Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC)-hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10× higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases.

The aim of this article is to provide an up-to-date review of the state-of-the-art in cerebral autoregulation, particularly as it may relate to the clinician scientist whose expertise is in the area of neuroscience in anesthesia and critical care. Topics covered range from biological mechanisms, methods used for assessment of autoregulation, effects of anesthetics, role in control of cerebral hemodynamics in health and disease such as traumatic brain injury where dysregulation is evident, and emerging areas such as role of age and sex in contribution to dysautoregulation. Emphasis will be placed on bidirectional translational research wherein the clinical informs the study design of basic science studies, which in turn, informs the clinical to result in development of improved therapies for treatment of CNS pathology.

Cerebral superoxide anion generation during reperfusion after total cerebral ischemia was measured in newborn pigs. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined using two closed cranial windows inserted over the parietal cortices. Twenty minutes of total cerebral ischemia was produced by increasing intracranial pressure, and SOD-inhibitable NBT reduction was determined during 20 min of reperfusion. SOD-inhibitable NBT reduction (8.7 +/- 1.5 pmol.mm-2.20 min-1) was greater in piglets subjected to cerebral ischemia followed by reperfusion than in control piglets not exposed to ischemia (1.6 +/- 1.3 pmol.mm-2.20 min-1). Pretreatment with indomethacin (5 mg/kg iv) markedly reduced postischemia SOD-inhibitable NBT reduction (2.8 +/- 1.1 pmol.mm-2.20 min-1). We conclude that superoxide anion radical is produced by newborn pig brain during postischemic reperfusion. Furthermore, cyclooxygenase metabolism of arachidonic acid appears to be a major source of this activated oxygen during reperfusion of ischemic piglet brain.

The present study was designed to characterize the influence of early developmental changes on the relationship among systemic arterial pressure, cerebral hemodynamics, and cerebral oxygenation during the first 3 h following percussion brain injury. Anesthetized newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Brain injury of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Mean arterial blood pressure increased after brain injury in juveniles (68 +/- 4 to 93 +/- 2 mm Hg within 3 min, n = 6), whereas it decreased after injury in newborns (70 +/- 3 to 51 +/- 3 mm Hg within 3 min, n = 6). Fluid percussion brain injury decreased pial artery diameter more in newborns (132 +/- 5 to 110 +/- 5 microns within 10 min, n = 5) than in juveniles (141 +/- 3 to 133 +/- 3 microns within 10 min, n = 5). Pial arterioles constricted to a greater extent than small pial arteries following brain injury in both age groups. Within 30 sec, brain injury produced a transient increase in cerebral hemoglobin O2 saturation (27 +/- 4%, n = 5) that was reversed to a profound decrease in cerebral hemoglobin O2 saturation (45 +/- 2%, n = 5) in the newborn as measured by near infrared spectroscopy. In contrast, brain injury produced modest increases in hemoglobin O2 saturation (10 +/- 1%, n = 5), followed by mild desaturation (4 +/- 1%, n = 5) in juveniles. Additionally, regional cerebral blood flow was reduced within 10 min of injury in both newborn and juvenile pigs and remained depressed for 180 min in newborns. In contrast, cerebral blood flow returned to control values within 180 min in juveniles. These data show that the effects of comparable brain injury level were very different in newborn and juvenile pigs. Further, these data suggest that reductions in cerebral blood flow following brain injury are more dependent on changes in reactivity of arterioles. Finally, these data suggest that the decrease in cerebral oxygenation, an index of metabolism, coupled with reduced cerebral blood flow, could result in profound hypoperfusion after brain injury.

Objective Traumatic brain injury (TBI) contributes to morbidity and mortality in children and boys are disproportionately represented. Hypotension is common and worsens outcome after TBI. Extracellular signal-related kinase (ERK) mitogen activated protein kinase (MAPK) is upregulated and reduces CBF after fluid percussion brain injury (FPI) in piglets. We hypothesized that increased CPP via phenylephrine (PHE) sex dependently reduces impairment of cerebral autoregulation during hypotension after FPI through modulation of ERK MAPK. Design Prospective, randomized animal study. Setting University laboratory. Subjects Newborn (1–5 day old) pigs. Interventions CBF, pial artery diameter, ICP and autoregulatory index (ARI) were determined before and after FPI in untreated, pre- and post-injury PHE (1 μg/kg/min iv) treated male and female pigs during normotension and hemorrhagic hypotension. CSF ERK MAPK was determined by ELISA. Measurements and Main Results Reductions in pial artery diameter, CBF, CPP and elevated ICP after FPI were greater in males, which were blunted by PHE pre- or post-FPI. During hypotension and FPI, pial artery dilation was impaired more in males. PHE decreased impairment of hypotensive pial artery dilation after FPI in females, but paradoxically caused vasoconstriction after FPI in males. Papaverine induced pial artery vasodilation was unchanged by FPI and PHE. CBF, CPP, and ARI decreased markedly during hypotension and FPI in males but less in females. PHE prevented reductions in CBF, CPP, and ARI during hypotension in females but increased reductions in males. CSF ERK MAPK was increased more in males than females after FPI. PHE blunted ERK MAPK upregulation in females, but increased ERK MAPK upregulation in males after FPI. Conclusions These data indicate that elevation of CPP with PHE sex dependently prevents impairment of cerebral autoregulation during hypotension after FPI through modulation of ERK MAPK. These data suggest the potential role for sex dependent mechanisms in cerebral autoregulation after pediatric TBI.