Clinical trial NCT04988932: Inhaled Nitric Oxide Treatment for Aneurysmal SAH Patients With Intractable Cerebral Vasospasm
Official title: Inhalative Stickstoffmonoxid (NO) Behandlung Bei Patienten Mit Schwerem, therapierefraktärem Zerebralen Vasospasmus Nach Subarachnoidalblutung
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: SAH
Inhaled Nitric Oxide
Cerebral Ischemia
Vasospasm
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2021-08-04
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Administration of iNO in SAH patients with severe vasospasm
Primary purpose: TREATMENT

Brief summary: Aneurysmal subarachnoid haemorrhage (aSAH) is a rare but severe subtype of stroke with high mortality and morbidity. Besides rebleeding, delayed cerebral ischaemia and cerebral vasospasm (CVS) are thought to be major reasons for the poor outcome in survivors of aSAH. Despite advances in the detection and treatment of CVS 20-40% of CVS patients experience cerebral Ischaemia. Experimental animal studies for ischaemic stroke, traumatic brain injury, and SAH showed that inhaled nitric oxide (iNO) selectively dilates cerebral arteries and arterioles in hypoperfused brain tissue. The investigators therefore performed this prospective pilot study to evaluate the effects of iNO on cerebral perfusion in patients with refractory vasospasm after aSAH.

Detailed description: Aneurysmal subarachnoid haemorrhage (aSAH) is a rare but severe subtype of stroke with high mortality and morbidity. Besides rebleeding, delayed cerebral ischaemia and cerebral vasospasm (CVS) are thought to be major reasons for the poor outcome in survivors of aSAH. CVS, thought to be caused by blood breakdown products, peak in the second week after hemorrhage and affect up 88% of patients with severe aSAH. Despite advances in the detection and treatment of CVS there is no established therapy and up 40% of patients experience cerebral ischemia. In symptomatic vasospasm and cerebral hypoperfusion various treatments like induced hypertension, angioplasty and intraarterial vasodilators are used as rescue therapies. Yet, their effect is not proven.

In recent experimental studies, inhaled nitric oxide (iNO) has been shown to induce a selective dilation of cerebral arteries and arterioles in hypoperfused brain tissue \[8, 9\]. After experimental SAH in mice, iNO significantly reduced the number and severity of SAH-induced spasms of cerebral microvessels, thereby improving cerebral perfusion. Inhaled NO has regulatory approval in man by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of several pulmonary pathologies. At first the efficacy of iNO was thought to be limited to the lungs but, based on the results of the experimental studies the investigators hypothesised that iNO may relieve CVS and improve cerebral perfusion in patients with aSAH.

The investigators performed this prospective trial to evaluate the effect of iNO on cerebral perfusion in patients with severe refractory CVS. Only patients with refractory CVS after maximum conservative treatment were included. Inhaled NO was administered to a maximum dose of 40ppm. The effect was assessed by digital subtraction angiography (DSA), tissue oxygen partial pressure (PtiO2), transcranial Doppler (TCD), and CT perfusion (CTP) imaging. Patiente outcome is assessed at 12 weeks an 6 months after hemorrhage and included NIHSS, Mini Mental State (MMS) test, and modified Rankin Scale (mRS).

Eligibility criteria: Inclusion Criteria:

* aSAH of all severities
* Aneurysm treated by either surgical clipping or endovascular coiling
* Age between 18 - 80 years
* Proven CVS
* Cerebral hypoperfusion and neurological deficit despite treatment (oral nimodipine, induced hypertension, hypervolaemia, central venous pressure \> 6 mmHg)
* A negative pregnancy test in women
* Signed informed consent from the next of kin and an independent physician

Exclusion Criteria:

* Unsecured aneurysm
* Cerebral infarction on imaging in the downstream brain parenchyma of spastic vessel
* Cerebral herniation
* Intracranial pressure \> 25 mmHg
* Pregnancy
* Mean arterial pressure ≤ 90 mmHg despite catecholamines

Primary outcomes:
measure: Improvement of severe vasospasm in digital subtraction angiography
timeFrame: Up to 5 days
measure: Improvement of severe vasospasm in tissue oxygen partial pressure (PtiO2)
timeFrame: Up to 5 days
measure: Improvement of severe vasospasm in transcranial Doppler
timeFrame: Up to 5 days
measure: Improvement of severe vasospasm in CT perfusion
timeFrame: Day 2
Secondary outcomes:
measure: Intracranial pressure
timeFrame: Up to 5 days
measure: Assessment of ischaemic events by CT Scan
timeFrame: 12 weeks after SAH
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Department of Neurosurgery, University Hospital Bern
Study officials:
affiliation: Inselspital Bern, Department of Neurosurgery
name: Juergen Beck, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Terpolilli NA, Feiler S, Dienel A, Muller F, Heumos N, Friedrich B, Stover J, Thal S, Scholler K, Plesnila N. Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms. J Cereb Blood Flow Metab. 2016 Dec;36(12):2096-2107. doi: 10.1177/0271678X15605848. Epub 2015 Nov 2.
citation: Terpolilli NA, Kim SW, Thal SC, Kataoka H, Zeisig V, Nitzsche B, Klaesner B, Zhu C, Schwarzmaier S, Meissner L, Mamrak U, Engel DC, Drzezga A, Patel RP, Blomgren K, Barthel H, Boltze J, Kuebler WM, Plesnila N. Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circ Res. 2012 Mar 2;110(5):727-38. doi: 10.1161/CIRCRESAHA.111.253419. Epub 2011 Dec 29.
citation: Terpolilli NA, Brem C, Buhler D, Plesnila N. Are We Barking Up the Wrong Vessels? Cerebral Microcirculation After Subarachnoid Hemorrhage. Stroke. 2015 Oct;46(10):3014-9. doi: 10.1161/STROKEAHA.115.006353. Epub 2015 Jul 7. No abstract available.
citation: Terpolilli NA, Kim SW, Thal SC, Kuebler WM, Plesnila N. Inhaled nitric oxide reduces secondary brain damage after traumatic brain injury in mice. J Cereb Blood Flow Metab. 2013 Feb;33(2):311-8. doi: 10.1038/jcbfm.2012.176. Epub 2012 Nov 28.
citation: Germann P, Braschi A, Della Rocca G, Dinh-Xuan AT, Falke K, Frostell C, Gustafsson LE, Herve P, Jolliet P, Kaisers U, Litvan H, Macrae DJ, Maggiorini M, Marczin N, Mueller B, Payen D, Ranucci M, Schranz D, Zimmermann R, Ullrich R. Inhaled nitric oxide therapy in adults: European expert recommendations. Intensive Care Med. 2005 Aug;31(8):1029-41. doi: 10.1007/s00134-005-2675-4. Epub 2005 Jun 23.
citation: Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005 Dec 22;353(25):2683-95. doi: 10.1056/NEJMra051884. No abstract available.