Effectiveness of Fludrocortisone Plus Hydrocortisone Versus Hydrocortisone Alone in Septic Shock: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

RATIONALE: The use of hydrocortisone in adult septic shock is controversial, and effectiveness of adding fludrocortisone to hydrocortisone remains uncertain. OBJECTIVE: To assess comparative effectiveness and safety of fludrocortisone plus hydrocortisone, hydrocortisone alone and placebo/usual care in adults with septic shock. METHODS: Systematic review and Bayesian network meta-analysis of peer-reviewed randomized trials. The primary outcome was all-cause mortality at last follow-up. Treatment effects were presented as relative risks (RR) with 95% credible intervals (CrI). Placebo/usual care was the reference treatment. MAIN RESULTS: Out of 7,553 references, we included 17 trials (7,688 patients). All-cause mortality at last follow-up was lowest with fludrocortisone plus hydrocortisone (RR: 0.85, 95% CrI: 0.72-0.99, 98.3% probability of superiority, moderate-certainty evidence), followed by hydrocortisone alone (RR: 0.97, 95% CrI: 0.87-1.07, 73.1% probability of superiority, low-certainty evidence). The comparison of fludrocortisone plus hydrocortisone versus hydrocortisone alone was primarily based on indirect evidence (only two trials with direct evidence). Fludrocortisone plus hydrocortisone was associated with a 12% lower risk of all-cause mortality compared to hydrocortisone alone (RR: 0.88, 95% CrI: 0.74-1.03, 94.2% probability of superiority, moderate-certainty evidence). CONCLUSIONS: In adult septic shock patients, fludrocortisone plus hydrocortisone was associated with lower risk of all-cause mortality at last follow-up than placebo and hydrocortisone alone. The scarcity of head-to-head trials comparing fludrocortisone plus hydrocortisone versus hydrocortisone alone led our network meta-analysis to rely primarily on indirect evidence for this comparison. Though we undertook several sensitivity analyses and assessments, these findings should be considered while also acknowledging the heterogeneity of included trials.

Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone Among Patients With Septic Shock.

Importance: Patients with septic shock may benefit from the initiation of corticosteroids. However, the comparative effectiveness of the 2 most studied corticosteroid regimens (hydrocortisone with fludrocortisone vs hydrocortisone alone) is unclear. Objective: To compare the effectiveness of adding fludrocortisone to hydrocortisone vs hydrocortisone alone among patients with septic shock using target trial emulation. Design, Setting, and Participants: This retrospective cohort study from 2016 to 2020 used the enhanced claims-based Premier Healthcare Database, which included approximately 25% of US hospitalizations. Participants were adult patients hospitalized with septic shock and receiving norepinephrine who began hydrocortisone treatment. Data analysis was performed from May 2022 to December 2022. Exposure: Addition of fludrocortisone on the same calendar day that hydrocortisone treatment was initiated vs use of hydrocortisone alone. Main Outcome and Measures: Composite of hospital death or discharge to hospice. Adjusted risk differences were calculated using doubly robust targeted maximum likelihood estimation. Results: Analyses included 88 275 patients, 2280 who began treatment with hydrocortisone-fludrocortisone (median [IQR] age, 64 [54-73] years; 1041 female; 1239 male) and 85 995 (median [IQR] age, 67 [57-76] years; 42 136 female; 43 859 male) who began treatment with hydrocortisone alone. The primary composite outcome of death in hospital or discharge to hospice occurred among 1076 (47.2%) patients treated with hydrocortisone-fludrocortisone vs 43 669 (50.8%) treated with hydrocortisone alone (adjusted absolute risk difference, -3.7%; 95% CI, -4.2% to -3.1%; P < .001). Conclusions and Relevance: In this comparative effectiveness cohort study among adult patients with septic shock who began hydrocortisone treatment, the addition of fludrocortisone was superior to hydrocortisone alone.

Culinary medicine and community partnership: hands-on culinary skills training to empower medical students to provide patient-centered nutrition education.

Given the economic burden and numerous morbidities associated with obesity and poor dietary choices, it is increasingly important for medical students to receive education on nutrition and preventive medicine so that they are equipped to advise patients about healthy lifestyle choices. Currently, 71% of US medical schools do not reach the minimum benchmark of 25 hours of nutrition education set by the National Academy of Sciences. In order to improve the quality and quantity of nutrition education at the Keck School of Medicine of USC (KSOM), medical students and faculty have partnered with LA Kitchen (LAK), a local teaching kitchen, and the Wellness Center at LA County Medical Center (LAC+USC). They developed a hands-on preclinical culinary and nutrition course that aims to teach students practical skills and knowledge that they will be able to apply to their own lives and pass onto patients. Following the completion of the first three years of the course (2016-2018), analysis suggests that the class was well-received and has improved students' nutrition knowledge, confidence in lifestyle counseling, and personal culinary skills. Given these highly encouraging observations, the project is currently aimed at incorporating nutrition education more broadly into the required preclinical curriculum at KSOM.

Mesenchymal Stromal Cells Isolated from Irradiated Human Skin Have Diminished Capacity for Proliferation, Differentiation, Colony Formation, and Paracrine Stimulation.

Ionizing radiation, commonly used in the treatment of solid tumors, has unintended but deleterious effects on overlying skin and is associated with chronic nonhealing wounds. Skin-derived mesenchymal stromal cells (SMSCs) are a pluripotent population of cells that are critically involved in skin homeostasis and wound healing. The aim of this study was to isolate and functionally characterize SMSCs from human skin that was previously irradiated as part of neoadjuvant or adjuvant cancer therapy. To this end, SMSCs were isolated from paired irradiated and nonirradiated human skin samples. Irradiated SMSCs expressed characteristic SMSC markers at lower levels, had disorganized cytoskeletal structure, and had disordered morphology. Functionally, these cells had diminished proliferative capacity and substantial defects in colony-forming capacity and differentiation in vitro. These changes were associated with significant differential expression of genes known to be involved in skin physiology and wound healing. Conditioned media obtained from irradiated SMSCs affected fibroblast but not endothelial cell proliferation and migration. These results suggest that in situ damage to SMSCs during neoadjuvant or adjuvant radiation may play a critical role in the pathogenesis of slow or nonhealing radiation wounds. Stem Cells Translational Medicine 2019;8:925&934.

Topical Fibronectin Improves Wound Healing of Irradiated Skin.

Wound healing is significantly delayed in irradiated skin. To better understand global changes in protein expression after radiation, we utilized a reverse phase protein array (RPPA) to identify significant changes in paired samples of normal and irradiated human skin. Of the 210 proteins studied, fibronectin was the most significantly and consistently downregulated in radiation-damaged skin. Using a murine model, we confirmed that radiation leads to decreased fibronectin expression in the skin as well as delayed wound healing. Topically applied fibronectin was found to significantly improve wound healing in irradiated skin and was associated with decreased inflammatory infiltrate and increased angiogenesis. Fibronectin treatment may be a useful adjunctive modality in the treatment of non-healing radiation wounds.