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Objectives: Sepsis is an evolving process and proposed subtypes may change over time. We hypothesized that previously established sepsis subtypes are dynamic, prognostic of outcome, and trajectories are associated with host response alterations., Design: A secondary analysis of two observational critically ill sepsis cohorts: the Molecular diAgnosis and Risk stratification of Sepsis (MARS) and the Medical Information Mart for Intensive Care-IV (MIMIC-IV)., Setting: ICUs in the Netherlands and United States between 2011-2014 and 2008-2019, respectively., Participants: Patient admission fulfilling the Sepsis-3 criteria upon ICU admission adjudicated to one of four previously identified subtypes, comprising 2,416 admissions in MARS and 10,745 in MIMIC-IV., Main Outcomes and Measures: Subtype stability and the changes per subtype on days 2, 4 and 7 of ICU admission were assessed. Next, the associated between change in clinical subtype and outcome and host response alterations., Results: In MARS, upon ICU admission, 6% ( n = 150) of the patient admissions were α-type, 3% ( n = 70) β-type, 55% ( n = 1317) γ-type, and 36% ( n = 879) δ-type; in MIMIC-IV, this was α = 22% ( n = 2398), β = 22% ( n = 2365), γ = 31% ( n = 3296), and δ = 25% (2686). Overall, prevalence of subtypes was stable over days 2, 4, and 7. However, 28-56% (MARS/MIMIC-IV) changed from α on ICU admission to any of the other subtypes on day 2, 33-71% from β, 57-32% from γ, and 50-48% from δ. On day 4, overall subtype persistence was 33-36%. γ or δ admissions remaining in, or transitioning to, subtype γ on days 2, 4, and 7 exhibited lower mortality rates compared with those remaining in, or transitioning to, subtype δ. Longitudinal host response biomarkers reflecting inflammation, coagulation, and endothelial dysfunction were most altered in the δ-δ group, followed by the γ-δ group, independent of the day or biomarker domain., Conclusions and Relevance: In two large cohorts, subtype change to δ was associated with worse clinical outcome and more aberrant biomarkers reflecting inflammation, coagulation, and endothelial dysfunction. These findings underscore the importance of monitoring sepsis subtypes and their linked host responses for improved prognostication and personalized treatment strategies., Competing Interests: The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Intensive care unit (ICU)-survivors have an increased risk of mortality after discharge compared to the general population. On ICU admission subphenotypes based on the plasma biomarker levels of interleukin-8, protein C and bicarbonate have been identified in patients admitted with acute respiratory distress syndrome (ARDS) that are prognostic of outcome and predictive of treatment response. We hypothesized that if these inflammatory subphenotypes previously identified among ARDS patients are assigned at ICU discharge in a more general critically ill population, they are associated with short- and long-term outcome., Methods: A secondary analysis of a prospective observational cohort study conducted in two Dutch ICUs between 2011 and 2014 was performed. All patients discharged alive from the ICU were at ICU discharge adjudicated to the previously identified inflammatory subphenotypes applying a validated parsimonious model using variables measured median 10.6 h [IQR, 8.0-31.4] prior to ICU discharge. Subphenotype distribution at ICU discharge, clinical characteristics and outcomes were analyzed. As a sensitivity analysis, a latent class analysis (LCA) was executed for subphenotype identification based on plasma protein biomarkers at ICU discharge reflective of coagulation activation, endothelial cell activation and inflammation. Concordance between the subphenotyping strategies was studied., Results: Of the 8332 patients included in the original cohort, 1483 ICU-survivors had plasma biomarkers available and could be assigned to the inflammatory subphenotypes. At ICU discharge 6% (n = 86) was assigned to the hyperinflammatory and 94% (n = 1397) to the hypoinflammatory subphenotype. Patients assigned to the hyperinflammatory subphenotype were discharged with signs of more severe organ dysfunction (SOFA scores 7 [IQR 5-9] vs. 4 [IQR 2-6], p < 0.001). Mortality was higher in patients assigned to the hyperinflammatory subphenotype (30-day mortality 21% vs. 11%, p = 0.005; one-year mortality 48% vs. 28%, p < 0.001). LCA deemed 2 subphenotypes most suitable. ICU-survivors from class 1 had significantly higher mortality compared to class 2. Patients belonging to the hyperinflammatory subphenotype were mainly in class 1., Conclusions: Patients assigned to the hyperinflammatory subphenotype at ICU discharge showed significantly stronger anomalies in coagulation activation, endothelial cell activation and inflammation pathways implicated in the pathogenesis of critical disease and increased mortality until one-year follow up., (© 2024. The Author(s).)

Background: The Coronavirus disease 2019 (COVID-19) pandemic has underlined the urgent need for reliable, multicenter, and full-admission intensive care data to advance our understanding of the course of the disease and investigate potential treatment strategies. In this study, we present the Dutch Data Warehouse (DDW), the first multicenter electronic health record (EHR) database with full-admission data from critically ill COVID-19 patients., Methods: A nation-wide data sharing collaboration was launched at the beginning of the pandemic in March 2020. All hospitals in the Netherlands were asked to participate and share pseudonymized EHR data from adult critically ill COVID-19 patients. Data included patient demographics, clinical observations, administered medication, laboratory determinations, and data from vital sign monitors and life support devices. Data sharing agreements were signed with participating hospitals before any data transfers took place. Data were extracted from the local EHRs with prespecified queries and combined into a staging dataset through an extract-transform-load (ETL) pipeline. In the consecutive processing pipeline, data were mapped to a common concept vocabulary and enriched with derived concepts. Data validation was a continuous process throughout the project. All participating hospitals have access to the DDW. Within legal and ethical boundaries, data are available to clinicians and researchers., Results: Out of the 81 intensive care units in the Netherlands, 66 participated in the collaboration, 47 have signed the data sharing agreement, and 35 have shared their data. Data from 25 hospitals have passed through the ETL and processing pipeline. Currently, 3464 patients are included in the DDW, both from wave 1 and wave 2 in the Netherlands. More than 200 million clinical data points are available. Overall ICU mortality was 24.4%. Respiratory and hemodynamic parameters were most frequently measured throughout a patient's stay. For each patient, all administered medication and their daily fluid balance were available. Missing data are reported for each descriptive., Conclusions: In this study, we show that EHR data from critically ill COVID-19 patients may be lawfully collected and can be combined into a data warehouse. These initiatives are indispensable to advance medical data science in the field of intensive care medicine., (© 2021. The Author(s).)

Objectives: Occurrence, risk factors, and impact on daily life of chronic pain after critical illness have not been systematically studied., Design: Cohort study., Setting: A tertiary ICU in The Netherlands., Patients: We surveyed patients who had been discharged from our ICU between 2013 and 2016. Three cohorts were defined as follows: 1) ICU survivors; 2) one-year survivors reporting newly-acquired chronic pain; and (3) one-year survivors with pain who lived within 50 km from the study hospital. In cohort 1, we estimated the prevalence of new chronic pain 1 year after ICU discharge and constructed a prediction model for its occurrence incorporating three outcomes: death during follow-up, surviving without new pain, and surviving with newly-acquired pain. In cohort 2, we determined clinical features of pain and its impact on daily life. In cohort 3, we assessed the presence of neuropathic characteristics of pain., Interventions: None., Measurements and Main Results: The three cohorts contained 1,842, 160, and 42 patients, respectively. Estimated occurrence of new chronic pain was 17.7% (95% CI, 15.8-19.8%; n = 242) in 1-year survivors (n = 1,368). Median pain intensity on the numeric rating scale was 4 (interquartile range, 2-6) in the week before survey response, with impact being most evident on activities of daily living, social activities, and mobility. Neuropathic pain features were present in 50% (95% CI, 37-68%) of affected subjects. Among nine predictor variables included in a multinomial model, only female gender and days in ICU with hyperinflammation were associated with pain., Conclusions: Newly-acquired chronic pain is a frequent consequence of critical illness, and its impact on daily life of affected patients is substantial.

Purpose: Survivors of critical illness often suffer from reduced health-related quality of life (HRQoL) due to long-term physical, cognitive, and mental health problems, also known as post-intensive care syndrome (PICS). Some intensive care unit (ICU) survivors even consider their state of health unacceptable. The aim of this study was to investigate the determinants of self-reported unacceptable outcome of ICU treatment., Methods: Patients who were admitted to the ICU for at least 48 h and survived the first year after discharge completed validated questionnaires on overall HRQoL and the components of PICS and stated whether they considered their current state of health an acceptable outcome of ICU treatment. The effects of overall HRQoL and components of PICS on unacceptable outcome were studied using multiple logistic regression analysis., Results: Of 1453 patients, 67 (5%) reported their health state an unacceptable outcome of ICU treatment. These patients had a lower score on overall HRQoL (EQ-5D-index value of 0.57 vs. 0.81; p < 0.001), but we could not determine a cutoff value of the EQ-5D-index value that reliably identified unacceptable outcome. In the multivariate analysis, only the hospital anxiety and depression scale was significantly associated with an unacceptable outcome (OR 2.06, 99% CI 1.18-3.61)., Conclusions: Although there is a strong association between low overall HRQoL and self-reported unacceptable outcome of ICU treatment, patients with low overall HRQoL may still consider their outcome acceptable. The mental component of PICS, but not the physical and cognitive component, is strongly associated with self-reported unacceptable outcome.

Rationale: Myocardial injury, as reflected by elevated cardiac troponin levels in plasma, is common in patients with community-acquired pneumonia (CAP), but its temporal dynamics and etiology remain unknown. Objectives: Our aim was to determine the incidence of troponin release in patients with CAP and identify risk factors that may point to underlying etiologic mechanisms. Methods: We included consecutive patients admitted with severe CAP to two intensive care units in the Netherlands between 2011 and 2015. High-sensitivity cardiac troponin I was measured daily during the first week. We used multivariable linear regression to identify variables associated with troponin release on admission, and we used mixed-effects regression to model the daily rise and fall of troponin levels over time. Results: Of 200 eligible patients, 179 were included, yielding 792 observation days. A total of 152 (85%) patients developed raised troponin levels greater than 26 ng/L. Baseline factors independently associated with troponin release included coronary artery disease (176% increase; 95% confidence interval [CI], 11-589), smoking (248% increase; 95% CI, 33-809), and higher Acute Physiology and Chronic Health Evaluation IV score (2% increase; 95% CI, 0.8-3.3), whereas Staphylococcus aureus as a causative pathogen was protective (70% reduction; 95% CI, 18-89). Time-dependent risk factors independently associated with daily increase in troponin concentrations included reduced platelet count (2.3% increase; 95% CI, 0.6-4), tachycardia (1.5% increase; 95% CI, 0.1-2.9), hypotension (6.2% increase; 95% CI, 2.1-10.6), dobutamine use (44% increase; 95% CI, 12-85), prothrombin time (8.2% increase; 95% CI, 0.2-16.9), white cell count (1.7% increase; 95% CI, 0-3.5), and fever (22.7% increase; 95% CI, 0.1-49.6). Conclusions: Cardiac injury develops in a majority of patients with severe CAP. Myocardial oxygen supply-demand mismatch and activated inflammation/coagulation are associated with this injury. Clinical trial registered with www.clinicaltrials.gov (NCT01905033).

Objectives: Discrimination between infectious and noninfectious causes of acute respiratory failure is difficult in patients admitted to the ICU after a period of hospitalization. Using a novel biomarker test (SeptiCyte LAB), we aimed to distinguish between infection and inflammation in this population., Design: Nested cohort study., Setting: Two tertiary mixed ICUs in the Netherlands., Patients: Hospitalized patients with acute respiratory failure requiring mechanical ventilation upon ICU admission from 2011 to 2013. Patients having an established infection diagnosis or an evidently noninfectious reason for intubation were excluded., Interventions: None., Measurement and Main Results: Blood samples were collected upon ICU admission. Test results were categorized into four probability bands (higher bands indicating higher infection probability) and compared with the infection plausibility as rated by post hoc assessment using strict definitions. Of 467 included patients, 373 (80%) were treated for a suspected infection at admission. Infection plausibility was classified as ruled out, undetermined, or confirmed in 135 (29%), 135 (29%), and 197 (42%) patients, respectively. Test results correlated with infection plausibility (Spearman's rho 0.332; p < 0.001). After exclusion of undetermined cases, positive predictive values were 29%, 54%, and 76% for probability bands 2, 3, and 4, respectively, whereas the negative predictive value for band 1 was 76%. Diagnostic discrimination of SeptiCyte LAB and C-reactive protein was similar (p = 0.919)., Conclusions: Among hospitalized patients admitted to the ICU with clinical uncertainty regarding the etiology of acute respiratory failure, the diagnostic value of SeptiCyte LAB was limited.

Objectives: The presence of respiratory viruses and the association with outcomes were assessed in invasively ventilated ICU patients, stratified by admission diagnosis., Design: Prospective observational study., Setting: Five ICUs in the Netherlands., Patients: Between September 1, 2013, and April 30, 2014, 1,407 acutely admitted and invasively ventilated patients were included., Interventions: None., Measurements and Main Results: Nasopharyngeal swabs and tracheobronchial aspirates were collected upon intubation and tested for 14 respiratory viruses. Out of 1,407 patients, 156 were admitted because of a severe acute respiratory infection and 1,251 for other reasons (non-severe acute respiratory infection). Respiratory viruses were detected in 28.8% of severe acute respiratory infection patients and 17.0% in non-severe acute respiratory infection (p < 0.001). In one third, viruses were exclusively detected in tracheobronchial aspirates. Rhinovirus and human metapneumovirus were more prevalent in severe acute respiratory infection patients (9.6% and 2.6% vs 4.5 and 0.2%; p = 0.006 and p < 0.001). In both groups, there were no associations between the presence of viruses and the number of ICU-free days at day 28, crude mortality, and mortality in multivariate regression analyses., Conclusions: Respiratory viruses are frequently detected in acutely admitted and invasively ventilated patients. Rhinovirus and human metapneumovirus are more frequently found in severe acute respiratory infection patients. Detection of respiratory viruses is not associated with worse clinically relevant outcomes in the studied cohort of patients.

Objectives: To develop and validate an abbreviated version of the Cognitive Failure Questionnaire that can be used by patients as part of self-assessment to measure functional cognitive outcome in ICU survivors., Design: A retrospective multicenter observational study., Setting: The ICUs of two Dutch university hospitals., Patients: Adult ICU survivors., Interventions: None., Measurements and Main Results: Cognitive functioning was evaluated between 12 and 24 months after ICU discharge using the full 25-item Cognitive Failure Questionnaire (CFQ-25). Incomplete CFQ-25 questionnaires were excluded from analysis. Forward selection in a linear regression model was used in hospital A to assess which of the CFQ-25 items should be included to prevent a significant loss of correlation between an abbreviated and the full CFQ-25. Subsequently, the performance of an abbreviated Cognitive Failure Questionnaire was determined in hospital B using Pearson's correlation. A Bland-Altman plot was used to examine whether the reduced-item outcome scores of an abbreviated Cognitive Failure Questionnaire were a replacement for the full CFQ-25 outcome scores. Among 1,934 ICU survivors, 1,737 were included, 819 in hospital A, 918 in hospital B. The Pearson's correlation between the abbreviated 14-item Cognitive Failure Questionnaire (CFQ-14) and the CFQ-25 was 0.99. The mean of the difference scores was -0.26, and 95% of the difference scores fell within +5 and -5.5 on a 100-point maximum score., Conclusions: It is feasible to use the abbreviated CFQ-14 to measure self-reported cognitive failure in ICU survivors as this questionnaire has a similar performance as the full CFQ-25.

Rationale: Sepsis can be complicated by secondary infections. We explored the possibility that patients with sepsis developing a secondary infection while in the intensive care unit (ICU) display sustained inflammatory, vascular, and procoagulant responses., Objectives: To compare systemic proinflammatory host responses in patients with sepsis who acquire a new infection with those who do not., Methods: Consecutive patients with sepsis with a length of ICU stay greater than 48 hours were prospectively analyzed for the development of ICU-acquired infections. Twenty host response biomarkers reflective of key pathways implicated in sepsis pathogenesis were measured during the first 4 days after ICU admission and at the day of an ICU-acquired infection or noninfectious complication., Measurements and Main Results: Of 1,237 admissions for sepsis (1,089 patients), 178 (14.4%) admissions were complicated by ICU-acquired infections (at Day 10 [6-13], median with interquartile range). Patients who developed a secondary infection showed higher disease severity scores and higher mortality up to 1 year than those who did not. Analyses of biomarkers in patients who later went on to develop secondary infections revealed a more dysregulated host response during the first 4 days after admission, as reflected by enhanced inflammation, stronger endothelial cell activation, a more disturbed vascular integrity, and evidence for enhanced coagulation activation. Host response reactions were similar at the time of ICU-acquired infectious or noninfectious complications., Conclusions: Patients with sepsis who developed an ICU-acquired infection showed a more dysregulated proinflammatory and vascular host response during the first 4 days of ICU admission than those who did not develop a secondary infection.

Importance: Cellulitis is a commonly occurring skin and soft tissue infection and one of the most frequently seen dermatological diseases in the intensive care unit (ICU). However, clinical characteristics of patients with cellulitis requiring intensive care treatment are poorly defined. Necrotizing fasciitis is often confused for cellulitis at initial presentation and is considered to be more severe and thus has previously been described in more detail., Objective: To describe the clinical presentation and outcomes of patients with ICU-necessitating cellulitis and to compare them with patients with necrotizing fasciitis., Design, Setting, and Participants: This prospective cohort study includes all ICU admissions from 2 tertiary hospitals in the Netherlands. Of 2562 sepsis admissions, 101 had possible, probable, or definite cellulitis or soft tissue infections. Retrospective review identified severe cellulitis was the reason for ICU admission in 23 patients, necrotizing fasciitis in 31 patients, and other diagnoses in 47 patients., Main Outcomes and Measures: Patient and disease characteristics, cultured pathogens, lengths of stay, and short-term and long-term mortality., Results: Overall, 54 patients with cellulitis (n = 23; mean [SD] age, 57.2 [17.7] years) or necrotizing fasciitis (n = 31; mean [SD] age, 54.3 [13.5]) were included in this study. Patients with cellulitis were found to be less severely ill than patients with necrotizing fasciitis. This is reflected in rates of shock (7 [30.4%] vs 19 [61.3%]; P = .03), need for mechanical ventilation (12 [52.2%] vs 19 [93.5%]; P = .003) and slightly lower mean Sequential Organ Failure Assessment scores (8 vs 10; P = .046). Median (interquartile range [IQR]) Acute Physiology and Chronic Health Evaluation IV scores did not differ significantly (82 [75-98] vs 76 [70-96]; P = .16). Patients with cellulitis had more chronic comorbidities than patients with necrotizing fasciitis (20 [87.0%] vs 17 [54.8%]; P = .02), especially cardiovascular insufficiencies (10 [43.5%] vs 4 [12.9%]; P = .02) and immunodeficiencies (9 [39.1%] vs 3 [9.7%]; P = .02). Among patients with cellulitis and patients with patients with necrotizing fasciitis, Staphylococcus aureus (10 [43.5%] vs 4 [12.9%]; P = .02), Streptococcus pyogenes (2 [8.7%] vs 19 [61.3%]; P < .001) and Escherichia coli (4 [17.4%] vs 5 [16.2%]; P = .90) were the most frequently observed pathogens. Median (IQR) length of ICU stay was shorter for patients with cellulitis vs patients with necrotizing fasciitis (3 [2-5] vs 5 [3-11]; P = .01), while median (IQR) hospital length of stay did not differ significantly (22 [10.25-32] vs 36 [14.25-40]; P = .16); and the in-hospital mortality rate (26.1% vs 22.6%, P > .99) and 90-day mortality rate (30.4% vs 22.6%; P = .54) were similar., Conclusions and Relevance: Patients with cellulitis patients are seldom admitted to the ICU. However, while these patients are less critically ill on admission than patients with necrotizing fasciitis, they have more chronic comorbidities and most notably similar short-term and long-term mortality., Trial Registration: clinicaltrials.gov Identifier: NCT01905033.

Objective: The prevailing theory of host response during sepsis states that an excessive production of pro-inflammatory mediators causes early deaths, whereas a predominantly anti-inflammatory response may lead to immunosuppression, secondary infection, and late deaths. We assessed inflammatory (im)balance by measuring pro-inflammatory interleukin-6 and anti-inflammatory interleukin-10 during three distinct time periods after sepsis, and assessed its association with mortality., Design: Prospective observational cohort., Setting: Two tertiary mixed ICUs in The Netherlands., Patients: Consecutive patients presenting with severe sepsis or septic shock from 2011 to 2013., Interventions: None., Measurements and Main Results: We repeatedly measured plasma interleukin-6 and interleukin-10 concentrations using cytometric bead array. Poisson regression was used to analyze the relation between inflammatory markers measured on 1) ICU admission and day 4 mortality, 2) day 4 and day 28 mortality, and 3) ICU discharge and 1-year mortality. Secondary outcome was development of ICU-acquired infections. Among 708 patients, 86 (12%) died within 4 days, 140 (20%) died between days 4 and 28, and an additional 155 (22%) died before 1 year. Interleukin-6 and interleukin-10 levels were both independently associated with mortality, but the balance of this response as modelled by an interleukin-6 and interleukin-10 interaction term was not (relative risk, 0.99; 95% CI, 0.95-1.04 on admission; relative risk, 1.02; 95% CI, 0.98-1.06 on day 4; and relative risk, 1.12; 95% CI, 0.98-1.29 at ICU discharge). However, inflammatory imbalance on day 4 was associated with development of ICU-acquired infections (subdistribution hazard ratio, 0.87; 95% CI, 0.77-0.98)., Conclusions: Although both interleukin-6 and interleukin-10 productions are associated with death, the balance of these inflammatory mediators does not seem to impact either early, intermediate, or late mortality in patients presenting to the ICU with sepsis.

Objectives: To describe the association between intensive care unit (ICU) delirium and self-reported cognitive problems in 1-year ICU survivors, and investigate whether this association was altered by exposure to systemic inflammation during ICU stay., Design: Prospective cohort study., Setting: Dutch medical-surgical ICU., Participants: One-year ICU survivors, admitted to the ICU ≥48 hours., Measurements: Self-reported cognitive problems were measured with the Cognitive Failures Questionnaire (CFQ). Cumulative exposure to systemic inflammation was based on all daily C-reactive protein (CRP) measurements during ICU stay, expressed as the area under the curve (AUC). Multivariable linear regression was conducted to evaluate the association between delirium and the CFQ. The effect of inflammation on the association between delirium and CFQ was assessed, comparing the effect estimate (B) of delirium and CFQ between models with and without inclusion of the AUC of CRP., Results: Among 567 1-year ICU survivors, the CFQ was completed by 363 subjects. Subjects with multiple days of delirium during ICU stay reported more self-reported cognitive problems (Badj = 5.10, 95% CI 1.01-9.20), whereas a single day delirium was not associated with higher CFQ scores (Badj = -0.72, 95% CI -5.75 to 4.31). Including the AUC of CRP did not change the association between delirium and the CFQ (ratio for a single and multiple days were respectively: 1.00, 95%CI 0.59-1.44 and 0.86, 95% CI 0.47-1.16)., Conclusion: Multiple days of delirium was associated with long-term self-reported cognitive problems. The cumulative exposure to systemic inflammation did not alter this association, suggesting that delirium in the context of little inflammation is also detrimental., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background: Sepsis is a prominent reason for intensive care unit (ICU) admission in patients with HIV. We aimed to investigate the impact of HIV infection on presentation, outcome and host response in sepsis., Methods: We performed a prospective observational study in the ICUs of two tertiary hospitals. For the current analyses, we selected all patients diagnosed with sepsis within 24 hours after admission. Host response biomarkers were analyzed in a more homogeneous subgroup of admissions involving HIV-positive patients with pneumosepsis, matched to admissions of HIV-negative patients for age, gender and race. Matching was done by nearest neighbor matching with R package "MatchIt"., Results: We analyzed 2251 sepsis admissions including 41 (1.8 %) with HIV infection (32 unique patients). HIV-positive patients were younger and admission of HIV-positive patients more frequently involved pneumonia (73.2 % versus 48.8 % of admissions of HIV-negative patients, P = 0.004). Disease severity and mortality up to one year after admission did not differ according to HIV status. Furthermore, sequential plasma levels of host response biomarkers, providing insight into activation of the cytokine network, the vascular endothelium and the coagulation system, were largely similar in matched admissions of HIV-positive and HIV-negative patients with pneumosepsis., Conclusions: Sepsis is more often caused by pneumonia in HIV-positive patients. HIV infection has little impact on the disease severity, mortality and host response during sepsis.

Objectives: To determine whether delirium during ICU stay is associated with long-term mental health problems defined as symptoms of anxiety, depression, and posttraumatic stress disorder., Design: Prospective cohort study., Setting: Survey study, 1 year after discharge from a medical-surgical ICU in the Netherlands., Patients: One-year ICU survivors of an ICU admission lasting more than 48 hours, without a neurologic disorder or other condition that would impede delirium assessment during ICU stay., Interventions: None., Measurements and Main Results: One year after discharge, ICU survivors received a survey containing the Hospital Anxiety and Depression Scale with a subscale for symptoms of depression and a subscale for symptoms of anxiety, and the Impact of Event Scale 15 item measuring symptoms of posttraumatic stress disorder. Participants were classified as having experienced no delirium (n = 270; 48%), a single day of delirium (n = 86; 15%), or multiple days of delirium (n = 211; 37%) during ICU stay. Log-binomial regression was used to assess the association between delirium and symptoms of anxiety, depression, and posttraumatic stress disorder. The study population consisted of 567 subjects; of whom 246 subjects (43%) reported symptoms of anxiety (Hospital Anxiety and Depression Scale with a subscale for anxiety, ≥ 8), and 254 (45%) symptoms of depression (Hospital Anxiety and Depression Scale with a subscale for depression, ≥ 8). In 220 patients (39%), the Impact of Event Scale 15 item was greater than or equal to 35, indicating a high probability of posttraumatic stress disorder. There was substantial overlap between these mental health problems-63% of the subjects who scored positive for the presence of any three of the mental health problems, scored positive for all three. No association was observed between either a single day or multiple days of delirium and symptoms of anxiety, depression, or posttraumatic stress disorder., Conclusions: Although symptoms of anxiety, depression, and posttraumatic stress disorder were found to be common 1 year after critical illness, the occurrence of delirium during ICU stay did not increase the risk of these long-term mental health problems.

Introduction: A clinical suspicion of infection is mandatory for diagnosing sepsis in patients with a systemic inflammatory response syndrome. Yet, the accuracy of categorizing critically ill patients presenting to the intensive care unit (ICU) as being infected or not is unknown. We therefore assessed the likelihood of infection in patients who were treated for sepsis upon admission to the ICU, and quantified the association between plausibility of infection and mortality., Methods: We studied a cohort of critically ill patients admitted with clinically suspected sepsis to two tertiary ICUs in the Netherlands between January 2011 and December 2013. The likelihood of infection was categorized as none, possible, probable or definite by post-hoc assessment. We used multivariable competing risks survival analyses to determine the association of the plausibility of infection with mortality., Results: Among 2579 patients treated for sepsis, 13% had a post-hoc infection likelihood of "none", and an additional 30% of only "possible". These percentages were largely similar for different suspected sites of infection. In crude analyses, the likelihood of infection was associated with increased length of stay and complications. In multivariable analysis, patients with an unlikely infection had a higher mortality rate compared to patients with a definite infection (subdistribution hazard ratio 1.23; 95% confidence interval 1.03-1.49)., Conclusions: This study is the first prospective analysis to show that the clinical diagnosis of sepsis upon ICU admission corresponds poorly with the presence of infection on post-hoc assessment. A higher likelihood of infection does not adversely influence outcome in this population., Trial Registration: ClinicalTrials.gov NCT01905033. Registered 11 July 2013.

Objective: Although cholinergic deficiency is presumed to increase delirium risk and use of medication with anticholinergic properties in the ICU is frequent, the relationship between anticholinergic medication use and delirium in this setting remains unclear. We investigated whether exposure to medication with anticholinergic properties increases the probability of transitioning to delirium in critically ill adults and whether this relationship is affected by age or the presence of acute systemic inflammation., Design: Prospective cohort study., Setting: A 32-bed medical-surgical ICU at an academic medical center., Patients: Critically ill adults admitted to the ICU for more than 24 hours without an acute neurological disorder or another condition that would hamper delirium assessment., Interventions: None., Measurements and Main Results: Daily anticholinergic burden was calculated for each patient based on the sum of the Anticholinergic Drug Scale score for each medication administered. Daily mental status was classified as "coma," "delirium," or an "awake without delirium" state. The primary outcome, the daily transition from an "awake without delirium" state to "delirium," was analyzed using a first-order Markov model that adjusted for eight covariables. A total of 1,112 patients were evaluated over 9,867 ICU days. The daily median summed Anticholinergic Drug Scale score was 2 (interquartile range, 1-3). The transition from being in an "awake without delirium" state to "delirium" occurred on 562 of ICU days (6%). After correcting for confounding, a one-unit increase in the Anticholinergic Drug Scale score resulted in a nonsignificant increase in the probability of delirium occurring the next day (odds ratio, 1.05; 95% CI, 0.99-1.10). Neither age nor the presence of acute systemic inflammation modified this relationship., Conclusions: Exposure to medication with anticholinergic properties, as defined by the Anticholinergic Drug Scale, does not increase the probability of delirium onset in patients who are awake and not delirious in the ICU.

Purpose: The goal of this study was to describe long-term survival and health-related quality of life (HRQoL), measured by EQ-6D, in a general intensive care unit (ICU) population., Materials and Methods: We included 5934 consecutive adult patients admitted to a mixed-population ICU. There were no exclusion criteria. One-year survival status was determined using the Dutch municipal population register. Subsequently, all survivors received the EuroQoL EQ-6D-3L questionnaire. The primary outcome was overall HRQoL and survival of the ICU survivors, compared to overall QoL of an age- and sex-matched reference population., Results: A total of 5138 patients (86.6%) survived until hospital discharge, with 4647 (78.3%) patients surviving the 1-year of follow-up. The EuroQoL questionnaire was sent to 4465 survivors and returned by 3034 (68.0%) of 4465. The median HRQoL in surviving patients was 0.83 (interquartile range [IQR], 0.64-1.00) vs 0.86 (IQR, 0.85-0.86) in the reference population (P < .001). There was marked variation across admission diagnosis groups: cardiac surgery patients had an HRQoL of 0.94 (IQR, 0.74-1.00), whereas patients admitted with chronic renal failure had an HRQoL of 0.65 (IQR, 0.47-0.83)., Conclusions: One year after ICU admission, HRQoL was significantly lower than in the reference population. Notably, marked variations were found across subgroups., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Cytomegalovirus reactivation may complicate critical illness in latent carriers of the virus, even in patients who were previously immunocompetent. Patients with acute respiratory distress syndrome are considered to be prone for reactivation. Prophylactic antiviral therapy in immunocompetent cytomegalovirus seropositive patients admitted to the ICU with acute respiratory distress syndrome has therefore been proposed. We assessed cytomegalovirus seroprevalence as a risk factor for morbidity and mortality in patients with acute respiratory distress syndrome., Design: Prospective observational cohort study. We used the number of days alive and free of mechanical ventilation on day 28 as a composite outcome measure and used multivariable ordinal logistic regression analyses to adjust for potential confounders., Setting: ICUs of two tertiary care hospitals in The Netherlands., Patients: We included all newly admitted patients with acute respiratory distress syndrome who received mechanical ventilation for at least 4 days. Patients with known immunocompromise and those receiving antiviral treatment prior to ICU admission were excluded., Interventions: None., Measurements and Main Results: Over a 2-year period, 306 patients were included, 209 (68%) of whom were cytomegalovirus seropositive. Cytomegalovirus reactivation occurred in 53 of these cases (26%). One hundred patients (33%) died or continued to be mechanically ventilated by day 28. After adjustment for confounding, cytomegalovirus seroprevalence was not associated with the primary outcome (crude odds ratio, 1.09; 95% CI, 0.70-1.70; adjusted odds ratio, 1.01; 95% CI, 0.64-1.59). Seroprevalence was also not associated with poor outcome in any of the prespecified subgroup analyses. However, a significant association was found in a post hoc subgroup of patients who had developed acute respiratory distress syndrome in a setting of septic shock (adjusted odds ratio, 2.86; 95% CI, 1.32-6.23). The time course of pulmonary markers in survivors was comparable between the two serogroups., Conclusions: Cytomegalovirus seroprevalence is not associated with prolonged mechanical ventilation or increased mortality in critically ill patients with acute respiratory distress syndrome, with possible exception of patients presenting with septic shock. Therefore, a prevention strategy targeting an unselected cohort of seropositive patients with acute respiratory distress syndrome is unlikely to show any meaningful benefit.

Objective: To determine the attributable mortality caused by delirium in critically ill patients., Design: Prospective cohort study., Setting: 32 mixed bed intensive care unit in the Netherlands, January 2011 to July 2013., Participants: 1112 consecutive adults admitted to an intensive care unit for a minimum of 24 hours., Exposures: Trained observers evaluated delirium daily using a validated protocol. Logistic regression and competing risks survival analyses were used to adjust for baseline variables and a marginal structural model analysis to adjust for confounding by evolution of disease severity before the onset of delirium., Main Outcome Measure: Mortality during admission to an intensive care unit., Results: Among 1112 evaluated patients, 558 (50.2%) developed at least one episode of delirium, with a median duration of 3 days (interquartile range 2-7 days). Crude mortality was 94/558 (17%) in patients with delirium compared with 40/554 (7%) in patients without delirium (P<0.001). Delirium was significantly associated with mortality in the multivariable logistic regression analysis (odds ratio 1.77, 95% confidence interval 1.15 to 2.72) and survival analysis (subdistribution hazard ratio 2.08, 95% confidence interval 1.40 to 3.09). However, the association disappeared after adjustment for time varying confounders in the marginal structural model (subdistribution hazard ratio 1.19, 95% confidence interval 0.75 to 1.89). Using this approach, only 7.2% (95% confidence interval -7.5% to 19.5%) of deaths in the intensive care unit were attributable to delirium, with an absolute mortality excess in patients with delirium of 0.9% (95% confidence interval -0.9% to 2.3%) by day 30. In post hoc analyses, however, delirium that persisted for two days or more remained associated with a 2.0% (95% confidence interval 1.2% to 2.8%) absolute mortality increase. Furthermore, competing risk analysis showed that delirium of any duration was associated with a significantly reduced rate of discharge from the intensive care unit (cause specific hazard ratio 0.65, 95% confidence interval 0.55 to 0.76)., Conclusions: Overall, delirium prolongs admission in the intensive care unit but does not cause death in critically ill patients. Future studies should focus on episodes of persistent delirium and its long term sequelae rather than on acute mortality.Trial registration Clinicaltrials.gov NCT01905033., (© Klein Klouwenberg et al 2014.)

Objective: To describe the frequency and type of potential drug-drug interactions (pDDIs) in a general intensive care unit (ICU) and to make recommendations to improve the management of these pDDIs., Design: Retrospective observational study., Setting: General ICU of a tertiary care hospital., Subjects: All patients admitted for more than 24 hours between May 2009 and December 2010 who were prescribed at least one medication., Measurement and Main Results: Based on the G-Standaard, the Dutch national drug database, pDDIs were identified and classified into categories of potential clinical outcome and management advice. In total, 35,784 medication episodes were identified, resulting in 2887 pDDIs (8.1%). These 2887 pDDIs occurred in 1659 patients for a mean frequency of 1.7 (95% confidence interval [CI] 1.6-1.9) pDDIs per patient. Overall, 54% of the patients experienced at least one pDDI with pDDIs present during 27% of all ICU admission days. All pDDIs could be reconstructed using 81 of the 358 (23%) relevant unique pDDI pairs described in the G-Standaard. The most frequently occurring potential clinical consequence was an increased risk of side effects or toxicity (91% of the pDDIs) such as electrolyte disturbances and masking of hypoglycemia. The most important advised management strategy was monitoring (81%), consisting of monitoring of laboratory values (52%), clinical monitoring of toxicity or effectiveness (48%), or monitoring of physical parameters such as electrocardiogram and blood pressure (11%)., Conclusion: Potential drug-drug interactions occur in 54% of all ICU patients, which is two times more than the rate seen in patients on general wards. A limited set of 20 pDDI pairs is responsible for more than 90% of all pDDIs. Therefore, it is worthwhile to develop guidelines for the management of these specific pDDIs. As the vast majority of the interactions can be managed by monitoring, advanced clinical decision support systems linking laboratory data to prescription data may be an effective risk management strategy., (© 2014 American College of Clinical Pharmacy.)

Objectives: Correct classification of the source of infection is important in observational and interventional studies of sepsis. Centers for Disease Control and Prevention criteria are most commonly used for this purpose, but the robustness of these definitions in critically ill patients is not known. We hypothesized that in a mixed ICU population, the performance of these criteria would be generally reduced and would vary among diagnostic subgroups., Design: Prospective cohort., Setting: Data were collected as part of a cohort of 1,214 critically ill patients admitted to two hospitals in The Netherlands between January 2011 and June 2011., Patients: Eight observers assessed a random sample of 168 of 554 patients who had experienced at least one infectious episode in the ICU. Each patient was assessed by two randomly selected observers who independently scored the source of infection (by affected organ system or site), the plausibility of infection (rated as none, possible, probable, or definite), and the most likely causative pathogen. Assessments were based on a post hoc review of all available clinical, radiological, and microbiological evidence. The observed diagnostic agreement for source of infection was classified as partial (i.e., matching on organ system or site) or complete (i.e., matching on specific diagnostic terms), for plausibility as partial (2-point scale) or complete (4-point scale), and for causative pathogens as an approximate or exact pathogen match. Interobserver agreement was expressed as a concordant percentage and as a kappa statistic., Interventions: None., Measurements and Main Results: A total of 206 infectious episodes were observed. Agreement regarding the source of infection was 89% (183/206) and 69% (142/206) for a partial and complete diagnostic match, respectively. This resulted in a kappa of 0.85 (95% CI, 0.79-0.90). Agreement varied from 63% to 91% within major diagnostic categories and from 35% to 97% within specific diagnostic subgroups, with the lowest concordance observed in cases of ventilator-associated pneumonia. In the 142 episodes for which a complete match on source of infection was obtained, the interobserver agreement for plausibility of infection was 83% and 65% on a 2- and 4-point scale, respectively. For causative pathogen, agreement was 78% and 70% for an approximate and exact pathogen match, respectively., Conclusions: Interobserver agreement for classifying sources of infection using Centers for Disease Control and Prevention criteria was excellent overall. However, full concordance on all aspects of the diagnosis between independent observers was rare for some types of infection, in particular for ventilator-associated pneumonia.

Background: Pancreatic stone protein (PSP) exhibits potential as a plasma biomarker for infection diagnosis and risk stratification in critically ill patients, but its significance in nosocomial infection and intensive care unit (ICU)-acquired bloodstream infection (BSI) remains unclear. This study explores the temporal responses of PSP in ICU-acquired BSI caused by different pathogens. Methods: From a large cohort of ICU patients, we selected episodes of ICU-acquired BSI caused by Gram-negative rods (GNRs), enterococci, or Candida species. Events were matched on length of ICU stay at infection onset, Severe Organ Failure Assessment (SOFA) score, presence of immune deficiency, and use of renal replacement therapy. PSP concentrations were measured at infection onset (T0) and at 24, 48 and 72 h prior to infection onset as defined by the first occurrence of a positive blood culture. Absolute and trend differences in PSP levels between pathogen groups were analysed using one-way analysis of variance. Sensitivity analyses were performed in events with a new or worsening systematic inflammatory response based on C-reactive protein, white cell count and fever. Results: We analysed 30 BSI cases per pathogen group. Median (IQR) BSI onset was on day 9 (6–12). Overall, PSP levels were high (381 (237–539) ng/ml), with 18% of values exceeding the assay's measurement range. Across all 90 BSI cases, there was no clear trend over time (median change 34 (− 75–189) ng/ml from T-72 to T0). PSP concentrations at infection onset were 406 (229–497), 350 (223–608), and 480 (327–965) ng/ml, for GNR, enterococci, and Candida species, respectively (p = 0.32). At every time point, absolute PSP levels and trends did not differ significantly between pathogens. PSP values at T0 correlated with SOFA scores. Eighteen (20%) of 90 BSI events did not exhibit a systemic inflammatory response, primarily in Candida species. No clear change in PSP concentration before BSI onset or between-group differences were found in sensitivity analyses of 72 cases. Conclusions: Against a background of overall (very) high plasma PSP levels in critically ill patients, we did not find clear temporal patterns or any pathogen-specific differences in PSP response in the days preceding onset of ICU-acquired BSI. [ABSTRACT FROM AUTHOR]

Background: Impaired intestinal barrier function can enable passage of enteric microorganisms into the bloodstream and lead to nosocomial bloodstream infections during critical illness. We aimed to determine the relative importance of gut translocation as a source for ICU-acquired enterococcal bacteremia of unknown origin. Methods: We conducted a nested case–control study in two mixed medical-surgical tertiary ICUs in the Netherlands among patients enrolled between 2011 and 2018. We selected 72 cases with ICU-acquired bacteremia due to enterococci (which are known gastrointestinal tract commensals) and 137 matched controls with bacteremia due to coagulase-negative staphylococci (CoNS) (which are of non-intestinal origin). We measured intestinal fatty acid-binding protein, trefoil factor-3, and citrulline 48 h before bacteremia onset. A composite measure for Gut Barrier Injury (GBI) was calculated as the sum of standardized z-scores for each biomarker plus a clinical gastrointestinal failure score. Results: No single biomarker yielded statistically significant differences between cases and controls. Median composite GBI was higher in cases than in controls (0.58, IQR − 0.36–1.69 vs. 0.32, IQR − 0.53–1.57, p = 0.33) and higher composite measures of GBI correlated with higher disease severity and ICU mortality (p < 0.001). In multivariable analysis, higher composite GBI was not significantly associated with increased occurrence of enterococcal bacteremia relative to CoNS bacteremia (adjusted OR 1.12 95% CI 0.93–1.34, p = 0.22). Conclusions: We could not demonstrate an association between biomarkers of gastrointestinal barrier dysfunction and an increased occurrence of bacteremia due to gut compared to skin flora during critical illness, suggesting against bacterial translocation as a major vector for acquisition of nosocomial bloodstream infections in the ICU. [ABSTRACT FROM AUTHOR]

Background: Transfusion-related acute lung injury (TRALI) is a severe complication of plasma transfusion, though the use of solvent/detergent pooled plasma (SDP) has nearly eliminated reported TRALI cases. The goal of this study was to investigate the incidence of TRALI in intensive care units (ICU) following the replacement of quarantined fresh frozen plasma (qFFP) by SDP.Study Design and Methods: A retrospective multicenter observational before-after cohort study was performed during two 6-month periods, before (April-October 2014) and after the introduction of SDP (April-October 2015), accounting for a washout period. A full chart review was performed for patients who received ≥1 plasma units and developed hypoxemia within 24 h.Results: During the study period, 8944 patients were admitted to the ICU. Exactly 1171 quarantine fresh frozen plasma (qFFP) units were transfused in 376 patients, and respectively, 2008 SDP units to 396 patients after implementation. Ten TRALI cases occurred during the qFFP and nine cases occurred during the SDP period, in which plasma was transfused. The incidence was 0.85% (CI95%: 0.33%-1.4%) per unit qFFP and 0.45% (CI95%: 0.21%-0.79%, p = 0.221) per SDP unit. One instance of TRALI occurred after a single SDP unit. Mortality was 70% for patients developing TRALI in the ICU compared with 22% in patients receiving at least one plasma transfusion.Conclusion: Implementation of SDP lowered the incidence of TRALI in which plasma products were implicated, though not significantly. Clinically diagnosed TRALI can still occur following SDP transfusion. Developing TRALI in the ICU was associated with high mortality rates, therefore, clinicians should remain vigilant. [ABSTRACT FROM AUTHOR]

Rationale: Myocardial injury occurs frequently during sepsis and is independently associated with mortality. However, its etiology remains largely unknown. Objectives: To assess the relative contributions of hyperinflammation, activated coagulation, and endothelial dysfunction to myocardial injury in critically ill patients with sepsis. Methods: We included consecutive patients with sepsis presenting to two tertiary intensive care units in the Netherlands between 2011 and 2013. High-sensitivity cardiac troponin I as well as a wide range of plasma biomarkers related to inflammation, coagulation, and endothelial function were measured. Structural equation modeling was used to construct latent variables representing each of these pathophysiological constructs and to subsequently study their associations with troponin elevation while adjusting for confounders. Results: We analyzed 908 (88%) of 1,037 eligible patients, 553 (61%) of whom had raised high-sensitivity cardiac troponin I levels upon intensive care unit admission. The latent variables included interleukin (IL)-6, IL-8, and IL-1β for inflammation; platelet count, prothrombin time, and protein C for coagulation; and soluble E-selectin, intercellular adhesion molecule-1, and angiopoietin-2 for endothelial function. After adjustment for age and cardiovascular comorbidities, structural equation modeling analysis showed that activated coagulation was independently associated with elevated troponin during sepsis (standardized regression coefficient, 0.551; 95% confidence interval [CI], 0.257-0.845; P < 0.001) whereas hyperinflammation and endothelial dysfunction were not (standardized regression coefficient, -0.161; 95% CI, -0.418 to 0.096 and -0.054; 95% CI, -0.168 to 0.060, respectively). Conclusions: Our findings suggest that myocardial injury during sepsis is mediated by systemic activation of coagulation rather than by circulating inflammatory mediators or activation of the endothelium. These findings may guide evaluation of strategies to protect the myocardium during sepsis. Clinical trial registered with clinicaltrials.gov (NCT01905033). [ABSTRACT FROM AUTHOR]

Purpose: There is limited knowledge on how the source of infection impacts the host response to sepsis. We aimed to compare the host response in sepsis patients with a single, known source at admission (< 24 h) to the intensive care unit. Methods: From the molecular diagnosis and risk stratification of sepsis (MARS) prospective cohort, we measured 16 plasma host response biomarkers reflective of key host response pathways in 621 sepsis patients. In a subgroup (n = 335), blood leukocyte transcriptomes were compared between the sources. Differences in clinical patient profiles and survival were compared in the whole sepsis cohort (n = 2019). Results: The plasma biomarker cohort was categorized into sepsis originating from the respiratory tract (n = 334, 53.8%), abdomen (n = 159, 25.6%), urinary tract (n = 44, 7.1%), cardiovascular (n = 41, 6.6%), central nervous system (CNS) (n = 18, 2.9%), or skin (n = 25, 4%). This analysis revealed stronger inflammatory and cytokine responses, loss of vascular integrity and coagulation activation in abdominal sepsis relative to respiratory. Endothelial cell activation was prominent in urinary, cardiovascular and skin infections, while CNS infection was associated with the least host response aberrations. The leukocyte transcriptional response showed the largest overlap between abdominal and pulmonary infections (76% in common); notable differences between the sources were detected regarding hemostasis, cytokine signaling, innate and adaptive immune, and metabolic transcriptional pathways. After adjustment for confounders, the source of infection remained an independent contributor to 30-day mortality (unadjusted p = 0.001, adjusted p = 0.028). Conclusion: Sepsis heterogeneity is partly explained by source-specific host response dysregulations and should be considered when selecting patients for trials testing immune modulatory drugs. [ABSTRACT FROM AUTHOR]

Background: A delay in admission to the intensive care unit (ICU) of patients with community-acquired pneumonia (CAP) has been associated with an increased mortality. Decisions regarding interventions and eligibility for immune modulatory therapy are often made at the time of admission to the ICU. The primary aim of this study was to compare the host immune response measured upon ICU admission in CAP patients admitted immediately from the emergency department (direct ICU admission) with those who were transferred within 72 h after admission to the general ward (delayed ICU admission). Methods: Sixteen host response biomarkers providing insight in pathophysiological mechanisms implicated in sepsis and blood leukocyte transcriptomes were analysed in patients with CAP upon ICU admission in two tertiary hospitals in the Netherlands. Results: Of 530 ICU admissions with CAP, 387 (73.0%) were directly admitted and 143 (27.0%) had a delayed admission. Patients with a delayed ICU admission were more often immunocompromised (35.0 versus 21.2%, P =.002) and had more malignancies (23.1 versus 13.4%, P =.011). Shock was more present in patients who were admitted to the ICU directly (46.6 versus 33.6%, P =.010). Delayed ICU admission was not associated with an increased hospital mortality risk (hazard ratio 1.25, 95% CI 0.89–1.78, P =.20). The plasma levels of biomarkers (n = 297) reflecting systemic inflammation, endothelial cell activation and coagulation activation were largely similar between groups, with exception of C-reactive protein, soluble intercellular adhesion molecule-1 and angiopoietin-1, which were more aberrant in delayed admissions compared to direct ICU admissions. Blood leukocyte transcriptomes (n = 132) of patients with a delayed ICU admission showed blunted innate and adaptive immune response signalling when compared with direct ICU admissions, as well as decreased gene expression associated with tissue repair and extracellular matrix remodelling pathways. Conclusions: Blood leukocytes of CAP patients with delayed ICU admission show evidence of a more immune suppressive phenotype upon ICU admission when compared with blood leukocytes from patients directly transferred to the ICU. Trial registration: Molecular Diagnosis and Risk Stratification of Sepsis (MARS) project, ClinicalTrials.gov identifier NCT01905033. [ABSTRACT FROM AUTHOR]

Community‐acquired pneumonia (CAP) is a major cause of sepsis. Despite several clinical trials targeting components of the inflammatory response, no specific treatment other than antimicrobial therapy has been approved. This argued for a deeper understanding of sepsis immunopathology, in particular factors that can modulate the host response. Small non‐coding RNA, for example, micro (mi)RNA, have been established as important modifiers of cellular phenotypes. Notably, miRNAs are not exclusive to the intracellular milieu but have also been detected extracellular in the circulation with functional consequences. Here, we sought to determine shifts in circulatory small RNA levels of critically ill patients with CAP‐associated sepsis and to determine the influence of clinical severity and causal pathogens on small RNA levels. Blood plasma was collected from 13 critically ill patients with sepsis caused by CAP on intensive care unit admission and from 5 non‐infectious control participants. Plasma small RNA‐sequencing identified significantly altered levels of primarily mature miRNAs in CAP relative to controls. Pathways analysis of high or low abundance miRNA identified various over‐represented cellular biological pathways. Analysis of small RNA levels against common clinical severity and inflammatory parameters indices showed direct and indirect correlations. Additionally, variance of plasma small RNA levels in CAP patients may be explained, at least in part, by differences in causal pathogens. Small nuclear RNA levels were specifically altered in CAP due to Influenza infection in contrast to Streptococcus pneumoniae infection. Pathway analysis of plasma miRNA signatures unique to Influenza or Streptococcus pneumoniae infections showed enrichment for specific proteoglycan, cell cycle, and immunometabolic pathways. [ABSTRACT FROM AUTHOR]

Background: The identification of risk factors for adverse outcomes and prolonged intensive care unit (ICU) stay in COVID-19 patients is essential for prognostication, determining treatment intensity, and resource allocation. Previous studies have determined risk factors on admission only, and included a limited number of predictors. Therefore, using data from the highly granular and multicenter Dutch Data Warehouse, we developed machine learning models to identify risk factors for ICU mortality, ventilator-free days and ICU-free days during the course of invasive mechanical ventilation (IMV) in COVID-19 patients. Methods: The DDW is a growing electronic health record database of critically ill COVID-19 patients in the Netherlands. All adult ICU patients on IMV were eligible for inclusion. Transfers, patients admitted for less than 24 h, and patients still admitted at time of data extraction were excluded. Predictors were selected based on the literature, and included medication dosage and fluid balance. Multiple algorithms were trained and validated on up to three sets of observations per patient on day 1, 7, and 14 using fivefold nested cross-validation, keeping observations from an individual patient in the same split. Results: A total of 1152 patients were included in the model. XGBoost models performed best for all outcomes and were used to calculate predictor importance. Using Shapley additive explanations (SHAP), age was the most important demographic risk factor for the outcomes upon start of IMV and throughout its course. The relative probability of death across age values is visualized in Partial Dependence Plots (PDPs), with an increase starting at 54 years. Besides age, acidaemia, low P/F-ratios and high driving pressures demonstrated a higher probability of death. The PDP for driving pressure showed a relative probability increase starting at 12 cmH2O. Conclusion: Age is the most important demographic risk factor of ICU mortality, ICU-free days and ventilator-free days throughout the course of invasive mechanical ventilation in critically ill COVID-19 patients. pH, P/F ratio, and driving pressure should be monitored closely over the course of mechanical ventilation as risk factors predictive of these outcomes. [ABSTRACT FROM AUTHOR]

Sepsis and septic shock remain the leading causes of death in intensive care units (ICUs), yet the pathogenesis originating from the inflammatory response during sepsis remains ambiguous. Acute-phase proteins are typically highly glycosylated, and the nature of the glycans have been linked to the incidence and severity of such inflammatory responses. To further build upon these findings we here monitored, the longitudinal changes in the plasma proteome and, in molecular detail, glycoproteoform profiles of alpha-1-antichymotrypsin (AACT) extracted from plasma of ten individual septic patients. For each patient we included four different time-points, including post-operative (before sepsis) and following discharge from the ICU. We isolated AACT from plasma depleted for albumin, IgG and serotransferrin and used high-resolution native mass spectrometry to qualitatively and quantitatively monitor the multifaceted glycan microheterogeneity of desialylated AACT, which allowed us to monitor how changes in the glycoproteoform profiles reflected the patient's physiological state. Although we observed a general trend in the remodeling of the AACT glycoproteoform profiles, e.g. increased fucosylation and branching/LacNAc elongation, each patient exhibited unique features and responses, providing a resilient proof-of-concept for the importance of personalized longitudinal glycoproteoform profiling. Importantly, we observed that the AACT glycoproteoform changes induced by sepsis did not readily subside after discharge from ICU. [ABSTRACT FROM AUTHOR]

Purpose: Sepsis is the most frequent cause of acute kidney injury (AKI). The "Acute Disease Quality Initiative Workgroup" recently proposed new definitions for AKI, classifying it as transient or persistent. We investigated the incidence, mortality, and host response aberrations associated with transient and persistent AKI in sepsis patients. Methods: A total of 1545 patients admitted with sepsis to 2 intensive care units in the Netherlands were stratified according to the presence (defined by any urine or creatinine RIFLE criterion within the first 48 h) and evolution of AKI (with persistent defined as remaining > 48 h). We determined 30-day mortality by logistic regression adjusting for confounding variables and analyzed 16 plasma biomarkers reflecting pathways involved in sepsis pathogenesis (n = 866) and blood leukocyte transcriptomes (n = 392). Results: AKI occurred in 37.7% of patients, of which 18.4% was transient and 81.6% persistent. On admission, patients with persistent AKI had higher disease severity scores and more frequently had severe (injury or failure) RIFLE AKI stages than transient AKI patients. Persistent AKI, but not transient AKI, was associated with increased mortality by day 30 and up to 1 year. Persistent AKI was associated with enhanced and sustained inflammatory and procoagulant responses during the first 4 days, and a more severe loss of vascular integrity compared with transient AKI. Baseline blood gene expression showed minimal differences with respect to the presence or evolution of AKI. Conclusion: Persistent AKI is independently associated with sepsis mortality, as well as with sustained inflammatory and procoagulant responses, and loss of vascular integrity as compared with transient AKI. [ABSTRACT FROM AUTHOR]

A novel multiplex real-time PCR for bloodstream infections (BSI-PCR) detects pathogens directly in blood. This study aimed at determining the positive predictive value (PPV) of BSI-PCR in critically ill patients with sepsis. We included consecutive patients with presumed sepsis upon admission to the intensive care unit (ICU). The multiplexed BSI-PCR included 17 individual PCRs for a broad panel of species- and genus-specific DNA targets. BSI-PCR results were compared with a reference diagnosis for which plausibility of infection and causative pathogen(s) had been prospectively assessed by trained observers, based on available clinical and microbiological evidence. PPV and false positive proportion (FPP) were calculated. Clinical plausibility of discordant positive results was adjudicated by an expert panel. Among 325 patients, infection likelihood was categorized as confirmed, uncertain, and ruled out in 210 (65%), 88 (27%), and 27 (8%) subjects, respectively. BSI-PCR identified one or more microorganisms in 169 (52%) patients, of whom 104 (61%) had at least one detection in accordance with the reference diagnosis. Discordant positive PCR results were observed in 95 patients, including 30 subjects categorized as having an "unknown" pathogen. Based on 5525 individual PCRs yielding 295 positive results, PPV was 167/295 (57%) and FPP was 128/5525 (2%). Expert adjudication of the 128 discordant PCR findings resulted in an adjusted PPV of 68% and FPP of 2%. BSI-PCR was all-negative in 156 patients, including 79 (51%) patients in whom infection was considered ruled out. BSI-PCR may complement conventional cultures and expedite the microbiological diagnosis of sepsis in ICU patients, but improvements in positive predictive value of the test are warranted before its implementation in clinical practice can be considered. [ABSTRACT FROM AUTHOR]

Background. Enteral and respiratory tract colonization with gram-negative bacteria may lead to subsequent infections in critically ill patients. We aimed to clarify the interdependence between gut and respiratory tract colonization and their associations with intensive care unit (ICU)-acquired infections in patients receiving selective digestive tract decontamination (SDD). Methods. Colonization status of the rectum and respiratory tract was determined using twice-weekly microbiological surveillance in mechanically ventilated subjects receiving SDD between May 2011 and June 2015 in a tertiary medical-surgical ICU in the Netherlands. Acquisition of infections was monitored daily by dedicated observers. Marginal structural models were used to determine the associations between gram-negative rectal colonization and respiratory tract colonization, ICU-acquired gram-negative infection, and ICU-acquired gram-negative bacteremia. Results. Among 2066 ICU admissions, 1157 (56.0%) ever had documented gram-negative carriage in the rectum during ICU stay. Cumulative incidences of ICU-acquired gram-negative infection and bacteremia were 6.0% (n = 124) and 2.1% (n = 44), respectively. Rectal colonization was an independent risk factor for both respiratory tract colonization (cause-specific hazard ratio [CSHR], 2.93 [95% confidence interval {CI}, 2.02-4.23]) and new gram-negative infection in the ICU (CSHR, 3.04 [95% CI, 1.99-4.65]). Both rectal and respiratory tract colonization were associated with bacteremia (CSHR, 7.37 [95% CI, 3.25-16.68] and 2.56 [95% CI, 1.9-6.03], respectively). Similar associations were observed when Enterobacteriaceae and glucose nonfermenting gram-negative bacteria were analyzed separately. Conclusions. Gram-negative rectal colonization tends to be stronger associated with subsequent ICU-acquired gram-negative infections than gram-negative respiratory tract colonization. Gram-negative rectal colonization seems hardly associated with subsequent ICU-acquired gram-negative respiratory tract colonization. [ABSTRACT FROM AUTHOR]

Background: Sepsis is frequently complicated by the release of cardiac troponin, but the clinical significance of this myocardial injury remains unclear. We studied the associations between troponin release during sepsis and 1-year outcomes.Methods and Results: We enrolled consecutive patients with sepsis in 2 Dutch intensive care units between 2011 and 2013. Subjects with a clinically apparent cause of troponin release were excluded. High-sensitivity cardiac troponin I (hs-cTnI) concentration in plasma was measured daily during the first 4 intensive care unit days, and multivariable Cox regression analysis was used to model its association with 1-year mortality while adjusting for confounding. In addition, we studied cardiovascular morbidity occurring during the first year after hospital discharge. Among 1258 patients presenting with sepsis, 1124 (89%) were eligible for study inclusion. Hs-cTnI concentrations were elevated in 673 (60%) subjects on day 1, and 755 (67%) ever had elevated levels in the first 4 days. Cox regression analysis revealed that high hs-cTnI concentrations were associated with increased death rates during the first 14 days (adjusted hazard ratio, 1.72; 95% confidence interval, 1.14-2.59 and hazard ratio, 1.70; 95% confidence interval, 1.10-2.62 for hs-cTnI concentrations of 100-500 and >500 ng/L, respectively) but not thereafter. Furthermore, elevated hs-cTnI levels were associated with the development of cardiovascular disease among 200 hospital survivors who were analyzed for this end point (adjusted subdistribution hazard ratio, 1.25; 95% confidence interval, 1.04-1.50).Conclusions: Myocardial injury occurs in the majority of patients with sepsis and is independently associated with early-but not late-mortality, as well as postdischarge cardiovascular morbidity. [ABSTRACT FROM AUTHOR]

Summary Background Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis. Methods This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort). We generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. We also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. Findings The discovery cohort had 306 patients, the first validation cohort had 216, and the second validation cohort had 265 patients. Four molecular endotypes for sepsis, designated Mars1–4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0·022). In the discovery cohort, the worst outcome was found for patients classified as having a Mars1 endotype, and at 28 days, 35 (39%) of 90 people with a Mars1 endotype had died (hazard ratio [HR] vs all other endotypes 1·86 [95% CI 1·21–2·86]; p=0·0045), compared with 23 (22%) of 105 people with a Mars2 endotype (HR 0·64 [0·40–1·04]; p=0·061), 16 (23%) of 71 people with a Mars3 endotype (HR 0·71 [0·41–1·22]; p=0·19), and 13 (33%) of 40 patients with a Mars4 endotype (HR 1·13 [0·63–2·04]; p=0·69). Analysis of the net reclassification improvement using a combined clinical and endotype model significantly improved risk prediction to 0·33 (0·09–0·58; p=0·008). A 140-gene expression signature reliably stratified patients with sepsis to the four endotypes in both the first and second validation cohorts. Only Mars1 was consistently significantly associated with 28-day mortality across the cohorts. To facilitate possible clinical use, a biomarker was derived for each endotype; BPGM and TAP2 reliably identified patients with a Mars1 endotype. Interpretation This study provides a method for the molecular classification of patients with sepsis to four different endotypes upon ICU admission. Detection of sepsis endotypes might assist in providing personalised patient management and in selection for trials. Funding Center for Translational Molecular Medicine, Netherlands. [ABSTRACT FROM AUTHOR]