Similar effects of hypertonic saline and mannitol on the inflammation of the blood-brain barrier microcirculation after brain injury in a mouse model

Abstract

There has been substantial debate regarding the efficacy of hypertonic saline (HTS) versus mannitol (MTL) in treating moderate and severe traumatic brain injury (TBI). HTS blunts polymorphonuclear neutrophil (PMN) and endothelial cell (EC) activation and reduces tissue edema after resuscitated shock in systemic microvascular beds. MTL also modulates PMN activation markers. It remains unknown if either of these osmotherapies exert similar anti-inflammatory effects along the blood-brain barrier (BBB). We hypothesized that HTS, as compared with MTL, would more greatly reduce PMN-EC interactions, thereby reducing BBB permeability and tissue edema after simulated TBI. CD1 male mice (25-30 g) underwent craniotomy and window placement for observation of in vivo PMN-EC interactions in pial venules using intravital video microscopy. TBI was simulated through local suffusion of the brain surface with interleukin 1β (100 ng/0.1 mL). Animals were randomized to receive a single, equiosmolar, intravenous dose of 20% MTL or 5% HTS after injury. Live microcirculatory footage was obtained every 15 minutes for 2 hours, after which fluorescent-labeled albumin was administered to assess microvascular permeability. PMN rolling and adhesion and macromolecular leakage were analyzed offline by a blinded observer and postmortem brain and lung edema assessed by wet-to-dry ratios. Student's t test and Mann-Whitney U test determined significance (p ≤ 0.05). Neither osmotherapy resulted in significant differences in PMN rolling or adhesion; however, both trended higher in HTS. Similarly, vessel permeability did not differ between groups but also trended higher with HTS. In contrast, brain and lung edema was greater in MTL than HTS as compared with controls (p = 0.05). MTL and HTS have indistinguishable effects on PMN-EC interactions in the brain after simulated TBI. Additional studies are needed to determine if either osmotherapy has more subtle effects on BBB PMN-EC interactions after injury exerting a potential clinical advantage.