NNS 2015 Abstract Book

A1-09

PROTECTIVE EFFECTS OF ESTROGEN IN VASCULAR

SMOOTH MUSCLE CELLS AFTER RAPID-STRETCH INJURY

Yaping Zeng

, Stacy L Sell, Donald S Prough, Douglas S DeWitt

UTMB, Anesthesiology, Galveston, USA

Reduced cerebral blood flow (CBF) and impaired compensatory cere-

bral vascular responses to reduced arterial blood pressure after TBI may

contribute to life-long disability or death. Cerebrovascular effects of

TBI are mediated in part by disruption of gap junctions (GJs), low

resistance channels between adjacent cells (Yu, et al., JNT, 2014). The

neuroprotective effects of estrogen are due, in part, to the maintenance

of adequate perfusion after TBI (Roof & Hall, JNT, 2000) but the

effects of estrogen on GJ function after vascular injury are unknown.

We examined the effects of 17-beta estradiol (E2) on intracellular

calcium (Ca

) and reactive oxygen species (ROS) levels and gap

junction (GJ) communication in vascular smooth muscle (VSM) cells

subjected to rapid stretch injury (RSI), an

in vitro

model that replicates

many features of TBI

in vivo

. Rat VSM cells were subjected to RSI (30,

40, 50 psi for 50ms) and treated with vehicle or E2 (80 nM) for 30min

immediately post-injury. Intracellular Ca

+ +

levels were measured with

Fura-4/AM. Intracellular ROS levels were measured with 5,6-Chlor-

omethyl-2

,7-dichlorodihydrofluorescein diacetate acetyl, mixed iso-

mers (CM-H2DCFDA). To assess GJ coupling, cells were loaded with

5,6-CFDA/AM and fluorescence recovery after photobleaching was

measured. In the cells subjected to RSI and treated with E2, intracellular

+ +

and ROS levels were reduced significantly (

0.01 RSI E2 vs.

RSI vehicle). GJ coupling also was significantly (

0.05 RSI E2 vs.

RSI vehicle). Our results that post treatment with E2 reduced intracel-

lular ROS and Ca

levels while improving GJ coupling after RSI

suggest that E2 protection of GJ coupling may be mediated through

reductions in intracellular ROS and Ca

These studies were supported

by The Moody Project for Translational TBI Research.

Keywords: estrogen, intracellular calcium, reactive oxygen species,

intercellular gap junction, Neuroprotection

A2 Poster Session I - Group A: Secondary Injury

A2-01

SAFETY, TOLERABILITY, AND EFFECTIVENESS OF DEX-

TROMETHORPHAN/QUINIDINE FOR PSEUDOBULBAR

AFFECT IN TRAUMATIC BRAIN INJURY: PRISM-II

Flora Hammond

, William Sauve

, Paul Shin

, Fred Ledon

, Charles

Davis

Charles Yonan

, Joao Siffert

Avanir Pharmaceuticals, Inc., R&D, Aliso Viejo, USA

Indiana University School of Medicine, Physical Medicine & Re-

habilitation, Indianapolis, USA

TMS NeuroHealth Centers, Medical Director, Richmond, USA

CSD Biostatistics, Inc., President, Tucson, USA

Pseudobulbar affect (PBA) is characterized by frequent, uncontrol-

lable episodes of crying and/or laughing that are exaggerated or

incongruous with mood or social context and can occur secondary to

a variety of unrelated neurologic conditions. A multicenter, open-

label study (PRISM-II) assessed the effectiveness, safety, and tol-

erability of dextromethorphan and quinidine (DM/Q) combination

for the treatment of PBA in patients with stroke, dementia, or

traumatic brain injury (TBI). This was a 12-week, US multicenter,

open-label trial of DM/Q for the treatment of PBA. All eligible

patients from the TBI cohort had a clinical diagnosis of PBA, a

Center for Neurologic Study-Lability Scale (CNS-LS) score

‡

(range 7–35), and a clinical diagnosis of non-penetrating TBI, which

was stable and non-evolving. Patients with unstable medical illness

or contraindications to DM/Q were excluded. Enrolled patients re-

ceived DM 20 mg/Q 10 mg twice daily for 12 weeks (once daily in

week 1). Concomitant mood/behavioral medications were allowed if

stable for

‡

2 months. The primary endpoint was change in CNS-LS

score from baseline to Day 90/early withdrawal. Additional end-

points included the change in PBA episodes/week, QOL Visual

Analogue Scale (VAS), Clinical and Patient Global Impression of

Change (CGI-C and PGI-C), Mini-Mental State Examination

(MMSE), the TBI Neurobehavioral Functioning Inventory (NFI),

patient treatment satisfaction, and the Patient Health Questionnaire

(PHQ-9) assessing depressive symptoms. Vital signs and adverse

events were monitored throughout. Enrollment in the PRISM-II TBI

cohort (n

120) has completed (last patient out April 2015). Final

results will be available and presented. PRISM-II is the first pro-

spective open-label study to systematically evaluate DM/Q safety,

tolerability, and effectiveness in patients with PBA secondary to TBI

as well as the impact of symptom relief on health-related outcomes.

Study supported by: Avanir Pharmaceuticals, Inc.

Keywords: pseudobulbar affect, affective symptoms, quinidine- dex-

tromethorphan combination, brain injuries, quality of life, depression

A2-02

DOES A HIGHER HEMOGLOBIN TRANSFUSION THRESH-

OLD AFFECT THE RISK OF PROGRESSIVE HEMOR-

RHAGE AFTER SEVERE TRAUMATIC BRAIN INJURY?

Aditya Vedantam

, Jose-Miguel Yamal

, Claudia Robertson

Shankar Gopinath

Baylor College of Medicine, Neurosurgery, Houston, USA

University of Texas School of Public Health, Biostatistics, Houston,

USA

Maintenance of a higher hemoglobin threshold after severe TBI can

increase the risk of delayed mortality. The objective of this study was to

determine if maintaining a higher hemoglobin transfusion threshold was

associated with an increased incidence of progressive hemorrhage after

severe TBI. Data was obtained from a recently performed prospective

randomized clinical trial studying the effects of erythropoietin and

blood transfusions on neurological recovery after severe TBI. We de-

fined progressive hemorrhage as the presence of new or enlarging in-

tracranial hematomas on computerized tomography up to 24 hours after

injury. Severe progressive hemorrhage included events that required an

escalation of medical management or surgical intervention. Multivariate

Cox regression analysis was used to identify independent risk factors for

progressive hemorrhage after severe TBI. Progressive hemorrhage was

detected on CT imaging in 61 severe TBI patients (30.5%). The com-

monest finding was a new, delayed contusion (n

30, 49.2%). Pro-

gressive hemorrhage was identified at a mean duration of 17.2

–

15.8

hours after injury. Ninety-nine patients were assigned a transfusion

threshold of 7 g/dl, and 101 patients were assigned a transfusion

threshold of 10 g/dl. Patients with a transfusion trigger of 10 gm/dl had a

higher risk of severe progressive hemorrhage (Hazard ratio 2.3, 95% CI

1.1–4.7, p

0.02). Factors that decreased the risk of severe progressive

hemorrhage included surgery on admission and diffuse brain injury,

while factors such as higher initial ICP increased the risk of severe

progressive hemorrhage. A higher transfusion threshold of 10 g/dl after

severe TBI increased the risk of severe PHI events, and these results

indicate the potential adverse effect of maintaining a higher hemoglobin

transfusion threshold after severe TBI.

Keywords: transfusion, traumatic brain injury, progressive hemor-

rhagic injury, decompressive craniectomy

A-19