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.
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.
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.
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).
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.
ClinicalTrials.gov NCT01905033. Registered 11 July 2013.
Background
Advanced glycation end products (AGEs) are potential biomarkers of biological age. Skin Auto Fluorescence (SAF) can assess AGEs non‐invasively. We evaluated the association of SAF levels ...with frailty and its predictive ability for adverse outcomes in older cardiac surgery patients.
Methods
This was a retrospective analysis of prospectively acquired data from a two‐center observational cohort study. We measured SAF level in cardiac surgery patients aged ≥70. Primary outcome was preoperative frailty. A comprehensive frailty assessment was performed before surgery based on 11 individual tests assessing the physical, mental, and social domain. Frailty was defined as at least 1 positive test in each domain. Secondary outcome measures were severe postoperative complications and a composite endpoint of 1‐year disability (defined by WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) questionnaire) or mortality.
Results
Among 555 enrolled patients, 122 (22%) were frail. SAF level was most strongly associated with dependent living status (aRR 2.45 (95% CI 1.28–4.66)) and impaired cognition (aRR 1.61 (95% CI 1.10–2.34)). A decision algorithm to identify frail patients including SAF level, sex, prescription drugs, preoperative hemoglobin, and EuroSCORE II resulted in a C‐statistic of 0.72 (95% CI 0.67–0.77). SAF level was also associated with disability or death after 1 year (aRR 1.38 (95% CI 1.06–1.80)). The aRR for severe complications was 1.28 (95% CI 0.87–1.88).
Conclusions
Higher SAF level is associated with frailty in older cardiac surgery patients, as well as an increased risk of death or disability. This biomarker could potentially optimize preoperative risk stratification for cardiac surgery.
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 follows1) 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 outcomesdeath 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.
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.
Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, ...which may delay appropriate cause-specific treatment.
To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission.
The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission.
Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients.
CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).
Purpose
The association between benzodiazepine use and delirium risk in the ICU remains unclear. Prior investigations have failed to account for disease severity prior to delirium onset, competing ...events that may preclude delirium detection, other important delirium risk factors, and an adequate number of patients receiving continuous midazolam. The aim of this study was to address these limitations and evaluate the association between benzodiazepine exposure and ICU delirium occurrence.
Methods
In a cohort of consecutive critically ill adults, daily mental status was classified as either awake without delirium, delirium, or coma. In a first-order Markov model, multinomial logistic regression analysis was used, which considered five possible outcomes the next day (i.e., awake without delirium, delirium, coma, ICU discharge, and death) and 16 delirium-related covariables, to quantify the association between benzodiazepine use and delirium occurrence the following day.
Results
Among 1112 patients, 9867 daily transitions occurred. Benzodiazepine administration in an awake patient without delirium was associated with increased risk of delirium the next day OR 1.04 (per 5 mg of midazolam equivalent administered) 95 % CI 1.02–1.05). When the method of benzodiazepine administration was incorporated in the model, the odds of transitioning to delirium was higher with benzodiazepines given continuously (OR 1.04, 95 % CI 1.03–1.06) compared to benzodiazepines given intermittently (OR 0.97, 95 % CI 0.88–1.05).
Conclusions
After addressing potential methodological limitations of prior studies, we confirm that benzodiazepine administration increases the risk for delirium in critically ill adults but this association seems to be limited to continuous infusion use only.
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.
Background. Metaanalyses failed to demonstrate clinical benefits of beta lactam plus aminoglycoside combination therapy compared to beta lactam monotherapy in patients with sepsis. However, few data ...exist on the effects of short-course adjunctive aminoglycoside therapy in sepsis patients with organ failure or shock. Methods. We prospectively enrolled consecutive patients with severe sepsis or septic shock in 2 intensive care units in the Netherlands from 2011 to 2015. Local antibiotic protocols recommended empirical gentamicin add-on therapy in only 1 of the units. We used logistic regression analyses to determine the association between gentamicin use and the number of days alive and free of renal failure, shock, and death, all on day 14. Results. Of 648 patients enrolled, 245 received gentamicin (222 of 309 72% in hospital A and 23 of 339 7% in hospital B) for a median duration of 2 days (interquartile range, 1–3). The adjusted odds ratios associated with gentamicin use were 1.39 (95% confidence interval CI, 1.00–1.94) for renal failure, 1.34 (95% CI, 0.96–1.86) for shock duration, and 1.41 (95% CI, 0.94–2.12) for day-14 mortality. Based on in vitro susceptibilities, inappropriate (initial) gram-negative coverage was given in 9 of 245 (4%) and 18 of 403 (4%) patients treated and not treated with gentamicin, respectively (P = .62). Conclusions. Short-course empirical gentamicin use in patients with sepsis was associated with an increased incidence of renal failure but not with faster reversal of shock or improved survival in a setting with low prevalence of antimicrobial resistance.
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