Johan Undén

Raised serum S100B levels after acute bone fractures without cerebral injury

BACKGROUND S100B, a protein abundant in astroglial cells within the central nervous system, has been shown to increase in cerebrospinal fluid and serum after various neurologic diseases. However, the cerebral specificity of S100B has been questioned. This study aims to show serum S100B levels after uncomplicated bone fractures in patients without current or prior neurologic diseases. METHODS Blood for sampling was drawn from patients seeking care at the emergency department presenting with various uncomplicated orthopedic fractures no older than 24 hours and having no previous or suspected neurologic disorder or head injury. RESULTS Fifty-five consecutive patients with acute fractures were included in the study. Serum S100B levels were raised above 0.15 microg/L in 16 of 55 (29%) patients (range, 0.02-0.51 microg/L; mean, 0.13 +/- 0.11 microg/L). CONCLUSION S100B levels were raised in 29% of patients with acute fractures without apparent cerebral injury, which suggests an extracerebral source of S100B. This information should be taken into account when interpreting S100B levels when dealing with brain damage.

Target temperature management after out-of-hospital cardiac arrest-a randomized, parallel-group, assessor-blinded clinical trial-rationale and design

BACKGROUND Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32°C to 34°C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known. METHODS The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33°C or 36°C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm. DISCUSSION The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.

Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update

BackgroundThe management of minimal, mild and moderate head injuries is still controversial. In 2000, the Scandinavian Neurotrauma Committee (SNC) presented evidence-based guidelines for initial management of these injuries. Since then, considerable new evidence has emerged.MethodsGeneral methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Systematic evidence-based review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, based upon relevant clinical questions with respect to patient-important outcomes, including Quality Assessment of Diagnostic Accuracy Studies (QUADAS) and Centre of Evidence Based Medicine (CEBM) quality ratings. Based upon the results, GRADE recommendations, guidelines and discharge instructions were drafted. A modified Delphi approach was used for consensus and relevant clinical stakeholders were consulted.ConclusionsWe present the updated SNC guidelines for initial management of minimal, mild and moderate head injury in adults including criteria for computed tomography (CT) scan selection, admission and discharge with suggestions for monitoring routines and discharge advice for patients. The guidelines are designed to primarily detect neurosurgical intervention with traumatic CT findings as a secondary goal. For elements lacking good evidence, such as in-hospital monitoring, routines were largely based on consensus. We suggest external validation of the guidelines before widespread clinical use is recommended.

Can low serum levels of S100B predict normal CT findings after minor head injury in adults?: an evidence-based review and meta-analysis.

ObjectiveTo determine whether low levels of S100B in serum can predict normal computed tomography (CT) findings after minor head injury (MHI) in adults. ParticipantsNot applicable. DesignSystematic evidence-based review of the peer-reviewed literature with meta-analytical interpretation. Primary MeasuresNot applicable. ResultsWe identified 12 eligible articles that specifically studied adult MHI patients with S100B and cranial CT scans in the acute phase after injury, comprising a total of 2466 separate patients. Individual negative predictive values of 90% to 100% were found for the ability of a negative (under cutoff) S100B level to predict a normal CT scan. A total of 6 patients included in the studies had low S100B levels and positive CT scans (0.26%) and only 1 of these patients (0.04%) had a clinically relevant CT finding. The pooled negative predictive value for all studies was more than 99% (95% CI 98%–100%), with an average prevalence for any CT finding at 8%. The studies are consistently classed as level 2 and level 3 grades of evidence, suggesting a grade B recommendation. ConclusionLow serum S100B levels accurately predict normal CT findings after MHI in adults. S100B sampling should be considered in MHI patients with no focal neurological deficit, an absence of significant extracerebral injury, should be taken within 3 hours of injury, and the cutoff for omitting CT set at less than 0.10 μg/L. Care givers should also be aware of other clinical factors predictive of intracranial complications after MHI.

Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33°C vs 36°C After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial

IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33°C vs 36°C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33°C group (interquartile range [IQR], 0-28) vs 17 in the 36°C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33°C and 36°C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33°C group median, 28; IQR, 26-30; vs 36°C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33°C group median, 79.5; IQR, 78.0-85.9; vs 36°C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33°C group vs 61.8% in the 36°C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33°C or 36°C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales. TRIAL REGISTRATION ClinicalTrials.gov NCT01020916.

Serum S100B levels in patients with cerebral and extracerebral infectious disease

S100B has been shown to increase in cerebrospinal fluid (CSF) and serum after various neurological diseases and it has been postulated that S100B could serve as a serum marker for brain damage. However there is limited information concerning serum S100B levels in infectious diseases of the brain. Blood samples were collected from patients at the Department of Infectious Diseases at or soon after admission. The different diagnoses studied were bacterial meningitis, pneumonia, viral meningitis, cerebral abscess, enteritis, erysipelas, viral encephalitis and neuroborreliosis. A serum S100B level >0.15 μg/l was defined as increased. 57 patients were included in the study. S100B was elevated in 33% of patients (19/57). 73% (8/11) of patients with bacterial meningitis showed increased levels compared to 7% (1/14) of patients with viral meningitis. Viral encephalitis showed the highest mean S100B levels (mean 0.58 μg/l). 25% (6/24) of patients with extracerebral infections showed raised S100B levels. S100B levels were generally higher in patients with cerebral infections than in extracerebral infections. However, both false negative and false positive S100B levels were observed which may limit the use of S100B as a brain specific serum marker.

Extravascular lung water index improves the diagnostic accuracy of lung injury in patients with shock.

IntroductionThe diagnosis of acute lung injury (ALI) may be more robust if more accurate physiological markers can be identified. Extravascular lung water (EVLW) is one possible marker, and it has been shown to correlate with respiratory function and mortality in patients with sepsis. Whether EVLW confers diagnostic value in a general population with shock, as well as which index performs best, is unclear. We investigated the diagnostic accuracy of various EVLW indices in patients with shock.MethodsWe studied a prospective, observational cohort of 51 patients with shock admitted to a tertiary ICU. EVLW was measured within 6 hours of ICU admission and indexed to actual body weight (EVLW/ABW), predicted body weight (EVLW/PBW) and pulmonary blood volume (EVLW/PBV). The relationship of these indices to the diagnosis and severity of lung injury and ICU mortality were studied. Positive and negative likelihood ratios, pre- and posttest odds for diagnosis of lung injury and mortality were calculated.ResultsAll EVLW indices were higher among patients with lung injury and significantly correlated with respiratory parameters. Furthermore, all EVLW indices were significantly higher in nonsurvivors. The use of EVLW improves the posttest OR for the diagnosis of ALI, acute respiratory distress syndrome (ARDS) and severe lung injury (sLI) by up to eightfold. Combining increased EVLW and a diagnosis of ALI, ARDS or sLI increases the posttest odds of ICU mortality. EVLW/ABW and EVLW/PBV demonstrated the best diagnostic performance in this population.ConclusionsEVLW was associated with degree of lung injury and mortality, regardless of the index used, confirming that it may be used as a bedside indicator of disease severity. The use of EVLW as a bedside test conferred added diagnostic value for the identification of patients with lung injury.

Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation

IntroductionA simple and accurate method of differentiating ischemic stroke and intracerebral hemorrhage (ICH) is potentially useful to facilitate acute therapeutic management. Blood measurements of biomarkers of brain damage and activation of the coagulation system may potentially serve as novel diagnostic tools for stroke subtypes.MethodsNinety-seven stroke patients were prospectively investigated in a multicenter design with blood levels of brain biomarkers S100B, neuron specific enolase (NSE), glial fibrillary acidic protein (GFAP) as well as a coagulation biomarker, activated protein C – protein C inhibitor complex (APC-PCI), within 24 hours of symptom onset.ResultsEighty-three patients (86 %) had ischemic stroke and fourteen patients (14 %) had ICH. There were no differences in S100B (p = 0.13) and NSE (p = 0.67) levels between patients with ischemic stroke or ICH. However, GFAP levels were significantly higher in ICH patients (p = 0.0057). APC-PCI levels were higher in larger ischemic strokes (p = 0.020). The combination of GFAP and APC-PCI levels, in patients with NIHSS score more than 3, had a sensitivity and negative predictive value of 100 % for ICH in our material (p = 0.0052).ConclusionThis exploratory study indicated that blood levels of biomarkers GFAP and APC-PCI, prior to neuroimaging, may rule out ICH in a mixed stroke population.

Analysis of protein S-100B in serum: a methodological study

Abstract Background: Dysfunction and damage of the human central nervous system can be detected with biochemical markers, and protein S-100B is the best-established such marker. The aim of this study was to evaluate whether the protein is stable during long-term storage, to establish reference values for the new Elecsys® S100 test and to compare this new method with the Liaison® Sangtec® 100 test. Methods: We analysed blood samples from 118 blood donors and 196 patients with subarachnoid haemorrhage or head injury. The long-term stability of S-100B in frozen serum samples was evaluated with repeated analysis in 1997 and 2003 using an immunoradiometric assay. Method comparison between the Liaison® Sangtec® 100 and Elecsys® S100 tests was performed using Bland-Altman difference plots. Results: Serum concentrations increased significantly during long-term storage (mean difference 0.15μg/L; ±2 SD, 0.55μg/L). Serum measurements using the Elecsys® S100 method in 118 healthy blood donors showed S-100B levels between 0.02 and 0.08μg/L (mean 0.05). The 95th percentile was 0.07μg/L. The Liaison® Sangtec® 100 test usually measured higher concentrations than the Elecsys® S100 method, and the difference between the two methods increased with increasing concentrations. The mean difference between the methods was 0.14μg/L (±2 SD, 0.39μg/L). Conclusions: Protein S-100B is not stable during long-term storage and the two analytical methods are not interchangeable. Clin Chem Lab Med 2006;44:1111–4.

A new objective method for CT triage after minor head injury – serum S100B

The risk of acute intracranial complication after minor head injury (MHI) is low. Despite this, a computed tomography (CT) scan is generally recommended for all patients following MHI. Admission for clinical observation is a secondary management option when a CT scan is unavailable or is judged inappropriate. Both alternatives are associated with disadvantages and several attempts at refining existing guidelines for MHI management have been proposed as a means of reducing CT and/or admission. However, they are based on potentially unreliable patient history and clinical examination and, furthermore, may be compromised by patient factors such as intoxication. Clinical studies from several research groups have shown the potential of brain biomarker S100B in this patient category. The specificity of S100B is poor, but a high sensitivity for brain damage effectively rules out relevant complications after MHI. Used in conjunction with existing guidelines, serum levels of S100B can accurately identify patients who do not need a CT scan after MHI. Based on 6 prospective studies comprising almost 2,000 patients with MHI, the sensitivity and negative predictive value of S100B for CT findings were 98.2 % and 99.5 %, respectively, and for clinically relevant intracranial complications 100 % and 100 %, respectively. Integration of S100B within existing management routines can reduce the need for CT scans by 30 %, resulting in improved and more efficient patient care.