Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage

JAMA. 2005 Mar 23;293(12):1477-84. doi: 10.1001/jama.293.12.1477.


Context: Delayed cerebral vasospasm causes permanent neurological deficits or death in at least 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm. Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm.

Objective: To determine whether infusions of nitrite will prevent delayed cerebral vasospasm.

Design, setting, and subjects: A total of 14 anesthetized cynomolgus monkeys had an autologous blood clot placed around the right middle cerebral artery. Cerebral arteriography was performed before clot placement and on days 7 and 14 to assess vasospasm. The study was conducted from August 2003 to February 2004.

Interventions: A 90-mg sodium nitrite intravenous solution infused over 24 hours plus a 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24 hours (n = 3); or a control saline solution infusion (n = 8). Each was infused continuously for 14 days.

Main outcome measures: Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinal fluid and degree of arteriographic vasospasm.

Results: In control monkeys, mean (SD) cerebrospinal fluid nitrite levels decreased from 3.1 (1.5) micromol/L to 0.4 (0.1) micromol/L at day 7 and to 0.4 (0.4) micromol/L at day 14 (P = .03). All 8 control monkeys developed significant vasospasm of the right middle cerebral artery, which was complicated by stroke and death in 1 animal. Sodium nitrite infusions increased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood and cerebrospinal fluid without evoking systemic hypotension. Nitrite infusion prevented development of vasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebral artery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47% [5%] in saline-treated controls; P<.001). There was a negative correlation between the concentration of nitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001). Pharmacological effects of nitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid. There was no clinical or pathological evidence of nitrite toxicity.

Conclusion: Subacute sodium nitrite infusions prevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.

MeSH terms

  • Animals
  • Cerebral Angiography
  • Disease Models, Animal
  • Infarction, Middle Cerebral Artery
  • Infusions, Intravenous
  • Macaca fascicularis
  • Methemoglobin / analysis
  • Nitrites / blood
  • Nitrites / cerebrospinal fluid
  • S-Nitrosothiols / blood
  • S-Nitrosothiols / cerebrospinal fluid
  • Sodium Nitrite / administration & dosage
  • Sodium Nitrite / therapeutic use*
  • Subarachnoid Hemorrhage / complications*
  • Vasospasm, Intracranial / diagnostic imaging
  • Vasospasm, Intracranial / etiology
  • Vasospasm, Intracranial / metabolism
  • Vasospasm, Intracranial / prevention & control*


  • Nitrites
  • S-Nitrosothiols
  • Methemoglobin
  • Sodium Nitrite