Linda Papa

Recommended guidelines for uniform reporting of data from drowning: the “Utstein style”

This document presents the consensus of a group of international investigators who met to establish guidelines for the uniform reporting of data from studies of drowning incidents. The consensus process consisted of formal discussions at 3 international meetings as well as expert review, endorsements from multiple organizations, and invited recommendations from other interested parties. The concept of using consensus workshops to formulate guidelines is not new. Similar consensus guidelines for reporting surveillance and resuscitation research have been developed for both adult and pediatric cardiac arrest.1–3 The principal purpose of the recommendations in this advisory is to establish consistency in the reporting of drowning-related studies, both in terms of nomenclature and guidelines for reporting data. These recommendations are intended to improve the clarity of scientific communication and the comparability of scientific investigations. Improved clarity and comparability of future scientific reports will advance the clinical and epidemiological knowledge base. In turn, such studies can help identify appropriate prevention strategies as well as the best treatment for victims of drowning and can ultimately save lives. Laboratory and clinical investigators from many different specialties contribute to the multidisciplinary knowledge base of injury prevention and resuscitation science. Although diversity can be a strength, it can also be an obstacle because of the lack of a common language and communication between investigators from different backgrounds. In response to these problems, in June 1990 an international group of scientists concerned with research involving out-of-hospital cardiac arrest met at the Utstein Abbey in Stavanger, Norway. Participants discussed the lack of standardized nomenclature and definitions as a key problem in research reports. A second meeting, the Utstein Consensus Conference, was held in December 1990 in Brighton, England. Recommendations from this follow-up conference were published simultaneously in American and European journals.4,5 The report included uniform definitions, terminology, and …

Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury

Objective:Ubiquitin C-terminal hydrolase (UCH-L1), also called neuronal-specific protein gene product (PGP 9.3), is highly abundant in neurons. To assess the reliability of UCH-L1 as a potential biomarker for traumatic brain injury (TBI) this study compared cerebrospinal fluid (CSF) levels of UCH-L1 from adult patients with severe TBI to uninjured controls; and examined the relationship between levels with severity of injury, complications and functional outcome. Design:This study was designed as prospective case control study. Patients:This study enrolled 66 patients, 41 with severe TBI, defined by a Glasgow coma scale (GCS) score of ≤8, who underwent intraventricular intracranial pressure monitoring and 25 controls without TBI requiring CSF drainage for other medical reasons. Setting:Two hospital system level I trauma centers. Measurements and Main Results:Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, and 168 hrs following TBI and analyzed for UCH-L1. Injury severity was assessed by the GCS score, Marshall Classification on computed tomography and a complicated postinjury course. Mortality was assessed at 6 wks and long-term outcome was assessed using the Glasgow outcome score 6 months after injury. TBI patients had significantly elevated CSF levels of UCH-L1 at each time point after injury compared to uninjured controls. Overall mean levels of UCH-L1 in TBI patients was 44.2 ng/mL (±7.9) compared with 2.7 ng/mL (±0.7) in controls (p <.001). There were significantly higher levels of UCH-L1 in patients with a lower GCS score at 24 hrs, in those with postinjury complications, in those with 6-wk mortality, and in those with a poor 6-month dichotomized Glasgow outcome score. Conclusions:These data suggest that this novel biomarker has the potential to determine injury severity in TBI patients. Further studies are needed to validate these findings in a larger sample.

Elevated Levels of Serum Glial Fibrillary Acidic Protein Breakdown Products in Mild and Moderate Traumatic Brain Injury Are Associated With Intracranial Lesions and Neurosurgical Intervention

STUDY OBJECTIVE This study examines whether serum levels of glial fibrillary acidic protein breakdown products (GFAP-BDP) are elevated in patients with mild and moderate traumatic brain injury compared with controls and whether they are associated with traumatic intracranial lesions on computed tomography (CT) scan (positive CT result) and with having a neurosurgical intervention. METHODS This prospective cohort study enrolled adult patients presenting to 3 Level I trauma centers after blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale (GCS) score of 9 to 15. Control groups included normal uninjured controls and trauma controls presenting to the emergency department with orthopedic injuries or a motor vehicle crash without traumatic brain injury. Blood samples were obtained in all patients within 4 hours of injury and measured by enzyme-linked immunosorbent assay for GFAP-BDP (nanograms/milliliter). RESULTS Of the 307 patients enrolled, 108 were patients with traumatic brain injury (97 with GCS score 13 to 15 and 11 with GCS score 9 to 12) and 199 were controls (176 normal controls and 16 motor vehicle crash controls and 7 orthopedic controls). Receiver operating characteristic curves demonstrated that early GFAP-BDP levels were able to distinguish patients with traumatic brain injury from uninjured controls with an area under the curve of 0.90 (95% confidence interval [CI] 0.86 to 0.94) and differentiated traumatic brain injury with a GCS score of 15 with an area under the curve of 0.88 (95% CI 0.82 to 0.93). Thirty-two patients with traumatic brain injury (30%) had lesions on CT. The area under these curves for discriminating patients with CT lesions versus those without CT lesions was 0.79 (95% CI 0.69 to 0.89). Moreover, the receiver operating characteristic curve for distinguishing neurosurgical intervention from no neurosurgical intervention yielded an area under the curve of 0.87 (95% CI 0.77 to 0.96). CONCLUSION GFAP-BDP is detectable in serum within an hour of injury and is associated with measures of injury severity, including the GCS score, CT lesions, and neurosurgical intervention. Further study is required to validate these findings before clinical application.

αII-Spectrin Breakdown Products (SBDPs): Diagnosis and Outcome in Severe Traumatic Brain Injury Patients

In this study we assessed the clinical utility of quantitative assessments of alphaII-spectrin breakdown products (SBDP145 produced by calpain, and SBDP120 produced by caspase-3) in cerebrospinal fluid (CSF) as markers of brain damage and outcome after severe traumatic brain injury (TBI). We analyzed 40 adult patients with severe TBI (Glasgow Coma Scale [GCS] score <or=8) who underwent ventriculostomy. Patients requiring CSF drainage for other medical reasons served as controls. CSF samples were taken at admission and every 6 h thereafter for a maximum of 7 days and assessed using novel quantitative fragment-specific ELISAs for SBDPs. Outcome was assessed using the 3-month Glasgow Outcome Scale. Mean CSF levels of SBDPs were significantly higher in TBI patients than in controls at all time points examined. Different temporal release patterns of CSF SBDP145 and SBDP120 were observed. SBDP145 provided accurate diagnoses at all time points examined, while SBDP120 release was more accurate 24 h after injury. Within 24 h after injury, SBDP145 CSF concentrations significantly correlated with GCS scores, while SBDP120 levels correlated with age. SBDP levels were significantly higher in patients who died than in those who survived. SBDP145 levels (>6 ng/mL) and SBDP120 levels (>17.55 ng/mL) strongly predicted death (odds ratio 5.9 for SBDP145, and 18.34 for SBDP120). The time course of SBDPs in nonsurvivors also differed from that of survivors. These results suggest that CSF SBDP levels can predict injury severity and mortality after severe TBI, and can be useful complements to clinical assessment.

Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: A case control study

IntroductionAuthors of several studies have studied biomarkers and computed tomography (CT) findings in the acute phase after severe traumatic brain injury (TBI). However, the correlation between structural damage as assessed by neuroimaging and biomarkers has not been elucidated. The aim of this study was to investigate the relationships among neuronal (Ubiquitin carboxy-terminal hydrolase L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels in serum, neuroradiological findings and outcomes after severe TBI.MethodsThe study recruited patients from four neurotrauma centers. Serum samples for UCH-L1 and GFAP were obtained at the time of hospital admission and every 6 hours thereafter. CT scans of the brain were obtained within 24hrs of injury. Outcome was assessed by Glasgow Outcome Scale (GOS) at discharge and at 6 months.Results81 severe TBI patients and 167 controls were enrolled. The mean serum levels of UCH-L1 and GFAP were higher (p < 0.001) in TBI patients compared to controls. UCH-L1 and GFAP serum levels correlated significantly with Glasgow Coma Scale (GCS) and CT findings. GFAP levels were higher in patients with mass lesions than in those with diffuse injury (2.95 ± 0.48 ng/ml versus 0.74 ± 0.11 ng/ml) while UCH-L1 levels were higher in patients with diffuse injury (1.55 ± 0.18 ng/ml versus 1.21 ± 0.15 ng/ml, p = 0.0031 and 0.0103, respectively). A multivariate logistic regression showed that UCH-L1 was the only independent predictor of death at discharge [adjusted odds ratios 2.95; 95% confidence interval, 1.46-5.97], but both UCH-L1 and GFAP levels strongly predicted death 6 months post-injury.ConclusionsRelationships between structural changes detected by neuroimaging and biomarkers indicate each biomarker may reflect a different injury pathway. These results suggest that protein biomarkers could provide better characterization of subjects at risk for specific types of cellular damage than that obtained with neuroimaging alone, as well as provide valuable information about injury severity and outcome after severe TBI.

Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention.

BACKGROUND: This study compared early serum levels of ubiquitin C-terminal hydrolase (UCH-L1) from patients with mild and moderate traumatic brain injury (TBI) with uninjured and injured controls and examined their association with traumatic intracranial lesions on computed tomography (CT) scan (CT positive) and the need for neurosurgical intervention (NSI). METHODS: This prospective cohort study enrolled adult patients presenting to three tertiary care Level I trauma centers after blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale (GCS) score 9 to 15. Control groups included normal uninjured controls and nonhead injured trauma controls presenting to the emergency department with orthopedic injuries or motor vehicle crash without TBI. Blood samples were obtained in all trauma patients within 4 hours of injury and measured by enzyme-linked immunosorbent assay for UCH-L1 (ng/mL ± standard error of the mean). RESULTS: There were 295 patients enrolled, 96 TBI patients (86 with GCS score 13–15 and 10 with GCS score 9–12), and 199 controls (176 uninjured, 16 motor vehicle crash controls, and 7 orthopedic controls). The AUC for distinguishing TBI from uninjured controls was 0.87 (95% confidence interval [CI], 0.82–0.92) and for distinguishing those TBIs with GCS score 15 from controls was AUC 0.87 (95% CI, 0.81–0.93). Mean UCH-L1 levels in patients with CT negative versus CT positive were 0.620 (±0.254) and 1.618 (±0.474), respectively (p < 0.001), and the AUC was 0.73 (95% CI, 0.62–0.84). For patients without and with NSI, levels were 0.627 (0.218) versus 2.568 (0.854; p < 0.001), and the AUC was 0.85 (95% CI, 0.76–0.94). CONCLUSION: UCH-L1 is detectable in serum within an hour of injury and is associated with measures of injury severity including the GCS score, CT lesions, and NSI. Further study is required to validate these findings before clinical application. LEVEL OF EVIDENCE: II, prognostic study.

Biokinetic Analysis of Ubiquitin C-Terminal Hydrolase-L1 (UCH-L1) in Severe Traumatic Brain Injury Patient Biofluids

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a neuron-specific enzyme that has been identified as a potential biomarker of traumatic brain injury (TBI). The study objectives were to determine UCH-L1 exposure and kinetic metrics, determine correlations between biofluids, and assess outcome correlations in severe TBI patients. Data were analyzed from a prospective, multicenter study of severe TBI (Glasgow Coma Scale [GCS] score ≤ 8). Cerebrospinal fluid (CSF) and serum data from samples taken every 6 h after injury were analyzed by enzyme-linked immunosorbent assay (ELISA). UCH-L1 CSF and serum data from 59 patients were used to determine biofluid correlations. Serum samples from 86 patients and CSF from 59 patients were used to determine outcome correlations. Exposure and kinetic metrics were evaluated acutely and up to 7 days post-injury and compared to mortality at 3 months. There were significant correlations between UCH-L1 CSF and serum median concentrations (r(s)=0.59, p<0.001), AUC (r(s)=0.3, p=0.027), Tmax (r(s)=0.68, p<0.001), and MRT (r(s)=0.65, p<0.001). Outcome analysis showed significant increases in median serum AUC (2016 versus 265 ng/mL*min, p=0.006), and Cmax (2 versus 0.4 ng/mL, p=0.003), and a shorter Tmax (8 versus 19 h, p=0.04) in those who died versus those who survived, respectively. In the first 24 h after injury, there was a statistically significant acute increase in CSF and serum median Cmax((0-24h)) in those who died. This study shows a significant correlation between UCH-L1 CSF and serum median concentrations and biokinetics in severe TBI patients, and relationships with clinical outcome were detected.

Ubiquitin C-terminal hydrolase-L1 as a biomarker for ischemic and traumatic brain injury in rats

Ubiquitin C‐terminal hydrolase‐L1 (UCH‐L1), also called neuronal‐specific protein gene product 9.5, is a highly abundant protein in the neuronal cell body and has been identified as a possible biomarker on the basis of a recent proteomic study. In this study, we examined whether UCH‐L1 was significantly elevated in cerebrospinal fluid (CSF) following controlled cortical impact (CCI) and middle cerebral artery occlusion (MCAO; model of ischemic stroke) in rats. Quantitative immunoblots of rat CSF revealed a dramatic elevation of UCH‐L1 protein 48 h after severe CCI and as early as 6 h after mild (30 min) and severe (2 h) MCAO. A sandwich enzyme‐linked immunosorbent assay constructed to measure UCH‐L1 sensitively and quantitatively showed that CSF UCH‐L1 levels were significantly elevated as early as 2 h and up to 48 h after CCI. Similarly, UCH‐L1 levels were also significantly elevated in CSF from 6 to 72 h after 30 min of MCAO and from 6 to 120 h after 2 h of MCAO. These data are comparable to the profile of the calpain‐produced αII‐spectrin breakdown product of 145 kDa biomarker. Importantly, serum UCH‐L1 biomarker levels were also significantly elevated after CCI. Similarly, serum UCH‐L1 levels in the 2‐h MCAO group were significantly higher than those in the 30‐min group. Taken together, these data from two rat models of acute brain injury strongly suggest that UCH‐L1 is a candidate brain injury biomarker detectable in biofluid compartments (CSF and serum).

αII-Spectrin Breakdown Product Cerebrospinal Fluid Exposure Metrics Suggest Differences in Cellular Injury Mechanisms after Severe Traumatic Brain Injury

Traumatic brain injury (TBI) produces alphaII-spectrin breakdown products (SBDPs) that are potential biomarkers for TBI. To further understand these biomarkers, the present study examined (1) the exposure and kinetic characteristics of SBDPs in cerebrospinal fluid (CSF) of adults with severe TBI, and (2) the relationship between these exposure and kinetic metrics and severity of injury. This clinical database study analyzed CSF concentrations of 150-, 145-, and 120-kDa SBDPs in 38 severe TBI patients. Area under the curve (AUC), mean residence time (MRT), maximum concentration (C(max)), time to maximum concentration (T(max)), and half-life (t(1/2)) were determined for each SBDP. Markers of calpain proteolysis (SBDP150 and SBDP145) had a greater median AUC and C(max) and a shorter MRT than SBDP120, produced by caspase-3 proteolysis in the CSF in TBI patients ( p < 0.001). AUC and MRT for SBDP150 and SBDP15 were significantly greater in patients with worse Glasgow Coma Scale (GCS) scores at 24 h after injury compared to those whose GCS scores improved (AUC p=0.013, MRT p=0.001; AUC p=0.009, MRT p=0.021, respectively). A positive correlation was found between patients with longer elevations in intracranial pressure (ICP) measurements of 25mmHg or higher and those with a greater AUC and MRT for all three biomarkers. This is the first study to show that the biomarkers of proteolysis differentially associated with calpain and caspase-3 activity have distinct CSF exposure profiles following TBI that suggest a prominent role for calpain activity. Further studies are being conducted to determine if exposure and kinetic metrics for biofluid-based biomarkers can predict clinical outcome.

GFAP out-performs S100β in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions.

Both glial fibrillary acidic protein (GFAP) and S100β are found in glial cells and are released into serum following a traumatic brain injury (TBI), however, the clinical utility of S100β as a biomarker has been questioned because of its release from bone. This study examined the ability of GFAP and S100β to detect intracranial lesions on computed tomography (CT) in trauma patients and also assessed biomarker performance in patients with fractures and extracranial injuries on head CT. This prospective cohort study enrolled a convenience sample of adult trauma patients at a Level I trauma center with and without mild or moderate traumatic brain injury (MMTBI). Serum samples were obtained within 4 h of injury. The primary outcome was the presence of traumatic intracranial lesions on CT scan. There were 397 general trauma patients enrolled: 209 (53%) had a MMTBI and 188 (47%) had trauma without MMTBI. Of the 262 patients with a head CT, 20 (8%) had intracranial lesions. There were 137 (35%) trauma patients who sustained extracranial fractures below the head to the torso and extremities. Levels of S100β were significantly higher in patients with fractures, compared with those without fractures (p<0.001) whether MMTBI was present or not. However, GFAP levels were not significantly affected by the presence of fractures (p>0.05). The area under the receiver operating characteristics curve (AUC) for predicting intracranial lesions on CT for GFAP was 0.84 (0.73-0.95) and for S100β was 0.78 (0.67-0.89). However, in the presence of extracranial fractures, the AUC for GFAP increased to 0.93 (0.86-1.00) and for S100β decreased to 0.75 (0.61-0.88). In a general trauma population, GFAP out-performed S100β in detecting intracranial CT lesions, particularly in the setting of extracranial fractures.