Sepsis

Introduction

Red blood cell (RBC) transfusion primarily aims to improve oxygen transport and tissue oxygenation. The transfusion strategy based on haemoglobin concentration could not accurately reflect cellular metabolism. The ratio of venous-arterial carbon dioxide tension difference to arterial-venous oxygen content difference (P(v-a)CO2/C(a-v)O2) is a good indicator of cellular hypoxia. We aim to explore the influence of P(v-a)CO2/C(a-v)O2 as an RBC transfusion trigger on outcomes in septic shock patients.

Methods and analysis

The study is a single-centre prospective cohort study. We consecutively enrol adult septic shock patients requiring RBC transfusion at intensive care unit (ICU) admission or during ICU stay. P(v-a)CO2/C(a-v)O2 will be recorded before and 1 hour after each transfusion. The primary outcome is ICU mortality. Binary logistic regression analyses will be performed to detect the independent association between P(v-a)CO2/C(a-v)O2 and ICU mortality. A cut-off value for P(v-a)CO2/C(a-v)O2 will be obtained by maximising the Youden index with the receiver operator characteristic curve. According to this cut-off value, patients included will be divided into two groups: one with the P(v-a)CO2/C(a-v)O2 >cut-off and the other with the P(v-a)CO2/C(a-v)O2 ≤cut off. Differences in clinical outcomes between the two groups will be assessed after propensity matching.

Ethics and dissemination

The study has been approved by the Institutional Review Board of Affiliated Hospital of Weifang Medical University (wyfy-2021-ky-059). Findings will be disseminated through conference presentations and peer-reviewed journals.

Trial registration number

ChiCTR2100051748.

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AbstractBackgroundSepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis.MethodsWe evaluated non-ICU adults on broad-spectrum antibiotics despite negative blood cultures at ten U.S. hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs. usual care. The primary outcome was 30-day post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If antibiotics were continued, clinicians discussed rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided two measures: 1) the odds ratio of antibiotic continuation and 2) ratio of mean DOT among those who continued antibiotics.ResultsAmong 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs. 84%, OR 0.68, 95% confidence interval (CI) [0.47, 0.98]). DOT among those who continued antibiotics were similar (ratio of means 1.06, 95% CI [0.88-1.26]). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% v. 44%. Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar.ConclusionsAn antibiotic opt-out protocol targeting patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm.

Objective

To explore the association between dynamic changes in red blood cell distribution width to platelet count ratio (RPR) during hospitalisation and short-term mortality in patients with sepsis.

Design

A retrospective cohort study using propensity score matching.

Setting

Intensive care units (ICUs) of Beth Israel Deaconess Medical Center.

Participants

A total of 8731 adult patients with sepsis were included in the study. The patients were identified from the ICU of the Medical Information Mart for Intensive Care database. The observed group included patients who experienced an increase in RPR of more than 30% during the first week of ICU admission, whereas the control group included the rest.

Main outcome and measure

Using propensity score matching, a matched control group was created. The primary outcome was 28-day mortality, and the length of hospital stay and in-hospital mortality were the secondary outcomes.

Results

The difference was evident in 28-day mortality between the two groups (85.8% vs 74.5%, p<0.001, Kaplan-Meier analysis, and HR=1.896, 95% CI=1.659 to 2.168, p<0.001, Cox regression). In the secondary outcomes, there was a significant difference in in-hospital mortality (p<0.001). In addition, the study discovered that the observed groups had a significantly longer hospital stay (p<0.001). Meanwhile, the results of subgroup analyses were consistent with those of the primary analyses.

Conclusions

In patients with sepsis, a significantly increased RPR is positively associated with the short-term death rate. Continuous RPR monitoring could be a valuable measure for predicting short-term mortality in patients with sepsis.

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Sepsis and septic shock are life-threatening organ dysfunctions caused by a dysregulated host response to severe infection, and β-lactams are the most widely used antibiotics in intensive care units (ICU) (Kadri et al., 2017, Drusano, 2004, Perner et al., 2017, Moriyama et al., 2009). As a time-dependent antibiotic, the bacterial killing by β-lactams depends on the duration of time that bacteria are exposed to a concentration exceeding the minimum inhibitory concentration (MIC). Additionally, effectiveness increases when the β-lactams plasma concentration at a steady state is more than four times of the pathogen's MIC.

American Journal of Respiratory and Critical Care Medicine, Volume 206, Issue 6, Page 783-786, September 15, 2022. …

Objective

A maternal sepsis management bundle for resource-limited settings was developed through a synthesis of evidence and international consensus. This bundle, called ‘FAST-M’ consists of: Fluids, Antibiotics, Source control, assessment of the need to Transport/Transfer to a higher level of care and ongoing Monitoring (of the mother and neonate). The study aimed to adapt the FAST-M intervention including the bundle care tools for early identification and management of maternal sepsis in a low-resource setting of Pakistan and identify potential facilitators and barriers to its implementation.

Setting

The study was conducted at the Liaquat University of Medical and Health Sciences, which is a tertiary referral public sector hospital in Hyderabad.

Design and participants

A qualitative exploratory study comprising key informant interviews and a focus group discussion was conducted with healthcare providers (HCPs) working in the study setting between November 2020 and January 2021, to ascertain the potential facilitators and barriers to the implementation of the FAST-M intervention. Interview guides were developed using the five domains of the Consolidated Framework for Implementation Research: intervention characteristics, outer setting, inner setting, characteristics of the individuals and process of implementation.

Results

Four overarching themes were identified, the hindering factors for implementation of the FAST-M intervention were: (1) Challenges in existing system such as a shortage of resources and lack of quality assurance; and (2) Clinical practice variation that includes lack of sepsis guidelines and documentation; the facilitating factors identified were: (3) HCPs’ perceptions about the FAST-M intervention and their positive views about its execution and (4) Development of HCPs readiness for FAST-M implementation that aided in identifying solutions to potential hindering factors at their clinical setting.

Conclusion

The study has identified potential gaps and probable solutions to the implementation of the FAST-M intervention, with modifications for adaptation in the local context

Trial registration number

ISRCTN17105658.

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Objectives

To identify the risk factors for neonatal sepsis in Sub-Saharan Africa.

Design

Systematic review and meta-analysis.

Data sources

PubMed, Embase, Web of Science, African Index Medicus and ClinicalTrials.gov were searched for observational studies from January 2010 to August 2020.

Setting

Sub-Saharan Africa, at all levels of healthcare facilities.

Participants

‘Neonates’ (<28 days of age) at risk of developing either clinical and/or laboratory-dependent diagnosis of sepsis.

Outcome measures

Identification of any risk factors for neonatal sepsis.

Results

A total of 36 studies with 23 605 patients from secondary or tertiary level of care facilities in 10 countries were included. Six studies were rated as good quality, 8 as fair and 22 as poor. Four studies were omitted in the meta-analysis due to insufficient data. The significant risk factors were resuscitation (OR 2.70, 95% CI 1.36 to 5.35), low birth weight <1.5 kg (OR 3.37, 95% CI 1.59 to 7.13) and 1.5–2.5 kg (OR 1.36, 95% CI 1.01 to 1.83), low Apgar score at the first minute (OR 3.69, 95% CI 2.34 to 5.81) and fifth minute (OR 2.55, 95% CI 1.46 to 4.45), prematurity <37 weeks (OR 1.91, 95% CI 1.27 to 2.86), no crying at birth (OR 3.49, 95% CI 1.42 to 8.55), male sex (OR 1.30, 95% CI 1.01 to 1.67), prolonged labour (OR 1.57, 95% CI 1.08 to 2.27), premature rupture of membranes (OR 2.15, 95% CI 1.34 to 3.47), multiple digital vaginal examinations (OR 2.22, 95% CI 1.27 to 3.89), meconium-stained amniotic fluid (OR 2.72, 95% CI 1.58 to 4.69), intrapartum maternal fever (OR 2.28, 95% CI 1.18 to 4.39), foul-smelling vaginal discharge (OR 3.31, 95% CI 2.16 to 5.09) and low socioeconomic status (OR 1.93, 95% CI 1.11 to 3.35). We found considerable heterogeneity in the meta-analysis of 11 out of 15 identified risk factors.

Conclusion

Multiple risk factors for neonatal sepsis in Sub-Saharan Africa were identified. We revealed risk factors not listed by the WHO guidelines. The included studies overall had high risk of bias and high heterogeneity and thus, additional research of high quality is needed.

PROSPERO registration number

CRD42020191067.

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Abstract

Background

The effect of coupled plasma filtration adsorption (CPFA) for the treatment of sepsis or septic shock is controversial. A systematic review and meta-analysis was performed to evaluate the impact of CPFA on all-cause mortality in patients with sepsis or septic shock.

Methods

We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of May 2022. We included studies involving patients (˃ 14 years) with sepsis or septic shock. All authors reported our primary outcome of all-cause mortality (hospital mortality, 28-day mortality or 30-day mortality). Results were expressed as odds ratio (OR) with accompanying 95% confidence interval (CI).

Results

Six studies including 537 patients were included. The primary outcome of this meta-analysis showed that the all-cause mortality was about 54.2% (119/243 in the CPFA group and 172/294 in the control group). There was no statistically significant difference in the all-cause mortality between two groups (odds ratio [OR] = 0.75; 95% CI 0.53 to 1.06; P = 0.11; Chi2 = 14.04; I2 = 64%).

Conclusions

The treatment of CPFA failed to decrease all-cause mortality of sepsis or septic shock patients. Further large-scale randomized controlled trials (RCTs) evaluating the ability of this therapy to improve clinical outcomes are still required to confirm these results.

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Abstract

Background

The effect of coupled plasma filtration adsorption (CPFA) for the treatment of sepsis or septic shock is controversial. A systematic review and meta-analysis was performed to evaluate the impact of CPFA on all-cause mortality in patients with sepsis or septic shock.

Methods

We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of May 2022. We included studies involving patients (˃ 14 years) with sepsis or septic shock. All authors reported our primary outcome of all-cause mortality (hospital mortality, 28-day mortality or 30-day mortality). Results were expressed as odds ratio (OR) with accompanying 95% confidence interval (CI).

Results

Six studies including 537 patients were included. The primary outcome of this meta-analysis showed that the all-cause mortality was about 54.2% (119/243 in the CPFA group and 172/294 in the control group). There was no statistically significant difference in the all-cause mortality between two groups (odds ratio [OR] = 0.75; 95% CI 0.53 to 1.06; P = 0.11; Chi2 = 14.04; I2 = 64%).

Conclusions

The treatment of CPFA failed to decrease all-cause mortality of sepsis or septic shock patients. Further large-scale randomized controlled trials (RCTs) evaluating the ability of this therapy to improve clinical outcomes are still required to confirm these results.

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by Alexandra Bick, Willem Buys, Andrea Engler, Rabea Madel, Mazen Atia, Francesca Faro, Astrid M. Westendorf, Andreas Limmer, Jan Buer, Frank Herbstreit, Carsten J. Kirschning, Jürgen Peters

Rationale The immune profile of sepsis patients is incompletely understood and hyperinflammation and hypoinflammation may occur concurrently or sequentially. Immune checkpoint inhibition (ICI) may counter hypoinflammation but effects are uncertain. We tested the reactivity of septic whole blood to bacteria, Toll-like receptor (TLR) ligands and to ICI. Methods Whole blood assays of 61 patients’ samples within 24h of meeting sepsis-3 criteria and 12 age and sex-matched healthy volunteers. Measurements included pattern/danger-associated molecular pattern (P/DAMP), cytokine concentrations at baseline and in response to TLR 2, 4, and 7/8 ligands, heat-inactivated Staphylococcus aureus or Escherichia coli, E.coli lipopolysaccharide (LPS), concentration of soluble and cellular immune checkpoint molecules, and cytokine concentrations in response to ICI directed against programmed-death receptor 1 (PD1), PD1-ligand 1, or cytotoxic T-lymphocyte antigen 4, both in the absence and presence of LPS. Main results In sepsis, concentrations of P/DAMPs and inflammatory cytokines were increased and the latter increased further upon incubation ex vivo. However, cytokine responses to TLR 2, 4, and 7/8 ligands, heat-inactivated S. aureus or E. coli, and E. coli LPS were all depressed. Depression of the response to LPS was associated with increased in-hospital mortality. Despite increased PD-1 expression on monocytes and T-cells, and monocyte CTLA-4 expression, however, addition of corresponding checkpoint inhibitors to assays failed to increase inflammatory cytokine concentrations in the absence and presence of LPS. Conclusion Patients first meeting Sepsis-3 criteria reveal 1) depressed responses to multiple TLR-ligands, bacteria, and bacterial LPS, despite concomitant inflammation, but 2) no response to immune checkpoint inhibition.…

Journal Name: The American Journal of Tropical Medicine and HygieneVolume: 107Issue: 2Pages: 393-396

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Abstract

Background

The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults.

Methods

Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements).

Results

Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment.

Conclusions

Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands.

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Abstract

Background

The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults.

Methods

Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements).

Results

Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment.

Conclusions

Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands.

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Abstract

Background

Vibrio vulnificus infections develop rapidly and are associated with a high mortality rate. The rates of diagnosis and treatment are directly associated with mortality.

Case presentation

We describe an unusual case of a 61-year-old male patient with chronic liver disease and diabetes who presented with a chief complaint of pain in both lower legs due to V. vulnificus infection in winter. Within 12 h of arrival, typical skin lesions appeared, and the patient rapidly developed primary sepsis. Despite prompt appropriate antibiotic and surgical treatment, the patient died 16 days after admission.

Conclusion

Our case findings suggest that V. vulnificus infection should be suspected in patients with an unclear infection status experiencing pain of unknown origin in the lower legs, particularly in patients with liver disease or diabetes, immunocompromised status, and alcoholism.

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Abstract

Background

Vibrio vulnificus infections develop rapidly and are associated with a high mortality rate. The rates of diagnosis and treatment are directly associated with mortality.

Case presentation

We describe an unusual case of a 61-year-old male patient with chronic liver disease and diabetes who presented with a chief complaint of pain in both lower legs due to V. vulnificus infection in winter. Within 12 h of arrival, typical skin lesions appeared, and the patient rapidly developed primary sepsis. Despite prompt appropriate antibiotic and surgical treatment, the patient died 16 days after admission.

Conclusion

Our case findings suggest that V. vulnificus infection should be suspected in patients with an unclear infection status experiencing pain of unknown origin in the lower legs, particularly in patients with liver disease or diabetes, immunocompromised status, and alcoholism.

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Abstract

Background

We aimed to explore the prognostic utilities of C-reactive protein (CRP), procalcitonin (PCT), neutrophil CD64 (nCD64) index, in combination or alone, in septic patients.

Methods

We retrospectively included 349 septic patients (based on Sepsis 3.0 definition). The primary outcome was 28-day all-cause mortality. Cox regression model, receiver-operating characteristic (ROC) curve, reclassification analysis, Kaplan–Meier survival curves were performed to evaluate the predictive efficacy of the above parameters.

Results

CRP, nCD64 index were independent predictors of 28-day mortality for sepsis in the Cox regression model [CRP, HR 1.004 (95% CI 1.002–1.006), P < 0.001; nCD64 index, HR 1.263 (95% CI 1.187–1.345, P < 0.001]. Area under the ROC curve (AUC) of CRP, PCT, nCD64 index, nCD64 index plus PCT, nCD64 index plus CRP, were 0.798 (95% CI 0.752–0.839), 0.833 (95% CI 0.790–0.871), 0.906 (95% CI 0.870–0.935), 0.910 (95% CI 0.875–0.938), 0.916 (95% CI 0.881–0.943), respectively. nCD64 plus CRP performed best in prediction, discrimination, and reclassification of the 28-day mortality risk in sepsis. The risk of 28-day mortality increased stepwise as the number of data exceeding optimal cut-off values increased.

Conclusions

nCD64 index combined with CRP was superior to CRP, PCT, nCD64 index and nCD64 index plus PCT in predicting 28-day mortality in sepsis. Multi-marker approach could improve the predictive accuracy and be beneficial for septic patients.

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Antimicrobial Agents and Chemotherapy, Ahead of Print. …

Nature Medicine, Published online: 21 July 2022; doi:10.1038/s41591-022-01878-0A real-time early warning system for sepsis detection shows promising adoption by healthcare providers and important improvements in patient outcomes.

Nature Medicine, Published online: 21 July 2022; doi:10.1038/s41591-022-01895-zProspective evaluation of a machine learning-based early warning system for sepsis, deployed at five hospitals, showed that healthcare providers interacted with the system at a high rate and that this interaction was associated with faster antibiotic ordering.

Nature Medicine, Published online: 21 July 2022; doi:10.1038/s41591-022-01894-0Prospective evaluation of a machine learning-based early warning system for sepsis, deployed at five hospitals, showed that interaction of health-care providers with the system was associated with better patient outcomes, including reduced in-hospital mortality.

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.