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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.

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.

Objectives: To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records., Design: Retrospective cohort study using electronic health records., Setting: Ten ICUs from four U.K. National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative., Patients: A total of 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical)., Measurements and Main Results: Twenty-nine thousand three hundred forty-three episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. A total of 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate greater than 2.0 mmol/L, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%; 95% CI, 21.9-25.6%), followed by hospital-acquired sepsis (18.6%; 95% CI, 17.5-19.9%), and community-acquired sepsis (12.9%; 95% CI, 12.1-13.6%) (p for comparison less than 0.0001)., Conclusions: We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding., Competing Interests: Drs. Shah’s, Watkinson’s, and Brett’s institutions received funding from the National Institute for Health Research (NIHR). Dr. Shah is supported by a postdoctoral fellowship funded by the Health Foundation's grant to the University of Cambridge for The Healthcare Improvement Studies Institute. Dr. Palmer received funding from the Medical Research Council and The London Clinic. Dr. Hetherington’s institution received funding from the United Kingdom Government; he received funding from Turing Institute and the Department of Health and Social Care; he received support for article research from Research Councils UK; he disclosed work for hire. Dr. Shi disclosed work for hire. Dr. Watkinson’s institution received funding from Wellcome and Sesnyne Health; he disclosed that he was the Chief Medical Officer for Sesnyne Health. Dr. Ashworth disclosed that he is an employee of Imperial College Healthcare National Health Service (NHS) Trust and the Clinical Director of Critical Care. Dr. Beale’s institution received funding from the Philips Medical Systems Medical Advisory Board; he disclosed that he is on the Steering Committee of the Surviving Sepsis Campaign. Dr. Singer’s institution received funding from Roche, Deltex, NewB, GE Healthcare, Pfizer, and Biomerieux. The views expressed are those of the authors and are not necessarily those of the NIHR, the NHS, or the United Kingdom Department of Health and Social Care. The remaining authors have disclosed that they do not have any potential conflicts of interest, (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Rationale: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration, but conflicting survival effects. Two transcriptomic sepsis response signatures (SRSs) have been identified. SRS1 is relatively immunosuppressed, whereas SRS2 is relatively immunocompetent., Objectives: We aimed to categorize patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock., Methods: A post hoc analysis was performed of a double-blind, randomized clinical trial in septic shock (VANISH [Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock]). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined by a previously established model using seven discriminant genes., Measurements and Main Results: Samples were available from 176 patients: 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (P = 0.50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (P = 0.02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (odds ratio = 7.9; 95% confidence interval = 1.6-39.9)., Conclusions: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immunocompetent SRS2 endotype had significantly higher mortality when given corticosteroids compared with placebo. Clinical trial registered with www.clinicaltrials.gov (ISRCTN 20769191).

Background and Rationale: β-Lactam antibiotics display a time-dependent mechanism of action, with evidence suggesting improved outcomes when administering these drugs via continuous infusion compared with standard intermittent infusion. However, there is no phase 3 randomised controlled trial (RCT) evidence to support one method of administration over another in critically ill patients with sepsis., Design and Setting: The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 RCT to compare continuous infusion with standard intermittent infusion of β-lactam antibiotics in critically ill patients with sepsis. The study will be conducted in about 70 intensive care units (ICUs) in Australia, New Zealand, the United Kingdom, Belgium and selected other countries, from 2018 to 2021., Participants and Interventions: BLING III will recruit 7000 critically ill patients with sepsis being treated with one of two β-lactam antibiotics (piperacillin-tazobactam or meropenem) to receive the β-lactam antibiotic by either continuous or intermittent infusion., Main Outcome Measures: The primary outcome is allcause mortality within 90 days after randomisation. Secondary outcomes are clinical cure at Day 14 after randomisation, new acquisition, colonisation or infection with a multiresistant organism or Clostridium difficile diarrhoea up to 14 days after randomisation, all-cause ICU mortality and all-cause hospital mortality. Tertiary outcomes are ICU length of stay, hospital length of stay and duration of mechanical ventilation and duration of renal replacement therapy up to 90 days after randomisation., Results and Conclusions: The BLING III study will compare the effect on 90-day mortality of β-lactam antibiotics administered via continuous versus intermittent infusion in 7000 critically ill patients with sepsis., Trial Registration: ClinicalTrials.gov Registry (NCT03213990).

Background: Prognostication is an essential tool for risk adjustment and decision making in the intensive care unit (ICU). Research into prognostication in ICU has so far been limited to data from admission or the first 24 hours. Most ICU admissions last longer than this, decisions are made throughout an admission, and some admissions are explicitly intended as time-limited prognostic trials. Despite this, temporal changes in prognostic ability during ICU admission has received little attention to date. Current predictive models, in the form of prognostic clinical tools, are typically derived from linear models and do not explicitly handle incremental information from trends. Machine learning (ML) allows predictive models to be developed which use non-linear predictors and complex interactions between variables, thus allowing incorporation of trends in measured variables over time; this has made it possible to investigate prognosis throughout an admission., Methods and Findings: This study uses ML to assess the predictability of ICU mortality as a function of time. Logistic regression against physiological data alone outperformed APACHE-II and demonstrated several important interactions including between lactate & noradrenaline dose, between lactate & MAP, and between age & MAP consistent with the current sepsis definitions. ML models consistently outperformed logistic regression with Deep Learning giving the best results. Predictive power was maximal on the second day and was further improved by incorporating trend data. Using a limited range of physiological and demographic variables, the best machine learning model on the first day showed an area under the receiver-operator characteristic curve (AUC) of 0.883 (σ = 0.008), compared to 0.846 (σ = 0.010) for a logistic regression from the same predictors and 0.836 (σ = 0.007) for a logistic regression based on the APACHE-II score. Adding information gathered on the second day of admission improved the maximum AUC to 0.895 (σ = 0.008). Beyond the second day, predictive ability declined., Conclusion: This has implications for decision making in intensive care and provides a justification for time-limited trials of ICU therapy; the assessment of prognosis over more than one day may be a valuable strategy as new information on the second day helps to differentiate outcomes. New ML models based on trend data beyond the first day could greatly improve upon current risk stratification tools., Competing Interests: The authors have declared that no competing interests exist. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Objectives: We sought to understand why randomised controlled trials in septic shock have failed to demonstrate effectiveness in the face of improving overall outcomes for patients and seemingly promising results of early phase trials of interventions., Design: We performed a retrospective analysis of large critical care trials of severe sepsis and septic shock. Data were collected from the primary trial manuscripts, prepublished statistical plans or by direct communication with corresponding authors., Setting: Critical care randomised control trials in severe sepsis and septic shock., Participants: 14 619 patients randomised in 13 trials published between 2005 and 2015, enrolling greater than 500 patients and powered to a primary outcome of mortality., Intervention: Multiple interventions including the evaluation of treatment strategies and novel therapeutics., Primary and Secondary Outcome Measures: Our primary outcome measure was the difference between the anticipated and actual control arm mortality. Secondary analysis examined the actual effect size and the anticipated effect size employed in sample size calculation., Results: In this post hoc analysis of 13 trials with 14 619 patients randomised, we highlight a global tendency to overestimate control arm mortality in estimating sample size (absolute difference 9.8%, 95% CI -14.7% to -5.0%, p<0.001). When we compared anticipated and actual effect size of a treatment, there was also a substantial overestimation in proposed values (absolute difference 7.4%, 95% CI -9.0% to -5.8%, p<0.0001)., Conclusions: An interpretation of our results is that trials are consistently underpowered in the planning phase by employing erroneous variables to calculate a satisfactory sample size. Our analysis cannot establish if, given a larger sample size, a trial would have had a positive result. It is disappointing so many promising phase II results have not translated into durable phase III outcomes. It is possible that our current framework has biased us towards discounting potentially life-saving treatments., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sepsis continues to escape a precise diagnostic definition. The most recent consensus definition, termed Sepsis-3, highlights the importance of the maladaptive and potentially life-threatening host response to infection. After briefly reviewing the history and epidemiology of sepsis, we go on to describe some of the challenges encountered when classifying such a heterogenous disease state. In the context of these new definitions for sepsis and septic shock, we explore current and potentially novel therapies, and conclude by mentioning some of the controversies of this most recent framework.

Objective: To assess the efficacy and safety of pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of baseline hypoalbuminaemia) in critically unwell adults with sepsis of any severity., Design: Systematic review and meta-analysis of randomised clinical trials, with trial sequential analysis, subgroup, and meta-regression analyses., Data Sources: PubMed, PubMed Central, Web of Science (includes Medline, Conference Proceedings Citation Index, Data Citation Index, Chinese Science Citation Database, CAB abstracts, Derwent Innovations Index), OvidSP (includes Embase, Ovid Medline, HMIC, PsycINFO, Maternity and Infant Care, Transport Database), Cochrane Library, clinicaltrials.gov, controlled-trials.com, online material, relevant conference proceedings, hand searching of reference lists, and contact with authors as necessary., Eligibility Criteria: Prospective randomised clinical trials of adults with sepsis of any severity (with or without baseline hypoalbuminaemia) in critical or intensive care who received pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of hypoalbuminaemia) compared with those who received control fluids (crystalloid or colloid), were included if all-cause mortality outcome data were available. No restriction of language, date, publication status, or primary study endpoint was applied., Data Extraction: Two reviewers independently assessed articles for inclusion, extracted data to assess risk of bias, trial methods, patients, interventions, comparisons, and outcome. The relative risk of all-cause mortality was calculated using a random effects model accounting for clinical heterogeneity., Primary Outcome Measure: All-cause mortality at final follow-up., Results: Eighteen articles reporting on 16 primary clinical trials that included 4190 adults in critical or intensive care with sepsis, severe sepsis, or septic shock. A median of 70.0 g daily of pooled human albumin was received over a median of 3 days by adults with a median age of 60.8 years as part of fluid volume expansion and resuscitation, with or without correction of hypoalbuminaemia. The relative risk of death was similar between albumin groups (that received a median of 175 g in total) and control fluid groups (relative risk 0.94; 95% confidence interval 0.87 to 1.01; P=0.11; I(2)=0%). Trial sequential analysis corrected the 95% confidence interval for random error (0.85 to 1.02; D(2)=0%). Eighty eight per cent of the required information size (meta-analysis sample size) of 4894 patients was achieved, and the cumulative effect size measure (z score) entered the futility area, supporting the notion of no relative benefit of albumin (GRADE quality of evidence was moderate). Evidence of no difference was also found when albumin was compared with crystalloid fluid (relative risk 0.93; 0.86 to 1.01; P=0.07; I(2)=0%) in 3878 patents (GRADE quality of evidence was high; 79.9% of required information size) or colloid fluids in 299 patients (relative risk 1.04; 0.79 to 1.38; P=0.76; I(2)=0%) (GRADE quality of evidence was very low; 5.8% of required information size). When studies at high risk of bias were excluded in a predefined subgroup analysis, the finding of no mortality benefit remained, and the cumulative z score was just outside the boundary of futility. Overall, the meta-analysis was robust to sensitivity, subgroup, meta-regression, and trial sequential analyses., Conclusions: In this analysis, human albumin solutions as part of fluid volume expansion and resuscitation for critically unwell adults with sepsis of any severity (with or without baseline hypoalbuminaemia) were not robustly effective at reducing all-cause mortality. Albumin seems to be safe in this setting, as a signal towards harm was not detected, but this analysis does not support a recommendation for use., (© Patel et al 2014.)

Purpose: To assess the impact of 6% tetrastarch [hydroxyethyl starch (HES) 130/0.4 and 130/0.42] in severe sepsis patients. The primary outcome measure was 90-day mortality., Methods: A structured literature search was undertaken to identify prospective randomised controlled trials (RCTs) in adult patients with severe sepsis receiving 6% tetrastarch (of potato or waxy maize origin) as part of fluid resuscitation in comparison with other non-HES fluids after randomisation in the critical care setting. A systematic review and meta-analysis were performed., Results: Six RCTs were included (n = 3,033): three from 2012 (n = 2,913) had low risk of bias. Median tetrastarch exposure was 37.4 ml/kg (range 30-43 ml/kg). Ninety-day mortality was associated with tetrastarch exposure [relative risk (RR) 1.13; 95% confidence interval (CI) 1.02-1.25; p = 0.02] compared with crystalloid. The number needed to harm (NNH) was 28.8 (95 % CI 14.6-942.5). Publication bias and statistical heterogeneity (I(2) = 0%) were not present. Tetrastarch exposure was also associated with renal replacement therapy (p = 0.01; NNH 15.7) and allogeneic transfusion support (p = 0.001; NNH 9.9). No difference between groups was observed for 28-day mortality, for comparison with colloid as control, or for waxy maize-derived tetrastarch, but power was lacking. Overall mortality was associated with tetrastarch exposure (RR 1.13; 95% CI 1.02-1.25; p = 0.02)., Conclusions: In our analysis, 6% tetrastarch as part of initial fluid resuscitation for severe sepsis was associated with harm and, as alternatives exist, in our view should be avoided.

Introduction: We determined the long-term mortality and renal allograft function of renal transplant recipients admitted to the intensive care unit (ICU)., Methods: A single institution retrospective observational cohort study of all renal transplant patients admitted to the ICU was performed. Serum creatinine was recorded up to one yr after hospital discharge and survival data were collected for three yr., Results: Chest sepsis was the commonest reason for ICU admission. ICU and hospital mortality were 32% and 19% respectively. Predictors of hospital mortality included the presence of sepsis and duration of mechanical ventilation (MV). Of the patients who were discharged from ICU, three-yr mortality was 50%. Renal function at one yr was worse than that at hospital discharge and at baseline, though not statistically significant. Death-censored allograft loss was 11% over the three-yr follow up period., Conclusions: Sepsis and requirement for MV are independent predictors of mortality in renal transplant recipients admitted to ICU. Renal transplant recipients with chest sepsis may warrant earlier ICU admission. Any loss of renal allograft function during an episode of critical illness appears to have a lasting effect, and longterm patient and allograft survival is poor., (© 2011 John Wiley & Sons A/S.)