Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns.

OBJECTIVE: The purpose of this observation was to evaluate the safety and efficacy of hydrocortisone (HC) for the treatment of refractory hypotension in term and preterm infants. A secondary purpose was to determine the utility of serum cortisol concentrations in predicting the response to treatment. STUDY DESIGN: This is a retrospective observational study of 117 infants treated with a standardized HC protocol for refractory hypotension. Refractory hypotension was defined as a mean arterial pressure (MAP) less than the gestational age (GA) despite a total inotrope dose of 20 microg per kg per min. Baseline serum cortisol concentrations were determined prior to treatment with stress dose HC. RESULT: Treatment with HC increased the MAP at 2, 6, 12 and 24 h after initiation, decreased the total inotrope dose at 6, 12 and 24 h, and was associated with resolution of oliguria. There was no correlation between the pretreatment baseline cortisol concentration and GA, birth weight or the response to treatment. The incidence of grades III to IV intraventricular hemorrhage, periventricular leukomalacia, bacterial or fungal sepsis and spontaneous intestinal perforation (SIP) after HC treatment was similar to institutional historic controls prior to institution of this standardized HC protocol. CONCLUSION: HC treatment was associated with a rapid resolution of cardiovascular compromise. The incidence of significant side effects was similar to that in previously published reports, including a comparable incidence of SIP. On the basis of our results, measuring baseline serum cortisol concentration to guide the management of refractory hypotension is unwarranted.

Subventricular zone proliferation after alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated neonatal brain injury.

The mammalian forebrain subventricular zone (SVZ) contains stem cells capable of generating new neurons and glia. Recent studies indicate that acute brain injury is a potent stimulus for SVZ stem cell proliferation. To better understand mechanisms of the SVZ response to neonatal brain injury, we used a model that focuses on a unique mechanism of vulnerability of the immature CNS, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitotoxicity. We previously demonstrated that intracerebroventricular injection of the glutamate analog AMPA in rats at postnatal day 7 (P7) caused bilateral periventricular gray and white matter injury. We hypothesized that excitotoxic injury would stimulate cellular proliferation in the SVZ; we used the AMPA intracerebroventricular injection model to test this hypothesis. P7 rat pups received either left or right intracerebroventricular injections of S-AMPA (2.5 nmol). Normal and PBS-injected littermates were included as controls. On P8 or P14, serial coronal sections through the SVZ were collected; an immunohistochemical assay was performed with an antibody to the cell proliferation marker Ki-67. Bilateral Ki-67+ cells/SVZ were quantitated stereologically using the optical disector method. The median number of Ki-67+ cells/SVZ was increased in the SVZ of AMPA-injected rats relative to normal controls on both P8 and P14. To evaluate neurogenesis, we assayed the expression of doublecortin, a microtubular protein expressed only by immature neurons. From P8 to P14, there was a marked increase in doublecortin immunoreactive cells in the AMPA-injected SVZ. Many Ki-67+ nuclei were immediately surrounded by doublecortin staining. This study indicates that there is a proliferative response in the immature SVZ after an excitotoxic stimulus. Our findings suggest that some of these newly generated cells differentiate as immature neurons. This model may provide information about the mechanisms that regulate SVZ responses to neonatal brain injury.