RETRACTED ARTICLE: Sex and age differences in phenylephrine mechanisms and outcomes after piglet brain injury

Abstract

Background Traumatic brain injury (TBI) is the leading cause of injury related death in children, with boys and children under 4 having particularly poor outcomes. Cerebral autoregulation is often impaired after TBI, contributing to poor outcome. In prior studies of newborn pigs, phenylephrine (Phe) preferentially protected cerebral autoregulation in females but not males after TBI. We hypothesized that, in contrast to the newborn, Phe prevents impairment of autoregulation and tissue injury following TBI in both sexes of older pigs. Methods Cerebral autoregulation, CSF ERK and endothelin, and histopathology were determined after moderate fluid percussion brain injury (FPI) in male and female juvenile pigs after Phe. Results Autoregulation was more impaired in male subjects than females. Phe protects autoregulation in both sexes after FPI, blocked ERK and endothelin, and decreased the number of necrotic neurons in males and females after FPI. Conclusions These data indicate that Phe protects autoregulation and limits neuronal necrosis via block of ERK and endothelin after FPI in maleas and females. Together with prior observations in newborn pigs where Phe protected autoregulation in female but not male subjects, these data suggest that use of Phe to improve outcome after TBI is both sex and age dependent.

RETRACTED: Dopamine protects cerebral autoregulation and prevents hippocampal necrosis after traumatic brain injury via block of ERK MAPK in juvenile pigs

“…Our other recent studies using different vasoactive agents have observed the opposite, building the argument for use of a precision medicine approach in treatment of pediatric TBI. For example, Phe and NE have been shown to worsen cerebral autoregulation and histopathology in male, but not female newborn piglets and male and female juvenile pigs after FPI (Armstead et al 2010 a,b, 2016 a,b; Curvello et al 2017). In contrast, EPI prevents impairment of cerebral autoregulation and histopathology in newborn male and female and juvenile female but not juvenile male pigs after FPI (Armstead et al 2017).…”

“…For example, Phe and NE has been shown to protect cerebral autoregulation and limit histopathology in newborn females, and juvenile male and female but not male newborn pigs after fluid percussion brain injury (FPI) (Armstead et al 2010b, 2016 a,b; Curvello et al 2017). In contrast, EPI prevents impairment of cerebral autoregulation and limits histopathology in newborn male and female and juvenile female but not juvenile male pigs after FPI (Armstead et al 2017).…”

Pre-clinical models in pediatric traumatic brain injury—challenges and lessons learned

“…Notably, the most common form of TBI in infants < 1 year of age is abusive head trauma (AHT), also known as the shaken baby syndrome [19]. In addition, a substantial body of work (discussed later in this review) has also focused on cerebrovascular derangements in juvenile piglets (3–4 weeks of age) in order to model findings to the neurocritical care of children with severe TBI [20–23]. A large animal model of developmental brain injury was also designed to study AHT using 7–10 day old lambs [24–27].…”

“…Following that work, the Armstead laboratory has used this model to study a large number of secondary injury mechanisms, with a general focus on studies germane to the cerebral circulation and its regulation. A complete review of the many studies performed is beyond the scope of this review, however, key issues such as the mechanisms of autoregulation and its impairment after injury [21], sex differences in both the injury and vascular responses as well as consequences of therapy [22], and reports on pre-clinical approaches to optimizing perfusion and mitigate neuronal death after injury [23] highlight some of the areas of investigation. Insight into the roles of prostanoids, oxidative signaling, kinases, and endothelin in vascular dysregulation has been provided.…”

“…Several of these recent reports should foster the development of clinical studies to evaluate translation of the findings. For example, recent work has suggested marked improvements in cerebral autoregulation and histology after injury with the use of the pressor agent phenylephrine [23]—with the greatest benefit in the female piglets. Choice of pressor after severe TBI in children to optimize cerebral perfusion pressure remains somewhat arbitrary in clinical care, and thus this study could translate to benefit if confirmed in clinical investigations and/or use.…”