Inhaled Nitric Oxide Treatment for Aneurysmal SAH Patients With Intractable Cerebral Vasospasm

July 23, 2021 updated by: University Hospital Inselspital, Berne

Inhalative Stickstoffmonoxid (NO) Behandlung Bei Patienten Mit Schwerem, therapierefraktärem Zerebralen Vasospasmus Nach Subarachnoidalblutung

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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).

Study Type

Interventional

Enrollment (Actual)

7

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
      • Bern, Switzerland, 3010
        • Department of Neurosurgery, University Hospital Bern

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Administration of iNO in SAH patients with severe vasospasm
iNO is started at a dose of 1 parts per million (ppm) and increased stepwise to 2 ppm, 5 ppm, 12 ppm, 25 ppm, until a maximum dose of 40 ppm is reached.
Drug: Inhaled nitric oxide
Each increase of iNO dose is followed by a 10-minute monitoring period and a DSA examination. After reaching the highest effective dose of iNO or the maximum of 40 ppm another DSA is performed. iNO is going to be continued until normalisation of CVS or for a maximum period of 5 days. During iNO treatment a DSA will be performed every 24 hours, followed by a decrease of iNO to the next-lower level. If tapering the iNO concentration is associated with increasing vasospasm, iNO is going to be increased again to the last effective dosage. For cessation of iNO administration, dosage will be tapered every 30 minutes using the same dosage steps as for initiation of iNO treatment. If the duration of iNO treatment will be more than 32 hours, tapering intervals are prolonged to 4 hours. Cessation of iNO will be followed by a DSA.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Improvement of severe vasospasm in digital subtraction angiography
Time Frame: Up to 5 days
> 10% increase in diameter of the vasospastic target vessel compared to baseline
Up to 5 days
Improvement of severe vasospasm in tissue oxygen partial pressure (PtiO2)
Time Frame: Up to 5 days
An increase of more than 5 mmHg with constant fraction of inspired oxygen (FiO2)
Up to 5 days
Improvement of severe vasospasm in transcranial Doppler
Time Frame: Up to 5 days
A decrease of more than 30 cm/s
Up to 5 days
Improvement of severe vasospasm in CT perfusion
Time Frame: Day 2
A reduction in the number of Region of interest with impaired perfusion (MTT > 6·5 s)
Day 2

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intracranial pressure
Time Frame: Up to 5 days
Intracranial pressure using an external ventricular drain catheter
Up to 5 days
Assessment of ischaemic events by CT Scan
Time Frame: 12 weeks after SAH
12 weeks after SAH

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Inselspital, Berne

Investigators

  • Principal Investigator: Juergen Beck, MD, Inselspital Bern, Department of Neurosurgery

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 31, 2012

Primary Completion (ACTUAL)

July 28, 2019

Study Completion (ACTUAL)

March 20, 2020

Study Registration Dates

First Submitted

July 12, 2021

First Submitted That Met QC Criteria

July 23, 2021

First Posted (ACTUAL)

August 4, 2021

Study Record Updates

Last Update Posted (ACTUAL)

August 4, 2021

Last Update Submitted That Met QC Criteria

July 23, 2021

Last Verified

July 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 019/10

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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