Julia S. Benoit

Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury: A Randomized Clinical Trial

IMPORTANCE There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold after a traumatic brain injury. OBJECTIVE To compare the effects of erythropoietin and 2 hemoglobin transfusion thresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 200 patients (erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to follow commands and were enrolled within 6 hours of injury at neurosurgical intensive care units in 2 US level I trauma centers between May 2006 and August 2012. The study used a factorial design to test whether erythropoietin would fail to improve favorable outcomes by 20% and whether a hemoglobin transfusion threshold of greater than 10 g/dL would increase favorable outcomes without increasing complications. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hour doses were stopped for the remainder of the patients (n = 126). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL. INTERVENTIONS Intravenous erythropoietin (500 IU/kg per dose) or saline. Transfusion threshold maintained with packed red blood cells. MAIN OUTCOMES AND MEASURES Glasgow Outcome Scale score dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead) at 6 months postinjury. RESULTS There was no interaction between erythropoietin and hemoglobin transfusion threshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to 49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI, 31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%], P < .001). Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusion threshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, -0.06 to 0.25, P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009). CONCLUSIONS AND RELEVANCE In patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events. These findings do not support either approach in this setting. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00313716.

Changes in the Regional Prevalence of Child Obesity in 4th, 8th, and 11th Grade Students in Texas From 2000–2002 to 2004–2005

Although national and state estimates of child obesity are available, data at these levels are insufficient to monitor effects of local obesity prevention initiatives. The purpose of this study was to examine regional changes in the prevalence of obesity due to statewide policies and programs among children in grades 4, 8, and 11 in Texas Health Services Regions (HSRs) between 2000–2002 and 2004–2005, and nine selected counties in 2004–2005. A cross‐sectional, probability‐based sample of 23,190 Texas students in grades 4, 8, and 11 were weighed and measured to obtain BMI. Obesity was >95th percentile for BMI by age/sex using Centers for Disease Control and Prevention growth charts. Child obesity prevalence significantly decreased between 2000–2002 and 2004–2005 for 4th grade students in the El Paso HSR (−7.0%, P = 0.005). A leveling off in the prevalence of obesity was noted for all other regions for grades 4, 8, and 11. County‐level data supported the statistically significant decreases noted in the El Paso region. The reduction of child obesity levels observed in the El Paso area is one of the few examples of effective programs and policies based on a population‐wide survey: in this region, a local foundation funded extensive regional implementation of community programs for obesity prevention, including an evidence‐based elementary school‐based health promotion program, adult nutrition and physical activity programs, and a radio and television advertising campaign. Results emphasize the need for sustained school, community, and policy efforts, and that these efforts can result in decreases in child obesity at the population level.

Effect of Hemoglobin Transfusion Threshold on Cerebral Hemodynamics and Oxygenation

Cerebral dysfunction caused by traumatic brain injury may adversely affect cerebral hemodynamics and oxygenation leading to worse outcomes if oxygen capacity is decreased due to anemia. In a randomized clinical trial of 200 patients comparing transfusion thresholds <7 g/dl versus 10 g/dl, where transfusion of leukoreduced packed red blood cells was used to maintain the assigned hemoglobin threshold, no long-term neurological difference was detected. The current study examines secondary outcome measures of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and brain tissue oxygenation (PbtO2) in patients enrolled in this randomized clinical trial. We observed a lower hazard for death (hazard ratio [HR]=0.12, 95% confidence interval [CI]=0.02-0.99) during the first 3 days post-injury, and a higher hazard for death after three days (HR=2.55, 95% CI=1.00-6.53) in the 10 g/dl threshold group as compared to the 7 g/dL threshold group. No significant differences were observed for ICP and CPP but MAP was slightly lower in the 7 g/dL group, although the decreased MAP did not result in increased hypotension. Overall brain tissue hypoxia events were not significantly different in the two transfusion threshold groups. When the PbtO2 catheter was placed in normal brain, however, tissue hypoxia occurred in 25% of patients in the 7 g/dL threshold group, compared to 10.2% of patients in the 10 g/dL threshold group (p=0.04). Although we observed a few differences in hemodynamic outcomes between the transfusion threshold groups, none were of major clinical significance and did not affect long-term neurological outcome and mortality.

The incidence of ARDS and associated mortality in severe TBI using the Berlin definition.

BACKGROUND The incidence of adult respiratory distress syndrome (ARDS) in severe traumatic brain injury (TBI) is poorly reported. Recently, a new definition for ARDS was proposed, the Berlin definition. The percentage of patients represented by TBI in the Berlin criteria study is limited. This study describes the incidence and associated mortality of ARDS in TBI patients. METHODS The study was an analysis of the safety of erythropoietin administration and transfusion threshold on the incidence of ARDS in severe TBI patients. Three reviewers independently assessed all patients enrolled in the study for acute lung injury/ARDS using the Berlin and the American-European Consensus Conference (AECC) definitions. A Cox proportional hazards model was used to assess the relationship between ARDS and mortality and 6-month Glasgow Outcome Scale (GOS) score. RESULTS Two hundred patients were enrolled in the study. Of the patients, 21% (41 of 200) and 26% (52 of 200) developed ARDS using the AECC and Berlin definitions, respectively, with a median time of 3 days (interquartile range, 3) after injury. ARDS by either definition was associated with increased mortality (p = 0.04) but not with differences in functional outcome as measured by the GOS score at 6 months. Adjusted analysis using the Berlin criteria showed an increased mortality associated with ADS (p = 0.01). CONCLUSION Severe TBI is associated with an incidence of ARDS ranging from 20% to 25%. The incidence is comparable between the Berlin and AECC definitions. ARDS is associated with increased mortality in severe TBI patients, but further studies are needed to validate these findings. LEVEL OF EVIDENCE Epidemiologic study, level II.

Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury.

BACKGROUND The effect of red blood cell (RBC) storage on oxygenation in critically ill patients is still unknown. The objective of this study was to determine the association of RBC storage with oxygenation, long-term neurologic recovery, and death after traumatic brain injury. METHODS We used data from a 2 × 2 factorial randomized controlled trial of administration of erythropoietin or placebo and of assignment to transfusion threshold of less than 7g/dL or less than 10 g/dL in neurosurgical intensive care units in two US Level 1 trauma centers. Patients had severe traumatic brain injury with closed head injury, were unable to follow commands, and were enrolled within 6 hours of injury. Blood oxygenation 1 hour after the transfusion as measured by jugular venous oxygen saturation (n = 59) was the primary outcome. Secondary outcomes were brain tissue oxygenation (n = 77), 6-month Glasgow Outcome Scale (GOS) score (n = 122) collected using a structured interview and dichotomized into favorable (good recovery or moderate disability) or unfavorable outcome (severe disability, vegetative state, or dead), and mortality (n = 125). RBC age was defined as the maximum age of RBCs over all units in one transfusion per patient. For long-term outcomes, RBC age was defined as the mean age over all units given. RESULTS We failed to detect an association of RBC age with jugular venous oxygen saturation (linear regression &bgr; = 1.59; 95% confidence interval [CI], −2.99 to 6.18; p = 0.49), brain tissue oxygenation (linear regression &bgr; = 0.20; 95% CI, −0.23 to 0.63; p = 0.36), GOS score (odds ratio, 1.37; 95% CI, 0.53–3.57; p = 0.52), and mortality (hazard ratio, 1.35; 95% CI, 0.61–2.98; p = 0.46). CONCLUSION Limitations of this study include the fact that the RBC ages were not randomized, although this was a prospective study. We conclude that older blood does not seem to have adverse effects in severe traumatic brain injury. LEVEL OF EVIDENCE Prognostic study, level III.

Enrollment of racially/ethnically diverse participants in traumatic brain injury trials: Effect of availability of exception from informed consent

Background The Final Rule regulations were developed to allow exception from informed consent (EFIC) to enable clinical trial research in emergency settings where major barriers exist for informed consent. There is little known evidence of the effect of the Final Rule in minority enrollment in clinical trials, particularly in traumatic brain injury (TBI) trials. A clinical trial funded by the National Institute of Neurological Disorders and Stroke was conducted to study the effects of erythropoietin on cerebral vascular dysfunction and anemia in subjects with TBI. There were periods of time when EFIC was and was not available for enrollment into the study. Purpose To explore the effect of EFIC availability on TBI trial enrollment of minority versus non-minority subjects. Methods Minority status of screened (n = 289) and enrolled (n = 191) TBI subjects was determined for this study. We tested for the presence of a minority and EFIC availability interaction in a multiple logistic regression model after controlling for EFIC and minority group main effects and other covariates. Results An interaction between the availability of EFIC minority and non-minority enrollment was not detected (odds ratio = 1.22; 95% confidence interval (CI) = 0.29–5.16). Limitations Our study was conducted at a single site, and the CI for the EFIC and minority interaction term was wide. Therefore, a small interaction effect cannot be ruled out. Conclusion EFIC increased the odds of being enrolled regardless of minority status.

Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior

Ocular hypertension is a causal risk-factor to developing glaucoma. This is associated with stiffening of the trabecular meshwork (TM), the primary site of resistance to aqueous-humor-outflow. The mechanisms underlying this stiffening or how pathologic extracellular matrix (ECM) affects cell function are poorly understood. It is recognized that mechanotransduction systems allow cells to sense and translate the intrinsic biophysical properties of ECM into intracellular signals to control gene transcription, protein expression, and cell behavior. Using an anterior segment perfusion model, we document that there are significantly more low flow regions that are much stiffer, and fewer high flow regions that are less stiff in glaucomatous TM (GTM) when compared to non-glaucomatous TMs (NTM). GTM tissue also has fewer cells overall when compared with NTM tissue. In order to study the role of pathologic ECM in glaucoma disease progression, we conducted studies using cell derived matrices (CDM). First, we characterized the mechanics, composition and organization of fibronectin in ECM deposited by GTM and NTM cells treated with glucocorticosteroids. Then, we determined that these GTM-derived ECM are able to induce stiffening of normal NTM cells, and alter their gene/protein expression to resemble that of a glaucomatous phenotype. Further, we demonstrate that GTM-derived ECM causes endoplasmic reticular stress in NTM. They also became resistant to being reorganized by these NTM cells. These phenomena were exacerbated by ECMs obtained from steroid treated glaucoma model groups. Collectively, our data demonstrates that CDMs represent a novel tool for the study of bidirectional interactions between TM cells and their immediate microenvironment. STATEMENT OF SIGNIFICANCE Extracellular matrix (ECM) changes are prevalent in a number of diseases. The precise mechanisms by which changes in the ECM contribute to disease progression is unclear, primarily due to absence of appropriate models. Here, using glaucoma as a disease model, we document changes in cell derived matrix (CDM) and tissue mechanics that contribute to the pathology. Subsequently, we determine the effect that ECMs from diseased and healthy individuals have on healthy cell behaviors. Data emanating from this study demonstrate that CDMs are a potent tool for the study of cell-ECM interactions.

Issues in Research Methodology on Educator Stress

Research on educator stress and its effects on health outcomes faces numerous methodological challenges that affect the design, execution and analysis of scientific investigations. The chapter begins with an overview of the statistical challenges associated with multilevel field studies, which are ubiquitous in research on educator stress. Secondly, we will examine the specific challenges posed by time in the study of stress and the various methods and models used to capture the many roles of time in stress research, including individualized developmental and dynamic models, and ecological momentary assessment (EMA). Finally, we conclude with an examination of the special challenges that arise in the study of event occurrence in multilevel settings, such as leaving the workforce, changing employers, or experiencing a medical incident. These challenges stem from the complex nature of the construct of stress, the time frame over which stress exerts its influences on behavior, health and emotional well-being the many levels at which occupational settings create and mitigate stress, and the many levels at which individuals experience stress and demonstrate its influence on health and work outcomes. The chapter provides an overview of some of the more salient methodological, measurement, and analysis related issues that affect the work reported on in this volume. Our goal is to provide the reader with a firm understanding of the more complex methods and analyses relevant to the study of educator stress in an effort to strengthen the readers’ ability to benefit from the science presented throughout the volume.

Simulated Keratometry Repeatability in Subjects with and without Down Syndrome

Purpose To assess the repeatability of simulated keratometry measures obtained with Zeiss Atlas topography for subjects with and without Down syndrome (DS). Methods Corneal topography was attempted on 140 subjects with DS and 138 controls (aged 7–59 years). Subjects who had at least three measures in each eye were included in analysis (DS: n = 140 eyes (70 subjects) and controls: n = 264 eyes (132 subjects)). For each measurement, the steep corneal power (K), corneal astigmatism, flat K orientation, power vector representation of astigmatism (J0, J45), and astigmatic dioptric difference were determined for each measurement (collectively termed keratometry values here). For flat K orientation comparisons, only eyes with >0.50 DC of astigmatism were included (DS: n = 131 eyes (68 subjects) and control: n = 217 eyes (119 subjects)). Repeatability was assessed using (1) group mean variability (average standard deviation (SD) across subjects), (2) coefficient of repeatability (COR), (3) coefficient of variation (COV), and (4) intraclass correlation coefficient (ICC). Results The keratometry values showed good repeatability as evidenced by low group mean variability for DS versus control eyes (⩽0.26D vs. ⩽0.09D for all dioptric values; 4.51° vs. 3.16° for flat K orientation); however, the group mean variability was significantly higher in DS eyes than control eyes for all parameters (p ⩽ 0.03). On average, group mean variability was 2.5 times greater in the DS eyes compared to control eyes across the keratometry values. Other metrics of repeatability also indicated good repeatability for both populations for each keratometry value, although repeatability was always better in the control eyes. Conclusions DS eyes showed more variability (on average: 2.5×) compared to controls for all keratometry values. Although differences were statistically significant, on average 91% of DS eyes had variability ⩽0.50D for steep K and astigmatism, and 75% of DS eyes had variability ⩽5 degrees for flat K orientation.

Joint coverage probability in a simulation study on continuous-time Markov chain parameter estimation

Parameter dependency within data sets in simulation studies is common, especially in models such as continuous-time Markov chains (CTMCs). Additionally, the literature lacks a comprehensive examination of estimation performance for the likelihood-based general multi-state CTMC. Among studies attempting to assess the estimation, none have accounted for dependency among parameter estimates. The purpose of this research is twofold: (1) to develop a multivariate approach for assessing accuracy and precision for simulation studies (2) to add to the literature a comprehensive examination of the estimation of a general 3-state CTMC model. Simulation studies are conducted to analyze longitudinal data with a trinomial outcome using a CTMC with and without covariates. Measures of performance including bias, component-wise coverage probabilities, and joint coverage probabilities are calculated. An application is presented using Alzheimers disease caregiver stress levels. Comparisons of joint and component-wise parameter estimates yield conflicting inferential results in simulations from models with and without covariates. In conclusion, caution should be taken when conducting simulation studies aiming to assess performance and choice of inference should properly reflect the purpose of the simulation.