Patient costs and patient flow after implementation of S100B in Scandinavian head trauma guidelines.

INTRODUCTION: The serum biomarker S100B has been implemented in the Scandinavian Neurotrauma Committee (SNC) 2013 Head Injury Guidelines for patients classified with mild head injury (MHI). Patients with a serum S100B level less-than 0.10 µg/l sampled within six hours after trauma can be discharged without further observation or investigation. The aim of this study was to examine the influence of S100B implementation on patient costs and patient flow in an emergency department. METHODS: In this retrospective study, we included MHI patients (≥ 18 years) admitted to Rigshospitalet, Copenhagen, Denmark, between 1 February 2013 and 31 January 2014. Medical records were examined for the time of trauma, time of S100B sampling, serum S100B level, the severity of the head injury, clinical symptoms, radiological examinations, hospitalisation, discharge, surgical intervention, readmission and mortality. RESULTS: Among 2,033 patients screened for potential study candidates, 227 patients met the inclusion criteria and were enrolled in the study. Among these patients, 119 (52%) were not treated according to SNC 2013 Head Injury Guidelines, leaving 108 (48%) with full guideline adherence. Compared with MHI management without S100B, implementation of S100B produced an additional cost of €1.26 per patient. Overall, the addition of S100B did not affect the waiting time for examination with S100B sampling or CT. CONCLUSION: The use of S100B in the SNC 2013 Head Injury Guidelines did not reduce patient costs, nor did it cause substantial additional patient costs or delayed patient flow. FUNDING: none. TRIAL REGISTRATION: The Danish Data Protection Agency (journal number 2012-58-0004 and I-suite number RH-2017-164).

Copenhagen Head Injury Ciclosporin Study: A Phase IIa Safety, Pharmacokinetics, and Biomarker Study of Ciclosporin in Severe Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) contributes to almost one third of all trauma-related deaths, and those that survive often suffer from long-term physical and cognitive deficits. Ciclosporin (cyclosporine, cyclosporin A) has shown promising neuroprotective properties in pre-clinical TBI models. The Copenhagen Head Injury Ciclosporin (CHIC) study was initiated to establish the safety profile and pharmacokinetics of ciclosporin in patients with severe TBI, using a novel parenteral lipid emulsion formulation. Exploratory pharmacodynamic study measures included microdialysis in brain parenchyma and protein biomarkers of brain injury in the cerebrospinal fluid (CSF). Sixteen adult patients with severe TBI (Glasgow Coma Scale 4-8) were included, and all patients received an initial loading dose of 2.5 mg/kg followed by a continuous infusion for 5 days. The first 10 patients received an infusion dosage of 5 mg/kg/day whereas the subsequent 6 patients received 10 mg/kg/day. No mortality was registered within the study duration, and the distribution of adverse events was similar between the two treatment groups. Pharmacokinetic analysis of CSF confirmed dose-dependent brain exposure. Between- and within-patient variability in blood concentrations was limited, whereas CSF concentrations were more variable. The four biomarkers, glial fibrillary acidic protein, neurofilament light, tau, and ubiquitin carboxy-terminal hydrolase L1, showed consistent trends to decrease during the 5-day treatment period, whereas the samples taken on the days after the treatment period showed higher values in the majority of patients. In conclusion, ciclosporin, as administered in this study, is safe and well tolerated. The study confirmed that ciclosporin is able to pass the blood-brain barrier in a TBI population and provided an initial biomarker-based signal of efficacy.

Clinical Use of the Calcium-Binding S100B Protein, a Biomarker for Head Injury.

S100B is a calcium-binding protein most abundant in neuronal tissue. It is expressed in glial cells and Schwann cells and exerts both intra- and extracellular effects. Depending on the concentration, secreted S100B exerts either trophic or toxic effects. Its functions have been extensively studied but are still not fully understood. It can be measured in cerebrospinal fluid and in blood, and increased S100B level in blood can be seen after, e.g., traumatic brain injury, certain neurodegenerative disorders, and malignant melanoma. This chapter provides a short background of protein S100B, commercially available methods of analysis, and its clinical use, especially as a biomarker in minor head injury.

Monitoring and Measurement of Intracranial Pressure in Pediatric Head Trauma.

Purpose of Review: Monitoring of intracranial pressure (ICP) is an important and integrated part of the treatment algorithm for children with severe traumatic brain injury (TBI). Guidelines often recommend ICP monitoring with a treatment threshold of 20 mmHg. This focused review discusses; (1) different ICP technologies and how ICP should be monitored in pediatric patients with severe TBI, (2) existing evidence behind guideline recommendations, and (3) how we could move forward to increase knowledge about normal ICP in children to support treatment decisions. Summary: Current reference values for normal ICP in adults lie between 7 and 15 mmHg. Recent studies conducted in "pseudonormal" adults, however, suggest a normal range below this level where ICP is highly dependent on body posture and decreases to negative values in sitting and standing position. Despite obvious physiological differences between children and adults, no age or body size related reference values exist for normal ICP in children. Recent guidelines for treatment of severe TBI in pediatric patients recommend ICP monitoring to guide treatment of intracranial hypertension. Decision on ICP monitoring modalities are based on local standards, the individual case, and the clinician's choice. The recommended treatment threshold is 20 mmHg for a duration of 5 min. Both prospective and retrospective observational studies applying different thresholds and treatment strategies for intracranial hypertension were included to support this recommendation. While some studies suggest improved outcome related to ICP monitoring (lower rate of mortality and severe disability), most studies identify high ICP as a marker of worse outcome. Only one study applied age-differentiated thresholds, but this study did not evaluate the effect of these different thresholds on outcome. The quality of evidence behind ICP monitoring and treatment thresholds in severe pediatric TBI is low and treatment can potentially be improved by knowledge about normal ICP from observational studies in healthy children and cohorts of pediatric "pseudonormal" patients expected to have normal ICP. Acceptable levels of ICP - and thus also treatment thresholds-probably vary with age, disease and whether the patient has intact cerebral autoregulation. Future treatment algorithms should reflect these differences and be more personalized and dynamic.

[A Scandinavian guideline for initial management of minimal, mild and moderate head trauma in children].

The Scandinavian Neurotrauma Committee has recently published an evidence- and consensus-based guideline for the management of minor and moderate head trauma in children. They aim is to select children for computed tomography (CT) scan, observation or early discharge, with the attempt to reduce the number of CT scans in children without missing any significant intracranial injury in need for treatment. A flow chart of the guidelines and a help sheet has been developed for clinical use. Suggestions for in-hospital observation and parental information are also presented. We present the guideline in Danish.

Scandinavian guidelines for initial management of minor and moderate head trauma in children.

BACKGROUND: The management of minor and moderate head trauma in children differs widely between countries. Presently, there are no existing guidelines for management of these children in Scandinavia. The purpose of this study was to produce new evidence-based guidelines for the initial management of head trauma in the paediatric population in Scandinavia. The primary aim was to detect all children in need of neurosurgical intervention. Detection of any traumatic intracranial injury on CT scan was an important secondary aim. METHODS: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used. Systematic evidence-based review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology and based upon relevant clinical questions with respect to patient-important outcomes. Quality ratings of the included studies were performed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and Centre of Evidence Based Medicine (CEBM)-2 tools. Based upon the results, GRADE recommendations, a guideline, discharge instructions and in-hospital observation instructions were drafted. For elements with low evidence, a modified Delphi process was used for consensus, which included relevant clinical stakeholders. RESULTS: The guidelines include criteria for selecting children for CT scans, in-hospital observation or early discharge, and suggestions for monitoring routines and discharge advice for children and guardians. The guidelines separate mild head trauma patients into high-, medium- and low-risk categories, favouring observation for mild, low-risk patients as an attempt to reduce CT scans in children. CONCLUSIONS: We present new evidence and consensus based Scandinavian Neurotrauma Committee guidelines for initial management of minor and moderate head trauma in children. These guidelines should be validated before extensive clinical use and updated within four years due to rapid development of new diagnostic tools within paediatric neurotrauma.

Can S100B Predict Cerebral Vasospasms in Patients Suffering from Subarachnoid Hemorrhage?

BACKGROUND: Protein S100B has proven to be a useful biomarker for cerebral damages. Increased levels of serum and cerebrospinal fluid (CSF) S100B have been shown in patients suffering subarachnoid hemorrhage (SAH), severe head injury and stroke. In patients with SAH, the course of S100B levels has been correlated with neurological deficits and outcome. Cerebral vasospasm is a major contributor to morbidity and mortality. The primary aim of this study was to investigate the potential of S100B protein as a predictor of cerebral vasospasm in patients with severe SAH. MATERIALS AND METHODS: Patients with SAH, Fisher grade 3 and 4, were included in the study. Five samples of CSF and serum S100B were collected from each patient. The first sample (baseline sample) was drawn within the first 3 days following ictus and the following four samples, once a day on days 5-8, with day of ictus defined as day 1. Clinical suspicion of cerebral vasospasm confirmed by computed tomography angiography was used to diagnose cerebral vasospasm. RESULTS: A total of 18 patients were included. Five patients (28%) developed cerebral vasospasm, two (11%) developed ventriculitis. There were no significant differences between S100B for those with and without vasospasm. Serum S100B levels in patients with vasospasm were slightly lower within the first 5 days following ictus, compared to patients without vasospasm. Two out of five patients had elevated and increasing serum S100B prior to vasospasm. Only one showed a peak level of S100B 1 day before vasospasm could be diagnosed. Due to the low number of patients in the study, statistical significance could not be reached. CONCLUSION: Neither serum nor CSF S100B can be used as predictor of cerebral vasospasm in patients suffering from SAH.

Clinical use of the calcium-binding S100B protein.

S100B is a calcium-binding protein most abundant in neuronal tissue. It is expressed in glia cells and Schwann cells and exerts both intra- and extracellular effects. Depending on the concentration, secreted S100B exerts either trophic or toxic effects. Its functions have been extensively studied but are still not fully understood. It can be measured in cerebrospinal fluid and blood, and increased S100B level in blood can be seen after, e.g., traumatic brain injury, certain neurodegenerative disorders and malignant melanoma. This chapter provides a short background of protein S100B, commercially available methods of analysis, and its clinical use.

Anticoagulation therapy a risk factor for the development of chronic subdural hematoma.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a common disease among the elderly and with increasing incidence we have chosen to focus on associations between development and recurrence of CSDH and anticoagulation and/or antiplatelet agent therapy. METHODS: We conducted a retrospective review of 239 patients undergoing surgery for CSDH over a period of six years (2006-2011). Risk factors such as age, head trauma, anticoagulant and/or antiplatelet agent therapy and co-morbidity were investigated along with gender, coagulation status, laterality, surgical method and recurrence. RESULTS: Seventy-two percent of the patients were male and the mean age was 71.8 years (range 28-97 years). Previous fall with head trauma was reported in 60% of the patients while 16% were certain of no previous head trauma. The majority of patients (63%) in the non-trauma group were receiving anticoagulants and/or antiplatelet agent therapy prior to CSDH presentation, compared to 42% in the trauma group. Twenty-four percent experienced recurrence of the CSDH. There was no association between recurrence and anticoagulant and/or antiplatelet agent therapy. CONCLUSION: Anticoagulant and/or antiplatelet aggregation agent therapy is more prevalent among non-traumatic CSDH patients but does not seem to influence the rate of CSDH recurrence.

Comparison between capillary, venous and arterial levels of protein S100B in patients with severe brain pathology.

BACKGROUND: Protein S100B is soon in clinical use as a sensitive marker after mild traumatic head injury in adults. Initial studies of S100B in pediatric head injury have shown promising results. Venous sampling can be challenging in children and capillary samples are often a preferred option. The aim of the study was to investigate the relation between capillary, venous and arterial measurements of protein S100B, primarily by determining whether capillary S100B differ from venous and if capillary S100B can predict venous S100B levels, and secondarily, if arterial S100B samples can substitute venous samples in severely brain-injured patients. METHODS: Venous, arterial and capillary blood samples for S100B were collected simultaneously once a day for a maximum of 6 days. Patients were ≥18 years old and admitted to neurointensive care due to severe brain pathology. RESULTS: Capillary S100B samples were on average 0.08 µg/L higher than venous S100B samples. Prediction of venous concentration from capillary samples yielded a prediction error of 0.07 µg/L. The mean difference between venous and arterial samples was 0.01 µg/L. The mean prediction error was 0.03 µg/L. CONCLUSIONS: Capillary and venous serum S100B are not interchangeable, and should be considered as two separate, although related, variables. Arterial measurements of S100B can successfully predict the corresponding venous concentration.

Reference values for venous and capillary S100B in children.

BACKGROUND: The current management guidelines for pediatric mild head injury (MHI) liberally recommend computed tomography (CT) and frequent admission. Serum protein S100B, currently used in management of adult head injury, has recently shown potential for reducing unnecessary CT scans after pediatric mild head injury. Capillary sampling in children is commonly used when venous sampling fails or is inappropriate. We present reference values for both venous and capillary samples of protein S100B in children. METHODS: Neurologically healthy children aged 1-16, scheduled for minor surgery requiring general anesthesia, were prospectively included. Samples for S100B were drawn before (venous) and after (venous and capillary) sedation. RESULTS: Serum values of 455 children (255 boys, 200 girls) aged 1-14 were computed. S100B was higher in younger children for both venous (r=-0.32) and capillary samples (r=-0.28). Reference levels for children aged 1 and 2 were significantly higher than for children aged 3-14 years (venous 0.15 µg/L, capillary 0.37 µg/L). For capillary blood, a gender difference was found in the youngest age groups. CONCLUSIONS: We present reference values for venous and capillary S100B in healthy children. These results can be utilized when considering future studies on pediatric head injury and S100B levels.

Clinical factors associated with intracranial complications after pediatric traumatic head injury: an observational study of children submitted to a neurosurgical referral unit.

BACKGROUND: Clinically validated guidelines for the management of head injury in children do not exist, and the treatment is often based upon adult management routines. In order to examine the safety of this procedure, an analysis of clinical factors associated with complications after pediatric head injury was attempted. METHOD: We performed a descriptive retrospective study, including patients who received any S06 diagnosis during treatment in the Neurointensive Care Unit at Lund University Hospital between 2002 and 2007. One hundred children were included during the 6 years. RESULTS: During 6 years, 100 children with head injury needed neurointensive care or neurosurgery for their injury in southern Sweden. Traffic accidents (50%) were the main cause of head trauma, followed by falls (36%). Thirty-two percent of all children were injured in bicycle and motorcycle accidents. Both loss of consciousness and amnesia were absent in 23% of the children with intracranial injury. Seven children with intracranial injury, 6 of them requiring neurosurgery, were classed as having minimal head injury according to the Head Injury Severity Scale (HISS). Interesting differences in intracranial injuries between helmet users and nonusers were observed. CONCLUSION: Children with minimal head injuries (according to HISS) may develop intracranial complications and may even require neurosurgical intervention. Hence, the HISS classification, as well as other risk classifications based upon unconsciousness and amnesia, are unreliable in children.

Clinical significance of serum S100B levels in neurointensive care.

OBJECTIVE: S100B is viewed as the most promising biomarker for brain damage. It has been proposed that this marker is useful in a Neurointensive Care Unit (NICU) as a monitoring parameter. This study aims to examine the clinical usefulness of daily serum S100B measurements in this setting. DESIGN: Prospective consecutive inclusion of patients. PATIENTS: A total of 79 patients with confirmed or suspected head injury or cerebrovascular insults (CVIs) (based upon patient history, computed tomography (CT) and/or magnetic resonance imaging (MRI) and neurological examination including coma scoring) who required neurointensive care were included in the study. INTERVENTIONS: Sampling for S100B was performed at admission and daily until patients were discharged from the NICU. S100B measurements were statistically compared to occurrence of secondary complications and outcome according to Glasgow Outcome Scale (GOS), with focus on clinical prediction. MEASUREMENTS AND MAIN RESULTS: 17 of 79 patients (22%) had secondary neurological complications. Mean S100B levels were found to be an independent parameter associated with these complications (P=0.03). Mean S100B levels were higher in patients with complications compared to those without on both the complication day (P=0.033) and the day after (P=0.015), but not the day prior to the complication (P=0.62). S100B did not predict secondary neurological complication. Neither mean (P=0.182) nor peak (P=0.370) S100B levels were associated with or predicted outcome according to dichotomised GOS. CONCLUSION: Daily S100B measurements are associated with secondary complications but not to outcome. However, daily S100B levels do not predict secondary complications, which limit the usefulness of this brain biomarker in this setting.