Retracted: Inhaled Nitric Oxide Protects Cerebral Autoregulation and Reduces Hippocampal Neuronal Cell Necrosis after Traumatic Brain Injury in Newborn and Juvenile Pigs

Abstract

Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Cerebral blood flow (CBF) is reduced and autoregulation is impaired after TBI, contributing to poor outcome. Cerebral perfusion pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP). In prior studies of male and female newborn and juvenile pigs, we observed that phenylephrine, norepinephrine, epinephrine, and dopamine demonstrated different sex- and age-dependent abilities to prevent impairment of cerebral autoregulation and limit histopathology after TBI, despite equivalent CPP values. This observation complicated treatment choice. Alternatively, administration of a cerebral vasodilator may improve cerebral hemodynamics after TBI by increasing CBF. In prior studies, intravenous sodium nitroprusside, a nitric oxide (NO) releaser, elevated CBF after TBI but failed to prevent impairment of cerebral autoregulation due to a confounding decrease in MAP, which lowered CPP. We presently test the hypothesis that inhaled NO (iNO) will protect cerebral autoregulation and prevent hippocampal histopathology after TBI. Results show that iNO administered at 30 min or 2 h after TBI protected cerebral autoregulation and prevented neuronal cell necrosis in CA1 and CA3 hippocampus equivalently in male and female newborn and juvenile pigs without change in MAP. Protection lasted for at least 2 h after iNO administration was stopped. Papaverine-induced dilation was unchanged by TBI and iNO. These data indicate that iNO offers the opportunity to have a single therapeutic that uniformly protects autoregulation and limits hippocampal neuronal cell necrosis across both ages and sexes.

Translational approach towards determining the role of cerebral autoregulation in outcome after traumatic brain injury

“…Somewhat surprisingly, though, statistically significant pial artery dilation, which reflects an increase in CBF, and an increase in calculated CPP were not consistently observed with iNO (Hekierski et al 2018). Nonetheless, it was observed that reductions in blood flow in the hippocampus associated with FPI were blocked by iNO (Hekierski et al 2018), supportive of the neurovascular unit concept and neuroprotection via improved CBF. Importantly, iNO did not produce a confounding drop in MAP.…”

“…An alternative strategy to normalize CPP could involve administration of a cerebrovasodilator to elevate CBF. Recently, it was observed that inhaled NO (iNO) prevented impairment of cerebral autoregulation and neuronal cell necrosis in hippocampal regions CA1 and CA3 after FPI in both male and female newborn and juvenile pigs (Hekierski et al 2018). The fact that outcome was improved regardless of sex and age is significant clinically since the above discussion centered on the need for use of a single vasoactive agent to elevate MAP and normalize CPP in treatment of pediatric TBI.…”

Propranolol protects cerebral autoregulation and reduces hippocampal neuronal cell death through inhibition of interleukin-6 upregulation after traumatic brain injury in pigs

“…Only one other medication has recently been observed to improve outcome in both newborn males and females after TBI, and that is inhaled nitric oxide. 13 The results of the present study show that there is at least one additional medication that can achieve protection in a sex-independent manner.…”

An H2-infused, nitric oxide-producing functional beverage as a neuroprotective agent for TBIs and concussions

“…One study found that when nitric oxide was administered post-TBI via inhalation in mice, there was a significantly reduced lesion volume and brain edema with less disruption to the blood-brain barrier and improved neurological function [61]. Similarly, another group reported that nitric oxide administration significantly protected against TBI-induced neuronal cell necrosis and maintained cerebral autoregulation of blood flow in juvenile pigs [62].…”