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This is the largest study describing the role of P450 epoxygenase metabolites in septic shock in humans and suggests a novel therapeutic target. OBJECTIVES: Oxylipins are oxidative breakdown products of cell membrane fatty acids. Animal models have demonstrated that oxylipins generated by the P450 epoxygenase pathway may be implicated in septic shock pathology. However, these mediators are relatively unexplored in humans with septic shock. We aimed to determine if there were patterns of oxylipins that were associated with 28-day septic shock mortality and organ dysfunction. DESIGN: Retrospective analysis of samples collected during the Vasopressin versus Norepinephrine as Initial Therapy in Septic Shock trial. SETTING: ICUs in the United Kingdom. PARTICIPANTS: Adults recruited within 6 hours of onset of septic shock. MAIN OUTCOMES AND MEASURES: Oxylipin profiling was performed on 404 serum samples from 152 patients using liquid chromatography-mass spectrometry. RESULTS: Nonsurvivors were found to have higher levels of 14,15-dihydroxyeicosatrienoic acid (DHET) at baseline than survivors (p = 0.02). Patients with 14,15-DHET levels above the lower limit of quantification of the assay were more likely to die than patients with levels below this limit (hazard ratio, 2.3; 95% CI, 1.2-4.5). Patients with measurable 14,15-DHET had higher levels of organ dysfunction and fewer renal failure-free days than those in whom it was unmeasurable. Considering samples collected over the first week of intensive care stay, measurable levels of DHET species were associated with higher daily Sequential Organ Failure Assessment scores that appeared to be accounted for predominantly by the liver component. Measurable 14,15-DHET showed positive correlation with bilirubin (r s = 0.38; p < 0.001) and lactate (r s = 0.27; p = 0.001). CONCLUSIONS AND RELEVANCE: The P450 epoxygenase-derived DHET species of oxylipins were associated with organ, particularly liver, dysfunction in septic shock and 14,15-DHET was associated with septic shock mortality. These results support further investigation into the role of the P450 epoxygenase-derived oxylipins in sepsis and suggest that this pathway may offer a novel therapeutic strategy in septic shock.
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AIMS: The CREST tool was recently developed to stratify the risk of circulatory-aetiology death (CED) in out-of-hospital cardiac arrest (OHCA) patients without ST-elevation myocardial infarction (STEMI). We aimed to validate the CREST score using an external cohort and determine whether it could be improved by the addition of serum lactate on admission. METHODS: The study involved the retrospective analysis of consecutive patients admitted to a single tertiary centre with OHCA of presumed cardiac origin over a 51-month period. The CREST score was calculated by attributing points to the following variables: Coronary artery disease (CAD), non-shockable Rhythm, Ejection fraction <30%, cardiogenic Shock at presentation and ischaemic Time ≥25 minutes. The primary endpoint was CED vs neurological aetiology death (NED) or survival. RESULTS: Of 500 patients admitted with OHCA, 211 did not meet criteria for STEMI and were included. 115 patients died in hospital (71 NED, 44 CED). When analysed individually, CED was associated with all CREST variables other than a previous diagnosis of CAD. The CREST score accurately predicted CED with excellent discrimination (C-statistic 0.880, 95% CI 0.813-0.946) and calibration (Hosmer and Lemeshow P=0.948). Although an admission lactate ≥7 mmol/L also predicted CED, its addition to the CREST score (the C-AREST score) did not significantly improve the predictive ability (CS 0.885, 0.815-0.954, HS P=0.942, X2 difference in -2 log likelihood =0.326, P=0.850). CONCLUSION: Our study is the first to independently validate the CREST score for predicting CED in patients presenting with OHCA without STEMI. Addition of lactate on admission did not improve its predictive ability.
RESUMO
BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a major cause of death worldwide. Recent guidelines recommend the centralisation of OHCA services in cardiac arrest centres to improve outcomes. In 2015, two major tertiary cardiac centres in London merged to form a large dedicated tertiary cardiac centre. This study aimed to compare the short-term mortality of patients admitted with an OHCA before-and-after the merger of services had taken place and admission criteria were relaxed, which led to managing OHCA in higher volume. METHODS: We retrospectively analysed the data of OHCA patients pre- and post-merger. Baseline demographic and medical characteristics were recorded, along with factors relating to the cardiac arrest. The primary endpoint was in-hospital mortality. RESULTS: OHCA patients (N =728; 267 pre- and 461 post-merger) between 2013 and 2018 were analysed. Patients admitted pre-merger were older (65.0 vs. 62.4 years, p=0.027), otherwise there were similar baseline demographic and peri-arrest characteristics. There was a greater proportion of non-acute coronary syndrome-related OHCA admission post-merger (10.1% vs. 23.4%, p=0.0001) and a corresponding decrease in those admitted with ST-elevation myocardial infarction (80.2% vs. 57.0%, p=0.0001) and those treated with percutaneous coronary intervention (78.8% vs. 54.0%, p=0.0001). Despite this, in-hospital mortality was lower post-merger (63.7% vs. 44.3%, p=0.0001), which persisted after adjustment for demographic and arrest-related characteristics using stepwise logistic regression (p=0.036) between the groups. CONCLUSION: Despite an increase in non-acute coronary syndrome-related OHCA cases, the formation of a centralised invasive heart centre was associated with improved survival in OHCA patients. This suggests there may be a benefit of a cardiac arrest centre model of care.
