Daily Sepsis Research Analysis

Intravenous (IV) vitamin C has been proposed as an adjuvant therapy in sepsis/septic shock due to its biological plausibility and safety profile, but the proliferation of reviews has not resolved its clinical utility. To synthesize the evidence on IV vitamin C (monotherapy, HAT-hydrocortisone+vitamin C+thiamine-and vitamin C+thiamine) in adults with sepsis/septic shock, prioritizing 28-30-day mortality. Umbrella review of systematic reviews and meta-analyses (MEDLINE/PubMed, Embase, Scopus, and Web of Science, without language restriction). Quality was assessed with AMSTAR 2, overlap with CCA, and when available, TSA and component/network meta-analysis (CINeMA). Certainty of evidence was graded using GRADE with an anchor estimator per outcome and regimen. Thirty-one reviews were included (30 quantitative: 28 SR/MA and 2 component/network MA; 1 qualitative). Combinations (HAT and vitamin C+thiamine) did not reduce mortality; hemodynamic improvements (small decreases in ΔSOFA and vasopressor hours) were modest, did not translate into survival benefits, and were primarily attributable to the corticosteroid. Monotherapy showed a possible mortality benefit signal under specific conditions (initiation ≤24 h, intermediate dose 25-100 mg/kg/day, 3-4-day courses; more pronounced in sepsis than shock), but with low-to-moderate certainty due to heterogeneity, imprecision, publication bias, and very high overlap among reviews. Combination regimens (HAT and vitamin C plus thiamine) did not reduce mortality; hemodynamic improvements were modest, did not translate into survival benefits, and were primarily attributable to the corticosteroid component. For monotherapy, a possible mortality benefit signal was identified under specific conditions (initiation within 24 h, intermediate dose 25-100 mg/kg/day, 3-4-day courses, more pronounced in sepsis than shock), but overall certainty remains low-to-moderate due to heterogeneity, imprecision, publication bias, and very high overlap among reviews. These findings do not support routine use of IV vitamin C in any regimen; for monotherapy, the identified signal warrants rigorous multicenter trials in well-defined clinical scenarios before any recommendation can be made.

BACKGROUND: Most mechanically ventilated intensive care unit patients require sedation and analgesia for comfort. Current usual care is propofol-based sedation plus an opioid analgesic. The alpha2 agonists dexmedetomidine and clonidine are potential alternative sedatives, but their clinical and cost-effectiveness are uncertain. OBJECTIVE(S): To evaluate the clinical and cost-effectiveness and safety of alpha2 agonists (dexmedetomidine and clonidine) compared with propofol for sedating adult intensive care unit patients. DESIGN AND METHODS: Pragmatic open-label three-arm trial. Embedded process and economic evaluation. SETTING AND PARTICIPANTS: Forty-one intensive care units in the UK. Recruitment from December 2018 to October 2023. Participants were 1437 adults within 48 hours of starting mechanical ventilation expected to require ≥ 48 hours of mechanical ventilation [analysis population: propofol ( INTERVENTIONS: In all groups, bedside algorithms targeted a Richmond Agitation Sedation Scale of -2 to + 1 unless clinicians requested deeper sedation. Intervention groups' algorithms supported alpha2-agonist up-titration and propofol down-titration followed by sedation primarily with allocated alpha2 agonist. Supplemental propofol was permitted if required. OUTCOMES: Primary outcome was time to successful extubation, analysed allowing for death as a competing risk. Secondary outcomes included mortality, sedation quality, rates of delirium and cardiovascular adverse events. Long-term outcomes included: experience of intensive care unit care; anxiety, depression and post-traumatic stress; cognitive function; health-related quality of life. RESULTS: Mean (standard deviation) patient age was 59.2 (14.9) years; 901 (65%) male. The sub-distribution hazard ratio for time to successful extubation for dexmedetomidine versus propofol was 1.09 (95% confidence interval 0.96 to 1.25; LIMITATIONS: This was a pragmatic unblinded trial, with associated risk of performance and ascertainment bias. FUTURE WORK: Future trials should explore the effectiveness of alpha2 agonists as sedatives in other populations, for example paediatric critical care and acute brain injury. CONCLUSIONS: In mechanically ventilated critically ill patients, neither dexmedetomidine- nor clonidine-based sedation was superior for major clinical outcomes or more cost-effective compared with propofol-based sedation. FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/93/01. Intensive care unit patients needing support from breathing machines need medications (sedatives and painkillers) to keep them comfortable. There is evidence that keeping people as awake as possible during care helps them recover, but the best way to achieve this is uncertain. This programme of work compared the use of propofol (currently the most widely used sedative) with two drugs called ‘alpha2 agonists’ (dexmedetomidine and clonidine). Some evidence suggests alpha2 agonists have advantages over propofol, by enabling patients to be more awake and comfortable on the breathing machine. They may also decrease confusion (delirium), which is common and distressing during intensive care unit care. However, there are also concerns that these drugs, especially dexmedetomidine, may not be safe for some patients. In a large trial randomising patients to receive either propofol (usual care) or dexmedetomidine or clonidine as their main sedative (with additional propofol if required), we found no important differences in the time taken to come off the breathing machine. Most measures of patient comfort were similar, but more patients experienced agitation with both dexmedetomidine and clonidine. These sedatives caused higher rates of abnormally slow heart rate compared with propofol, which was a concern to medical and nursing staff caring for patients. We found no important differences in patient survival or well-being during 6 months’ follow-up, and no evidence that either drug offers better value for money if used as the main sedation agent compared with propofol. Our work suggests we should not use alpha2agonists as the main sedative for all intensive care unit patients. There is some uncertainty about our findings, because we found issues like clinician experience and pre-existing beliefs and concerns about alpha2 agonists influenced how they were used. We also cannot exclude that they may have advantages in specific patients based on individual clinicians’ judgement.

PURPOSE: Neonates admitted to intensive care units are at high risk of hospital-acquired infections. While blood cultures remain the gold standard for sepsis diagnosis, they do not detect infection in every case. Host immune response markers, such as C-reactive protein and procalcitonin, can assist in earlier detection but also have limitations and carry additional costs. We have developed a Neonatal Intensive Care Infection Score (NICIS), which leverages extended complete blood count (CBC+Diff + EIP) parameters, which may require specific analyser configuration or software licensing, to extract additional diagnostic value. METHODS: We conducted a retrospective cohort study of neonates admitted to the Neonatal Intensive Care Unit at the John Radcliffe Hospital (Oxford, UK) over one year. Eighteen CBC+Diff + EIP parameters were initially considered based on their ability to differentiate culture-positive patients from those without clinical suspicion of infection. NICIS was developed as a weighted score and validated internally using a temporally distinct dataset and externally using a four-year retrospective cohort from Erasmus University Medical Center (Rotterdam, The Netherlands). RESULTS: Incorporating eight CBC+Diff + EIP parameters, NICIS values ranged from 0 to 25, with higher scores indicating a greater likelihood of sepsis. NICIS achieved an area under the curve of 0.906 in training, 0.879 in internal validation, and 0.841 in external validation, outperforming C-reactive protein and total white blood cell count in all datasets. CONCLUSIONS: NICIS provides an interpretable tool for sepsis detection using routinely collected CBC+Diff + EIP data without additional sampling. Its performance across internal and external cohorts suggests sufficient diagnostic accuracy, although prospective studies are warranted to further assess generalisability and clinical utility. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44253-026-00121-9.