Concentration-dependent microvascular responses to repeated iontophoresis of acetylcholine.

BACKGROUND: Iontophoresis studies face challenges due to the unknown absolute drug dose delivered and the possible effect of the current used in drug delivery on the microvessels, known as current-induced vasodilation. This study aimed to investigate how various concentrations of acetylcholine (ACh), delivered through transdermal iontophoresis using repeated current pulses, impact the recovery profile of the microvascular response. METHODS: The study included fifteen healthy volunteers, and microvascular responses to five concentrations of iontophorised ACh (ranging from 0.0055 mM to 55 mM) and sterile water were assessed at six forearm skin sites using polarized reflectance spectroscopy. Iontophoresis at each concentration involved three consecutive pulses separated 8 recovery periods. RESULTS: Current-induced responses were more pronounced for lower concentrations of ACh and for sterile water. With repeated pulses, lower concentrations of ACh exhibited a recovery profile more akin to higher concentrations. PERSPECTIVE: Through repeated iontophoresis of ACh, microvascular responses exhibit variation based on the drug concentration and the number of pulses administered. These variations are likely attributed to changes in skin conductivity and permeability.

Frailty is associated with 30-day mortality: a multicentre study of Swedish emergency departments.

BACKGROUND: Older patients living with frailty have an increased risk for adverse events. The Clinical Frailty Scale (CFS) is a 9-point frailty assessment instrument that has shown promise to identify frail emergency department (ED) patients at increased risk of adverse outcomes. The aim of this study was to investigate the association between CFS scores and 30-day mortality in an ED setting when assessments are made by regular ED staff. METHOD: This was a prospective multicentre observational study carried out between May and November 2021 at three EDs in Sweden, where frailty via CFS is routinely assessed by ED staff. All patients ≥65 years of age were eligible for inclusion. Mortality at 7, 30 and 90 days, admission rate, ED and hospital length of stay (LOS) were compared between patients living with frailty (CFS≥5) and robust patients. Logistic regression was used to adjust for confounders. RESULTS: A total of 1840 ED visits of patients aged ≥65 years with CFS assessments done during the study period were analysed, of which 606 (32.9%) were patients living with frailty. Mortality after the index visit was higher in patients living with frailty at 7 days (2.6% vs 0.2%), 30 days (7.9% vs 0.9%) and 90 days (15.5% vs 2.4%). Adjusted ORs for mortality for those with frailty compared with more robust patients were 9.9 (95% CI 2.1 to 46.5) for 7-day, 6.0 (95% CI 3.0 to 12.2) for 30-day and 5.7 (95% CI 3.6 to 9.1) 90-day mortality. Patients living with frailty had higher admission rates, 58% versus 36%, a difference of 22% (95% CI 17% to 26%), longer ED LOS, 5 hours:08 min versus 4 hours:36 min, a difference of 31 min (95% CI 14 to 50), and longer in-hospital LOS, 4.8 days versus 2.7 days, a difference of 2.2 days (95% CI 1.2 to 3.0). CONCLUSION: Patients living with frailty, had significantly higher mortality and admission rates as well as longer ED and in-hospital LOS compared with robust patients. The results confirm the capability of the CFS to risk stratify short-term mortality in older ED patients. TRIAL REGISTRATION NUMBER: NCT04877028.

Revisits and frailty in older patients in the emergency department - a prospective observational multicenter study.

BACKGROUND: An increased number of revisits may signal that the immediate medical needs of patients seeking care at Emergency Departments (EDs) are not being met. The prevalence and characteristics of revisits to the EDs in Sweden among older patients, and its association to frailty, are unknown. We aimed to investigate the prevalence of ED revisits among patients over 65 years of age, living with or without frailty, and its association with rate of admission, and mortality; in the Swedish ED setting. METHODS: This was a prospective, multicentre study of patients over 65 years of age with an index visit to one of three Swedish EDs during May-Nov 2021. Frailty was assessed in conjunction with standard triage, using the 9-level Clinical Frailty Scale (CFS) with a CFS score of 5 to 8 as cut-off for identifying frailty. For all patients who made a revisit within 90 days of their index visit, we collected information about the revisit, admission, and mortality. RESULTS: A total of 1835 patients made an index visit which were included, and out of those, 595 patients made a revisit within 90 days of the index visit. Patients living with frailty (CFS 5 to 8) were more likely to make a revisit to the ED at 8 to 30 days (17% vs. 11%, diff 6%, 95% CI 2-10%, p < 0.001) and at 31 to 90 days (19% vs. 12%, diff 7%, 95% CI 3-10%, p < 0.001) and be admitted to in-hospital care during their revisit (57% vs. 47%, diff 10%, 95% CI, 1-18%, p < 0.05), compared to patients living without frailty. Results also show that patients living with frailty had a higher overall mortality rate (17% vs. 5%, diff 12%, 95% CI 7-18%, p < 0.001). However, among patients living without frailty, making a revisit slightly increased the mortality rate compared to those who did not (5% vs. 2%, diff 3%, 95% CI 1-10%, p < 0.05). CONCLUSIONS: Patients living with frailty make more revisits, are more often admitted to in-hospital care, and have a higher overall mortality rate than patients not living with frailty. Frailty, assessed with the CFS may be a simple and useful indicator of increased risk of adverse events, including revisits, in the ED.

Is the clinical frailty scale feasible to use in an emergency department setting? A mixed methods study.

BACKGROUND: The Clinical Frailty Scale (CFS) is a frailty assessment tool used to identify frailty in older patients visiting the emergency department (ED). However, the current understanding of how it is used and accepted in ED clinical practice is limited. This study aimed to assess the feasibility of CFS in an ED setting. METHODS: This was a prospective, mixed methods study conducted in three Swedish EDs where CFS had recently been introduced. We examined the completion rate of CFS assessments in relation to patient- and organisational factors. A survey on staff experience of using CFS was also conducted. All quantitative data were analysed descriptively, while free text comments underwent a qualitative content analysis. RESULTS: A total of 4235 visits were analysed, and CFS assessments were performed in 47%. The completion rate exceeded 50% for patients over the age of 80. Patients with low triage priority were assessed to a low degree (24%). There was a diurnal variation with the highest completion rates seen for arrivals between 6 and 12 a.m. (58%). The survey response rate was 48%. The respondents rated the perceived relevance and the ease of use of the CFS with a median of 5 (IQR 2) on a scale with 7 being the highest. High workload, forgetfulness and critical illness were ranked as the top three barriers to assessment. The qualitative analysis showed that CFS assessments benefit from a clear routine and a sense of apparent relevance to emergency care. CONCLUSION: Most emergency staff perceived CFS as relevant and easy to use, yet far from all older ED patients were assessed. The most common barrier to assessment was high workload. Measures to facilitate use may include clarifying the purpose of the assessment with explicit follow-up actions, as well as formulating a clear routine for the assessment. REGISTRATION: The study was registered on ClinicalTrials.gov 2021-06-18 (identifier: NCT04931472).

Airway management procedures in Swedish emergency department patients - a national retrospective study.

BACKGROUND: With the on-going debate about which specialty should be responsible for intubations in the emergency department in mind, the aim of this study was to describe the prevalence of endotracheal intubation and other airway management procedures in emergency department patients in Sweden. METHODS: All patients registered in the Swedish Intensive Care Registry with admission date from January 1 2013 until June 7 2018 and reported admission type "from the emergency department" or "emergency department" reported in the SAPS3 scoring were included. All patients missing codes for procedures were excluded. RESULTS: A total of 110,072 admissions from an emergency department to an ICU were registered during the study period. Of these, 41,619 admissions (37.8%) were excluded due to lack of codes for medical procedures. The remaining 68,453 admissions (62.2%) were included, and 31,888 emergency airway procedures (within 3 h from admission time to the intensive care unit) were registered. Invasive emergency airway procedures were the most common type of airway procedure (n = 23,446), followed by non-invasive airway procedures (n = 8377) and high-flow nasal cannula (n = 880). In 2017 a total of 4720 invasive emergency airway management procedures were registered. CONCLUSIONS: The frequency of invasive airway management procedures in Swedish EDs is low. With approximately 1.9 million adult ED visits per year, this gives an estimated incidence of 2.4 invasive airway management procedures per thousand ED visits in 2017. TRIAL REGISTRATION: Not applicable.

Pathways to the emergency department - a national, cross-sectional study in Sweden.

BACKGROUND: Swedish Emergency Departments (EDs) see 2.6 million visits annually. Sweden has a strong tradition of health care databases, but information on patients' pathways to the ED is not documented in any registry. The aim of this study was to provide a national overview of pathways, degree of medical acuteness according to triage, chief complaints, and hospital admission rates for adult patients (≥18 years) visiting Swedish EDs during 24 h. METHODS: A national cross-sectional study including all patients at 43 of Sweden's 72 EDs during 24 h on April 25th, 2018. Pathway to the ED, medical acuteness at triage, admission and basic demographics were registered by dedicated assessors present at every ED for the duration of the study. Descriptive data are reported. RESULTS: A total of 3875 adult patients (median age 59; range 18 to 107; 50% men) were included in the study. Complete data for pathway to the ED was reported for 3693 patients (98%). The most common pathway was self-referred walk-in (n = 1310; 34%), followed by ambulance (n = 920; 24%), referral from a general practitioner (n = 497; 1 3%), and telephone referral by the national medical helpline "1177" (n = 409; 10%). In patients 18 to 64 years, self-referred walk-in was most common, whereas transport by ambulance dominated in patients > 64 years. Of the 3365 patients who received a medical acuteness level at triage, 4% were classified as Red (Immediate), 18% as Orange (very urgent), 47% as Yellow (Urgent), 26% as Green (Standard), and 5% as Blue (Non-Urgent). Abdominal or chest pain were the most common chief complaints representing approximately 1/3 of all presentations. Overall, the admission rate was 27%. Arrival by ambulance was associated with the highest rate of admission (53%), whereas walk-in patients and telephone referrals were less often admitted. CONCLUSION: Self-referred walk-in was the overall most common pathway followed by ambulance. Patients arriving by ambulance were often elderly, critically ill and often admitted to in-patient care, whereas arrival by self-referred walk-in was more common in younger patients.

Emergency department admissions to the intensive care unit - a national retrospective study.

BACKGROUND: Emergency departments (EDs) see a rising number of patients, but only a small fraction of ED patients need immediate intensive care. The characteristics of these patients are mostly unknown and there is reason to believe that there are large inter-hospital differences in thresholds for intensive care admissions from the ED. The purpose of this study was to give a nationwide overview of ED admissions directly to intensive care units. METHODS: We used the Swedish Intensive care Registry to identify all patients admitted to intensive care from the ED (January 1, 2013 until June 7, 2018). The primary outcome was discharge diagnosis after intensive care (primary ICU diagnosis code). ICU mortality and" ICU admission due to only observation" were analyzed as secondary outcomes. RESULTS: 110,072 ICU admissions were included, representing 94,546 unique patients. Intoxication, trauma and neurological conditions were the most common causes for intensive care, but large variations according to age, sex and hospital type were seen. Intoxication was the most prevalent diagnosis in young adults (46.8% of admissions in 18-29 years old), whereas infectious diseases predominated in the elderly (17.0% in 65-79 years old). Overall, ICU mortality was 7.2%, but varied substantially with age, sex, type of hospital and medical condition. Cardiac conditions had the highest mortality rates, reaching 32.9%. The mortality was higher in academic centers compared to rural hospitals (9.3% vs 5.0%). It was more common to be admitted to ICU for only observation in rural hospitals than in academic centers (20.1% vs 7.8%). Being admitted to ICU only for observation was most common in patients with intoxication (30.6%). CONCLUSIONS: Overall, intoxication was the most common cause for ICU admission from the ED. However, causes of ED ICU admissions differ substantially according to age, sex and hospital type. Being admitted to the ICU only for observation was most common in intoxicated patients. TRIAL REGISTRATION: Not applicable (no interventions).

Validation of the modified Skåne emergency department assessment of patient load (mSEAL) model for emergency department crowding and comparison with international models; an observational study.

BACKGROUND: Emergency Department crowding is associated with increased morbidity and mortality but no measure of crowding has been validated in Sweden. We have previously derived and internally validated the Skåne Emergency Department Assessment of Patient Load (SEAL) score as a measure of crowding in Emergency Departments (ED) in a large regional healthcare system in Sweden. Due to differences in electronic health records (EHRs) between health care systems in Sweden, all variables in the original SEAL-score could not be measured reliably nationally. We aimed to derive and validate a modified SEAL (mSEAL) model and to compare it with established international measures of crowding. METHODS: This was an observational cross sectional study at four EDs in Sweden. All clinical staff assessed their workload (1-6 where 6 is the highest workload) at 5 timepoints each day. We used linear regression with stepwise backward elimination on the original SEAL dataset to derive and internally validate the mSEAL score against staff workload assessments. We externally validated the mSEAL at four hospitals and compared it with the National Emergency Department Overcrowding Score (NEDOCS), the simplified International Crowding Measure in Emergency Department (sICMED), and Occupancy Rate. Area under the receiver operating curve (AuROC) and coefficient of determination was used to compare crowding models. Crowding was defined as an average workload of 4.5 or higher. RESULTS: The mSEAL score contains the variables Patient Hours and Time to physician and showed strong correlation with crowding in the derivation (r2 = 0.47), internal validation (r2 = 0.64 and 0.69) and in the external validation (r2 = 0.48 to 0.60). AuROC scores for crowding in the external validation were 0.91, 0.90, 0.97 and 0.80 for mSEAL, Occupancy Rate, NEDOCS and sICMED respectively. CONCLUSIONS: The mSEAL model can measure crowding based on workload in Swedish EDs with good discriminatory capacity and has the potential to systematically evaluate crowding and help policymakers and researchers target its causes and effects. In Swedish EDs, Occupancy Rate and NEDOCS are good alternatives to measure crowding based on workload.

Key occupational stressors in the ED: an international comparison.

BACKGROUND: The ED Stressor Scale outlines 15 stressors that are of importance for ED staff. Limited research has identified how commonly such stressors occur, or whether such factors are perceived with similar importance across different hospitals. This study sought to examine the frequency or perceived severity of these 15 stressors using a multicentre cohort of emergency clinicians (nurses and physicians) in EDs in two countries (Australia and Sweden). METHOD: This was a cross-sectional survey of staff working in eight hospitals in Australia and Sweden. Data were collected between July 2016 and June 2017 (depending on local site approvals) via a printed survey incorporating the 15-item ED stressor scale. The median stress score for each item and the frequency of experiencing each event was reported. RESULTS: Events causing most distress include heavy workload, death or sexual abuse of a child, inability to provide optimum care and workplace violence. Stressors reported most frequently include dealing with high acuity patients, heavy workload and crowding. Violence, workload, inability to provide optimal care, poor professional relations, poor professional development and dealing with high-acuity patients were reported more commonly by Australian staff. Swedish respondents reported more frequent exposure to mass casualty incidents, crisis management and administrative concerns. CONCLUSIONS: Workload, inability to provide optimal care, workplace violence and death or sexual abuse of a child were consistently reported as the most distressing events across sites. The frequency with which these occurred differed in Australia and Sweden, likely due to differences in the healthcare systems.

Prevalence of crowding, boarding and staffing levels in Swedish emergency departments - a National Cross Sectional Study.

BACKGROUND: Emergency Department (ED) crowding occurs when demand for care exceeds the available resources. Crowding has been associated with decreased quality of care and increased mortality, but the prevalence on a national level is unknown in most countries. METHOD: We performed a national, cross-sectional study on staffing levels, staff workload, occupancy rate and patients waiting for an in-hospital bed (boarding) at five time points during 24 h in Swedish EDs. RESULTS: Complete data were collected from 37 (51% of all) EDs in Sweden. High occupancy rate indicated crowding at 12 hospitals (37.5%) at 31 out of 170 (18.2%) time points. Mean workload (measured on a scale from 1, no workload to 6, very high workload) was moderate at 2.65 (±1.25). Boarding was more prevalent in academic EDs than rural EDs (median 3 vs 0). There were an average of 2.6, 4.6 and 3.2 patients per registered nurse, enrolled nurse and physician, respectively. CONCLUSION: ED crowding based on occupancy rate was prevalent on a national level in Sweden and comparable with international data. Staff workload, boarding and patient to staff ratios were generally lower than previously described.

Man versus machine: comparison of naked-eye estimation and quantified capillary refill.

BACKGROUND: Capillary refill (CR) time is traditionally assessed by 'naked-eye' inspection of the return to original colour of a tissue after blanching pressure. Few studies have addressed intra-observer reliability or used objective quantification techniques to assess time to original colour. This study compares naked-eye assessment with quantified CR (qCR) time using polarisation spectroscopy and examines intra-observer and interobserver agreements in using the naked eye. METHOD: A film of 18 CR tests (shown in a random fixed order) performed in healthy adults was assessed by a convenience sample of 14 doctors, 15 nurses and 19 secretaries (Department of Emergency Medicine, Linköping University, September to November 2017), who were asked to estimate the time to return to colour and characterise it as 'fast', 'normal' or 'slow'. The qCR times and corresponding naked-eye time assessments were compared using the Kruskal-Wallis test. Three videos were shown twice without observers' knowledge to measure intra-observer repeatability. Intra-observer categorical assessments were compared using Cohen's Kappa analysis. Interobserver repeatability was measured and depicted with multiple-observer Bland-Altman plotting. Differences in naked-eye estimation between professions were analysed using ANOVA. RESULTS: Naked-eye assessed CR time and qCR time differ substantially, and agreement for the categorical assessments (naked-eye assessment vs qCR classification) was poor (Cohen's kappa 0.27). Bland-Altman intra-observer repeatability ranged from 6% to 60%. Interobserver agreement was low as shown by the Bland-Altman plotting with a 95% limit of agreement with the mean of ±1.98 s for doctors, ±1.6 s for nurses and ±1.75 s for secretaries. The difference in CR time estimation (in seconds) between professions was not significant. CONCLUSIONS: Our study suggests that naked-eye-assessed CR time shows poor reproducibility, even by the same observers, and differs from an objective measure of CR time.

Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.

Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10µg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.

Deletion of prostaglandin E2 synthesizing enzymes in brain endothelial cells attenuates inflammatory fever.

Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE2 remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammation-induced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE2 synthesis in brain endothelial cells is critical for inflammation-induced fever.

Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells.

Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

Addition of the clinical frailty scale to triage tools and early warning scores improves mortality prognostication at 30 days: A prospective observational multicenter study.

Objectives: Frailty, assessed with clinical frailty scale (CFS), alone or in combination with aggregated vital signs, has been proposed as a measure to better predict mortality of older patients in the emergency department (ED), but the added predictive value to conventional triage is unclear. Methods: This was a secondary analysis of a prospective observational study in three EDs in Sweden that evaluated the prognostic performance of the CFS alone or in combination with the national early warning score (NEWS), triage early warning score (TEWS) or the rapid emergency triage and treatment system (RETTS) triage tool using logistic regression. The primary outcome was 30-day mortality with 7- and 90-day mortality and admission as secondary outcomes reported as area under the receiver operating curve (AuROC) scores with 95% confidence intervals (CIs). The sensitivity, specificity, accuracy, predictive values, and likelihood ratios are reported for all models. Results: A total of 1832 patients were included with 17 (0.9%), 57 (3.1%), and 121 (6.6%) patients dying within 7, 30, and 90 days, respectively. The admission rate was 43% (795/1832). Frailty (CFS > 4) was significantly associated with 30-day mortality (odds ratio 6, 95% CI 3‒12, p < 0.01). Prognostication of 30-day mortality was similar for all CFS-based models and better compared with models without CFS. The AuROC (95% CI) improved for RETTS from 0.67 (0.61‒0.74) to 0.83 (0.79‒0.88) (p = 0.008), for NEWS from 0.53 (0.45‒0.61) to 0.82 (0.77‒0.87) (p < 0.001), and for TEWS from 0.63 (0.55‒0.71) to 0.82 (0.77‒0.87) (p = 0.002). Conclusion: Frailty measured with the CFS in combination with RETTS or structured vital sign assessment using NEWS or TEWS was better at prognosticating 30-day mortality compared to RETTS or early warnings score alone. Improved prognostication provides more realistic expectations and allows for informed discussions with patients and initiation of individualized treatment plans early in the ED process.

The Effect of Repeated Capillary Refill Tests on the Cutaneous Microcirculation.

OBJECTIVE: The capillary refill test (CR test) is often used in emergency care, and the capillary refill time (CR time) is used to assess a patient's circulatory condition. The objective of this study was to investigate if repeated CR tests affect CR time. METHODS: Thirteen healthy volunteers had repeated CR tests performed on the sternum, forehead, and fingers. The tests were filmed using polarized reflectance spectroscopy and dedicated software for objective quantification of the CR time. RESULTS: There were no statistical differences between the first CR test in a series and the following. However, there were statistically significant differences in CR time between the different anatomical sites. CONCLUSION: Repeated CR tests, separated by a minimum of 2 min, do not affect CR time in healthy volunteers. The site where the test is performed is of importance for CR time.

NK1 receptor mediates cerebral cellular and extracellular morphological changes during the LPS-induced febrile response.

Fever elicited by bacterial lypopolyssacharide (LPS) is mediated by pro-inflammatory cytokines, which activate central mediators and regulate the hypothalamic temperature setpoint. This response is often accompanied by morphological changes involving the extracellular matrix, neurons and glial cells, with significant health impacts. The NK1 receptor is involved in the febrile response induced by LPS but its effects over the extracellular matrix in the context of neuroinflammation remain unknown. The present work aims to clarify the extracellular changes associated with NK1 signaling in LPS-induced fever. Male Wistar rats were exposed to LPS intraperitoneally. Experimental groups were pre-treated intracerebroventricularly with the NK1 selective inhibitor SR140333B or saline. Histological changes involving the brain extracellular matrix were evaluated using hematoxylin and eosin, Mason's trichrome, picrosirius, alcian blue, periodic acid Schiff's stains. The expression of matrix metalloproteinase 9 (MMP9) was studied using confocal microscopy. Fever was accompanied by edema, perivascular lymphoplamacytic and neutrophylic infiltration, spongiosis and MMP9 overexpression. SR140333B significantly reduced LPS-induced fever (p < 0.0001), MMP9 overexpression (p < 0.01) and associated histological changes. These results contribute to characterize cerebral extracellular matrix changes associated with LPS-induced fever. Overall, the present work supports a role for NK1 receptor in these neuroinflammatory changes, involving MMP9 overexpression, edema and leukocytic infiltration.

Emergency department crowding and mortality: an observational multicenter study in Sweden.

Background: Emergency department (ED) crowding is a serious problem worldwide causing decreased quality of care. It is reasonable to assume that the negative effects of crowding are at least partially due to high staff workload, but previous crowding metrics based on high workload have not been generalisable to Swedish EDs and have not been associated with increased mortality, in contrast to, e.g., occupancy rate. We recently derived and validated the modified Skåne Emergency Department Assessment of Patient Load model (mSEAL) that measures crowding based on staff workload in Swedish EDs, but its ability to identify situations with increased mortality is unclear. In this study, we aimed to investigate the association between ED crowding measured by mSEAL model, or occupancy rate, and mortality. Methods: All ED patients from 2017-01-01 to 2017-06-30 from two regional healthcare systems (Skåne and Östergötland Counties with a combined population of approximately 1.8 million) in Sweden were included. Exposure was ED- and hour-adjusted mSEAL or occupancy rate. Primary outcome was mortality within 7 days of ED arrival, with one-day and 30-day mortality as secondary outcomes. We used Cox regression hazard ratio (HR) adjusted for age, sex, arrival by ambulance, hospital admission and chief complaint. Results: We included a total of 122,893 patients with 168,900 visits to the six participating EDs. Arriving at an hour with a mSEAL score above the 95th percentile for that ED and hour of day was associated with an non-significant HR for death at 7 days of 1.04 (95% CI 0.96-1.13). For one- and 30-day mortality the HR was non-significant at 1.03 (95% CI 0.9-1.18) and 1.03 (95% CI 0.97-1.09). Similarly, occupancy rate above the 95th percentile with a HR of 1.04 (95% CI 0.9-1.19), 1.03 (95%CI 0.95-1.13) and 1.04 (95% CI 0.98-1.11) for one-, 7- and 30-day mortality, respectively. Conclusion: In this multicenter study in Sweden, ED crowding measured by mSEAL or occupancy rate was not associated with a significant increase in short-term mortality.