Patients with hypothermic sepsis have a unique gene expression profile compared to patients with fever and sepsis.

The pathophysiology of hypothermia during sepsis is unclear. Using genomic profiling of blood leukocytes, we aimed to determine if hypothermia is associated with a different gene expression profile compared to fever during sepsis. Patients with sepsis and either hypothermia or fever within 24 hours after ICU admission were included in the study (n = 168). Hypothermia was defined as body temperature below 36 °C. Fever was defined as body temperature equal to or above 38.3°C. We compared blood gene expression (whole-genome transcriptome in leukocytes) in hypothermic septic compared to febrile septic patients in an unmatched analysis and matched for APACHE IV score and the presence of shock. In total, 67 septic patients were hypothermic and 101 patients were febrile. Hypothermia was associated with a distinct gene expression profile in both unmatched and matched analyses. There were significant differences related to the up- and downregulation of canonical signalling pathways. In the matched analysis, the top upregulated gene was cold-inducible mRNA binding protein (CIRBP) which plays a role in cold-induced suppression of cell proliferation. In addition, we found three signalling pathways significantly upregulated in hypothermic patients compared to febrile patients; tryptophan degradation X, phenylalanine degradation IV and putrescine degradation III. In conclusion, there are distinct signalling pathways and genes associated with hypothermia, including tryptophan degradation and CIRBP expression, providing a possible link to the modulation of body temperature and early immunosuppression. Future studies may focus on the canonical signalling pathways presented in this paper to further investigate spontaneous hypothermia in sepsis.

Immune suppression is associated with enhanced systemic inflammatory, endothelial and procoagulant responses in critically ill patients.

OBJECTIVE: Patients admitted to the Intensive Care Unit (ICU) oftentimes show immunological signs of immune suppression. Consequently, immune stimulatory agents have been proposed as an adjunctive therapy approach in the ICU. The objective of this study was to determine the relationship between the degree of immune suppression and systemic inflammation in patients shortly after admission to the ICU. Design: An observational study in two ICUs in the Netherlands. METHODS: The capacity of blood leukocytes to produce cytokines upon stimulation with lipopolysaccharide (LPS) was measured in 77 patients on the first morning after ICU admission. Patients were divided in four groups based on quartiles of LPS stimulated tumor necrosis factor (TNF)-α release, reflecting increasing extents of immune suppression. 15 host response biomarkers indicative of aberrations in inflammatory pathways implicated in sepsis pathogenesis were measured in plasma. RESULTS: A diminished capacity of blood leukocytes to produce TNF-α upon stimulation with LPS was accompanied by a correspondingly reduced ability to release of IL-1ß and IL-6. Concurrently measured plasma concentrations of host response biomarkers demonstrated that the degree of reduction in TNF-α release by blood leukocytes was associated with increasing systemic inflammation, stronger endothelial cell activation, loss of endothelial barrier integrity and enhanced procoagulant responses. CONCLUSIONS: In patients admitted to the ICU the strongest immune suppression occurs in those who simultaneously display signs of stronger systemic inflammation. These findings may have relevance for the selection of patients eligible for administration of immune enhancing agents. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01905033.

Impact of a Machine Learning-Based Decision Support System for Urinary Tract Infections: Prospective Observational Study in 36 Primary Care Practices.

BACKGROUND: There is increasing attention on machine learning (ML)-based clinical decision support systems (CDSS), but their added value and pitfalls are very rarely evaluated in clinical practice. We implemented a CDSS to aid general practitioners (GPs) in treating patients with urinary tract infections (UTIs), which are a significant health burden worldwide. OBJECTIVE: This study aims to prospectively assess the impact of this CDSS on treatment success and change in antibiotic prescription behavior of the physician. In doing so, we hope to identify drivers and obstacles that positively impact the quality of health care practice with ML. METHODS: The CDSS was developed by Pacmed, Nivel, and Leiden University Medical Center (LUMC). The CDSS presents the expected outcomes of treatments, using interpretable decision trees as ML classifiers. Treatment success was defined as a subsequent period of 28 days during which no new antibiotic treatment for UTI was needed. In this prospective observational study, 36 primary care practices used the software for 4 months. Furthermore, 29 control practices were identified using propensity score-matching. All analyses were performed using electronic health records from the Nivel Primary Care Database. Patients for whom the software was used were identified in the Nivel database by sequential matching using CDSS use data. We compared the proportion of successful treatments before and during the study within the treatment arm. The same analysis was performed for the control practices and the patient subgroup the software was definitely used for. All analyses, including that of physicians' prescription behavior, were statistically tested using 2-sided z tests with an α level of .05. RESULTS: In the treatment practices, 4998 observations were included before and 3422 observations (of 2423 unique patients) were included during the implementation period. In the control practices, 5044 observations were included before and 3360 observations were included during the implementation period. The proportion of successful treatments increased significantly from 75% to 80% in treatment practices (z=5.47, P<.001). No significant difference was detected in control practices (76% before and 76% during the pilot, z=0.02; P=.98). Of the 2423 patients, we identified 734 (30.29%) in the CDSS use database in the Nivel database. For these patients, the proportion of successful treatments during the study was 83%-a statistically significant difference, with 75% of successful treatments before the study in the treatment practices (z=4.95; P<.001). CONCLUSIONS: The introduction of the CDSS as an intervention in the 36 treatment practices was associated with a statistically significant improvement in treatment success. We excluded temporal effects and validated the results with the subgroup analysis in patients for whom we were certain that the software was used. This study shows important strengths and points of attention for the development and implementation of an ML-based CDSS in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04408976; https://clinicaltrials.gov/ct2/show/NCT04408976.

Intracellular expression of granzymes A, B, K and M in blood lymphocyte subsets of critically ill patients with or without sepsis.

Sepsis is a complex syndrome related to an infection-induced exaggerated inflammatory response, which is associated with a high mortality. Granzymes (Gzm) are proteases mainly found in cytotoxic lymphocytes that not only have a role in target cell death, but also as mediators of infection and inflammation. In this study we sought to analyse the intracellular expression of GzmA, B, M and K by flow cytometry in diverse blood lymphocyte populations from 22 sepsis patients, 12 non-infected intensive care unit (ICU) patients and 32 healthy controls. Additionally, we measured GzmA and B plasma levels. Both groups of patients presented decreased percentage of natural killer (NK) cells expressing GzmA, B and M relative to healthy controls, while sepsis patients showed an increased proportion of CD8+ T cells expressing GzmB compared to controls. Expression of GzmK remained relatively unaltered between groups. Extracellular levels of GzmB were increased in non-infected ICU patients relative to sepsis patients and healthy controls. Our results show differential alterations in intracellular expression of Gzm in sepsis patients and non-infected critically ill patients compared to healthy individuals depending on the lymphocyte population and on the Gzm.

The leukocyte non-coding RNA landscape in critically ill patients with sepsis.

The extent of non-coding RNA alterations in patients with sepsis and their relationship to clinical characteristics, soluble mediators of the host response to infection, as well as an advocated in vivo model of acute systemic inflammation is unknown. Here we obtained whole blood from 156 patients with sepsis and 82 healthy subjects among whom eight were challenged with lipopolysaccharide in a clinically controlled setting (human endotoxemia). Via next-generation microarray analysis of leukocyte RNA we found that long non-coding RNA and, to a lesser extent, small non-coding RNA were significantly altered in sepsis relative to health. Long non-coding RNA expression, but not small non-coding RNA, was largely recapitulated in human endotoxemia. Integrating RNA profiles and plasma protein levels revealed known as well as previously unobserved pathways, including non-sensory olfactory receptor activity. We provide a benchmark dissection of the blood leukocyte 'regulome' that can facilitate prioritization of future functional studies.

Increased mortality in elderly patients with acute respiratory distress syndrome is not explained by host response.

BACKGROUND: Advanced age is associated with increased mortality in acute respiratory distress syndrome (ARDS) patients. Preclinical studies suggest that the host response to an injurious challenge is age-dependent. In ARDS patients, we investigated whether the association between age and mortality is mediated through age-related differences in the host response. METHODS: This was a prospective longitudinal observational cohort study, performed in the ICUs of two university-affiliated hospitals. The systemic host response was characterized in three predefined age-groups, based on the age-tertiles of the studied population: young (18 to 54 years, N = 209), middle-aged (55 to 67 years, N = 213), and elderly (67 years and older, N = 196). Biomarkers of inflammation, endothelial activation, and coagulation were determined in plasma obtained at the onset of ARDS. The primary outcome was 90-day mortality. A mediation analysis was performed to examine whether age-related differences in biomarker levels serve as potential causal pathways mediating the association between age and mortality. RESULTS: Ninety-day mortality rates were 30% (63/209) in young, 37% (78/213) in middle-aged, and 43% (84/196) in elderly patients. Middle-aged and elderly patients had a higher risk of death compared to young patients (adjusted odds ratio, 1.5 [95% confidence interval 1.0 to 2.3] and 2.1 [1.4 to 3.4], respectively). Relative to young patients, the elderly had significantly lower systemic levels of biomarkers of inflammation and endothelial activation. Tissue plasminogen activator, a marker of coagulation, was the only biomarker that showed partial mediation (proportion of mediation, 10 [1 to 28] %). CONCLUSION: Little evidence was found that the association between age and mortality in ARDS patients is mediated through age-dependent differences in host response pathways. Only tissue plasminogen activator was identified as a possible mediator of interest. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (identifier NCT01905033 , date of registration July 23, 2013).

Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study.

BACKGROUND: Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin-angiotensin system (RAS) are responsible for observed differences in epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS. METHODS: In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates (< 28 days corrected postnatal age), 29 children (28 days-18 years), 26 adults (18-65 years), and 17 older adults (> 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid. RESULTS: Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups. CONCLUSIONS: Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS.

The host response in critically ill sepsis patients on statin therapy: a prospective observational study.

BACKGROUND: Statins can exert pleiotropic anti-inflammatory, vascular protective and anticoagulant effects, which in theory could improve the dysregulated host response during sepsis. We aimed to determine the association between prior statin use and host response characteristics in critically ill patients with sepsis. METHODS: We performed a prospective observational study in 1060 patients admitted with sepsis to the mixed intensive care units (ICUs) of two hospitals in the Netherlands between January 2011 and July 2013. Of these, 351 patients (33%) were on statin therapy before admission. The host response was evaluated by measuring 23 biomarkers providing insight into key pathways implicated in sepsis pathogenesis and by analyzing whole-blood leukocyte transcriptomes in samples obtained within 24 h after ICU admission. To account for indication bias, a propensity score-matched cohort was created (N = 194 in both groups for protein biomarkers and N = 95 in both groups for gene expression analysis). RESULTS: Prior statin use was not associated with an altered mortality up to 90 days after admission (38.0 vs. 39.7% in the non-statin users in the propensity-matched analysis). Statin use did not modify systemic inflammatory responses, activation of the vascular endothelium or the coagulation system. The blood leukocyte genomic response, characterized by over-expression of genes involved in inflammatory and innate immune signaling pathways as well as under-expression of genes associated to T cell function, was not different between patients with and without prior statin use. CONCLUSIONS: Statin therapy is not associated with a modified host response in sepsis patients on admission to the ICU.

A chip-based rapid genotyping assay to discriminate between rhinovirus species A, B and C.

BACKGROUND: Human rhinoviruses (RVs) are increasingly associated with severe disease of the respiratory tract. Multiple studies highlighted the clinical significance of different RV species; RV-C is linked to asthma exacerbations and increased disease severity in children, whereas RV-B seems to correlate with milder disease. OBJECTIVES: Current typing strategies for differentiation of RV species are time consuming and require extensive equipment. Here we present a novel genotyping tool to discriminate RV species A, B and C. STUDY DESIGN: The method encompasses a VP4/VP2 polymerase chain reaction (PCR), followed by hybridization of the product on a macro array with probes covering RV-A, B, and C, produced by Chipron as custom array. Validation was performed with respiratory specimens submitted for diagnostic evaluation to the Academic Medical Center. A selection of RV PCR-positive samples genotyped based on VP4/VP2 sequencing was evaluated. Diagnostic performance was tested on respiratory samples positive for RV in an in-house multiplex respiratory PCR from January 2016 to January 2017. In-house primers and additional genotype-specific primers were used for sequencing to investigate array-negative and array-double-positive samples. RESULTS: The majority of samples pretyped RVs (n = 135) were classified correctly, except for one that was assigned RV-C instead of RV-A, and 3 samples tested negative. The array gave four double-positive results; the presence of more than one genotype was confirmed in two samples. In 173/187 (92.5%) RV-positive tested patient samples from 2016, the test resulted in a designated species. RV species A was identified in 109 specimens (58.3%), RV-B in 26 (13.9%), and RV-C in 56 (29.9%) samples. Sequencing of the probe region of 14 (7.6%) negative samples revealed up to 3 mismatches to the probes for 12 samples; in 2 cases no PCR product was generated. Notably, in 18 samples the chip detected more than one species, of which 16 were confirmed by sequencing. DISCUSSION: The Chipron LCD RV array provides a fast and highly sensitive method for discrimination between rhinovirus species, and has the power to detect dual infections.

Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study.

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.

Quantifying the Effects of Prior Acetyl-Salicylic Acid on Sepsis-Related Deaths: An Individual Patient Data Meta-Analysis Using Propensity Matching.

OBJECTIVE: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. STUDY SELECTION: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. DATA SOURCES: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. DATA EXTRACTION: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. DATA SYNTHESIS: Use of aspirin was associated with a 7% (95% CI, 2-12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I = 61.6%). CONCLUSIONS: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis.

Association of Gender With Outcome and Host Response in Critically Ill Sepsis Patients.

OBJECTIVE: To determine the association of gender with the presentation, outcome, and host response in critically ill patients with sepsis. DESIGN AND SETTING: A prospective observational cohort study in the ICU of two tertiary hospitals between January 2011 and January 2014. PATIENTS: All consecutive critically ill patients admitted with sepsis, involving 1,815 admissions (1,533 patients). INTERVENTIONS: The host response was evaluated on ICU admission by measuring 19 plasma biomarkers reflecting organ systems implicated in sepsis pathogenesis (1,205 admissions) and by applying genome-wide blood gene expression profiling (582 admissions). MEASUREMENTS AND MAIN RESULTS: Sepsis patients admitted to the ICU were more frequently males (61.0%; p < 0.0001 vs females). Baseline characteristics were not different between genders. Urosepsis was more common in females; endocarditis and mediastinitis in men. Disease severity was similar throughout ICU stay. Mortality was similar up to 1 year after ICU admission, and gender was not associated with 90-day mortality in multivariate analyses in a variety of subgroups. Although plasma proteome analyses (including systemic inflammatory and cytokine responses, and activation of coagulation) were largely similar between genders, females showed enhanced endothelial cell activation; this difference was virtually absent in patients more than 55 years old. More than 80% of the leukocyte blood gene expression response was similar in male and female patients. CONCLUSIONS: The host response and outcome in male and female sepsis patients requiring ICU admission are largely similar.

Clinical Characteristics and Outcomes of Patients With Cellulitis Requiring Intensive Care.

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.

Sepsis Patients Display a Reduced Capacity to Activate Nuclear Factor-κB in Multiple Cell Types.

OBJECTIVES: Sepsis is a complex clinical condition associated with high morbidity and mortality. A distinctive feature of sepsis is the reduced capacity of leukocytes to release proinflammatory cytokines in response to ex vivo stimulation. Cellular signaling events leading to immunosuppression in sepsis are not well defined. We investigated cell-specific signaling events underlying the immunosuppressed phenotype in sepsis. DESIGN: Ex vivo study. SETTING: ICU of an academic hospital. PATIENTS: Nineteen patients with sepsis and 19 age-matched healthy controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The phosphorylation state of p38 mitogen activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells were determined in ex vivo stimulated CD4 T cells, CD8 T cells, B cells, monocytes, and neutrophils. Messenger RNA expression levels of p38 mitogen activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells and negative regulators tumor necrosis factor-α-induced protein 3 (A20) and mitogen activated protein kinase phosphatase-1 were determined in neutrophils and peripheral blood mononuclear cells. Upon ex vivo stimulation, monocytes of sepsis patients were less capable in phosphorylating nuclear factor kappa-light-chain-enhancer of activated B cells. Sepsis was also associated with reduced phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells in stimulated B cells, CD4 and CD8 T cells. Messenger RNA expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells and A20 were diminished in peripheral blood mononuclear cells of sepsis patients, whereas p38 mitogen activated protein kinase messenger RNA was up-regulated. In neutrophils of sepsis patients, mitogen activated protein kinase phosphatase-1 messenger RNA levels were down-regulated. CONCLUSIONS: Sepsis-induced immunosuppression associates with a defect in the capacity to phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells in lymphoid cells and monocytes.

Prior Use of Calcium Channel Blockers Is Associated With Decreased Mortality in Critically Ill Patients With Sepsis: A Prospective Observational Study.

OBJECTIVES: Experimental studies suggest that calcium channel blockers can improve sepsis outcome. The aim of this study was to determine the association between prior use of calcium channel blockers and the outcome of patients admitted to the ICU with sepsis. DESIGN: A prospective observational study. SETTING: The ICUs of two tertiary care hospitals in the Netherlands. PATIENTS: In total, 1,060 consecutive patients admitted with sepsis were analyzed, 18.6% of whom used calcium channel blockers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Considering large baseline differences between calcium channel blocker users and nonusers, a propensity score matched cohort was constructed to account for differential likelihoods of receiving calcium channel blockers. Fifteen plasma biomarkers providing insight in key host responses implicated in sepsis pathogenesis were measured during the first 4 days after admission. Severity of illness over the first 24 hours, sites of infection and causative pathogens were similar in both groups. Prior use of calcium channel blockers was associated with improved 30-day survival in the propensity-matched cohort (20.2% vs 32.9% in non-calcium channel blockers users; p = 0.009) and in multivariate analysis (odds ratio, 0.48; 95% CI, 0.31-0.74; p = 0.0007). Prior calcium channel blocker use was not associated with changes in the plasma levels of host biomarkers indicative of activation of the cytokine network, the vascular endothelium and the coagulation system, with the exception of antithrombin levels, which were less decreased in calcium channel blocker users. CONCLUSIONS: Prior calcium channel blocker use is associated with reduced mortality in patients following ICU admission with sepsis.

The Host Response in Patients with Sepsis Developing Intensive Care Unit-acquired Secondary Infections.

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.

Risk factors, host response and outcome of hypothermic sepsis.

BACKGROUND: Hypothermia is associated with adverse outcome in patients with sepsis. The objective of this study was to characterize the host immune response in patients with hypothermic sepsis in order to determine if an excessive anti-inflammatory response could explain immunosuppression and adverse outcome. Markers of endothelial activation and integrity were also measured to explore potential alternative mechanisms of hypothermia. Finally we studied risk factors for hypothermia in an attempt to find new clues to the etiology of hypothermia in sepsis. METHODS: Consecutive patients diagnosed with sepsis within 24 hours after admission to ICUs in two tertiary hospitals in the Netherlands were included in the study (n = 525). Hypothermia was defined as body temperature below 36 °C in the first 24 h of ICU admission. RESULTS: Hypothermia was identified in 186 patients and was independently associated with mortality. Levels of proinflammatory and anti-inflammatory cytokines were not different between groups. Hypothermia was also not associated with an altered response to ex vivo stimulation with lipopolysaccharide in a subset of 15 patients. Risk factors for hypothermia included low body mass index, hypertension and chronic cardiovascular insufficiency. Levels of the endothelial activation marker fractalkine were increased during the first 4 days of ICU stay. CONCLUSIONS: Hypothermia during sepsis is independently associated with mortality, which cannot be attributed to alterations in the host immune responses that were measured in this study. Given that risk factors for hypothermic sepsis are mainly cardiovascular and that the endothelial activation marker fractalkine increased in hypothermia, these findings may suggest that vascular dysfunction plays a role in hypothermic sepsis.