Association Between Premorbid Beta-Blocker Exposure and Sepsis Outcomes-The Beta-Blockers in European and Australian/American Septic Patients (BEAST) Study.

OBJECTIVES: To examine the effect of premorbid ß-blocker exposure on mortality and organ dysfunction in sepsis. DESIGN: Retrospective observational study. SETTING: ICUs in Australia, the Czech Republic, and the United States. PATIENTS: Total of 4,086 critical care patients above 18 years old with sepsis between January 2014 and December 2018. INTERVENTION: Premorbid beta-blocker exposure. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred fifty-six patients (38%) with premorbid ß-blocker exposure were identified. Overall ICU mortality rate was 15.1%. In adjusted models, premorbid ß-blocker exposure was associated with decreased ICU (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97; p = 0.025) and hospital (adjusted odds ratio, 0.83; 95% CI, 0.71-0.99; p = 0.033) mortality. The risk reduction in ICU mortality of 16% was significant (hazard ratio, 0.84, 95% CI, 0.71-0.99; p = 0.037). In particular, exposure to noncardioselective ß-blocker before septic episode was associated with decreased mortality. Sequential Organ Failure Assessment score analysis showed that premorbid ß-blocker exposure had potential benefits in reducing respiratory and neurologic dysfunction. CONCLUSIONS: This study suggests that ß-blocker exposure prior to sepsis, especially to noncardioselective ß blockers, may be associated with better outcome. The findings suggest prospective evaluation of ß-blocker use in the management of sepsis.

Correction to: The association between premorbid beta blocker exposure and mortality in sepsis-a systematic review.

In the publication of this article [1], there was an error in the cited reference 23 [2] within the Family Name. This has now been updated in the original article.

The association between premorbid beta blocker exposure and mortality in sepsis-a systematic review.

BACKGROUND: The effect of premorbid ß-blocker exposure on clinical outcomes in patients with sepsis is not well characterized. We aimed to examine the association between premorbid ß-blocker exposure and mortality in sepsis. METHODS: EMBase, MEDLINE, and Cochrane databases were searched for all studies of premorbid ß-blocker and sepsis. The search was last updated on 22 June 2019. Two reviewers independently assessed, selected, and abstracted data from studies reporting chronic ß-blocker use prior to sepsis and mortality. Main data extracted were premorbid ß-blocker exposure, mortality, study design, and patient data. Two reviewers independently assessed the risk of bias and quality of evidence. RESULTS: In total, nine studies comprising 56,414 patients with sepsis including 6576 patients with premorbid exposure to ß-blockers were eligible. For the primary outcome of mortality, two retrospective studies reported adjusted odds ratios showing a reduction in mortality with premorbid ß-blocker exposure. One study showed that premorbid ß-blocker exposure decreases mortality in patients with septic shock. Another study showed that continued ß-blockade during sepsis is associated with decreased mortality. CONCLUSION: This systematic review suggests that ß-blocker exposure prior to sepsis is associated with reduced mortality. There was insufficient data to conduct a bona fide meta-analysis. Whether the apparent reduction in mortality may be attributed to the mitigation of catecholamine excess is unclear. TRIAL REGISTRATION: PROSPERO, CRD42019130558 registered June 12, 2019.

Timely Endocytosis of Cytokinetic Enzymes Prevents Premature Spindle Breakage during Mitotic Exit.

Cytokinesis requires the spatio-temporal coordination of membrane deposition and primary septum (PS) formation at the division site to drive acto-myosin ring (AMR) constriction. It has been demonstrated that AMR constriction invariably occurs only after the mitotic spindle disassembly. It has also been established that Chitin Synthase II (Chs2p) neck localization precedes mitotic spindle disassembly during mitotic exit. As AMR constriction depends upon PS formation, the question arises as to how chitin deposition is regulated so as to prevent premature AMR constriction and mitotic spindle breakage. In this study, we propose that cells regulate the coordination between spindle disassembly and AMR constriction via timely endocytosis of cytokinetic enzymes, Chs2p, Chs3p, and Fks1p. Inhibition of endocytosis leads to over accumulation of cytokinetic enzymes during mitotic exit, which accelerates the constriction of the AMR, and causes spindle breakage that eventually could contribute to monopolar spindle formation in the subsequent round of cell division. Intriguingly, the mitotic spindle breakage observed in endocytosis mutants can be rescued either by deleting or inhibiting the activities of, CHS2, CHS3 and FKS1, which are involved in septum formation. The findings from our study highlight the importance of timely endocytosis of cytokinetic enzymes at the division site in safeguarding mitotic spindle integrity during mitotic exit.

Blood urea nitrogen - independent marker of mortality in sepsis.

BACKGROUND: This retrospective study examines the relationship between admission Blood Urea Nitrogen (BUN) levels and clinical outcomes in patients with sepsis from two separate cohorts in the Czech Republic and the United States. METHODS: The study included 9126 patients with sepsis between January 2014 and December 2018. Kaplan-Meier survival curves and Cox regression were used to analyse the data. An optimal cut-off was calculated by means of the Youden-Index. RESULTS: BUN at ICU admission was categorized as 10-20, 20-40 and >40 mg/dL. Comparing the group with the highest BUN levels to the one with lowest levels, we found HR for 28 days mortality 2.764 (CI 95% 2.37-3.20; P<0.001). We derived an optimal cut-off for prediction of 28 days mortality of 23 mg/dL. The association between BUN and 28 days mortality remained significant after adjusting for potential confounders - for APACHE IV (HR 1.374; 95%CI 1.20-1.58; P<0.001), SAPS2 (HR 1.545; 95%CI 1.35-1.77; P<0.001), eGFR (HR 1.851; 95%CI 1.59-2.16; P<0.001) and several other variables in an integrative model. CONCLUSIONS: Our findings support the BUN level as an independent and easily available predictor of 28 days mortality in septic critically ill patients admitted to an ICU.

The Association of Premorbid Metformin Exposure With Mortality and Organ Dysfunction in Sepsis: A Systematic Review and Meta-Analysis.

To examine the association between premorbid metformin exposure and mortality, hyperlactatemia, and organ dysfunction in sepsis. DATA SOURCES: PubMed and EMBASE (with Medline via Ovid) databases were searched for all studies of premorbid metformin exposure and sepsis published between January 1974 and August 2018. STUDY SELECTION: Studies of at least 20 patients with sepsis that reported data on metformin use, mortality, and/or organ dysfunction were independently selected. DATA EXTRACTION: Two reviewers abstracted data on study design, settings, study quality, participants, metformin exposure, mortality, initial lactate levels, and organ dysfunction. Risk of bias was independently assessed. DATA SYNTHESIS: Eight observational studies fulfilled our criteria, comprising 4,144 patients with sepsis including 562 diabetics on metformin. Premorbid metformin exposure was associated with reduced mortality in sepsis (odds ratio, 0.57; 95% CI, 0.40-0.80). Between studies heterogeneity was low (i 2 = 43%; τ2 = 0.1; p = 0.09). Premorbid metformin exposure was not significantly associated with initial lactate levels (mean difference, 0.39 [-0.50 to 1.28]; i 2 = 72%; p = 0.39). CONCLUSIONS: The meta-analysis suggests that premorbid metformin exposure is associated with decreased mortality in sepsis but not with hyperlactatemia. What are the potential mechanisms and whether there is any effect on organ dysfunction remain unclear.