Matteo Parotto

Mechanical stress induces lung fibrosis by epithelial–mesenchymal transition*

Objectives: Many mechanically ventilated patients with acute respiratory distress syndrome develop pulmonary fibrosis. Stresses induced by mechanical ventilation may explain the development of fibrosis by a number of mechanisms (e.g., damage the alveolar epithelium, biotrauma). The objective of this study was t test the hypothesis that mechanical ventilation plays an important role in the pathogenesis of lung fibrosis. Methods: C57BL/6 mice were randomized into four groups: healthy controls; hydrochloric acid aspiration alone; vehicle control solution followed 24 hrs later by mechanical ventilation (peak inspiratory pressure 22 cm H2O and positive end-expiratory pressure 2 cm H2O for 2 hrs); and acid aspiration followed 24 hrs later by mechanical ventilation. The animals were monitored for up to 15 days after acid aspiration. To explore the direct effects of mechanical stress on lung fibrotic formation, human lung epithelial cells (BEAS-2B) were exposed to mechanical stretch for up to 48 hrs. Measurement and Main Results: Impaired lung mechanics after mechanical ventilation was associated with increased lung hydroxyproline content, and increased expression of transforming growth factor-&bgr;, &bgr;-catenin, and mesenchymal markers (&agr;-smooth muscle actin and vimentin) at both the gene and protein levels. Expression of epithelial markers including cytokeratin-8, E-cadherin, and prosurfactant protein B decreased. Lung histology demonstrated fibrosis formation and potential epithelia–mesenchymal transition. In vitro direct mechanical stretch of BEAS-2B cells resulted in similar fibrotic and epithelia–mesenchymal transition formation. Conclusions: Mechanical stress induces lung fibrosis, and epithelia–mesenchymal transition may play an important role in mediating the ventilator-induced lung fibrosis.

Mechanical ventilation-associated lung fibrosis in acute respiratory distress syndrome: a significant contributor to poor outcome.

One of the most challenging problems in critical care medicine is the management of patients with the acute respiratory distress syndrome. Increasing evidence from experimental and clinical studies suggests that mechanical ventilation, which is necessary for life support in patients with acute respiratory distress syndrome, can cause lung fibrosis, which may significantly contribute to morbidity and mortality. The role of mechanical stress as an inciting factor for lung fibrosis versus its role in lung homeostasis and the restoration of normal pulmonary parenchymal architecture is poorly understood. In this review, the authors explore recent advances in the field of pulmonary fibrosis in the context of acute respiratory distress syndrome, concentrating on its relevance to the practice of mechanical ventilation, as commonly applied by anesthetists and intensivists. The authors focus the discussion on the thesis that mechanical ventilation—or more specifically, that ventilator-induced lung injury—may be a major contributor to lung fibrosis. The authors critically appraise possible mechanisms underlying the mechanical stress–induced lung fibrosis and highlight potential therapeutic strategies to mitigate this fibrosis.

Circadian rhythms: From basic mechanisms to the intensive care unit

Objective:Circadian rhythms are intrinsic timekeeping mechanisms that allow for adaptation to cyclic environmental changes. Increasing evidence suggests that circadian rhythms may influence progression of a variety of diseases as well as effectiveness and toxicity of drugs commonly used in the intensive care unit. In this perspective, we provide a brief review of the molecular mechanisms of circadian rhythms and its relevance to critical care. Data Sources, Study Selection, Data Extraction, and Data Synthesis:Articles related to circadian rhythms and organ systems in normal and disease conditions were searched through the PubMed library with the goal of providing a concise review. Conclusions:Critically ill patients may be highly vulnerable to disruption of circadian rhythms as a result of the severity of their underlying diseases as well as the intensive care unit environment where noise and frequent therapeutic/diagnostic interventions take place. Further basic and clinical research addressing the importance of circadian rhythms in the context of critical care is warranted to develop a better understanding of the complex pathophysiology of critically ill patients as well as to identify novel therapeutic approaches for these patients.

The Essential Autophagy Gene ATG7 Modulates Organ Fibrosis via Regulation of Endothelial-to-Mesenchymal Transition

Background: Endothelial-to-mesenchymal transition (EndMT) is implicated in the development of organ fibrosis. Results: Loss of the autophagy gene ATG7 promotes EndMT and up-regulates TGFβ signaling and the associated pro-fibrotic genes. Endothelial-specific ATG7 knock-out mice exhibited increased bleomycin-induced pulmonary fibrosis. Conclusion: ATG7 is a novel regulator of EndMT-induced organ fibrosis. Significance: Intact endothelial autophagy prevents aberrant EndMT and represents a potential target to limit organ fibrosis. Pulmonary fibrosis is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix components. Although the origin of fibroblasts is multifactorial, recent data implicate endothelial-to-mesenchymal transition as an important source of fibroblasts. We report herein that loss of the essential autophagy gene ATG7 in endothelial cells (ECs) leads to impaired autophagic flux accompanied by marked changes in EC architecture, loss of endothelial, and gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition. Loss of ATG7 also up-regulates TGFβ signaling and key pro-fibrotic genes in vitro. In vivo, EC-specific ATG7 knock-out mice exhibit a basal reduction in endothelial-specific markers and demonstrate an increased susceptibility to bleomycin-induced pulmonary fibrosis and collagen accumulation. Our findings help define the role of endothelial autophagy as a potential therapeutic target to limit organ fibrosis, a condition for which presently there are no effective available treatments.

Volatile Anesthetics. Is a New Player Emerging in Critical Care Sedation

Volatile anesthetic agent use in the intensive care unit, aided by technological advances, has become more accessible to critical care physicians. With increasing concern over adverse patient consequences associated with our current sedation practice, there is growing interest to find non-benzodiazepine-based alternative sedatives. Research has demonstrated that volatile-based sedation may provide superior awakening and extubation times in comparison with current intravenous sedation agents (propofol and benzodiazepines). Volatile agents may possess important end-organ protective properties mediated via cytoprotective and antiinflammatory mechanisms. However, like all sedatives, volatile agents are capable of deeply sedating patients, which can have respiratory depressant effects and reduce patient mobility. This review seeks to critically appraise current volatile use in critical care medicine including current research, technical consideration of their use, contraindications, areas of controversy, and proposed future research topics.

Safety and Efficacy of Volatile Anesthetic Agents Compared With Standard Intravenous Midazolam/propofol Sedation in Ventilated Critical Care Patients: A Meta-analysis and Systematic Review of Prospective Trials.

BACKGROUND: Inhalation agents are being used in place of intravenous agents to provide sedation in some intensive care units. We performed a systematic review and meta-analysis of prospective randomized controlled trials, which compared the use of volatile agents versus intravenous midazolam or propofol in critical care units. METHODS: A search was conducted using MEDLINE (1946–2015), EMBASE (1947–2015), Web of Science index (1900–2015), and Cochrane Central Register of Controlled Trials. Eligible studies included randomized controlled trials comparing inhaled volatile (desflurane, sevoflurane, and isoflurane) sedation to intravenous midazolam or propofol. Primary outcome assessed the effect of volatile-based sedation on extubation times (time between discontinuing sedation and tracheal extubation). Secondary outcomes included time to obey verbal commands, proportion of time spent in target sedation, nausea and vomiting, mortality, length of intensive care unit, and length of hospital stay. Heterogeneity was assessed using the I2 statistic. Outcomes were assessed using a random or fixed-effects model depending on heterogeneity. RESULTS: Eight trials with 523 patients comparing all volatile agents with intravenous midazolam or propofol showed a reduction in extubation times using volatile agents (difference in means, −52.7 minutes; 95% confidence interval [CI], −75.1 to −30.3; P < .00001). Reductions in extubation time were greater when comparing volatiles with midazolam (difference in means, −292.2 minutes; 95% CI, −384.4 to −200.1; P < .00001) than propofol (difference in means, −29.1 minutes; 95% CI, −46.7 to −11.4; P = .001). There was no significant difference in time to obey verbal commands, proportion of time spent in target sedation, adverse events, death, or length of hospital stay. CONCLUSIONS: Volatile-based sedation demonstrates a reduction in time to extubation, with no increase in short-term adverse outcomes. Marked study heterogeneity was present, and the results show marked positive publication bias. However, a reduction in extubation time was still evident after statistical correction of publication bias. Larger clinical trials are needed to further evaluate the role of these agents as sedatives for critically ill patients.

Cohort study of the depression, anxiety, and anhedonia components of the Edinburgh Postnatal Depression Scale after delivery

To investigate the applicability of the Edinburgh Postnatal Depression Scale (EPDS) for identifying depressive symptoms following vaginal or cesarean delivery.

Association of Rewarming Rate on Neonatal Outcomes in Extremely Low Birth Weight Infants with Hypothermia.

OBJECTIVE To explore the possible association between rewarming rate and neonatal outcomes in extremely low birth weight infants (ELBWIs) with hypothermia. STUDY DESIGN All ELBWIs with hypothermia (temperature < 36.0°C) on neonatal intensive care unit (NICU) admission were retrospectively evaluated. Rewarming rate was analyzed as both a dichotomous (≥ 0.5°C/h rapid group; < 0.5°C/h slow group) and a continuous variable. Multivariable analysis was performed to explore the relation between rewarming rate and several outcomes, adjusting for clinically relevant confounders. RESULTS Hypothermia on NICU admission was present in 182 out of 744 ELBWIs (24.5%). The rewarming rate was slow in 109 subjects (59.9%) and rapid in 73 subjects (40.1%), with a median rewarming rate of 0.29°C/h (IQR 0.2-0.35) and 0.76°C/h (IQR 0.61-1.09), respectively (P < .0001). The median rewarming time was 340 minutes (IQR 250-480) and 170 minutes (IQR 110-230), respectively (P < .0001). After adjusting for clinically relevant confounders, we did not find significant associations between rewarming rate group (≥ 0.5°C/h vs < 0.5°C/h) and neonatal outcomes. When we considered the rewarming rate as continuous variable, a higher rewarming rate was identified as a protective factor for respiratory distress syndrome (OR 0.39, 95% CI 0.17-0.87; P = .02). CONCLUSIONS In ELBWIs with hypothermia upon NICU admission, there were no significant differences between rapid or slow rewarming rate and major neonatal outcomes. A higher rewarming rate was associated with a reduced incidence of respiratory distress syndrome.

Inspiratory Muscle Rehabilitation in Critically Ill Adults. A Systematic Review and Meta-Analysis

Rationale: Respiratory muscle weakness is common in critically ill patients; the role of targeted inspiratory muscle training (IMT) in intensive care unit rehabilitation strategies remains poorly defined. Objectives: The primary objective of the present study was to describe the range and tolerability of published methods for IMT. The secondary objectives were to determine whether IMT improves respiratory muscle strength and clinical outcomes in critically ill patients. Methods: We conducted a systematic review to identify randomized and nonrandomized studies of physical rehabilitation interventions intended to strengthen the respiratory muscles in critically ill adults. We searched the MEDLINE, Embase, HealthSTAR, CINAHL, and CENTRAL databases (inception to September Week 3, 2017) and conference proceedings (2012 to 2017). Data were independently extracted by two authors and collected on a standardized report form. Results: A total of 28 studies (N = 1,185 patients) were included. IMT was initiated during early mechanical ventilation (8 studies), after patients proved difficult to wean (14 studies), or after extubation (3 studies), and 3 other studies did not report exact timing. Threshold loading was the most common technique; 13 studies employed strength training regimens, 11 studies employed endurance training regimens, and 4 could not be classified. IMT was feasible, and there were few adverse events during IMT sessions (nine studies; median, 0%; interquartile range, 0‐0%). In randomized trials (n = 20), IMT improved maximal inspiratory pressure compared with control (15 trials; mean increase, 6 cm H2O; 95% confidence interval [CI], 5‐8 cm H2O; pooled relative ratio of means, 1.19; 95% CI, 1.14‐1.25) and maximal expiratory pressure (4 trials; mean increase, 9 cm H2O; 95% CI, 5‐14 cm H2O). IMT was associated with a shorter duration of ventilation (nine trials; mean difference, 4.1 d; 95% CI, 0.8‐7.4 d) and a shorter duration of weaning (eight trials; mean difference, 2.3 d; 95% CI, 0.7‐4.0 d), but confidence in these pooled estimates was low owing to methodological limitations, including substantial statistical and methodological heterogeneity. Conclusions: Most studies of IMT in critically ill patients have employed inspiratory threshold loading. IMT is feasible and well tolerated in critically ill patients and improves both inspiratory and expiratory muscle strength. The impact of IMT on clinical outcomes requires future confirmation.

Evaluation of a low-cost, 3D-printed model for bronchoscopy training

BACKGROUND Flexible bronchoscopy is a fundamental procedure in anaesthesia and critical care medicine. Although learning this procedure is a complex task, the use of simulation-based training provides significant advantages, such as enhanced patient safety. Access to bronchoscopy simulators may be limited in low-resource settings. We have developed a low-cost 3D-printed bronchoscopy training model. METHODS A parametric airway model was obtained from an online medical model repository and fabricated using a low-cost 3D printer. The participating physicians had no prior bronchoscopy experience. Participants received a 30-minute lecture on flexible bronchoscopy and were administered a 15-item pre-test questionnaire on bronchoscopy. Afterwards, participants were instructed to perform a series of predetermined bronchoscopy tasks on the 3D printed simulator on 4 consecutive occasions. The time needed to perform the tasks and the quality of task performance (identification of bronchial anatomy, technique, dexterity, lack of trauma) were recorded. Upon completion of the simulator tests, participants were administered the 15-item questionnaire (post-test) once again. Participant satisfaction data on the perceived usefulness and accuracy of the 3D model were collected. A statistical analysis was performed using the t-test. Data are reported as mean values (± standard deviation). RESULTS The time needed to complete all tasks was 152.9 ± 71.5 sec on the 1st attempt vs. 98.7 ± 40.3 sec on the 4th attempt (P = 0.03). Likewise, the quality of performance score improved from 8.3 ± 6.7 to 18.2 ± 2.5 (P < 0.0001). The average number of correct answers in the questionnaire was 6.8 ± 1.9 pre-test and 13.3 ± 3.1 post-test (P < 0.0001). Participants reported a high level of satisfaction with the perceived usefulness and accuracy of the model. CONCLUSIONS We developed a 3D-printed model for bronchoscopy training. This model improved trainee performance and may represent a valid, low-cost bronchoscopy training tool.