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Abstract Purpose Coroners’ Prevention of Future Death (PFDs) reports are an under-utilized resource to learn about preventable deaths in England and Wales. We aimed to identify sepsis-related PFDs and explore the causes and concerns in this subset of preventable sepsis deaths. Methods Four thousand three hundred five reports were acquired from the Courts and Tribunals Judiciary website between July 2013 and November 2022, which were screened for sepsis. Demographic information, coroners concerns and responses to these reports were extracted and analyzed, including a detailed paediatric subgroup analysis. Results Two hundred sixty-five reports (6% of total PFDs) involved sepsis-related deaths. The most common cause of death in these reports was “sepsis without septic shock” (42%) and the most common site of infection was the respiratory system (18%) followed by gastrointestinal (16%) and skin (13%) infections. Specific pathogens were named in few reports (27%). Many deaths involved multimorbid patients (49%) or those with recent surgery (26%). Coroners named 773 individual concerns, the most frequent were: a failure to keep accurate records or notes (28%), failure in communication or handover (27%) or failure to recognize risk factors or comorbidities (20%). Paediatric cases frequently reported issues with sepsis screening tools (26%). Sepsis PFDs resulted in 421 individual reports being sent, of which 45% received no response. Most organisations who did respond acknowledged concerns and initiated a new change (74%). Conclusion Sepsis-related PFDs provide valuable insights into preventable causes of sepsis and identify important sources of improvement in sepsis care. Wider dissemination of findings is vital to learn from these reports. …

Abstract Purpose Coroners’ Prevention of Future Death (PFDs) reports are an under-utilized resource to learn about preventable deaths in England and Wales. We aimed to identify sepsis-related PFDs and explore the causes and concerns in this subset of preventable sepsis deaths. Methods Four thousand three hundred five reports were acquired from the Courts and Tribunals Judiciary website between July 2013 and November 2022, which were screened for sepsis. Demographic information, coroners concerns and responses to these reports were extracted and analyzed, including a detailed paediatric subgroup analysis. Results Two hundred sixty-five reports (6% of total PFDs) involved sepsis-related deaths. The most common cause of death in these reports was “sepsis without septic shock” (42%) and the most common site of infection was the respiratory system (18%) followed by gastrointestinal (16%) and skin (13%) infections. Specific pathogens were named in few reports (27%). Many deaths involved multimorbid patients (49%) or those with recent surgery (26%). Coroners named 773 individual concerns, the most frequent were: a failure to keep accurate records or notes (28%), failure in communication or handover (27%) or failure to recognize risk factors or comorbidities (20%). Paediatric cases frequently reported issues with sepsis screening tools (26%). Sepsis PFDs resulted in 421 individual reports being sent, of which 45% received no response. Most organisations who did respond acknowledged concerns and initiated a new change (74%). Conclusion Sepsis-related PFDs provide valuable insights into preventable causes of sepsis and identify important sources of improvement in sepsis care. Wider dissemination of findings is vital to learn from these reports. …

IMPORTANCE: The interhospital transfer (IHT) of patients with sepsis to higher-capability hospitals may improve outcomes. Little is known about patient and hospital factors associated with sepsis IHT. OBJECTIVES: We evaluated patterns of hospitalization and IHT and determined patient and hospital factors associated with the IHT of adult patients with sepsis. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: A total of 349,938 adult patients with sepsis at 329 nonfederal hospitals in California, 2018–2019. MAIN OUTCOMES AND MEASURES: We evaluated patterns of admission and outward IHT between low sepsis-, intermediate sepsis-, and high sepsis-capability hospitals. We estimated odds of IHT using generalized estimating equations logistic regression with bootstrap stepwise variable selection. RESULTS: Among the cohort, 223,202 (66.4%) were initially hospitalized at high-capability hospitals and 10,870 (3.1%) underwent IHT. Nearly all transfers (98.2%) from low-capability hospitals were received at higher-capability hospitals. Younger age (< 65 yr) (adjusted odds ratio [aOR] 1.54; 95% CI, 1.40–1.69) and increasing organ dysfunction (aOR 1.22; 95% CI, 1.19–1.25) were associated with higher IHT odds, as were admission to low-capability (aOR 2.79; 95% CI, 2.33–3.35) or public hospitals (aOR 1.35; 95% CI, 1.09–1.66). Female sex (aOR 0.88; 95% CI, 0.84–0.91), Medicaid insurance (aOR 0.59; 95% CI, 0.53–0.66), home to admitting hospital distance less than or equal to 10 miles (aOR 0.92; 95% CI, 0.87–0.97) and do-not-resuscitate orders (aOR 0.48; 95% CI, 0.45–0.52) were associated with lower IHT odds, as was admission to a teaching hospital (aOR 0.83; 95% CI, 0.72–0.96). CONCLUSIONS AND RELEVANCE: Most patients with sepsis are initially hospitalized at high-capability hospitals. The IHT rate for sepsis is low and more likely to originate from low-capability and public hospitals than from high-capability and for-profit hospitals. Transferred patients with sepsis are more likely to be younger, male, sicker, with private medical insurance, and less likely to have care limitation orders. Future studies should evaluate the comparative benefits of IHT from low-capability hospitals.

by Petek Eylul Taneri, Jamie J. Kirkham, Eleanor J. Molloy, Linda Biesty, Richard A. Polin, James L. Wynn, Barbara J. Stoll, Niranjan Kissoon, Kondwani Kawaza, Mandy Daly, Aoife Branagan, Lívia Nagy Bonnard, Eric Giannoni, Tobias Strunk, Magdalena Ohaja, Kenneth Mugabe, Denise Suguitani, Fiona Quirke, Declan Devane Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients’ parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

Abstract Objective To evaluate the association between traditional laboratory findings and death, and to find risk factors for death in infants with early onset sepsis (EOS). Study design This was a single-center, case–control, retrospective trial conducted between January 2020 and August 2021. Infants with EOS were enrolled and divided into two groups based on outcome before hospital discharge: non-survivors (Mortality group) and survivors (Survival group). Results Out of 556 eligible neonates, there were 38 (6.8%) deaths. After univariate analysis and ROC curve analysis, there were a total of 12 values with significant differences (p 

Abstract Introduction The neutrophil to lymphocyte ratio (NLR), an inflammatory biomarker, measures innate-adaptive immune system balance. In this systematic review and meta-analysis, we aim to analyze the current literature to evaluate the diagnostic role of NLR in neonatal sepsis. Methods PubMed, Web of Science, and Scopus were used to conduct a systematic search for relevant publications published before May 14, 2022. Results Thirty studies, including 2328 neonates with sepsis and 1800 neonates in the control group, were included in our meta-analysis. The results indicated that NLR is higher in neonates with sepsis compared to healthy controls (SMD = 1.81, 95% CI = 1.14–2.48, P-value 

Abstract Objective To evaluate the association between traditional laboratory findings and death, and to find risk factors for death in infants with early onset sepsis (EOS). Study design This was a single-center, case–control, retrospective trial conducted between January 2020 and August 2021. Infants with EOS were enrolled and divided into two groups based on outcome before hospital discharge: non-survivors (Mortality group) and survivors (Survival group). Results Out of 556 eligible neonates, there were 38 (6.8%) deaths. After univariate analysis and ROC curve analysis, there were a total of 12 values with significant differences (p 

Objectives: We hypothesized that the immunosuppressive effects associated with antibiotics, sedatives, and catecholamines amplify sepsis-associated immune suppression through mitochondrial dysfunction, and there is a cumulative effect when used in combination. We thus sought to determine the impact of the exemplar drugs ciprofloxacin, propofol, and norepinephrine, used alone and in combination, at clinically relevant concentrations, on the ex vivo functionality of peripheral blood mononuclear cells (PBMCs) drawn from healthy, infected, and septic individuals. Design: In vitro/ex vivo investigation. Setting: University laboratory. Subjects: Healthy volunteers, infected (nonseptic) patients in the emergency department, and septic ICU patients. Interventions: PBMCs were isolated from these subjects and treated with ciprofloxacin (100 µg/mL), propofol (50 µg/mL), norepinephrine (10 µg/mL), or all three drugs combined, with and without lipopolysaccharide (100 ng/mL) for 6 or 24 hours. Comparison was made between study groups and against untreated cells. Measurements were made of cell viability, cytokine production, phagocytosis, human leukocyte antigen-DR (HLA-DR) status, mitochondrial membrane potential, mitochondrial reactive oxygen species production, and oxygen consumption. Gene expression in immune and metabolic pathways was investigated in PBMCs sampled from healthy volunteers coincubated with septic serum. Measurements and Results: Coincubation with each of the drugs reduced cytokine production and phagocytosis in PBMCs isolated from septic patients, and healthy volunteers coincubated with septic serum. No effect was seen on HLA-DR surface expression. No cumulative effects were seen with the drug combination. Sepsis-induced changes in gene expression and mitochondrial functionality were not further affected by addition of any of the drugs. Conclusion: Drugs commonly used in critical care lead to significant immune dysfunction ex vivo and enhance sepsis-associated immunosuppression. Further studies are required to identify underlying mechanisms and potential impact on patient outcomes.

In this Medical News article, Johns Hopkins University computer scientist Suchi Saria, PhD, MSc, discusses the use of AI tools in early sepsis detection and other clinical applications.

Abstract Introduction The neutrophil to lymphocyte ratio (NLR), an inflammatory biomarker, measures innate-adaptive immune system balance. In this systematic review and meta-analysis, we aim to analyze the current literature to evaluate the diagnostic role of NLR in neonatal sepsis. Methods PubMed, Web of Science, and Scopus were used to conduct a systematic search for relevant publications published before May 14, 2022. Results Thirty studies, including 2328 neonates with sepsis and 1800 neonates in the control group, were included in our meta-analysis. The results indicated that NLR is higher in neonates with sepsis compared to healthy controls (SMD = 1.81, 95% CI = 1.14–2.48, P-value 

Abstract Introduction The neutrophil to lymphocyte ratio (NLR), an inflammatory biomarker, measures innate-adaptive immune system balance. In this systematic review and meta-analysis, we aim to analyze the current literature to evaluate the diagnostic role of NLR in neonatal sepsis. Methods PubMed, Web of Science, and Scopus were used to conduct a systematic search for relevant publications published before May 14, 2022. Results Thirty studies, including 2328 neonates with sepsis and 1800 neonates in the control group, were included in our meta-analysis. The results indicated that NLR is higher in neonates with sepsis compared to healthy controls (SMD = 1.81, 95% CI = 1.14–2.48, P-value 

Abstract Introduction The neutrophil to lymphocyte ratio (NLR), an inflammatory biomarker, measures innate-adaptive immune system balance. In this systematic review and meta-analysis, we aim to analyze the current literature to evaluate the diagnostic role of NLR in neonatal sepsis. Methods PubMed, Web of Science, and Scopus were used to conduct a systematic search for relevant publications published before May 14, 2022. Results Thirty studies, including 2328 neonates with sepsis and 1800 neonates in the control group, were included in our meta-analysis. The results indicated that NLR is higher in neonates with sepsis compared to healthy controls (SMD = 1.81, 95% CI = 1.14–2.48, P-value 

Abstract Background Sepsis in low-birth-weight neonates remains one of the most significant causes of neonatal morbidity and mortality. Approximately 3 million newborns suffer from sepsis globally every year. The aim of this study was to compare demographic and clinical features, as well as etiology and antibiotic susceptibility, of the main pathogens related to neonatal sepsis in two neonatal intensive units during a two-year period. Methods We observed early-onset (EO-BSI) and late-onset bloodstream infections (LO-BSI) cases in two high-reference neonatal intensive care units (NICU) over a 24-month period (2016–2017). Samples of patients’ blood were tested for the presence of the microorganisms. All bacterial isolates were tested for susceptibility to antibiotics. Results The majority of sepsis cases weighed above 1000 g and were born by cesarean section. About 10% of the EO-BSI group died. There were differences in the EO-BSI /LO-BSI ratio in the compared wards due to differences among the admitted children. The most common pathogens isolated from blood were coagulase-negative staphylococci (CoNS) were represented by two dominating species: S. epidermidis and S. haemolyticus, followed by Klebsiella spp. strains and E.coli, which were mostly found in EO-BSI cases. No single S. agalactiae (GBS) strain was isolated. The majority of CoNS strains were resistant to methicillin, half were resistant to aminoglycosides, and one-third were resistant to macrolides and lincosamides. Half of the Gram-negative rods were resistant to beta-lactams. Conclusions The epidemiology of sepsis in two observed NICUs is comparable to data obtained from other studies with a predominance of methicillin-resistant CoNS in LO-BSI and beta-lactam resistant E. coli in EO-BSI. It is of importance that the campaign for controlling GBS carriage in pregnant women in Poland resulted in the disappearance of GBS as a cause of sepsis. Unfortunately, there are no such measures to control E.coli related sepsis. …

Abstract Background Sepsis in low-birth-weight neonates remains one of the most significant causes of neonatal morbidity and mortality. Approximately 3 million newborns suffer from sepsis globally every year. The aim of this study was to compare demographic and clinical features, as well as etiology and antibiotic susceptibility, of the main pathogens related to neonatal sepsis in two neonatal intensive units during a two-year period. Methods We observed early-onset (EO-BSI) and late-onset bloodstream infections (LO-BSI) cases in two high-reference neonatal intensive care units (NICU) over a 24-month period (2016–2017). Samples of patients’ blood were tested for the presence of the microorganisms. All bacterial isolates were tested for susceptibility to antibiotics. Results The majority of sepsis cases weighed above 1000 g and were born by cesarean section. About 10% of the EO-BSI group died. There were differences in the EO-BSI /LO-BSI ratio in the compared wards due to differences among the admitted children. The most common pathogens isolated from blood were coagulase-negative staphylococci (CoNS) were represented by two dominating species: S. epidermidis and S. haemolyticus, followed by Klebsiella spp. strains and E.coli, which were mostly found in EO-BSI cases. No single S. agalactiae (GBS) strain was isolated. The majority of CoNS strains were resistant to methicillin, half were resistant to aminoglycosides, and one-third were resistant to macrolides and lincosamides. Half of the Gram-negative rods were resistant to beta-lactams. Conclusions The epidemiology of sepsis in two observed NICUs is comparable to data obtained from other studies with a predominance of methicillin-resistant CoNS in LO-BSI and beta-lactam resistant E. coli in EO-BSI. It is of importance that the campaign for controlling GBS carriage in pregnant women in Poland resulted in the disappearance of GBS as a cause of sepsis. Unfortunately, there are no such measures to control E.coli related sepsis. …

Objective: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin–angiotensin system (RAS) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that RAS dysfunction (elevated active renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients. Design: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial. Setting: Forty-three hospitals across the United States. Patients: Biorepository samples of 103 patients. Interventions: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples (n = 103 and 95, respectively) for assessment of the RAS. The association of RAS values with 30-day mortality was determined using Cox proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use. Measurements and Main Results: High baseline active renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10–7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HRQ2 = 2.01 [0.37–11.04], HRQ3 = 3.22 [0.64–16.28], HRQ4 = 5.58 [1.18–26.32], p for linear trend = 0.023). A 1-sd (593.6 pg/mL) increase in renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94–7.22], p < 0.001), and patients whose renin decreased had improved survival compared with those whose renin increased (HR 0.22 [95% CI, 0.08–0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with renin over the median on day 0 who received the VICTAS intervention, but not on day 3 (p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the RAS from the VICTAS intervention. Conclusions: Baseline serum active renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating renin from day 0 to day 3 was associated with a higher risk of death.

To the Editor The MERCY randomized clinical trial in critically ill patients with sepsis found that the meropenem dosing strategy (continuous infusion vs intermittent bolus) did not improve the composite outcome of mortality and emergence of drug-resistant bacteria. However, we are concerned that the population for whom the administration of meropenem as a continuous infusion is expected to be most beneficial was not well represented in the trial.

In Reply Augmented kidney clearance (defined as a GFR ≥130 mL/min/1.73 m2) may increase meropenem clearance, resulting in a lower chance of achieving a target plasma concentration with a bolus administration. Augmented kidney clearance occurs in approximately 20% of patients with critical illness, especially in younger patients, in those with burns, and during the first week of hospital admission. None of these circumstances were frequent in the MERCY trial; patients were older (mean age, 64 years) and mainly had respiratory infections (33% of patients). Meropenem therapy was usually initiated later than 1 week after hospital admission, following failure of other antibiotics (66% were already receiving treatment at randomization).

OBJECTIVES: To identify opportunities for improving hospital-based sepsis care and to inform an ongoing statewide quality improvement initiative in Michigan. DESIGN: Surveys on hospital sepsis processes, including a self-assessment of practices using a 3-point Likert scale, were administered to 51 hospitals participating in the Michigan Hospital Medicine Safety Consortium, a Collaborative Quality Initiative sponsored by Blue Cross Blue Shield of Michigan, at two time points (2020, 2022). Forty-eight hospitals also submitted sepsis protocols for structured review. SETTING: Multicenter quality improvement consortium. SUBJECTS: Fifty-one hospitals in Michigan. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the included hospitals, 92.2% (n = 47/51) were nonprofit, 88.2% (n = 45/51) urban, 11.8% (n = 6/51) rural, and 80.4% (n = 41/51) teaching hospitals. One hundred percent (n = 51/51) responded to the survey, and 94.1% (n = 48/51) provided a sepsis policy/protocol. All surveyed hospitals used at least one quality improvement approach, including audit/feedback (98.0%, n = 50/51) and/or clinician education (68.6%, n = 35/51). Protocols included the Sepsis-1 (18.8%, n = 9/48) or Sepsis-2 (31.3%, n = 15/48) definitions; none (n = 0/48) used Sepsis-3. All hospitals (n = 51/51) used at least one process to facilitate rapid sepsis treatment, including order sets (96.1%, n = 49/51) and/or stocking of commonly used antibiotics in at least one clinical setting (92.2%, n = 47/51). Treatment protocols included guidance on antimicrobial therapy (68.8%, n = 33/48), fluid resuscitation (70.8%, n = 34/48), and vasopressor administration (62.5%, n = 30/48). On self-assessment, hospitals reported the lowest scores for peridischarge practices, including screening for cognitive impairment (2.0%, n = 1/51 responded “we are good at this”) and providing anticipatory guidance (3.9%, n = 2/51). There were no meaningful associations of the Centers for Medicare and Medicaid Services’ Severe Sepsis and Septic Shock: Management Bundle performance with differences in hospital characteristics or sepsis policy document characteristics. CONCLUSIONS: Most hospitals used audit/feedback, order sets, and clinician education to facilitate sepsis care. Hospitals did not consistently incorporate organ dysfunction criteria into sepsis definitions. Existing processes focused on early recognition and treatment rather than recovery-based practices.

OBJECTIVES: Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies—lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN: Genetic and clinical epidemiology, and experimental models. SETTING: Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS: Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS: Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS: Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67–1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32–1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS: PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.

Challenging conventional wisdom is important and frequently useful. Septic shock is a form of distributive shock in which hypotension results from vasodilation. Although myocardial performance may not always be entirely normal, a phenomenon termed septic cardiomyopathy, cardiac output is usually preserved, in part by increased heart rate. Therapy of septic shock refractory to fluid administration entails administration of vasopressor agents; norepinephrine is generally preferred as an initial agent. In those cases in which cardiac output is felt to be low enough to compromise perfusion, inotropic agents may be used. In this context, use of β-blockers may well be regarded as counterintuitive inasmuch as their hemodynamic effects would tend to decrease arterial pressure and cardiac output. Despite this, investigators have challenged conventional wisdom and evaluated the effects of β-blockade for treating sepsis.

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.

Supplemental oxygen is often administered liberally to acutely ill adults, but the credibility of the evidence for this practice is unclear. We systematically reviewed the efficacy and safety of liberal versus conservative oxygen therapy in acutely ill adults.

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.