BACKGROUND:Robotic-assisted laparoscopic surgery (RALS) in a steep Trendelenburg position creates conditions conducive to cyclical alveolar collapse when using standard lung protective ventilation settings (LPV). The magnitude of force induced by alveolar collapse and expansion is predicted to cause a localized injury, but biological evidence of perioperative atelectrauma is lacking. We hypothesized that the negative transpulmonary pressures and increased dissipated power of ventilation encountered during RALS lead to injury of the dependent (apical) lung despite the use of LPV settings. METHODS:We conducted a single-center, observational study of lung mechanics and injury in 15 subjects (8 M/7F; mean ± standard deviation: 59.5 ± 7.4 years) without lung disease undergoing RALS with LPV at an academic hospital in the United States. Subjects had a median body mass index of 32.5 kg/m2 with a range of 24.3 to 50.9 kg/m2. We continuously measured lung mechanics, including transpulmonary pressures. Bronchoalveolar lavages (BAL) were obtained from apical and anteromedial subsegments after intubation and from contralateral subsegments before extubation. During RALS, the apical lung is dependent and the anteromedial lung in nondependent. BAL analyses included total protein concentrations, proteomics, lipidomics, and leukocyte counts. RESULTS:Lung mechanics were impaired, with elevated respiratory elastance and driving pressures, and negative end-expiratory transpulmonary pressures, despite standard LPV settings (tidal volume 7.0 ± 0.8 mL/kg ideal body weight; positive end-expiratory pressure 8.7 ± 3.4 cm H2O). Increases in total protein (median [interquartile range], 131 [27-193] µg/mL), extracellular matrix components (fibulin-1: 2.1 [1.6-4.0] fold; microfibril-associated glycoprotein-4: 2.2 [1.3-4.0] fold), and procoagulants (prothrombin: 1.7 [1.3-4.8] fold; plasminogen: 3.2 [1.9-4.5] fold) were observed in apical BAL after surgery (adj. P < .001 for all), but not in anteromedial BAL (adj. P > .05). No differences in percent leukocyte composition were observed among lavages (P > .287 for all cell types). Phosphatidylglycerol abundance was increased in apical BAL after surgery in unadjusted analyses (5.8 [1.9-7.9] %, P = .021), but no changes in phospholipid abundance were noted in adjusted analysis. Increases in apical BAL total protein were positively correlated with the dissipated mechanical power of ventilation (r2 = 0.434, P = .014). CONCLUSIONS:In this focused biomechanical study, we found molecular evidence for alveolar-capillary damage in the dependent apical lobes, consistent with localized atelectrauma. Regional atelectrauma from impaired lung mechanics can occur in the positionally dependent lung while using LPV settings during RALS, most likely from insufficient end-expiratory pressure.

Most people with severe asthma have obesity. Metabolic dysfunction, often associated with obesity, is particularly associated with severe asthma. Mechanisms linking metabolic dysfunction with asthma, and whether improving metabolic function can affect asthma, are not known. The endocannabinoid system plays a significant role in metabolism; inhibition of cannabinoid receptor 1 (CB1R) induces weight loss and improves serum lipid profiles. We used a CB1R inverse agonist, INV-202, in a mouse model of obese asthma and investigated changes in weight, inflammation, airway reactivity, and surfactant lipids. Mice were fed low or high-fat diets (LFD, HFD), and house dust mite (HDM) extract was delivered intranasally to induce allergic airway inflammation. Mice received INV-202 by oral gavage. Airway hyperresponsiveness was measured by FlexiVent, and lung tissue cytokines were measured by ELISA. Leukocytes and lipids in the bronchoalveolar lavage fluid (BALF) were analyzed by flow cytometry and mass spectroscopy, respectively. LFD and HFD mice lost an average of 11% and 27% of their body weight, respectively. LFD mice had a 33% decrease in CCL20 in lung tissue and a 55% decrease in neutrophils in BALF. LFD and HFD mice had improvements in airway hyperresponsiveness, particularly as measured by reduced elastance. Phosphatidylglycerol in BALF increased with INV-202, which significantly correlated with compliance in LFD mice. This study supports a significant contribution of metabolic factors related to the endocannabinoid system in lung compliance and airway reactivity, in part through effects on surfactant lipid composition, and demonstrates the potential of CB1R inverse agonists to treat obese asthma.NEW & NOTEWORTHY Inhibition of the cannabinoid receptor 1, through a pharmacological inverse agonist, not only induces weight loss in a mouse model of obese asthma but also reduces airway hyperresponsiveness, particularly through decreasing elastance/increasing compliance.

BACKGROUND:Mechanical ventilation and selecting optimal positive end-expiratory pressure (PEEP) in patients across a wide range of body mass indexes (BMI) is challenging. Adjusting PEEP to BMI using the equation BMI divided by 3 ('BMI/3') or setting a PEEP of 10 cmH2O in obesity has been proposed; our objective is to describe the difference between 'BMI/3' and PEEP 10 cmH2O as compared to optimal PEEP by esophageal manometry. METHODS:Esophageal manometry was used in patients undergoing laparoscopic abdominal surgery to estimate pleural pressure, transpulmonary pressure, and optimal physiological PEEP across a range of BMIs. Methods of estimating optimal PEEP in patients with normal and elevated BMI, namely 'BMI/3' and PEEP of 10 cmH2O, were compared to estimates of optimal physiological PEEP as measured by an end-expiratory esophageal pressure-based transpulmonary pressure of 0 cmH2O. RESULTS:A total of 109 patients were included for analysis. Thirty-seven percent had 'BMI/3' estimated PEEP values within ±2 cmH2O of optimal physiological PEEP measured by esophageal pressure-based transpulmonary pressure. A set PEEP of 10 cmH2O correctly estimated optimal physiologic PEEP (±2 cmH2O) in only 27% of patients. The mean optimal physiologic PEEP measured by esophageal pressure-based transpulmonary pressure is closely approximated by the mean estimated PEEP derived by 'BMI/3'. However, the ranges of individualized optimal physiologic PEEP are wider than PEEP estimated by 'BMI/3' across BMI categories. CONCLUSIONS:BMI/3' estimated the mean optimal PEEP as measured by esophageal pressure-based transpulmonary pressure and may serve as a starting point for PEEP in patients with increased BMI. However, this purely anthropometric method fails to capture the individual variability of the chest wall and pleural pressure and most often results in inadequate or excessive PEEP as compared to optimal PEEP based on esophageal manometry.

Obesity contributes to pulmonary dysfunction through poorly understood biochemical mechanisms. Chronic inflammation and altered cellular metabolism have emerged as pathological changes across organ systems in obesity, but whether similar changes occur in lungs with obesity is unknown. We collected bronchoalveolar lavage fluid (BALF) from right upper lobe and lingula pulmonary subsegments of 14 adults (7 males/7 females) with body mass indexes (BMIs) ranging from 24.3 to 50.9 kg/m2 without lung disease. Proteomes were measured using sequential window acquisition of all theoretical fragment ion spectra (SWATH) mass spectrometry. Proteomic composition and pathway enrichments were examined for the cohort and as a function of BMI. BALF proteomic compositions were consistent with earlier studies and had improved protein identification. We found minimal differences in BALF proteomes between lavage regions. Five proteins were strongly correlated with BMI (False Detection Rate/FDR-adjusted P values < 0.05) and 11 had weaker correlation (FDR-adjusted P values 0.05-0.1). These proteins included acute phase reactants and complement factors. Few proteomic differences between biological sexes were detected, but some of them coincided with BMI-related proteins. Pathway enrichments impacted by BMI included innate immunity, antifibrinolysis, oxidative stress, and lipid metabolism. The bronchoalveolar microenvironment is altered by obesity in humans without lung disease. Pathway alterations associated with BMI included coagulation and fibrinolysis, redox and oxidative stress, energy metabolism, and humoral immune function. Our data support the theory that conserved biochemical and cellular changes in obesity may be fundamental mechanisms of dysfunction in multiple tissues but the specific impact on pulmonary function or disease is not yet known.NEW & NOTEWORTHY Obesity is thought to cause deleterious changes in lung biochemistry, but data in humans are lacking. We measured the alveolar proteome in bronchoalveolar lavages from subjects with a wide range of body mass index and no lung disease. We found changes in proteins and pathways associated with increasing body mass index that are similar to pathological changes observed in other tissues and may constitute mechanisms of pulmonary dysfunction in obesity.

RATIONALE: Lung protective ventilation is the standard of care in intraoperative ventilation. However, these strategies have been shown to cause impairment in lung mechanics and may be suboptimal in patients undergoing robotic assisted laparoscopic surgery (RALS). Nonlinear mathematical descriptors of lung mechanics (volume dependent elastance %E2, and the stress index) quantify lung overdistension and/or regional collapse in acute respiratory distress syndrome. Accordingly, we used nonlinear models to understand the mechanical impairments in ventilation during RALS. METHODS: In a secondary analysis of airway and esophageal pressures and gas flows collected from 109 subjects (45/65 M/F, Age 27 to 77) with body mass index (BMI) ranging from 18 to 60 kg/m2 undergoing RALS, we calculated %E2 and the stress index at 4 surgical stages: flat after intubation, with pneumoperitoneum, in steep Trendelenburg, and after desufflation. We determined %E2 in 109 subjects (71 to 106 subjects per position) and the stress index in 48 subjects (29 to 48 subjects per position). Association between %E2 and the stress index was determined by analysis of variance (ANOVA). RESULTS: The average %E2 was -14±14 in the flat stage and averaged -11.8±16 in pneumoperitoneum and steep Trendelenburg (p<0.001) as seen in Figure 1A. The average stress index was 0.4±0.16 in the flat stage and increased to an average of 0.6±0.14 in pneumoperitoneum and steep Trendelenburg (p<0.001) as seen in Figure 1B. Both %E2 and stress index were invariant to BMI, and the two parameters were not correlated (r2=0.031, p=0.078). CONCLUSION: Our consistent finding of %E2<0 and stress index<1 suggests significant levels of lung derecruitment in our patients, despite the lack of correlation between the two parameters. Studies in animal models have shown that these parameters correlate strongly in non-injured lungs but become discordant in lung injury. While the lungs of our patients were not injured, they were operating far from normal conditions, which we speculate may have caused a similar effect due to the mechanical instabilities caused by positional depressions in lung volume.

The purpose of this chapter is to describe the clinical outcomes for obese patients with acute respiratory distress syndrome (ARDS). We review the pathogenesis of ARDS and how it is modified by the pathophysiologic changes of obesity. We discuss the potential impact of obesity on ventilator-induced lung injury in ARDS and outline strategies for management of critically ill ventilated patients with obesity.

Obesity may lead to pulmonary dysfunction through complex and incompletely understood cellular and biochemical effects. Altered lung lipid metabolism has been identified as a potential mechanism of lung dysfunction in obesity. Although murine models of obesity demonstrate changes in pulmonary surfactant phospholipid composition and function, data in humans are lacking. We measured untargeted shotgun lipidomes in two bronchoalveolar lavages (BALs) from apical and anteromedial pulmonary subsegments of 14 adult subjects (7 males and 7 females) with body mass indexes (BMIs) ranging from 24.3 to 50.9 kg/m2. The lipidome composition was characterized at the class, species, and fatty acyl/alkyl level using total lipid molecular ion signal intensities normalized to BAL protein concentration and epithelial lining fluid volumes. Multivariate analyses were conducted to identify potential changes with increasing BMI. The alveolar lipidomes contained the expected composition of surfactant-associated phospholipids, sphingolipids, and sterols in addition to cardiolipin and intracellular signaling lipid species. No significant differences in lipidomes were detected between the two BAL regions. Though a small number of lipid species were associated with BMI in multivariate analyses, no robust differences in lipidome composition or specific lipid species were identified over the range of body habitus. The magnitude of obesity alone does not substantially alter the alveolar lipidome in patients without lung disease. Differences in lung function in patients with obesity and no lung disease are unlikely related to changes in alveolar lipid composition.NEW & NOTEWORTHY Altered lung lipid metabolism has been identified as a potential mechanism of lung dysfunction in obesity, but data in humans are lacking. We measured the alveolar lipidome in bronchoalveolar lavages from subjects with healthy lungs with a wide range of body mass index. There were no differences in lipidome composition in association with the magnitude of obesity. In patients with healthy lungs, obesity alone does not alter the alveolar lipidome.

Alterations in perioperative metabolic function, particularly hyperglycemia, are associated with increased post-operative complications, even in patients without preexisting metabolic abnormalities. Anesthetic medications and the neuroendocrine stress response to surgery may both contribute to altered energy metabolism through impaired glucose and insulin homeostasis but the discrete pathways involved are unclear. Prior human studies, though informative, have been limited by analytic sensitivity or technique, preventing resolution of underlying mechanisms. We hypothesized that general anesthesia with a volatile agent would suppress basal insulin secretion without altering hepatic insulin extraction, and that surgical stress would promote hyperglycemia through gluconeogenesis, lipid oxidation, and insulin resistance. In order to address these hypotheses, we conducted an observational study of subjects undergoing multi-level lumbar surgery with an inhaled anesthetic agent. We measured circulating glucose, insulin, c-peptide, and cortisol frequently throughout the perioperative period and analyzed the circulating metabolome in a subset of these samples. We found volatile anesthetic agents suppress basal insulin secretion and uncouple glucose-stimulated insulin secretion. Following surgical stimulus, this inhibition disappeared and there was gluconeogenesis with selective amino acid metabolism. No robust evidence of lipid metabolism or insulin resistance was observed. These results show that volatile anesthetic agents suppress basal insulin secretion, which results in reduced glucose metabolism. The neuroendocrine stress response to surgery ameliorates the inhibitory effect of the volatile agent on insulin secretion and glucose metabolism, promoting catabolic gluconeogenesis. A better understanding of the complex metabolic interaction between anesthetic medications and surgical stress is needed to inform design of clinical pathways aimed at improving perioperative metabolic function.

Mechanical power describes the complex interaction between a patient’s lungs and the ventilator and may be useful in predicting lung injury. However, its behavior in obesity and during dynamic surgical conditions is not understood. We comprehensively quantified ventilation bioenergetics and effects of body habitus and common surgical conditions. These data show body habitus is a prime determinant of intraoperative mechanical power and provide quantitative context for future translation toward a useful perioperative prognostic measurement.

Pioglitazone, a PPARγ agonist, is used to treat type 2 diabetes (T2D). PPARγ is highly expressed in adipose tissue (AT), however the effects of pioglitazone to improve insulin sensitivity are also evident in other tissues and PPARγ agonism has been shown to alter cancer derived extracellular vesicle (EV)-miRNAs. We hypothesized that pioglitazone modifies the cargo of circulating AT-derived EVs to alter interorgan crosstalk in people with diabetes. We tested our hypothesis in a 3-month trial in which 24 subjects with T2D were randomized to treatment with either pioglitazone 45 mg/day or placebo (NCT00656864). Levels of 42 adipocyte-derived EV-miRNAs were measured in plasma EVs using low density TaqMan arrays. Levels of differentially expressed EV-miRNAs and their most relevant target genes were also measure in adipose tissue from the same participants, using individual TaqMan assays. Levels of 5 miRNAs (i.e., miR-7-5p, miR-20a-5p, miR-92a-3p, miR-195-5p, and miR-374b-5p) were significantly downregulated in EVs in response to pioglitazone treatment relative to placebo. The opposite occurred for miR-195-5p in subcutaneous AT. Changes in miRNA expression in EVs and AT correlated with changes in suppression of lipolysis and improved insulin sensitivity, among others. DICER was downregulated and exosomal miRNA sorting-related genes YBX1 and hnRNPA2B1 displayed a downregulation trend in AT. Furthermore, analysis of EV-miRNA targeted genes identified a network of transcripts that changed in a coordinated manner in AT. Collectively, our results suggest that some beneficial pharmacologic effects of pioglitazone are mediated by adipose-specific miRNA regulation and exosomal/EV trafficking.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT00656864.