Sex and gender are fundamental health determinants and their role as modifiers of treatment response is increasingly recognized. Norepinephrine is a cornerstone of septic shock management and its use is based on the highest level of evidence compared to dopamine. The related 2021 Surviving Sepsis Campaign (SCC) recommendation is presumably applicable to both females and males; however, a sex- and gender-based analysis is lacking, thus not allowing generalizable conclusions. This paper was aimed at exploring whether sex- and gender-disaggregated data are available in the evidence supporting this recommendation. For all the studies underpinning it, four pairs of authors, including a woman and a man, extracted data concerning sex and gender, according to the Sex and Gender Equity in Research guidelines. Nine manuscripts were included with an overall population of 2126 patients, of which 43.2% were females. No sex analysis was performed and gender was never reported. In conclusion, the present manuscript highlighted that the clinical studies underlying the SCC recommendation of NE administration in septic shock have neglected the likely role of sex and gender as modifiers of treatment response, thus missing the opportunity of sex- and gender-specific guidelines.

Background: Cardiac arrest with refractory ventricular fibrillation (rVF) represents a dramatic medical emergency. Despite recent advances, its treatment is challenging and burdened by limited evidence. This systematic review and meta-analysis aims at establishing whether alternative defibrillation strategies (ADS), i.e. double sequential external defibrillation (DSED) or vector-change defibrillation (VCD), improve survival among patients with rVF compared to standard defibrillation (SD). Methods: Randomized clinical trials (RCTs), prospective and retrospective studies were included if: (1) compared ADS with SD in rVF; (2) conducted on patients ≥ 18 years old; (3) reported survival to hospital admission. English-language papers from MEDLINE, Google Scholar, Cochrane Library, World Health Organization, EMBASE and CINAHL, published from inception to December 2022, were retrieved. The risk of bias was assessed following the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies and the revised Cochrane risk of bias tool for randomized trials, as appropriate. A random-effects meta-analysis was performed to estimate the pooled Odds Ratio (pOR) with 95% Confidence Interval (95%CI) of ADS and survival to hospital admission. Furthermore, a subgroup analysis was performed to compare SD with each type of ADS. The protocol was registered on PROSPERO (CRD42022379049). Results: Eight studies (2 RCTs, 5 retrospective and 1 case-control study) were retrieved for qualitative and quantitative analyses. The study population included 1405 patients (ADS = 493 vs. SD = 912) with a pooled mean age of 61.9 ± 1.1 years; among them, 277 (19.7%) were female. The random-effect meta-analysis did not show differences in survival to hospital admission among ADS vs. SD (pOR = 1.12, 95%CI: 0.62-2.01). The subgroup analysis confirmed that neither DSED (pOR = 1.20, 95%CI: 0.56-2.58) nor VCD (pOR = 1.66, 95%CI: 0.10-27.02) were associated with improved survival to hospital admission. Main limitations were: i) few numbers of studies included with small sample size; and ii) female under-representation. Conclusion: The present manuscript did not show any difference on survival to hospital admission between the considered defibrillation strategies in rVF. This result highlights the need for further ad hoc clinical trials assessing the actual role of ADS.