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Objective To evaluate the effects of intraoperative protective ventilation on major postoperative respiratory complications and to define safe intraoperative mechanical ventilator settings that do not translate into an increased risk of postoperative respiratory complications.Design Hospital based registry study.Setting Academic tertiary care hospital and two affiliated community hospitals in Massachusetts, United States.Participants 69 265 consecutively enrolled patients over the age of 18 who underwent a non-cardiac surgical procedure between January 2007 and August 2014 and required general anesthesia with endotracheal intubation.Interventions Protective ventilation, defined as a median positive end expiratory pressure (PEEP) of 5 cmH2O or more, a median tidal volume of less than 10 mL/kg of predicted body weight, and a median plateau pressure of less than 30 cmH2O.Main outcome measure Composite outcome of major respiratory complications, including pulmonary edema, respiratory failure, pneumonia, and re-intubation.Results Of the 69 265 enrolled patients 34 800 (50.2%) received protective ventilation and 34 465 (49.8%) received non-protective ventilation intraoperatively. Protective ventilation was associated with a decreased risk of postoperative respiratory complications in multivariable regression (adjusted odds ratio 0.90, 95% confidence interval 0.82 to 0.98, P=0.013). The results were similar in the propensity score matched cohort (odds ratio 0.89, 95% confidence interval 0.83 to 0.97, P=0.004). A PEEP of 5 cmH2O and median plateau pressures of 16 cmH2O or less were associated with the lowest risk of postoperative respiratory complications.Conclusions Intraoperative protective ventilation was associated with a decreased risk of postoperative respiratory complications. A PEEP of 5 cmH2O and a plateau pressure of 16 cmH2O or less were identified as protective mechanical ventilator settings. These findings suggest that protective thresholds differ for intraoperative ventilation in patients with normal lungs compared with those used for patients with acute lung injury.

The contribution of aeration heterogeneity to lung injury during early mechanical ventilation of uninjured lungs is unknown. To test the hypotheses that a strategy consistent with clinical practice does not protect from worsening in lung strains during the first 24 hours of ventilation of initially normal lungs exposed to mild systemic endotoxemia in supine versus prone position, and that local neutrophilic inflammation is associated with local strain and blood volume at global strains below a proposed injurious threshold. Voxel-level aeration and tidal strain were assessed by computed tomography in sheep ventilated with low Vt and positive end-expiratory pressure while receiving intravenous endotoxin. Regional inflammation and blood volume were estimated from 2-deoxy-2-[(18)F]fluoro-d-glucose ( F-FDG) positron emission tomography. Spatial heterogeneity of aeration and strain increased only in supine lungs (P < 0.001), with higher strains and atelectasis than prone at 24 hours. Absolute strains were lower than those considered globally injurious. Strains redistributed to higher aeration areas as lung injury progressed in supine lungs. At 24 hours, tissue-normalized F-FDG uptake increased more in atelectatic and moderately high-aeration regions (>70%) than in normally aerated regions (P < 0.01), with differential mechanistically relevant regional gene expression. F-FDG phosphorylation rate was associated with strain and blood volume. Imaging findings were confirmed in ventilated patients with sepsis. Mechanical ventilation consistent with clinical practice did not generate excessive regional strain in heterogeneously aerated supine lungs. However, it allowed worsening of spatial strain distribution in these lungs, associated with increased inflammation. Our results support the implementation of early aeration homogenization in normal lungs.

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.

Postoperative pulmonary complications (PPCs) are a major cause of morbidity and mortality after open abdominal surgery. Optimized perioperative lung expansion may minimize the synergistic factors responsible for the multiple-hit perioperative pulmonary dysfunction. This ongoing study will assess whether an anesthesia-centered bundle focused on perioperative lung expansion results in decreased incidence and severity of PPCs after open abdominal surgery. Prospective multicenter randomized controlled pragmatic trial in 750 adult patients with at least moderate risk for PPCs undergoing prolonged (≥2 hour) open abdominal surgery. Participants are randomized to receive either a bundle intervention focused on perioperative lung expansion or usual care. The bundle intervention includes preoperative patient education, intraoperative protective ventilation with individualized positive end-expiratory pressure to maximize respiratory system compliance, optimized neuromuscular blockade and reversal management, and postoperative incentive spirometry and early mobilization. Primary outcome is the distribution of the highest PPC severity by postoperative day 7. Secondary outcomes include the proportion of participants with: PPC grades 1-2 through POD 7; PPC grades 3-4 through POD 7, 30 and 90; intraoperative hypoxemia, rescue recruitment maneuvers, or cardiovascular events; and any major extrapulmonary postoperative complications. Additional secondary and exploratory outcomes include individual PPCs by POD 7, length of postoperative oxygen therapy or other respiratory support, hospital resource use parameters, Patient-Reported Outcomes Measurements (PROMIS®) questionnaires for dyspnea and fatigue collected before and at days 7, 30 and 90 after surgery, and plasma concentrations of lung injury biomarkers (IL6, IL-8, RAGE, CC16, Ang-2) analyzed from samples obtained before, end of, and 24 hours after surgery. Participant recruitment for this study started January 2020; results are expected in 2024. At the conclusion of this trial, we will determine if this anesthesia-centered strategy focused on perioperative lung expansion reduces lung morbidity and healthcare utilization after open abdominal surgery. ClinicalTrial.gov NCT04108130.

Atelectasis is a frequent clinical condition, yet knowledge is limited and controversial on its biological contribution towards lung injury. We assessed the regional proteomics of atelectatic versus normally-aerated lung tissue to test the hypothesis that immune and alveolar-capillary barrier functions are compromised by purely atelectasis and dysregulated by additional systemic inflammation (lipopolysaccharide, LPS). Without LPS, 130 proteins were differentially abundant in atelectasis versus aerated lung, mostly (n = 126) with less abundance together with negatively enriched processes in immune, endothelial and epithelial function, and Hippo signaling pathway. Instead, LPS-exposed atelectasis produced 174 differentially abundant proteins, mostly (n = 108) increased including acute lung injury marker RAGE and chemokine CCL5. Functional analysis indicated enhanced leukocyte processes and negatively enriched cell–matrix adhesion and cell junction assembly with LPS. Additionally, extracellular matrix organization and TGF-β signaling were negatively enriched in atelectasis with decreased adhesive glycoprotein THBS1 regardless of LPS. Concordance of a subset of transcriptomics and proteomics revealed overlap of leukocyte-related gene-protein pairs and processes. Together, proteomics of exclusively atelectasis indicates decreased immune response, which converts into an increased response with LPS. Alveolar-capillary barrier function-related proteomics response is down-regulated in atelectasis irrespective of LPS. Specific proteomics signatures suggest biological mechanistic and therapeutic targets for atelectasis-associated lung injury.

Background: Lysosomal-associated membrane protein 1 (LAMP1), typically localized to the lysosomal membrane, is increasingly implicated as a marker of cancer aggressiveness and metastasis when expressed on the cell surface. This study aimed to develop a LAMP1-targeted antibody-based PET tracer and assess its efficacy in mouse models of human breast and colon adenocarcinoma. Methods: To determine the source of LAMP1 expression, we utilized human single-cell RNA sequencing and spatial transcriptomics, complemented by in-house flow cytometry on xenografted mouse models. Tissue microarrays of multiple epithelial cancers and normal tissue were stained for LAMP-1, and staining was quantified. An anti-LAMP1 monoclonal antibody was conjugated with desferrioxamine (DFO) and labeled with zirconium-89 (89Zr). Human triple-negative breast cancer (MDA-MB-231) and colon cancer (Caco-2) cell lines were implanted in nude mice. PET/CT imaging was conducted at 24, 72, and 168 h post-intravenous injection of 89Zr-DFO-anti-LAMP1 and 89Zr-DFO-IgG (negative control), followed by organ-specific biodistribution analyses at the final imaging time point. Results: Integrated single-cell and spatial RNA sequencing demonstrated that LAMP1 expression was localized to myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) in addition to the cancer cells. Tissue microarray showed significantly higher staining for LAMP-1 in tumor tissue compared to normal tissue (3986 ± 2635 vs. 1299 ± 1291, p < 0.001). Additionally, xenograft models showed a significantly higher contribution of cancer cells than the immune cells to cell surface LAMP1 expression. In vivo, PET imaging with 89Zr-DFO-anti-LAMP1 PET/CT revealed detectable tumor uptake as early as 24 h post-injection. The 89Zr-DFO-anti-LAMP1 tracer demonstrated significantly higher uptake than the control 89Zr-DFO-IgG in both models across all time points (MDA-MB-231 SUVmax at 168 h: 12.9 ± 5.7 vs. 4.4 ± 2.4, p = 0.003; Caco-2 SUVmax at 168 h: 8.53 ± 3.03 vs. 3.38 ± 1.25, p < 0.01). Conclusions: Imaging of cell surface LAMP-1 in breast and colon adenocarcinoma is feasible by immuno-PET. LAMP-1 imaging can be expanded to adenocarcinomas of other origins, such as prostate and pancreas.

To develop and validate a delirium risk prediction preoperative model for patients undergoing cardiac surgery. Observational prospective multicentre study. Six intensive care units in Spain. 689 patients undergoing cardiac surgery consecutively, aged ≥18 years. The primary outcome measure was the development of delirium, diagnosed using the Confusion Assessment Method in Intensive Care Units (CAM-ICU), during the stay in the intensive care unit after cardiac surgery. The model was developed with 345 consecutive patients undergoing cardiac surgery at six hospitals and validated with another 344 patients from the same hospitals. The prediction model contained four preoperative risk factors: age over 65 years, Mini-Mental State Examination (MMSE) score of 25–26 points (possible impairment of cognitive function) or < 25 (impairment of cognitive function), insomnia needing medical treatment and low physical activity (walk less than 30 min a day). The model had an area under the receiver operating characteristics curve of 0.825 (95% confidence interval: 0.76–0.89). The validation resulted in an area under the curve of 0.79 (0.73–0.85) and the pooled area under the receiver operating characteristics curve (n = 689) was 0.81 (0.76–0.85). We stratified patients in groups of low (0%–20%), moderate (> 20%–40%), high (> 40%–60%) and very high (> 60%) risk of developing delirium, with a positive and negative predictive value for the very high risk group of 70.97% and 85.56%, respectively. The DELIPRECAS model (DELIrium PREvention CArdiac Surgery), consisting of four well-defined clinical risk factors, can predict in the preoperative period the risk of developing postoperative delirium in patients undergoing cardiac surgery. An automatic version of the risk calculator is available. •A delirium prediction model has been developed and validated for cardiac surgery patients.•The DELIPRECAS model predicts the risk of postoperative delirium with 4 preoperative risk factors.•This new model facilitates the use of preventive measures in high-risk patients.

Low-tidal volume (Vt) ventilation might protect healthy lungs from volutrauma but lead to inflammation resulting from other mechanisms, namely alveolar derecruitment and the ensuing alveolar collapse and tidal reexpansion. We hypothesized that the different mechanisms of low- and high-volume injury would be reflected in different mechanical properties being associated with development of pulmonary inflammation and mortality: an increase of hysteresis, reflecting progressive alveolar derecruitment, at low Vt; an increase of elastance, as a result of overdistension, at higher Vt. Mice were allocated to \"protective\" (6 ml/kg) or \"injurious\" (15-20 ml/kg) Vt groups and ventilated for 16 hours or until death. We measured elastance and hysteresis; pulmonary IL-6, IL-1β, and MIP-2 (macrophage inflammatory protein 2); wet-to-dry ratio; and blood gases. Survival was greater in the protective group (60%) than in the injurious group (25%). Nonsurvivors showed increased pulmonary cytokines, particularly in the injurious group, with the increase of elastance reflecting IL-6 concentration. Survivors instead showed only modest increases of cytokines, independent of Vt and unrelated to the increase of elastance. No single lung strain threshold could discriminate survivors from nonsurvivors. Hysteresis increased faster in the protective group, but, contrary to our hypothesis, its change was inversely related to the concentration of cytokines. In this model, significant mortality associated with pulmonary inflammation occurred even for strain values as low as about 0.8. Low Vt improved survival. The accompanying increase of hysteresis was not associated with greater inflammation.

To assess whether, in a lung resection cohort with a low probability of confounding by indication, higher FiO2 is associated with an increased risk of impaired postoperative oxygenation – a clinical manifestation of lung injury/dysfunction. Pre-specified registry-based retrospective cohort study. Two large academic hospitals in the United States. 2936 lung resection patients with an overall good intraoperative oxygenation (median intraoperative SpO2 ≥ 95 %). We compared patients with a higher (≥0.8) and lower (<0.8) median intraoperative FiO2 after propensity score-weighting for 75 perioperative variables based on a causal inference framework. The primary outcome of impaired oxygenation was defined as at least one of the following within seven postoperative days: (1) SpO2 < 92 %; (2) imputed PaO2/FiO2 < 300 mmHg [(1) or (2) at least twice within 24 h]; (3) intensive oxygen therapy (mechanical ventilation or > 50 % oxygen or high-flow oxygen). Among the 2936 included patients, 2171 (73.8 %) received median intraoperative FiO2 ≥ 0.8. Impaired postoperative oxygenation occurred in 1627 (74.9 %) and 422 (55.2 %) patients in the higher and lower FiO2 groups, respectively. In a propensity score-weighted analysis, higher intraoperative FiO2 was associated with an 84 % increase in the likelihood of impaired postoperative oxygenation (OR 1.84; 95 % CI 1.60 to 2.12; P < 0.001). Despite plausible harm from hyperoxia, high intraoperative FiO2 is extremely common during lung resection. Nearly three-quarters of lung resection patients with acceptable oxygenation received median intraoperative FiO2 ≥ 0.8. Such higher FiO2 was associated with an increased risk of impaired postoperative oxygenation – a clinically relevant manifestation of lung injury or dysfunction. This observation supports the administration of a lower (< 0.8) intraoperative FiO2 and its further assessment in clinical trials. •FiO2 as a component of protective ventilation received minimal attention in lung resection•We assessed the effects of intraoperative FiO2 on postoperative oxygenation in lung resection patients•To address confounding by indication, we studied only patients who had an overall good intraoperative oxygenation•After adjusting for over 70 variables, higher intraoperative FiO2 was associated with worse postoperative oxygenation

To estimate the incidence of postoperative oxygenation impairment after lung resection in the era of lung-protective management, and to identify perioperative factors associated with that impairment. Registry-based retrospective cohort study. Two large academic hospitals in the United States. 3081 ASA I-IV patients undergoing lung resection. 79 pre- and intraoperative variables, selected for inclusion based on a causal inference framework. The primary outcome of impaired oxygenation, an early marker of lung injury, was defined as at least one of the following within seven postoperative days: (1) SpO2 < 92%; (2) imputed PaO2/FiO2 < 300 mmHg [(1) or (2) occurring at least twice within 24 h]; (3) intensive oxygen therapy (mechanical ventilation or > 50% oxygen or high-flow oxygen). Oxygenation was impaired within seven postoperative days in 70.8% of patients (26.6% with PaO2/FiO2 < 200 mmHg or intensive oxygen therapy). In multivariable analysis, each additional cmH2O of intraoperative median driving pressure was associated with a 7% higher risk of impaired oxygenation (OR 1.07; 95%CI 1.04 to 1.10). Higher median intraoperative FiO2 (OR 1.23; 95%CI 1.14 to 1.31 per 0.1) and PEEP (OR 1.12; 95%CI 1.04 to 1.21 per 1 cm H2O) were also associated with increased risk. History of COPD (OR 2.55; 95%CI 1.95 to 3.35) and intraoperative albuterol administration (OR 2.07; 95%CI 1.17 to 3.67) also showed reliable effects. Impaired postoperative oxygenation is common after lung resection and is associated with potentially modifiable pre- and intraoperative respiratory factors. •Optimal approach to perioperative lung protection remains unknown in lung resection.•Risk scores are designed for PREoperative use and do not inform INTRAoperative care.•We assessed detailed intraoperative physiology during lung resection.•We identified potentially modifiable pre- /intra-operative respiratory risk factors.