Safety and pharmacokinetics of sodium nitrite in patients with subarachnoid hemorrhage: A Phase IIA study

Edward H. Oldfield, Johanna J. Loomba, Stephen J. Monteith, R. Webster Crowley, Ricky Medel, Daryl R. Gress, Neal F. Kassell, Aaron S. Dumont, Craig Sherman

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Object. 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. Methods. 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. Results. 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. Conclusions. 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).

Original languageEnglish (US)
Pages (from-to)634-641
Number of pages8
JournalJournal of neurosurgery
Volume119
Issue number3
DOIs
StatePublished - Sep 2013

Keywords

  • Nitric oxide
  • Sodium nitrite
  • Subarachnoid hemorrhage
  • Vascular disorders
  • Vasospasm

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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