Traumatic brain injury (TBI) causes the brain to susceptible to secondary insults. The secondary insult model that we have developed directly mimics the circumstances of a mild TBI patient who may have systemic injuries that may result in hypotension or hypoxia. The secondary insult model also represent the circumstance in moderate and severe TBI patients who have areas in the brain that are injured and vulnerable to secondary insults, but potentially salvageable if managed optimally. The primary mechanism for the increased vulnerability of traumatized brain to secondary insults appears to be vascular. One possible cause of these findings is impairment of the normal vasodilatory mechanisms, in particular nitric oxide. Another possible cause is release by the trauma of vasoconstrictive substances that prevent vasodilation. We have preliminary evidence that alterations in nitric oxide function play a role in the reduction in rCBF, and treat treatment with L-arginine reverses these findings and improves outcome after severe cortical impact injury. Interestingly, the increase in CBF induced by L-arginine infusion is not associated with an increase in ICP; in fact the ICP is lower with L- arginine treatment than in the saline controls. This is uncharacteristic for vasodilating agents, such as nitroprusside and nitroglycerin. which typically raise ICP in the injured brain. The studies that we propose in this project will extend these studies into the secondary insult model, and examine in more detail how trauma alters nitric oxide metabolism. and how L-arginine ameliorates the situation. The 4 specific aims for the project are: 1. To study the effect of L-arginine and D-arginine on physiological, histological and behavioral measures after the 3m/sec impact injury complicate by a secondary insult. 2. To study the mechanism of the reduced CBF after traumatic brain injury and the L-arginine effect of increasing the reduced CBF. 3. To study the effect of timing of L-arginine dosage on behavior and histological outcome. 4. To study the effect of L-arginine infusion on endothelial and neuronal isoforms of NOS after TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
3P01NS038660-01S1
Application #
6302899
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
1999-07-26
Project End
2000-06-30
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
$407,142
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Rubin, Maria Laura; Chan, Wenyaw; Yamal, Jose-Miguel et al. (2017) A joint logistic regression and covariate-adjusted continuous-time Markov chain model. Stat Med 36:4570-4582
Aisiku, Imoigele P; Yamal, Jose-Miguel; Doshi, Pratik et al. (2016) The incidence of ARDS and associated mortality in severe TBI using the Berlin definition. J Trauma Acute Care Surg 80:308-12
Aisiku, Imo P; Yamal, Jose-Miguel; Doshi, Pratik et al. (2016) Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury. Crit Care 20:288
Vedantam, Aditya; Yamal, Jose-Miguel; Rubin, Maria Laura et al. (2016) Progressive hemorrhagic injury after severe traumatic brain injury: effect of hemoglobin transfusion thresholds. J Neurosurg 125:1229-1234
Lazaridis, Christos; Yang, Ming; DeSantis, Stacia M et al. (2015) Predictors of intensive care unit length of stay and intracranial pressure in severe traumatic brain injury. J Crit Care 30:1258-62
Yamal, José-Miguel; Benoit, Julia S; Doshi, Pratik et al. (2015) Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury. J Trauma Acute Care Surg 79:843-9
Yamal, Jose-Miguel; Rubin, M Laura; Benoit, Julia S et al. (2015) Effect of Hemoglobin Transfusion Threshold on Cerebral Hemodynamics and Oxygenation. J Neurotrauma 32:1239-45
Yamal, Jose-Miguel; Robertson, Claudia S; Rubin, M Laura et al. (2014) Enrollment of racially/ethnically diverse participants in traumatic brain injury trials: effect of availability of exception from informed consent. Clin Trials 11:187-94
Robertson, Claudia S; Yamal, Jose-Miguel; Tilley, Barbara C (2014) Erythropoietin for traumatic brain injury--reply. JAMA 312:1929
Robertson, Claudia S; Hannay, H Julia; Yamal, José-Miguel et al. (2014) Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 312:36-47

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