Edward H. Oldfield, Johanna J. Loomba, Stephen J. Monteith, R. Webster Crowley, Ricky Medel, Daryl R. Gress, Neal F. Kassell, Aaron S. Dumont and Craig Sherman
Intravenous sodium nitrite has been shown to prevent and reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). The present Phase IIA dose-escalation study of sodium nitrite was conducted to determine the compound's safety in humans with aneurysmal SAH and to establish its pharmacokinetics during a 14-day infusion.
In 18 patients (3 cohorts of 6 patients each) with SAH from a ruptured cerebral aneurysm, nitrite (3 patients) or saline (3 patients) was infused. Sodium nitrite and saline were delivered intravenously for 14 days, and a dose-escalation scheme was used for the nitrite, with a maximum dose of 64 nmol/kg/min. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy, and blood methemoglobin levels were continuously monitored using a pulse oximeter.
In the 14-day infusions in critically ill patients with SAH, there was no toxicity or systemic hypotension, and blood methemoglobin levels remained at 3.3% or less in all patients. Nitrite levels increased rapidly during intravenous infusion and reached steady-state levels by 12 hours after the start of infusion on Day 1. The nitrite plasma half-life was less than 1 hour across all dose levels evaluated after stopping nitrite infusions on Day 14.
Previous preclinical investigations of sodium nitrite for the prevention and reversal of vasospasm in a primate model of SAH were effective using doses similar to the highest dose examined in the current study (64 nmol/kg/min). Results of the current study suggest that safe and potentially therapeutic levels of nitrite can be achieved and sustained in critically ill patients after SAH from a ruptured cerebral aneurysm. Clinical trial registration no.: NCT00873015 (ClinicalTrials.gov).
Ricky Medel, Stephen J. Monteith, R. Webster Crowley and Aaron S. Dumont
Although initially described in the 19th century, cerebral venous sinus thrombosis (CVST) remains a diagnostic and therapeutic dilemma. It has an unpredictable course, and the propensity for hemorrhagic infarction produces significant consternation among clinicians when considering anticoagulation. It is the purpose of this review to analyze the evidence available on the management of CVST and to provide appropriate recommendations.
A thorough literature search was conducted through MEDLINE and PubMed, with additional sources identified through cross-referencing. A classification and level of evidence assignment is provided for recommendations based on the American Heart Association methodologies for guideline composition.
Of the publications identified, the majority were isolated case reports or small case series. Few prospective trials have been conducted. Existing data support the use of systemic anticoagulation as an initial therapy in all patients even in the presence of intracranial hemorrhage. Chemical and/or mechanical thrombectomy, in conjunction with systemic anticoagulation, is an alternative strategy in patients with progressive deterioration on heparin therapy or in those who are moribund on presentation. Mechanical thrombectomy is probably preferred in patients with preexisting intracranial hemorrhage.
Effective treatments exist for the management of CVST, and overall outcomes are more favorable than those for arterial stroke. Further research is necessary to determine the role of individual therapies; however, the rarity of the condition poses a significant limitation.