crisis. We propose that our model could help health authorities to: (a) establish a better ventilator distribution strategy and (b) be ready to reinstate restrictions only when necessary so as not to paralyze the economy as much.

Background It is known that tight control of glucose in the Intensive Care Unit reduces morbidity and mortality not only in diabetic patients but also in those non-diabetics who become transiently hyperglycemic. Taking advantage of a recently marketed subcutaneous glucose sensor we designed an Automatic Insulin Infusion System (AIIS) for inpatient treatment, and tested its stability under simulated clinical conditions. Methods The system included: reference glucose, glucose sensor, insulin and glucose infusion controllers and emergency infusion logic. We carried out computer simulations using Matlab/Simulink ® , in both common and worst-case conditions. Results The system was capable of controlling glucose levels without entering in a phase of catastrophic instability, even under severe simulated challenges. Care was taken to include in all simulations the 5-10 minute delay of the subcutaneous glucose signal when compared to the real-time serum glucose signal, a well-known characteristic of all subcutaneous glucose sensors. Conclusions When tested in-Silico , a commercially available subcutaneous glucose sensor allowed the stable functioning of a proportional-derivative Automatic Insulin Infusion System, which was able to maintain glucose within acceptable limits when using a well-established glucose response model simulating a patient. Testing of the system in vivo using animal models is now warranted.

To measure the impact of a “Preventive Letter” designed to encourage the return of gestational diabetes mellitus (GDM) mothers to follow up visit after delivery, in the context of a worldwide concern about low return rates after delivery of these patients. Mothers with GDM require medical evaluation and an oral glucose tolerance test (OGTT) 6 weeks after delivery, in order to: [a] confirm remission of GDM and [b] provide advice on the prevention of type 2 diabetes. In the year 2003 we developed a “Preventive Letter”, containing three aspects: [a] current treatment, [b] suggested management during labor, and [c] a stapled laboratory order for OGTT to be performed 6 weeks after delivery. The return rate after delivery was assessed in two groups of GDM mothers: [a] “Without Preventive Letter” (n = 253), and “With Preventive Letter” (n = 215). Both groups, similar with respect to age (33.0 ± 5.4 and 32.3 ± 4.9 years respectively, p  = 0.166) and education time (14.9 ± 1.8 and 15.0 ± 1.8 years respectively, p  = 0.494), showed a significant difference in the 1-year return rate after delivery, as assessed by the Kaplan–Meier test: 32.0 % for the group “Without Preventive Letter”, and 76.0 % for the group “With Preventive Letter” ( p  < 0.001). The 1-year return rate after delivery of GDM mothers was 2.4 times higher in the group “With Preventive Letter” than in the group without it. We believe that this low-cost approach could be useful in other institutions caring for pregnant women with diabetes.

It is recognized that respiratory muscle dysfunction due to excessive respiratory muscle loading may contribute to the development of ventilatory failure in patients with cardiopulmonary disease. Injury of the muscles through oxidant stress induced by excessive contractile activity is one of the postulated mechanisms of respiratory muscle dysfunction. First, the main antioxidant defense systems of the rat diaphragm and intercostal muscles were characterized. Second, the response of these systems to increased loads was studied in a model of incremental inspiratory resistive loading in vivo, and third, electron spin resonance spectroscopy was used to directly detect the presence of free radical species in the diaphragm following the experimental protocol. The physiologic responses together with the status of the high-energy phosphate compounds were characterized and correlated to the changes in the antioxidant systems. The respiratory muscles were found to be well protected with a variety of antioxidant systems. The diaphragm was found to have a larger antioxidant defense system than the intercostal muscles, largely in relation to the oxidative capacity. Increased free radical generation associated with a decrease in total glutathione without an increase in oxidized glutathione are the major findings in this model, in which the high-energy phosphates are well preserved. The increase in free radical production was found to correlate with the intensity of respiratory muscle activity, while changes in glutathione correlated with the degree of acidosis, hypoventilation and CO$\\sb2$ retention, and did not show correlation with the level of respiratory muscle activity.