The Effect of Inhalation Therapy with Exogenous Nitric Oxide on Oxidative Stress and Endogenous Vascular Regulation Markers in Patients with Ruptured Cerebral Aneurysms

Introduction. Non-traumatic subarachnoid hemorrhage (SAH) due to ruptured cerebral aneurysms remains one of the most severe forms of acute cerebrovascular disease with a high risk of delayed cerebral ischemia. One of the key pathogenetic mechanisms in this pathology is severe impairment of endogenous regulation of vascular tone and the development of oxidative stress. Inhaled nitric oxide therapy is considered a potential method for modulating vascular tone and reducing the risk of vasospasm.

The aim of the study. Was to evaluate the effect of inhaled nitric oxide therapy on the severity of oxidative stress and endogenous factors involved in regulation of vascular tone in patients with acute non-traumatic SAH due to ruptured cerebral aneurysms.

Materials and methods. The study included 57 patients with acute SAH hospitalized at the N.V. Sklifosovsky Research Institute for Emergency Medicine between 2020 and 2025. The study group consisted of 25 patients receiving inhaled nitric oxide therapy (50–80 ppm, 3–24 hours per day, 4–7 days postoperatively); the comparison group consisted of 32 patients without this therapy. Inclusion criteria: massive basal hemorrhage, aneurysm clipping within the first 72 hours, and Hunt-Hess stage II–IV. Levels of malondialdehyde (MDA), total antioxidant activity, stable nitric oxide (NOx) metabolites, angiotensin-converting enzyme (ACE), glucose, and lactate dehydrogenase (LDH) were assessed in serum and cerebrospinal fluid. Statistical analysis was performed using the Mann-Whitney U test, with a significance level of p<0.05.

Results. In patients receiving therapy, serum NOx levels increased statistically significantly at all observation periods (p<0.05). The NOx/ACE ratio was higher than in the untreated group and approached the control group’s values, indicating restoration of the balance between vasodilatory and vasoconstrictive mechanisms. MDA levels and the oxidative stress index were elevated in both groups, but no significant differences were found. Serum and cerebrospinal fluid LDH and glucose levels increased in both groups, with statistically insignificant differences.

Conclusions. Inhaled nitric oxide therapy helps restore the balance of endogenous factors involved in regulation of vascular tone without increasing oxidative stress and ischemic damage. This method can be considered as an additional component of complex therapy, but requires further study.

1. Krylov VV, Shatokhin TA, Shetova IM, Eliava ShSh, Belousova OB, Airapetyan AA, et al. Russian study on brain aneurysm surgery: a continuation (RIHA II). Burdenko’s Journal of Neurosurgery. 2024;88(1):7–20. https://doi.org/10.17116/neiro2024880117

2. SVIN COVID-19 Global SAH Registry. Global impact of the COVID-19 pandemic on subarachnoid haemorrhage hospitalisations, aneurysm treatment and in-hospital mortality: 1-year follow-up. J Neurol Neurosurg Psychiatry. 2022;93(10):1028–1038. PMID: 35902229 https://doi.org/10.1136/jnnp-2022-329200

3. Klychnikova EV, Petrikov SS, Prirodov AV, Bakharev EYu, Silkin SV, Tazina EV, et al. Dynamics of Oxidative Stress Indices and Endogenous Factors of Vascular Regulation in Patients with Non-Traumatic Subarachnoid Hemorrhage Due to Rupture of Cerebral Aneurysms. Russian Sklifosovsky Journal Emergency Medical Care. 2024;13(4):562–569. https://doi.org/10.23934/2223-9022-2024-13-4-562-569

4. Frontera JA, Claassen J, Schmidt JM, Wartenberg KE, Temes R, Connolly ES Jr, et al. Prediction of symptomatic vasospasmafter subarachnoid hemorrhage: the modified fisher scale. Neurosurgery. 2006;59(1):21–27. PMID: 16823296 https://doi.org/10.1227/01.neu.0000243277.86222.6c

5. Sehba FA, Bederson JB. Nitric oxide in early brain injury after subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;110(Pt 1):99–103. PMID: 21116923 https://doi.org/10.1007/978-3-7091-0353-1_18

6. Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev. 2009;61(1):62–97. PMID: 19293146 https://doi.org/10.1124/pr.108.000547

7. Siuta M, Zuckerman SL, Mocco J. Nitric oxide in cerebral vasospasm: theories, measurement, and treatment. Neurol Res Int. 2013;2013:972417. PMID: 23878735 https://doi.org/10.1155/2013/972417

8. Kho GS, Kandasamy R, Bujang MA, Swammy M, Mustapha M, Abdullah JM. et al. Ratio of nitric oxide metabolite levels in cerebrospinal fluid and serum, and their correlation with severity and outcome in patients with subarachnoid haemorrhage. Malays J Med Sci. 2021;28(6):42–54. PMID: 35002489 https://doi.org/10.21315/mjms2021.28.6.5

9. Ramesh SS, Prasanthi A, Bhat DI, Devi BI, Cristopher R, Philip M. Correlation between plasma total nitric oxide levels and cerebral vasospasm and clinical outcome in patients with aneurysmal subarachnoid hemorrhage in Indian population. J Neurosci Rural Pract. 2014;5(Suppl 1):S22–S27. PMID: 25540533 https://doi.org/10.4103/0976-3147.145196

10. Tas N, Nehir A, Ugur BK, Geyik AM, Ucler N, Saracaloglu A, et al. Evaluations of Oxidative Stress, Thiol/Disulphide Homeostasis, and Nitric Oxide in Patients with Aneurysmal Subarachnoid Hemorrhage. Turk Neurosurg. 2024;34(6):1040–1049. PMID: 39474959 https://doi.org/10.5137/1019-5149.JTN.45638-23.2

11. Suzuki Y, Osuka K, Noda A, Tanazawa T, Takayasu M, Shibuya M, et al. Nitric oxide metabolites in the cisternal cerebral spinal fluid of patients with subarachnoid hemorrhage. Neurosurgery. 1997;41(4):807–811. PMID: 9316041 https://doi.org/10.1097/00006123-199710000-00008

12. Suzuki M, Asahara H, Endo S, Inada K, Doi M, Kuroda K, et al. Increased levels of nitrite/nitrate in the cerebrospinal fluid of patients with subarachnoid hemorrhage. Neurosurg Rev. 1999;22(2-3):96–98. PMID: 10547005 https://doi.org/10.1007/s101430050038

13. Durmaz R, Ozkara E, Kanbak G, Arslan OC, Dokumacioğlu A, Kartkaya K, et al. Nitric oxide level and adenosine deaminase activity in cerebrospinal fluid of patients with subarachnoid hemorrhage. Turk Neurosurg. 2008;18(2):157–164. PMID: 18597230

14. Pluta RM. Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther. 2005;105(1):23–56. PMID: 15626454 https://doi.org/10.1016/j.pharmthera.2004.10.002

15. Kaynar MY, Tanriverdi T, Kemerdere R, Atukeren P, Gumustas K. Cerebrospinal fluid superoxide dismutase and serum malondialdehyde levels in patients with aneurysmal subarachnoid hemorrhage: preliminary results. Neurol Res. 2005;27(5):562–567. PMID: 15978186 https://doi.org/10.1179/016164105X17288

16. Kaneda K, Fujita M, Yamashita S, Kaneko T, Kawamura Y, Izumi T, et al. Prognostic value of biochemical markers of brain damage and oxidative stress in post-surgical aneurysmal subarachnoid hemorrhage patients. Brain Res Bull. 2010;81(1):173–177. PMID: 19887101 https://doi.org/10.1016/j.brainresbull.2009.10.020

17. Chen YH, Chou SC, Tang SC, Lee JE, Tsai JC, Lai DM, et al. Continuous lumbar drainage after aneurysmal subarachnoid hemorrhage decreased malondialdehyde in cerebrospinal fluid and improved outcome. J Formos Med Assoc. 2023;122(2):164–171. PMID: 36117035 https://doi.org/10.1016/j.jfma.2022.09.001

18. Takeuchi S, Kumagai K, Toyooka T, Otani N, Wada K, Mori K. Intravenous hydrogen therapy with intracisternal magnesium sulfate infusion in severe aneurysmal subarachnoid hemorrhage. Stroke. 2021;52(1):20–27. PMID: 33349011 https://doi.org/10.1161/STROKEAHA.120.031260

19. Cavalli I, Stella C, Stoll T, Mascia L, Salvagno M, Coppalini G, et al. Serum LDH levels may predict poor neurological outcome after aneurysmal subarachnoid hemorrhage. BMC Neurol. 2023;23(1):228. PMID: 37312033 https://doi.org/10.1186/s12883-023-03282-8

20. Zheng S, Wang H, Chen G, Shangguan H, Yu L, Lin Z, et al. Higher serum levels of lactate dehydrogenase before microsurgery predict poor outcome of aneurysmal subarachnoid hemorrhage. Front Neurol. 2021;12:720574. PMID: 34456854 https://doi.org/10.3389/fneur.2021.720574 eCollection 2021.

21. Shimoda M, Yamada S, Yamamoto I, Tsugane R, Sato O. Time course of csf lactate level in subarachnoid haemorrhage correlation with clinical grading and prognosis. Acta Neurochir (Wien). 1989;99(3–4):127–134. PMID: 2773682 https://doi.org/10.1007/BF01402321

22. Anan M, Nagai Y, Fudaba H, Fujiki M. Lactate and lactate dehydrogenase in cistern as biomarkers of early brain injury and delayed cerebral ischemia of subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 2020;29(5):104765. PMID: 32173227 https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104765