OBJECTIVES:To develop a practical consensus-based framework for 10 steps to improve sepsis care in low-resource settings (LRSs), aligned with the sepsis chain of survival and informed by global expertise. DATA SOURCES:We reviewed peer-reviewed literature on sepsis epidemiology, prevention, recognition, and management in LRS; international guidelines, including the Surviving Sepsis Campaign; and prior "10-step" consensus frameworks for resuscitation and emergency care. STUDY SELECTION:A Task Force representing adult and pediatric sepsis care, emergency care, critical care, infectious diseases, public health, and implementation science identified key domains from the above data sources. DATA EXTRACTION:With guidance from methodologists and implementation science experts, we utilized an iterative, consensus-based process-literature review, Delphi survey, Utstein-style conference, stakeholder input, and public comment-to first define and then refine steps and implementation strategies. DATA SYNTHESIS:The process resulted in 10 nonsequential, actionable steps covering governance and commodities, provider and caregiver education, community and facility prevention, early recognition and rapid response, timely guideline-based interventions, structured post-sepsis care, data systems, quality improvement, a culture of excellence and respect, and holistic well-being of patients, caregivers, and providers. Each step includes a rationale and potential implementation strategies adaptable to local resources and needs. Collectively, the ten steps emphasize integration across the continuum of care, equitable access to essential interventions, and the role of emerging technologies to prevent, recognize, monitor, and follow-up sepsis. CONCLUSIONS:The 10 steps provide a consensus-driven roadmap for health leaders, clinicians, and policymakers to improve sepsis care, strengthen the sepsis chain of survival, reduce preventable morbidity and mortality, and address global inequities in sepsis outcomes.

BACKGROUND:The ratio of arterial oxygen partial pressure to fraction of inspired oxygen (PaO2/FiO2, hereafter P/F ratio) is a key component of the Sequential Organ Failure Assessment (SOFA) score. It reflects the severity of hypoxaemic respiratory failure. The ongoing revision of the SOFA score requires data-driven cutoffs for P/F ratio as well as rational criteria for respiratory support. In this study, we aimed to determine the optimal P/F ratio cutoffs for determining respiratory failure categories in the revised SOFA score and examined whether advanced respiratory support should be a prerequisite for the most severe categories. METHODS:We used the database of the intensive care unit of Kuopio University Hospital, Finland, for cutoff derivation and the eICU database, a multicenter U.S. intensive care registry, for external validation. We identified cutoffs most discriminative for hospital mortality using the log-rank statistic test with the Contal and O'Quigley method. In external validation, these cutoffs were compared with those in the current respiratory SOFA score. RESULTS:Optimal cutoffs were identified as follows: P/F ratio > 40 kPa (normal), 30-40 kPa (mild impairment), 20-30 kPa (moderate impairment), 10-20 kPa (severe impairment), and ≤ 10 kPa (critical impairment). These cutoffs resulted in clear separation of the severity categories (chi-square for log-rank statistic 356.9). They outperformed the current respiratory SOFA score cutoffs in the validation cohort (AUROC 0.615, 95% CI 0.607-0.622 vs. AUROC 0.610, 95% CI 0.603-0.618, p < 0.001). Advanced respiratory support was associated with higher mortality, but its inclusion as a prerequisite improved discrimination only in the moderately impaired respiratory function category, not in the severely or critically impaired categories. CONCLUSION:P/F ratio cutoffs using 10 kPa (75 mmHg) intervals were identified to be optimal for distinguishing stages of respiratory failure severity. The impact of respiratory support on P/F ratio-mortality associations suggests the need to calibrate any P/F ratio-based score by support level, but optimal calibration methods require further study. EDITORIAL COMMENT:In this study, the cut-off values for the partial pressure of arterial oxygen to the fraction of inspired oxygen (P/F ratio) were investigated in a large Finnish intensive care database and validated externally with the US intensive care registry. The aim was to support a revision of the cut-off values for the P/F ratio in the Sequential Organ Failure Assessment (SOFA) score. The results showed that incremental changes in the P/F ratio of 10 kPa are better than 13 kPa and emphasize the need for critical assessment of the current SOFA score.

PURPOSE OF REVIEW:For three decades, the Sequential Organ Failure Assessment (SOFA) score has been central to critical care, offering a simple, reproducible measure of organ dysfunction. Since the original score [Sequential Organ Failure Assessment-1 (SOFA-1)] [1], advances in organ support, drugs, and monitoring, and an ageing, comorbid population have reshaped practice and rendered several tools outdated. This prompted an international initiative to modernize SOFA while preserving its core strengths: simplicity, reproducibility, feasibility across diverse settings, and longitudinal assessment of organ dysfunction. RECENT FINDINGS:SOFA-2 was developed through a modified Delphi process with 60 international experts and dedicated methodology and validation committees. Expert consensus, systematic reviews, and analyses of multinational databases (high-income, middle-income, and lower-middle-income systems) established its face, content, and predictive validity. The six original organ systems were retained; the gastrointestinal and immune domains were examined but not included because current datasets did not support them. SOFA-2 keeps the architecture of SOFA-1 while updating definitions, reflecting contemporary therapies, and standardizing missing-data handling and the scoring of acute-on-chronic dysfunction. SUMMARY:SOFA-2 is an evolution rather than a reinvention. It must now be tested in the real-world - within definitions such as Sepsis-3, across its derived variables (admission, maximum, delta, discharge), and in varied settings, including low-income and middle-income countries.

OBJECTIVES:Almost 80% of sepsis cases occur in low-resource settings (LRS), where limited resources impede the effective implementation of international guidelines for sepsis management. In addition, existing sepsis guidelines have not fully addressed specific issues relevant to LRS. Therefore, an international panel of 20 multiprofessional sepsis experts was convened to generate consensus on the gaps in and strategies for sepsis care in LRS. The recently developed "sepsis chain of survival" was used as a framework. DATA SOURCES:MEDLINE, Embase. STUDY SELECTION:Studies selected included human studies (clinical trials, cohort, case-control, and case series) reporting clinical outcomes in patients with sepsis from LRS between January 1, 2000, and July 4, 2024. Search terms included "developing countries," "LMIC," "resource-poor settings," and regional terms such as Africa, Southeast Asia, and Latin America. The Delphi process involved iterative, anonymous voting by the expert panel to achieve consensus to draft clinical practice statements. DATA EXTRACTION:A detailed literature review was conducted using the "sepsis chain of survival" as a basis, with an emphasis on sepsis prevention, detection, therapy, post-sepsis care, education, and future research priorities. A total of 8865 studies were identified and screened, with 155 included in the review. DATA SYNTHESIS:Based on literature review, the Delphi process achieved a stable consensus for 58 of 62 (94%) of the proposed clinical practice statements after eight survey rounds. These statements offer guidance on measures to improve the prevention, early recognition and time-sensitive, comprehensive management of sepsis in LRS through the continuum of care from first response to post-sepsis care and follow-up. CONCLUSIONS:There remains a significant lack of high-quality evidence to support improvements in sepsis care for patients in LRS. Pending new data, the clinical practice statements identified here complement the existing international guidelines for sepsis management by serving as a basis for immediate care and future research in LRS.

OBJECTIVES:Sepsis is a time-sensitive cause of preventable death worldwide, with disproportionate mortality in low-resource settings (LRS). Many recommendations in international sepsis guidance presume resources unavailable in many facilities and communities. We sought to develop a practical framework that helps health systems embed feasible sepsis actions within broader emergency and essential critical care systems, while highlighting where evidence is limited and where local learning systems are needed. DATA SOURCES:A targeted scoping review of peer-reviewed and grey literature on sepsis epidemiology, emergency care systems, essential emergency and critical care, implementation strategies, and quality improvement (QI) in LRS; and key guideline and policy documents relevant to sepsis and emergency care. STUDY SELECTION:We prioritized publications and guidance relevant to LRS, including observational studies, pragmatic implementation reports, consensus statements, and policies addressing emergency care organization, workforce, supply chains, diagnostics, and QI. DATA EXTRACTION:Task force members abstracted actionable strategies, implementation barriers/enablers, and feasibility considerations across the care continuum (community, transport/prehospital, facility-based acute care, and referral). We also identified domains where guideline certainty is low or indirect for LRS. DATA SYNTHESIS:A Society of Critical Care Medicine-convened multidisciplinary task force iteratively developed the "Sepsis Frame of Survival" using a structured process that included 1) scoping evidence review, 2) a Delphi-style prioritization of candidate framework elements by importance and feasibility, and 3) a structured consensus meeting ("Utstein-style" conference format) to finalize the model and its priority actions. We produced a concise implementation roadmap and a feasible measurement set aligned with resource constraints. CONCLUSIONS:The Sepsis Frame of Survival is a pragmatic model to organize sepsis improvement as part of emergency and essential critical care strengthening. It emphasizes high-impact actions that can be implemented with limited resources (triage and early recognition, timely antimicrobials, oxygen and basic supportive care, cautious fluid resuscitation with reassessment, source control and referral, diagnostics/microbiology where feasible, and QI). The framework explicitly distinguishes near-term, feasible changes from longer-term system investments and highlights the need for locally generated evidence to guide quality indicators and resuscitation strategies in LRS.

Background: Clarithromycin is a commonly used macrolide antibiotic. Infection is a major source of mortality and morbidity in critical care units. Pharmacokinetics may vary during critical illness and suboptimal antimicrobial exposure has been shown to be associated with treatment failure. The pharmacokinetics of intravenous clarithromycin in critical illness have not previously been described. Methods: Pharmacokinetic, clinical and demographic data were collected from critically ill adults receiving intravenous clarithromycin. Drug concentrations were measured using high-performance liquid chromatography/mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM version 7.5.1. Allometric weight scaling was added, and periods of renal replacement therapy were excluded a priori. Simulations of 10,000 patients were performed to assess pharmacokinetic-pharmacodynamic (PKPD) target attainment. Results: The analysis included 121 samples taken from 19 participants. A two-compartment model was found to provide the best fit. The addition of covariates did not improve model fit. There was no evidence of auto-inhibition in this population. Population parameter estimates of clearance and volume of distribution were lower than previously reported, with high interindividual variability. Simulations suggested reasonable pharmacokinetic-pharmacodynamic (PKPD) target attainment with current dosing regimens for most organisms that clarithromycin is used to treat with known clinical breakpoints. Conclusions: To our knowledge, this is the first study to describe the pharmacokinetics of intravenous clarithromycin in humans. Although our simulations suggest reasonable target attainment, further investigation into appropriate PKPD targets and clinical breakpoints for clarithromycin may enable dosing optimisation in this population.

Aim: Levetiracetam is a widely used anti-epileptic in the critical care setting that is almost exclusively (>90%) renally excreted. The altered pharmacokinetics of levetiracetam have been widely studied in intermittent haemodialysis but the evidence and guidance on dosage in continuous renal replacement therapy is varied and poorly defined. Understanding this is critical as a significant number of critically unwell patients develop renal failure requiring continuous renal replacement therapy. The aim of this systematic review is to investigate the pharmacokinetics of levetiracetam in such patients and to understand the implications on dosing strategies. Methods: A systematic review of the available literature from 2000 to November 2022 was conducted. Seven articles were identified for inclusion from 54 records. A novel hybrid model was developed to evaluate the quality of pharmacokinetic and haemofiltration data. This data was used to develop a one-compartment model that simulated dosing strategies in 10,000 patients based on an assumed steady state of 72 hr and target trough concentrations of 12-46 mcg/mL. Results: From the seven articles included, pharmacokinetic data was retrieved for 24 individual patients. Total clearance was 3.49-4.63 L/hr (mean 3.55, S.D. 0.52). Elimination half-life was 5.66-12.88 hr (mean 9.41, S.D. 2.86). Volume of distribution was 0.45-0.73 L/kg. The proportion of total clearance attributable to continuous renal replacement therapy was 52%-73% (mean 54.7%, S.D. 13.5). Our simulations demonstrate that more than half of patients who received twice daily doses of 750 mg or greater without a loading dose achieved therapeutic drug concentrations. The time to achievement of therapeutic drug concentrations was greatly reduced by the addition of a 60 mg/kg loading dose (up to a maximum of 4.5 g). The use of a reduced loading dose or twice daily doses of 500 mg or less without loading were more likely to result in prolonged sub-therapeutic drug concentrations. Conclusion: Levetiracetam clearance in haemofiltration is similar to healthy adults with normal renal function (GFR > 90 mL/min). The use of reduced doses due to renal failure in critically ill patients may result in sub-therapeutic drug concentrations in a high number of patients. A twice daily dosing of 750-1000 mg with an initial loading dose of 60 mg/kg should be considered in such patients alongside therapeutic drug monitoring.

Importance:The Sequential Organ Failure Assessment (SOFA) score was published in 1996 to describe organ dysfunction in critically ill adult patients in a readily quantifiable and sequential manner. Considerable changes have occurred over the last 3 decades in the use of organ support drugs and devices and in patient outcomes, necessitating revision of the score. Objectives:To develop definitions of organ dysfunction that reflect current understanding and to identify representative variables to generate a revised SOFA score (SOFA-2) of individual organ dysfunction. Evidence Review:A task force of experts in intensive care medicine and epidemiology generated definitions of organ dysfunction, identified relevant variables (physiological and laboratory data specific to the organ system, pharmacological and mechanical organ support), and proposed a 0 to 4-point grading of dysfunction severity through meetings, Delphi processes, and explicit rules, informed by data synthesis, including systematic reviews and meta-analysis. Variables were tested in 2 validation exercises using separate datasets totaling 3.34 million patients within 10 representative databases from diverse geographical and socioeconomic settings to assess distribution and predictive validity (mortality at intensive care unit discharge). Findings:A total of 60 experts participated, with 18 (30%) female participants. Overall, 65 countries were represented, with 33 (51%) from Europe and Central Asia, 13 (20%) from North America; and 8 (12%) from Latin America and the Caribbean. The physiological variables within the 6 organ systems used in the original SOFA score were retained, although some categories were renamed (ie, central nervous system was changed to brain, renal to kidney, coagulation to hemostasis, and hepatic to liver). Revisions of organ support drug and device variables were made to reflect current practice. Alternative variables were added for instances when laboratory data and/or organ support interventions would be inaccessible (eg, in some low-resource settings) or not indicated (eg, ceiling of treatment). Some point cutoff thresholds were modified based on evidence from systematic reviews and data analyses. Scores could not be developed for 2 additional organ systems (gastrointestinal and immune) due to insufficient data, complexity, or lack of content and predictive validity for the variables assessed. Explicit rules were developed to facilitate scoring consistency. Conclusions and Relevance:Through a methodologically robust development process, the SOFA-2 score offers updated definitions to describe organ dysfunction in adult patients requiring critical care and readily quantifiable criteria to grade the degree of dysfunction in individual organ systems. This score considers contemporaneous changes in patient management and outcomes.

Noradrenaline is currently the first-line vasopressor in treatment of circulatory failure. Its dose reflects illness severity, and together with dopamine, dobutamine and adrenaline, it is used in the Sequential Organ Failure Assessment (SOFA) score to grade cardiovascular dysfunction. Over the years, noradrenaline use has increased and it has largely replaced dopamine. As part of the SOFA-2 update, we conducted a systematic review and dose-response meta-analysis to assess the association between noradrenaline dose and mortality. We searched MEDLINE, Embase, and Web of Science from 1 January 2013 to 30 October 2024 for studies reporting mortality by noradrenaline dose in critically ill adults. The primary outcome was mortality. We generated pooled relative risks (RR) and assessed linear and non-linear dose–response relationships. Mortality was also analysed by SOFA-2 noradrenaline categories. The study followed PRISMA guidelines and was registered with PROSPERO (CRD42024501533). Nineteen studies, including totally 29,935 patients, were included in the systematic review, and six in the meta-analysis. We observed a consistent increase in mortality: the relative risk escalated by a factor of 1.5 for every 0.1 µg/kg/min increase in peak noradrenaline dose. We did not find inflection points in the dose-mortality curve. In SOFA-2 categories, hospital mortality was 16.5

Background: Patients in critical care units (CCUs) are at an increased risk of bloodstream infections (BSIs), which can be associated with central vascular catheters (CVCs). This study describes BSIs, CVC-BSIs, organism distribution, percentage of antimicrobial resistant (AMR) organisms, and case fatality rates (CFRs) over the first six years of a voluntary national CCU surveillance programme in England. Methods: Surveillance data on BSIs, CVCs, and bed-days between 04/2017 and 03/2023 for adult CCUs were linked to mortality and AMR data, and crude rates were calculated. Results: The rates of CCU-BSIs and CCU-CVC-BSIs were stable for the first three years (3.6 and 1.7 per 1000 bed-days in 2019/20), before increasing by 75% and 94% in 2020/21, respectively, and returning to near pre-pandemic levels by 2022/23. Gram-negative bacteria accounted for 50.3% of all CCU-BSIs, followed by Gram-positive bacteria (39.6%) and Candida spp. (8.6%). Klebsiella spp. saw increases in percentage AMR, whereas other organisms saw declines or similar levels. The overall CFR was 30.2%. Conclusions: BSI incidence in CCUs remained stable across the study period, except for an increase in 2020/21 which reverted by 2022/23. These data provide a benchmark for CCUs and give insight into long-term AMR patterns where comparable national data are limited.

Too high or too low patient volumes and work amounts may overwhelm health care professionals and obstruct processes or lead to inadequate personnel routine and process flow. We sought to evaluate, whether an association between current caseload, current workload, and outcomes exists in intensive care units (ICU). Retrospective cohort analysis of data from an Austrian ICU registry. Data on patients aged ≥ 18 years admitted to 144 Austrian ICUs between 2013 and 2022 were included. A Cox proportional hazards model with ICU mortality as the outcome of interest adjusted with patients’ respective SAPS 3, current ICU caseload (measured by ICU occupancy rates), and current ICU workload (measured by median TISS-28 per ICU) as time-dependent covariables was constructed. Subgroup analyses were performed for types of ICUs, hospital care level, and pre-COVID or intra-COVID period. 415 584 patient admissions to 144 ICUs were analysed. Compared to ICU caseloads of 76 to 100

OBJECTIVES:. We sought to assess whether genetic associations with metabolite concentrations in septic shock patients could be used to identify pathways of potential importance for understanding sepsis pathophysiology. DESIGN:. Retrospective multicenter cohort studies of septic shock patients. SETTING:. All participants who were admitted to 27 participating hospital sites in three countries (Australia, New Zealand, and the United Kingdom) were eligible for inclusion. PATIENTS:. Adult, critically ill, mechanically ventilated patients with septic shock (n = 230) who were a subset of the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock trial (ClinicalTrials.gov number: NCT01448109). INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. A genome-wide association study was conducted for a range of serum metabolite levels for participants. Genome-wide significant associations (p ≤ 5 × 10–8) were found for the two major ketone bodies (3-hydroxybutyrate [rs2456680] and acetoacetate [rs2213037] and creatinine (rs6851961). One of these single-nucleotide polymorphisms (SNPs) (rs2213037) was located in the alcohol dehydrogenase cluster of genes, which code for enzymes related to the metabolism of acetoacetate and, therefore, presents a plausible association for this metabolite. None of the three SNPs showed strong associations with risk of sepsis, 28- or 90-day mortality, or Acute Physiology and Chronic Health Evaluation score (a measure of sepsis severity). CONCLUSIONS:. We suggest that the genetic associations with metabolites may reflect a starvation response rather than processes involved in sepsis pathophysiology. However, our results require further investigation and replication in both healthy and diseased cohorts including those of different ancestry.

The Sequential Organ Failure Assessment (SOFA) score was developed almost 30 years ago. It rapidly became one of the most widely used scoring systems in intensive care, both for clinical practice and research,(,) and remains one of the most cited scores in our speciality. Since its original description, there have been substantial changes in clinical […]

O escore Sequential Organ Failure Assessment (SOFA) foi desenvolvido há quase 30 anos. Rapidamente, tornou-se um dos sistemas de pontuação mais utilizados em terapia intensiva, tanto para a prática clínica quanto para a pesquisa,(,) e continua sendo uma das pontuações mais citadas em nossa especialidade. Desde sua descrição original, houve mudanças substanciais na prática clínica […]

Importance Whether β-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective To evaluate whether continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention Eligible patients were randomized to receive an equivalent 24-hour dose of a β-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, −1.9% [95% CI, −4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance The observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration ClinicalTrials.gov Identifier: NCT03213990