IMPORTANCE: Sepsis is considered to induce immune suppression, leading to increased susceptibility to secondary infections with associated late mortality. OBJECTIVE: To determine the clinical and ...host genomic characteristics, incidence, and attributable mortality of intensive care unit (ICU)–acquired infections in patients admitted to the ICU with or without sepsis. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study comprising consecutive admissions of more than 48 hours in 2 ICUs in the Netherlands from January 2011 to July 2013 stratified according to admission diagnosis (sepsis or noninfectious). MAIN OUTCOMES AND MEASURES: The primary outcome was ICU-acquired infection (onset >48 hours). Attributable mortality risk (fraction of mortality that can be prevented by elimination of the risk factor, acquired infection) was determined using time-to-event models accounting for competing risk. In a subset of sepsis admissions (n = 461), blood gene expression (whole-genome transcriptome in leukocytes) was analyzed at baseline and at onset of ICU-acquired infectious (n = 19) and noninfectious (n = 9) events. RESULTS: The primary cohort included 1719 sepsis admissions (1504 patients; median age, 62 years; interquartile range IQR, 51-71 years; 924 men 61.4%). A comparative cohort included 1921 admissions (1825 patients, median age, 62 years; IQR, 49-71 years; 1128 men 61.8% in whom infection was not present in the first 48 hours. Intensive care unit–acquired infections occurred in 13.5% of sepsis ICU admissions (n = 232) and 15.1% of nonsepsis ICU admissions (n = 291). Patients with sepsis who developed an ICU-acquired infection had higher disease severity scores on admission than patients with sepsis who did not develop an ICU-acquired infection (Acute Physiology and Chronic Health Evaluation IV APACHE IV median score, 90 IQR, 72-107 vs 79 IQR, 62-98; P < .001) and throughout their ICU stay but did not have differences in baseline gene expression. The population attributable mortality fraction of ICU-acquired infections in patients with sepsis was 10.9% (95% CI, 0.9%-20.6%) by day 60; the estimated difference between mortality in all patients with a sepsis admission diagnosis and mortality in those without ICU-acquired infection was 2.0% (95% CI, 0.2%-3.8%; P = .03) by day 60. Among nonsepsis ICU admissions, ICU-acquired infections had a population attributable mortality fraction of 21.1% (95% CI, 0.6%-41.7%) by day 60. Compared with baseline, blood gene expression at the onset of ICU-acquired infections showed reduced expression of genes involved in gluconeogenesis and glycolysis. CONCLUSIONS AND RELEVANCE: Intensive care unit–acquired infections occurred more commonly in patients with sepsis with higher disease severity, but such infections contributed only modestly to overall mortality. The genomic response of patients with sepsis was consistent with immune suppression at the onset of secondary infection.
The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By ...transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.
Recent years have seen an increase in Bayesian reanalyses of clinical trials, with proponents arguing that it helps in the interpretation of trial results. However, there is skepticism towards ...Bayesian inference, with concerns that the many priors mode of Bayesian reanalyses disregards the communal aspects of evidence-based medicine. The key reason for conducting randomized controlled trials is to resolve uncertainty and disagreement in the clinical community, and successful trials forge consensus among reasonable parties who previously disagreed. Unfortunately, the results of many trials are not convincing, leading investigators to turn to Bayesian methods to reanalyze trials using a range of priors. However, there is no widely accepted framework to translate the spectrum of posterior results into a consensus viewpoint about treatment efficacy. The use of subjective priors is not necessarily at odds with evidence-based medicine, as consensus arises when the data are strong enough to convince even a reasonable adversary. Focusing Bayesian reanalyses on the adversarial prior reduces the overwhelming amount of posterior probabilities and limits the potential points of disagreement. The pick your own prior paradigm of Bayesian reanalyses appears vacuous to many, and it would be simpler to urge clinicians to enlist their own beliefs when faced with unconvincing data. The evidence base itself cannot be made contingent on personal beliefs, and the discourse about the effectiveness of a treatment is better served by focusing on whether the matter can be considered settled or if the evidence is too weak to reach consensus.
Critically ill patients with sepsis are prone to develop cardiac dysrhythmias, most commonly atrial fibrillation (AF). Systemic inflammation, circulating stress hormones, autonomic dysfunction, and ...volume shifts are all possible triggers for AF in this setting. We conducted a systematic review to describe the incidence, risk factors and outcomes of new-onset AF in patients with sepsis.
MEDLINE, EMBASE and Web Of Science were searched for studies reporting the incidence of new-onset AF, atrial flutter or supraventricular tachycardia in patients with sepsis admitted to an intensive care unit, excluding studies that primarily focused on postcardiotomy patients. Studies were assessed for methodological quality using the GRADE system. Risk factors were considered to have a high level of evidence if they were reported in ≥ 2 studies using multivariable analyses at a P value <0.05. Subsequently, the strength of association was classified as strong, moderate or weak, based on the reported odds ratios.
Eleven studies were included. Overall quality was low to moderate. The weighted mean incidence of new-onset AF was 8% (range 0 to 14%), 10% (4 to 23%) and 23% (6 to 46%) in critically ill patients with sepsis, severe sepsis and septic shock, respectively. Independent risk factors with a high level of evidence included advanced age (weak strength of association), white race (moderate association), presence of a respiratory tract infection (weak association), organ failure (moderate association), and pulmonary artery catheter use (moderate association). Protective factors were a history of diabetes mellitus (weak association) and the presence of a urinary tract infection (weak association). New-onset AF was associated with increased short-term mortality in five studies (crude relative effect estimates ranging from 1.96 to 3.32; adjusted effects 1.07 to 3.28). Three studies reported a significantly increased length of stay in the ICU (weighted mean difference 9 days, range 5 to 13 days), whereas an increased risk of ischemic stroke was reported in the single study that looked at this outcome.
New-onset AF is a common consequence of sepsis and is independently associated with poor outcome. Early risk stratification of patients may allow for pharmacological interventions to prevent this complication.
Delirium is associated with impaired outcome, but it is unclear whether this relationship is limited to in-hospital outcomes and whether this relationship is independent of the severity of underlying ...conditions. The aim of this study was to investigate the association between delirium in the intensive care unit (ICU) and long-term mortality, self-reported health-related quality of life (HRQoL), and self-reported problems with cognitive functioning in survivors of critical illness, taking severity of illness at baseline and throughout ICU stay into account.
A prospective cohort study was conducted. We included patients who survived an ICU stay of at least a day; exclusions were neurocritical care patients and patients who sustained deep sedation during the entire ICU stay. Delirium was assessed twice daily with the Confusion Assessment Method for the ICU (CAM-ICU) and additionally, patients who received haloperidol were considered delirious. Twelve months after ICU admission, data on mortality were obtained and HRQoL and cognitive functioning were measured with the European Quality of Life - Six dimensions self-classifier (EQ-6D). Regression analyses were used to assess the associations between delirium and the outcome measures adjusted for gender, type of admission, the Acute Physiology And Chronic Health Evaluation IV (APACHE IV) score, and the cumulative Sequential Organ Failure Assessment (SOFA) score throughout ICU stay.
Of 1101 survivors of critical illness, 412 persons (37%) had been delirious during ICU stay, and 198 (18%) died within twelve months. When correcting for confounders, no significant association between delirium and long-term mortality was found (hazard ratio: 1.26; 95% confidence interval (CI) 0.93 to 1.71). In multivariable analysis, delirium was not associated with HRQoL either (regression coefficient: -0.04; 95% CI -0.10 to 0.01). Yet, delirium remained associated with mild and severe problems with cognitive functioning in multivariable analysis (odds ratios: 2.41; 95% CI 1.57 to 3.69 and 3.10; 95% CI 1.10 to 8.74, respectively).
In this group of survivors of critical illness, delirium during ICU stay was not associated with long-term mortality or HRQoL after adjusting for confounding, including severity of illness throughout ICU stay. In contrast, delirium appears to be an independent risk factor for long-term self-reported problems with cognitive functioning.
The association of ageing with increased sepsis mortality is well established. Nonetheless, current investigations on the influence of age on host response aberrations are largely limited to plasma ...cytokine levels while neglecting other pathophysiological sepsis domains like endothelial cell activation and function, and coagulation activation. The primary objective of this study was to gain insight into the association of ageing with aberrations in key host response pathways and blood transcriptomes in sepsis.
We analysed the clinical outcome (n = 1952), 16 plasma biomarkers providing insight in deregulation of specific pathophysiological domains (n = 899), and blood leukocyte transcriptomes (n = 488) of sepsis patients stratified according to age decades. Blood transcriptome results were validated in an independent sepsis cohort and compared with healthy individuals.
Older age was associated with increased mortality independent of comorbidities and disease severity. Ageing was associated with lower endothelial cell activation and dysfunction, and similar inflammation and coagulation activation, despite higher disease severity scores. Blood leukocytes of patients ≥ 70 years, compared to patients < 50 years, showed decreased expression of genes involved in cytokine signaling, and innate and adaptive immunity, and increased expression of genes involved in hemostasis and endothelial cell activation. The diminished expression of gene pathways related to innate immunity and cytokine signaling in subjects ≥ 70 years was sepsis-induced, as healthy subjects ≥ 70 years showed enhanced expression of these pathways compared to healthy individuals < 50 years.
This study provides novel evidence that older age is associated with relatively mitigated sepsis-induced endothelial cell activation and dysfunction, and a blood leukocyte transcriptome signature indicating impaired innate immune and cytokine signaling. These data suggest that age should be considered in patient selection in future sepsis trials targeting the immune system and/or the endothelial cell response.
Accurate surveillance of ventilator-associated pneumonia (VAP) is hampered by subjective diagnostic criteria. A novel surveillance paradigm for ventilator-associated events (VAEs) was introduced.
To ...determine the validity of surveillance using the new VAE algorithm.
Prospective cohort study in two Dutch academic medical centers (2011-2012). VAE surveillance was electronically implemented and included assessment of (infection-related) ventilator-associated conditions (VAC, IVAC) and VAP. Concordance with ongoing prospective VAP surveillance was assessed, along with clinical diagnoses underlying VAEs and associated mortality of all conditions. Consequences of minor differences in electronic VAE implementation were evaluated.
The study included 2,080 patients with 2,296 admissions. Incidences of VAC, IVAC, VAE-VAP, and VAP according to prospective surveillance were 10.0, 4.2, 3.2, and 8.0 per 1000 ventilation days, respectively. The VAE algorithm detected at most 32% of the patients with VAP identified by prospective surveillance. VAC signals were most often caused by volume overload and infections, but not necessarily VAP. Subdistribution hazards for mortality were 3.9 (95% confidence interval, 2.9-5.3) for VAC, 2.5 (1.5-4.1) for IVAC, 2.0 (1.1-3.6) for VAE-VAP, and 7.2 (5.1-10.3) for VAP identified by prospective surveillance. In sensitivity analyses, mortality estimates varied considerably after minor differences in electronic algorithm implementation.
Concordance between the novel VAE algorithm and VAP was poor. Incidence and associated mortality of VAE were susceptible to small differences in electronic implementation. More studies are needed to characterize the clinical entities underlying VAE and to ensure comparability of rates from different institutions.
Preclinical studies have suggested that platelets influence the host response during sepsis. We sought to assess the association of admission thrombocytopenia with the presentation, outcome, and host ...response in patients with sepsis. Nine hundred thirty-one consecutive sepsis patients were stratified according to platelet counts (very low <50 × 109/L, intermediate-low 50 × 109 to 99 × 109/L, low 100 × 109 to 149 × 109/L, or normal 150 × 109 to 399 × 109/L) on admission to the intensive care unit. Sepsis patients with platelet counts <50 × 109/L and 50 × 109 to 99 × 109/L presented with higher Acute Physiology and Chronic Health Evaluation scores and more shock. Both levels of thrombocytopenia were independently associated with increased 30-day mortality (hazard ratios with 95% confidence intervals 2.00 1.32-3.05 and 1.72 1.22-2.44, respectively). To account for baseline differences besides platelet counts, propensity matching was performed, after which the association between thrombocytopenia and the host response was tested, as evaluated by measuring 17 plasma biomarkers indicative of activation and/or dysregulation of pathways implicated in sepsis pathogenesis and by whole genome blood leukocyte expression profiling. In the propensity matched cohort, platelet counts < 50 × 109/L were associated with increased cytokine levels and enhanced endothelial cell activation. All thrombocytopenic groups showed evidence of impaired vascular integrity, whereas coagulation activation was similar between groups. Blood microarray analysis revealed a distinct gene expression pattern in sepsis patients with <50 × 109/L platelets, showing reduced signaling in leukocyte adhesion and diapedesis and increased complement signaling. These data show that admission thrombocytopenia is associated with enhanced mortality and a more disturbed host response during sepsis independent of disease severity, thereby providing clinical validity to animal studies on the role of platelets in severe infection.
•Thrombocytopenia on intensive care unit admission is independently associated with increased mortality in patients with sepsis.•Thrombocytopenia is associated with a more disturbed host response in critically ill patients with sepsis independent of disease severity.
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.
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.
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