Inhaled Nitric Oxide Treatment for Aneurysmal SAH Patients With Intractable Cerebral Vasospasm
Condition: SAH; Inhaled Nitric Oxide; Cerebral Ischemia; Vasospasm
MeSH terms: Respiratory Aspiration; Brain Ischemia; Cerebral Infarction; Ischemia
Study type: Interventional

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).
    

Intervention name(s): Inhaled nitric oxide
Intervention type(s): Drug
Intervention description(s): 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.
Intervention MeSH terms: Nitric Oxide
Intervention model: Single Group Assignment
Intervention model description: Administration of iNO in SAH patients with severe vasospasm
Masking: None (Open Label)
Primary purpose: Treatment