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Science Advances, Volume 9, Issue 21, May 2023.

IntroductionIntravenous crystalloid fluid resuscitation forms a crucial part of the early intervention bundle for sepsis and septic shock, with the Surviving Sepsis Campaign guidelines recommending a 30 mL/kg fluid bolus within the first hour. Compliance with this suggested target varies in patients with comorbidities such as congestive heart failure, chronic kidney disease and cirrhosis due to concerns regarding iatrogenic fluid overload. However, it remains unclear whether resuscitation with higher fluid volumes puts them at greater risk of adverse outcomes. Thus, this systematic review will synthesise evidence from existing studies to assess the effects of a conservative as compared with a liberal approach to fluid resuscitation in patients at greater perceived risk of fluid overload due to comorbid conditions. Methods and analysisThis protocol was registered on PROSPERO and has been drafted following the checklist of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We will search MEDLINE, MEDLINE Epub Ahead of Print and In-Process, In-Data-Review & Other Non-Indexed Citations, Embase, Embase Classic, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection, CINAHL Complete and ClinicalTrials.gov. A preliminary search of these databases was performed from their inception to 30 August 2022. The risk of bias and random errors will be assessed using the revised Cochrane risk-of-bias tool for randomised clinical trials and the Newcastle-Ottawa Scale for case–control and cohort studies. If a sufficient number of comparable studies are identified, we will perform a meta-analysis applying random effects model. We will investigate heterogeneity using a combination of visual inspection of the funnel plot as well as the Egger’s test. Ethics and disseminationNo ethics approval is required for this study since no original data will be collected. The findings will be disseminated through peer-reviewed publication and conference presentation. PROSPERO registration numberCRD42022348181. …

Given the potential benefits of shortened antibiotic courses, prior studies comparing shorter versus longer antibiotic courses have typically adopted a non-inferiority design [3,11]. However, in a study of critically ill patients in whom suboptimal treatment could result in death, a non-inferiority trial would pose a serious ethical dilemma – how to select an “acceptable” increased risk of mortality to use as a non-inferiority margin? For these reasons, we have designed a trial that requires shorter antibiotic therapy demonstrate superior clinical outcomes over longer antibiotic therapy, allowing partial/full credit to be awarded based on patient and clinicians’ perceptions of outcome importance and severity. Should clinical outcomes be comparable among the study arms, the DOOR/RADAR framework acknowledges potential unmeasured benefits of shorter courses (e.g., reduced costs, unmeasured toxicity, and antibiotic pressures selecting for individual and global microbial resistance) and accordingly assigns superiority to shorter antibiotic courses. The duration of antibiotic therapy reflected in this adjustment would be the actual (rather than assigned) duration, allowing for a pragmatic analysis of the interventions as applied in practice while mitigating differences between intention-to-treat and per-protocol analyses resulting from poor protocol adherence.

IMPORTANCE: The Surviving Sepsis Campaign recommends standard operating procedures for patients with sepsis. Real-world evidence about sepsis order set implementation is limited. OBJECTIVES: To estimate the effect of sepsis order set usage on hospital mortality. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Fifty-four acute care hospitals in the United States from December 1, 2020 to November 30, 2022 involving 104,662 patients hospitalized for sepsis. MAIN OUTCOMES AND MEASURES: Hospital mortality. RESULTS: The sepsis order set was used in 58,091 (55.5%) patients with sepsis. Initial mean sequential organ failure assessment score was 0.3 lower in patients for whom the order set was used than in those for whom it was not used (2.9 sd [2.8] vs 3.2 [3.1], p < 0.01). In bivariate analysis, hospital mortality was 6.3% lower in patients for whom the sepsis order set was used (9.7% vs 16.0%, p < 0.01), median time from emergency department triage to antibiotics was 54 minutes less (125 interquartile range [IQR, 68–221] vs 179 [98–379], p < 0.01), and median total time hypotensive was 2.1 hours less (5.5 IQR [2.0–15.0] vs 7.6 [2.5–21.8], p < 0.01) and septic shock was 3.2% less common (22.0% vs 25.4%, p < 0.01). Order set use was associated with 1.1 fewer median days of hospitalization (4.9 [2.8–9.0] vs 6.0 [3.2–12.1], p < 0.01), and 6.6% more patients discharged to home (61.4% vs 54.8%, p < 0.01). In the multivariable model, sepsis order set use was independently associated with lower hospital mortality (odds ratio 0.70; 95% CI, 0.66–0.73). CONCLUSIONS AND RELEVANCE: In a cohort of patients hospitalized with sepsis, order set use was independently associated with lower hospital mortality. Order sets can impact large-scale quality improvement efforts.

American Journal of Respiratory and Critical Care Medicine, Volume 207, Issue 10, Page 1283-1299, May 15, 2023.

OBJECTIVES: The Surviving Sepsis Campaign Guidelines 2021 recommends that adult patients with sepsis requiring intensive care should be admitted to the ICU within 6 hours of their emergency department (ED) visits. However, there is limited evidence on whether 6 hours is the best target time for compliance with the sepsis bundle. We aimed to investigate the association between time from ED visits to ICU admission (i.e., ED length of stay [ED-LOS]) and mortality and identify the optimal ED-LOS for patients with sepsis. DESIGN: Retrospective cohort study. SETTING: The Medical Information Mart for Intensive Care Emergency Department and Medical Information Mart for Intensive Care IV databases. PATIENTS: Adult patients (≥ 18 yr old) who were transferred from the ED to the ICU and subsequently diagnosed with sepsis based on the Sepsis-3 criteria within 24 hours of ICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 1,849 patients with sepsis, we found a disproportionally higher mortality rate in patients immediately admitted to the ICU (e.g., < 2 hr). When using ED-LOS as a continuous variable, ED-LOS was not significantly associated with 28-day mortality (adjusted odds ratio [OR] per hour increase, 1.04; 95% CI, 0.96–1.13; p = 0.3) after an adjustment for potential confounders (e.g., demographics, triage vital signs, and laboratory results) in the multivariable analysis. However, when we categorized all patients into time quartiles (ED-LOS: < 3.3 hr, 3.3–4.5 hr, 4.6–6.1 hr, and > 6.1 hr), patients in the higher time quartiles (e.g., 3.3–4.5 hr) had higher 28-day mortality compared with those in the lowest time quartile (< 3.3 hr) (e.g., adjusted OR for patients in the second time quartile [3.3–4.5 hr] 1.59; 95% CI, 1.03–2.46; p = 0.04). CONCLUSIONS: Earlier admission to the ICU (e.g., within 3.3 hr of ED visits) was associated with lower 28-day mortality in patients with sepsis. Our findings suggest patients with sepsis who require intensive care may benefit from a more immediate ICU admission than 6 hours.

Objectives: To assess the association between levels of intensive care and in-hospital mortality in patients hospitalized for sepsis, stratified by Sequential Organ Failure Assessment (SOFA) score at admission. Design: A nationwide, propensity score-matched, retrospective cohort study. Setting: A Japanese national inpatient database with data on 70–75% of all ICU and high-dependency care unit (HDU) beds in Japan. Patients: Adult patients hospitalized for sepsis with SOFA scores greater than or equal to 2 on their day of admission between April 1, 2018, and March 31, 2021, were recruited. Propensity score matching was performed to compare in-hospital mortality, and patients were stratified into 10 groups according eto SOFA scores. Interventions: Two exposure and control groups according to treatment unit on day of admission: 1) ICU + HDU versus general ward and 2) ICU versus HDU. Measurements and Main Results: Of 97,070 patients, 19,770 (20.4%), 23,066 (23.8%), and 54,234 (55.9%) were treated in ICU, HDU, and general ward, respectively. After propensity score matching, the ICU + HDU group had significantly lower in-hospital mortality than the general ward group, among cohorts with SOFA scores greater than or equal to 6. There were no significant differences in in-hospital mortality among cohorts with SOFA scores 3–5. The ICU + HDU group had significantly higher in-hospital mortality than the general ward among cohorts with SOFA scores of 2. The ICU group had lower in-hospital mortality than the HDU group among cohorts with SOFA scores greater than or equal to 12. There were no significant differences in in-hospital mortality among cohorts with SOFA scores 5–11. The ICU group had significantly higher in-hospital mortality than the general ward group among cohorts with SOFA scores less than or equal to 4. Conclusions: Patients hospitalized for sepsis with SOFA scores greater than or equal to 6 in the ICU or HDU had lower in-hospital mortality than those in the general ward, as did those with SOFA scores greater than or equal to 12 in the ICU versus HDU.

No abstract available…

Abstract Background The early diagnosis of sepsis is hampered by the lack of reliable laboratory measures. There is growing evidence that presepsin and Mid-regional pro-adrenomedullin (MR-proADM) are promising biomarkers in the diagnosis of sepsis. This study was conducted to evaluate and compare the diagnostic value of MR-proADM and presepsin in sepsis patients. Methods We searched Web of Science, PubMed, Embase, China national knowledge infrastructure, and Wanfang up to 22th July, 2022, for studies evaluating the diagnosis performance of presepsin and MR-proADM in adult sepsis patients. Risk of bias was assessed using quadas-2. Pooled sensitivity and specificity were calculated using bivariate meta-analysis. Meta-regression and subgroup analysis were used to find source of heterogeneity. Results A total of 40 studies were eventually selected for inclusion in this meta-analysis, including 33 for presepsin and seven for MR-proADM. Presepsin had a sensitivity of 0.86 (0.82–0.90), a specificity of 0.79 (0.71–0.85), and an AUC of 0.90 (0.87–0.92). The sensitivity of MR-proADM was 0.84 (0.78–0.88), specificity was 0.86 (0.79–0.91), and AUC was 0.91 (0.88–0.93). The profile of control group, population, and standard reference may be potential sources of heterogeneity. Conclusions This meta-analysis demonstrated that presepsin and MR-proADM exhibited high accuracy (AUC ≥ 0.90) in the diagnosis of sepsis in adults, with MR-proADM showing significantly higher accuracy than presepsin. …

OBJECTIVES: The 2020 pediatric Surviving Sepsis Campaign (pSSC) recommends measuring lactate during the first hour of resuscitation for severe sepsis/shock. We aimed to improve compliance with this recommendation for patients who develop severe sepsis/shock while admitted to the PICU. DESIGN: Structured, quality improvement initiative. SETTING: Single-center, 26-bed, quaternary-care PICU. PATIENTS: All patients with PICU-onset severe sepsis/shock from December 2018 to December 2021. INTERVENTIONS: Creation of a multidisciplinary local sepsis improvement team, education program targeting frontline providers (nurse practitioners, resident physicians), and peer-to-peer nursing education program with feedback to key stakeholders. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was compliance with obtaining a lactate measurement within 60 minutes of the onset of severe sepsis/shock originating in our PICU using a local Improving Pediatric Sepsis Outcomes database and definitions. The process measure was time to first lactate measurement. Secondary outcomes included number of IV antibiotic days, number of vasoactive days, number of ICU days, and number of ventilator days. A total of 166 unique PICU-onset severe sepsis/shock events and 156 unique patients were included. One year after implementation of our first interventions with subsequent Plan-Do-Study-Act cycles, overall compliance increased from 38% to 47% (24% improvement) and time to first lactate decreased from 175 to 94 minutes (46% improvement). Using a statistical process control I chart, the preshift mean for time to first lactate measurement was noted to be 179 minutes and the postshift mean was noted to be 81 minutes demonstrating a 55% improvement. CONCLUSIONS: This multidisciplinary approach led to improvement in time to first lactate measurement, an important step toward attaining our target of lactate measurement within 60 minutes of septic shock identification. Improving compliance is necessary for understanding implications of the 2020 pSSC guidelines on sepsis morbidity and mortality.

Volume 14, Issue 1, December 2023 .

ObjectivesIn the early stage of sepsis, identifying high-risk paediatric patients with a poor prognosis and providing timely and adequate treatment are critical. This study aimed to evaluate the effect of average body temperature within 24 hours of admission on the short-term prognosis of paediatric patients with sepsis. DesignA retrospective cohort study. SettingA single-centre, tertiary care hospital in China, containing patient data from 2010 to 2018. Participants1144 patients with sepsis were included. InterventionNone. Primary and secondary outcome measuresThe main outcome measure was in-hospital mortality, which was defined as death from any cause during hospitalisation. The secondary outcome was the length of hospital stay. ResultsThe LOWESS method showed a roughly ‘U’-shaped relationship between body temperature on the first day and in-hospital mortality. Multivariate logistic regression showed that severe hypothermia (OR 14.72, 95% CI 4.84 to 44.75), mild hypothermia (OR 3.71, 95% CI 1.26 to 10.90), mild hyperthermia (OR 3.41, 95% CI 1.17 to 9.90) and severe hyperthermia (OR 5.15, 95% CI 1.84 to 14.43) were independent risk factors for in-hospital mortality. Compared with other variables, the Wald 2 value of temperature on the first day minus the degree of freedom was the highest. ConclusionsWhether hypothermic or hyperthermic, the more abnormal the temperature on the first day is, the higher the risk of in-hospital death in children with sepsis. …

Objectives: The Lessening Organ Dysfunction with Vitamin C trial showed a harmful effect of vitamin C on 28-day death or persistent organ dysfunction. To maximize interpretation, we present a post hoc Bayesian reanalysis. Design: Bayesian reanalysis of a randomized placebo-controlled trial. Setting: Thirty-five ICUs. Patients: Adults with proven or suspected infection, vasopressor support, and no more than 24 hours of ICU admission. Interventions: Patients were allocated to receive either vitamin C (50 mg/kg of body weight) or placebo every 6 hours for up to 96 hours. Measurements and Main Results: The primary outcome was the composite of death or persistent organ dysfunction (i.e., vasopressor use, invasive mechanical ventilation, or new renal replacement therapy) at 28 days. We used Bayesian log-binomial models with random effects for hospital site and varying informative prior beliefs for the effect of vitamin C to estimate risk ratios (RRs) with 95% credible intervals (Crls) in the intention to treat population (vitamin C, 435 patients; placebo, 437 patients). Using weakly neutral priors, patients allocated to vitamin C had a higher risk of death or persistent organ dysfunction at 28 days (RR, 1.20; 95% Crl, 1.04–1.39; probability of harm, 99%). This effect was consistent when using optimistic (RR, 1.14; 95% Crl, 1.00–1.31; probability of harm, 98%) and empiric (RR, 1.09; 95% Crl, 0.97–1.22; probability of harm, 92%) priors. Patients allocated to vitamin C also had a higher risk of death at 28 days under weakly neutral (RR, 1.17; 95% Crl, 0.98–1.40; probability of harm, 96%), optimistic (RR, 1.10; 95% Crl, 0.94–1.30; probability of harm, 88%), and empiric (RR, 1.05; 95% Crl, 0.92–1.19; probability of harm, 76%) priors. Conclusions: The use of vitamin C in adult patients with proven or suspected infection and vasopressor support is associated with high probability of harm.

American Journal of Respiratory and Critical Care Medicine, Volume 207, Issue 8, Page 1030-1041, April 15, 2023.

Abstract Background Bacillus cereus infections in immunocompetent patients are uncommon and mainly observed in fragile patients. It can cause lethal infections with multiple organ dysfunction syndrome (MODS). However, a patient presenting as venous sinus thrombosis and survival without sequela has not been reported. Case presentation A 20-year-old previously healthy male developed gastroenteritis after a meal, followed by fever, convulsions, and severe disturbance of consciousness. The patient had significant leukocytosis with a mildly elevated D-dimer, creatinine level, and respiratory failure. The CT(computed tomography) revealed fatal brain edema and subarachnoid hemorrhage. Previous blood culture in a local hospital revealed B. cereus, which was confirmed by mNGS(metagenomic next-generation sequencing) using blood and urine in our hospital. Accordingly, B. cereus sepsis with MODS were considered. Later, cerebral venous sinus thrombosis was proved. After anti-infection (linezolid 0.6 g, Q12h; and meropenem 1.0 g, Q8h), anti-coagulant (enoxaparin 6000U, Q12h), and other symptomatic treatments, the patient recovered completely without sequela at the 6-month follow-up. Conclusions This case suggests that in immunocompetent adults, there is still a risk of infection with B. cereus, causing severe MODS. Special attention should be paid to venous sinus thrombosis and subarachnoid hemorrhage in such cases, while, anti-coagulant is essential therapy. …

ObjectiveThe important effect modifiers of high disease severity on the relationship between the different volumes of early fluid resuscitation and prognosis in septic patients are unknown. Thus, this study was designed to assess whether the efficacy of different volumes in the early fluid resuscitation treatment of sepsis is affected by disease severity. DesignRetrospective cohort study. SettingAdult intensive care unit (ICU) patients with sepsis from 2001 to 2012 in the MIMIC-III database. InterventionsThe intravenous fluid volume within 6 hours after the sepsis diagnosis serves as the primary exposure. The patients were divided into the standard (≥ 30 mL/kg) and restrict (<30 mL/kg) groups. Disease severity was defined by the sequential organ failure assessment (SOFA) score at ICU admission. Propensity score matching analysis was performed to ensure the robustness of our results. Primary and secondary outcome measuresThe primary endpoint of this study was 28-day mortality. Days without needing mechanical ventilation or vasopressor administration within 28-day of ICU admission serving as the secondary endpoint. ResultsIn total, 5154 consecutive individuals were identified in data analysis, 776 patients had a primary end-point event, 386 (49.68%) in the restrict group and 387 (49.81%) in the standard group. Compared with the restrict group, the standard group had higher 28-day mortality (adjusted HR, 1.32; 95% CI 1.03 to 1.70; p=0.03) in the subgroup with a sequential organ failure assessment (SOFA) score ≥10. By contrast, the risk of mortality reduction was modest in the subgroup with an SOFA score <10 (adjusted HR, 0.85; 95% CI 0.70 to 1.03; p=0.10). The effect of the interaction between the SOFA score and fluid resuscitation strategies on the 28-day mortality was significant (p=0.0035). ConclusionsHigh disease severity modifies the relationship between the volume of fluid resuscitation and mortality in patients with sepsis in the ICU; future studies investigating this interaction are warranted. …

Objectives: To describe frequency of positive blood cultures, patterns of pathogens’ characteristics and their resistance profile in patients with blood cultures drawn due to a presumed diagnosis of community-onset sepsis, and to examine the association between blood culture-positive pathogens and hospital mortality. Design: Retrospective cohort study. Setting: Two hundred one U.S. hospitals from 2016 to 2020 using the Premier Healthcare Database. Subjects: Adult patients presenting with community-onset sepsis who had blood cultures collected within 2 days of hospital admission. We defined sepsis using the U.S. Centers for Disease Control Adult Sepsis Event Surveillance criteria. Interventions: None. Measurements and Main Results: We identified 147,061 patients with community-onset sepsis. The number of blood culture-positive sepsis episodes was 21,167 (14%) and the number of nonblood culture-positive sepsis episodes was 20,326 (14%). Among patients with blood culture-positive sepsis, Gram-negative rods were isolated in 55% of patients, Gram-positive cocci were isolated in 47%. Of those, methicillin-resistant Staphylococcus aureus (MRSA) was 11%, ceftriaxone-resistant Enterobacterales/extended-spectrum β-lactamase was 7%, and carbapenem-resistant Enterobacterales was 1.3%. The crude in-hospital mortality was 17% for culture-negative sepsis, 13% for nonblood culture-positive sepsis, and 17% for blood culture-positive sepsis. In multilevel logistic regression models, compared with culture-negative sepsis, blood culture-positive sepsis (adjusted odds ratio [aOR], 0.89; 95% CI, 0.85–0.94) and nonblood culture-positive sepsis (aOR, 0.82; 95% CI, 0.78–0.87) were associated with lower odds of in-hospital mortality. Acinetobacter species, Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus, and MRSA were associated with higher in-hospital mortality, whereas Escherichia coli, Klebsiella species, Proteus species, and Streptococcus species were associated with lower in-hospital mortality. Conclusions: In patients hospitalized with community-onset sepsis, the prevalence of blood culture-positive sepsis was 14%. Among positive blood culture sepsis resistant organisms were infrequent. Compared with culture-negative sepsis, blood culture-positive sepsis and nonblood culture-positive sepsis were associated with lower in-hospital mortality.

Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited.

Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU).

The effect of the timing of norepinephrine initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early and late start of norepinephrine support on clinical outcomes in patients with septic shock.

Although early antimicrobial discontinuation guided by procalcitonin (PCT) has shown decreased antibiotic consumption in lower respiratory tract infections, the outcomes in long-term sepsis sequelae remain unclear. To investigate if PCT guidance may reduce the incidence of long-term infection-associated adverse events in sepsis. In this multicenter trial, 266 patients with sepsis (by Sepsis-3 definitions) with lower respiratory tract infections, acute pyelonephritis, or primary bloodstream infection were randomized (1:1) to receive either PCT-guided discontinuation of antimicrobials or standard of care. The discontinuation criterion was ≥80% reduction in PCT levels or any PCT ≤0.5 μg/L at Day 5 or later. The primary outcome was the rate of infection-associated adverse events at Day 180, a composite of the incidence of any new infection by or multidrug-resistant organisms, or any death attributed to baseline or multidrug-resistant organism infection. Secondary outcomes included 28-day mortality, length of antibiotic therapy, and cost of hospitalization. The rate of infection-associated adverse events was 7.2% (95% confidence interval [CI], 3.8-13.1%; 9/125) versus 15.3% (95% CI, 10.1-22.4%; 20/131) (hazard ratio, 0.45; 95% CI, 0.20-0.98;  = 0.045); 28-day mortality 15.2% (95% CI, 10-22.5%; 19/125) versus 28.2% (95% CI, 21.2-36.5%; 37/131) (hazard ratio, 0.51; 95% CI, 0.29-0.89;  = 0.02); and median length of antibiotic therapy 5 (range, 5-7) versus 10 (range, 7-15) days ( < 0.001) in the PCT and standard-of-care arms, respectively. The cost of hospitalization was also reduced in the PCT arm. In sepsis, PCT guidance was effective in reducing infection-associated adverse events, 28-day mortality, and cost of hospitalization.Clinical trial registered with www.clinicaltrials.gov (NCT03333304).

Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017.

Procalcitonin (PCT)-guided antibiotic discontinuation appears to decrease antibiotic use in critically ill patients, but its impact on survival remains less certain.

Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU).

Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.

Several studies were published to validate the quick Sepsis-related Organ Failure Assessment (qSOFA), namely in comparison with the systemic inflammatory response syndrome (SIRS) criteria. We performed a systematic review and meta-analysis with the aim of comparing the qSOFA and SIRS in patients outside the ICU.

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) present clinical criteria for the classification of patients with sepsis. We investigated incidence and long-term outcomes of patients diagnosed with these classifications, which are currently unknown.

The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.

We assessed the effects of a protocol restricting resuscitation fluid vs. a standard care protocol after initial resuscitation in intensive care unit (ICU) patients with septic shock.

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.

Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.

The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.

Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.

Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.

In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established.

The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.

Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.

For patients in intensive care units, sepsis is a common and potentially deadly complication and prompt initiation of appropriate antimicrobial therapy improves prognosis. The objective of this trial was to determine whether a strategy of antimicrobial spectrum escalation, guided by daily measurements of the biomarker procalcitonin, could reduce the time to appropriate therapy, thus improving survival.

In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes.

To define the terms "sepsis" and "organ failure" in a precise manner.