Resolution of inflammation via RvD1/FPR2 signaling mitigates Nox2 activation and ferroptosis of macrophages in experimental abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. Resolvin D1 (RvD1) is derived from ω-3 polyunsaturated fatty acids and is involved in the resolution phase of chronic inflammatory diseases. The aim of this study was to decipher the protective role of RvD1 via formyl peptide receptor 2 (FPR2) receptor signaling in attenuating abdominal aortic aneurysms (AAA). The elastase-treatment model of AAA in C57BL/6 (WT) mice and human AAA tissue was used to confirm our hypotheses. Elastase-treated FPR2-/- mice had a significant increase in aortic diameter, proinflammatory cytokine production, immune cell infiltration (macrophages and neutrophils), elastic fiber disruption, and decrease in smooth muscle cell α-actin expression compared to elastase-treated WT mice. RvD1 treatment attenuated AAA formation, aortic inflammation, and vascular remodeling in WT mice, but not in FPR2-/- mice. Importantly, human AAA tissue demonstrated significantly decreased FPR2 mRNA expression compared to non-aneurysm human aortas. Mechanistically, RvD1/FPR2 signaling mitigated p47phox phosphorylation and prevented hallmarks of ferroptosis, such as lipid peroxidation and Nrf2 translocation, thereby attenuating HMGB1 secretion. Collectively, this study demonstrates RvD1-mediated immunomodulation of FPR2 signaling on macrophages to mitigate ferroptosis and HMGB1 release, leading to resolution of aortic inflammation and remodeling during AAA pathogenesis.

Sex-based differences in patients undergoing thoracic endovascular aortic repair for acute complicated type B dissection.

OBJECTIVE: Sex-based differences in outcomes for patients undergoing degenerative aortic aneurysm repair have been well described, with female patients having worse early and long-term outcomes compared with male patients. However, differences between men and women after thoracic endovascular aortic repair (TEVAR) of acute complicated type B aortic dissection (TBAD) have not been well characterized. Therefore, the objective of the present study was to assess the sex-based differences in clinical presentation, time to repair, morbidity, and mortality for patients undergoing TEVAR for TBAD. METHODS: All TEVAR procedures performed for acute complicated TBAD from a single academic medical center from August 2005 to January 2020 were analyzed. The clinical presentation, time to repair, and outcomes were compared by sex. The primary outcome was 30-day mortality. The secondary outcomes were in-hospital complications, reintervention, aorta-related death, and out of hospital survival. The predictors of mortality, including sex, were determined using multivariable logistic regression. RESULTS: A total of 159 patients (38 women [24%]) were included in the analysis. No sex-based differences were found in clinical presentation or comorbidity prevalence between the female and male patients. The female patients had had a longer overall time from initial symptom onset to TEVAR (female patients: median, 3.5 days [interquartile range (IQR), 1-10 days]; male patients: median, 1 day [IQR, 1-3]; P = .007). However, no differences were found in the time to repair after admission to the academic medical center (female patients: median, 1 day [IQR, 0-5 days]; male patients: median, 1 day [IQR, 0-3]; P = .176). No differences were found in the unadjusted aortic-related, in-hospital, or 30-day death between the female and male patients. Similarly, the risk-adjusted analysis revealed that sex was not associated with adverse outcomes. The 1- and 5-year freedom from aortic-related mortality were 82% ± 4% and 87% ± 6% and 79% ± 4% and 80% ± 8% for the men and women, respectively. CONCLUSIONS: We found no differences between the female and male patients with acute complicated TBAD who had undergone TEVAR in the clinical presentation or comorbidities. The female patients had undergone TEVAR after a longer duration of symptoms, but this was not associated with sex-based differences in early or late morbidity or mortality.

Maresin 1 activates LGR6 signaling to inhibit smooth muscle cell activation and attenuate murine abdominal aortic aneurysm formation.

The specialized pro-resolving lipid mediator maresin 1 (MaR1) is involved in the resolution phase of tissue inflammation. It was hypothesized that exogenous administration of MaR1 would attenuate abdominal aortic aneurysm (AAA) growth in a cytokine-dependent manner via LGR6 receptor signaling and macrophage-dependent efferocytosis of smooth muscle cells (SMCs). AAAs were induced in C57BL/6 wild-type (WT) mice and smooth muscle cell specific TGF-ß2 receptor knockout (SMC-TGFßr2-/- ) mice using a topical elastase AAA model. MaR1 treatment significantly attenuated AAA growth as well as increased aortic SMC α-actin and TGF-ß2 expressions in WT mice, but not SMC-TGFßr2-/- mice, compared to vehicle-treated mice. In vivo inhibition of LGR6 receptors obliterated MaR1-dependent protection in AAA formation and SMC α-actin expression. Furthermore, MaR1 upregulated macrophage-dependent efferocytosis of apoptotic SMCs in murine aortic tissue during AAA formation. In vitro studies demonstrate that MaR1-LGR6 interaction upregulates TGF-ß2 expression and decreases MMP2 activity during crosstalk of macrophage-apoptotic SMCs. In summary, these results demonstrate that MaR1 activates LGR6 receptors to upregulate macrophage-dependent efferocytosis, increases TGF-ß expression, preserves aortic wall remodeling and attenuate AAA formation. Therefore, this study demonstrates the potential of MaR1-LGR6-mediated mitigation of vascular remodeling through increased efferocytosis of apoptotic SMCs via TGF-ß2 to attenuate AAA formation.

Pediatric perioperative adverse events requiring rapid response: a retrospective case-control study.

BACKGROUND: Perioperative pediatric adverse events have been challenging to study within and across institutions due to varying definitions, low event rates, and incomplete capture. AIM: The aim of this study was to determine perioperative adverse event prevalence and to evaluate associated case characteristics and potential contributing factors at an academic pediatric quaternary-care center. METHODS: At the Children's Hospital of Philadelphia (CHOP), perioperative adverse events requiring rapid response assistance are termed Anesthesia Now (AN!) events. They have been accurately captured and entered into a quality improvement database since 2010. Adverse events involving open heart and cardiac catheterization cases are managed separately and not included in this database. We conducted a retrospective case-control study utilizing Compurecord (Phillips Healthcare, Andover, MA, USA), EPIC (EPIC, Verona, WI, USA), and Chartmaxx (MedPlus, Mason, OH, USA) systems matching AN! event cases to noncardiac controls (1 : 2) based on surgical date. RESULTS: From April 16, 2010 to September 25, 2012, we documented 213 AN! events in the noncardiac perioperative complex and remote sites at our main hospital. AN! prevalence was 0.0043 (1 : 234) with a 95% confidence interval (CI) (0.0037, 0.0049). Respiratory events, primarily laryngospasm, were most common followed by events of cardiovascular etiology. Median age was lower in the AN! group than in controls, 2.86 years (interquartile range 0.94, 10.1) vs 6.20 (2.85, 13.1), P < 0.0001. Odds ratios (with 95% CI) for age, 0.969 (0.941, 0.997); American Society of Anesthesiologists physical status, 1.67 (1.32, 2.12); multiple (≥2) services, 2.27 (1.13, 4.55); nonoperating room vs operating room location, 0.240 (0.133, 0.431); and attending anesthesiologist's experience, 0.976 (0.959, 0.992) were all significant. CONCLUSIONS: Decreased age, increased comorbidities, multiple (vs single) surgical services, operating room (vs nonoperating room) location, and decreased staff experience were associated with increased risk of AN! events, which were predominantly respiratory in origin.

Evaluation of central venous pressure monitoring in children undergoing craniofacial reconstruction surgery.

BACKGROUND: Massive hemorrhage during craniofacial surgery is common and often results in hypovolemia and hypotension. We conducted this study to assess the effect of the addition of routine central venous pressure (CVP) monitoring on the incidence of intraoperative hypotension and to evaluate the relationship between CVP and hypotension in this population. METHODS: Data from our prospective craniofacial perioperative registry for children 6 to 24 months of age undergoing cranial vault reconstruction with CVP monitoring were compared with data from a historical cohort without CVP monitoring. The incidence and duration of hypotension in the 2 cohorts were compared. In the cohort of subjects with CVP monitoring who experienced hypotension, CVP at the onset of hypotension (T0) was compared with CVP 5 minutes before (T-5) and 5 minutes after (T+5) the onset of hypotension and with the baseline CVP. The amount of time spent at various CVP levels below the baseline, and the associated incidence of hypotension were also determined. RESULTS: Data from 57 registry subjects were compared with data from 115 historical cohort subjects. The median total duration of hypotension in subjects experiencing hypotension was 278 seconds in the CVP cohort versus 165 seconds in the historical cohort; the median difference was 98 seconds (95% confidence interval [CI], -45 to 345 seconds). The incidence of hypotension was 18% in the CVP cohort versus 21% in the historical cohort; the difference in the incidence of hypotension was -3% (95% CI, -10% to 15%). Analysis using a linear mixed effects model showed a significant decrease in CVP from T-5 to T0 (95% CI, -0.9 to -2.2 mm Hg), a significant increase in CVP from T0 to T+5 (95% CI, 1.0-2.4 mm Hg), no significant difference in CVP between T-5 and T+5 (95% CI, -0.9 to 0.9 mm Hg), and a significant decrease in CVP from baseline to T0 (95% CI, -3.4 to -2.1 mm Hg). CVP at T0 was less than the baseline CVP in 97% of hypotensive episodes. When all cases were examined, CVP was ≥3 mm Hg below the baseline for 16% of the total time studied, with an associated incidence of hypotension of 2%. CONCLUSIONS: The implementation of routine CVP monitoring was not associated with a decreased incidence and likely was not associated with a decreased duration of hypotension in this population experiencing massive hemorrhage. Hypotension was associated with a decrease in CVP, and resolution of hypotension was associated with an increase in CVP to prehypotensive levels. However, significant decreases in CVP below the baseline were common and usually not associated with hypotension. The routine use of CVP monitoring in these children is of questionable utility as a means to decrease the incidence and duration of hypotension.

Sex differences in specialized pro-resolving lipid mediators and their receptors in abdominal aortic aneurysms.

Objective: In this study, we tested the hypothesis that endogenous expression of specialized pro-resolving lipid mediators (SPMs) that facilitate the resolution of inflammation, specifically Resolvin D1and -D2, as well as Maresin1 (MaR1), can impact abdominal aortic aneurysm (AAA) formation and progression in a sex-specific manner. Methods: SPM expression was quantified in aortic tissue from human AAA samples and from a murine in vivo AAA model via liquid chromatography-tandem mass spectrometry. mRNA expression for SPM receptors FPR2, LGR6, and GPR18 were quantified by real-time polymerase chain reaction. A Student t test with nonparametric Mann-Whitney or Wilcoxon test was used for pair-wise comparisons of groups. One-way analysis of variance after post hoc Tukey test was used to determine the differences among multiple comparative groups. Results: Human aortic tissue analysis revealed a significant decrease in RvD1 levels in male AAAs compared with controls, whereas FPR2 and LGR6 receptor expressions were downregulated in male AAAs compared with male controls. In vivo studies of elastase-treated mice showed higher levels of RvD2 and MaR1 as well as the SPM precursors, omega-3 fatty acids DHA and EPA, in aortic tissue from males compared with females. FPR2 expression was increased in elastase-treated females compared with males. Conclusions: Our findings demonstrate that specific differences in SPMs and their associated G-protein coupled receptors exist between sexes. These results indicate the relevance of SPM-mediated signaling pathways in sex differences impacting the pathogenesis of AAAs.

Effect of transfusion guidelines on postoperative transfusion in children undergoing craniofacial reconstruction surgery.

OBJECTIVE: To assess the effect of implementation of population-specific postoperative management guidelines on postoperative transfusion in children undergoing cranial vault reconstruction surgery. DESIGN: Retrospective observational study with historical controls. SETTING: Single, large, academic tertiary pediatric hospital. PATIENTS: : Children aged 6 months to 17 yrs undergoing fronto-orbital advancement or posterior cranial vault reconstruction surgery enrolled in our craniofacial surgery perioperative registry from April 14, 2008 to September 7, 2011. INTERVENTION: Postoperative management guidelines for children undergoing cranial vault reconstruction surgery were implemented on December 1, 2009. These management guidelines included projected surgical drain output as well as specific transfusion thresholds for packed red blood cells and hemostatic blood products. MEASUREMENTS AND MAIN RESULTS: We queried our craniofacial surgery perioperative registry for children who underwent cranial vault reconstruction to assess transfusion practices before and after the implementation of the postoperative guidelines. Subjects were divided into a preguideline cohort and a postguideline cohort. Perioperative demographic data and postoperative transfusion data were compared between the two groups. The registry query returned data on 59 procedures in the preguideline cohort and 58 procedures in the postguideline cohort. The immediate postoperative hematocrit and the postoperative blood loss through surgical drains were not statistically different in the two groups. The prevalence of postoperative transfusion of any blood product was significantly less in the postguideline cohort (17% vs. 42%, p = .003). Most of the transfusion reduction was achieved through a reduction in fresh frozen plasma transfusion (5% vs. 25%, p = .002). CONCLUSIONS: In this observational study, the implementation of postoperative management guidelines was associated with a 60% reduction in postoperative transfusion. The use of transfusion thresholds is a simple, inexpensive, and effective strategy for transfusion reduction and should be a first-line approach to perioperative transfusion reduction in this population.

The reliability of manual reporting of clinical events in an anesthesia information management system (AIMS).

Manual incident reports significantly under-report adverse clinical events when compared with automated recordings of intraoperative data. Our goal was to determine the reliability of AIMS and CQI reports of adverse clinical events that had been witnessed and recorded by research assistants. The AIMS and CQI records of 995 patients aged 2-12 years were analyzed to determine if anesthesia providers had properly documented the emesis events that were observed and recorded by research assistants who were present in the operating room at the time of induction. Research assistants recorded eight cases of emesis during induction that were confirmed with the attending anesthesiologist at the time of induction. AIMS yielded a sensitivity of 38 % (95 % confidence interval [CI] 8.5-75.5 %), while the sensitivity of CQI reporting was 13 % (95 % CI 0.3-52.7 %). The low sensitivities of the AIMS and CQI reports suggest that user-reported AIMS and CQI data do not reliably include significant clinical events.

Current Penetration, Completeness, and Representativeness of The Society of Thoracic Surgeons Adult Cardiac Surgery Database.

BACKGROUND: The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) is the largest cardiac surgical database in the world. Linked data from STS ACSD and the Centers for Medicare and Medicaid Services (CMS) database were used to determine contemporary completeness, penetration, and representativeness of STS ACSD. METHODS: Variables common to both STS and CMS databases were used to link STS procedures to CMS data for all CMS coronary artery bypass grafting surgery (CABG) discharges between 2000 and 2018, inclusive. For each CMS CABG hospitalization, it was determined whether a matching STS record existed. RESULTS: Center-level penetration (number of CMS sites with at least 1 matched STS participant divided by total number of CMS CABG sites) increased from 45% in 2000 to 95% in 2018. In 2018, 949 of 1004 CMS CABG sites (95%) were linked to an STS site. Patient-level penetration (number of CMS CABG hospitalizations at STS sites divided by total number of CMS CABG hospitalizations) increased from 51% in 2000 to 97% in 2018. In 2018, 68,584 of 70,818 CMS CABG hospitalizations (97%) occurred at an STS site. Completeness of case inclusion at STS sites (number of CMS CABG cases at STS sites linked to STS records divided by total number of CMS CABG cases at STS sites) increased from 88% in 2000 to 98% in 2018. In 2018, 66,673 of 68,108 CMS CABG hospitalizations at STS sites (98%) were linked to an STS record. CONCLUSIONS: Linkage of the STS and CMS databases demonstrates high and increasing penetration and completeness of STS ACSD. STS ACSD now includes 97% of CABG in the United States.

A validated mouse model capable of recapitulating the protective effects of female sex hormones on ascending aortic aneurysms and dissections (AADs).

Fewer females develop AADs (ascending aortic aneurysms and dissections) and the reasons for this protection remain poorly understood. The present study seeks to develop a mouse model that may be utilized to address this sexual dimorphism. Adult normolipidemic mice were challenged with BAPN (ß-aminopropionitrile), AngII (angiotensin II), or BAPN + AngII. An initial protocol optimization found that 0.2% BAPN in drinking water plus AngII-infusion at 1,000 ng kg-1  min-1 produced favorable rates of AAD rupture (~50%) and dilation (~40%) in 28 days. Using these dosages, further experiments revealed that BAPN is toxic to naïve mature aortas and it acted synergistically with AngII to promote aortic tears and dissections. BAPN + AngII provoked early infiltration of myeloid cells and subsequent recruitment of lymphoid cells to the aortic wall. AADs established with BAPN + AngII, but not AngII alone, continued to expand after the cessation of AngII-infusion. This indefinite growth precipitated a 61% increase in the AAD diameter in 56 days. More importantly, with the optimized protocol, significant differences in AAD dilation (p = .012) and medial degeneration (p = .036) were detected between male and female mice. Treatment of ovariectomized mice with estradiol protected AAD formation (p = .014). In summary, this study developed a powerful mouse AAD model that can be used to study the sexual dimorphism in AAD formation.

Complicated acute type B aortic dissection: update on management and results.

BACKGROUND: The role of thoracic endovascular aortic repair (TEVAR) has evolved and is now firmly established as a mainstay of therapy for acute complicated type B aortic dissection (acTBAD). However, several important issues remain unresolved including the optimal timing, sizing, graft selection, coverage length and utilization of adjunctive therapies to address false lumen perfusion. Therefore, the purpose of this study was to provide a contemporary perspective on the management and results for TEVAR of acTBAD. METHODS: All TEVAR patients (N.=159) with acTBAD from a single high-volume, academic medical center were analyzed. Comparative results across time-dependent cohorts (2005-2009 [N.=43] vs. 2010-2014 [N.=56] vs. 2015-2020 [N.=60]) are presented. RESULTS: 30-day mortality was 13%(N.=21) with a trend towards improvement over time (2005-2009, 18% vs. 2010-2020, 12%; P=0.1). Similarly, incidence of postoperative complications also declined: 2005-2009, 70% vs. 2010-2020, 36%(P-trend=0.08). One and 2-year freedom from aorta-related reintervention was 78±7% and 73±9% and did not differ across cohorts (log-rank P=0.5). Respective one and 5-year survival was 75±3% and 64±7%, but significantly improved with time (log-rank P<0.001). The corresponding one and five-year freedom from aorta-related mortality was 82±4% and 78±7% but did not change during the study interval (log-rank P=0.3). CONCLUSIONS: Outcomes for TEVAR of acTBAD continue to improve over time. This time-dependent analysis delineates how results have changed due to increasing experience, technologic evolution, and maturation of the peer reviewed evidence. These results along with the evidence-based review provided herein, provide an update on the management and results of TEVAR of acTBAD while highlighting specific controversies unique to the management of this challenging clinical problem.