Hypotension and low cerebral perfusion pressure (CPP, mean arterial pressure [MAP] minus intracranial pressure [ICP]) are associated with low cerebral blood flow (CBF), cerebral ischemia, and poor outcomes after traumatic brain injury (TBI). TBI is the leading cause of injury related death in children and young adults, with boys and children under 4 years having particularly poor outcomes. Cerebral autoregulation is often impaired after TBI and with concomitant hypotension and high ICP, lead to poor outcome. Current 2012 Pediatric Guidelines recommend maintaining CPP above 40 mm Hg, noting that an age-related continuum for the optimal CPP is between 40 and 65 mm Hg. Maintaining CPP within these levels is often managed by the use of vasopressors to increase MAP/CPP and optimize CBF. However, vasopressors clinically used to elevate MAP after TBI, such as phenylephrine (Phe), epinephrine (EPI), and norepinephrine (NE) have not sufficiently been compared regarding effect on CPP, CBF, autoregulation, and outcomes after TBI and virtually nothing is known about their mechanisms of action. Since ethical considerations constrain mechanistic studies in children with TBI, we have used an established porcine model of fluid percussion injury (FPI) to gain greater understanding of vasopressor mechanism in TBI. Like humans, pigs have gyrencephalic brains, are sensitive to TBI, and newborn and juvenile pigs correspond with children and young adult humans. Impaired cerebral hemodynamics and disturbed autoregulation post FPI is caused by an age dependent increase in endothelin-1 (ET-1) and decrease in prostaglandins (PG). We observed that the vasopressor phenylephrine (Phe) prevented in female but exacerbated impairment of cerebral autoregulation in male newborn pigs. This differential outcome related to an increase in ET-1 in males compared to a minimal increase in ET-1 in female newborns after FPI. Provocative Preliminary Data indicate that, in contrast to newborn pigs, impaired autoregulation is equivalently protected by Phe in male and female juvenile pigs after FPI. These data suggest that pressor support choice after TBI differentially influences protection of autoregulation as a function of both age and sex. The overarching hypothesis is that vasopressors differentially influence protection of autoregulation after TBI and these differences are attributable to age- and sex-dependent modulation of cerebral dilator (PGE2, ADM) and cerebral constrictor (ET-1) ratios.
The Aims are: # 1. Compare the effect of systemic administration of Phe, EPI, and NE on cerebral hemodynamics and autoregulation after TBI in male and female pigs as a function of age. # 2: Compare the mechanism by which Phe, EPI, and NE impacts cerebral hemodynamics and autoregulation after TBI in pigs as a function of age and sex. #3: Determine the functional significance of Phe, EPI, and NE induced modulation of cerebral hemodynamics and protection of autoregulation after TBI in pigs as a function of age and sex.

Public Health Relevance

Traumatic brain injury is the leading cause of death and disability in children and young adults worldwide. This proposal addresses an underserved area of scientific investigation. This research will characterize basic mechanisms involved in impaired brain blood flow regulation post trauma and will identify potential avenues for clinical therapeuti intervention in brain injured patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bellgowan, Patrick S F
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University of Pennsylvania
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Curvello, Victor; Hekierski, Hugh; Pastor, Philip et al. (2017) Dopamine protects cerebral autoregulation and prevents hippocampal necrosis after traumatic brain injury via block of ERK MAPK in juvenile pigs. Brain Res 1670:118-124
Curvello, Victor; Hekierski, Hugh; Riley, John et al. (2017) Sex and age differences in phenylephrine mechanisms and outcomes after piglet brain injury. Pediatr Res 82:108-113
Armstead, William M; Riley, John; Vavilala, Monica S (2017) K channel impairment determines sex and age differences in epinephrine-mediated outcomes after brain injury. J Neurosci Res 95:1917-1926
Armstead, William M; Riley, John; Vavilala, Monica S (2017) Sex and Age Differences in Epinephrine Mechanisms and Outcomes after Brain Injury. J Neurotrauma 34:1666-1675
Armstead, William M (2016) Cerebral Blood Flow Autoregulation and Dysautoregulation. Anesthesiol Clin 34:465-77
Armstead, William M; Riley, John; Vavilala, Monica S (2016) Preferential Protection of Cerebral Autoregulation and Reduction of Hippocampal Necrosis With Norepinephrine After Traumatic Brain Injury in Female Piglets. Pediatr Crit Care Med 17:e130-7
Armstead, William M; Riley, John; Vavilala, Monica S (2016) Norepinephrine Protects Cerebral Autoregulation and Reduces Hippocampal Necrosis after Traumatic Brain Injury via Blockade of ERK MAPK and IL-6 in Juvenile Pigs. J Neurotrauma 33:1761-1767