William D. Whetstone

Blood-spinal cord barrier after spinal cord injury: Relation to revascularization and wound healing

Spinal cord injury produces prominent disruption of the blood‐spinal cord barrier. We have defined the blood‐spinal cord barrier breakdown to the protein luciferase (61 kDa) in the acutely injured murine spinal cord and during revascularization. We show that newly formed and regenerating blood vessels that have abnormal permeability exhibit differential expression of the glucose‐1 transporter (Glut‐1), and that its expression is dependent on astrocytes. There was overt extravasation of luciferase within the first hour after injury, a period that coincided with marked tissue disruption within the epicenter of the lesion. Although there was a significant reduction in the number of blood vessels relative to controls by 24 hr after injury, abnormal barrier permeability remained significantly elevated. A second peak of abnormal barrier permeability at 3–7 days postinjury coincided with prominent revascularization of the epicenter. The barrier to luciferase was restored by 21 days postinjury and vascularity was similar to that of controls. During wound‐healing process, the cord was reorganized into distinct domains. Between 14 and 21 days postinjury, each domain consisted primarily of nonneuronal cells, including macrophages. Astrocytes were limited characteristically to the perimeter of each domain. Only blood vessels affiliated closely with astrocytes in the perimeter expressed Glut‐1, whereas blood vessels within each domain of the repairing cord did not express it. Together, these data demonstrate that both injured and regenerating vessels exhibit abnormal permeability and suggest that Glut‐1 expression during revascularization is dependent on the presence of astrocytes.

Traumatic Injury to the Immature Brain: Inflammation, Oxidative Injury, and Iron-Mediated Damage as Potential Therapeutic Targets

SummaryTraumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBI — inflammation, oxidative injury, and iron-induced damage — and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.

Application of the ABCD2 Score to Identify Cerebrovascular Causes of Dizziness in the Emergency Department

Background and Purpose— Dizziness can herald a cerebrovascular event. The ABCD2 score predicts the risk of stroke after transient ischemic attack partly by distinguishing transient ischemic attack from mimics. We evaluated whether this score would also identify cerebrovascular events among emergency department patients with dizziness. Methods— We retrospectively identified consecutive adults presenting to a university emergency department with a primary symptom of dizziness, vertigo, or imbalance. Two neurologists independently reviewed medical records to determine whether the presenting symptom was caused by a cerebrovascular event (ischemic stroke, transient ischemic attack, or intracranial hemorrhage). ABCD2 scores were then assigned using clinical information from the medical record. The ability of the score to discriminate between patients with cerebrovascular events and those with other diagnoses was quantified using the c statistic. Results— Among 907 dizzy patients (mean age, 59 years; 58% female), 37 (4.1%) had a cerebrovascular cause, the majority of which were ischemic strokes (n=24). The median ABCD2 score was 3 (interquartile range, 3–4). The ABCD2 score predicted ultimate diagnosis of a cerebrovascular event (c statistic, 0.79; 95% CI, 0.73–0.85). Only 5 of 512 (1.0%) patients with a score of ⩽3 had a cerebrovascular event compared to 25 of 369 patients (6.8%) with a score of 4 or 5 and 7 of 26 patients (27.0%) with a score of 6 or 7. Conclusions— The ABCD2 score may provide useful information on dizzy emergency department patients at low-risk for having a cerebrovascular diagnosis and may aid frontline providers in acute management if validated prospectively.

Rate and Predictors of Serious Neurologic Causes of Dizziness in the Emergency Department

OBJECTIVE To describe the rate and predictors of central nervous system (CNS) disease in emergency department (ED) patients with dizziness in the modern era of neuroimaging. PATIENTS AND METHODS We retrospectively reviewed the medical records of all adults presenting between January 1, 2007, and December 31, 2009, to an academic ED for a primary triage complaint of dizziness, vertigo, or imbalance. The final diagnosis for the cause of dizziness was independently assigned by 2 neurologists, with a third neurologist resolving any disagreements. The primary outcome was a composite of ischemic stroke, intracranial hemorrhage, transient ischemic attack, seizure, brain tumor, demyelinating disease, and CNS infection. Univariate and multivariate logistic regression were used to assess the association between clinical variables and serious CNS causes of dizziness. RESULTS Of 907 patients experiencing dizziness (mean age, 59 years; 58% women [n=529]), 49 (5%) had a serious neurologic diagnosis, including 37 cerebrovascular events. Dizziness was often caused by benign conditions, such as peripheral vertigo (294 patients [32%]) or orthostatic hypotension (121 patients [13%]). Age 60 years or older (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.5-11.2), a chief complaint of imbalance (OR, 5.9; 95% CI, 2.3-15.2), and any focal examination abnormality (OR, 5.9; 95% CI, 3.1-11.2) were independently associated with serious neurologic diagnoses, whereas isolated dizziness symptoms were inversely associated (OR, 0.2; 95% CI, 0.0-0.7). CONCLUSION Dizziness in the ED is generally benign, although a substantial fraction of patients harbor serious neurologic disease. Clinical suspicion should be heightened for patients with advanced age, imbalance, or focal deficits.

Age Is a Determinant of Leukocyte Infiltration and Loss of Cortical Volume after Traumatic Brain Injury

There is increasing evidence that the inflammatory response differs in the injured developing brain as compared to the adult brain. Here we compared cerebral blood flow and profiled the inflammatory response in mice that had been subjected to traumatic brain injury (TBI) at postnatal day (P)21 or at adulthood. Relative blood flow, determined by laser Doppler, revealed a 30% decrease in flow immediately after injury followed by prominent hyperemia between 7 and 35 days after injury in both age groups. The animals were euthanized at 1–35 days after injury and the brains prepared for the immunolocalization and quantification of CD45-, GR-1-, CD4- and CD8-positive (+) cells. On average, the number of CD45+ leukocytes in the cortex was significantly higher in the P21 as compared to the adult group. A similar trend was seen for GR-1+ granulocytes, whereas no age-related differences were noted for CD4+ and CD8+ cells. While CD45+ and GR-1+ cells in the P21 group remained elevated, relative to shams, over the first 2 weeks after injury, the adult group showed a time course limited to the first 3 days after injury. The loss of ipsilateral cortical volumes at 2 weeks after injury was significantly greater in the adult relative to the P21 group. While the adult group showed no further change in cortical volumes, there was a significant loss of cortical volumes between 2 and 5 weeks after injury in the P21 group, reaching values similar to that of the adult group by 5 weeks after injury. Together, these findings demonstrate age-dependent temporal patterns of leukocyte infiltration and loss of cortical volume after TBI.

Complications and outcomes of vasopressor usage in acute traumatic central cord syndrome

OBJECT The optimal mean arterial pressure (MAP) for spinal cord perfusion after trauma remains unclear. Although there are published data on MAP goals after spinal cord injury (SCI), the specific blood pressure management for acute traumatic central cord syndrome (ATCCS) and the implications of these interventions have yet to be elucidated. Additionally, the complications of specific vasopressors have not been fully explored in this injury condition. METHODS The present study is a retrospective cohort analysis of 34 patients with ATCCS who received any vasopressor to maintain blood pressure above predetermined MAP goals at a single Level 1 trauma center. The collected variables were American Spinal Injury Association (ASIA) grades at admission and discharge, administered vasopressor and associated complications, other interventions and complications, and timing of surgery. The relationship between the 2 most common vasopressors-dopamine and phenylephrine-and complications within the cohort as a whole were explored, and again after stratification by age. RESULTS The mean age of the ATCCS patients was 62 years. Dopamine was the most commonly used primary vasopressor (91% of patients), followed by phenylephrine (65%). Vasopressors were administered to maintain MAP goals fora mean of 101 hours. Neurological status improved by a median of 1 ASIA grade in all patients, regardless of the choice of vasopressor. Sixty-four percent of surgical patients underwent decompression within 24 hours. There was no observed relationship between the timing of surgical intervention and the complication rate. Cardiogenic complications associated with vasopressor usage were notable in 68% of patients who received dopamine and 46% of patients who received phenylephrine. These differences were not statistically significant (OR with dopamine 2.50 [95% CI 0.82-7.78], p = 0.105). However, in the subgroup of patients > 55 years, dopamine produced statistically significant increases in the complication rates when compared with phenylephrine (83% vs 50% for dopamine and phenylephrine, respectively; OR with dopamine 5.0 [95% CI 0.99-25.34], p = 0.044). CONCLUSIONS Vasopressor usage in ATCCS patients is associated with complication rates that are similar to the reported literature for SCI. Dopamine was associated with a higher risk of complications in patients > 55 years. Given the increased incidence of ATCCS in older populations, determination of MAP goals and vasopressor administration should be carefully considered in these patients. While a randomized control trial on this topic may not be practical, a multiinstitutional prospective study for SCI that includes ATCCS patients as a subpopulation would be useful for examining MAP goals in this population.

The Use of Neuroimaging Studies and Neurological Consultation to Evaluate Dizzy Patients in the Emergency Department

Background and Purpose: Dizziness is a frequent reason for neuroimaging and neurological consultation, but little is known about the utility of either practice. We sought to characterize the patterns and yield of neuroimaging and neurological consultation for dizziness in the emergency department (ED). Methods: We retrospectively identified consecutive adults presenting to an academic ED from 2007 to 2009, with a primary complaint of dizziness, vertigo, or imbalance. Neurologists reviewed medical records to determine clinical characteristics, whether a neuroimaging study (head computed tomography [CT] or brain magnetic resonance imaging [MRI]) or neurology consultation was obtained in the ED, and to identify relevant findings on neuroimaging studies. Two neurologists assigned a final diagnosis for the cause of dizziness. Logistic regression was used to evaluate bivariate and multivariate predictors of neuroimaging and consultation. Results: Of 907 dizzy patients (mean age 59 years; 58% women), 321 (35%) had a neuroimaging study (28% CT, 11% MRI, and 4% both) and 180 (20%) had neurological consultation. Serious neurological disease was ultimately diagnosed in 13% of patients with neuroimaging and 21% of patients with neurological consultation, compared to 5% of the overall cohort. Headache and focal neurological deficits were associated with both neuroimaging and neurological consultation, while age ≥60 years and prior stroke predicted neuroimaging but not consultation, and positional symptoms predicted consultation but not neuroimaging. Conclusion: In a tertiary care ED, neuroimaging and neurological consultation were frequently utilized to evaluate dizzy patients, and their diagnostic yield was substantial.

Higher Mean Arterial Pressure Values Correlate with Neurologic Improvement in Patients with Initially Complete Spinal Cord Injuries

BACKGROUND Traumatic spinal cord injury (SCI) guidelines recommend to maintain mean arterial pressures (MAPs) above 85 mm Hg for 7 days following SCI to minimize spinal cord ischemia. Some physicians doubt that patients with initially complete injuries benefit. OBJECTIVE To assess the relationship between MAP augmentation and neurologic improvement in SCI patients stratified by initial American Spinal Injury Association Impairment Scale (AIS) score. METHODS High-frequency MAP values of acute SCI patients admitted over a 6-year period were recorded, and values were correlated with degree of neurologic recovery in an analysis stratified by postresuscitation AIS score. RESULTS Sixty-two patients with SCI were analyzed. Thirty-three patients were determined to have complete injuries, and of those 11 improved at least 1 AIS grade by discharge. The average MAP of initially AIS A patients who improved versus those who did not was significantly higher (96.6 ± 0.07 mm Hg vs. 94.4 ± 0.06 mm Hg, respectively; P < 0.001), and the proportion of MAP values <85 mm Hg was significantly lower (13.5% vs. 25.6%, respectively; P < 0.001). A positive correlation between MAP values and outcome was also observed in AIS B and C patients but was not observed in patients who were initially AIS D. CONCLUSION A positive correlation was observed between MAP values and neurologic recovery in AIS A, B, and C patients but not AIS D patients. These data raise the possibility that patients with an initially complete SCI may derive greater benefit from MAP augmentation than patients with initial AIS D injuries.

Failure of Mean Arterial Pressure Goals to Improve Outcomes Following Penetrating Spinal Cord Injury.

BACKGROUND Increased spinal cord perfusion and blood pressure goals have been recommended for spinal cord injury (SCI). Penetrating SCI is associated with poor prognosis, but there is a paucity of literature examining the role of vasopressor administration for the maintenance of mean arterial pressure (MAP) goals in this patient population. OBJECTIVE To elucidate this topic and to determine the efficacy of vasopressor administration in penetrating SCI by examining a case series of consecutive penetrating SCIs. METHODS We reviewed consecutive patients with complete penetrating SCI who met inclusion and exclusion criteria, including the administration of vasopressors to maintain MAP goals. We identified 14 patients with complete penetrating SCIs with an admission American Spinal Injury Association grade of A from 2005 to 2011. The neurological recovery, complications, interventions, and vasopressor administration strategies were reviewed and compared with those of a cohort with complete blunt SCI. RESULTS In our patient population, only 1 patient with penetrating SCI (7.1%) experienced neurological recovery, as determined by improvement in the American Spinal Injury Association grade, despite the administration of vasopressors for supraphysiological MAP goals for an average of 101.07 ± 34.96 hours. Furthermore, 71.43% of patients with penetrating SCI treated with vasopressors experienced associated cardiogenic complications. CONCLUSION Given the decreased likelihood of neurological improvement in penetrating injuries, it may be important to re-examine intervention strategies in this population. Specifically, the use of vasopressors, in particular dopamine, with their associated complications is more likely to cause complications than to result in neurological improvement. Our experience shows that patients with acute penetrating SCI are unlikely to recover, despite aggressive cardiopulmonary management. ABBREVIATIONS ASIA, American Spinal Injury AssociationMAP, mean arterial pressureSCI, spinal cord injury.

Simple Text-Messaging Intervention Is Associated With Improved Door-to-Needle Times for Acute Ischemic Stroke

Background and Purpose— Timely administration of intravenous tissue-type plasminogen activator (IV tPA) is associated with improved outcomes for acute ischemic stroke; yet, developing processes to consistently provide prompt treatment remains a challenge. We developed and evaluated a simple quality improvement intervention designed to improve door-to-needle (DTN) times for resident-led Code Stroke teams at an academic medical center. Methods— We evaluated a simple text-messaging based intervention with real-time feedback to improve DTN times for intravenous tissue-type plasminogen activator. We used the rank-sum test and linear regression to evaluate for a change in DTN times that was temporally associated with the rollout of the intervention. Results— A total of 202 patients received intravenous tissue-type plasminogen activator; 94 preintervention and 108 postintervention. The median DTN time was significantly lower in the postintervention period (56 minutes [interquartile range 44–71] versus 82 minutes [IQR 68–103], P<0.0001) and a significantly higher proportion of patients were treated within 60 minutes (61% versus 16%, P<0.001). Conclusions— A simple real-time text-messaging intervention was associated with a significant improvements in DTN times for acute ischemic stroke.