Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor-4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI.
Renal insufficiency is common after non-renal organ transplants. The predictors of long-term renal outcomes are not well established. A total of 219 lung and heart-lung transplant recipients surviving more than 6 months after transplantation were studied to determine predictors of time to doubling of serum creatinine and end-stage kidney disease (ESKD) with death as a competing risk. Median follow-up was 79 months (range 9-222 months). Baseline estimated glomerular filtration rate (GFR) was 96.3 ± 34.5 mL/min/ 1.73 m 2 . One hundred twenty-two recipients (55%) doubled their serum creatinine, 16 (7.3%) progressed to ESKD and 143 (65%) died. The majority of recipients who survived >6 years had a GFR < 60 mL/min at both 1 and 7 years. Most of the loss of renal function occurred in the first year post-transplant. Older age at transplant, lower GFR at 1 month and cyclosporine use in the first 6 months predicted shorter time to doubling of serum creatinine when death was handled as a competing risk. Based on this prevalence data and using GFR decay and death as study endpoints, we offer sample size estimates for a prospective, interventional trial that is aimed at slowing or preventing the progression of kidney disease.
Thromboembolic complications remain a major risk of endovascular neurosurgery during the treatment of intracranial aneurysms, despite the use of therapeutic heparinization and oral antiplatelet therapy when indicated. Glycoprotein (GP) IIb/IIIa inhibitors target a nonredundant pathway of platelet aggregation following adhesion and activation. Initially established and implemented in the cardiovascular arena, this drug class has provided a new tool in the neurovascular armamentarium as well. Numerous case reports, case series, and retrospective reviews have evaluated the safety and efficacy of abciximab, eptifibatide, and tirofiban in the treatment of acute thromboembolic complications during the endovascular treatment of intracranial aneurysms. The use of this drug class has also been found to be beneficial as a prophylactic agent, providing ischemia protection during the placement of intracranial stents, flow diverters, and thrombogenic coils in the setting of subarachnoid hemorrhage and during elective aneurysmal embolization. While the current published literature clearly establishes efficacy and safety of GP IIb/IIIa inhibitors in the prevention of thromboembolic complications, there does not yet exist an established protocol for their administration in endovascular neurosurgery. This review provides a comprehensive evaluation of the current published literature pertaining to the use of all available GP IIb/IIIa inhibitors for thromboembolic complications, providing recommendations for dosing and administration of abciximab, eptifibatide, and tirofiban based on previously published rates of efficacy and intracranial hemorrhage.
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