Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence.

Steiner have served as consultants to NovoNordisk and are members of the Recombinant Factor VII ICH Study Team. All authored materials constitute the personal statements of Maj Barbara J. Hoeben and are not intended to constitute an endorsement by Wilford Hall Medical Center, Lackland AFB, or any other federal government entity.

Aerosolized evaporative precipitation into aqueous solution and spray freezing into liquid nanostructured formulations of itraconazole as prophylaxis significantly improved survival relative to commercial itraconazole oral solution and the control in a murine model of invasive pulmonary aspergillosis. Aerosolized administration of nanostructured formulations also achieved high lung tissue concentrations while limiting systemic exposure.Aerosolized administration of antifungals is gaining favor for the prevention of invasive pulmonary mycoses (4). Aerosolized administration can achieve high, localized lung tissue concentrations while avoiding systemic toxicities. However, the formulations currently used clinically include intravenous preparations that are not specifically designed for aerosolized administration. Evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) are novel technologies utilized to improve the dissolution and bioavailability of poorly water-soluble drugs (8). Both technologies can produce nanostructured particles (Ͻ1 micron in diameter) capable of drug delivery to the alveolar space (5).We hypothesized that aerosolized administration of EPAS and SFL formulations of itraconazole (ITZ) would be an effective prophylaxis strategy against invasive pulmonary aspergillosis. An established murine model was used to simulate the pathogenesis of invasive pulmonary aspergillosis and assess survival following pulmonary inoculation. We also measured steady-state lung tissue and serum ITZ concentrations.Five-week-old male outbred ICR mice (Harlan SpragueDawley, Indianapolis, IN) were rendered immunosuppressed by cortisone acetate administered subcutaneously at a dose of 100 mg/kg of body weight on days Ϫ1, 0, ϩ1, and ϩ6 and were inoculated with Aspergillus flavus ATCC MYA-1004 (ITZ MIC, 0.125 g/ml per CLSI M38-A microdilution methodology) (14) via an inhalation chamber as previously described (13, 16). Animals were divided into four groups: ITZ oral solution (Sporanox oral liquid [SOL]) administered by oral gavage (30 mg/kg three times a day), aerosolized EPAS (30 mg/kg twice a day), aerosolized SFL (30 mg/kg twice a day), and control (aerosolized sterile distilled water). EPAS and SFL formulations were manufactured using pharmaceutical grade ITZ powder (Hawkins, Inc., Minneapolis, MN) (3,17,18,20,21). For the EPAS formulation, ITZ and poloxamer 407 were dissolved in dichloromethane and the solution was sprayed into a heated aqueous solution containing 4% polysorbate 80, causing rapid evaporation of the dichloromethane and subsequent precipitation of nanostructured crystalline ITZ. For SFL, an organic feed solution was prepared by dissolving ITZ (0.1% wt/vol), polysorbate 80 (0.75% wt/vol), and poloxamer 407 (0.75% wt/vol) into acetonitrile. The organic feed solution was atomized into liquid nitrogen to produce frozen amorphous particles. Lyophilization of the particles yielded stabilized nanostructured particle aggregates. EPAS, SFL, and control were administered via a 20...