Objectives: To describe the quality of life among sepsis survivors. Design: Secondary analyses of two international, randomized clinical trials (A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis [derivation cohort] and PROWESS-SHOCK [validation cohort]). Setting: ICUs in North and South America, Europe, Africa, Asia, and Australia. Patients: Adults with severe sepsis. We analyzed only patients who were functional and living at home without help before sepsis hospitalization (n = 1,143 and 987 from A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis and PROWESS-SHOCK, respectively). Interventions: None. Measurements and main results: In A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis and PROWESS-SHOCK, the average age of patients living at home independently was 63 and 61 years; 400 (34.9%) and 298 (30.2%) died by 6 months. In A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis, 580 patients had a quality of life measured using EQ-5D at 6 months. Of these, 41.6% could not live independently (22.7% were home but required help, 5.1% were in nursing home or rehabilitation facilities, and 5.3% were in acute care hospitals). Poor quality of life at 6 months, as evidenced by problems in mobility, usual activities, and self-care domains were reported in 37.4%, 43.7%, and 20.5%, respectively, and the high incidence of poor quality of life was also seen in patients in PROWESS-SHOCK. Over 45% of patients with mobility and self-care problems at 6 months in A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis died or reported persistent problems at 1 year. Conclusions: Among individuals enrolled in a clinical trial who lived independently prior to severe sepsis, one third had died and of those who survived, a further one third had not returned to independent living by 6 months. Both mortality and quality of life should be considered when designing new interventions and considering endpoints for sepsis trials. Weniger anzeigen

Importance: 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. Objective: To evaluate and, as needed, update definitions for sepsis and septic shock. Process: A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). Key findings from evidence synthesis: Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. Recommendations: Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. Conclusions and relevance: These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis. Weniger anzeigen

Importance: Severe sepsis and septic shock are major causes of mortality in intensive care unit (ICU) patients. It is unknown whether progress has been made in decreasing their mortality rate. Objective: To describe changes in mortality for severe sepsis with and without shock in ICU patients. Design, setting, and participants: Retrospective, observational study from 2000 to 2012 including 101,064 patients with severe sepsis from 171 ICUs with various patient case mix in Australia and New Zealand. Main outcomes and measures: Hospital outcome (mortality and discharge to home, to other hospital, or to rehabilitation). Results: Absolute mortality in severe sepsis decreased from 35.0% (95% CI, 33.2%-36.8%; 949/2708) to 18.4% (95% CI, 17.8%-19.0%; 2300/12,512; P < .001), representing an overall decrease of 16.7% (95% CI, 14.8%-18.6%), an annual rate of absolute decrease of 1.3%, and a relative risk reduction of 47.5% (95% CI, 44.1%-50.8%). After adjusted analysis, mortality decreased throughout the study period with an odds ratio (OR) of 0.49 (95% CI, 0.46-0.52) in 2012, using the year 2000 as the reference (P < .001). The annual decline in mortality did not differ significantly between patients with severe sepsis and those with all other diagnoses (OR, 0.94 [95% CI, 0.94-0.95] vs 0.94 [95% CI, 0.94-0.94]; P = .37). The annual increase in rates of discharge to home was significantly greater in patients with severe sepsis compared with all other diagnoses (OR, 1.03 [95% CI, 1.02-1.03] vs 1.01 [95% CI, 1.01-1.01]; P < .001). Conversely, the annual increase in the rate of patients discharged to rehabilitation facilities was significantly less in severe sepsis compared with all other diagnoses (OR, 1.08 [95% CI, 1.07-1.09] vs 1.09 [95% CI, 1.09-1.10]; P < .001). In the absence of comorbidities and older age, mortality was less than 5%. Conclusions and relevance: In critically ill patients in Australia and New Zealand with severe sepsis with and without shock, there was a decrease in mortality from 2000 to 2012. These findings were accompanied by changes in the patterns of discharge to home, rehabilitation, and other hospitals. Weniger anzeigen

Background: Survivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized. Methods: We enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders. Results: Of the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer’s disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer’s disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P=0.001 and P=0.04, respectively) and worse executive function at 3 and 12 months (P=0.004 and P=0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months. Conclusions: Patients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.). Weniger anzeigen

Sepsis is one of the oldest and most elusive syndromes in medicine. Hippocrates claimed that sepsis (σήψις) was the process by which flesh rots, swamps generate foul airs, and wounds fester. Galen later considered sepsis a laudable event, necessary for wound healing. With the confirmation of germ theory by Semmelweis, Pasteur, and others, sepsis was recast as a systemic infection, often described as “blood poisoning,” and assumed to be the result of the host’s invasion by pathogenic organisms that then spread in the bloodstream. However, with the advent of modern antibiotics, germ theory did not fully explain the pathogenesis of sepsis: many patients with sepsis died despite successful eradication of the inciting pathogen. Thus, researchers suggested that it was the host, not the germ, that drove the pathogenesis of sepsis. In 1992, an international consensus panel defined sepsis as a systemic inflammatory response to infection, noting that sepsis could arise in response to multiple infectious causes and that septicemia was neither a necessary condition nor a helpful term. Instead, the panel proposed the term “severe sepsis” to describe instances in which sepsis is complicated by acute organ dysfunction, and they codified “septic shock” as sepsis complicated by either hypotension that is refractory to fluid resuscitation or by hyperlactatemia. In 2003, a second consensus panel endorsed most of these concepts, with the caveat that signs of a systemic inflammatory response, such as tachycardia or an elevated white-cell count, occur in many infectious and noninfectious conditions and therefore are not helpful in distinguishing sepsis from other conditions. Thus, “severe sepsis” and “sepsis” are sometimes used interchangeably to describe the syndrome of infection complicated by acute organ dysfunction. Weniger anzeigen

Studies on procalcitonin (PCT) for identifying sepsis were published as early as 1993 and since then, PCT has been the topic of over 8,500 studies. Several studies show PCT to be superior to CRP in differentiating invasive infections such as sepsis from viral infections, especially early in the disease course. However, its actual use in clinical practice is poorly documented. Our aim was to study the use of PCT in febrile children attending the ED across Europe and compare this to the use of CRP. The MOFICHE/PERFORM study, a prospective multicenter study, took place at 12 European EDs in eight countries and included febrile children < 18 years. In this secondary analysis of nine participating EDs that used PCT, descriptive analyses were performed, describing the use of PCT in all febrile children and for different age groups, foci of fever and fever duration. In total, 31,612 pediatric febrile episodes were available for analyses. Blood tests were performed in 15,812 (50.0%, range 9.6-92.6%)) febrile episodes. CRP was included in 98.3% of blood tests (range between hospitals 80-100%), while PCT was included in only 3.9% (range 0.1-86%). PCT was most often performed in children below 3 months (12.0% versus 3.6% in older children, p < 0.001). PCT was used slightly more often in children with fever less than 24 h in comparison to children with a duration of fever ≥ 24 h (4.9% versus 3.4%, p < 0.001). Regarding clinical alarming signs, PCT was used most often in children with meningeal signs (7.0%) or a non-blanching rash (10.9%). Actual PCT use in febrile children at European EDs is limited and varies largely between hospitals. Possible explanations include lack of guidelines, limited availability, higher costs and lack of readiness to adapt new clinical strategies. Weniger anzeigen

There is no consensus and wide practice variation in the choice of initial vasoactive agent in children with septic shock. To determine whether receipt of epinephrine compared with norepinephrine as the first vasoactive medication administered is associated with improved outcomes among children with septic shock without known cardiac dysfunction. This single-center, retrospective cohort study used propensity score matching to examine encounters in which a patient was diagnosed with septic shock and required a vasoactive infusion within 24 hours of ED arrival at a freestanding quaternary care children’s hospital. Participants included patients aged 1 month to 18 years who presented to the ED and were diagnosed with septic shock without known cardiac dysfunction and began an epinephrine or norepinephrine infusion within 24 hours of ED arrival between June 1, 2017, and December 31, 2023. Data were analyzed from March 1 to December 31, 2024. Epinephrine vs norepinephrine as the first vasoactive medication received. The primary outcome was major adverse kidney events by 30 days (MAKE30). Secondary outcomes were 30-day in-hospital mortality, 3-day mortality, need for kidney replacement therapy or persistent kidney dysfunction, endotracheal intubation, mechanical ventilation days, extracorporeal membrane oxygenation, and hospital and intensive care unit length of stay. Primary and secondary outcomes were assessed with the χ2 test of proportions for binary variables and Wilcoxon rank sum test for continuous variables. Among 231 included encounters, the median (IQR) age was 11.4 (5.6-15.4) years, 126 were female (54.6%), and 142 had a medical history that predisposed them to sepsis (61.5%). Most (147 [63.6%]) initially received an epinephrine infusion and 84 (36.4%) received norepinephrine. In the epinephrine group, 9 of 147 (6.1%) met the outcome of MAKE30 and 6 of 147 (4.1%) died within 30 days. In the norepinephrine group, 3 of 84 (3.6%) met MAKE30 and there were no deaths. After inverse probability of treatment weighting, there were no significant differences in the primary outcome, MAKE30. With 2:1 propensity matching, epinephrine was associated with greater 30-day mortality compared with norepinephrine (3.7% vs 0%; risk difference: 3.7%; 95% CI, 0.2%-7.2%). In this study, those receiving epinephrine had greater 30-day mortality but no difference in MAKE30. Prospective, confirmatory studies are needed to determine if norepinephrine should be the first-line vasoactive agent in pediatric septic shock. Weniger anzeigen

Hypotension is common in septic children, mean blood pressure (MBP) guides vasoactive agent titration. However, the Surviving Sepsis Guidelines for children were unable to recommend whether to target the 5th or 50th MBP percentile for septic shock. We aim to compare two MBP targets (5th vs. 50th percentile) for titrating vasoactive agents in septic shock patients. Single-center, open-label, randomized noninferiority trial. It was conducted in a tertiary care PICU in India from April 2021 to March 2024. Patients 1 month to 16 years old with septic shock unresponsive to fluids and requiring vasopressors. Children with septic shock were randomly assigned to either the 5th or 50th percentile MBP group, with vasopressor treatment adjusted to maintain the target blood pressure (BP) for each group. The primary outcome was 28-day all-cause mortality. Secondary outcomes included PICU/hospital stay, duration of vasoactive use, vasopressor-related adverse events, need for continuous renal replacement therapy (CRRT), invasive ventilation, and prevalence of acute respiratory distress syndrome (ARDS). A total of 144 children were enrolled. At 28 days, mortality did not differ significantly between groups: 16.9% (12/71) in the 5th centile group vs. 23.2% (17/73) in the 50th centile group (p = 0.41; risk difference, 6.3; 95% CI, -6.9 to 19.2). Norepinephrine use was higher in the 50th centile group (85% vs. 67%; p = 0.04). Vasoactive duration was longer in the 50th centile group (30.4 ± 13.3 vs. 18.8 ± 10.8; p = 0.001). The Vasoactive-Inotropic Score was also higher (64.0 ± 35.7 vs. 45.2 ± 29.6; p = 0.001). ARDS prevalence was significantly higher in the 50th centile group (32.8% vs. 16.9%; p = 0.02). No significant differences were found in other secondary outcomes like length of stay, ventilation duration, need for CRRT, or adverse events. Targeting a lower MBP (5th vs. 50th centile) in septic shock showed no significant difference in 28-day mortality. This suggests a lower BP target may be safe, reducing vasoactive drug use and related side effects. Weniger anzeigen

Functional recovery after intensive care is an important patient-centered outcome. In this study, we investigated risk factors for poor outcome after intensive care for sepsis using serial health-related quality of life (HRQoL) assessments and the burden of work incapacity as an objective proxy for functional recovery. We acquired data on all adult intensive care unit (ICU) patients with sepsis in Sweden between 2008 and 2020. Primary outcome was HRQoL assessed with RAND-36 at follow-up after ICU discharge. Sick-leave information was acquired on the working-age subpopulation to assess the burden of work incapacity. RAND-36 data were available for 14,006 individuals and was lower than Swedish population reference levels. Males had higher RAND-36. Age had varying associations. Pre-ICU comorbidities were associated with lower RAND-36, whereas severity of illness was associated with lower general health. Invasive ventilation was associated with higher RAND-36, while continuous renal replacement therapy and length of stay (LoS) were associated with lower RAND-36. RAND-36 increased with time after ICU. Sick-leave length was associated with lower RAND-36. High levels of sick leave were seen in patients before intensive care for sepsis, suggesting pre-existing vulnerability. Sick leave increased further after sepsis and did not return to baseline, suggesting incomplete functional recovery, with lower education, female sex, and comorbidities as risk factors. In conclusion, in a Swedish national cohort of ICU patients surviving sepsis, HRQoL was low but improved over time. Severity of illness had minimal impact on HRQoL, while LoS and comorbidities were negative factors. Functional recovery in the form of days on sick leave showed a similar pattern. The study was registered with clinicaltrials.gov: NCT06368336, on the 15th of April 2024. Weniger anzeigen

Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection. Immune dysregulation arises from responses that initially were activated to protect against pathogens and preserve tissue integrity. Disturbed resistance mechanisms can result in excessive inflammation alongside immunosuppression, each of which is considered important biological drivers of the immunopathology of sepsis. Key inflammatory drivers are excessive proinflammatory cytokine activity, complement and coagulation system activation and endothelial dysfunction. Conversely, sepsis-induced immunosuppression is marked by lymphocyte exhaustion, reduced monocyte human leucocyte antigen-DR expression, and the emergence of myeloid-derived suppressor cells. Within this complex immunological environment, the gut microbiome influences host immunity through the release of short-chain fatty acids and bacterial metabolites. Thus far, immunomodulatory trials in patients with sepsis paid little attention to the identification of dominant biological drivers, which might enrich the population for those who are more likely to respond to a certain intervention. Recently, retrospective analyses of such trials, as well as small prospective trials, have provided proof of concept that subgroups of sepsis patients can be identified with specific immunological profiles, either based on a single biomarker or on high-dimensional data, that respond differently to immunomodulation. This review explores the biological drivers of sepsis immunopathology, highlighting the challenges in translating preclinical insights into effective therapies and the potential of personalised medicine approaches to improve sepsis outcomes. Weniger anzeigen