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Background: Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown.Research Question: What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States?Study Design and Methods: We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pao2 to Fio2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed.Results: A total of 2,466 patients were enrolled. Median baseline Pao2 to Fio2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR.Interpretation: Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes.Trial Registry: ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

RA Right atrium, IAS Interatrial septum, PAC Pulmonary artery catheter Declarations Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. RA: Right atrium; IAS: Interatrial septum; PAC: Pulmonary artery catheter Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. A tubular fibrin sheath in his right atrium (RA) extending to the superior vena cava to RA junction, was found due to the presence of his ECMO drainage cannula (Fig. [Extracted from the article]

Autoimmune diseases encompass a broad spectrum of disorders characterized by disturbed immunoregulation leading to the development of specific autoantibodies, resulting in inflammation and multiple organ involvement. A distinction should be made between connective tissue diseases (mainly systemic lupus erythematosus, systemic scleroderma, inflammatory muscle diseases, and rheumatoid arthritis) and vasculitides (mainly small-vessel vasculitis such as antineutrophil cytoplasmic antibody-associated vasculitis and immune-complex mediated vasculitis). Admission of patients with autoimmune diseases to the intensive care unit (ICU) is often triggered by disease flare-ups, infections, and organ failure and is associated with high mortality rates. Management of these patients is complex, including prompt disease identification, immunosuppressive treatment initiation, and life-sustaining therapies, and requires multi-disciplinary involvement. Data about autoimmune diseases in the ICU are limited and there is a need for multicenter, international collaboration to improve patients' diagnosis, management, and outcomes. The objective of this narrative review is to summarize the epidemiology, clinical features, and selected management of severe systemic autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Several plasma volume expander alternatives exist to enhance intravascular volume status in patients undergoing surgery. The optimal intravascular volume expander in the perioperative setting is currently unknown. Low molecular weight hetastarch, Voluven® (130/0.4), may have a better safety profile than high molecular weight hetastarch, Hextend® (450/0.7). We examined the clinical and cost outcomes of converting from Hextend® to Voluven® in a large tertiary medical center. Methods: Using a large electronic database, we retrospectively compared two different time periods (2009 and 2010) where the availability of semisynthetic colloids changed. Perioperative and postoperative outcomes including the use of red blood cells (RBC), platelets and coagulation factors, length of stay in the postoperative acute care unit (PACU), intensive care unit and hospital, as well as 30-day and 1-year mortality were compared. In addition, direct acquisition costs of all intraoperative and PACU colloids and crystalloid use were determined. Results: A total of 4,888 adult subjects were compared of which 1,878 received Hextend® (pre-conversion) and 2,759 received Voluven® (post-conversion) during two separate 7-month periods within 1 year apart, with the remainder receiving Plasmanate. The patients were similar in terms of patient demographics, preoperative comorbidities, ASA status, emergency surgery, types of surgery, intraoperative, and PACU times. In unadjusted outcomes, patients in the Hextend® group received more lactated Ringer's than in the Voluven® group (2,220 + 1,312 vs. 1,946 ± 1,097 ml; P < 0.0001). The use of albumin (Plasmanate) was reduced from 10.5% of patients to 1.1% when Voluven® was substituted for Hextend®. Unadjusted outcomes were similar in each group including hospital LOS, percent change from baseline creatinine and receipt of intraoperative and PACU blood product administration. However, overall unadjusted total fluid costs were greater in the Voluven® compared to Hextend® group ($116.7 compared to $59.3; P < 0.001). Conclusions: Conversion from Hextend® to Voluven® in the perioperative period resulted in decreased albumin use and was not associated with changes in clinical outcomes and short- and long-term mortality. The conversion was associated with decreases in crystalloid use and an increase in colloid use and hence IV fluid acquisition costs in the Voluven® group. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection. [ABSTRACT FROM AUTHOR]

: Background:Mechanical ventilation for ventilatory failure has been considered a relative contraindication to subsequent lung transplantation. The purpose of this study was to test the hypothesis that patients with cystic fibrosis (CF) who are intubated and mechanically ventilated before transplantation have poorer post-transplant outcomes than do patients who are not ventilated.: Methods:We compared the outcomes of 8 patients with CF who underwent mechanical ventilation for 62 ±20 days (range, 3–153 days) before bilateral lung transplantation with outcomes of 24 patients with CF who did not undergo pre-transplant mechanical ventilation.: Results:Although time to extubation after transplantation was prolonged significantly (11 vs 4 days) for the pre-transplant ventilated group, days to hospital discharge, forced expiratory volume in 1 second (percent predicted) at 1 year after transplantation, and post-transplant survival as determined using the Kaplan-Meier method did not differ statistically between the 2 groups.: Conclusions:Patients with CF who undergo pre-transplant endotracheal intubation and mechanical ventilation for respiratory failure have outcomes that do not differ significantly from those of patients with CF who do not require invasive ventilatory support before bilateral lung transplantation. [Copyright &y& Elsevier]

As patients continue to live longer from diseases that predispose them to right ventricular (RV) dysfunction or failure, many more patients will require surgery for acute or chronic health issues. Because RV dysfunction results in significant perioperative morbidity if not adequately assessed or managed, understanding appropriate assessment and treatments is important in preventing subsequent morbidity and mortality in the perioperative period. In light of the epidemiology of right heart disease, a working knowledge of right heart anatomy and physiology and an understanding of the implications of right-sided heart function for perioperative care are essential for perioperative practitioners. However, a significant knowledge gap exists concerning this topic. This manuscript is one part of a collection of papers from the PeriOperative Quality Initiative (POQI) IX Conference focusing on "Current Perspectives on the Right Heart in the Perioperative Period." This review aims to provide perioperative clinicians with an essential understanding of right heart physiology by answering five key questions on this topic and providing an explanation of seven fundamental concepts concerning right heart physiology. [ABSTRACT FROM AUTHOR]

Purpose: To identify tidal volume (VT) and positive end-expiratory pressure (PEEP) associated with the lowest incidence and severity of postoperative pulmonary complications (PPCs) for each phenotype based on preoperative characteristics. Methods: The subjects of this retrospective observational cohort study were 34,910 adults who underwent surgery, using general anesthesia with mechanical ventilation. Initially, the least absolute shrinkage and selection operator regression was employed to select relevant preoperative characteristics. Then, the classification and regression tree (CART) was built to identify phenotypes. Finally, we computed the area under the receiver operating characteristic curves from logistic regressions to identify VT and PEEP associated with the lowest incidence and severity of PPCs for each phenotype. Results: CARTs classified seven phenotypes for each outcome. A probability of the development of PPCs ranged from the lowest (3.51%) to the highest (68.57%), whereas the probability of the development of the highest level of PPC severity ranged from 3.3% to 91.0%. Across all phenotypes, the VT and PEEP associated with the most desirable outcomes were within a small range of VT 7–8 ml/kg predicted body weight with PEEP of between 6 and 8 cmH2O. Conclusions: The ranges of optimal VT and PEEP were small, regardless of the phenotypes, which had a wide range of risk profiles. [ABSTRACT FROM AUTHOR]

An editorial is presented on a study within the issue on use of extracorporeal membrane oxygenation (ECMO) therapy in treatment of community-acquired pneumonia. Topics discussed include analysis of use of inhaled pulmonary vasodilators and neuromuscular blockade, higher mortality of patients diagnosed with fungal pneumonia than those diagnosed with bacterial or viral pneumonias, and change in management of and support for patients with severe respiratory failure.

The article focuses on the development of treatment modalities focused on end stage cardiovascular diseases. It mentions that the U.S. Food and Drug Administration approved the HeartMate II for destination therapy, as compared to transplantation. It focuses on the isolation of endothelial progenitor cells (EPC) from the peripheral circulation following granulocyte colony-stimulating factor (G-CSF) administration.

OBJECTIVES: To describe frequency of positive blood cultures, patterns of pathogens' characteristics and their resistance profile in patients with blood cultures drawn due to a presumed diagnosis of community-onset sepsis, and to examine the association between blood culture-positive pathogens and hospital mortality. DESIGN: Retrospective cohort study. SETTING: Two hundred one U.S. hospitals from 2016 to 2020 using the Premier Healthcare Database. SUBJECTS: Adult patients presenting with community-onset sepsis who had blood cultures collected within 2 days of hospital admission. We defined sepsis using the U.S. Centers for Disease Control Adult Sepsis Event Surveillance criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 147,061 patients with community-onset sepsis. The number of blood culture-positive sepsis episodes was 21,167 (14%) and the number of nonblood culture-positive sepsis episodes was 20,326 (14%). Among patients with blood culture-positive sepsis, Gram-negative rods were isolated in 55% of patients, Gram-positive cocci were isolated in 47%. Of those, methicillin-resistant Staphylococcus aureus (MRSA) was 11%, ceftri-axone-resistant Enterobacterales/extended-spectrum ^-lactamase was 7%, and carbapenem-resistant Enterobacterales was 1.3%. The crude in-hospital mortality was 17% for culture-negative sepsis, 13% for nonblood culture-positive sepsis, and 17% for blood culture-positive sepsis. In multilevel logistic regression models, compared with culture-negative sepsis, blood culture-positive sepsis (adjusted odds ratio [aOR], 0.89; 95% CI, 0.85-0.94) and nonblood culture-positive sepsis (aOR, 0.82; 95% CI, 0.78-0.87) were associated with lower odds of in-hospital mortality. Acinetobacter species, Pseudomonas aeruginosa, methicillin-sensi-tive Staphylococcus aureus, and MRSA were associated with higher in-hospi-tal mortality, whereas Escherichia coli, Klebsiella species, Proteus species, and Streptococcus species were associated with lower in-hospital mortality. CONCLUSIONS: In patients hospitalized with community-onset sepsis, the prevalence of blood culture-positive sepsis was 14%. Among positive blood culture sepsis resistant organisms were infrequent. Compared with culture-negative sepsis, blood culture-positive sepsis and nonblood culture-positive sepsis were associated with lower in-hospital mortality. [ABSTRACT FROM AUTHOR]

The use of venovenous extracorporeal membrane oxygenation is increasing worldwide. These patients often require noncardiac surgery. In the perioperative period, preoperative assessment, patient transport, choice of anesthetic type, drug dosing, patient monitoring, and intraoperative and postoperative management of common patient problems will be impacted. Furthermore, common monitoring techniques will have unique limitations. Importantly, patients on venovenous extracorporeal membrane oxygenation remain subject to hypoxemia, hypercarbia, and acidemia in the perioperative setting despite extracorporeal support. Treatments of these conditions often require both manipulation of extracorporeal membrane oxygenation settings and physiologic interventions. Perioperative management of anticoagulation, as well as thresholds to transfuse blood products, remain highly controversial and must take into account the specific procedure, extracorporeal membrane oxygenation circuit function, and patient comorbidities. We will review the physiologic management of the patient requiring surgery while on venovenous extracorporeal membrane oxygenation. [ABSTRACT FROM AUTHOR]

Mitochondrial damage is often overlooked in acute lung injury (ALI), yet most of the lung's physiological processes, such as airway tone, mucociliary clearance, ventilation-perfusion (Va/Q) matching, and immune surveillance require aerobic energy provision. Because the cell's mitochondrial quality control (QC) process regulates the elimination and replacement of damaged mitochondria to maintain cell survival, we serially evaluated mitochondrial biogenesis and mitophagy in the alveolar regions of mice in a validated Staphylococcus aureus pneumonia model. We report that apart from cell lysis by direct contact with microbes, modest epithelial cell death was detected despite significant mitochondrial damage. Cell death by TdT-mediated dUTP nick-end labeling staining occurred on days 1 and 2 postinoculation: apoptosis shown by caspase-3 cleavage was present on days 1 and 2, while necroptosis shown by increased levels of phospho-mixed lineage kinase domain-like protein (MLKL) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) was present on day 1. Cell death in alveolar type I (AT1) cells assessed by bronchoalveolar lavage fluid receptor for advanced glycation end points (RAGE) levels was high, yet AT2 cell death was limited while both mitochondrial biogenesis and mitophagy were induced. These mitochondrial QC mechanisms were evaluated mainly in AT2 cells by localizing increases in citrate synthase content, increases in nuclear mitochondrial biogenesis regulators nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-β coactivator-1β (PGC-1β), and increases in light chain 3B protein (LC3-I)/LC3II ratios. Concomitant changes in p62, Pink 1, and Parkin protein levels indicated activation of mitophagy. By confocal microscopy, mitochondrial biogenesis and mitophagy were often observed on day 1 within the same AT2 cells. These findings imply that mitochondrial QC activation in pneumoniadamaged AT2 cells promotes cell survival in support of alveolar function. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) after noncardiac surgery is common and has substantial health impact. Preclinical and clinical studies examining the influence of sex on AKI have yielded conflicting results, although they typically do not account for age-related changes. The objective of the study was to determine the association of age and sex groups on postoperative AKI. The authors hypothesized that younger females would display lower risk of postoperative AKI than males of similar age, and the protection would be lost in older females. Methods: This was a multicenter retrospective cohort study across 46 institutions between 2013 and 2019. Participants included adult inpatients without pre-existing end-stage kidney disease undergoing index major noncardiac, nonkidney/urologic surgeries. The authors' primary exposure was age and sex groups defined as females 50 yr or younger, females older than 50 yr, males 50 yr or younger, and males older than 50 yr. The authors' primary outcome was development of AKI by Kidney Disease-Improving Global Outcomes serum creatinine criteria. Exploratory analyses included associations of ascending age groups and hormone replacement therapy home medications with postoperative AKI. Results: Among 390,382 patients, 25,809 (6.6%) developed postoperative AKI (females 50 yr or younger: 2,190 of 58,585 [3.7%]; females older than 50 yr: 9,320 of 14,4047 [6.5%]; males 50 yr or younger: 3,289 of 55,503 [5.9%]; males older than 50 yr: 11,010 of 132,447 [8.3%]). When adjusted for AKI risk factors, compared to females younger than 50 yr (odds ratio, 1), the odds of AKI were higher in females older than 50 yr (odds ratio, 1.51; 95% CI, 1.43 to 1.59), males younger than 50 yr (odds ratio, 1.90; 95% CI, 1.79 to 2.01), and males older than 50 yr (odds ratio, 2.06; 95% CI, 1.96 to 2.17). Conclusions: Younger females display a lower odds of postoperative AKI that gradually increases with age. These results suggest that age-related changes in women should be further studied as modifiers of postoperative AKI risk after noncardiac surgery. In this large retrospective cohort analysis, younger females were at lower odds of postoperative acute kidney injury than females of older age and males of all ages. [ABSTRACT FROM AUTHOR]

Background: Older adults suffering from traumatic brain injury (TBI) are subject to higher injury burden and mortality. Do Not Resuscitate (DNR) orders are used to provide care aligned with patient wishes, but they may not be equitably distributed across racial/ethnic groups. We examined racial/ethnic differences in the prevalence of DNR orders at hospital admission in older patients with severe TBI. Methods: We conducted a retrospective cohort study using the National Trauma Databank (NTDB) between 2007 to 2016. We examined patients ≥ 65 years with severe TBI. For our primary aim, the exposure was race/ethnicity and outcome was the presence of a documented DNR at hospital admission. We conducted an exploratory analysis of hospital outcomes including hospital mortality, discharge to hospice, and healthcare utilization (intracranial pressure monitor placement, hospital LOS, and duration of mechanical ventilation). Results: Compared to White patients, Black patients (OR 0.48, 95% CI 0.35-0.64), Hispanic patients (OR 0.54, 95% CI 0.400.70), and Asian patients (OR 0.63, 95% CI 0.44-0.90) had decreased odds of having a DNR order at hospital admission. Patients with DNRs had increased odds of hospital mortality (OR 2.16, 95% CI 1.94-2.42), discharge to hospice (OR 2.08, 95% CI 1.75-2.46), shorter hospital LOS (-2.07 days, 95% CI -3.07 to -1.08) and duration of mechanical ventilation (-1.09 days, 95% CI -1.52 to -0.67). There was no significant difference in the utilization of ICP monitoring (OR 0.94, 95% CI 0.78-1.12). Conclusions: We found significant racial and ethnic differences in the utilization of DNR orders among older patients with severe TBI. Additionally. DNR orders at hospital admission were associated with increased in-hospital mortality, increased hospice utilization, and decreased healthcare utilization. Future studies should examine mechanisms underlying race-based differences in DNR utilization. [ABSTRACT FROM AUTHOR]

Background: Heart failure affects >6 million people in the United States alone and is most prevalent in Black patients who suffer the highest mortality risk. Yet prior studies have suggested that Black patients are less likely to receive advanced heart failure therapy. We hypothesized that Black patients would have decreased rates of durable left ventricular assist device (LVAD) implantation within our expansive heart failure program.Methods: A retrospective single-center cohort study was conducted at a single high-volume academic medical center. Patients between 18 and 85 years admitted with a diagnosis of cardiogenic shock or congestive heart failure between 1, 2013 and 12, 2017 with a left ventricular ejection fraction < 30% and inotropic dependence or need for mechanical circulatory support were included. Patients with contraindications to durable LVAD were excluded. An adjusted logistic regression model for durable LVAD implantation within 90 days of the index admission was used to determine the effect of race on durable LVAD implantation.Results: Among the 702 study patients (60.9% White, 34.1% Black), durable LVAD implantation was performed within 90 days of the index admission in 183 (26%) of the cohort. After multivariate analysis, Black patients were not found to have a statistically significant difference in durable LVAD implantation rates compared to White patients in our study (OR: 0.68 [95% confidence interval: 0.45-1.04; p: .074]).Conclusions: Black patients in our study did not have a statistically significant difference in the rate of durable LVAD implantation compared with White patients after adjustments were made for age, sex, socioeconomic, and clinical covariates. Larger prospective studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Introduction: Older adults are more vulnerable to opioid-associated morbidity. The purpose of this study was to determine the frequency and timing of acetaminophen and opioid use in the postoperative period.Methods: Older adult trauma patients (≥65 years) with hip fractures requiring femur or hip fixation were reviewed (Premier Database 2008-2014). We examined rates of acetaminophen use on the day of surgery and prior to receipt of oral opioids. Mixed-effects linear regression models were used to examine the effects of an acetaminophen-first approach on opioid use the day prior to and on the day of discharge.Results: Of the 192 768 patients, 81.6% were Caucasian; 74.0% were female; and the mean age was 82.0 years [± 7.0]. Only 16.8% (32 291) of patients received acetaminophen prior to being prescribed opioids. 27.4% (52 779) received an acetaminophen-opioid combination, and 9.2% (17 730) received opioids without acetaminophen first. Acetaminophen first was associated with reduced opioid use on the day prior to and on the day of discharge (3.52 parenteral morphine equivalent doses (PMEs) less [95% CI: 3.33, 3.70]; P < .0001). A statistically but not clinically significant reduction in length of stay was observed in the acetaminophen-first group.Conclusion: Nearly 37% of older adult patients did not receive acetaminophen as first-line analgesia after hip surgery. Multimodal analgesia, including non-opioid medications as first-line, should be encouraged. [ABSTRACT FROM AUTHOR]

A key transcriptional regulator of cell metabolism, the peroxisome proliferator-activated receptor γ co-activator 1-α (PPARGC-1-α or PGC-1α), also regulates mitochondrial biogenesis, but its role in antioxidant gene regulation is not well understood. Here, we asked whether genetic heterozygosity of PGC-1α modulates gene expression for the mitochondrial antioxidant enzyme SOD-2 during hepatic inflammatory stress. Using Staphylococcus aureus peritonitis in mice, we found significant Sod2 gene induction in WT mice, whereas PGC-1α heterozygotes (PGC-1α+/-) failed to augment Sod2 mRNA and protein levels. Impaired Sod2 regulation in PGC-1α+/- mice was accompanied by oxidative stress shown by elevated mitochondrial GSSG/GSH and protein carbonyls. In silico analysis of the mouse proximal Sod2 promoter region revealed consensus binding sites for the Nfe2l2 (Nrf2) transcription factor. Chromatin immunoprecipitation demonstrated diminished Nfe2l2 protein binding to the antioxidant response element promoter site proximal to the Sod2 start site in PGC-1α heterozygous mice, implicating PGC-1α in facilitation of Nfe2l2 DNA binding. Nuclear protein co-immunoprecipitation demonstrated an interaction between hepatic Nfe2l2 and PGC-1α in WT mice that was greatly reduced in PGC-1α+/- mice. The data indicate that PGC-1α promotes mitochondrial antioxidant enzyme expression through Nfe2l2-mediated SOD-2 expression in sepsis. The presence of this new PGC-1α-dependent signaling axis indicates that PGC-1α opposes mitochondrial oxidative stress by means of selective induction of one or more antioxidant response element-driven genes. By implication, exploitation of this axis could lead to new pharmacological interventions to improve the antioxidant defenses during oxidative stress-induced mitochondrial damage. [ABSTRACT FROM AUTHOR]

Objective: To examine racial and ethnic differences in the utilization of 3 interventions (tracheostomy placement, gastrostomy tube placement, and hospice utilization) among patients with severe acute brain injury (SABI). Design: Retrospective cohort study. Setting: Data from the National Inpatient Sample, from 2002 to 2012. Patients: Adult patients with SABI defined as a primary diagnosis of stroke, traumatic brain injury, or post-cardiac arrest who received greater than 96 hours of mechanical ventilation. Exposure: Race/ethnicity, stratified into 5 categories (white, black, Hispanic, Asian, and other). Measurements and Main Results: Data from 86 246 patients were included in the cohort, with a mean (standard deviation) age of 60 (18) years. In multivariable analysis, compared to white patients, black patients had an 20% increased risk of tracheostomy utilization (relative risk [RR]: 1.20, 95% CI: 1.16-1.24, P < .001), Hispanic patients had a 10% increased risk (RR: 1.10, 95% CI: 1.06-1.14, P < .001), Asian patients had an 8% increased risk (RR: 1.08, 95% CI: 1.01-1.16, P = .02), and other race patients had an 10% increased risk (RR: 1.10, 95% CI: 1.04-1.16, P < .001). A similar relationship was observed for gastrostomy utilization. In multivariable analysis, compared to white patients, black patients had a 25% decreased risk of hospice discharge (RR: 0.75, 95% CI: 0.67-0.85, P < .001), Hispanic patients had a 20% decreased risk (RR: 0.80, 95% CI: 0.69-0.94, P < .01), and Asian patients had a 47% decreased risk (RR: 0.53, 95% CI: 0.39-0.73, P < .001). There was no observed relationship between race/ethnicity and in-hospital mortality. Conclusions: Minority race was associated with increased utilization of tracheostomy and gastrostomy, as well as decreased hospice utilization among patients with SABI. Further research is needed to better understand the mechanisms underlying these race-based differences in critical care. [ABSTRACT FROM AUTHOR]

Background/Objective: Traumatic brain injury (TBI) is a leading cause of morbidity, mortality, and disability in the USA. While cardiopulmonary dysfunction can result in poor outcomes following severe TBI, the impact of acute kidney injury (AKI) is poorly understood. We examined the association of severe AKI with hospital mortality and healthcare utilization following isolate severe TBI. Methods: We conducted a retrospective cohort study using the National Trauma Data Bank from 2007 to 2014. We identified a cohort of adult patients with isolated severe TBI and described the incidence of severe AKI, corresponding to Acute Kidney Injury Network stage 3 disease or greater. We examined the association of severe AKI with the primary outcome of hospital mortality using multivariable logistic regression models. In secondary analyses, we examined the association of severe AKI with dialysis catheter placement, tracheostomy and gastrostomy utilization, and hospital length of stay. Results: There were 37,851 patients who experienced isolated severe TBI during the study period. Among these patients, 787 (2.1%) experienced severe (Stage 3 or greater) AKI. In multivariable models, the development of severe AKI in the hospital was associated with in-hospital mortality (OR 2.03, 95% CI 1.64–2.52), need for tracheostomy (OR 2.10, 95% CI 1.52–2.89), PEG tube placement (OR 1.88, 95% CI 1.45–2.45), and increased hospital length of stay (p < 0.001). Conclusions: The overall incidence of severe AKI is relatively low (2.1%), but is associated with increased mortality and multiple markers of increased healthcare utilization following severe TBI. [ABSTRACT FROM AUTHOR]

Objectives: Traumatic brain injury is a leading cause of death and disability in the United States. While the impact of early multiple organ dysfunction syndrome has been studied in many critical care paradigms, the clinical impact of early multiple organ dysfunction syndrome in traumatic brain injury is poorly understood. We examined the incidence and impact of early multiple organ dysfunction syndrome on clinical, functional, and disability outcomes over the year following traumatic brain injury.Design: Retrospective cohort study.Setting: Patients enrolled in the Transforming Clinical Research and Knowledge in Traumatic Brain Injury study, an 18-center prospective cohort study of traumatic brain injury patients evaluated in participating level 1 trauma centers.Subjects: Adult (age > 17 yr) patients with moderate-severe traumatic brain injury (Glasgow Coma Scale < 13). We excluded patients with major extracranial injury (Abbreviated Injury Scale score ≥ 3).Interventions: Development of early multiple organ dysfunction syndrome, defined as a maximum modified Sequential Organ Failure Assessment score greater than 7 during the initial 72 hours following admission.Measurements and Main Results: The main outcomes were: hospital mortality, length of stay, 6-month functional and disability domains (Glasgow Outcome Scale-Extended and Disability Rating Scale), and 1-year mortality. Secondary outcomes included: ICU length of stay, 3-month Glasgow Outcome Scale-Extended, 3-month Disability Rating Scale, 1-year Glasgow Outcome Scale-Extended, and 1-year Disability Rating Scale. We examined 373 subjects with moderate-severe traumatic brain injury. The mean (SD) Glasgow Coma Scale in the emergency department was 5.8 (3.2), with 280 subjects (75%) classified as severe traumatic brain injury (Glasgow Coma Scale 3-8). Among subjects with moderate-severe traumatic brain injury, 252 (68%) developed early multiple organ dysfunction syndrome. Subjects that developed early multiple organ dysfunction syndrome had a 75% decreased odds of a favorable outcome (Glasgow Outcome Scale-Extended 5-8) at 6 months (adjusted odds ratio, 0.25; 95% CI, 0.12-0.51) and increased disability (higher Disability Rating Scale score) at 6 months (adjusted mean difference, 2.04; 95% CI, 0.92-3.17). Subjects that developed early multiple organ dysfunction syndrome experienced an increased hospital length of stay (adjusted mean difference, 11.4 d; 95% CI, 7.1-15.8), with a nonsignificantly decreased survival to hospital discharge (odds ratio, 0.47; 95% CI, 0.18-1.2).Conclusions: Early multiple organ dysfunction following moderate-severe traumatic brain injury is common and independently impacts multiple domains (mortality, function, and disability) over the year following injury. Further research is necessary to understand underlying mechanisms, improve early recognition, and optimize management strategies. [ABSTRACT FROM AUTHOR]

The induction of heme oxygenase-1 (HO-1; Hmox1) by inflammation, for instance in sepsis, is associated both with an anti-inflammatory response and with mitochondrial biogenesis. Here, we tested the idea that HO-1, acting through the Nfe2l2 (Nrf2) transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO-1 induction after LPS stimulated anti-inflammatory IL-10 and IL-1 receptor antagonist (IL-1Ra) expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-α expression. This was accompanied by nuclear Nfe2l2 accumulation and led us to identify abundant Nfe2l2 and other mitochondrial biogenesis transcription factor binding sites in the promoter regions of IL10 and IL1Ra compared with pro-inflammatory genes regulated by NF-κ?. Mechanistically, HO-1, through its CO product, enabled these transcription factors to bind the core IL10 and IL1Ra promoters, which for IL10 included Nfe2l2, nuclear respiratory factor (NRF)-2 (Gabpa), and MEF2, and for IL1Ra, included NRF-1 and MEF2. In cells, Hmox1 or Nfe2l2 RNA silencing prevented IL-10 and IL-1Ra up-regulation, and HO-1 induction failed post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2-/- mice. Nfe2l2-/- mice compared with WT mice, showed more liver damage, higher mortality, and ineffective CO rescue in sepsis. Nfe2l2-/- mice in sepsis also generated higher hepatic TNF-α mRNA levels, lower NRF-1 and PGC-1α mRNA levels, and no enhancement of anti-inflammatory Il10, Socs3, or bcl-xL gene expression. These findings disclose a highly structured transcriptional network that couples mitochondrial biogenesis to counter-inflammation with major implications for immune suppression in sepsis. [ABSTRACT FROM AUTHOR]

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research. [ABSTRACT FROM AUTHOR]

Background: The transition to the new ICD-10 (International Classification of Diseases, Tenth Revision) coding system in the U.S. poses challenges to the ability to consistently and accurately measure trends in comorbidities and complications. We examined the prevalence of comorbidities and postoperative medical complications before and after the transition from ICD-9 to ICD-10 among patients who underwent primary total hip or knee arthroplasty (THA or TKA). We hypothesized that the transition to ICD-10 codes was associated with discontinuity and slope change in comorbidities and medical complications.Methods: The Elixhauser comorbidities and medical complications were identified using the Premier Healthcare database from fiscal year (FY)2011 to FY2018. Using multivariable segmented regression models, we examined the changes in the levels and slopes after the transition from ICD-9 to ICD-10 coding. Odds ratios (ORs) of <1 and >1 indicate decreases and increases, respectively, in levels and slopes.Results: Overall, 2,006,581 patients who underwent primary THA or TKA were identified. The mean age was 65.9 ± 10.5 years, and the median length of the hospital stay was 2 days (interquartile range [IQR], 2 to 3 days). Of the comorbidities studied, congestive heart failure, hypertension, and obesity had a statistically significant but clinically small discontinuity after the transition from ICD-9 to ICD-10 coding. Of the complications, pneumonia (OR = 0.66, 95% confidence interval [CI] = 0.48 to 0.90), acute respiratory failure (OR = 1.88, 95% CI = 1.52 to 2.33), sepsis (OR = 2.54, 95% CI = 1.45 to 4.44), and urinary tract infection (OR = 1.79, 95% CI = 1.32 to 2.42) demonstrated statistically significant discontinuity. Alcohol abuse and paralysis had an increasing prevalence before the ICD transition, followed by a decreasing prevalence after the transition. In contrast, metastatic cancer, weight loss, and acquired immunodeficiency syndrome (AIDS) showed a decreasing prevalence before the ICD transition followed by an increasing prevalence after the transition. Generally, complications showed a decreasing prevalence over time.Conclusions: The discontinuities after the transition from ICD-9 to ICD-10 coding were relatively small for most comorbidities. Medical complications generally showed a decreasing trend over the quarters studied. These findings support caution when conducting joint replacement studies that rely on ICD coding and include the ICD coding transition period. [ABSTRACT FROM AUTHOR]

Objective Multimodal analgesia has gained popularity in total hip arthroplasty (THA) and total knee arthroplasty (TKA), but large multicenter studies evaluating specific analgesic combinations are lacking. Design A retrospective study using the Premier Healthcare Database (2009–2014). Subjects Adults who underwent elective primary THA or TKA. Methods We categorized day-of-surgery analgesic exposure using eight mutually exclusive categories: acetaminophen (Ac), nonsteroidal anti-inflammatory drugs (Ns), gabapentinoids (Ga; gabapentin or pregabalin), Ac+Ns, Ac+Ga, Ns+Ga, Ac+Ns+Ga, and none of the three drugs. Multilevel models measured associations of the analgesic categories with a composite of postoperative pulmonary complications (PPCs). Results Among 863,139 patients, 75.2% received at least one of the three drugs. In multilevel models, compared with none of the three drugs, Ga use was associated with increased odds of PPCs when used alone (adjusted odds ratio [aOR] = 1.35, 95% confidence interval [CI] = 1.27 to 1.44), combined with Ac (aOR = 1.16, 95% CI = 1.08 to 1.26), or combined with Ns (aOR = 1.28, 95% CI = 1.21 to 1.34). In contrast, the Ac+Ns pair was associated with decreased odds of PPCs (OR = 0.86, 95% CI = 0.83 to 0.90) and lower opioid consumption. Ac+Ns+Ga was not associated with PPCs, whereas it was associated with the lowest opioid consumption on the day of surgery. Conclusions Gabapentinoids, alone and in single combination with either acetaminophen or nonsteroidal anti-inflammatory drugs, were associated with higher PPCs, whereas the Ac+Ns pair was associated with fewer PPCs and an opioid-sparing effect. Ac+Ns+Ga was not associated with PPCs, whereas it was associated with the lowest opioid consumption on the day of surgery. [ABSTRACT FROM AUTHOR]

Summary: Acute kidney injury (AKI) and primary graft dysfunction (PGD) are serious complications after heart transplantation (HT). The relationship between AKI and PGD is poorly understood. We sought to examine the incidence of AKI and identify risk factors associated with AKI. We hypothesized that PGD is one of the risk factors independently associated with post‐HT AKI. We gathered data for all adult patients who underwent HT between 2009 and 2014. AKI was defined by the KDIGO criteria. PGD was categorized using ISHLT criteria. We assessed univariable and multivariable logistic regression to identify risk factors independently associated with post‐HT AKI. Out of 316 patients, postoperative AKI occurred in 273 (86%) patients: 188 (68%) stage I, 44 (16%) stage II, and 41 (15%) stage III. Stage II/III AKI was associated with increased risk of mortality at 1 year. There was significant association between severe PGD and stage II/III AKI (P = 0.001, OR 3.63, 95% CI: 1.69–7.94). Other clinical factors significantly associated with stage II/III AKI included longer donor brain death duration and lower recipient baseline creatinine. We found that stage II/III AKI is common and independently associated with severe PGD. Another potentially modifiable risk factor is donor brain death duration. [ABSTRACT FROM AUTHOR]

Optimal administration of fluids is an important part of enhanced recovery after surgery (ERAS) protocols. We sought to examine the relationship between perioperative crystalloid volume and adverse outcomes in five common types of surgical procedures with ERAS fluid guidelines in place where large randomized controlled trials have not been conducted: breast reconstruction, bariatric, major urologic, gynoncologic, and head and neck oncologic procedures. This retrospective cohort study included patients who had undergone any one of the aforementioned procedures within any facility in a large multihospital alliance (Premier, Inc, Charlotte, NC) between 2008 and 2014. We used multivariable generalized additive models to examine relationships between the total crystalloid volume (TCV) on the day of surgery and a composite adverse outcome of prolonged (>75th percentile) hospital or intensive care unit stay or in-hospital mortality. Models were constructed separately within each surgical category and adjusted for demographic, clinical, and hospital characteristics. Informed consent requirements were waived because deidentified data were used. We identified 83,685 patients within 312 US hospitals undergoing breast reconstruction (n = 8738), bariatric surgery (n = 8067), major urologic surgery (n = 28,654), gynoncologic surgery (n = 34,559), and head/neck oncology surgery (n = 3667). There was significant patient-independent variation in TCV. Probabilities of adverse outcomes increased at a TCV below 3 L and above 6 L for all types of surgeries except bariatric surgery, where larger volumes were associated with progressively better outcomes. Relationships between TCV and adverse outcomes were generally J shaped with higher volumes (>6 L) associated with increased risk. As per current ERAS guidelines, it is important to avoid excessive crystalloid volume in most surgical procedures except for bariatric surgery. [ABSTRACT FROM AUTHOR]

Background: Gabapentinoids are commonly prescribed in perioperative multimodal analgesia protocols. Despite widespread use, the optimal dose to reduce opioid consumption while minimizing risks is unknown. We assessed dose-dependent effects of gabapentinoids on opioid consumption and postoperative pulmonary complications following total hip or knee arthroplasty (THA or TKA). We hypothesized that use of a gabapentinoid on the day of THA or TKA is associated with an increased risk of postoperative pulmonary complications in a dose-response fashion compared with the risk for patients who did not receive the drug.Methods: Using the Premier Database, we identified adults who underwent elective primary THA or TKA from 2009 to 2014. The exposure was receipt of a gabapentinoid (gabapentin or pregabalin) on the day of surgery. Gabapentin dose was categorized into 5 groups: none, 1 to 350, 351 to 700, 701 to 1,050, and >1,050 mg per day. Pregabalin dose was categorized into 4 groups: none, 1 to 110, 111 to 250, and >250 mg per day. The primary outcome was a composite of postoperative pulmonary complications, defined as respiratory failure, pneumonia, reintubation, pulmonary edema, noninvasive ventilation, or invasive mechanical ventilation.Results: Of 858,306 patients who underwent THA or TKA, 11.0% received gabapentin and 10.2% received pregabalin. The mean age (and standard deviation) of the patients was 65.6 ± 10.7 years, 39.6% were male, 78.2% were Caucasian, and 55.2% were covered by Medicare. In multilevel regression analysis, receipt of gabapentinoid at any dose on the day of surgery was associated with increased odds of postoperative pulmonary complications. Compared with no exposure to the drug being used by the particular group, all dose ranges of gabapentin and pregabalin were associated with greater odds of postoperative pulmonary complications (odds ratio, 95% confidence interval = 1.51, 1.40 to 1.63, for >1,050 mg of gabapentin and 1.81, 1.57 to 2.09, for >250 mg of pregabalin). We found no clinically meaningful associations between exposure to either gabapentin or pregabalin and perioperative opioid consumption or the length of the hospital stay.Conclusions: Exposure to gabapentinoids at any dose on the day of THA or TKA was associated with increased odds of postoperative pulmonary complications in a dose-response fashion, with minimal effects on perioperative opioid consumption.Level Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Purpose: Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis.Methods: Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters.Results: Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase.Conclusions: In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any 'cytokine storm'. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02960854. [ABSTRACT FROM AUTHOR]

Background: Lung protective ventilation strategies utilizing lower tidal volumes per predicted body weight (PBW) and positive end-expiratory pressure (PEEP) have been suggested to be beneficial in a variety of surgical populations. Recent clinical studies have used control groups ventilated with high tidal volumes without PEEP based on the assumption that this reflects current clinical practice. We hypothesized that ventilation strategies have changed over time, that most anesthetics in U.S. academic medical centers are currently performed with lower tidal volumes, and that most receive PEEP. Methods: Intraoperative data were pooled for adults undergoing general anesthesia with tracheal intubation. Median tidal volumes per kilogram of PBW were categorized as > 10, 8-10 and < 8 mL per kg of PBW. The percentages of cases in 2013 that were performed with median tidal volumes < 8 mL per kg of PBW and PEEP were determined. As a secondary analysis, a proportional odds model using institution, year, height, weight and gender determined the relative associations of these factors using categorical and interquartile odds ratios. Results: 295,540 cases were analyzed from 5 institutions over a period of 10 years. In 2013, 59.3% of cases used median tidal volumes < 8 mL per kg of PBW, 83.3% used PEEP, and 51.0% used both. Of those cases with PEEP, 60.9% used a median pressure of ≥ 5 cmH2O. Predictors of lower categories of tidal volumes included height (odds ratio (OR) 10.83, 95% confidence interval [10.50, 11.16]), institution (lowest OR 0.98 [0.96,1.00], highest OR 9.63 [9.41, 9.86]), year (lowest OR 1.32 [1.21, 1.44], highest OR 6.31 [5.84, 6.82]), male gender (OR 1.10 [1.07, 1.12]), and weight (OR 0.30 [0.29, 0.31]). Conclusion: Most general anesthetics with tracheal intubation at the institutions surveyed are currently performed with a median tidal volume < 8 mL per kg of PBW, most are managed with PEEP of ≥5 cmH2O and approximately half utilize both. Given the diversity of the institutions included, this is likely reflective of practice in U.S. academic medical centers. The utilization of higher tidal volumes without PEEP in control groups for clinical research studies should be reconsidered. [ABSTRACT FROM AUTHOR]

The article looks at a meta-analysis of the patient cohort of the Lung Injury Prediction Score (LIPS) study to identify the characteristics of patients hospitalized following pulmonary aspiration, recognized to be a major cause of acute respiratory distress syndrome (ARDS). It reports that aspiration was associated with older age, admission from a nursing home low Glasgow Coma Scale (GCS) score, and a history of alcohol abuse. Aspiration patients were also twice as likely to die in-hospital.

Using a multivariable mixed logistic regression model, we estimated odds of medication use in various racial/ethnic groups (versus non-Hispanic White patients) adjusted for the characteristics listed above and for clustering of treatments (individual hospitals treated as random effects). B Introduction: b Although minorities have higher rates of COVID-19-related hospitalizations, discharge rates do not differ across race/ethnicity. [Extracted from the article]

Background: Acute respiratory distress syndrome (ARDS) remains a serious postoperative complication. Although ARDS prevention is a priority, the inability to identify patients at risk for ARDS remains a barrier to progress. The authors tested and refined the previously reported surgical lung injury prediction (SLIP) model in a multicenter cohort of at-risk surgical patients.Methods: This is a secondary analysis of a multicenter, prospective cohort investigation evaluating high-risk patients undergoing surgery. Preoperative ARDS risk factors and risk modifiers were evaluated for inclusion in a parsimonious risk-prediction model. Multiple imputation and domain analysis were used to facilitate development of a refined model, designated SLIP-2. Area under the receiver operating characteristic curve and the Hosmer-Lemeshow goodness-of-fit test were used to assess model performance.Results: Among 1,562 at-risk patients, ARDS developed in 117 (7.5%). Nine independent predictors of ARDS were identified: sepsis, high-risk aortic vascular surgery, high-risk cardiac surgery, emergency surgery, cirrhosis, admission location other than home, increased respiratory rate (20 to 29 and ≥30 breaths/min), FIO2 greater than 35%, and SpO2 less than 95%. The original SLIP score performed poorly in this heterogeneous cohort with baseline risk factors for ARDS (area under the receiver operating characteristic curve [95% CI], 0.56 [0.50 to 0.62]). In contrast, SLIP-2 score performed well (area under the receiver operating characteristic curve [95% CI], 0.84 [0.81 to 0.88]). Internal validation indicated similar discrimination, with an area under the receiver operating characteristic curve of 0.84.Conclusions: In this multicenter cohort of patients at risk for ARDS, the SLIP-2 score outperformed the original SLIP score. If validated in an independent sample, this tool may help identify surgical patients at high risk for ARDS. [ABSTRACT FROM AUTHOR]

Abstract: Acute lung injury (ALI) initiates protective responses involving genes downstream of the Nrf2 (Nfe2l2) transcription factor, including heme oxygenase-1 (HO-1), which stimulates mitochondrial biogenesis and related anti-inflammatory processes. We examined mitochondrial biogenesis during Staphylococcus aureus pneumonia in mice and the effect of Nrf2 deficiency on lung mitochondrial biogenesis and resolution of lung inflammation. S. aureus pneumonia established by nasal insufflation of live bacteria was studied in mitochondrial reporter (mt-COX8-GFP) mice, wild-type (WT) mice, and Nrf2 −/− mice. Bronchoalveolar lavage, wet/dry ratios, real-time RT-PCR and Western analysis, immunohistochemistry, and fluorescence microscopy were performed on the lung at 0, 6, 24, and 48h. The mice survived S. aureus inoculations at 5×108 CFU despite diffuse lung inflammation and edema, but the Nrf2 −/− lung showed increased ALI. In mt-COX8-GFP mice, mitochondrial fluorescence was enhanced in bronchial and alveolar type II (AT2) epithelial cells. WT mice displayed rapid HO-1 upregulation and lower proinflammatory TNF-α, IL-1β, and CCL2 and, especially in AT2 cells, higher anti-inflammatory IL-10 and suppressor of cytokine signaling-3 than Nrf2 −/− mice. In the alveolar region, WT but not Nrf2 −/− mice showed strongly induced nuclear respiratory factor-1, PGC-1α, mitochondrial transcription factor-A, SOD2, Bnip3, mtDNA copy number, and citrate synthase. These findings indicate that S. aureus pneumonia induces Nrf2-dependent mitochondrial biogenesis in the alveolar region, mainly in AT2 cells. Absence of Nrf2 suppresses the alveolar transcriptional network for mitochondrial biogenesis and anti-inflammation, which worsens ALI. The findings link redox activation of mitochondrial biogenesis to ALI resolution. [Copyright &y& Elsevier]

Abstract: Nitric oxide synthase-2 (NOS2) plays a critical role in reactive nitrogen species generation and cysteine modifications that influence mitochondrial function and signaling during inflammation. Here, we investigated the role of NOS2 in hepatic mitochondrial biogenesis during Escherichia coli peritonitis in mice. NOS2−/− mice displayed smaller mitochondrial biogenesis responses than Wt mice during E. coli infection according to differences in mRNA levels for the PGC-1α coactivator, nuclear respiratory factor-1, mitochondrial transcription factor-A (Tfam), and mtDNA polymerase (Polγ). NOS2−/− mice did not significantly increase mitochondrial Tfam and Polγ protein levels during infection in conjunction with impaired mitochondrial DNA (mtDNA) transcription, loss of mtDNA copy number, and lower State 3 respiration rates. NOS2 blockade in mitochondrial-GFP reporter mice disrupted Hsp60 localization to mitochondria after E. coli exposure. Mechanistically, biotin-switch and immunoprecipitation studies demonstrated NOS2 binding to and S-nitros(yl)ation of Hsp60 and Hsp70. Specifically, NOS2 promoted Tfam accumulation in mitochondria by regulation of Hsp60–Tfam binding via S-nitros(yl)ation. In hepatocytes, site-directed mutagenesis identified 237Cys as a critical residue for Hsp60 S-nitros(yl)ation. Thus, the role of NOS2 in inflammation-induced mitochondrial biogenesis involves both optimal gene expression for nuclear-encoded mtDNA-binding proteins and functional regulation of the Hsp60 chaperone that enables their importation for mtDNA transcription and replication. [Copyright &y& Elsevier]

The number of older adults who receive life support in an intensive care unit (ICU), now 2 million per year, is increasing while survival remains unchanged. Because the quality of ICU-based palliative care is highly variable, we developed a mobile app intervention that integrates into the electronic health records (EHR) system called PCplanner (Palliative Care planner) with the goal of improving collaborative primary and specialist palliative care delivery in ICU settings. To describe the methods of a randomized clinical trial (RCT) being conducted to compare PCplanner vs. usual care. The goal of this two-arm, parallel group mixed methods RCT is to determine the clinical impact of the PCplanner intervention on outcomes of interest to patients, family members, clinicians, and policymakers over a 3-month follow up period. The primary outcome is change in unmet palliative care needs measured by the NEST instrument between baseline and 1 week post-randomization. Secondary outcomes include goal concordance of care, patient-centeredness of care, and quality of communication at 1 week post-randomization; length of stay; as well as symptoms of depression, anxiety, and post-traumatic stress disorder at 3 months post-randomization. We will use general linear models for repeated measures to compare outcomes across the main effects and interactions of the factors. We hypothesize that compared to usual care, PCplanner will have a greater impact on the quality of ICU-based palliative care delivery across domains of core palliative care needs, psychological distress, patient-centeredness, and healthcare resource utilization. • The quality of intensive care unit (ICU)-based palliative care delivery is highly variable across clinicians and hospitals. • The PCplanner mobile app automatically identifies high risk older adults, facilitates report of palliative care needs, and coordinates care. • This randomized clinical trial (RCT) tests the impact of PCplanner vs. usual care on unmet needs, psychological distress, and clinical outcomes. [ABSTRACT FROM AUTHOR]

Although non-opioid (and non-pharmacologic) alternatives are available, opioids are routinely administered for analgesia and facilitation of mechanical ventilation in the intensive care units (ICUs) and are recommended by national guidelines. The objective of this study was to estimate the incidence of new persistent opioid use in opioid naïve patients undergoing open thoracic surgery and requiring postoperative ICU admission. B Conclusions: b We found that a significant proportion of opioid naïve patients that underwent open thoracic surgery and required postoperative ICU care in the veteran affairs (VA) system developed new persistent opioid use. [Extracted from the article]