Use of Inhaled Nitric Oxide as Part of Combination Therapy for Symptomatic Cerebral Vasospasm in Patients in the Acute Period After Rupture of Cerebral Aneurysms

Introduction Symptomatic cerebral vasospasm (CVS) is one of the most severe complications of subarachnoid hemorrhage (SAH) due to ruptured cerebral aneurysms, leading to delayed cerebral ischemia. The pathogenesis of CVS is associated, among other factors, with a deficiency of the endothelial vasorelaxant factor — nitric oxide (NO). Administration of inhaled NO can replenish this deficit and help reduce the severity of CVS; however, clinical data remain limited.

Aim To evaluate the feasibility of inhaled nitric oxide (iNO) therapy in patients with signs of symptomatic vasospasm in the acute period of non-traumatic SAH caused by ruptured cerebral aneurysms.

Material and methods A case series was carried out involving 9 patients (5 women, 4 men; aged 35–74 years) admitted to the N.V. Sklifosovsky Research Institute for Emergency Medicine in 2022–2024 during the hyperacute period after cerebral aneurysm rupture. The main inclusion criterion was the development of symptomatic CVS resistant to standard therapy (calcium channel blockers, induced hypertension) for at least 1 hour. All the patients underwent microsurgical aneurysm clipping. Inhalation of NO was performed via a face mask using a “Tianox” device at a concentration of 55–80 ppm with FiO₂ 21% until regression of symptoms. Clinical neurological status, jugular venous oximetry, markers of oxidative stress (malondialdehyde (MDA), total antioxidant status (TAS)) and endogenous vascular regulation (nitric oxide metabolites (NOx), angiotensin-converting enzyme (ACE)), video-EEG monitoring and CT perfusion data were assessed.

Results Inhalation therapy resulted in regression of symptomatic CVS in 8 of 9 patients, including complete neurological recovery in 5 patients. The mean time to symptom regression ranged from 3 to 21 hours. In 2 patients, premature discontinuation of therapy led to symptom recurrence, requiring resumption of inhalations. CT perfusion on day 7 revealed reversible focal cerebral perfusion deficits in 4 patients. No adverse effects (methemoglobinemia >3.5%, hypotension, toxic NO₂ concentrations) were recorded. Mortality (n=2) was due to extracranial complications.

Conclusion Inhaled NO therapy in SAH patients with symptomatic CVS on spontaneous breathing is safe and potentially effective for rapid regression of neurological symptoms and improvement of cerebral perfusion.

1. Krylov VV, Vinokurov AG, Dash’yan VG, Luk’yanchikov VA, Polunina NA, Prirodov AV. Mikrokhirurgiya anevrizm sosudov golovnogo mozga. Moscow: ABV-Press; 2022. (In Russ.)

2. Krylov VV, Shatokhin TA, Shetova IM, Eliava Sh. Sh., Belousova O.B., Ayrapetyan A.A.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

3. 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

4. Hijdra A, Brouwers PJ, Vermeulen M, van Gijn J. Grading the amount of blood on computed tomograms after subarachnoid hemorrhage. Stroke. 1990;21(8):1156–1161. PMID: 2389295 https://doi.org/10.1161/01.str.21.8.1156

5. 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

6. Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010;41(10):2391–2395. PMID: 20798370 https://doi.org/10.1161/STROKEAHA.110.589275

7. Fung C, Z’Graggen WJ, Jakob SM, Gralla J, Haenggi M, Rothen HU, et al. Inhaled nitric oxide treatment for aneurysmal SAH patients with delayed cerebral ischemia. Front Neurol. 2022;13:817072. PMID: 35250821 https://doi.org/10.3389/fneur.2022.817072

8. Vanin AF. The influence of exogenous and endogenous nitric oxide on the human and animal body. Pulmonologiya. 2024;34(3):311–325. (In Russ.) https://doi.org/10.18093/0869-0189-2024-34-3-311-325

9. Price AD, Baucom MR, Blakeman TC, Smith M, Gomaa D, Caskey C, et al. Just Say NO: Inhaled Nitric Oxide Effect on Respiratory Parameters Following Traumatic Brain Injury in Humans and a Porcine Model. J Surg Res. 2024;296:497–506. PMID: 38325012 https://doi.org/10.1016/j.jss.2023.12.045

10. Barr FE, Macrae D. Inhaled nitric oxide and related therapies. Pediatr Crit Care Med. 2010;11(2 Suppl):S30–S36. PMID: 20216160 https://doi.org/10.1097/PCC.0b013e3181c76b42

11. Sardo S, Osawa EA, Finco G, Gomes Galas FRB, de Almeida JP, Cutuli SL, et al. Nitric oxide in cardiac surgery: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth. 2018;32(6):2512–2519. PMID: 29703580 https://doi.org/10.1053/j.jvca.2018.02.003

12. Kalashnikova TP, Kamenshchikov NO, Arsenyeva YA, Podoksenov YK, Kravchenko IV, Kozulin MS, et al. High-dose inhaled NO for the prevention of nosocomial pneumonia after cardiac surgery under cardiopulmonary bypass: A proof-of-concept prospective randomised study. Pulmonology. 2025;31(1):2471706. PMID: 40019284 https://doi.org/10.1080/25310429.2025.2471706