Gisella Borzone

Breathing pattern and gas exchange at peak exercise in COPD patients with and without tidal flow limitation at rest

Expiratory flow limitation (FL) at rest is frequently present in chronic obstructive pulmonary disease (COPD) patients. It promotes dynamic hyperinflation with a consequent decrease in inspiratory capacity (IC). Since in COPD resting IC is strongly correlated with exercise tolerance, this study hypothesized that this is due to limitation of the maximal tidal volume (VT,max) during exercise by the reduced IC. The present study investigated the role of tidal FL at rest on: 1) the relationship of resting IC to VT,max; and 2) on gas exchange during peak exercise in COPD patients. Fifty-two stable COPD patients were studied at rest, using the negative expiratory pressure technique to assess the presence of FL, and during incremental symptom-limited cycling exercise to evaluate exercise performance. At rest, FL was present in 29 patients. In the 52 patients, a close relationship of VT,max to IC was found using non-normalized values (r=0.77; p < 0.0001), and stepwise regression analysis selected IC as the only significant predictor of VT,max. Subgroup analysis showed that this was also the case for patients both with and without FL (r=0.70 and 0.76, respectively). In addition, in FL patients there was an increase (p < 0.002) in arterial carbon dioxide partial pressure at peak exercise, mainly due to a relatively low VT,max and consequent increase in the physiological dead space (VD)/VT ratio. The arterial oxygen partial pressure also decreased at peak exercise in the FL patients (p < 0.05). In conclusion, in chronic obstructive pulmonary disease patients the maximal tidal volume, and hence maximal oxygen consumption, are closely related to the reduced inspiratory capacity. The flow limited patients also exhibit a significant increase in arterial carbon dioxide partial pressure and a decrease in arterial oxygen partial pressure during peak exercise.

Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation

IntroductionWhen 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.MethodsA 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 (VT) = 10 ml/kg and positive end-expiratory pressure (PEEP) = 3 cmH2O (VT10/PEEP3); and 2) VT = 20 ml/kg and PEEP = 0 cmH2O (VT20/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.ResultsAtelectasis 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 cm3. 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 VT20/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-1β and cytokine-induced neutrophil chemoattractant-1 between regions.ConclusionsThe 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.

Gestational diabetes and pre‐pregnancy overweight: Possible factors involved in newborn macrosomia

Aim:  Good glycemic control in gestational diabetes mellitus (GDM) seems not to be enough to prevent macrosomia (large‐for‐gestational‐age newborns). In GDM pregnancies we studied the effects of glycemic control (as glycosylated hemoglobin [HbA1c]), pre‐pregnancy body mass index (PP‐BMI) and gestational weight gain per week (GWG‐W) on the frequency of macrosomia.

Maternal hypertriglyceridemia: A link between maternal overweight-obesity and macrosomia in gestational diabetes

Infants born from overweight and obese mothers with glucose‐controlled gestational diabetes (GDM) tend to be large‐for‐gestational age (LGA). It is hypothesized that this is due to an excessive rise in maternal triglyceride levels.

Differences in lung glutathione metabolism may account for rodent susceptibility in elastase-induced emphysema development

Syrian Golden hamsters develop more severe emphysema than Sprague-Dawley rats after intratracheal instillation of the same dose of elastase/body weight. Although species variations in antielastase defenses may largely explain these results, other variables, such as differences in lung antioxidants, cannot be overlooked since oxidative stress modulates antiprotease activity. We propose that elastase instillation might affect lung glutathione (GSH) metabolism differently in these species. Our aim was to study in hamsters and rats, lung glutathione metabolism at different times, from the stage of diffuse alveolar damage to advanced emphysema. We measured total and oxidized glutathione content as well as activity and expression of enzymes related to GSH synthesis and redox cycling: gamma-glutamylcysteine synthetase, glutathione peroxidase, and glutathione reductase. Whereas rats showed no significant changes in these measurements, hamsters showed significant derangement in GSH metabolism early after elastase instillation: 25% fall in total GSH (P < 0.05) with no increase in oxidized glutathione associated with reduced enzyme activities 24 h after elastase [60% for gamma-glutamylcysteine synthetase (P < 0.01), 30% for glutathione peroxidase (P < 0.01), and 75% for glutathione reductase (P < 0.001)]. GSH homeostasis was restored at the end of the first week, involving transient increased expression of these enzymes. We conclude that elastase induces significant alterations in GSH metabolism of hamster lungs and no overall change in rat lungs. Although differences in disease severity may account for our findings, the hamster becomes vulnerable to functional inhibition of alpha(1)-antitrypsin by oxidants and thus, even more susceptible to injury than it would be, considering only its low alpha(1)-antitrypsin level.

Limitaciones de la técnica de determinación de peróxido de hidrógeno en el condensado del aire espirado de pacientes con síndrome de distrés respiratorio del adulto

Objetivo: El condensado del aire espirado es una alternativa al lavado broncoalveolar para estudiar marcadores de inflamacion y estres oxidativo en pacientes con sindrome de distres respiratorio del adulto (SDRA). Sin embargo, el estudio del peroxido de hidrogeno (H2O2) ofrece resultados variables que no se relacionan con la gravedad del cuadro clinico. El objetivo del presente estudio ha sido identificar las posibles limitaciones de la tecnica mas utilizada para medir el H2O2 en condensado que expliquen esta variabilidad. Pacientes y metodos: Se analizaron muestras seriadas de condensado de la via espiratoria del ventilador de 6 pacientes con SDRA mediante la tecnica de Gallati (lineal entre 0,3-10 µM, r = 0,99; p < 0,05) para H2O2. Resultados: El volumen de condensado se relaciono con la ventilacion minuto (r = 0,96; p < 0,05). En 11 de 23 muestras se obtuvo lectura a 450 nm sin el color caracteristico de la reaccion y en algunas se obtuvo tambien lectura espontanea indicativa de contaminantes. El espectro de absorcion de estas muestras no mostro el pico caracteristico del H2O2 a 450 nm y el pretratamiento de algunas muestras con catalasa no modifico la absorbancia a 450 nm. Conclusiones: El metodo espectrofotometrico frecuentemente empleado para medir el H2O2 en condensado es inespecifico en el SDRA por la presencia en las muestras de cantidades variables de contaminantes que determinan falsos positivos.

Differences in acute lung response to elastase instillation in two rodent species may determine differences in severity of emphysema development

Elastase intratracheal instillation induces early emphysema in rodents. However, Syrian Golden hamsters develop more severe emphysema than Sprague-Dawley rats. We have reported species differences in oxidant/antioxidant balance modulating antiprotease function early after instillation. We now hypothesize that other components of the initial lung response to elastase might also be species-dependent. Sprague-Dawley rats and Syrian Golden hamsters received a single dose of pancreatic elastase (0.55 U/100 g body wt) to study acute lung injury biomarkers. Using serum, lung, and bronchoalveolar lavage fluid (BALF) samples, we evaluated changes in alveolar-capillary permeability, alpha 1-antitrypsin (α(1)-AT) concentration and activity, glutathione content, and proinflammatory cytokines. Rats showed a large increase in alveolar-capillary permeability and few hemorrhagic changes, whereas hamsters exhibited large hemorrhagic changes (P < 0.01) and mild transendothelial passage of proteins. Western blots showed a 30-fold increase in BALF α(1)-AT concentration in rats and only a 7-fold increase in hamsters (P < 0.001), with [α(1)-AT-elastase] complexes only in rats, suggesting differences in antiprotease function. This was confirmed by the α(1)-AT bioassay showing 20-fold increase in α(1)-AT activity in rats and only twofold increase in hamsters (P < 0.001). In rats, results were preceded by a 3-, 60-, and 20-fold increase in IL-6, IL-1β, and TNF-α respectively (P < 0.001). In hamsters, only IL-1β and TNF-α showed mild increases. All parameters studied were back to baseline by 4 days. In conclusion, several components of the initial lung response showed species differences. Cytokine release pattern and functional inhibition of α(1)-AT were the most significant components differing among species and could account for differences in susceptibility to elastase.

Limitations of the Technique to Determine Hydrogen Peroxide Levels in Exhaled Breath Condensate From Patients With Adult Respiratory Distress Syndrome

OBJECTIVE Exhaled breath condensate represents an alternative to bronchoalveolar lavage for the analysis of markers of inflammation and oxidative stress in patients with adult respiratory distress syndrome (ARDS). However, analysis of hydrogen peroxide (H2O2) yields variable results that do not correlate with severity of the clinical presentation. In an attempt to explain this variability, the aim of the present study was to assess the possible limitations of the most commonly used technique for analyzing H2O2 in breath condensate. PATIENTS AND METHODS H2O2 levels were analyzed using the Gallati technique (linear range between 0.3 and 10 microM, r=0.99; P<.05) in serial samples of condensate taken from the expiratory tube of a mechanical ventilator in 6 patients with ARDS. RESULTS The volume of condensate obtained correlated to minute ventilation (r=0.96; P<.05). In 11 out of 23 samples, a spectrophotometer reading was obtained at 450 nm despite the absence of the characteristic color of the reaction and in some of these samples a spontaneous reading was obtained that was indicative of contamination. The absorbance spectrum of these samples did not contain the characteristic peak for H2O2 at 450 nm and pretreatment of some samples with catalase did not affect the absorbance at 450 nm. CONCLUSIONS The spectrophotometric method commonly used to measure H2O2 levels in breath condensate lacks specificity in ARDS due to the presence of variable levels of contaminants in the samples, which lead to false positives.

Reference Values for Inspiratory Capacity in Healthy Nonsmokers Over Age 50 Years

OBJECTIVE The role of dynamic hyperinflation in triggering dyspnea and limiting exercise capacity in patients with chronic obstructive pulmonary disease has been recognized in recent years. The degree of dynamic hyperinflation can be assessed by measuring reduction in inspiratory capacity (IC). The aim of this study was to establish reference values for IC in healthy individuals of both sexes between the ages of 50 and 87 years, as such data are scarce in the literature. SUBJECTS AND METHODS We studied 155 healthy volunteers (93 women) with normal spirometry. None had a prior history of respiratory, cardiovascular, or systemic diseases that might alter lung function. All were never-smokers. IC was measured during a normal, unforced inspiration to total lung capacity starting from functional residual capacity. The highest value of 6 satisfactory maneuvers was recorded. Sex, height, age, and weight were included in the regression equations. One thousand bootstrap samples for each sex were also analyzed. RESULTS For each sex, we found that a model including age, height, and weight produced IC prediction equations with a coefficient of determination (r2) of 0.414 for women and 0.447 for men. The mean (SD) intrasubject coefficient of variation was 4.3% (2%) for IC measured during a single session and 5.1% (0.4%) for measurements from 5 weekly sessions. CONCLUSIONS Our results provide reference equations for IC that are valid for a healthy population over 50 years of age. Predicted values were similar to those recently obtained in an Italian population aged between 65 and 85 years.

In silico evaluation of a control system and algorithm for automated insulin infusion in the ICU setting.

BackgroundIt 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.MethodsThe 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.ResultsThe 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.ConclusionsWhen 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.