Controlled Mechanical Ventilation Research Articles

Transcriptome profiling of the diaphragm in a controlled mechanical ventilation model reveals key genes involved in ventilator-induced diaphragmatic dysfunction

BackgroundVentilator-induced diaphragmatic dysfunction (VIDD) is associated with weaning difficulties, intensive care unit hospitalization (ICU), infant mortality, and poor long-term clinical outcomes. The expression patterns of long noncoding RNAs (lncRNAs) and mRNAs in the diaphragm in a rat controlled mechanical ventilation (CMV) model, however, remain to be investigated.ResultsThe diaphragms of five male Wistar rats in a CMV group and five control Wistar rats were used to explore lncRNA and mRNA expression profiles by RNA-sequencing (RNA-seq). Muscle force measurements and immunofluorescence (IF) staining were used to verify the successful establishment of the CMV model. A total of 906 differentially expressed (DE) lncRNAs and 2,139 DE mRNAs were found in the CMV group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the biological functions or pathways of these DE mRNAs. Our results revealed that these DE mRNAs were related mainly related to complement and coagulation cascades, the PPAR signaling pathway, cholesterol metabolism, cytokine-cytokine receptor interaction, and the AMPK signaling pathway. Some DE lncRNAs and DE mRNAs determined by RNA-seq were validated by quantitative real-time polymerase chain reaction (qRT-PCR), which exhibited trends similar to those observed by RNA-sEq. Co-expression network analysis indicated that three selected muscle atrophy-related mRNAs (Myog, Trim63, and Fbxo32) were coexpressed with relatively newly discovered DE lncRNAs.ConclusionsThis study provides a novel perspective on the molecular mechanism of DE lncRNAs and mRNAs in a CMV model, and indicates that the inflammatory signaling pathway and lipid metabolism may play important roles in the pathophysiological mechanism and progression of VIDD.

Multi-omics reveals age-related differences in the diaphragm response to mechanical ventilation: a pilot study

BackgroundOld age is associated with a significantly increased mortality in COVID-19 patients exposed to long-term controlled mechanical ventilation (CMV) and suggested to be due to the hyperinflammatory response associated with the viral infection. However, our understanding of age-related differences in the response to CMV in the absence of a viral infection remains insufficient.MethodsYoung (7–8 months) and old (28–32 months) F344 BN hybrid rats were exposed to the ICU condition for 5 days, i.e., complete immobilization, mechanical ventilation, and extensive monitoring. Transcriptomic (RNA-Seq) and proteomics (Proximity Extension Assay) analyses of the diaphragm and proteomics analysis of plasma were conducted to investigate the molecular differences between young and old rats exposed to the ICU condition.ResultsAccording to multi-omics analyses, significant differences were observed in the diaphragm between young and old rats in response to 5 days CMV and immobilization. In young rats, metabolic pathways were primarily downregulated in response to immobilization (post-synaptic blockade of neuromuscular transmission). In old rats, on the other hand, dramatic immune and inflammatory responses were observed, i.e., an upregulation of specific related pathways such as “IL-17 signaling pathway”, along with a higher level of inflammatory factors and cytokine/chemokine in plasma.ConclusionsThe dramatically increased mortality in old ICU patients with COVID-19-associated hyperinflammation and cytokine storm need not only reflect the viral infection but may also be associated with the ventilator induced diaphragm dysfunction (VIDD) and hyperinflammatory responses induced by long-term CMV per se. Although mechanical ventilation is a life-saving intervention in COVID-19 ICU patients, CMV should be cautiously used especially in old age and other means of respiratory support may be considered, such as negative pressure ventilation.

A Centrally Acting Antihypertensive, Clonidine, Sedates Patients Presenting With Acute Respiratory Distress Syndrome Evoked by Severe Acute Respiratory Syndrome-Coronavirus 2.

A Centrally Acting Antihypertensive, Clonidine, Sedates Patients Presenting With Acute Respiratory Distress Syndrome Evoked by Severe Acute Respiratory Syndrome-Coronavirus 2.

Magnesium sulfate ameliorates sepsis-induced diaphragm dysfunction in rats via inhibiting HMGB1/TLR4/NF-κB pathway.

BackgroundDiaphragm dysfunction could be induced by sepsis with subsequent ventilatory pump failure that is associated with local infiltration of inflammatory factors in the diaphragm. It has been shown that the administration of anticonvulsant agent, magnesium sulfate (MgSO4) could decrease systematic inflammatory response. We recently reported that MgSO4 could inhibit macrophages high mobility group box 1 (HMGB1) secretion that confirms its anti-inflammatory properties. Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signal pathway appears to be involved in the pathology of septic experimental animal’s inflammatory response and involve in the pathogenic mechanisms of sepsis-induced diaphragm dysfunction. Thus, in this study, we are aiming to explore whether MgSO4 could ameliorate sepsis-induced diaphragm dysfunction via TLR4/NF-κB pathway in a rodent model with controlled mechanical ventilation (CMV) and subsequent septic challenge.MethodsRats were randomly assigned into (1) control group: having an identical laparotomy but without ligation or puncture in the cecum; (2) CLP group: cecal ligation and puncture (CLP) with continuous saline infusion; (3) CLP + MgSO4 group: CLP with continuous MgSO4 administration; and (4) MgSO4 group: a sham surgery with MgSO4 administration. After surgery, all rats were submitted to CMV for 18 h. After completion of the study protocol, blood inflammatory cytokine/chemokine was detected by ELISA, as well as diaphragm contractility, TLR4, NF-κB (p65), phospho-NF-κB (p65) and HMGB1 protein expression.ResultsThe level of inflammatory cytokine/chemokine includes interleukin-6, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and HMGB1 in blood were significantly increased at 18-h post-CLP compared with the control group. We found that rats in the CLP group had substantial diaphragm dysfunction with a distinct downshift of the force–frequency curve. Furthermore, expression of HMGB1, TLR4, NF-κB (p65) and phospho-NF-κB (p65) in diaphragm were significantly increased in the CLP group. In contrast, MgSO4 attenuated the septic inflammation reaction in diaphragm and serum and preserved diaphragm function.ConclusionMgSO4 protects against sepsis-induced diaphragm dysfunction. This may be associated with its anti-inflammatory effect on HMGB1/TLR4/NF-κB signal pathway

Maintenance of spontaneous breathing at an intensity of 60%-80% may effectively prevent mechanical ventilation-induced diaphragmatic dysfunction.

Controlled mechanical ventilation (CMV) can cause diaphragmatic motionlessness to induce diaphragmatic dysfunction. Partial maintenance of spontaneous breathing (SB) can reduce ventilation-induced diaphragmatic dysfunction (VIDD). However, to what extent SB is maintained in CMV can attenuate or even prevent VIDD has been rarely reported. The current study aimed to investigate the relationship between SB intensity and VIDD and to identify what intensity of SB maintained in CMV can effectively avoid VIDD. Adult rats were randomly divided according to different SB intensities: SB (0% pressure controlled ventilation (PCV)), high-intensity SB (20% PCV), medium-intensity SB (40% PCV), medium-low intensity SB (60% PCV), low-intensity SB (80% PCV), and PCV (100% PCV). The animals underwent 24-h controlled mechanical ventilation (CMV). The transdiaphragmatic pressure (Pdi), the maximal Pdi (Pdi max) when phrenic nerves were stimulated, Pdi/Pdi max, and the diaphragmatic tonus under different frequencies of electric stimulations were determined. Calpain and caspase-3 were detected using ELISA and the cross-section areas (CSAs) of different types of muscle fibers were measured. The Pdi showed a significant decrease from 20% PCV and the Pdi max showed a significant decrease from 40% PCV (P<0.05). In vivo and vitro diaphragmatic tonus exhibited a significant decrease from 40% PCV and 20% PCV, respectively (P<0.05). From 20% PCV, the CSAs of types I, IIa, and IIb/x muscle fibers showed significant differences, which reached the lowest levels at 100% PCV. SB intensity is negatively associated with the development of VIDD. Maintenance of SB at an intensity of 60%-80% may effectively prevent the occurrence of VIDD.

Effects of variable versus nonvariable controlled mechanical ventilation on pulmonary inflammation in experimental acute respiratory distress syndrome in pigs

BackgroundMechanical ventilation with variable tidal volumes (VT) may improve lung function and reduce ventilator-induced lung injury in experimental acute respiratory distress syndrome (ARDS). However, previous investigations were limited to less than 6 h, and control groups did not follow clinical standards. We hypothesised that 24 h of mechanical ventilation with variable VT reduces pulmonary inflammation (as reflected by neutrophil infiltration), compared with standard protective, nonvariable ventilation. MethodsExperimental ARDS was induced in 14 anaesthetised pigs with saline lung lavage followed by injurious mechanical ventilation. Pigs (n=7 per group) were randomly assigned to using variable VT or nonvariable VT modes of mechanical ventilation for 24 h. In both groups, ventilator settings including positive end-expiratory pressure and oxygen inspiratory fraction were adjusted according to the ARDS Network protocol. Pulmonary inflammation (primary endpoint) and perfusion were assessed by positron emission tomography using 2-deoxy-2-[18F]fluoro-d-glucose and 68Gallium (68Ga)-labelled microspheres, respectively. Gas exchange, respiratory mechanics, and haemodynamics were quantified. Lung aeration was determined using CT. ResultsThe specific global uptake rate of 18F-FDG increased to a similar extent regardless of mode of mechanical ventilation (median uptake for variable VT=0.016 min−1 [inter-quartile range, 0.012–0.029] compared with median uptake for nonvariable VT=0.037 min−1 [0.008–0.053]; P=0.406). Gas exchange, respiratory mechanics, haemodynamics, and lung aeration and perfusion were similar in both variable and nonvariable VT ventilatory modes. ConclusionIn a porcine model of ARDS, 24 h of mechanical ventilation with variable VT did not attenuate pulmonary inflammation compared with standard protective mechanical ventilation with nonvariable VT.

Maintaining spontaneous ventilation during surgery—a review article

Mechanical ventilation is necessary during many surgical procedures, however a paradigm shift in ventilation has taken place in the past decades. There is convincing evidence that neuromuscular blockade and subsequent controlled mechanical ventilation applying intermittent positive pressure, also in patients with non-injured, healthy lungs, may impair the respiratory system, leading to postoperative pulmonary complications (PPCs), resulting in worse clinical outcome, prolonged hospitalization time and increased cost of hospital care. Multifactorial pathophysiology of ventilator induced lung injury (VILI) has been evaluated and a pulmonary protective ventilatory strategy [lung protective ventilation (LPV)], including the use of low tidal volumes [6 mL/kg, ideal body weight (IBW)], moderate or optimal levels of positive end-expiratory pressure (PEEP) and applying regular or targeted alveolar recruitment maneuvers (ARMs), has been developed. Recognizing the role of neuromuscular blockade during general anesthesia and even the importance of avoiding residual neuromuscular blockade in the early postoperative period regarding to postoperative respiratory impairment have become another, newer direction of research. Despite promising and convincing results of recent clinical trials, incidence of PPCs could not be reduced significantly and lung protective ventilation has remained to be a “hot topic” among researchers in the field of anesthesia and critical care. Maintaining spontaneous breathing during general anesthesia has some pathophysiological rationale worth to be dealt with, because it may be one of the options for further improvement. Physiology, advantages, disadvantages and potential role of spontaneous breathing during surgery as compared to intermittent positive pressure ventilation will be described in this article.

Oesophageal balloon calibration during pressure support ventilation: a proof of concept study.

Oesophageal balloon calibration improves the oesophageal pressure (Pes) assessment during invasive controlled mechanical ventilation. The primary aim of the present investigation was to ascertain the feasibility of oesophageal balloon calibration during pressure support ventilation (PSV). Secondarily, the calibrated Pes (Pescal) was compared to uncalibrated one acquired at 4ml-filling volume (PesV4), as per manufacturer recommendation. After a naso-gastric tube equipped with oesophageal balloon was correctly positioned in 21 adult patients undergoing invasive volume-controlled ventilation (VCV) for acute hypoxemic respiratory failure, the balloon was progressively inflated, applying a series of end-inspiratory and end-expiratory holds at each filling volume during VCV and PSV. Upon optimal balloon filling volume (Vbest) was identified, Pescal was computed by correcting the Pes measured at Vbest for the oesophageal wall pressure elicited at same filling volume. Finally, end-expiratory and end-inspiratory PesV4 were recorded too. A total of 42 calibrations, 21 per ventilatory mode, were performed. Vbest was 1.9 ± 1.6ml in VCV and 1.7 ± 1.6ml in PSV (p = 0.5217). PesV4 was overestimated compared to Pescal at end-expiration and end-inspiration (p <0.0001 for all comparisons) in both VCV (13.4 ± 3.4 cmH2O and 15.4 ± 3 cmH2O vs. 8.5 ± 2.9 cmH2O and 11.4 ± 3 cmH2O) and PSV (14.7 ± 4.2 cmH2O and 17 ± 3.9 cmH2O vs. 8.9 ± 3.4 cmH2O and 12.4 ± 3.9 cmH2O). In PSV, oesophageal balloon calibration is feasible and allows to obtain a reliable Pes assessment compared to uncalibrated approach.

Neurally adjusted ventilatory assist mitigates ventilator-induced diaphragm injury in rabbits

BackgroundVentilator-induced diaphragmatic dysfunction is a serious complication associated with higher ICU mortality, prolonged mechanical ventilation, and unsuccessful withdrawal from mechanical ventilation. Although neurally adjusted ventilatory assist (NAVA) could be associated with lower patient-ventilator asynchrony compared with conventional ventilation, its effects on diaphragmatic dysfunction have not yet been well elucidated.MethodsTwenty Japanese white rabbits were randomly divided into four groups, (1) no ventilation, (2) controlled mechanical ventilation (CMV) with continuous neuromuscular blockade, (3) NAVA, and (4) pressure support ventilation (PSV). Ventilated rabbits had lung injury induced, and mechanical ventilation was continued for 12 h. Respiratory waveforms were continuously recorded, and the asynchronous events measured. Subsequently, the animals were euthanized, and diaphragm and lung tissue were removed, and stained with Hematoxylin-Eosin to evaluate the extent of lung injury. The myofiber cross-sectional area of the diaphragm was evaluated under the adenosine triphosphatase staining, sarcomere disruptions by electron microscopy, apoptotic cell numbers by the TUNEL method, and quantitative analysis of Caspase-3 mRNA expression by real-time polymerase chain reaction.ResultsPhysiological index, respiratory parameters, and histologic lung injury were not significantly different among the CMV, NAVA, and PSV. NAVA had lower asynchronous events than PSV (median [interquartile range], NAVA, 1.1 [0–2.2], PSV, 6.8 [3.8–10.0], p = 0.023). No differences were seen in the cross-sectional areas of myofibers between NAVA and PSV, but those of Type 1, 2A, and 2B fibers were lower in CMV compared with NAVA. The area fraction of sarcomere disruptions was lower in NAVA than PSV (NAVA vs PSV; 1.6 [1.5–2.8] vs 3.6 [2.7–4.3], p < 0.001). The proportion of apoptotic cells was lower in NAVA group than in PSV (NAVA vs PSV; 3.5 [2.5–6.4] vs 12.1 [8.9–18.1], p < 0.001). There was a tendency in the decreased expression levels of Caspase-3 mRNA in NAVA groups. Asynchrony Index was a mediator in the relationship between NAVA and sarcomere disruptions.ConclusionsPreservation of spontaneous breathing using either PSV or NAVA can preserve the cross sectional area of the diaphragm to prevent atrophy. However, NAVA may be superior to PSV in preventing sarcomere injury and apoptosis of myofibrotic cells of the diaphragm, and this effect may be mediated by patient-ventilator asynchrony.

Oxidants Regulated Diaphragm Proteolysis during Mechanical Ventilation in Rats.

Diaphragm dysfunction and atrophy develop during controlled mechanical ventilation. Although oxidative stress injures muscle during controlled mechanical ventilation, it is unclear whether it causes autophagy or fiber atrophy. Pretreatment of rats undergoing 24 h of mechanical ventilation with N-acetylcysteine prevents decreases in diaphragm contractility, inhibits the autophagy and proteasome pathways, but has no influence on the development of diaphragm fiber atrophy. Diaphragm dysfunction and atrophy develop during prolonged controlled mechanical ventilation. Fiber atrophy has been attributed to activation of the proteasome and autophagy proteolytic pathways. Oxidative stress activates the proteasome during controlled mechanical ventilation, but it is unclear whether it also activates autophagy. This study investigated whether pretreatment with the antioxidant N-acetylcysteine affects controlled mechanical ventilation-induced diaphragm contractile dysfunction, fiber atrophy, and proteasomal and autophagic pathway activation. The study also explored whether proteolytic pathway activity during controlled mechanical ventilation is mediated by microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes. Three groups of adult male rats were studied (n = 10 per group). The animals in the first group were anesthetized and allowed to spontaneously breathe. Animals in the second group were pretreated with saline before undergoing controlled mechanical ventilation for 24 h. The animals in the third group were pretreated with N-acetylcysteine (150 mg/kg) before undergoing controlled mechanical ventilation for 24 h. Diaphragm contractility and activation of the proteasome and autophagy pathways were measured. Expressions of microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes were measured with quantitative polymerase chain reaction. Controlled mechanical ventilation decreased diaphragm twitch force from 428 ± 104 g/cm (mean ± SD) to 313 ± 50 g/cm and tetanic force from 2,491 ± 411 g/cm to 1,618 ± 177 g/cm. Controlled mechanical ventilation also decreased diaphragm fiber size, increased expression of several autophagy genes, and augmented Atrogin-1, MuRF1, and Nedd4 expressions by 36-, 41-, and 8-fold, respectively. Controlled mechanical ventilation decreased the expressions of six microRNAs (miR-20a, miR-106b, miR-376, miR-101a, miR-204, and miR-93) that regulate autophagy genes. Pretreatment with N-acetylcysteine prevented diaphragm contractile dysfunction, attenuated protein ubiquitination, and downregulated E3 ligase and autophagy gene expression. It also reversed controlled mechanical ventilation-induced microRNA expression decreases. N-Acetylcysteine pretreatment had no affect on fiber atrophy. Prolonged controlled mechanical ventilation activates the proteasome and autophagy pathways in the diaphragm through oxidative stress. Pathway activation is accomplished, in part, through inhibition of microRNAs that negatively regulate autophagy-related genes.

Do fish oil supplements benefit people with hypertension? Results from the 45 and Up Study

The paper presents a case of fatal intoxication after massive sustained-release clomipramine overdosage with prolonged toxicity related to a large gastric pharmacobezoar. 42-year-old female was admitted to the toxicology unit 14 h after drugs ingestion. At admission patient was deeply unconscious, required controlled mechanical ventilation. Serum total level of TCAs was 1955 ng/mL. Gastric lavage revealed no pills. Within the next 12 h the patient's clinical condition improved. TCAs level decreased to 999 ng/mL. However, after another 10 h the clinical condition started deteriorating again and the patient went into a deep coma requiring controlled mechanical ventilation. TCAs level increased to 2011 ng/mL. X-ray and computed tomography revealed large pharmacobezoar consisted from radio-opaque pills. In the 28th h of hospitalization gastrotomy was performed, confirming presence of pharmacobezoar formed from Anafranil SR tablets. After surgery TCAs level was gradually decreasing. However, the patient's condition did not improve, she died 32 h after gastrotomy. Post-mortem analyses revealed drug and its metabolite toxic levels in blood (clomipramine – 1729 ng/mL, norclomipramine – 431 ng/mL) and toxic levels in internal organs: myocardium (clomipramine – 14,420 ng/g, norclomipramine – 35,930 ng/g), vitreous humor (clomipramine – 1000 ng/mL, norclomipramine – 3110 ng/mL).Described case report indicates that sustained release clomipramine tablets may form pharmacobezoar. X-ray and computed tomography examinations should be considered in cases of massive abuse of sustained release clomipramine, particularly if symptoms of intoxication are recurrent or persistent.

Mandatory criteria for the application of variability-based parameters of fluid responsiveness: a prospective study in different groups of ICU patients.

Stroke volume variation (SVV) has high sensitivity and specificity in predicting fluid responsiveness. However, sinus rhythm (SR) and controlled mechanical ventilation (CV) are mandatory for their application. Several studies suggest a limited applicability of SVV in intensive care unit (ICU) patients. We hypothesized that the applicability of SVV might be different over time and within certain subgroups of ICU patients. Therefore, we analysed the prevalence of SR and CV in ICU patients during the first 24 h of PiCCO-monitoring (primary endpoint) and during the total ICU stay. We also investigated the applicability of SVV in the subgroups of patients with sepsis, cirrhosis, and acute pancreatitis. The prevalence of SR and CV was documented immediately before 1241 thermodilution measurements in 88 patients. In all measurements, SVV was applicable in about 24%. However, the applicability of SVV was time-dependent: the prevalence of both SR and CV was higher during the first 24 h compared to measurements thereafter (36.1% vs. 21.9%; P<0.001). Within different subgroups, the applicability during the first 24 h of monitoring ranged between 0% in acute pancreatitis, 25.5% in liver failure, and 48.9% in patients without pancreatitis, liver failure, pneumonia or sepsis. The applicability of SVV in a predominantly medical ICU is only about 25%-35%. The prevalence of both mandatory criteria decreases over time during the ICU stay. Furthermore, the applicability is particularly low in patients with acute pancreatitis and liver failure.

Impact of intraoperative mechanical ventilation on left ventricular lead function in cardiac resynchronization therapy.

Intraoperative controlled mechanical ventilation (CMV) changes the intrathoracic geometry and may impact postoperative left ventricular (LV) lead function after CRT implantation. This multicenter study investigates the effect of intraoperative ventilation setting (spontaneous breathing[SB] vs CMV) on postoperative LV lead function taking into account patients' body mass index (BMI). CRT implantation was performed at two centers during SB in 92 and during CMV in 73 patients. Follow-up was carried out after 3 ± 5 and 36 ± 53 days. Functional lead parameters (FLP; pacing threshold and impedance), postoperative adverse events (A; phrenic nerve stimulation [PNS] and lead malfunction), and patients' BMI were assessed. Delta values of FLP between baseline and follow-up visits were analyzed applying an analysis of covariance model to detect subclinical alterations in LV lead function. AE occurred in a total of 36 (21%) patients. PNS was observed in 26 (15%) patients and LV lead repositioning due to malfunction was necessary in 10 (6%) patients. Both AE and FLP delta values between baseline and follow-up were not associated with intraoperative ventilation settings nor the patients' BMI. This study demonstrates that there is no impact of the intraoperative ventilation setting (SB vs CMV) on postoperative FLP or the occurrence of AE. This is also the case taking into account the BMI. With respect to these findings both approaches-sedation only or general anaesthesia including CMV-can be safely implemented during CRT implantation.

Activation of mammalian target of rapamycin induces lipid accumulation in the diaphragm of ventilated rats and hypoxia-treated C2C12 cells

BackgroundOur previous study demonstrated that ventilators increase diaphragmatic lipid accumulation in rabbits, but their cellular mechanism is poorly understood. Mammalian target of rapamycin (mTOR) plays an important role in atherosclerosis in rat vascular smooth muscle cells. The present study investigated the role of mTOR pathway activation in the diaphragmatic muscle of ventilated rats and hypoxia-induced C2C12 cells. Materials and methodsMale Sprague-Dawly rats were randomized into a control group (n = 8), controlled mechanical ventilation (CMV) group (n = 8), and CMV + Rapa group (n = 8). We evaluated the diaphragmatic contractility, lipid accumulation, and protein expression of the mTOR pathways. To explore the mechanism underlying ventilator-induced lipid accumulation, we observed protein expression of the mTOR and low-density lipoprotein receptor (LDLr) pathways in C2C12 cells under hypoxic and mTOR pathway inhibitor treatments. ResultsCompared with the control group, there was a significant decrease in the peak twitch and peak tetanic forces in the CMV group (384.24 ± 70.39 versus 496.33 ± 78.64 g/cm2, P < 0.05, and 869.24 ± 76.67 versus 1090.72 ± 118.91 g/cm2, P < 0.05, respectively). There was a significant increase in peak twitch and peak tetanic forces in the CMV + Rapa group compared with that in the CMV group (501.81 ± 23.15 versus 384.24 ± 70.39 g/cm2, P < 0.05, and 992.91 ± 88.99 versus 869.24 ± 76.67 g/cm2, P < 0.05, respectively). In the CMV group, there were significant increases in lipid accumulation (0.086 ± 0.009 versus 0.005 ± 0.002, P < 0.05) and expression of mTOR in diaphragmatic fibers compared with those in the control group (P < 0.05). Rapamycin prevented lipid accumulation in rats of the CMV + Rapa group compared with that in the CMV group rats (0.024 ± 0.004 versus 0.086 ± 0.009, P < 0.05). Compared with the CMV group, there was a significant decrease in the phosphorylated protein expression levels of mTOR in rats of the CMV + Rapa group (P < 0.05). Hypoxic conditions activated the mTOR and LDLr pathways in C2C12 cells, which were correlated with an increase in expression of the mTOR and LDLr pathways compared with the control group (P < 0.05). In C2C12 cells treated with hypoxia + rapamycin, activation of the mTOR and LDLr pathways was blocked compared with C2C12 cells treated with hypoxia (P < 0.05). ConclusionsThese data suggest that CMV and hypoxia-induced activation of the mTOR pathway, resulting in lipid accumulation, and impaired the diaphragmatic contractile function. Therefore, pharmacologic agents that inhibit the mTOR pathway could potentially be useful for mitigating the diaphragmatic contractile dysfunction induced by mechanical ventilation.

A Proteomic Approach to Identify Alterations in the Small Ubiquitin-like Modifier (SUMO) Network during Controlled Mechanical Ventilation in Rat Diaphragm Muscle

The small ubiquitin-like modifier (SUMO) is as a regulator of many cellular functions by reversible conjugation to a broad number of substrates. Under endogenous or exogenous perturbations, the SUMO network becomes a fine sensor of stress conditions by alterations in the expression level of SUMO enzymes and consequently changing the status of SUMOylated proteins. The diaphragm is the major inspiratory muscle, which is continuously active under physiological conditions, but its structure and function is severely affected when passively displaced for long extents during mechanical ventilation (MV). An iatrogenic condition called Ventilator-Induced Diaphragm Dysfunction (VIDD) is a major cause of failure to wean patients from ventilator support but the molecular mechanisms underlying this dysfunction are not fully understood. Using a unique experimental Intensive Care Unit (ICU) rat model allowing long-term MV, diaphragm muscles were collected in rats control and exposed to controlled MV (CMV) for durations varying between 1 and 10 days. Endogenous SUMOylated diaphragm proteins were identified by mass spectrometry and validated with in vitro SUMOylation systems. Contractile, calcium regulator and mitochondrial proteins were of specific interest due to their putative involvement in VIDD. Differences were observed in the abundance of SUMOylated proteins between glycolytic and oxidative muscle fibers in control animals and high levels of SUMOylated proteins were present in all fibers during CMV. Finally, previously reported VIDD biomarkers and therapeutic targets were also identified in our datasets which may play an important role in response to muscle weakness seen in ICU patients. Data are available via ProteomeXchange with identifier PXD006085. Username: reviewer26663@ebi.ac.uk, Password: rwcP5W0o.

Evaluation of three tidal volumes (10, 12 and 15 mL kg−1) in dogs for controlled mechanical ventilation assessed by volumetric capnography: a randomized clinical trial

ObjectiveTo evaluate three routinely used tidal volumes (VT; 10, 12 and 15 mL kg−1) for controlled mechanical ventilation (CMV) in lung-healthy anaesthetized dogs by assessing alveolar ventilation (VTalv) and dead space (DS). Study designProspective, randomized clinical trial. AnimalsA total of 36 client-owned dogs. MethodsDogs were randomly allocated to a VT of 10 (G10), 12 (G12) or 15 (G15) mL kg−1. After induction CMV was started. End-tidal carbon dioxide tension was maintained at 4.7–5.3 kPa by changing the respiratory frequency (fR; 6<fR<30 breaths minute−1). After 29 minutes, cardiovascular and respiratory variables were recorded for 3 minutes using a multiparameter monitor, volumetric capnography (VCap) and a blood gas analyser. The ratios of VTalv to body weight (VTalv kg−1) and airway DS to VT (VDaw/VT), Bohr's DS (VDBohr), Enghoff's DS (VDBE) and the volume of expired carbon dioxide per breath (VTCO2,br) were calculated. Mean airway pressure (MawP), fR and peak inspiratory pressure (PIP) were recorded. Data were analysed using one-way anova and Student–Newman–Keuls tests with a statistical significance set at p<0.05. ResultsNo differences were observed for demographic data and cardiovascular variables between groups. A total of three dogs were excluded because of technical difficulties and one because of fR>30. VTalv kg−1 (p=0.001) increased and VDBohr (p=0.002) decreased with greater VT. VTCO2,br (p=0.017) increased and VDaw/VT (p=0.006), VDBE (p=0.008) and fR (p=0.002) decreased between G10 and G15. PIP (p=0.013) was significantly higher in G15 compared with that in G10 and G12. No changes were observed in MawP. Conclusions and clinical relevanceA VT of 15 mL kg−1 is most appropriate for CMV in lung-healthy dogs (as evaluated by respiratory mechanics and VCap) and does not impair cardiovascular variables.

Controlled mechanical ventilation systems in residential buildings: Primary energy balances and financial issues

The aim of this paper is to investigate the technical, energy and financial convenience of Controlled Mechanical Ventilation (CMV) systems in residential units. With reference to a residential unit belonging to an apartment block, a mechanical ventilation system is first conceived according to different possible configurations (constant or hygro-adjustable flow, single or double flow). All the proposed configurations are suitable to provide fresh outdoor air and dilute indoor pollutants; this preliminary analysis allows to evaluate the overall costs for installation.Then, the paper determines the energy consumption for the operation of all the proposed configurations, both in terms of electricity to feed the blower fan and of fuel to preheat the cold air stream up to the indoor air temperature. Finally, these results are compared to the energy needs for a building without CMV systems, where air renewal is left to the occupants, who open and close windows at will. This analysis is proposed for three different sites in Italy, that show different climatic conditions.The results suggest that the adoption of controlled mechanical ventilation in residential units is a convenient practice under several points of view. Indeed, they undeniably allow to save primary energy, and the financial payback time is fairly low, particularly in cold climates.

Experimental evaluation of four airway devices in anaesthetized New Zealand White rabbits

ObjectiveTo compare airway management during induction of anaesthesia, spontaneous ventilation (SV) and controlled mechanical ventilation (CMV), using an endotracheal tube (ETT), laryngeal mask (LM), rabbit-specific supraglottic airway device (v-gel) or facemask (FM). Study designProspective randomized crossover experiment. AnimalsTen New Zealand White rabbits. MethodsAfter premedication, rabbits were randomly allocated to four groups: 1) ETT; 2) LM; 3) v-gel or 4) FM. The required dose of propofol, duration and number of attempts to place an airway device and leakage during SV and CMV at different peak inspiratory pressures (6, 10, 12, 14 and 16 cmH2O) were recorded. Computed tomography (CT) of the head, neck and abdomen were performed before and after CMV. ResultsSignificantly less propofol and time [2.0±0.5 mg kg−1, 82±34 seconds, p<0.001] were needed to place the FM compared to the three other groups [v-gel 5.1±2.1 mg kg−1, 302±124 seconds; LM 4.8±1.2 mg kg−1, 275±89 seconds; ETT 5.5±1.4 mg kg−1, 315±147 seconds]. A leak > 25% of the tidal volume occurred at the lowest pressure in FM [median (range), 6 (6–8) cmH2O], which was significantly lower than with v-gel [16 (6–no leak at 16) cmH2O], LM [>16 (6–no leak at 16)] or ETT [>16 (no leak at 16) cmH2O] (p<0.001). On CT images, the height and width of the larynx were significantly smaller with v-gel in comparison to FM and LM (p=0.004). A significant increase in the amount of gas in the stomach (p=0.007), but not gastric volume, was detected in FM and LM. Conclusions and clinical relevanceThe v-gel is a practical alternative to LM and ETT for airway management and CMV, but can compress the larynx. The FM is easily placed, but significant leakage occurs during CMV.

Controlled mechanical ventilation with constant positive end-expiratory pressure and alveolar recruitment manoeuvres during anaesthesia in laterally or dorsally recumbent horses

ObjectiveTo compare the effects of controlled mechanical ventilation (CMV) and constant positive end-expiratory pressure (PEEP) and interposed recruitment manoeuvres (RMs) with those of CMV without PEEP on gas exchange during general anaesthesia and the early recovery period. Study designProspective, randomized clinical trial. AnimalsA total of 48 Warmblood horses undergoing elective surgery in lateral (Lat) (n = 24) or dorsal (Dors) (n = 24) recumbency. MethodsPremedication (romifidine), induction (diazepam and ketamine) and maintenance (isoflurane in oxygen) were identical in all horses. Groups Lat- CMV and Dors-CMV (each n = 12) were ventilated using CMV. Groups Lat-RM and Dors-RM (each n = 12) were ventilated using CMV with constant PEEP (10 cmH2O) and intermittent RMs (three consecutive breaths with peak inspiratory pressure of 60 cmH2O, 80 cmH2O and 60 cmH2O, respectively). RMs were applied as required to maintain PaO2 at > 400 mmHg (> 53.3 kPa). Dobutamine was given to maintain mean arterial blood pressure at > 60 mmHg. Physiological parameters were recorded every 10 minutes. Arterial blood gases were measured intra- and postoperatively. Statistical analyses were conducted using analyses of variance (anova),t tests and the Mann–Whitney U-test. ResultsHorses in Dors-RM had higher PaO2 values [478 ± 35 mmHg (63.7 ± 4.6 kPa)] than horses in Dors-CMV [324 ± 45 mmHg (43.2 ± 6 kPa)] during anaesthesia and the early recovery period. There were no differences between horses in groups Lat-CMV and Lat-RM. Other measured parameters did not differ between groups. Conclusions and clinical relevanceVentilation with CMV, constant PEEP and interposed RM provided improved arterial oxygenation in horses in dorsal recumbency that lasted into the early recovery period, but had no benefit in horses in lateral recumbency. This mode of ventilation may provide a clinically practicable method of improving oxygenation in anaesthetized horses, especially in dorsal recumbency.

Regional distribution of ventilation in horses in dorsal recumbency during spontaneous and mechanical ventilation assessed by electrical impedance tomography: a case series

ObjectiveTo evaluate the regional distribution of ventilation in horses during spontaneous breathing and controlled mechanical ventilation (CMV) using electrical impedance tomography (EIT). Study designProspective, experimental case series. AnimalsFour anaesthetized experimental horses. MethodsHorses were anaesthetized with isoflurane in an oxygen-air mixture and medetomidine continuous rate infusion, placed in dorsal recumbency with an EIT belt around the thorax, and allowed to breathe spontaneously until PaCO2 reached 13.3 kPa (100 mmHg), when volume CMV was started. For each horse, the EIT signal was recorded for at least 2 minutes immediately before (T1), and at 30 (n = 3) or 60 (n = 1) minutes after the start of CMV (T2). The centre of ventilation (CoV), dependent silent spaces (DSS) (likely to represent atelectatic lung areas), non-dependent silent spaces (NSS) (likely to represent lung areas with low ventilation) and total ventilated area (TVA) were evaluated. Cardiac output (CO) was measured and venous admixture and oxygen delivery (DO2) were calculated at T1 and T2. Data are presented as median and range. ResultsAfter the initiation of CMV, the CoV moved ventrally towards the non-dependent lung by 10% [from 57.4% (49.6–60.2%) to 48.3% (41.9–54.4%)]. DSS increased [from 4.1% (0.2–13.9%) to 18.7% (7.5–27.5%)], while NSS [21.7% (9.4–29.2%) to 9.9% (1.0–20.7%)] and TVA [920 (699–1051) to 837 (662–961) pixels] decreased. CO, venous admixture and DO2 also decreased. Conclusions and clinical relevanceIn spontaneously breathing anaesthetized horses in dorsal recumbency, ventilation was essentially centred within the dependent dorsal lung regions and moved towards non-dependent ventral regions as soon as CMV was started. This shows a major lack of ventilation in the dependent lung, which may be indicative of atelectasis.