Onset of Prolonged High-Potency Benzodiazepine Use Among ICU Survivors: A Nationwide Cohort Study.

OBJECTIVES: Exposure to critical illness and intensive care may lead to long-term psychologic and physical impairments. To what extent ICU survivors become prolonged users of benzodiazepines after exposure to critical care is not fully explored. This study aimed to describe the extent of onset of prolonged high-potency benzodiazepine use among ICU survivors not using these drugs before admission, identify factors associated with this use, and analyze whether such usage is associated with increased mortality. DESIGN: Retrospective cohort study. SETTING: Sweden, including all registered ICU admissions between 2010 and 2017. PATIENTS: ICU patients surviving for at least 3 months, not using high-potency benzodiazepine before admission, were eligible for inclusion. INTERVENTIONS: Admission to intensive care. MEASUREMENTS AND MAIN RESULTS: A total of 237,904 patients were screened and 137,647 were included. Of these 5338 (3.9%) became prolonged users of high-potency benzodiazepines after ICU discharge. A peak in high-potency benzodiazepine prescriptions was observed during the first 3 months, followed by sustained usage throughout the follow-up period of 18 months. Prolonged usage was associated with older age, female sex, and a history of both somatic and psychiatric comorbidities, including substance abuse. Additionally, a longer ICU stay, a high estimated mortality rate, and prior consumption of low-potency benzodiazepines were associated with prolonged use. The risk of death between 6 and 18 months post-ICU admission was significantly higher among high-potency benzodiazepine users, with an adjusted hazard ratio of 1.8 (95% CI, 1.7-2.0; p < 0.001). No differences were noted in causes of death between users and nonusers. CONCLUSIONS: Despite the lack of evidence supporting long-term treatment, prolonged usage of high-potency benzodiazepines 18 months following ICU care was notable and associated with an increased risk of death. Considering the substantial number of ICU admissions, prevention of benzodiazepine misuse may improve long-term outcomes following critical care.

Using the GAP score as a complement to the new injury severity score in identifying severely injured patients- A registry-based cohort study of adult trauma patients in Sweden.

BACKGROUND: New Injury Severity Score (NISS) and Glasgow Coma Scale, Age and Pressure (GAP) scoring systems have cutoffs to define severe injury and identify high-risk patients. This is important in trauma quality monitoring and improvement. The overall aim was to explore if GAP scoring system can be a complement or an alternative to the traditional NISS scoring system. METHODS: Adults exposed to trauma between 2017 and 2021 were included in the study, using data from The Swedish Trauma Registry. The performance of NISS and GAP scores in predicting mortality, and ICU admissions were assessed using the area under the receiver operator characteristics (AUROC) in all patients and in subgroups (blunt, penetrating trauma and older (≥65 years) trauma patients). Patients were classified as severely injured by NISS >15 as Severely Injured NISS (SIN) or with a high-risk for mortality, by GAP 3-18 as High Risk GAP (HRG). Undertriage was calculated based on the cutoffs HRG and SIN. RESULTS: Overall, 37,017 patients were included. The AUROC (95 % CI) for mortality using NISS was 0.84 (0.83-0.85) and for GAP 0.92 (0.91-0.93) (p-value <0.001), the AUROC (95 % CI) for ICU-admissions was 0.82 (0.82-0.83) using NISS and for GAP 0.70 (0.70-0.71) p-value <0.001, in the overall cohort. In older patients the AUROC (95 % CI) for mortality was 0.76 (0.75-0.78) using NISS and 0.79 (0.78-0.81) using GAP, p-value <0.001. Overall, 8,572 (23.2 %) and 2,908 (7.9 %) were classified as SIN and HRG, respectively, with mortality rates of 13.7 % and 34.3 %. In the HRG group low-energy falls dominated and in the SIN group most patients were exposed to MVCs. In the SIN and HRG groups the rate of Emergency Trauma Interventions according to Utstein guidelines (ETIU) and ICU admission was 14.0 vs 9.5 % and 47.0 vs 62.5 % respectively. CONCLUSION: Our findings suggest that the GAP score and its cutoff 3-18 can be used to define severe trauma as complement to NISS >15 and can be a valuable tool in trauma quality monitoring and improvement. However, both scoring systems were less accurate in predicting mortality for the older trauma patients and should be explored further.

Onset of Prolonged High-Potency Benzodiazepine Use Among ICU Survivors: A Nationwide Cohort Study.

OBJECTIVES: Exposure to critical illness and intensive care may lead to long-term psychologic and physical impairments. To what extent ICU survivors become prolonged users of benzodiazepines after exposure to critical care is not fully explored. This study aimed to describe the extent of onset of prolonged high-potency benzodiazepine use among ICU survivors not using these drugs before admission, identify factors associated with this use, and analyze whether such usage is associated with increased mortality. DESIGN: Retrospective cohort study. SETTING: Sweden, including all registered ICU admissions between 2010 and 2017. PATIENTS: ICU patients surviving for at least 3 months, not using high-potency benzodiazepine before admission, were eligible for inclusion. INTERVENTIONS: Admission to intensive care. MEASUREMENTS AND MAIN RESULTS: A total of 237,904 patients were screened and 137,647 were included. Of these 5338 (3.9%) became prolonged users of high-potency benzodiazepines after ICU discharge. A peak in high-potency benzodiazepine prescriptions was observed during the first 3 months, followed by sustained usage throughout the follow-up period of 18 months. Prolonged usage was associated with older age, female sex, and a history of both somatic and psychiatric comorbidities, including substance abuse. Additionally, a longer ICU stay, a high estimated mortality rate, and prior consumption of low-potency benzodiazepines were associated with prolonged use. The risk of death between 6 and 18 months post-ICU admission was significantly higher among high-potency benzodiazepine users, with an adjusted hazard ratio of 1.8 (95% CI, 1.7-2.0; p < 0.001). No differences were noted in causes of death between users and nonusers. Conclusions: Despite the lack of evidence supporting long-term treatment, prolonged usage of high-potency benzodiazepines 18 months following ICU care was notable and associated with an increased risk of death. Considering the substantial number of ICU admissions, prevention of benzodiazepine misuse may improve long-term outcomes following critical care.

Performance of Subcutaneous Continuous Glucose Monitoring in Adult Critically Ill Patients Receiving Vasopressor Therapy.

Background: Subcutaneous continuous glucose monitoring (CGM) may facilitate glucose control in the ICU. We aimed to assess the accuracy of CGM (Dexcom G6) against arterial blood glucose (ABG) in adult critically ill patients receiving intravenous insulin infusion and vasopressor therapy. We also aimed to assess feasibility and tolerability of CGM in this setting. Methods: We included ICU patients receiving mechanical ventilation, insulin, and vasopressor therapy. Numerical accuracy was assessed by the mean absolute relative difference (MARD), overall, across arterial glucose strata, over different noradrenaline equivalent infusion rates, and over time since CGM start. MARD <14% was considered acceptable. Clinical accuracy was assessed using Clarke Error Grid (CEG) analysis. Feasibility outcome included number and duration of interrupted sensor readings due to signal loss. Tolerability outcome included skin reactions related to sensor insertion or sensor adhesives. Results: We obtained 2946 paired samples from 40 patients (18 with type 2 diabetes) receiving a median (IQR) maximum noradrenaline equivalent infusion rate of 0.18 (0.08-0.33) µg/kg/min during CGM. Overall, MARD was 12.7% (95% CI 10.7-15.3), and 99.8% of CGM readings were within CEG zones A and B. MARD values ≥14% were observed when ABG was outside target range (6-10 mmol/L [108-180 mg/dL]) and with noradrenaline equivalent infusion rates above 0.10 µg/kg/min. Accuracy improved with time after CGM start, reaching MARD values <14% after 36 h. We observed four episodes of interrupted sensor readings due to signal loss, ranging from 5 to 20 min. We observed no skin reaction related to sensor insertion or sensor adhesives. Conclusions: In our ICU cohort of patients receiving vasopressor infusion, subcutaneous CGM demonstrated acceptable overall numerical and clinical accuracy. However, suboptimal accuracy may occur outside glucose ranges of 6-10 mmol/L (108-180 mg/dL), during higher dose vasopressor infusion, and during the first 36 h after CGM start.

Cognitive functioning in adolescents with severe obesity undergoing bariatric surgery or intensive non-surgical treatment in Sweden (AMOS2): a multicentre, open-label, randomised controlled trial.

Background: Severe obesity during childhood is associated with cognitive deficits. Studies in adults have suggested improvements in executive functioning and memory after bariatric surgery. Our aim was to explore changes in cognitive function in adolescents over two years after bariatric surgery or intensive non-surgical treatment. Methods: The Adolescent Morbid Obesity Surgery 2 (AMOS2) is a multicentre, open-label, randomised controlled trial in which adolescents (aged 13-16 years) with severe obesity (defined as body mass index (BMI) ≥35 kg/m2) at three specialised obesity centres in Sweden, were randomly assigned to receive bariatric surgery or intensive non-surgical treatment. Herein we report the results of the prespecified exploratory endpoint of change in cognitive functioning. Inclusion in AMOS2 required Tanner pubertal stage ≥3, previous participation in lifestyle obesity treatment for at least one year, and passed assessment form a paediatrician and a paediatric psychologist. Adolescents with severe intellectual disability or other severe, pervasive developmental disorder were excluded. Participants underwent baseline assessment of general intellectual ability, executive functioning, and memory before randomisation. Tests were administrated by clinical psychologists and repeated at one- and two-year follow-up timepoints. Differences in means between groups during follow-up are provided with confidence intervals. The trial is registered at ClinicalTrials.gov, NCT02378259. Findings: Between October 28 2015 and June 7 2017, 46 adolescents (74% girls), with a mean age of 15.8 (±0.92) years and a mean BMI of 42.8 (±5.4) kg/m2, were included and randomised (23 to bariatric surgery and 23 to intensive non-surgical treatment). At baseline 23/46 (50%) of the adolescents had general intellectual functioning classified as borderline or below. For 15/18 (83%) aspects of cognitive functioning, no significant differences in change over two years were identified between groups; Immediate (average difference during follow-up 1.0 [95% CI: -2.6 to 4.6]) and Delayed (0.5 [95% CI: -0.6 to 1.6]) Verbal Recall, Category Fluency (1.1 [95% CI: -1.6 to 3.8]) and Switching (1.5 [95% CI: -0.0 to 2.9]), Number (-6.0 [95% CI: -12.3 to 0.3]) and Letter (0.1 [95% CI: -5.2 to 5.3]) Sequencing, Number-Letter Switching (-10.3 [95% CI: -26.4 to 5.8]), Motor Speed (-8.3 [95% CI: -17.5 to 0.9]), Colour Naming (-1.9 [95% CI: -4.2 to 0.3]), Inhibition (-3.6 [95% CI: -9.6 to 2.5]), Inhibition Switching (-6.7 [95% CI: -15.3 to 1.9]), Mazes (-0.5 [95% CI: -4.9 to 3.9]), Digit Span Forward (0.1 [95% CI: -0.6 to 0.9 ]) and Backward (0.6 [95% CI: -0.4 to 1.6 ]), and Estimated IQ (0.4 [95% CI: -3.9 to 4.8]; all p > 0.05). Three sub-tests assessing fundamental cognitive skills improved more over two years in operated adolescents than in intensive non-surgical treatment; Letter Fluency (average difference during follow-up 3.8 [95% CI: 0.1-7.5]; p = 0.046), Visual Scanning (-6.5 [95% CI: -11.6 to -1.5]; p = 0.011), and Word Reading (-1.9 [95% CI: -3.3 to -0.4]; p = 0.011). Interpretation: In contrast to non-randomised studies in adults, we could not demonstrate an association of bariatric surgery and its accompanying significant weight loss with overall greater improvement in executive functions and memory in adolescents over two years compared with a non-surgical group without weight loss. However, lack of statistical power is a potential limitation. The clinical relevance of greater improvements in basic cognitive skills needs to be explored. Funding: Sweden's innovation agency (VINNOVA), Swedish Research Council, Joanna Cocozza foundation for paediatric research, The Skane University Hospital Psychology Research and Development Grant, Tore Nilsson's Foundation, SUS Foundations and Donations, and Mary von Sydow's Foundation.

Interplay of socioeconomic status, cognition, and school performance in the ABCD sample.

Coming from a disadvantaged background can have negative impact on an individual's educational trajectory. Some people however seem unaffected and cope well with the demands and challenges posed by school education, despite growing up in adverse conditions, a phenomenon termed academic resilience. While it is uncertain which underlying factors make some people more likely to circumvent unfavorable odds than others, both socioeconomic status (SES) and cognitive ability have robustly been linked to school performance. The objective of the present work is to investigate if individual cognitive abilities and SES interact in their effect on grades. For this purpose, we analyzed SES, cognitive, and school performance data from 5001 participants from the Adolescent Brain Cognitive Development (ABCD) Study. Ordinal logistic regression models suggest similar patterns of associations between three SES measures (parental education, income-to-needs ratio, and neighborhood deprivation) and grades at two timepoints, with no evidence for interaction effects between SES and time. Parental education and income-to-needs ratio were associated with grades at both timepoints, irrespective of whether cognitive abilities were modeled or not. Neighborhood deprivation, in contrast, was only a statistically significant predictor of reported grades when cognitive abilities were not factored in. Cognitive abilities interacted with parental education level, meaning that they could be a safeguard against effects of SES on school performance.

Adverse Events of Peripherally Administered Norepinephrine During Surgery: A Prospective Multicenter Study.

BACKGROUND: Perioperative treatment of hypotension by intravenous administration of norepinephrine in a peripheral vein can lead to adverse events, for example, tissue necrosis. However, the incidence and severity of adverse events during perioperative administration are unknown. METHODS: This was a prospective observational study conducted at 3 Swedish hospitals from 2019 to 2022. A total of 1004 patients undergoing surgery, who met the criteria for perioperative peripheral norepinephrine administration, were included. The infusion site was inspected regularly. If swelling or paleness of skin was detected, the infusion site was changed to a different peripheral line. Systolic blood pressure and pulse frequency were monitored during the infusion time and defined as adverse events at >220 mm Hg and <40 beats•min -1 . In case of adverse events, patients were observed for up to 48 hours. The primary outcome was prevalence of extravasation, defined as swelling around the infusion site. Secondary outcomes were all types of adverse events and associations between predefined clinical variables and risk of adverse events. RESULTS: We observed 2.3% (95% confidence interval [CI], 1.4%-3.2%) extravasation of infusion and 0.9% (95% CI, 0.4%-1.7%) bradycardia. No cases of tissue necrosis or severe hypertension were detected. All adverse events had dissipated spontaneously within 48 hours. Proximal catheter placement was associated with more adverse events. CONCLUSIONS: Extravasation of peripherally administrated norepinephrine in the perioperative period occurred at similar rates as in previous studies in critically ill patients. In our setting, where we regularly inspected the infusion site and shifted site in case of swelling or paleness of skin, we observed no case of severe adverse events. Given that severe adverse events were absent, the potential benefit of this preventive approach requires confirmation in a larger population.

Trends in Incidence and Outcomes of Cardiac Arrest Occurring in Swedish ICUs.

OBJECTIVE: To determine temporal trends in the incidence of cardiac arrest occurring in the ICU (ICU-CA) and its associated long-term mortality. DESIGN: Retrospective observational study. SETTING: Swedish ICUs, between 2011 and 2017. PATIENTS: Adult patients (≥18 yr old) recorded in the Swedish Intensive Care Registry (SIR). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ICU-CA was defined as a first episode of cardiopulmonary resuscitation and/or defibrillation following an ICU admission, as recorded in SIR or the Swedish Cardiopulmonary Resuscitation Registry. Annual adjusted ICU-CA incidence trend (all admissions) was estimated using propensity score-weighted analysis. Six-month mortality trends (first admissions) were assessed using multivariable mixed-effects logistic regression. Analyses were adjusted for pre-admission characteristics (sex, age, socioeconomic status, comorbidities, medications, and healthcare utilization), illness severity on ICU admission, and admitting unit. We included 231,427 adult ICU admissions. Crude ICU-CA incidence was 16.1 per 1,000 admissions, with no significant annual trend in the propensity score-weighted analysis. Among 186,530 first admissions, crude 6-month mortality in ICU-CA patients was 74.7% (95% CI, 70.1-78.9) in 2011 and 68.8% (95% CI, 64.4-73.0) in 2017. When controlling for multiple potential confounders, the adjusted 6-month mortality odds of ICU-CA patients decreased by 6% per year (95% CI, 2-10). Patients admitted after out-of-hospital or in-hospital cardiac arrest had the highest ICU-CA incidence (136.1/1,000) and subsequent 6-month mortality (76.0% [95% CI, 73.6-78.4]). CONCLUSIONS: In our nationwide Swedish cohort, the adjusted incidence of ICU-CA remained unchanged between 2011 and 2017. More than two-thirds of patients with ICU-CA did not survive to 6 months following admission, but a slight improvement appears to have occurred over time.

Beyond the language network: Associations between reading, receptive vocabulary, and grey matter volume in 10-year-olds.

Most research on the neurostructural basis of language abilities in children stems from small samples and surface-based measures. To complement and expand the existent knowledge, we investigated associations between grey matter volume and language performance in a large sample of 9-to-11-year-old children, using data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 1865) and an alternative measure of grey matter morphology. We estimated whole-brain grey matter volume for one half of the sample (N = 939) and tested for correlations with scores on a picture vocabulary and a letter and word reading test, with and without factoring in general intelligence and total grey matter volume as additional covariates. The initial analyses yielded correlations between grey matter in the right occipital fusiform gyrus, the right lingual gyrus, and the cerebellum for both vocabulary and reading. Employing the significant clusters from the first analyses as regions of interest in the second half of the cohort (N = 926) in correlational and multiple regression analyses suggests the cluster in the right occipital fusiform and lingual gyri to be most robust. Overall, the amount of variance explained by grey matter volume is limited and factoring in additional covariates paints an inconsistent picture. The present findings reinforce existent doubt with respect to explaining individual differences in reading and vocabulary performance based on unique contributions of macrostructural brain features.

Clinical outcomes during and beyond different COVID-19 critical illness variant periods compared with other lower respiratory tract infections.

BACKGROUND: It is yet to be better understood how outcomes during and after the critical illness potentially differ between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants from other lower respiratory tract infections (LRTIs). We aimed to compare outcomes in adults admitted to an intensive care unit (ICU) with coronavirus disease 2019 (COVID-19) during the Wild-type, Alpha, Delta, and Omicron periods with individuals admitted with other LRTI. METHODS: Population-based cohort study in Stockholm, Sweden, using health registries with high coverage, including ICU-admitted adults from 1 January 2016 to 15 September 2022. Outcomes were in-hospital mortality, 180-day post-discharge mortality, 180-day hospital readmission, 180-day days alive and at home (DAAH), and incident diagnoses registered during follow-up. RESULTS: The number of ICU admitted individuals were 1421 Wild-type, 551 Alpha, 190 Delta, 223 Omicron, and 2380 LRTI. In-hospital mortality ranged from 28% (n = 665) in the LRTI cohort to 35% (n = 77) in the Delta cohort. The adjusted cause-specific hazard ratio (CSHR) compared with the LRTI cohort was 1.33 (95% confidence interval [CI] 1.16-1.53) in the Wild-type cohort, 1.53 (1.28-1.82) in the Alpha cohort, 1.70 (1.30-2.24) in the Delta cohort, and 1.59 (1.24-2.02) in the Omicron cohort. Among patients discharged alive from their COVID-19 hospitalization, the post-discharge mortality rates were lower (1-3%) compared with the LRTI cohort (9%), and the risk of hospital readmission was lower (CSHRs ranging from 0.42 to 0.68). Moreover, all COVID-19 cohorts had compared with the LRTI cohort more DAAH after compared with before the critical illness. CONCLUSION: Overall, COVID-19 critical was associated with an increased hazard of in-hospital mortality, but among those discharged alive from the hospital, less severe long-term outcomes were observed compared with other LRTIs.

A retrospective multicenter cohort study of the association between anti-Factor Xa values and death, thromboembolism, and bleeding in patients with critical COVID-19.

BACKGROUND: Patients with critical COVID-19 have a high risk of thromboembolism, but intensified thromboprophylaxis has not been proven beneficial. The activity of low-molecular-weight heparins can be monitored by measuring anti-Factor Xa. We aimed to study the association between anti-Factor Xa values and death, thromboembolism, and bleeding in patients with critical COVID-19. METHOD: This retrospective cohort study included adult patients with critical COVID-19 admitted to an intensive care unit at three Swedish hospitals between March 2020 and May 2021 with at least one valid peak and/or trough anti-Factor Xa value. Within the peak and trough categories, patients' minimum, median, and maximum values were determined. Logistic regressions with splines were used to assess associations. RESULTS: In total, 408 patients had at least one valid peak and/or trough anti-Factor Xa measurement, resulting in 153 patients with peak values and 300 patients with trough values. Lower peak values were associated with thromboembolism for patients' minimum (p = 0.01), median (p = 0.005) and maximum (p = 0.001) values. No association was seen between peak values and death or bleeding. Higher trough values were associated with death for median (p = 0.03) and maximum (p = 0.002) values and with both bleeding (p = 0.01) and major bleeding (p = 0.02) for maximum values, but there were no associations with thromboembolism. CONCLUSIONS: Measuring anti-Factor Xa activity may be relevant for administrating low-molecular-weight heparin to patients with critical COVID-19. Lower peak values were associated with an increased risk of thromboembolism, and higher trough values were associated with an increased risk of death and bleeding. Prospective studies are needed to confirm the results. TRIAL REGISTRATION: The study was retrospectively registered at Clinicaltrials.gov, NCT05256524, February 24, 2022.

Prevalence and impact of chronic dysglycaemia among patients with COVID-19 in Swedish intensive care units: a multicentre, retrospective cohort study.

OBJECTIVE: Using glycated haemoglobin A1c (HbA1c) screening, we aimed to determine the prevalence of chronic dysglycaemia among patients with COVID-19 admitted to the intensive care unit (ICU). Additionally, we aimed to explore the association between chronic dysglycaemia and clinical outcomes related to ICU stay. DESIGN: Multicentre retrospective observational study. SETTING: ICUs in three hospitals in Stockholm, Sweden. PARTICIPANTS: COVID-19 patients admitted to the ICU between 5 March 2020 and 13 August 2020 with available HbA1c at admission. Chronic dysglycaemia was determined based on previous diabetes history and HbA1c. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was the actual prevalence of chronic dysglycaemia (pre-diabetes, unknown diabetes or known diabetes) among COVID-19 patients. Secondary outcome was the association of chronic dysglycaemia with 90-day mortality, ICU length of stay, duration of invasive mechanical ventilation (IMV) and renal replacement therapy (RRT), accounting for treatment selection bias. RESULTS: A total of 308 patients with available admission HbA1c were included. Chronic dysglycaemia prevalence assessment was restricted to 206 patients admitted ICUs in which HbA1c was measured on all admitted patients. Chronic dysglycaemia was present in 82.0% (95% CI 76.1% to 87.0%) of patients, with pre-diabetes present in 40.2% (95% CI 33.5% to 47.3%), unknown diabetes in 20.9% (95% CI 15.5% to 27.1%), well-controlled diabetes in 7.8% (95% CI 4.5% to 12.3%) and uncontrolled diabetes in 13.1% (95% CI 8.8% to 18.5%). All patients with available HbA1c were included for the analysis of the relationship between chronic dysglycaemia and secondary outcomes. We found no independent association between chronic dysglycaemia and 90-day mortality, ICU length of stay or duration of IMV. After excluding patients with specific treatment limitations, no association between chronic dysglycaemia and RRT use was observed. CONCLUSIONS: In our cohort of critically ill COVID-19 patients, the prevalence of chronic dysglycaemia was 82%. We found no robust associations between chronic dysglycaemia and clinical outcomes when accounting for treatment limitations.

Analysis of Calprotectin as an Early Marker of Infections Is Economically Advantageous in Intensive Care-Treated Patients.

Calprotectin is released from neutrophil granulocytes upon activation. Several studies have indicated that plasma calprotectin is an early determinant of bacterial infections, which may serve as a diagnostic tool facilitating decision making on antibiotic treatment. The study objective was to explore the health and economic implications of calprotectin as a predictive tool to initiate antimicrobial therapy in a cohort of critically ill patients. Thus, data obtained from a previously published study on calprotectin as a hypothetical early biomarker of bacterial infections in critically ill patients were evaluated regarding the potential cost-effective impact of early analysis of calprotectin on an earlier start of antibiotic treatment. Under the assumption that calprotectin is used predictively and comparators (white blood cells, procalcitonin, and C-reactive protein) are used diagnostically, a cost-effective impact of EUR 11,000-12,000 per patient would be obtained. If calprotectin would be used predictively and comparators would be used predictively for 50% of patients, it is hypothesized that cost-effectiveness would be between EUR 6000 and 7000 per patient, based on reduced stay in the ICU and general ward, respectively. Furthermore, predictive use of calprotectin seems to reduce both mortality and the length of hospital stay. This health economic analysis on the predictive use of plasma calprotectin, which facilitates clinical decision making in cases of suspected sepsis, indicates that such determination has a cost-saving and life-saving impact on the healthcare system.

Probing brain tissue microstructure with MRI: principles, challenges, and the role of multidimensional diffusion-relaxation encoding.

Diffusion MRI uses the random displacement of water molecules to sensitize the signal to brain microstructure and to properties such as the density and shape of cells. Microstructure modeling techniques aim to estimate these properties from acquired data by separating the signal between virtual tissue 'compartments' such as the intra-neurite and the extra-cellular space. A key challenge is that the diffusion MRI signal is relatively featureless compared with the complexity of brain tissue. Another challenge is that the tissue microstructure is wildly different within the gray and white matter of the brain. In this review, we use results from multidimensional diffusion encoding techniques to discuss these challenges and their tentative solutions. Multidimensional encoding increases the information content of the data by varying not only the b-value and the encoding direction but also additional experimental parameters such as the shape of the b-tensor and the echo time. Three main insights have emerged from such encoding. First, multidimensional data contradict common model assumptions on diffusion and T2 relaxation, and illustrates how the use of these assumptions cause erroneous interpretations in both healthy brain and pathology. Second, many model assumptions can be dispensed with if data are acquired with multidimensional encoding. The necessary data can be easily acquired in vivo using protocols optimized to minimize Cramér-Rao lower bounds. Third, microscopic diffusion anisotropy reflects the presence of axons but not dendrites. This insight stands in contrast to current 'neurite models' of brain tissue, which assume that axons in white matter and dendrites in gray matter feature highly similar diffusion. Nevertheless, as an axon-based contrast, microscopic anisotropy can differentiate gray and white matter when myelin alterations confound conventional MRI contrasts.

A neurophenomenological fMRI study of a spontaneous automatic writer and a hypnotic cohort.

PURPOSE: To evaluate the neurophenomenology of automatic writing (AW) in a spontaneous automatic writer (NN) and four high hypnotizables (HH). METHODS: During fMRI, NN and the HH were cued to perform spontaneous (NN) or induced (HH) AW, and a comparison task of copying complex symbols, and to rate their experience of control and agency. RESULTS: Compared to copying, for all participants AW was associated with less sense of control and agency and decreased BOLD signal responses in brain regions implicated in the sense of agency (left premotor cortex and insula, right premotor cortex, and supplemental motor area), and increased BOLD signal responses in the left and right temporoparietal junctions and the occipital lobes. During AW, the HH differed from NN in widespread BOLD decreases across the brain and increases in frontal and parietal regions. CONCLUSIONS: Spontaneous and induced AW had similar effects on agency, but only partly overlapping effects on cortical activity.

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock.

PURPOSE: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. METHODS: We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. RESULTS: Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) - 4.8 to 7.8]. Mean differences were 0.00 (99% CI - 0.06 to 0.05) for EQ-5D-5L index values, - 0.65 for EQ VAS (- 5.40 to 4.08), and - 0.14 for Mini MoCA (- 1.59 to 1.14) for the restrictive-fluid group versus the standard-fluid group. The results for survivors only were similar in both groups. CONCLUSIONS: Among adult ICU patients with septic shock, restrictive versus standard IV fluid therapy resulted in similar survival, HRQoL, and cognitive function at 1 year, but clinically important differences could not be ruled out.

Sodium glucose co-transporter-2 inhibitors in intensive care unit patients with type 2 diabetes: a pilot case control study.

BACKGROUND: Sodium glucose co-transporter-2 (SGLT2) inhibitors improve long-term cardiovascular and renal outcomes in individuals with type 2 diabetes. However, the safety of SGLT2 inhibitors in ICU patients with type 2 diabetes is uncertain. We aimed to perform a pilot study to assess the relationship between empagliflozin therapy and biochemical, and clinical outcomes in such patients. METHODS: We included 18 ICU patients with type 2 diabetes receiving empagliflozin (10 mg daily) and insulin to target glucose range of 10-14 mmol/l according to our liberal glucose control protocol for patients with diabetes (treatment group). Treatment group patients were matched on age, glycated hemoglobin A1c, and ICU duration with 72 ICU patients with type 2 diabetes exposed to the same target glucose range but who did not receive empagliflozin (control group). We compared changes in electrolyte and acid-base parameters, hypoglycemia, ketoacidosis, worsening kidney function, urine culture findings, and hospital mortality between the groups. RESULTS: Median (IQR) maximum increase in sodium and chloride levels were 3 (1-10) mmol/l and 3 (2-8) mmol/l in the control group and 9 (3-12) mmol/l and 8 (3-10) mmol/l in the treatment group (P = 0.045 for sodium, P = 0.059 for chloride). We observed no differences in strong ion difference, pH or base excess. Overall, 6% developed hypoglycemia in each group. No patient in the treatment group and one patient in the control group developed ketoacidosis. Worsening kidney function occurred in 18% and 29% of treatment and control group patients, respectively (P = 0.54). Urine cultures were positive in 22% of treatment group patients and 13% of control group patients (P = 0.28). Overall, 17% of treatment group patients and 19% of control group patients died in hospital (P = 0.79). CONCLUSIONS: In our pilot study of ICU patients with type 2 diabetes, empagliflozin therapy was associated with increases in sodium and chloride levels but was not significantly associated with acid-base changes, hypoglycemia, ketoacidosis, worsening kidney function, bacteriuria, or mortality.

Nonlinear brain correlates of trait self-boundarylessness.

Alterations of the sense of self induced by meditation include an increased sense of boundarylessness. In this study, we investigated behavioural and functional magnetic resonance imaging correlates of trait self-boundarylessness during resting state and the performance of two experimental tasks. We found that boundarylessness correlated with greater self-endorsement of words related to fluidity and with longer response times in a math task. Boundarylessness also correlated negatively with brain activity in the posterior cingulate cortex/precuneus during mind-wandering compared to a task targeting a minimal sense of self. Interestingly, boundarylessness showed quadratic relations to several measures. Participants reporting low or high boundarylessness, as compared to those in between, showed higher functional connectivity within the default mode network during rest, less brain activity in the medial prefrontal cortex during self-referential word processing, and less self-endorsement of words related to constancy. We relate these results to our previous findings of a quadratic relation between boundarylessness and the sense of perspectival ownership of experience. Additionally, an instruction to direct attention to the centre of experience elicited brain activation similar to that of meditation onset, including increases in anterior precentral gyrus and anterior insula and decreases in default mode network areas, for both non-meditators and experienced meditators.

Effects of 12 mg vs. 6 mg dexamethasone on thromboembolism and bleeding in patients with critical COVID-19 - a post hoc analysis of the randomized, blinded COVID STEROID 2 trial.

BACKGROUND: Thromboembolism is more common in patients with critical COVID-19 than in other critically ill patients, and inflammation has been proposed as a possible mechanism. The aim of this study was to investigate if 12 mg vs. 6 mg dexamethasone daily reduced the composite outcome of death or thromboembolism in patients with critical COVID-19. METHODS: Using additional data on thromboembolism and bleeding we did a post hoc analysis of Swedish and Danish intensive care unit patients enrolled in the blinded randomized COVID STEROID 2 trial comparing 12 mg vs. 6 mg dexamethasone daily for up to 10 days. The primary outcome was a composite outcome of death or thromboembolism during intensive care. Secondary outcomes were thromboembolism, major bleeding, and any bleeding during intensive care. RESULTS: We included 357 patients. Whilst in intensive care, 53 patients (29%) in the 12 mg group and 53 patients (30%) in the 6 mg group met the primary outcome with an unadjusted absolute risk difference of - 0.5% (95% CI - 10 to 9.5%, p = 1.00) and an adjusted OR of 0.93 (CI 95% 0.58 to 1.49, p = 0.77). We found no firm evidence of differences in any of the secondary outcomes. CONCLUSIONS: Among patients with critical COVID-19, 12 mg vs. 6 mg dexamethasone daily did not result in a statistically significant difference in the composite outcome of death or thromboembolism. However, uncertainty remains due to the limited number of patients.