Reversal of cerebral vasospasm via intravenous sodium nitrite after subarachnoid hemorrhage in primates

Laboratory investigation

Ali Reza Fathi M.D.1,2, Ryszard M. Pluta M.D., Ph.D.1, Kamran D. Bakhtian M.S.1, Meng Qi M.D.1,3, and Russell R. Lonser M.D.1
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  • 1 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and
  • | 2 Department of Neurosurgery, Kantonsspital Aarau AG, Aarau, Switzerland; and
  • | 3 Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Jiangsu Province, China
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Object

Subarachnoid hemorrhage (SAH)-induced vasospasm is a significant underlying cause of aneurysm rupture-related morbidity and death. While long-term intravenous infusion of sodium nitrite (NaNO2) can prevent cerebral vasospasm after SAH, it is not known if the intravenous administration of this compound can reverse established SAH-induced vasospasm. To determine if the intravenous infusion of NaNO2 can reverse established vasospasm, the authors infused primates with the compound after SAH-induced vasospasm was established.

Methods

Subarachnoid hemorrhage–induced vasospasm was created in 14 cynomolgus macaques via subarachnoid implantation of a 5-ml blood clot. On Day 7 after clot implantation, animals were randomized to either control (saline infusion, 5 monkeys) or treatment groups (intravenous NaNO2 infusion at 300 μg/kg/hr for 3 hours [7 monkeys] or 8 hours [2 monkeys]). Arteriographic vessel diameter was blindly analyzed to determine the degree of vasospasm before, during, and after treatment. Nitric oxide metabolites (nitrite, nitrate, and S-nitrosothiols) were measured in whole blood and CSF.

Results

Moderate-to-severe vasospasm was present in all animals before treatment (control, 36.2% ± 8.8% [mean ± SD]; treatment, 45.5% ± 12.5%; p = 0.9). While saline infusion did not reduce vasospasm, NaNO2 infusion significantly reduced the degree of vasospasm (26.9% ± 7.6%; p = 0.008). Reversal of the vasospasm lasted more than 2 hours after cessation of the infusion and could be maintained with a prolonged infusion. Nitrite (peak value, 3.7 ± 2.1 μmol/L), nitrate (18.2 ± 5.3 μmol/L), and S-nitrosothiols (33.4 ± 11.4 nmol/L) increased significantly in whole blood, and nitrite increased significantly in CSF.

Conclusions

These findings indicate that the intravenous infusion of NaNO2 can reverse SAH-induced vasospasm in primates. Further, these findings indicate that a similar treatment paradigm could be useful in reversing cerebral vasospasm after aneurysmal SAH.

Abbreviations used in this paper:

MCA = middle cerebral artery; NaNO2 = sodium nitrite; NIH = National Institutes of Health; NO = nitric oxide; NO2 = nitrite; NO3 = nitrate; SAH = subarachnoid hemorrhage; SNO = S-nitrosothiol.

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