The effect of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under isoflurane anaesthesia in an ovine model

Publisher's copy made available with the permission of the publisher © Australian Society of AnaesthetistsThe effects of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under steady-state isoflurane anaesthesia were compared with the awake state. Six studies each were conducted in two cohorts of adult ewes: awake sheep and those anaesthetized with 2% isoflurane anaesthesia. In random order, each animal received ramped infusions of adrenaline, noradrenaline (0-40 µg/min) and dopamine (0-40 µg/kg/min). Cerebral blood flow was measured continuously from changes in Doppler velocities in the sagittal sinus. Autoregulation was determined by linear regression analysis between cerebral blood flow and mean arterial pressure. Isoflurane did not significantly alter cerebral blood flow relative to pre-anaesthesia values (P>0.05). All three catecholamines significantly and equivalently increased MAP from baseline in a dose dependent manner in both the awake and isoflurane cohorts. Although adrenaline significantly increased cerebral blood flow from baseline in the awake cohort (P0.05). Over a specific dose range, systemic hypertension induced by adrenaline, noradrenaline and dopamine did not significantly increase cerebral blood flow under 2% isoflurane anaesthesia. The concomitant administration of isoflurane and the catecholamines was not associated with altered autoregulatory function compared to the awake state.http://www.aaic.net.au/Article.asp?D=200236

Mechanisms of Post-hemorrhagic Hydrocephalus after Germinal Matrix Hemorrhage

The inherently fragile vasculature of the germinal matrix is susceptible to rupture, possibly as a result of hemodynamic and cardiorespiratory instability associated with prematurity. Germinal matrix hemorrhage is a leading cause of morbidity and mortality in preterm and/or very low birthweight infants, and post-hemorrhagic hydrocephalus is major consequence of severe grade hemorrhages. Chronic post-hemorrhagic hydrocephalus treatment involves surgical insertion of shunts, which are costly and prone to complications. Thus, a safe non-invasive therapeutic approach towards post-hemorrhagic hydrocephalus clinical management would significantly improve the quality of life for this patient population. Thrombin, cerebroventricular blood clots, and iron have been identified as causative factors of hydrocephalus formation. Thrombin stimulates proteinase-activated receptors, leading to subsequent mTOR activation and extracellular matrix protein proliferation, which possibly obstruct the cerebroventricular system. Blood clots may directly impair cerebrospinal fluid circulation and absorption. PPARγ stimulation enhances micgroglial/macrophage phagocytosis of erythrocytes via CD36 scavenger receptor, augmenting clot resolution and improving outcomes after adult cerebral hemorrhage. Additionally, lysed erythrocytes and metabolized hemoglobin release iron, which is associated with brain injury after adult cerebral hemorrhage and contribute to post-hemorrhagic hydrocephalus development. The central aim of this proposal is to determine the role of activated thrombin/PAR-1/mTOR pathway as well as the role of hematoma resolution by PPARγ/CD36 and iron chelation by Deferoxamine in hydrocephalus development after germinal matrix hemorrhage. Direct thrombin inhibition reduced short-term mTOR activation and ameliorated long-term post-hemorrhagic hydrocephalus development, neurocogntive deficits, and extracellular matrix protein proliferation, although PAR-1 inhibition alone did not achieve the same therapeutic benefits. PPARγ stimulation improved short-term hematoma resolution, which was reversed by PPARγ antagonism and CD36 knockdown. PPARγ stimulation attenuated long-term neurocognitive deficits and post-hemorrhagic hydrocephalus, which was reversed by PPARγ antagonism. Acute and delayed iron chelation also reduced long-term post-hemorrhagic hydrocephalus development, neurocognitive deficits, and extracellular matrix protein proliferation. Thus, thrombin/PAR/mTOR pathway inhibition, enhanced PPARγ/CD36 mediated hematoma resolution, and iron chelation significantly ameliorated short and long-term brain sequelae after germinal matrix hemorrhage and are clinically viable therapeutic targets warranting further investigation