Reinforcement of emergency department reduces acute admissions to medical department.

INTRODUCTION: The medical decision capacity of emergency departments (ED) may rest within the department itself or depend on external consultation. The stepwise development of the ED at Zealand University Hospital, Køge, was used to analyse the influence of medical organisation in the ED on the hospital admission pattern. METHODS: Data were recorded for the month of September of 2009, 2012 and 2014. These periods corresponded to the establishment of the department in 2009 and the 2012-period before organisational change was initiated in 2013, with a substantial increase in the number of senior physicians directly in charge of clinical decisions and the establishment of a limited bedding capacity. In 2014, the changes had been fully implemented. We analysed the number of patients admitted and their length of stay (LOS) in the ED and in the Department of Internal Medicine (DoM). The 30-day readmission and mortality rates were used as quality indicators. RESULTS: A total of 1,106, 1,354 and 1,470 patients were admitted to the ED in 2009, 2012 and 2014, respectively. In 2009 and 2012, 42% of the patients were admitted to the DoM. In 2014, only 22% were admitted. The mean LOS for long-term admission at the DoM increased by 1.4 days from 2009 to 2014. Readmission and mortality rates did not change in three periods analysed. CONCLUSION: Independent medical decision capacity and bed resources in the ED effectively change hospital logistics and reduce the number of admissions without negatively affecting patient safety in terms of readmission or short-term mortality. FUNDING: none. TRIAL REGISTRATION: not relevant.

Readmittance rates within seven days are preferable in quality measuring of emergency departments.

INTRODUCTION: The objective of this article was to qualify and test the recommendations of a national Danish report. We conducted an investigation on the readmittance rate as well as reasons for readmittance in a patient cohort defined through the process of internal audit at the Emergency Department at Zealand University Hospital, Køge, Denmark. METHODS: A retrospective, descriptive study of admitted patients in November 2014, including a total of 1,440 patients. Data and parameters were obtained from electronic patient records. RESULTS: A total of 162 patients were readmitted within 30 days from their initial admission (11% of the cohort). Of this group, 139 (86%) readmittances were unpreventable or planned. Readmissions caused by missed diagnosis or insufficient treatment accounted for 8% and 6%, respectively. The median time until readmission in these cases were two and four and a half days, respectively. The median time to readmission for the unpreventable readmissions ranged from 13 to 18.5 days. CONCLUSION: In terms of patient safety, our data support a seven-day observation period for readmission rates when measuring or monitoring quality of care in emergency departments. FUNDING: none. TRIAL REGISTRATION: none.

Use of biomarker S100B for traumatic brain damage in the emergency department may change observation strategy.

INTRODUCTION: The revised Scandinavian Neurotrauma Committee (SNC) guidelines on management of patients with head trauma include an option for measurement of S100B in peripheral blood with 100% sensitivity for neurosurgical intervention. A medical technology assessment was conducted to evaluate any impact of using S100B on the use of computed tomographies (CT) of the brain and admission for observation. MATERIAL AND METHODS: Patients referred for assessment of head injury over a period of 1.5 months had their blood sampled for measurement of S100B in serum. Results were not available to the treating physician and treatment was conducted according to existing practice. Patient records were reviewed retrospectively and post hoc divided into two groups depending on whether the SNC criteria for taking the blood sample were met. The use of CT and admission was analysed. RESULTS: A total of 39 patients had their blood sampled for analysis. In all, 12 patients were excluded in pursuance of SNC guidelines, which left 27 patients for analysis. A total of 15 patients had abnormally high S100B levels. Using the SNC criteria, only eight of these qualified a priori for blood sampling. Furthermore, seven of the 11 patients who were admitted had normal S100B levels. CONCLUSION: The number of patients with an above-threshold concentration of S100B was almost equally distributed between those fulfilling the SNC criteria for S100B assessment and those who could have been discharged without further evaluation. Using S100B as a screening tool may lead to an increase in the use of CTs of the brain. In relation to admission, measurement of S100B may contribute to the adoption of an appropriate observation strategy. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Drug-induced hypothermia as beneficial treatment before and after cerebral ischemia.

OBJECTIVES: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when conditioning before (preconditioning) and after (postconditioning) experimental stroke. METHODS: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2-vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced either immediately or with 3 h delay. Rats survived ischemia for 2, 7 or 90 days. Infarct volumes were quantified by stereology. Additional experiments of methodological relevance were included in the study. RESULTS: Talipexole induced mild hypothermia (35.1±1.1 to 36.0±0.5°C) for <20 h. Hypothermic pre- and postconditioning reduced infarct sizes by more than 60% as monitored during the first 90 days after experimental stroke (p<0.05). CONCLUSION: Talipexole is registered for use as a dopamine substitute in humans with Parkinson's disease. Although dosages cannot be directly translated to patients, our study exemplifies in an animal model that drug-induced hypothermia in a clinical setting might reduce cerebral ischemic damage before neuro- and cardiac surgical procedures and after stroke.

Mechanism of injury and microbiological flora of the geographical location are essential for the prognosis in soldiers with serious warfare injuries.

INTRODUCTION: Denmark has been engaged in the Afghanistan war and as a result, Rigshospitalet has received a number of multi-traumatized Danish soldiers. Lesions sustained in armed conflict differ from their civilian counterparts and knowledge of the pathophysiology related to these types of lesions is essential when engaging in the intensive care of these patients. MATERIAL AND METHODS: The study was conducted as a retrospective survey of Danish soldiers evacuated from Afghanistan to the Intensive Care Unit at Rigshospitalet in the 2002-2012 period. The following data were recorded: age, gender, hospitalization (days), mortality, organ involvement, respiratory therapy, dialysis, circulatory supportive care, antibiotic treatment and bacteriology. Furthermore, Acute Physiology and Chronic Health Evaluation, Simplified Acute Physiology Score and Sequential Organ Failure Assessment scores were calculated. RESULTS: A total of twenty patients were identified and included in the study. All patients had sustained serious blast injuries as a result of explosion. Primarily the central nervous system, respiratory, musculoskeletal and abdominal systems were affected by the explosions. Eighteen patients survived to discharge and two patients died. DISCUSSION: Explosion was the most frequent cause of injury in all cases and caused damage to several organ systems. Infections after combat injuries are a major problem because of the different microbiological profile. CONCLUSION: The use of explosives has been and remains a substantial part of warfare, and this review has showed us that the knowledge of the mechanism of injury is indeed essential, and that intelligence on the microbiological flora of the geographical location of the conflict is essential. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Remote post-conditioning reduces hypoxic damage early after experimental stroke.

OBJECTIVES: Given that reliable markers for early ischemic brain damage are lacking, we set out to test whether pimonidazole can be used as a reliable tool in the quantification of hypoxic insults, at early time points following experimental stroke. METHODS: We have used semi-quantitative Western blotting detection of pimonidazole adducts in a rat model of reversible middle cerebral artery occlusion (MCAO), treated with remote post-conditioning. RESULTS: First, we demonstrated that a linear relationship exist between pimonidazole binding in the ischemic hemisphere and duration of ischemia, in animals subjected to 5, 15, 30, or 60 minutes of occlusion followed by 120 minutes of reflow. Then we showed a significant reduction in pimonidazole binding in the infarcted hemisphere, when rats with 60 minutes of MCAO, immediately after establishment of cerebral reflow, had 3×15 minutes intermittent hind limb ischemia followed by 24-hour survival. We analysed the middle cerebral arteries from animals with 60 minutes of MCAO and early remote post-conditioning, followed by 30 minutes, 24, or 48 hours of reflow. At 24 hours of reflow increases in phosphorylated protein kinase C-alpha with concomitantly increased levels of p38 phosphorylation were observed. CONCLUSIONS: Our investigation demonstrates that pimonidazole can be used for quantifying ischemic impact in stroke, even after very short survival times. It furthermore shows that early remote post-conditioning reduces ischemic damage, probably through hyperpolarization and reduced reflow vasospasm in the conduit middle cerebral arteries.

Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage.

The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects.

Advances in treatment of cerebral vasospasm: an update.

An update of published clinical advances in the treatment of cerebral vasospasm after subarachnoid haemorrhage was provided. Searching MEDLINE using the search terms "cerebral vasospasm" and "clinical trials" 46 papers were identified that had been published since the International Conference on Cerebral Vasospasm in Istanbul, Turkey in 2006. Of these 26 were either safety studies or case reports leaving 20 papers for consideration. The major topics covered were calcium antagonists, magnesium sulphate, statins, and fasudil hydrochloride. The studies published did not reach an impact justified recommended routine use, but certainly as options. Results of the CONSCIOUS trials on endothelin receptor antagonists are awaited.

Blood coagulation and fibrinolysis after experimental subarachnoid hemorrhage.

BACKGROUND: Aneurysmal rebleeding poses a serious risk in patients with subarachnoid hemorrhage (SAH). Studies have shown that antifibrinolytic therapy with tranexamic acid has a dramatic effect on the rate of rebleeding. Therefore, changes in the fibrinolytic system could be hypothesized. METHODS: We have used an experimental SAH rat model to demonstrate serial changes in the haemostatic system as evaluated by Thromboelastography (TEG). RESULTS: In the SAH group, a shorter reaction time (R-time) and higher maximum amplitude (MA) were observed. In the saline group, only a shorter R-time was observed. CONCLUSIONS: The study has shown that a hypercoagulable state is present immediately after experimental SAH is induced as determined by TEG. The reduction in R-time and rise in MA observed in the SAH group indicate that blood in the subarachnoid space is necessary to accomplish a full systemic coagulation response. This abnormality in coagulation profile seems to be a response to the acute traumatic event caused by induction of SAH.

Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought.

OBJECTIVE: Delayed cerebral vasospasm has long been recognized as an important cause of poor outcome after an otherwise successful treatment of a ruptured intracranial aneurysm, but it remains a pathophysiological enigma despite intensive research for more than half a century. METHOD: Summarized in this review are highlights of research from North America, Europe and Asia reflecting recent advances in the understanding of delayed ischemic deficit. RESULT: It will focus on current accepted mechanisms and on new frontiers in vasospasm research. CONCLUSION: A key issue is the recognition of events other than arterial narrowing such as early brain injury and cortical spreading depression and of their contribution to overall mortality and morbidity.

Seizure deterioration in women treated with oxcarbazepine during pregnancy.

Thirteen pregnancies in ten women on oxcarbazepine (OXC) monotherapy and one pregnancy in a woman on OXC and topiramate therapy were retrospectively analyzed. A significant decrease of ratio plasma concentration of 10-monohydroxy derivate (MHD) of oxcarbazepine to dosage was found by 26.2% during first trimester, by 36.5% during second trimester and by 38.2% during third trimester when compared to pre-pregnant levels. Eight patients experienced seizure deterioration during the pregnancy, five of which had been seizure-free before the pregnancy. In seven pregnancies (50%) the seizure frequency was at least doubled during pregnancy compared to a pre-pregnancy baseline. There was a trend toward a correlation between seizure deterioration and decrease in plasma concentration of MHD.

Cerebral vasoconstriction after subarachnoid hemorrhage--role of changes in vascular receptor phenotype.

The pathological constriction of cerebral arteries known as cerebral vasospasm (CVS) is with a delay of 4 to 10 days linked to subarachnoid hemorrhage. Several agents have been suggested as being responsible; amongst these perhaps 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) are the most prominent given their ability to elicit powerful constriction of cerebral arteries. Investigating both 5-HT and ET receptors we have observed that there are distinct changes in receptor phenotype after experimental SAH, namely upregulation of the ETB and 5-HT1B receptors, and that this upregulation is linked to a higher sensitivity to the endogenous agonists. It has also been shown that reduction in regional cerebral blood flow (CBF) is associated with receptor upregulation and interventional animal experiments have shown a benefit from inhibiting the PKC and MAP kinase pathways on receptor upregulation, CBF and neurological outcome.

Cerebral vasospasm: looking beyond vasoconstriction.

Cerebral vasospasm is an important syndrome that afflicts 30% of patients in the aftermath of, and secondary to, subarachnoid hemorrhage. Starting approximately one week after the hemorrhage, the condition worsens the prognosis of the hemorrhage significantly. Apart from general supportive care, no treatment exists for cerebral vasospasm. During the past 50 years, it was thought that the ischemia that signifies poor outcome is more or less exclusively caused by arterial narrowing. However, this idea has recently been challenged by the failure of the drug clazosentan to improve patient outcome, despite reversing vasoconstriction. In this article, we discuss the opinion that factors other than vasoconstriction are important in the pathophysiology and prognosis of cerebral vasospasm. Such factors include global ischemia, disruption of the blood-brain barrier, activation of apoptotic and inflammatory pathways, and cortical spreading depression.

Protein kinase C inhibition prevents upregulation of vascular ET(B) and 5-HT(1B) receptors and reverses cerebral blood flow reduction after subarachnoid haemorrhage in rats.

The pathogenesis of cerebral ischaemia after subarachnoid haemorrhage (SAH) still remains elusive. The purpose of the present study was to examine whether specific protein kinas C (PKC) inhibition in rats could alter the transcriptional SAH induced Endothelin (ET) type B and 5-hydroxytryptamine type 1B (5-HT(1B)) receptor upregulation and prevent the associated cerebral blood flow (CBF) reduction. The PKC inhibitor RO-31-7549 or vehicle was injected intracisternally after the induced SAH in rats (n=3 to 10 in each groups for each method). The involvement of the PKC isoforms was investigated with Western blot; only PKCdelta and PKCalpha subtypes were increased after SAH RO-31-7549 treatment abolished this. At 2 days after the SAH basilar and middle cerebral arteries were harvested and the contractile response to endothelin-1 (ET-1; ET(A) and ET(B) receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT(1) receptor agonist) were investigated with a myograph. The contractile responses to ET-1 and 5-CT were increased (P<0.05) after SAH compared with sham operated rats. In parallel, the ET(B) and 5-HT(1B) receptor mRNA and protein expression were significantly elevated after SAH, as analysed by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. Administration of RO-31-7549 prevented the upregulated contraction elicited by application of ET-1 and 5-CT in cerebral arteries and kept the ET(B) and 5-HT(1B) receptor mRNA and protein levels at pre-SAH levels. Regional and global CBF evaluated by an autoradiographic technique were reduced by 60%+/-4% after SAH (P<0.05) and prevented by treatment with RO-31-7549. Our study suggests that PKC plays an important role in the pathogenesis of cerebral ischaemia after SAH.

Gene expression and molecular changes in cerebral arteries following subarachnoid hemorrhage in the rat.

OBJECT: The authors investigated early changes in the cerebral arteries of rats that occur after subarachnoid hemorrhage (SAH). METHODS: Messenger RNA was investigated by performing microarray and quantitative real-time polymerase chain reaction (PCR) analyses, and protein expression was shown by performing immunohistochemical studies. The array data indicated that the initial processes that occur after SAH involve activation of genes involved in angiogenesis, inflammation, and extracellular matrix (ECM) remodeling. The real-time PCR investigation confirmed upregulation of genes that were observed using the microarray to be regulated, including iNOS, MMP13, and cxcl2. The authors also verified the upregulation of previously implicated genes for G-protein-coupled receptors (endothelin B [ETB], angiotensin 1 [AT1], and AT2) and metalloproteinase 9. The results of an immunohistochemical study confirmed that receptor genes that were seen to be regulated produced an increase in protein expression. Double immunostaining of rat cerebral arteries with endothelial cell- or smooth-muscle cell-specific antibodies verified that an increase in ETB, 5-hydrotryptamine (5-HT1B), and 5-HT1D receptor expression occurs in smooth-muscle cells. CONCLUSIONS: Processes occurring after SAH lead to enhanced arterial contractility and ECM remodeling either directly or through angiogenesis and inflammation. These processes are active via an increase in metalloproteinase expression, the presence of proangiogenic factors, and the expression of proinflammatory genes.

ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ET(B) and 5-HT(1B) receptor upregulation after subarachnoid hemorrhage in rat.

Upregulation of endothelin B (ET(B)) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ET(B) and 5-HT(1B) receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ET(A) and ET(B) receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ET(B) and 5-HT(1B) receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH.

The course of adjustment disorder in Danish male conscripts.

Conscription has been employed for more than a century. To evaluate the course and fate of conscripts deemed mentally unfit for immediate continued service, a prospective questionnaire study of conscripts referred for mental evaluation was conducted. Questionnaires were completed at the time of enrollment, time of admittance for evaluation, time of discharge from their evaluation and at 1-year follow-up. Out of a class of 6949 conscripts, 93 were referred for psychiatric evaluation and 69 of those referred decided to enter the study (60 of these were in time deemed unfit for further military service). At the time of admittance, on average after 79 days of service, there was a significant 36%, 34%, 20% and 20% increase in depression, sleep, somatization and interpersonality scores, respectively. At the time of discharge 14 days after admittance, the symptom scores had dropped to a level comparable to scores at the time of enrollment. At 1-year follow-up, the descending trend in scores was maintained, though not reaching statistical significance compared with scores at time of discharge. The scores at 1-year follow-up were also, except for a higher depression score, comparable with the scores of a control group of conscripts evaluated 1 year after service. The psychological profile of conscripts referred for evaluation was different at the time of enrollment compared with conscripts in general, the scores being between 9% (interpersonality) and 29% (depression) higher. They also had a higher prevalence of adverse family events in their history. The course observed is indifferent from other situations of enforced stress.

Individual changes in lamotrigine plasma concentrations during pregnancy.

Eleven pregnant women on lamotrigine (LTG) monotherapy were retrospectively reviewed. A significant decrease in the ratio of plasma LTG concentration-to-dose by 65.1% was observed during the second trimester (TM2) (p=0.0058) and by 65.8% during TM3 (p=0.0045) compared to pre-pregnancy values. Five patients experienced seizure deterioration during pregnancy. The pharmacokinetic changes display marked inter-patient variation, which stresses the importance of evaluating each woman individually by closely monitoring LTG concentrations until term.

Heregulin ameliorates the dystrophic phenotype in mdx mice.

Duchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by absence of dystrophin. Utrophin is a chromosome 6-encoded dystrophin-related protein (DRP), sharing functional motifs with dystrophin. Utrophin's ability to compensate for dystrophin during development and when transgenically overexpressed has provided an important impetus for identifying activators of utrophin expression. The utrophin promoter A is transcriptionally regulated in part by heregulin-mediated, extracellular signal-related kinase-dependent activation of the GABP(alpha/beta) transcription factor complex. Therefore, this pathway offers a potential mechanism to modulate utrophin expression in muscle. We tested the ability of heregulin to improve the dystrophic phenotype in the mdx mouse model of DMD. Intraperitoneal injections of a small peptide encoding the epidermal growth factor-like region of heregulin ectodomain for 3 months in vivo resulted in up-regulation of utrophin, a marked improvement in the mechanical properties of muscle as evidenced by resistance to eccentric contraction mediated damage, and a reduction of muscle pathology. The amelioration of dystrophic phenotype by heregulin-mediated utrophin up-regulation offers a pharmacological therapeutic modality and obviates many of the toxicity and delivery issues associated with viral vector-based gene therapy for DMD.