Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Design, setting, and participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. Main outcome and measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Conclusions and relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. Trial registration: ClinicalTrials.gov Identifier: NCT04291508. Weniger anzeigen

Importance: In-hospital mortality of patients with sepsis is frequently measured for benchmarking, both by researchers and policymakers. Prior studies have reported higher in-hospital mortality among patients with sepsis at safety-net hospitals compared with non-safety-net hospitals; however, in critically ill patients, in-hospital mortality rates are known to be associated with hospital discharge practices, which may differ between safety-net hospitals and non-safety-net hospitals. Objective: To assess how admission to safety-net hospitals is associated with 2 metrics of short-term mortality (in-hospital mortality and 30-day mortality) and discharge practices among patients with sepsis. Design, setting, and participants: Retrospective, national cohort study of Medicare fee-for-service beneficiaries aged 66 years and older, admitted with sepsis to an intensive care unit from January 2011 to December 2019 based on information from the Medicare Provider Analysis and Review File. Data were analyzed from October 2022 to September 2023. Exposure: Admission to a safety-net hospital (hospitals with a Medicare disproportionate share index in the top quartile per US region). Main outcomes and measures: Coprimary outcomes: in-hospital mortality and 30-day mortality. Secondary outcomes: (1) in-hospital do-not-resuscitate orders, (2) in-hospital palliative care delivery, (3) discharge to a postacute facility (skilled nursing facility, inpatient rehabilitation facility, or long-term acute care hospital), and (4) discharge to hospice. Results: Between 2011 and 2019, 2 551 743 patients with sepsis (mean [SD] age, 78.8 [8.2] years; 1 324 109 [51.9%] female; 262 496 [10.3%] Black, 2 137 493 [83.8%] White, and 151 754 [5.9%] other) were admitted to 666 safety-net hospitals and 1924 non-safety-net hospitals. Admission to safety-net hospitals was associated with higher in-hospital mortality (odds ratio [OR], 1.09; 95% CI, 1.06-1.13) but not 30-day mortality (OR, 1.01; 95% CI, 0.99-1.04). Admission to safety-net hospitals was associated with lower do-not-resuscitate rates (OR, 0.86; 95% CI, 0.81-0.91), palliative care delivery rates (OR, 0.66; 95% CI, 0.60-0.73), and hospice discharge (OR, 0.82; 95% CI, 0.78-0.87) but not with discharge to postacute facilities (OR, 0.98; 95% CI, 0.95-1.01). Conclusions and relevance: In this cohort study, among patients with sepsis, admission to safety-net hospitals was associated with higher in-hospital mortality but not with 30-day mortality. Differences in in-hospital mortality may partially be explained by greater use of hospice at non-safety-net hospitals, which shifts attribution of death from the index hospitalization to hospice. Future investigations and publicly reported quality measures should consider time-delimited rather than hospital-delimited measures of short-term mortality to avoid undue penalty to safety-net hospitals with similar short-term mortality. Weniger anzeigen

Background: Despite the fact that red blood cell (RBC) transfusion is commonly applied in surgical intensive care unit (ICU), the effect of RBC transfusion on long-term outcomes remains undetermined. We aimed to explore the association between RBC transfusion and the long-term prognosis of surgical sepsis survivors. Methods: This retrospective study was conducted on adult sepsis patients admitted to a tertiary surgical ICU center in China. Patients were divided into transfusion and non-transfusion groups based on the presence of RBC transfusion. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW)were performed to balance the potential confounders. Results: A total of 1421 surgical sepsis survivors were enrolled, including 403 transfused patients and 1018 non-transfused patients. There was a significant difference in 1-year mortality between the two groups (23.1 % vs 12.7 %, HR: 1.539, 95 % confidence interval [CI]: 1.030-2.299, P < 0.001). After PSM and IPTW, transfused patients still showed significantly increased 1-year mortality risks compared to non-transfused individuals (PSM: 23.6 % vs 15.9 %, HR 1.606, 95 % CI 1.036-2.488 P = 0.034; IPTW: 20.1 % vs 12.9 %, HR 1.600, 95 % CI 1.040-2.462 P = 0.032). Among patients with nadir hemoglobin below 70 g/L, 1-year mortality risks in both groups were similar (HR 1.461, 95 % CI 0.909-2.348, P = 0.118). However, among patients with nadir hemoglobin above 70 g/L, RBC transfusion was correlated with increased 1-year mortality risk (HR 1.556, 95 % CI 1.020-2.374, P = 0.040). Conclusion: For surgical sepsis survivors, RBC transfusion during ICU stay was associated with increased 1-year mortality, especially when patients show hemoglobin levels above 70 g/L. Keywords: Red blood cell transfusion, Sepsis survivor, Surgical intensive care unit, Surgical sepsis Weniger anzeigen

Importance: There is uncertainty about whether prolonged infusions of β-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. Objective: To determine whether prolonged β-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. Data sources: The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Study selection: Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of β-lactam antibiotics in critically ill adults with sepsis or septic shock. Data extraction and synthesis: Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. Main outcomes and measures: The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. Results: From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of β-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of β-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Conclusions and relevance: Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged β-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. Trial registration: PROSPERO Identifier: CRD42023399434. Weniger anzeigen

Rationale: Shorter time-to-antibiotics is lifesaving in sepsis, but programs to hasten antibiotic delivery may increase unnecessary antibiotic use and adverse events. Objectives: We sought to estimate both the benefits and harms of shortening time-to-antibiotics for sepsis. Methods: We conducted a simulation study using a cohort of 1,559,523 hospitalized patients admitted through the emergency department with meeting two or more systemic inflammatory response syndrome criteria (2013-2018). Reasons for hospitalization were classified as septic shock, sepsis, infection, antibiotics stopped early, and never treated (no antibiotics within 48 h). We simulated the impact of a 50% reduction in time-to-antibiotics for sepsis across 12 hospital scenarios defined by sepsis prevalence (low, medium, or high) and magnitude of „spillover“ antibiotic prescribing to patients without infection (low, medium, high, or very high). Outcomes included mortality and adverse events potentially attributable to antibiotics (e.g., allergy, organ dysfunction, Clostridiodes difficile infection, and culture with multidrug-resistant organism). Results: A total of 933,458 (59.9%) hospitalized patients received antimicrobial therapy within 48 hours of presentation, including 38,572 (2.5%) with septic shock, 276,082 (17.7%) with sepsis, 370,705 (23.8%) with infection, and 248,099 (15.9%) with antibiotics stopped early. A total of 199,937 (12.8%) hospitalized patients experienced an adverse event; most commonly, acute liver injury (5.6%), new MDRO (3.5%), and Clostridiodes difficile infection (1.7%). Across the scenarios, a 50% reduction in time-to-antibiotics for sepsis was associated with a median of 1 to 180 additional antibiotic-treated patients and zero to seven additional adverse events per death averted from sepsis. Conclusions: The impacts of faster time-to-antibiotics for sepsis vary markedly across simulated hospital types. However, even in the worst-case scenario, new antibiotic-associated adverse events were rare. Weniger anzeigen

Introduction: Despite advances in neonatal care, late-onset sepsis remains an important cause of preventable morbidity and mortality. Neonatal late-onset sepsis rates have decreased in some countries, while in others they have not. Our objective was to compare trends in late-onset sepsis rates in 9 population-based networks from 10 countries and to assess the associated mortality within 7 days of late-onset sepsis. Methods: We performed a retrospective population-based cohort study. Infants born at 24-28 weeks‘ gestation between 2007 and 2019 were eligible for inclusion. Late-onset sepsis was defined as a positive blood or cerebrospinal fluid culture. Late-onset sepsis rates were calculated for 3 epochs (2007-11, 2012-15, and 2016-19). Adjusted risk ratios (aRRs) for late-onset sepsis were calculated for each network. Results: Of a total of 82,850 infants, 16,914 (20.4%) had late-onset sepsis, with Japan having the lowest rate (7.1%) and Spain the highest (44.6%). Late-onset sepsis rates decreased in most networks and remained unchanged in a few. Israel, Sweden, and Finland showed the largest decrease in late-onset sepsis rates. The aRRs for late-onset sepsis showed wide variations between networks. The rate of mortality temporally related to late-onset sepsis was 10.9%. The adjusted mean length of stay for infants with late-onset sepsis was increased by 5-18 days compared to infants with no late-onset sepsis. Conclusions: One in 5 neonates of 24-28 weeks‘ gestation develops late-onset sepsis. Wide variability in late-onset sepsis rates exists between networks with most networks exhibiting improvement. Late-onset sepsis was associated with increased mortality and length of stay. Weniger anzeigen

Objectives: International guidelines recommend IV crystalloid as the primary fluid for sepsis resuscitation, with 5% human albumin solution (HAS) as the second line. However, it is unclear which fluid has superior clinical effectiveness. We conducted a trial to assess the feasibility of delivering a randomized controlled trial comparing balanced crystalloid against 5% HAS as sole early resuscitation fluid in patients with sepsis presenting to hospital. Design: Multicenter, open, parallel-group randomized feasibility trial. Setting: Emergency departments (EDs) in 15 U.K. National Health Service (NHS) hospitals. Patients: Adult patients with sepsis and a National Early Warning Score 2 greater than or equal to five requiring IV fluids withing one hour of randomization. Interventions: IV fluid resuscitation with balanced crystalloid or 5% HAS for the first 6 hours following randomization. Measurements and main results: Primary feasibility outcomes were recruitment rate and 30-day mortality. We successfully recruited 301 participants over 12 months. Mean (sd) age was 69 years (± 16 yr), and 151 (50%) were male. From 1303 participants screened; 502 participants were potentially eligible and 300 randomized to receive trial intervention with greater than 95% of participants receiving the intervention. The median number of participants per site was 19 (range, 1-63). Thirty-day mortality was 17.9% (n = 53). Thirty-one participants died (21.1%) within 30 days in the 5% HAS arm, compared with 22 participants (14.8%) in the crystalloid arm (adjusted odds ratio, 1.50; 95% CIs, 0.84-2.83). Conclusions: Our results suggest it is feasible to recruit critically ill patients to a fluid resuscitation trial in U.K. EDs using 5% HAS as a primary resuscitation fluid. There was lower mortality in the balanced crystalloid arm. Given these findings, a definitive trial is likely to be deliverable, but the point estimates suggest such a trial would be unlikely to demonstrate a significant benefit from using 5% HAS as a primary resuscitation fluid in sepsis. Weniger anzeigen

Background: Survivors of sepsis may experience long-term risk of increased morbidity and mortality, but estimations of cause-specific effects beyond 1 year after a sepsis episode are lacking. Method: This nationwide population-based cohort study linked data from national registers to compare patients aged ≥18 years in Sweden admitted to an intensive care unit from 2008 to 2019 with severe community-acquired sepsis. Patients were identified through the Swedish Intensive Care Registry, and randomly selected population controls were matched for age, sex, calendar year, and county of residence. Confounding from comorbidities, health care use, and socioeconomic and demographic factors was accounted for by using entropy-balancing methods. Long-term mortality and readmission rates, total and cause specific, were compared for 20 313 patients with sepsis and 396 976 controls via Cox regression. Results: During the total follow-up period, 56% of patients with sepsis died, as opposed to 26% of the weighted controls. The hazard ratio for all-cause mortality was attenuated with time but remained elevated in all periods: 3.0 (95% CI, 2.8-3.2) at 2 to 12 months after admission, 1.8 to 1.9 between 1 and 5 years, and 1.6 (95% CI, 1.5-1.8) at >5 years. The major causes of death and readmission among the sepsis cases were infectious diseases, cancer, and cardiovascular diseases. The hazard ratios were larger among those without underlying comorbidities. Conclusions: Severe community-acquired sepsis was associated with substantial long-term effects beyond 1 year, as measured by mortality and rehospitalization. The cause-specific rates indicate the importance of underlying or undetected comorbidities while suggesting that survivors of sepsis may face increased long-term mortality and morbidity not explained by underlying health factors. Keywords: epidemiology, long-term, mortality, readmission, sepsis Weniger anzeigen

Objective: To evaluate the prevalence, timing, clinical risk factors, and adverse outcomes associated with postpartum readmissions for maternal sepsis. Methods: We conducted a retrospective cohort study of delivery hospitalizations and 60-day postpartum readmissions for females aged 15-54 years with and without sepsis using the 2016-2020 Nationwide Readmissions Database. Temporal trends in sepsis diagnoses during delivery hospitalizations and 60-day postpartum readmissions were analyzed with the National Cancer Institute’s Joinpoint Regression Program to estimate the average annual percent change with 95% CIs. Logistic regression models were fit to determine whether delivery hospitalization characteristics were associated with postpartum sepsis readmissions, and unadjusted and adjusted odds ratios with 95% CIs were reported. Adverse outcomes associated with sepsis during delivery hospitalization and readmission were described, including death, severe morbidity, a critical care composite, and renal failure. Results: Overall, 15,268,190 delivery hospitalizations and 256,216 associated 60-day readmissions were included after population weighting, of which 16,399 (1.1/1,000 delivery hospitalizations) had an associated diagnosis of sepsis at delivery, and 20,130 (1.3/1,000 delivery hospitalizations) had an associated diagnosis of sepsis with postpartum readmission. A sepsis diagnosis was present in 7.9% of all postpartum readmissions. Characteristics associated with postpartum sepsis readmission included younger age at delivery, Medicaid insurance, lowest median ZIP code income quartile, and chronic medical conditions such as obesity, pregestational diabetes, and chronic hypertension. Postpartum sepsis readmissions were associated with infection during the delivery hospitalization, including intra-amniotic infection or endometritis, wound infection, and delivery sepsis. Sepsis diagnoses were associated with 24.4% of maternal deaths at delivery and 38.4% postpartum, 2.2% cases of nontransfusion severe morbidity excluding sepsis at delivery and 13.6% postpartum, 15.6% of critical care composite diagnoses at delivery and 30.1% postpartum, and 11.1% of acute renal failure diagnoses at delivery and 36.4% postpartum. Conclusion: Sepsis accounts for a significant proportion of postpartum readmissions and is a major contributor to adverse outcomes during delivery hospitalizations and postpartum readmissions. Weniger anzeigen