Search

Introduction: Concern for loss of physical performance and Health-Related Quality of Life (HRQoL) may raise doubts regarding the meaningfulness of an Intensive Care (ICU) admission in elderly patients. We evaluated self-perceived long-term recovery and satisfaction in elderly surviving an abdominal sepsis related ICU-admission and related this to objective measures of HRQoL., Methods: A cross-sectional survey study was performed in all ICU-survivors with age ≥70 admitted with abdominal sepsis. HRQoL, frailty and self-perceived long-term recovery were measured using the EQ-5D-3L, Groningen Frailty Indicator, and a self-developed questionnaire, respectively., Results: Of 144 patients admitted, 48 were alive at follow up (2.42 [0.92; 3.83] years), and 29 (60%) returned the survey. Eleven patients out of 29 (38%) recovered to baseline functioning, and reported higher HRQoL compared to unrecovered patients (0.861 [0.807; 1.000] and 0.753 [0.499; 0.779] respectively, p=0.005). Of the unrecovered patients, 53% were satisfied with their functioning, and 94% were willing to return to ICU., Conclusions: Mortality in elderly patients with abdominal sepsis is high and ICU-admission should be weighed carefully. However, despite substantial functional decline in survivors, it does not necessarily cause self-perceived unsatisfactory functioning, poor HRQoL and unwillingness to receive life-sustaining therapy again. Caution is advised to use an anticipated loss of functioning as an argument to deny an ICU-admission.

Objectives: To determine the appropriateness of empiric antibiotic therapy and the possible benefit of adding short-course gentamicin in septic shock patients with abdominal, urogenital, or an unknown focus. Secondary objectives were the effect of gentamicin addition on shock reversal and the incidence of a fungal infection., Methods: Microbiological cultures, antibiotic treatment, and antibiotic resistance patterns of the cultured microorganisms were recorded during the first 5 days of admission. Inappropriate antibiotic therapy was defined as a prescription within the first 24 h that did not cover cultured bacteria during the first 5 days of admission and was determined in the overall group and in patients receiving adjunctive gentamicin (combination therapy) versus patients receiving monotherapy. Binomial logistic regression analysis was used to investigate the association of gentamicin addition with shock reversal., Results: Of 203 septic shock patients, with abdominal ( n  = 143), urogenital ( n  = 27) or unknown ( n  = 33) focus, 115 patients received monotherapy, and 88 patients received combination therapy. Inappropriate therapy occurred in 29 patients (14%), more frequently in monotherapy (17%) versus combination therapy (10%). Combination therapy would have been effective in 55% of patients with inappropriate monotherapy. We found no association between gentamicin addition and shock reversal ( p  = .223). A fungal infection was present in 22 patients (11%)., Conclusion: Inappropriate empirical antibiotic therapy occurs in 17% of septic shock patients receiving monotherapy. In 55% of these patients, additional gentamicin would have resulted in appropriate therapy. When clinical course is unfavourable, lowering the threshold for administering adjunctive aminoglycoside and antifungal therapy should be considered.

Early death in sepsis occurs frequently; however, specific causes are largely unknown. An autopsy can contribute to ascertain causes of death. The objective of the study was to determine discrepancies in clinical diagnosis and postmortem findings in septic intensive care unit (ICU) patients deceased within 48 h after ICU admission. All septic ICU patients who deceased within 48 h after ICU admission were identified and included. Four intensivists determined the clinical cause of death by medical record review. An autopsy was performed within 24 h of death. Clinical diagnosis and postmortem findings were compared and classified as autopsy-identified missed clinical diagnoses and autopsy-refuted diagnoses. Class I and II missed major diagnoses using the Goldman criteria were scored. Between 2012 and 2017, 1107 septic patients were admitted to ICU. Of these, 344 patients (31%) died, of which 97 patients (28%) deceased within 48 h. In 32 (33%) early deceased patients, an autopsy was agreed. There were 26 autopsy-identified missed clinical diagnoses found, mostly myocardial infarction (n = 4) and pneumonia (n = 4). In four patients (13%), a class I discrepancy was found. In fourteen patients (42%), a class II discrepancy was found. In conclusion, an autopsy is an important diagnostic tool that can identify definite causes of death. These diagnoses deviate from diagnoses established during admission in early deceased sepsis patients.

Background: Sepsis is a global health care problem with a high mortality. Early death seems common; however, data are sparse. The objective of the present study was to report causes and influencing factors of early death in sepsis and septic shock., Methods: All septic ICU patients were included from 2012 to 2017. Early death was predefined as occurring within 48 h. Causes and factors leading up to death were reported by a panel of four intensivists, independently reviewing the medical files. Following factors were assessed: (1) delay in ICU admission; (2) futile ICU treatment; (3) missed diagnosis or inadequate treatment on the ICU. Fleiss kappa was used to assess inter-observer agreement., Results: 1107 septic patients (APACHE II score 25 ± 8) were included. 344 patients died of which 97 (28%) within 48 h. In 33% an autopsy was performed. Primary causes of early death were multiple organ failure, mesenteric ischaemia and death after cardio-pulmonary resuscitation (CPR). Delay in ICU admission was scored in 32% of early deaths with slight agreement (κ = 0.180), futile ICU treatment in 29% with moderate agreement (κ = 0.415) and missed diagnosis or treatment in 7% of cases with slight agreement (κ = 0.122)., Conclusions: Early death after ICU admission in sepsis is common and primarily caused by multiple organ failure, mesenteric ischaemia and death after unsuccessful CPR. Influencing factors were delay in ICU admission and futile ICU admission. Fleiss kappa indicates substantial variability in clinical judgement between intensivists, strengthening the necessity for shared decision making.

Background: The pathophysiology of septic acute kidney injury is inadequately understood. Recently, subphenotypes for sepsis and AKI have been derived. The objective of this study was to assess whether a combination of comorbidities, baseline clinical data, and biomarkers could classify meaningful subphenotypes in septic AKI with different outcomes., Methods: We performed a post hoc analysis of the prospective Finnish Acute Kidney Injury (FINNAKI) study cohort. We included patients admitted with sepsis and acute kidney injury during the first 48 h from admission to intensive care (according to Kidney Disease Improving Global Outcome criteria). Primary outcomes were 90-day mortality and renal recovery on day 5. We performed latent class analysis using 30 variables obtained on admission to classify subphenotypes. Second, we used logistic regression to assess the association of derived subphenotypes with 90-day mortality and renal recovery on day 5., Results: In total, 301 patients with septic acute kidney injury were included. Based on the latent class analysis, a two-class model was chosen. Subphenotype 1 was assigned to 133 patients (44%) and subphenotype 2 to 168 patients (56%). Increased levels of inflammatory and endothelial injury markers characterized subphenotype 2. At 90 days, 29% of patients in subphenotype 1 and 41% of patients in subphenotype 2 had died. Subphenotype 2 was associated with a lower probability of short-term renal recovery and increased 90-day mortality., Conclusions: In this post hoc analysis, we identified two subphenotypes of septic acute kidney injury with different clinical outcomes. Future studies are warranted to validate the suggested subphenotypes of septic acute kidney injury.

This study applied machine learning for the early prediction of 30-day mortality at sepsis diagnosis time in critically ill patients. Retrospective study using data collected from the Medical Information Mart for Intensive Care IV database. The data of the patient cohort was divided on the basis of the year of hospitalization, into training (2008-2013), validation (2014-2016), and testing (2017-2019) datasets. 24,377 patients with the sepsis diagnosis time < 24 h after intensive care unit (ICU) admission were included. A gradient boosting tree-based algorithm (XGBoost) was used for training the machine learning model to predict 30-day mortality at sepsis diagnosis time in critically ill patients. Model performance was measured in both discrimination and calibration aspects. The model was interpreted using the SHapley Additive exPlanations (SHAP) module. The 30-day mortality rate of the testing dataset was 17.9%, and 39 features were selected for the machine learning model. Model performance on the testing dataset achieved an area under the receiver operating characteristic curve (AUROC) of 0.853 (95% CI 0.837-0.868) and an area under the precision-recall curves of 0.581 (95% CI 0.541-0.619). The calibration plot for the model revealed a slope of 1.03 (95% CI 0.94-1.12) and intercept of 0.14 (95% CI 0.04-0.25). The SHAP revealed the top three most significant features, namely age, increased red blood cell distribution width, and respiratory rate. Our study demonstrated the feasibility of using the interpretable machine learning model to predict mortality at sepsis diagnosis time., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: To determine the predictive value of serum albumin (SA) at admission to the intensive care unit (ICU) on the cumulative dose of noradrenaline, the fluids administered, the lactate level, and mortality during the first 24 h of ICU admission., Methods: A total of 100 ICU patients were included. The association between SA and the cumulative dose of noradrenaline was analyzed using logistic regression. For the total amount of fluids administered linear regression, for the lactate level and for 24 h mortality logistic regression was used. Age, gender, patient category, type of surgery, severe sepsis, lactate level, estimated glomerular filtration rate, c-reactive protein level, and the target mean arterial pressure were considered effect modifiers., Results: SA was significantly associated with the dose of noradrenaline (OR 0.92, 95% CI 0.84–0.99, p = 0.028), lower lactate levels (OR 1.14, 95% CI 1.00–1.30, p = 0.049), and with the amount of fluids administered (B -0.02, 95% CI −0.03/−0.00, p = 0.016), but not with mortality (OR 0.95, 95% CI 0.85–1.07, p = 0.41)., Conclusions: SA significantly predicts noradrenaline and fluid requirements as well as the change in lactate level during the first 24 h of ICU admission. Our observations have to be validated in another large cohort.

Hypovolemia is frequent in patients with sepsis and may contribute to worse outcome. The management of these patients is impeded by the low quality of the evidence for many of the specific components of the care. In this paper, we discuss recent advances and controversies in this field and give expert statements for the management of hypovolemia in patients with sepsis including triggers and targets for fluid therapy and volumes and types of fluid to be given. Finally, we point to unanswered questions and suggest a roadmap for future research.

The heart is one of the most common organs involved in sepsis-induced organ dysfunction and about 50% septic patients complicated with myocardial injury. So far, the molecular mechanisms underlying sepsis-induced cardiac damage remain unclear. In this study we aimed to evaluate the effect of miR-642a on sepsis-induced cardiac injury in vitro and explore the possible lncRNA-microRNA mechanism. We first downloaded GSE101639 to identify differentially expressed genes (DEGs) in sepsis. The expression of miR-642a in LPS-induced H9C2 cells was detected by qRT-PCR. MTT assay, cell migration, flow cytometry analysis, ELISA, qRT-PCR and Western blotting analysis were applied to evaluating the effect of miR-642a mimic on LPS-induced H9C2 cells. The bioinformatics analysis and the rescue experiment were devoted to the underlying mechanism. The results showed miR-642a expression was decreased in septic patients and LPS-induced H9C2 cells. Besides, MiR-642a mimic promoted cell viability and migration, inhibited cell apoptosis of LPS-induced H9C2 cells. Bioinformatics analysis showed miR-642a directly targets with 3'-UTR of ROCK1. Moreover, LUCAT1 regulated ROCK1 expression act as a competing endogenous RNA (ceRNA) for miR-642a. Our data demonstrated that lncRNA LUCAT1 could function via sponging miR-642a to regulate ROCK1 expression in LPS-induced H9C2 cells. And knockdown of lncRNA LUCAT1 could suppress LPS-induced cardiac injury in vitro., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Recent studies have failed to show significant benefit from a uniform strategy, suggesting that hemodynamic management must be individually adapted in septic shock depending on different phenotypes. Different approaches that may be used to this end will be discussed., Recent Findings: Fluid management is a cornerstone of resuscitation, as the positive fluid balance has been associated with higher mortality and right ventricular failure. Myocardial evaluation is mandatory, as sepsis patients may present with a hyperkinetic state, left ventricular (systolic and diastolic) and/or right ventricular dysfunction, the latter being associated with higher mortality. Statistical approaches with the identification of hemodynamic clusters based on echocardiographic and clinical parameters might be integrated into daily practice to develop precision medicine. Such approaches may also predict the progression of septic shock., Summary: Different hemodynamic phenotypes can occur at any stage of sepsis and be associated with one another. The clinician must regularly assess dynamic changes in phenotypes in septic shock patients. Statistical approaches based on machine learning need to be validated by prospective studies., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Sepsis-associated AKI is a heterogeneous clinical entity. We aimed to agnostically identify sepsis-associated AKI subphenotypes using deep learning on routinely collected data in electronic health records., Design, Setting, Participants, & Measurements: We used the Medical Information Mart for Intensive Care III database, which consists of electronic health record data from intensive care units in a tertiary care hospital in the United States. We included patients ≥18 years with sepsis who developed AKI within 48 hours of intensive care unit admission. We then used deep learning to utilize all available vital signs, laboratory measurements, and comorbidities to identify subphenotypes. Outcomes were mortality 28 days after AKI and dialysis requirement., Results: We identified 4001 patients with sepsis-associated AKI. We utilized 2546 combined features for K -means clustering, identifying three subphenotypes. Subphenotype 1 had 1443 patients, and subphenotype 2 had 1898 patients, whereas subphenotype 3 had 660 patients. Subphenotype 1 had the lowest proportion of liver disease and lowest Simplified Acute Physiology Score II scores compared with subphenotypes 2 and 3. The proportions of patients with CKD were similar between subphenotypes 1 and 3 (15%) but highest in subphenotype 2 (21%). Subphenotype 1 had lower median bilirubin levels, aspartate aminotransferase, and alanine aminotransferase compared with subphenotypes 2 and 3. Patients in subphenotype 1 also had lower median lactate, lactate dehydrogenase, and white blood cell count than patients in subphenotypes 2 and 3. Subphenotype 1 also had lower creatinine and BUN than subphenotypes 2 and 3. Dialysis requirement was lowest in subphenotype 1 (4% versus 7% [subphenotype 2] versus 26% [subphenotype 3]). The mortality 28 days after AKI was lowest in subphenotype 1 (23% versus 35% [subphenotype 2] versus 49% [subphenotype 3]). After adjustment, the adjusted odds ratio for mortality for subphenotype 3, with subphenotype 1 as a reference, was 1.9 (95% confidence interval, 1.5 to 2.4)., Conclusions: Utilizing routinely collected laboratory variables, vital signs, and comorbidities, we were able to identify three distinct subphenotypes of sepsis-associated AKI with differing outcomes., (Copyright © 2020 by the American Society of Nephrology.)

Background: Sepsis-associated acute kidney injury (SA-AKI) has high mortality rates. The osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK)/Toll-like receptor 4 (TLR4) pathway and its potential role in SA-AKI pathogenesis remain to be fully understood. Herein, we addressed this issue using mouse models. Methods: An SA-AKI mouse model was established using the cecal ligation and puncture method (CLP). Mice were grouped into sham, CLP model, CLP + recombinant RANKL, and CLP + anti-RANKL groups. Serum creatinine (Scr) and blood urea nitrogen (BUN) levels were measured to assess kidney function. ELISA was used to detect serum IL-1β, TNF-α, and IL-6 levels. Real-time quantitative PCR and Western blot were used to detect the mRNA and protein expression levels of OPG, RANKL, RANK, and TLR4 in kidney tissues. HE staining was performed to evaluate the pathological changes. Results: The CLP model group showed higher levels of Scr and BUN, indicating impaired kidney function in SA-AKI, compared to the sham group. Treatment with recombinant RANKL in the CLP + recombinant RANKL group reduced Scr and BUN levels, while anti-RANKL treatment in the CLP + anti-RANKL group elevated their levels. Moreover, the CLP model group had significantly increased IL-1β, TNF-α, and IL-6 than the sham group, indicating elevated inflammation in SA-AKI. The CLP + recombinant RANKL group demonstrated decreased cytokine levels, whereas the CLP + anti-RANKL group showed an increase. Additionally, the histopathological evaluation revealed distinct kidney tissue damage in the CLP model group. Recombinant RANKL treatment reduced this damage, while anti-RANKL treatment exacerbated it. Mechanically, the mRNA and protein expression of RANKL were significantly decreased, while those of OPG, RANK, and TLR4 were significantly increased in the CLP model group and the CLP + anti-RANKL group. Interestingly, treatment with recombinant RANKL reversed these changes, as evidenced by significantly increased RANKL but decreased OPG, RANK, and TLR4. Conclusion: The OPG/RANKL/RANK/TLR4 pathway is involved in SA-AKI pathogenesis. Recombinant RANKL treatment attenuates the inflammatory response and kidney tissue damage in SA-AKI, possibly via regulating this pathway. This pathway shows promise as a therapeutic target for SA-AKI. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a heterogenous syndrome with limited therapeutic options. Identifying immunological endotypes through gene expression patterns in septic patients may lead to targeted interventions. We investigated whether patients admitted to a surgical intensive care unit (ICU) with sepsis and with high risk of mortality express similar endotypes to non-septic, but still critically ill patients using two multiplex transcriptomic metrics obtained both on admission to a surgical ICU and at set intervals. Methods: We analyzed transcriptomic data from 522 patients in two single-site, prospective, observational cohorts admitted to surgical ICUs over a 5-year period ending in July 2020. Using an FDA-cleared analytical platform (nCounter FLEX®, NanoString, Inc.), we assessed a previously validated 29-messenger RNA transcriptomic classifier for likelihood of 30-day mortality (IMX-SEV-3) and a 33-messenger RNA transcriptomic endotype classifier. Clinical outcomes included all-cause mortality, development of chronic critical illness, and secondary infections. Univariate and multivariate analyses were performed to assess for true effect and confounding. Results: Sepsis was associated with a significantly higher predicted and actual hospital mortality. At enrollment, the predominant endotype for both septic and non-septic patients was adaptive, though with significantly different distributions. Inflammopathic and coagulopathic septic patients, as well as inflammopathic non-septic patients, showed significantly higher frequencies of secondary infections compared to those with adaptive endotypes (p < 0.01). Endotypes changed during ICU hospitalization in 57.5% of patients. Patients who remained adaptive had overall better prognosis, while those who remained inflammopathic or coagulopathic had worse overall outcomes. For severity metrics, patients admitted with sepsis and a high predicted likelihood of mortality showed an inflammopathic (49.6%) endotype and had higher rates of cumulative adverse outcomes (67.4%). Patients at low mortality risk, whether septic or non-septic, almost uniformly presented with an adaptive endotype (100% and 93.4%, respectively). Conclusion: Critically ill surgical patients express different and evolving immunological endotypes depending upon both their sepsis status and severity of their clinical course. Future studies will elucidate whether endotyping critically ill, septic patients can identify individuals for targeted therapeutic interventions to improve patient management and outcomes. [ABSTRACT FROM AUTHOR]

This study aimed to determine the impact of current hepatitis B virus (HBV) infection on patients hospitalised with sepsis. This was a retrospective cohort study. Patients from three medical centres in Suzhou from 10 January 2016 to 23 July 2022 participated in this study. Demographic characteristics and clinical characteristics were collected. A total of 945 adult patients with sepsis were included. The median age was 66.0 years, 68.6% were male, 13.1% presented with current HBV infection, and 34.9% of all patients died. In the multivariable-adjusted Cox model, patients with current HBV infection had significantly higher mortality than those without (hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.11–2.02). A subgroup analysis showed that being infected with HBV significantly increased in-hospital mortality in patients younger than 65 years old (HR 1.74, 95% CI 1.16–2.63), whereas no significant impact was observed in patients ≥65 years. The propensity score-matched case–control analysis showed that the rate of septic shock (91.4% vs. 62.1%, P  < 0.001) and in-hospital mortality (48.3% vs. 35.3%, P  = 0.045) were much higher in the propensity score-matched HBV infection group compared with the control group. In conclusion, current HBV infection was associated with mortality in adults with sepsis. [ABSTRACT FROM AUTHOR]

The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment failure and the development of antimicrobial resistance. Therefore, we seek to optimize antimicrobial therapy in sepsis by selecting the right drug and the correct dosage. A prerequisite for achieving this goal is characterization and understanding of the mechanisms of pharmacokinetic alterations. However, most infections take place not in blood but in different body compartments. Since tissue pharmacokinetic assessment is not feasible in daily practice, we need to tailor antibiotic treatment according to the specific patient's pathophysiological processes. The complex pathophysiology of sepsis and the ineffectiveness of current targeted therapies suggest that treatments guided by biomarkers predicting target-site concentration could provide a new therapeutic strategy. Inflammation, endothelial and coagulation activation markers, and blood flow parameters might be indicators of impaired tissue distribution. Moreover, hepatic and renal dysfunction biomarkers can predict not only drug metabolism and clearance but also drug distribution. Identification of the right biomarkers can direct drug dosing and provide timely feedback on its effectiveness. Therefore, this might decrease antibiotic resistance and the mortality of critically ill patients. This article fills the literature gap by characterizing patient biomarkers that might be used to predict unbound plasma-to-tissue drug distribution in critically ill patients. Although all biomarkers must be clinically evaluated with the ultimate goal of combining them in a clinically feasible scoring system, we support the concept that the appropriate biomarkers could be used to direct targeted antibiotic dosing. [ABSTRACT FROM AUTHOR]

Clinical and pathophysiological understanding of septic shock has progressed exponentially in the previous decades, translating into a steady decrease in septic shock-related morbidity and mortality. Even though large randomized, controlled trials have addressed fundamental aspects of septic shock resuscitation, many questions still exist. In this review, we will describe the current standards of septic shock resuscitation, but the emphasis will be placed on evolving concepts in different domains such as clinical resuscitation targets, adequate use of fluids and vasoactive drugs, refractory shock, and the use of extracorporeal therapies. Multiple research opportunities remain open, and collaborative endeavors should be performed to fill in these gaps. [ABSTRACT FROM AUTHOR]

Background: Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions. Main text: Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described. Conclusions: Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies. [ABSTRACT FROM AUTHOR]

Background: Heterogeneity in sepsis expression is multidimensional, including highly disparate data such as the underlying disorders, infection source, causative micro-organismsand organ failures. The aim of the study is to identify clusters of patients based on clinical and biological characteristic available at patients' admission. Methods: All patients included in a national prospective multicenter ICU cohort OUTCOMEREA and admitted for sepsis or septic shock (Sepsis 3.0 definition) were retrospectively analyzed. A hierarchical clustering was performed in a training set of patients to build clusters based on a comprehensive set of clinical and biological characteristics available at ICU admission. Clusters were described, and the 28-day, 90-day, and one-year mortality were compared with log-rank rates. Risks of mortality were also compared after adjustment on SOFA score and year of ICU admission. Results: Of the 6,046 patients with sepsis in the cohort, 4,050 (67%) were randomly allocated to the training set. Six distinct clusters were identified: young patients without any comorbidities, admitted in ICU for community-acquired pneumonia (n = 1,603 (40%)); young patients without any comorbidities, admitted in ICU for meningitis or encephalitis (n = 149 (4%)); elderly patients with COPD, admitted in ICU for bronchial infection with few organ failures (n = 243 (6%)); elderly patients, with several comorbidities and organ failures (n = 1,094 (27%)); patients admitted after surgery, with a nosocomial infection (n = 623 (15%)); young patients with immunosuppressive conditions (e.g., AIDS, chronic steroid therapy or hematological malignancy) (n = 338 (8%)). Clusters differed significantly in early or late mortality (p <.001), even after adjustment on severity of organ dysfunctions (SOFA) and year of ICU admission. Conclusions: Clinical and biological features commonly available at ICU admission of patients with sepsis or septic shock enabled to set up six clusters of patients, with very distinct outcomes. Considering these clusters may improve the care management and the homogeneity of patients in future studies. [ABSTRACT FROM AUTHOR]

Sepsis is a highly lethal syndrome resulting from dysregulated immune and metabolic responses to infection, thereby compromising host homeostasis. Activation of the hypothalamic–pituitary–adrenal (HPA) axis and subsequently adrenocortical glucocorticoid (GC) production during sepsis are important regulatory processes to maintain homeostasis. Multiple preclinical studies have proven the pivotal role of endogenous GCs in tolerance against sepsis by counteracting several of the sepsis characteristics, such as excessive inflammation, vascular defects, and hypoglycemia. Sepsis is however often complicated by dysfunction of the HPA axis, resulting from critical-illness-related corticosteroid insufficiency (CIRCI) and GC resistance. Therefore, GCs have been tested as an adjunctive therapy in sepsis and septic shock in different randomized clinical trials (RCTs). Nonetheless, these studies produced conflicting results. Interestingly, adding vitamin C and thiamin to GC therapy enhances the effects of GCs, probably by reducing GC resistance, and this results in an impressive reduction in sepsis mortality as was shown in two recent preliminary retrospective before–after studies. Multiple RCTs are currently underway to validate this new combination therapy in sepsis. [ABSTRACT FROM AUTHOR]

Background: Conducting research in critically-ill patient populations is challenging, and most randomized trials of critically-ill patients have not achieved pre-specified statistical thresholds to conclude that the intervention being investigated was beneficial.Methods: In 2019, a diverse group of patient representatives, regulators from the USA and European Union, federal grant managers, industry representatives, clinical trialists, epidemiologists, and clinicians convened the First Critical Care Clinical Trialists (3CT) Workshop to discuss challenges and opportunities in conducting and assessing critical care trials. Herein, we present the advantages and disadvantages of available methodologies for clinical trial design, conduct, and analysis, and a series of recommendations to potentially improve future trials in critical care.Conclusion: The 3CT Workshop participants identified opportunities to improve critical care trials using strategies to optimize sample size calculations, account for patient and disease heterogeneity, increase the efficiency of trial conduct, maximize the use of trial data, and to refine and standardize the collection of patient-centered and patient-informed outcome measures beyond mortality. [ABSTRACT FROM AUTHOR]

Purpose: To determine if a regimen of restricted fluids and early vasopressor compared to usual care is feasible for initial resuscitation of hypotension due to suspected sepsis.Methods: A prospective, randomised, open-label, clinical trial of a restricted fluid resuscitation regimen in the first 6 h among patients in the emergency department (ED) with suspected sepsis and a systolic blood pressure under 100 mmHg, after minimum 1000 ml of IV fluid. Primary outcome was total fluid administered within 6 h post randomisation.Results: There were 99 participants (50 restricted volume and 49 usual care) in the intention-to-treat analysis. Median volume from presentation to 6 h in the restricted volume group was 2387 ml [first to third quartile (Q1-Q3) 1750-2750 ml]; 30 ml/kg (Q1-Q3 32-39 ml/kg) vs. 3000 ml (Q1-Q3 2250-3900 ml); 43 ml/kg (Q1-Q3 35-50 ml/kg) in the usual care group (p < 0.001). Median duration of vasopressor support was 21 h (Q1-Q3 9-42 h) vs. 33 h (Q1-Q3 15-50 h), (p = 0.13) in the restricted volume and usual care groups, respectively. At 90-days, 4 of 48 (8%) in the restricted volume group and 3 of 47 (6%) in the usual care group had died. Protocol deviations occurred in 6/50 (12%) in restricted group and 11/49 (22%) in the usual care group, and serious adverse events in four cases (8%) in each group.Conclusions: A regimen of restricted fluids and early vasopressor in ED patients with suspected sepsis and hypotension appears feasible. Illness severity was moderate and mortality rates low. A future trial is necessary with recruitment of high-risk patients to determine effects on clinical outcomes in this setting. [ABSTRACT FROM AUTHOR]

Background: Multiple corticosteroids and treatment regimens have been used as adjuncts in the treatment of septic shock. Qualitative and quantitative differences exist at cellular and tissular levels between the different drugs and their patterns of delivery. The objective of this study was to elucidate any differences between the drugs and their treatment regimens regarding outcomes for corticosteroid use in adult patients with septic shock.Methods: Network meta-analysis of the data used for the recently conducted Cochrane review was performed. Studies that included children and were designed to assess respiratory function in pneumonia and acute respiratory distress syndrome, as well as cross-over studies, were excluded. Network plots were created for each outcome, and all analyses were conducted using a frequentist approach assuming a random-effects model.Results: Complete data from 22 studies and partial data from 1 study were included. Network meta-analysis provided no clear evidence that any intervention or treatment regimen is better than any other across the spectrum of outcomes. There was strong evidence of differential efficacy in only one area: shock reversal. Hydrocortisone boluses and infusions were more likely than methylprednisolone boluses and placebo to result in shock reversal.Conclusions: There was no clear evidence that any one corticosteroid drug or treatment regimen is more likely to be effective in reducing mortality or reducing the incidence of gastrointestinal bleeding or superinfection in septic shock. Hydrocortisone delivered as a bolus or as an infusion was more likely than placebo and methylprednisolone to result in shock reversal. [ABSTRACT FROM AUTHOR]

Background: Despite many ongoing, prospective studies on the topic, sepsis still remains one of the main causes of death in hospital. The hormone insulin-like growth factor 1 (IGF-1) has a similar molecular structure to that of insulin. IGF-1 exerts anabolic effects and plays important roles in both normal physiology and pathologic processes. Previous studies have observed low serum IGF-1 level in patients with critical illnesses. Here, we evaluated changes in IGF-1 level based on survival of septic patients. Methods: We evaluated 140 patients with sepsis and septic shock (21 with sepsis and 119 with septic shock) admitted to the intensive care unit of a university-affiliated hospital in Korea. Serum IGF-1 level was measured on days 0, 1, 3, and 7. Patients with liver disease were excluded from this study. All data were analyzed using SPSS version 20 (SPSS Inc., Chicago, IL, USA). Results: Patients with septic shock had significantly lower serum IGF-1 level on days 1 and 3 than patients without septic shock (p = 0.002 and p = 0.007, respectively). Generally, there was a negative relationship between IGF-1 and serum cortisol levels; however, this relationship was only significant on day 3 (p = 0.029). Furthermore, renin showed significantly negative correlation with IGF-1 on day 3 (p = 0.038). IGF-1 level did not show significant difference between survivors and non-survivors. Conclusions: Our results showed that IGF-1 was associated with septic shock, and that the IGF-1 axis is severely disrupted in septic patients. Additionally, serum cortisol and renin levels were associated with IGF-1 level. [ABSTRACT FROM AUTHOR]

High glycemic variability, rather than a mean glucose level, is an important factor associated with sepsis and hospital mortality in critically ill patients. In this retrospective study we analyze the blood glucose data of 172 nondiabetic patients 18-60 yrs old with second and third-degree burns of total body surface area greater than 30% and 5%, respectively, admitted to ICU in 2004-2008. The analysis identified significant association of increasing daily glucose excursion (DELTA) accompanied by evident episodes of hyperglycemia (>11 mmol/l) and hypoglycemia (<2.8 mmol/l), with sepsis and forthcoming death, even when the mean daily glucose was within a range of acceptable glycemia. No association was found in sepsis complication and hospital mortality with doses of intravenous insulin and glucose infusion. A strong increase in DELTA before sepsis and death is treated as fluctuation amplification near the onset of dynamical instability. [ABSTRACT FROM AUTHOR]

Aim: Urinary oxygen tension (uPO2) may provide an estimate of renal medullary PO2 (mPO2) and thus risk of acute kidney injury (AKI). We assessed the potential for variations in urine flow and arterial PO2 (aPO2) to confound these estimates. Methods: In 28 sheep urine flow, uPO2, aPO2 and mPO2 were measured during development of septic AKI. In 65 human patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) uPO2 and aPO2 were measured continuously during CPB, and in a subset of 20 patients, urine flow was estimated every 5 minutes. Results: In conscious sheep breathing room air, uPO2 was more closely correlated with mPO2 than with aPO2 or urine flow. The difference between mPO2 and uPO2 varied little with urine flow or aPO2. In patients, urine flow increased abruptly from 3.42 ± 0.29 mL min−1 to 6.94 ± 0.26 mL min−1 upon commencement of CPB, usually coincident with reduced uPO2. During hyperoxic CPB high values of uPO2 were often observed at low urine flow. Low urinary PO2 during CPB (<10 mm Hg at any time during CPB) was associated with greater (4.5‐fold) risk of AKI. However, low urine flow during CPB was not significantly associated with risk of AKI. Conclusions: uPO2 provides a robust estimate of mPO2, but this relationship is confounded by the simultaneous presence of systemic hyperoxia and low urine flow. Urine flow increases and uPO2 decreases during CPB. Thus, CPB is probably the best time to use uPO2 to detect renal medullary hypoxia and risk of post‐operative AKI. [ABSTRACT FROM AUTHOR]

Background: Vasopressors are commonly applied to restore and maintain blood pressure in patients with sepsis. We aimed to evaluate the current practice and therapeutic goals regarding vasopressor use in septic shock as a basis for future studies and to provide some recommendations on their use.Methods: From November 2016 to April 2017, an anonymous web-based survey on the use of vasoactive drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 17 questions focused on the profile of respondents, triggering factors, first choice agent, dosing, timing, targets, additional treatments, and effects of vasopressors. We investigated whether the answers complied with current guidelines. In addition, a group of 34 international ESICM experts was asked to formulate recommendations for the use of vasopressors based on 6 questions with sub-questions (total 14).Results: A total of 839 physicians from 82 countries (65% main specialty/activity intensive care) responded. The main trigger for vasopressor use was an insufficient mean arterial pressure (MAP) response to initial fluid resuscitation (83%). The first-line vasopressor was norepinephrine (97%), targeting predominantly a MAP > 60-65 mmHg (70%), with higher targets in patients with chronic arterial hypertension (79%). The experts agreed on 10 recommendations, 9 of which were based on unanimous or strong (≥ 80%) agreement. They recommended not to delay vasopressor treatment until fluid resuscitation is completed but rather to start with norepinephrine early to achieve a target MAP of ≥ 65 mmHg.Conclusion: Reported vasopressor use in septic shock is compliant with contemporary guidelines. Future studies should focus on individualized treatment targets including earlier use of vasopressors. [ABSTRACT FROM AUTHOR]