Explore the vast range of titles available.

Background Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. Methods We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA - (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. Results Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4 , PDE4D , MMP8 , CRISP3 , and BCL2L15 . Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay ( pre-DEXA : 42 [29–49] vs. 18 [13–27] days, p < 0.001; DEXA : 42 [28–57] vs. 13 [7–24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes. Conclusions ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.

Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods. Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20 ± 4 % and 13 ± 3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7 ± 3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques. In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.

This study aimed to assess the effectiveness of an architectural redesign and a multicomponent intervention bundle on noise reduction to enhance workplace safety. Quasi-experimental study with a time-series and intensified intervention design conducted in an intermediate care unit. Two interventions were sequential introduced: the installation of a partition wall in the medication preparation room (architectural redesign) and the implementation of an a bundle. Effects on outcomes were evaluated comparing baseline, after architectural redesign (period-1) and after implementation of the bundle (period-2). Intermediate care unit. A-weighted sound levels (LAeq), alarms/day/bed, annoyance ratings (numeric rating scale 0–10) and number of distractions of nurses during the medication preparation process. LAeq baseline vs period-1, decreased in the medication preparation area from 56.8 (±5.0) to 53.7 (±7.2) dBA (p < 0.001) and in the nursing station from 56.8 (±5.0) to 54.3 (±4.0) dBA (p < 0.001). During period-2, further noise reduction was minimal to absent. Distractions decreased from 58 % during baseline to 45 % (p < 0.001) during period-1, with no further reduction during period-2. The median [IQR] number of alarms/day/bed increased from 263 [IQR 193–320] during baseline to 394 [IQR 258–474] during period-1 (p < 0.001), then decreased to 303 [IQR 264–370] (p < 0.05) during period-2. Median annoyance ratings decreased from baseline 3.0 [IQR 2.0–6.0] to 2.0 [IQR 1.0–3.0] (p < 0.001) during period-2. An architectural redesign resulted in a significant, clinically relevant decrease in sound levels along with a notable reduction in distractions. The multicomponent bundle lowered alarms and annoyance ratings; however, its effectiveness on other outcomes seems less persuasive. Architectural redesign seems to be effective in controlling environmental noise. Architectural redesign results in a decrease in nurses’ distractions during the medication preparation process. The effect of an intervention bundle is, despite a positive effect on alarms and perceived annoyance, still insufficiently clear.

BackgroundBurnout threatens intensive care unit (ICU) professionals’ capacity to provide high-quality care. Moral distress is previously considered a root cause of burnout, but there are other risk factors of burnout such as personality, work–life balance and culture. This study aimed to disentangle the associations of ICU professionals’ moral distress and other risk factors with the components of burnout—emotional exhaustion, depersonalisation and personal accomplishment—suggesting informed burnout prevention strategies.MethodsCross-sectional survey completed in 2019 of ICU professionals in two Dutch hospitals. The survey included validated measure for burnout (the Dutch Maslach Burnout Inventory), moral distress (Moral Distress Scale), personality (short Big Five Inventory), work–home balance (Survey Work–Home Interaction Nijmegen) and organisational culture (Culture of Care Barometer). Each of the three components of burnout was analysed as a separate outcome, and for each of the components, a separate regression analysis was carried out.Results251 ICU professionals responded to the survey (response rate: 53.3%). Burnout prevalence was 22.7%. Findings showed that moral distress was associated with emotional exhaustion (β=0.18, 95% CI 0.9 to 0.26) and depersonalisation (β=0.19, 95% CI 0.10 to 0.28) and with increased emotional exhaustion mediated by negative work-to-home spillover (β=0.09, 95% CI 0.04 to 0.13). Support from direct supervisors mitigates the association between moral distress and emotional exhaustion (β=0.16, 95% CI 0.04 to 0.27).ConclusionsUnderstanding moral distress as a root cause of burnout is too simplified. There is an important interplay between moral distress and work–home imbalance. Interventions that support individual coping with moral distress and a work–home imbalance, and the support of direct supervisors, are paramount to prevent burnout in physicians and nurses.

Background Neuroinflammation is thought to play an important role in the pathogenesis of ICU-acquired delirium, but the association between inflammatory and brain-specific proteins and ICU delirium is poor. We investigated whether or not serial determinations of markers may improve this association. Methods Critically ill patients with a high risk of ICU delirium and with an ICU length of stay of at least 6 days were included in the study. Blood was drawn on days 1, 2, 4 and 6 after ICU admission and analyzed for different markers of inflammation and several brain proteins. Differences in courses over time prior to and following the onset of delirium and absolute differences over time were analyzed in patients with and without delirium using repeated measurement analysis of variance. In addition, a cross-sectional analysis of levels of these markers before the first onset of delirium was performed. Results Fifty patients were included in this study. In the longitudinal analysis, there were no differences in the levels of any of the markers immediately prior to and following the onset of delirium, but overall, median levels of adiponectin (9019 (IQR 5776–15,442) vs. 6148 (IQR 4447–8742) ng/ml, p  = 0.05) were significantly higher in patients with delirium compared to patients without delirium. In the cross-sectional analysis, median levels of the brain protein Tau (90 (IQR 46–224) vs. 31 (IQR 31–52) pg/ml, p  = 0.009) and the ratio Tau/amyloid β 1–42 (1.42 ((IQR 0.9–2.57) vs. 0.68 (IQR 0.54–0.96), p  = 0.003) were significantly higher in patients with hypoactive delirium compared to patients without. Levels of neopterin (111 (IQR 37–111) vs. 29 (IQR 16–64) mmol/l, p  = 0.004) and IL-10 (28 (IQR 12–39) vs. 9 (IQR 4–12) pg/ml, p  = 0.001) were significantly higher in patients with hypoactive delirium compared to patients with mixed-type delirium. Conclusions While there are differences in markers (adiponectin and several brain proteins) between patients with and without delirium, the development of delirium is not preceded by a change in the biomarker profile of inflammatory markers or brain proteins. Patients with hypoactive delirium account for the observed differences in biomarkers. Trial registration ClinicalTrials.gov, NCT 01274819 . Registered on 12 January 2011.

Background Variation in intensive care unit (ICU) readmissions and in-hospital mortality after ICU discharge may indicate potential for improvement and could be explained by ICU discharge practices. Our objective was threefold: (1) describe variation in rates of ICU readmissions within 48 h and post-ICU in-hospital mortality, (2) describe ICU discharge practices in Dutch hospitals, and (3) study the association between rates of ICU readmissions within 48 h and post-ICU in-hospital mortality and ICU discharge practices. Methods We analysed data on 42,040 admissions to 82 (91.1%) Dutch ICUs in 2011 from the Dutch National Intensive Care Evaluation (NICE) registry to describe variation in standardized ICU readmission and post-ICU mortality rates using funnel-plots. We send a questionnaire to all Dutch ICUs. 75 ICUs responded and their questionnaire data could be linked to 38,498 admissions in the NICE registry. Generalized estimation equations analyses were used to study the association between ICU readmissions and post-ICU mortality rates and the identified discharge practices, i.e. (1) ICU discharge criteria; (2) bed managers; (3) early discharge planning; (4) step-down facilities; (5) medication reconciliation; (6) verbal and written handover; (7) monitoring of post-ICU patients; and (8) consulting ICU nurses. In all analyses, the outcomes were corrected for patient-related confounding factors. Results The standardized rate of ICU readmissions varied between 0.14 and 2.67 and 20.8% of the hospitals fell outside the 95% control limits and 3.6% outside the 99.8% control limits. The standardized rate of post-ICU mortality varied between 0.07 and 2.07 and 17.1% of the hospitals fell outside the 95% control limits and 4.9% outside the 99.8% control limits. We could not demonstrate an association between the eight ICU discharge practices and rates of ICU readmissions or post-ICU in-hospital mortality. Implementing a higher number of ICU discharge practices was also not associated with better patient outcomes. Conclusions We found both variation in patient outcomes and variation in ICU discharge practices between ICUs. However, we found no association between discharge practices and rates of ICU readmissions or post-ICU mortality. Further research is necessary to find factors, which may influence these patient outcomes, in order to improve quality of care.

Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot be voluntarily influenced. Herein, we evaluated the effects of a training program on the autonomic nervous system and innate immune response. Healthy volunteers were randomized to either the intervention (n = 12) or control group (n = 12). Subjects in the intervention group were trained for 10 d in meditation (third eye meditation), breathing techniques (i.a., cyclic hyperventilation followed by breath retention), and exposure to cold (i.a., immersions in ice cold water). The control group was not trained. Subsequently, all subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli endotoxin). In the intervention group, practicing the learned techniques resulted in intermittent respiratory alkalosis and hypoxia resulting in profoundly increased plasma epinephrine levels. In the intervention group, plasma levels of the anti-inflammatory cytokine IL-10 increased more rapidly after endotoxin administration, correlated strongly with preceding epinephrine levels, and were higher. Levels of proinflammatory mediators TNF-α, IL-6, and IL-8 were lower in the intervention group and correlated negatively with IL-10 levels. Finally, flu-like symptoms were lower in the intervention group. In conclusion, we demonstrate that voluntary activation of the sympathetic nervous system results in epinephrine release and subsequent suppression of the innate immune response in humans in vivo. These results could have important implications for the treatment of conditions associated with excessive or persistent inflammation, such as autoimmune diseases.

Septic shock is a major cause of death worldwide and a considerable healthcare burden in the twenty-first century. Attention has shifted from damaging effects of the proinflammatory response to the detrimental role of antiinflammation, a phenomenon known as sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis may render patients vulnerable to secondary infections and is associated with impaired outcome. The immunoparalysis hypothesis compels us to reevaluate the current management of septic shock and to assess whether we are inadvertently compromising or altering the host immune response. In this perspective, we discuss the potential detrimental role of norepinephrine, the cornerstone treatment for septic shock, in sepsis-induced immunoparalysis. We provide a short overview of the current understanding of the immunologic pathophysiology of sepsis, followed by a detailed description of the immunomodulatory effects of norepinephrine and alternative vasopressors. We conclude that although the development of novel therapies aimed at reversing immunoparalysis is underway, the use of norepinephrine may aggravate the development, extent, and duration of sepsis-induced immunoparalysis. Current in vitro and animal data indicate that norepinephrine treatment exerts immunosuppressive and bacterial growth–promoting effects and may increase susceptibility toward infections. However, evidence in humans is circumstantial, as immunologic effects of norepinephrine have not been investigated properly in experimental or clinical studies. Alternatives such as vasopressin/selepressin, angiotensin II, and phenylephrine could have a fundamental advantage over norepinephrine with respect to their immunologic properties. However, also for these agents, in vivo immunologic data in humans are largely lacking. As such, human studies on the immunomodulatory properties of norepinephrine and viable alternatives are highly warranted.

Background A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation. Methods In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day − 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment. Results Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) ( p  = 0.0002), ferritin ( p  = 0.009), and temperature ( p  = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature ( p  = 0.03), white blood cell counts ( p  = 0.02), and plasma levels of ferritin ( p  = 0.003), procalcitonin ( p  = 0.001), creatinine ( p  = 0.01), and bilirubin ( p  = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results. Conclusions Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.

Abstract Sepsis is the leading cause of death in the intensive care unit and ranks in the top 10 causes of death in general worldwide. Proinflammatory mediators are related to symptoms observed early in patients with sepsis, such as fever and hemodynamic instability. However, in recent years it has become clear that most septic patients do not die from an overwhelming proinflammatory immune response but in an immunosuppressive state, which can last for days or even weeks, and that results in increased susceptibility to secondary (opportunistic) infections. Although infection control and supportive therapies will remain the cornerstone of treatment, especially in the early phase of sepsis, the identification of this so-called “immunoparalysis” is currently causing a paradigm shift in the adjunctive treatment of sepsis from therapies that suppress the immune system toward immunostimulation. In this Critical Care Perspective we give an overview of the pathophysiology of sepsis, with a focus on immunosuppressive mechanisms that play an important role in outcome. In addition, we present an appraisal of the recent advances in immunotherapy as an adjunctive treatment for sepsis.