Lung Stretch Research Articles

TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.

Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.

Driving Pressure: What Is the Harm?

Driving Pressure: What Is the Harm?

How do you feel? The molecules that sense touch.

Mechanotransduction was perhaps the last major sensory modality not understood at the molecular level. Proteins/ion channels that sense mechanical force are postulated to play critical roles in sensing touch/pain (somatosensation), sound (hearing), shear stress (cardiovascular function), etc.; however, the identity of ion channels involved in sensing mechanical force had remained elusive. The Patapoutian lab identified PIEZO1 and PIEZO2, mechanically-activated cation channels that are expressed in many mechanosensitive cell types. Genetic studies established that PIEZO2 is the principal mechanical transducer for touch, proprioception, baroreception and bladder & lung stretch, and that PIEZO1 mediates blood-flow sensing, which impacts vascular development and iron homeostasis. Clinical investigations have confirmed the importance of these channels in human physiology.

HLMSC Secretome Affects Macrophage Activity Differentially Depending on Lung-Mimetic Environments.

Mesenchymal stromal cell (MSC)-based therapies for inflammatory diseases rely mainly on the paracrine ability to modulate the activity of macrophages. Despite recent advances, there is scarce information regarding changes of the secretome content attributed to physiomimetic cultures and, especially, how secretome content influence on macrophage activity for therapy. hLMSCs from human donors were cultured on devices developed in house that enabled lung-mimetic strain. hLMSC secretome was analyzed for typical cytokines, chemokines and growth factors. RNA was analyzed for the gene expression of CTGF and CYR61. Human monocytes were differentiated to macrophages and assessed for their phagocytic capacity and for M1/M2 subtypes by the analysis of typical cell surface markers in the presence of hLMSC secretome. CTGF and CYR61 displayed a marked reduction when cultured in lung-derived hydrogels (L-Hydrogels). The secretome showed that lung-derived scaffolds had a distinct secretion while there was a large overlap between L-Hydrogel and the conventionally (2D) cultured samples. Additionally, secretome from L-Scaffold showed an HGF increase, while IL-6 and TNF-α decreased in lung-mimetic environments. Similarly, phagocytosis decreased in a lung-mimetic environment. L-Scaffold showed a decrease of M1 population while stretch upregulated M2b subpopulations. In summary, mechanical features of the lung ECM and stretch orchestrate anti-inflammatory and immunosuppressive outcomes of hLMSCs.

This Month in Anesthesiology

This Month in Anesthesiology

Beyond audit: Embracing QI methodology to drive improvements in lung-protective ventilation.

Mechanical ventilation supports patients with respiratory failure during critical illness. Evidence suggests that excessive tidal volumes (regarded as >8 mL/kg predicted body weight [PBW]) cause lung damage through increased lung stretch and alveolar inflammation. Lung-protective ventilation strategies have been shown to decrease morbidity and mortality, and that all patients should receive tidal volumes between 6 and 8 mls/kg PBW. Despite this, studies demonstrate that fewer than half of patients in critical care successfully receive lung-protective ventilation. The primary aim was to reduce tidal volumes delivered to all patients receiving mandatory ventilation, with a target of >85% of tidal volumes delivered to be compliant with lung-protective ventilation strategies by the end of November 2019. A multidisciplinary team of nurses and doctors, based in a UK tertiary hospital, utilized the Institute for Healthcare Improvement's (IHI) quality improvement methodology to improve compliance with lung-protective ventilation. Baseline data demonstrated that only 60.1% of tidal volumes recorded were compliant with lung-protective ventilation. Quality improvement (QI) methodology was utilized to systematically diagnose the aetiology of poor compliance and to produce and implement solutions. Real-time data collection and reporting were utilized to monitor and report improvement. Following 8 months of continuous data collection and repeated PDSA cycles, sustainable compliance with lung-protective ventilation for >85% of tidal volumes was achieved. The use of QI methodology to implement low tidal volume ventilation has shown a significant improvement in the delivery of lung-protective ventilation. Using QI methodology is central to this sustained improvement and offers a useful tool to systematically approach complex clinical problems. Lung protective ventilation is critically important in the management of ventilated patients, although compliance in intensive care is variable. Here, we describe how quality improvement methodology can lead to consistent and sustainable improvement in the delivery of lung protective ventilation.

Assessment of Postnatal Pulmonary Adaption in Bovine Neonates Using Electric Impedance Tomography (EIT).

Simple SummaryThe lungs of the neonate must oxygenate the blood and eliminate carbon dioxide at birth. Efficient gas exchange requires ventilation of the pulmonary alveoli to meet rapidly increasing oxygen demands. It is not entirely clear how quickly the different regions of the lungs become ventilated and when ventilation of all lung regions is achieved. We used electric impedance tomography (EIT) to measure lung stretch and aeration in 20 non-sedated neonatal calves born without difficulty. For EIT measurement, an electrode belt was placed around the thorax of each calf positioned in sternal recumbency immediately after birth and at various other times until 3 weeks of age to measure aeration and ventilation in different regions of the lungs. Standard EIT variables describing distribution of ventilation, respiratory rate, and several blood gas variables were determined. Most lung regions were ventilated immediately after birth. Ventilation of the ventral regions increased during the first hour, after which it decreased. Dorsal lung regions and the right lung had the greatest ventilation. The respiratory rate decreased, and the tidal impedance change as a surrogate for tidal volume increased in the first 3 weeks of life. The study showed that most regions of the lungs are ventilated immediately after birth. However, this is followed by a reduction in ventilation of ventral regions of the lungs, presumably because of gravity-driven ventral movement of residual amniotic fluid. These findings may allow identification of calves with insufficient lung expansion and ventilation after birth.Several aspects of postnatal pulmonary adaption in the bovine neonate remain unclear, particularly the dynamics and regional ventilation of the lungs. We used electric impedance tomography (EIT) to measure changes in ventilation in the first 3 weeks of life in 20 non-sedated neonatal calves born without difficulty in sternal recumbency. Arterial blood gas variables were determined in the first 24 h after birth. Immediately after birth, dorsal parts of the lungs had 4.53% ± 2.82% nondependent silent spaces (NSS), and ventral parts had 5.23% ± 2.66% dependent silent spaces (DSS). The latter increased in the first hour, presumably because of gravity-driven ventral movement of residual amniotic fluid. The remaining lung regions had good ventilation immediately after birth, and the percentage of lung regions with high ventilation increased significantly during the study period. The centre of ventilation was always dorsal to and on the right of the theoretical centre of ventilation. The right lung was responsible for a significantly larger proportion of ventilation (63.84% ± 12.74%, p < 0.00001) compared with the left lung. In the right lung, the centrodorsal lung area was the most ventilated, whereas, in the left lung, it was the centroventral area. Tidal impedance changes, serving as a surrogate for tidal volume, increased in the first 3 weeks of life (p < 0.00001). This study shows the dynamic changes in lung ventilation in the bovine neonate according to EIT measurements. The findings form a basis for the recognition of structural and functional lung disorders in neonatal calves.

Regional Gas Transport During Conventional and Oscillatory Ventilation Assessed by Xenon-Enhanced Computed Tomography.

Enhanced intrapulmonary gas transport enables oscillatory ventilation modalities to support gas exchange using extremely low tidal volumes at high frequencies. However, it is unknown whether gas transport rates can be improved by combining multiple frequencies of oscillation simultaneously. The goal of this study was to investigate distributed gas transport in vivo during multi-frequency oscillatory ventilation (MFOV) as compared with conventional mechanical ventilation (CMV) or high-frequency oscillatory ventilation (HFOV). We hypothesized that MFOV would result in more uniform rates of gas transport compared to HFOV, measured using contrast-enhanced CT imaging during wash-in of xenon gas. In 13 pigs, xenon wash-in equilibration rates were comparable between CMV and MFOV, but 21 to 39% slower for HFOV. By contrast, the root-mean-square delivered volume was lowest for MFOV, increased by 70% during HFOV and 365% during CMV. Overall gas transport heterogeneity was similar across all modalities, but gravitational gradients and regional patchiness of specific ventilation contributed to regional ventilation heterogeneity, depending on ventilator modality. We conclude that MFOV combines benefits of low lung stretch, similar to HFOV, but with fast rates of gas transport, similar to CMV.

Modeling lung stretch in 3D could help reduce injuries for lungs on ventilators

3D in-vitro models of lung vessels show how they react to the mechanical stresses of breathing. The findings sharply differ from previous research in 2D.

Novel Mechanical Strain Characterization of Ventilated ex vivo Porcine and Murine Lung using Digital Image Correlation.

Respiratory illnesses, such as bronchitis, emphysema, asthma, and COVID-19, substantially remodel lung tissue, deteriorate function, and culminate in a compromised breathing ability. Yet, the structural mechanics of the lung is significantly understudied. Classical pressure-volume air or saline inflation studies of the lung have attempted to characterize the organ’s elasticity and compliance, measuring deviatory responses in diseased states; however, these investigations are exclusively limited to the bulk composite or global response of the entire lung and disregard local expansion and stretch phenomena within the lung lobes, overlooking potentially valuable physiological insights, as particularly related to mechanical ventilation. Here, we present a method to collect the first non-contact, full-field deformation measures of ex vivo porcine and murine lungs and interface with a pressure-volume ventilation system to investigate lung behavior in real time. We share preliminary observations of heterogeneous and anisotropic strain distributions of the parenchymal surface, associative pressure-volume-strain loading dependencies during continuous loading, and consider the influence of inflation rate and maximum volume. This study serves as a crucial basis for future works to comprehensively characterize the regional response of the lung across various species, link local strains to global lung mechanics, examine the effect of breathing frequencies and volumes, investigate deformation gradients and evolutionary behaviors during breathing, and contrast healthy and pathological states. Measurements collected in this framework ultimately aim to inform predictive computational models and enable the effective development of ventilators and early diagnostic strategies.

Treatment-emergent central sleep apnea: a unique sleep-disordered breathing.

Treatment-emergent central sleep apnea (TECSA) is a specific form of sleep-disordered breathing, characterized by the emergence or persistence of central apneas during treatment for obstructive sleep apnea. The purpose of this review was to summarize the definition, epidemiology, potential mechanisms, clinical characteristics, and treatment of TECSA. We searched for relevant articles up to January 31, 2020, in the PubMed database. The prevalence of TECSA varied widely in different studies. The potential mechanisms leading to TECSA included ventilatory control instability, low arousal threshold, activation of lung stretch receptors, and prolonged circulation time. TECSA may be a self-limited disorder in some patients and could be resolved spontaneously over time with ongoing treatment of continuous positive airway pressure (CPAP). However, central apneas persist even with the regular CPAP therapy in some patients, and new treatment approaches such as adaptive servo-ventilation may be necessary. We concluded that several questions regarding TECSA remain, despite the findings of many studies, and it is necessary to carry out large surveys with basic scientific design and clinical trials for TECSA to clarify these irregularities. Further, it will be vital to evaluate the baseline demographic and polysomnographic data of TECSA patients more carefully and comprehensively.

Retracted: Control of hypoglossal pre-inspiratory discharge.

What is the topic of this review? This review explores the modulatory role of lung vagal afferents and intra-neuraxial and carotid body chemoreceptors upon hypoglossal pre-inspiratory activity. What advances does it highlight? Pre-inspiratory activity manifesting in hypoglossal neural efferent discharge may be potentiated by mechanical interruption of vagal continuity and challenge with administration of a hypoxic and/or hypercapnic gas mixture and attenuated by static and/or dynamic pulmonary stretch. Differential excitability of, or premotoneuronal volleys exhibiting distinct spatiotemporal patterns of discharge arriving at, motoneurons residing within the hypoglossal motor nucleus may emergently generate phase-spanning pre-inspiratory inspiratory activity of hypoglossal neural efferent discharge manifest at the population level. The hypoglossal nerve (XII) innervates muscles mediating excursive movements of the tongue. The population discharge of hypoglossalmotoneuronal axons constituting the hypoglossal nerve precedes and extends through the inspiratory epoch. The epoch subtended between the onsets of hypoglossal and phrenic neural discharge constitutes so-called pre-inspiration. Hypoglossal pre-inspiratory neural discharge serendipitously displaces the tongue along a tensor reducing upper airway resistance anticipative of succeeding inspiratory efforts. Hypoglossal motoneurons exhibiting discharge onset during pre-inspiration experience successive hyperpolarization of membrane voltage and attenuation of unitary spiking frequency, although a subset may, paradoxically and state-dependently, exhibit depolarization of membrane voltage and augmentation of neuronal spiking frequency, by dynamic stretch placed upon the alveolar walls and interstitium. Marked static elevation of positive-end expiratory pressure may induce hypoglossal bursting decoupled from phasic rhythmic phrenic discharge. Augmentation of the amplitude and/or duration of hypoglossal inspiratory discharge during successive pre-inspiratory and inspiratory epochs by inhalation of a hypoxic and/or hypercapnic gas mixture remains restrained in the presence of intact vagal inputs and is potentiated by interruptions of vagal continuity. Unravelling the mechanisms underlying the genesis of pre-inspiratory activity will inform our understanding of respiratory rhythm generation and pattern shaping. In the present work, I seek to explore the mechanisms underlying modulation of hypoglossal pre-inspiratory discharge by hypercapnia, hypoxia and static and dynamic lung stretch placed upon hypoglossal pre-inspiratory activity, the mechanisms underlying the generation of hypoglossal pre-inspiratory activity, and the extent of microanatomical and functional overlap between propriobulbar interneuronal microcircuits generating hypoglossal pre-inspiratory activity and propriobulbar interneuronal microcircuit oscillators generating pre-inspiratory activity inaugurally inducing respiratory rhythmic activity and thus use experimental data from previous work and that developed by other investigators to explore the modulatory role of lung vagal afferents and intra-neuraxial and carotid body chemoreceptors upon hypoglossal pre-inspiratory activity.

Autophagy in pulmonary macrophages mediates lung inflammatory injury via c-Src tyrosine kinase pathway activation during mechanical ventilation.

It has been clearly demonstrated that autophagy plays a critical role in mechanical ventilation-Induced lung injury (VILI). Herein, we first evaluated the mutual effects of autophagy and c-Src signaling on the lung inflammatory response to mechanical ventilation. Mice were respectively subjected to a lower or higher lung stretch induced by mechanical ventilation with low (7 mL/kg) or high (28 mL/kg) tidal volume, before measuring the activation of autophagy and c-Src signaling through LC3 lipidation and c-Src phosphorylation, respectively. Bone marrow-derived macrophages (BMDMs) were transfected with Atg5 siRNA and administered to AM-depleted mice to generate an autophagy-deficient phenotype, and c-Src signaling was evaluated by Western blot assay to determine the impact of autophagy on c-Src activation during VILI. Afterwards, the c-Src pathway was then blocked using PP2, prior to the evaluation of polymorphonuclear neutrophils (PMN), total cell counts in BAL fluid, and lung injury scores, in order to elucidate the role of the c-Src pathway in autophagy-mediated VILI. Both LC3-II and p-c-Src were remarkably increased after mechanical ventilation, in a time-dependent and tidal volume-dependent manner. Moreover, c-Src phosphorylation induced by ventilation was significantly compromised in autophagy-deficient mice. On the other hand, LC3-II expression did not change due to c-Src signaling abolishment. But the inflammatory response induced by injurious ventilation was markedly attenuated by PP2 or AM-abolishment, shown by PMN and total cell counts in BAL fluid, as well as lung injury scores. Our results suggested that autophagy caused VILI via regulating c-Src activation, which implies that c-Src may serve as a promising therapeutic target in VILI.

Mechanisms of sympathetic regulation during Apnea.

Volitional Apnea produces a robust peak sympathetic response through several interacting mechanisms. However, the specific contribution of each mechanism has not been elucidated. Muscle sympathetic activity was collected in participants (n = 10; 24 ± 3 years) that performed four maximal volitional apneas aimed at isolating lung‐stretch (mechanical) and chemoreflex drive: (Ainslie and Duffin 2009) end‐expiratory breath‐hold, (Ainslie et al. 2013) end‐inspiratory breath‐hold, (Alpher et al. 1986) prehyperventilation breath‐hold, and (Andersson and Schagatay 1998) prehyperoxia breath‐hold. A final repeated rebreathe breath‐hold protocol was performed to measure the peak sympathetic response during successive breath‐holds at increasing chemoreflex stress. Finally, the influence of dynamic ventilation was assessed through asphyxic rebreathe. Muscle sympathetic activity was calculated as the change in burst frequency (burst/min), burst incidence (burst/100 heart‐beats), and amplitude (au) between baseline and prevolitional breakpoint. Rebreathe was analyzed at similar chemoreflex stress as inspiratory breath‐hold. All maneuvers increased muscle sympathetic activity compared to baseline (P < 0.01). However, prehyperoxia exhibited a smaller increase (+22.18 ± 9.13 burst/min; +25.52 ± 11.7 burst/100 heart‐beats) compared to inspiratory, expiratory, and prehyperventilation breath‐holds. At similar chemoreflex strain, rebreathe sympathetic activity was blunted compared to inspiratory breath‐hold (P < 0.01). Finally, muscle sympathetic activity was not different between the repeated rebreathe trials, despite elevated chemoreflex stress and lower breath‐hold duration with each subsequent breath‐hold. We have demonstrated an obligatory role of the peripheral, but not central, chemoreflex (prehyperventilation vs. prehyperoxia) in producing peak sympathetic responses. At similar chemoreflex stresses the act of dynamic ventilation, but not static lung stretch per se, blunts muscle sympathetic activity. Finally, similar peak sympathetic responses during successive repeated breath‐holds suggest a sympathetic ceiling may exist.

Mechanical ventilation and Streptococcus pneumoniae pneumonia alter mitochondrial homeostasis

Required mechanical ventilation (MV) may contribute to bacterial dissemination in patients with Streptococcus pneumoniae pneumonia. Significant variations in plasma mitochondrial DNA (mtDNA) have been reported in sepsis according to the outcome. The impact of lung stretch during MV was addressed in a model of pneumonia. Healthy or S. pneumoniae infected rabbits were submitted to MV or kept spontaneously breathing (SB). Bacterial burden, cytokines release, mitochondrial DNA levels, integrity and transcription were assessed along with 48-hour mortality. Compared with infected SB rabbits, MV rabbits developed more severe pneumonia with greater concentrations of bacteria in the lungs, higher rates of systemic dissemination, higher levels of circulating inflammatory mediators and decreased survival. Pulmonary mtDNA levels were significantly lower in infected animals as compared to non-infected ones, whenever they were SB or MV. After a significant early drop, circulating mtDNA levels returned to baseline values in the infected SB rabbits, but remained low until death in the MV ones. Whole blood ex-vivo stimulation with Streptococcus pneumoniae resulted in a reduction of polymorphonuclear leukocytes mitochondrial density and plasma mtDNA concentrations. Thus, persistent mitochondrial depletion and dysfunction in the infected animals submitted to MV could account for their less efficient immune response against S. pneumoniae.

Role for Cela1 in Postnatal Lung Remodeling and Alpha-1 Antitrypsin-Deficient Emphysema.

Alpha-1 antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplant. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro. We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and to detect any effects it may have in the context of AAT deficiency. The lungs of Cela1-/- mice had aberrant lung elastin structure and higher elastance as assessed with the flexiVent system. On the basis of in situ zymography with ex vivo lung stretch, Cela1 was solely responsible for stretch-inducible lung elastase activity. By mass spectrometry, Cela1 degraded mature elastin similarly to pancreatic elastase. Cela1 promoter and protein sequences were phylogenetically distinct in the placental mammal lineage, suggesting an adaptive role for lung-expressed Cela1 in this clade. A 6-week antisense oligonucleotide mouse model of AAT deficiency resulted in emphysema with increased Cela1 mRNA and reduction of approximately 70 kD Cela1, consistent with covalent binding of Cela1 by AAT. Cela1-/- mice were completely protected against emphysema in this model. Cela1 was increased in human AAT-deficient emphysema. Cela1 is important in physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung. AAT is an important regulator of this process. Our findings provide proof of concept for the development of anti-Cela1 therapies to prevent and/or treat AAT-deficient emphysema.

Mechanical Ventilation Induces Desensitization of Lung Axl Tyrosine Kinase Receptors.

Lower tidal volumes are increasingly used in acute respiratory distress syndrome, but mortality has changed little in the last 20 yr. Therefore, in addition to ventilator settings, it is important to target molecular mediators of injury. Sepsis and other inflammatory states increase circulating concentrations of Gas6, a ligand for the antiinflammatory receptor Axl, and of a soluble decoy form of Axl. We investigated the effects of lung stretch on Axl signaling. We used a mouse model of early injury from high tidal volume and assessed the effects of inhibiting Axl on in vivo lung injury (using an antagonist R428, n = 4/group). We further determined the effects of stretch on Axl activation using in vitro lung endothelial cells. High tidal volume caused mild injury (compliance decreased 6%) as intended, and shedding of the Axl receptor (soluble Axl in bronchoalveolar fluid increased 77%). The Axl antagonist R428 blocked the principal downstream Axl target (suppressor of cytokine signaling 3 [SOCS3]) but did not worsen lung physiology or inflammation. Cyclic stretch in vitro caused Axl to become insensitive to activation by its agonist, Gas6. Finally, in vitro Axl responses were rescued by blocking stretch-activated calcium channels (using guanidinium chloride [GdCl3]), and the calcium ionophore ionomycin replicated the effect of stretch. These data suggest that lung endothelial cell overdistention activates ion channels, and the resultant influx of Ca inactivates Axl. Downstream inactivation of Axl by stretch was not anticipated; preventing this would be required to exploit Axl receptors in reducing lung injury.

Abstract PCCLB-59: MORPHOLOGICAL CHANGES FOLLOWING EXPERIMENTAL LUNG RECRUITMENT IN DIFFERENT CHEST WALL ELASTANCE

Aims & Objectives: Background: The previous studies have showed the evidence of high-end inspiratory lung stretch lead to diffuse alveolar damage as an impact of the stress and strain during mechanical ventilation. Aims: To observe the morphological changes of the lung tissues and cells following acute experimental lung recruitment. Methods We conduct the experimental study using piglet as animal model of VILI. Nine eligible healthy mixed breed domestic piglets were divided into 2 groups: splinted chest wall (weight 5.680 ± 1.362 kg) and control (weight 6.250 ± 1.121 kg). Animals were anesthetized, paralyzed with supine position and ventilated in pressure control mode with the target tidal volume 4–5 mL/kgBW. After warm saline bronchial lavage, recruitment maneuver was performed in staircase increment-decrement technique. The lung tissues were obtained the morphologic changes by using the modified American Thoracic Society lung injury score. The cellular damages were recognized by detected apoptosis with TUNEL assay. Results Recruitment maneuver was proven improve the oxygenation and maintain the gas exchange in all of groups. The lung tissue infiltrated of neutrophils in alveolar and interstitial space, formation of hyaline membranes and proteinaceous debris filling the airspaces. Apoptosis of the epithelium cells was no statistically significant difference between intervention and control group. The ultra-structure analysis showed that lamellar bodies of pneumocyte type II of control group were intact. The lamellar bodies of pneumocytes type II in intervention group were condensate and forming lumps, some nuclear membrane was rupture. Conclusions There were different changes of lung tissues and cells morphology following lung recruitment in the different chest wall elastance.

High Positive End-Expiratory Pressure Renders Spontaneous Effort Noninjurious.

In acute respiratory distress syndrome (ARDS), atelectatic solid-like lung tissue impairs transmission of negative swings in pleural pressure (Ppl) that result from diaphragmatic contraction. The localization of more negative Ppl proportionally increases dependent lung stretch by drawing gas either from other lung regions (e.g., nondependent lung [pendelluft]) or from the ventilator. Lowering the level of spontaneous effort and/or converting solid-like to fluid-like lung might render spontaneous effort noninjurious. To determine whether spontaneous effort increases dependent lung injury, and whether such injury would be reduced by recruiting atelectatic solid-like lung with positive end-expiratory pressure (PEEP). Established models of severe ARDS (rabbit, pig) were used. Regional histology (rabbit), inflammation (positron emission tomography; pig), regional inspiratory Ppl (intrabronchial balloon manometry), and stretch (electrical impedance tomography; pig) were measured. Respiratory drive was evaluated in 11 patients with ARDS. Although injury during muscle paralysis was predominantly in nondependent and middle lung regions at low (vs. high) PEEP, strong inspiratory effort increased injury (indicated by positron emission tomography and histology) in dependent lung. Stronger effort (vs. muscle paralysis) caused local overstretch and greater tidal recruitment in dependent lung, where more negative Ppl was localized and greater stretch was generated. In contrast, high PEEP minimized lung injury by more uniformly distributing negative Ppl, and lowering the magnitude of spontaneous effort (i.e., deflection in esophageal pressure observed in rabbits, pigs, and patients). Strong effort increased dependent lung injury, where higher local lung stress and stretch was generated; effort-dependent lung injury was minimized by high PEEP in severe ARDS, which may offset need for paralysis.

Mechanisms involved in brain dysfunction in mechanically ventilated critically ill patients: implications and therapeutics.

Critical illness may lead to significant long-term neurological morbidity and patients frequently develop neuropsychological disturbances including acute delirium or memory impairment after intensive care unit (ICU) discharge. Mechanical ventilation (MV) is a risk factor to the development of adverse neurocognitive outcomes. Patients undergoing MV for long periods present neurologic impairment with memory and cognitive alteration. Delirium is considered an acute form of brain dysfunction and its prevalence rises in mechanically ventilated patients. Delirium duration is an independent predictor of mortality, ventilation time, ICU length of stay and short- and long-term cognitive impairment in the ICU survivors. Although, neurocognitive sequelae tend to improve after hospital discharge, residual deficits persist even 6 years after ICU stay. ICU-related neurocognitive impairments occurred in many cognitive domains and are particularly pronounced with regard to memory, executive functions, attentional functions, and processing speed. These sequelae have an important impact on patients' lives and ICU survivors often require institutionalization and hospitalization. Experimental studies have served to explore the possible mechanisms or pathways involved in this lung to brain interaction. This communication can be mediated via a complex web of signaling events involving neural, inflammatory, immunologic and neuroendocrine pathways. MV can affect respiratory networks and the application of protective ventilation strategies is mandatory in order to prevent adverse effects. Therefore, strategies focused to minimize lung stretch may improve outcomes, avoiding failure of distal organ, including the brain. Long-term neurocognitive impairments experienced by critically ill survivors may be mitigated by early interventions, combining cognitive and physical therapies. Inpatient rehabilitation interventions in ICU promise to improve outcomes in critically ill patients. The cross-talk between lung and brain, involving specific pathways during critical illness deserves further efforts to evaluate, prevent and improve cognitive alterations after ICU admission, and highlights the crucial importance of tailoring MV to prevent adverse outcomes.