Enhanced Recovery Protocols Reduce Mortality Across Eight Surgical Specialties at Academic and University-affiliated Community Hospitals.

OBJECTIVE: To determine if implementation of a simplified ERP across multiple surgical specialties in different hospitals is associated with improved short and long-term mortality. Secondary aims were to examine ERP effect on length of stay, 30-day readmission, discharge disposition, and complications. SUMMARY BACKGROUND DATA: Enhanced recovery after surgery and various derivative ERPs have been successfully implemented. These protocols typically include elaborate sets of multimodal and multidisciplinary approaches, which can make implementation challenging or are variable across different specialties. Few studies have shown if a simplified version of ERP implemented across multiple surgical specialties can improve clinical outcomes. METHODS: A simplified ERP with 7 key domains (minimally invasive surgical approach when feasible, pre-/intra-operative multimodal analgesia, postoperative multimodal analgesia, postoperative nausea and vomiting prophylaxis, early diet advancement, early ambulation, and early removal of urinary catheter) was implemented in 5 academic and community hospitals within a single health system. Patients who underwent nonemergent, major orthopedic or abdominal surgery including hip/knee replacement, hepatobiliary, colorectal, gynecology oncology, bariatric, general, and urological surgery were included. Propensity-matched, retrospective case-control analysis was performed on all eligible surgical patients between 2014 and 2017 after ERP implementation or in the 12 months preceding ERP implementation (control population). RESULTS: A total of 9492 patients (5185 ERP and 4307 controls) underwent ERP eligible surgery during the study period. Three thousand three hundred sixty-seven ERP patients were matched by surgical specialty and hospital site to control non-ERP patients. Short and long-term mortality was improved in ERP patients: 30 day: ERP 0.2% versus control 0.6% ( P = 0.002); 1-year: ERP 3.9% versus control 5.1% ( P < 0.0001); 2-year: ERP 6.2% versus control 9.0% ( P < 0.0001). Length of stay was significantly lower in ERP patients (ERP: 3.9 ± 3.8 days; control: 4.8 ± 5.0 days, P < 0.0001). ERP patients were also less likely to be discharged to a facility (ERP: 11.3%; control: 14.8%, P < 0.0001). There was no significant difference for 30-day readmission. All complications except venous thromboembolism were significantly reduced in the ERP population (P < 0.02). CONCLUSIONS: A simplified ERP can uniformly be implemented across multiple surgical specialties and hospital types. ERPs improve short and long-term mortality, clinical outcomes, length of stay, and discharge disposition to home.

The Effect of Scheduled Intravenous Acetaminophen in an Enhanced Recovery Protocol Pathway in Patients Undergoing Major Abdominal Procedures: A Prospective, Randomized, and Placebo-Controlled Clinical Trial.

OBJECTIVE: Enhanced recovery protocols (ERPs) utilize multi-modal analgesia regimens. Individual regimen components should be evaluated for their analgesic efficacy. We evaluated the effect of scheduled intravenous (IV) acetaminophen within an ERP on analgesia and recovery after a major abdominal surgery. DESIGN: This study is a prospective, randomized, double-blinded clinical trial. SETTING: The study setting was a tertiary care, academic medical center. SUBJECTS: Adult patients scheduled for elective major abdominal surgical procedures. METHODS: Patients in group A received 1 g IV acetaminophen, while patients in group P received IV placebo every six hours for 48 hours postoperatively within an ERP. Pain scores, opioid requirements, nausea and vomiting, time to oral intake and mobilization, length of stay, and patient satisfaction scores were measured and compared. RESULTS: From 412 patients screened, 154 patients completed the study (Group A: 76, Group P: 78). Primary outcome was the number of patients with unsatisfactory pain relief, defined as a composite of average Numeric Rating Scale (NRS) scores above 5 and requirement of IV patient-controlled analgesia for pain relief during the first 48 hours postoperatively, and was not significantly different between the two groups (33 (43.4%) in group A versus 42 (53.8%) patients in group P, P = .20). Opioid consumption was comparable between two groups. Group A utilized significantly less postoperative rescue antiemetics compared to group P (41% vs. 58%, P = .02). CONCLUSIONS: Scheduled administration of IV acetaminophen did not improve postoperative analgesia or characteristics of postoperative recovery in patients undergoing major abdominal surgery within an ERP pathway.

BAL Cell Gene Expression in Severe Asthma Reveals Mechanisms of Severe Disease and Influences of Medications.

Rationale: Gene expression of BAL cells, which samples the cellular milieu within the lower respiratory tract, has not been well studied in severe asthma.Objectives: To identify new biomolecular mechanisms underlying severe asthma by an unbiased, detailed interrogation of global gene expression.Methods: BAL cell expression was profiled in 154 asthma and control subjects. Of these participants, 100 had accompanying airway epithelial cell gene expression. BAL cell expression profiles were related to participant (age, sex, race, and medication) and sample traits (cell proportions), and then severity-related gene expression determined by correlating transcripts and coexpression networks to lung function, emergency department visits or hospitalizations in the last year, medication use, and quality-of-life scores.Measurements and Main Results: Age, sex, race, cell proportions, and medications strongly influenced BAL cell gene expression, but leading severity-related genes could be determined by carefully identifying and accounting for these influences. A BAL cell expression network enriched for cAMP signaling components most differentiated subjects with severe asthma from other subjects. Subsequently, an in vitro cellular model showed this phenomenon was likely caused by a robust upregulation in cAMP-related expression in nonsevere and ß-agonist-naive subjects given a ß-agonist before cell collection. Interestingly, ELISAs performed on BAL lysates showed protein levels may partly disagree with expression changes.Conclusions: Gene expression in BAL cells is influenced by factors seldomly considered. Notably, ß-agonist exposure likely had a strong and immediate impact on cellular gene expression, which may not translate to important disease mechanisms or necessarily match protein levels. Leading severity-related genes were discovered in an unbiased, system-wide analysis, revealing new targets that map to asthma susceptibility loci.

Ex vivo lung perfusion as a human platform for preclinical small molecule testing.

The acute respiratory distress syndrome (ARDS) causes an estimated 70,000 US deaths annually. Multiple pharmacologic interventions for ARDS have been tested and failed. An unmet need is a suitable laboratory human model to predictively assess emerging therapeutics on organ function in ARDS. We previously demonstrated that the small molecule BC1215 blocks actions of a proinflammatory E3 ligase-associated protein, FBXO3, to suppress NF-κB signaling in animal models of lung injury. Ex vivo lung perfusion (EVLP) is a clinical technique that maintains lung function for possible transplant after organ donation. We used human lungs unacceptable for transplant to model endotoxemic injury with EVLP for 6 hours. LPS infusion induced inflammatory injury with impaired oxygenation of pulmonary venous circulation. BC1215 treatment after LPS rescued oxygenation and decreased inflammatory cytokines in bronchoalveolar lavage. RNA sequencing transcriptomics from biopsies taken during EVLP revealed robust inflammatory gene induction by LPS with a strong signal for NF-κB-associated transcripts. BC1215 treatment reduced the LPS induction of genes associated with inflammatory and host defense gene responses by Gene Ontology (GOterm) and pathways analysis. BC1215 also significantly antagonized LPS-mediated NF-κB activity. EVLP may provide a unique human platform for preclinical study of chemical entities such as FBXO3 inhibitors on tissue physiology.

The aldehyde dehydrogenase, AldA, is essential for L-1,2-propanediol utilization in laboratory-evolved Escherichia coli.

Most Escherichia coli strains are naturally unable to grow on 1,2-propanediol (PDO) as a sole carbon source. Recently, however, a K-12 descendent E. coli strain was evolved to grow on 1,2-PDO, and it was hypothesized that this evolved ability was dependent on the aldehyde dehydrogenase, AldA, which is highly conserved among members of the family Enterobacteriacea. To test this hypothesis, we first performed computational model simulation, which confirmed the essentiality of the aldA gene for 1,2-PDO utilization by the evolved PDO-degrading E. coli. Next, we deleted the aldA gene from the evolved strain, and this deletion was sufficient to abolish the evolved phenotype. On re-introducing the gene on a plasmid, the evolved phenotype was restored. These findings provide experimental evidence for the computationally predicted role of AldA in 1,2-PDO utilization, and represent a good example of E. coli robustness, demonstrated by the bacterial deployment of a generalist enzyme (here AldA) in multiple pathways to survive carbon starvation and to grow on a non-native substrate when no native carbon source is available.