Electrical Stimulated Glut4 Signaling Attenuates Critical Illness-Associated Muscle Wasting

Background: Critical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a byproduct of critical care, attributed to impaired recovery, longterm complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood, however loss of mechanical stimuli contributes to critical illness associated muscle atrophy and weakness. Passive mechanical loading (ML) and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care. Methods: Rats were subjected to 8 days critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and Western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM. Results: Following 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, Myosin:Actin ratio and single muscle fiber maximum force normalized to cross-sectional area (specific force) were reduced by 40-50% (p< 0.0001). ES significantly reduced the loss of soleus muscle fiber cross-sectional area (CSA) and Myosin:Actin ratio by approximately 30% (p< 0.05) yet failed to effect specific force. RNAseq pathway analysis revealed downregulation of insulin signaling in the soleus muscle following critical care and GLUT4 trafficking was reduced by 55% leading to an 85% reduction of muscle glycogen content (p< 0.01). ES promoted phosphofructokinase and insulin signaling pathways to control levels (p< 0.05), consistent with the maintenance of GLUT4 translocation and glycogen levels. AMPK, but not AKT, signaling pathway was stimulated following ES, where the downstream target TBC1D4 increased 3 logFC (p= 0.029) and AMPK-specific P-TBC1D4 levels were increased approximately 2-fold (p= 0.06). Reduction of muscle protein degradation rather than protein synthesis promoted soleus CSA, as ES reduced E3 ubiquitin proteins, Atrogin-1 (p= 0.006) and MuRF1 (p= 0.08) by approximately 50%, downstream of AMPK-FoxO3. Conclusions: ES maintained GLUT4 translocation through increased AMPK-TBC1D4 signaling leading to improved muscle glucose homeostasis. Soleus CSA and myosin content was promoted through reduced protein degradation via AMPK-FoxO3 E3 ligases, Atrogin-1 and MuRF1. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signaling and reduced muscle protein degradation in CIM.

JUSTIFICATION FOR THE COMBINED USE OF PROPOFOL AND DEXMEDETOMIDINE IN ELECTIVE PROCEDURAL SEDATION

Procedural sedation (PS) is the technique of administering sedatives with or without analgesics to induce a condition in which the patient can tolerate unpleasant procedures while maintaining cardio-respiratory function. Planned PSs are performed with procedures of various invasiveness, painfulness and duration, but by definition, they do not reach the depth of general anesthesia and do not require the use of respiratory support or controlled mechanical ventilation, and even more – muscle relaxants. For effective PS, it is extremely important to establish verbal contact with the patient and achieve a stable emotional state of the patient and carefully explain to him the details of the PS. When choosing the depth of PS, it’s necessary to reach a compromise between the degree of anesthesia and amnesia, on the one hand, and the effectiveness of spontaneous breathing, as well as the possibility of an early recovery of consciousness, on the other. If possible, the problem of pain (when consciousness is partially preserved) or nociceptive stimuli (when the level of consciousness is reduced or absent) is solved separately through the use of local or regional anesthesia. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and some other drugs with analgesic properties are often used, and opioid analgesics are avoided or used in small or minimal doses. Unlike anesthesia, even deep sedation cannot and should not completely prevent the patient from moving during intense pain / nociceptive stimuli. If necessary, the problem of patient movements is solved not only and not so much by further deepening sedation, but precisely by improving analgesia and/or fixing the patient for the duration of short-term painful manipulations. To achieve these goals, PS is most often used propofol, or its dexmedetomidine or midazolam. This publication focuses on the advantages of using a multimodal approach for prolonged PS, which allows for a significant reduction in the dose of corresponding drugs and rate of complications in comparison with sedation with a single anaesthetic at significantly higher doses.

Altered expression of microRNAs in the rat diaphragm in a model of ventilator-induced diaphragm dysfunction after controlled mechanical ventilation

Background Ventilator-induced diaphragm dysfunction (VIDD) is a common complication of life support by mechanical ventilation observed in critical patients in clinical practice and may predispose patients to severe complications such as ventilator-associated pneumonia or ventilator discontinuation failure. To date, the alterations in microRNA (miRNA) expression in the rat diaphragm in a VIDD model have not been elucidated. This study was designed to identify these alterations in expression. Results Adult male Wistar rats received conventional controlled mechanical ventilation (CMV) or breathed spontaneously for 12 h. Then, their diaphragm tissues were collected for RNA extraction. The miRNA expression alterations in diaphragm tissue were investigated by high-throughput microRNA-sequencing (miRNA-seq). For targeted mRNA functional analysis, gene ontology (GO) analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were subsequently conducted. qRT-PCR validation and luciferase reporter assays were performed. We successfully constructed a model of ventilator-induced diaphragm dysfunction and identified 38 significantly differentially expressed (DE) miRNAs, among which 22 miRNAs were upregulated and 16 were downregulated. GO analyses identified functional genes, and KEGG pathway analyses revealed the signaling pathways that were most highly correlated, which were the MAPK pathway, FoxO pathway and Autophagy–animal. Luciferase reporter assays showed that STAT3 was a direct target of both miR-92a-1-5p and miR-874-3p and that Trim63 was a direct target of miR-3571. Conclusions The current research supplied novel perspectives on miRNAs in the diaphragm, which may not only be implicated in diaphragm dysfunction pathogenesis but could also be considered as therapeutic targets in diaphragm dysfunction.

Unusual pericuff leak around proseal-laryngeal mask airway corrected by clamping gastric drain port: A case report

ProSealTM-Laryngeal Mask Airway (PLMA) (Laryngeal Mask Company, Henley-on Thames, UK) is commonly used for securing the airway with an added advantage over classic LMA as its gastric drain tube allows the insertion of Ryle’s tube and suctioning of gastric contents. The ProSeal LMA is designed in such a way that it allows controlled mechanical ventilation. During controlled mechanical ventilation, air leaks can occur because of positive airway pressures. Air leaks from the gastric drain port are almost always due to the malposition of PLMA. Here, we report a case of air leak from gastric drain port despite correctly placed PLMA and its successful management without removing the device.

Endotracheal Tubes Design: The Role of Tube Bending

Endotracheal tubes (ETT) passed inside the human trachea witness tube bending at different angles, affecting the ocal fluid flow dynamics. This induces a variable mechanical ventilation performance across patients’ comfortability evels. Our understanding of the ocal fluid flow dynamics phenomena is thus crucial to enhance the maneuverability of ETT under operation. For the first time to our knowledge, we shed ight on ETT through computational fluid dynamics (CFD) to investigate the bending effect of ETT on the ocal airflow in volume-controlled mechanical ventilation. We considered an ETT with 180° arc bend configuration, including Murphy’s eye. We identified several flow phenomena associated with the bending, such as flow asymmetries, secondary flows, and vortex dynamics throughout the tube.

Intrapulmonary percussive ventilation via Mini-Trach II in critical care: a case report

Background Intrapulmonary percussive ventilation (IPV) facilitates the mobilization and clearance of bronchial secretions. Cricothyroidotomy using a Mini-Trach II device is a minimally invasive method used for secretion clearance. To our knowledge, there are no previous reports regarding IPV combined with Mini-Trach II. Case presentation An 82-year-old man underwent controlled mechanical ventilation and IPV via an endotracheal tube to treat atelectasis following emergency surgical repair of a traumatic diaphragm laceration. He underwent cricothyroidotomy using Mini-Trach II for ensuring airway management after extubation. On resumption, IPV through a mouthpiece or face mask was unsuccessful owing to air leakage from his mouth. However, IPV via the already inserted Mini-Trach II could deliver the percussion flow and led to a marked improvement in his condition. Conclusion This experience indicates that Mini-Trach II is beneficial as a minimally invasive interface for IPV that can deliver percussion flow efficiently.

Optimization of Controlled Mechanical Ventilation Systems for Indoor Acoustic Comfort

The indoor air quality inside living spaces is a fundamental factor in providing adequate comfort. In order to do this, a minimum air exchange must be ensured. This can be obtained by means of natural or mechanical ventilation or using the Controlled Mechanical Ventilation system (CMV). CMV ensures better energy performance, as in the winter period, the warm air that comes out of the building preheats the cold air that enters, and the opposite occurs in the summer period. A possible problem with CMV is the noise of the fans due to the movement of air and to the electric motor rotation. This work presents the results of acoustic measurements performed on an apartment equipped with CMV, operating in a single and simultaneous mode. Acoustic simulations are also presented using raytracing software on three typical apartments. The acoustic simulation carried out using an adequately calibrated 3D model has proved to be a valid support for the study of noise in rooms connected by doors and corridors. By differentiating the fan speed of the CMV, a considerable acoustic comfort improvement was obtained in the bedrooms and in the living room/kitchen. Class I for living rooms and class I or II for bedrooms according to the EN 16798-1 standard were achieved through speed optimization.

Static compliance and driving pressure are associated with ICU mortality in intubated COVID-19 ARDS

Background Pathophysiological features of coronavirus disease 2019-associated acute respiratory distress syndrome (COVID-19 ARDS) were indicated to be somewhat different from those described in nonCOVID-19 ARDS, because of relatively preserved compliance of the respiratory system despite marked hypoxemia. We aim ascertaining whether respiratory system static compliance (Crs), driving pressure (DP), and tidal volume normalized for ideal body weight (VT/kg IBW) at the 1st day of controlled mechanical ventilation are associated with intensive care unit (ICU) mortality in COVID-19 ARDS. Methods Observational multicenter cohort study. All consecutive COVID-19 adult patients admitted to 25 ICUs belonging to the COVID-19 VENETO ICU network (February 28th–April 28th, 2020), who received controlled mechanical ventilation, were screened. Only patients fulfilling ARDS criteria and with complete records of Crs, DP and VT/kg IBW within the 1st day of controlled mechanical ventilation were included. Crs, DP and VT/kg IBW were collected in sedated, paralyzed and supine patients. Results A total of 704 COVID-19 patients were screened and 241 enrolled. Seventy-one patients (29%) died in ICU. The logistic regression analysis showed that: (1) Crs was not linearly associated with ICU mortality (p value for nonlinearity = 0.01), with a greater risk of death for values < 48 ml/cmH2O; (2) the association between DP and ICU mortality was linear (p value for nonlinearity = 0.68), and increasing DP from 10 to 14 cmH2O caused significant higher odds of in-ICU death (OR 1.45, 95% CI 1.06–1.99); (3) VT/kg IBW was not associated with a significant increase of the risk of death (OR 0.92, 95% CI 0.55–1.52). Multivariable analysis confirmed these findings. Conclusions Crs < 48 ml/cmH2O was associated with ICU mortality, while DP was linearly associated with mortality. DP should be kept as low as possible, even in the case of relatively preserved Crs, irrespective of VT/kg IBW, to reduce the risk of death.

Measurement of Electrical Impedance Tomography-Based Regional Ventilation Delay for Individualized Titration of End-Expiratory Pressure

Rationale: Individualized positive end-expiratory pressure (PEEP) titration might be beneficial in preventing tidal recruitment. To detect tidal recruitment by electrical impedance tomography (EIT), the time disparity between the regional ventilation curves (regional ventilation delay inhomogeneity [RVDI]) can be measured during controlled mechanical ventilation when applying a slow inflation of 12 mL/kg of body weight (BW). However, repeated large slow inflations may result in high end-inspiratory pressure (PEI), which might limit the clinical applicability of this method. We hypothesized that PEEP levels that minimize tidal recruitment can also be derived from EIT-based RVDI through the use of reduced slow inflation volumes. Methods: Decremental PEEP trials were performed in 15 lung-injured pigs. The PEEP level that minimized tidal recruitment was estimated from EIT-based RVDI measurement during slow inflations of 12, 9, 7.5, or 6 mL/kg BW. We compared RVDI and PEI values resulting from different slow inflation volumes and estimated individualized PEEP levels. Results: RVDI values from slow inflations of 12 and 9 mL/kg BW showed excellent linear correlation (R2 = 0.87, p < 0.001). Correlations decreased for RVDI values from inflations of 7.5 (R2 = 0.68, p < 0.001) and 6 (R2 = 0.42, p < 0.001) mL/kg BW. Individualized PEEP levels estimated from 12 and 9 mL/kg BW were comparable (bias −0.3 cm H2O ± 1.2 cm H2O). Bias and scatter increased with further reduction in slow inflation volumes (for 7.5 mL/kg BW, bias 0 ± 3.2 cm H2O; for 6 mL/kg BW, bias 1.2 ± 4.0 cm H2O). PEI resulting from 9 mL/kg BW inflations were comparable with PEI during regular tidal volumes. Conclusions: PEEP titration to minimize tidal recruitment can be individualized according to EIT-based measurement of the time disparity of regional ventilation courses during slow inflations with low inflation volumes. This sufficiently decreases PEI and may reduce potential clinical risks.