Remote Ischemic Conditioning in Aneurysmal SAH

Subarachnoid Hemorrhage, Aneurysmal Clinical Trial

— RESCUE-SAH  

Official title:

The Effect of Remote Ischemic Conditioning on Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Prospective, Randomized, Patient-assessor Blinded, Sham-controlled Pilot Study Investigating Effect on Clinical Outcome.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06032533
• Other study ID #: 1-16-02-429-22
• Secondary ID: 7873942304824
• Status: Recruiting
• Phase: N/A
• Start date: September 9, 2023
• Est. completion date: November 30, 2027

Study information

• Verified date: September 2023
• Source: Aarhus University Hospital
• Contact: Kim M Ørskov, MD
• Phone: +4542791933
• Email: kimoer[@]rm.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to examine the effect of limb occlusion therapy (remote ischemic conditioning, RIC) in subjects with aneurysmal subarachnoid hemorrhage. The main question it aims to answer is whether RIC can improve long-term recovery in participants with aneurysmal subarachnoid hemorrhage. Researchers will compare levels of functional independence in participants in the RIC-group to participants in the sham-group.

Description:

Aneurysmal subarachnoid hemorrhage (aSAH) is one of the most devastating types of stroke. Half of the patients die during the acute ictus, and those who survive have a poor prognosis as 20-30% are disabled or eventually die from the disease. In the acute phase after aSAH, the most devastating complication is rebleeding, whereas in the late phase, delayed cerebral ischemia (DCI) is another feared complication, associated with high morbidity and mortality. Symptoms of DCI occur in 30 % of patients and 15-20 % of patients will develop a disabling stroke due to DCI. DCI typically occurs between days 4 and 14 after the initial bleeding. The cause of DCI is not fully understood. Cerebral vasospasms (CVS) are commonly seen on angiography in the first 4-14 days after initial bleeding, and have been linked to late onset of symptoms of focal ischaemia since the 60s. Modern research suggests that the pathophysiology is multifactorial, but CVS is still thought to be a major contributor. Other contributing factors are thought to be microthrombosis, microvascular spasm, oxidative stress, cortically spreading depolarizations, cell death, breakdown of blood-brain barrier, among others. Treatment with nimodipine is standard-of-care and is the only pharmacological intervention that has been shown to improve outcome in aSAH patients, although it has no impact on large-vessel CVS[. The need for developing effective methods for prevention or treatment of DCI persists, and an effective prophylactic treatment may have a large impact on the general outcome of aSAH. Ischemic conditioning is a potent activator of endogenous protection against ischemic injury. RIC can be applied as repeated short-lasting ischemia in a distant tissue that results in protection against subsequent long-lasting ischemic injury in the target organ. This protection can be applied prior to or during a prolonged ischemic event as remote ischemic preconditioning (RIPreC) and perconditioning (RIPerC), respectively. RIC is commonly achieved by inflation of a blood pressure cuff to induce 5-minute cycles of limb ischemia alternating with 5 minutes of reperfusion. RIC activates several protective mechanisms, through humoral and neural pathways and shows promise in the setting of acute stroke. Inflammation initiated by cerebral ischemia can contribute to secondary brain injury and is correlated with poor outcome. Following ischemia there is a harmful excess leukocyte infiltration in the brain parenchyma, and in experimental studies on aSAH, pharmacological inhibition of cytokines has been associated with improved outcome. RIC has been demonstrated to reduce inflammation and downregulate inflammatory markers. In addition, RIC has protective effects on cerebral endothelial function and induces vasodilation, increasing cerebral blood flow (CBF). Angiogenesis, erythropoietin and nitric oxide (NO) are suggested to induce neuroprotection and stimulation of these strategies by conditioning including inhibition of inflammation has the potential to play an important part in treatment of patients after aSAH. The effect of RIC on blood and cerebrospinal fluid biomarkers has never been explored in the setting of aSAH. To-date, no serious adverse events have been documented in RIC. The procedure has been applied in numerous cardiovascular ischemic patients and in patients suffering from ischemic stroke and cerebral hemorrhage (ICH/SAH). A recent smaller randomized trials of RIPreC after aSAH showed promising results with regards to functional outcomes and incidence of cerebral oxygen desaturation, likewise without adverse effects of RIC. RIC is a non-pharmacologic and non-invasive treatment without noticeable discomfort that has neuroprotective potential worldwide. Aneurysmal SAH and subsequent DCI represents a unique clinical opportunity to test RIC as DCI typically manifests within the first 14 days after ictus and is often a significant contributor to neurological injury. The treatment is feasible, safe, and rooted in well-explored physiological concepts. There is a clear scientific gap and opportunity to explore RIC in the setting of aSAH and DCI in larger randomized trials.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: November 30, 2027
• Est. primary completion date: November 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Aneurysmal subarachnoid hemorrhage confirmed by computed tomography (CT) with aneurysm origin confirmed by computed tomography angiography (CTA) or digital subtraction angiography (DSA)
• Aneurysmal subarachnoid hemorrhage symptom-onset = 3 days
• Aneurysm protected by clipping or coiling
• Independent in daily living before symptom onset (mRS = 2)

Exclusion Criteria:

• Subarachnoid hemorrhage caused by a lesion other than cerebral aneurysm
• Symptomatic vasospasm at the time of enrollment
• Previous cerebral lesion e.g. symptomatic cerebral infarction (>2cm), multiple sclerosis, symptomatic intracerebral hemorrhage, tumour, prior neurosurgery (excluding prior clipping or coiling of cold aneurysms without complications).
• History of severe peripheral vascular disease or signs of severe peripheral vascular disease on physical examination
• History of deep vein thrombosis or signs of deep vein thrombosis on physical examination
• Kidney involvement or prior kidney disease with an estimated glomerular filtration rate (eGFR) below safe levels for contrast infusion in relation to CT-perfusion.
• Pregnancy (Women of child-bearing age will have serum-Humane Choriogonadotropine taken prior to final inclusion. If pregnancy cannot be ruled out,the patient can't be included. Women with a safe birth control method will be encouraged to use this method during the entire period of active treatment.)
• Concomitant other acute life-threatening medical or surgical condition

Related Conditions & MeSH terms

• Brain Ischemia
• Cerebral Infarction
• Delayed Cerebral Ischemia
• Hemorrhage
• Ischemia
• Subarachnoid Hemorrhage
• Subarachnoid Hemorrhage, Aneurysmal

Intervention

Device:
• Remote Ischemic Conditioning with Automatic Tourniquet Device
5 Cycles of Remote Ischemic Conditioning performed on the leg. One cycle consists of 5 minutes of arterial occlusion followed by 5 minutes of reperfusion. The above is repeated daily for 14 days or until patient is discharged. Patients are randomized to either active Remote Ischemic Conditioning or Sham-treatment.
• Sham Remote Ischemic Conditioning with Automatic Tourniquet Device
5 Cycles of sham-treatment performed on the leg. One cycle consists of 5 minutes of sham-treatment followed by 5 minutes of pause. The above is repeated daily for 14 days or until patient is discharged. Patients are randomized to either active Remote Ischemic Conditioning or Sham-treatment.

Locations

Country	Name	City	State
Denmark	Department of Neurosurgery, Aarhus University Hospital	Aarhus N	Danmark

Sponsors (1)

Lead Sponsor	Collaborator
Aarhus University Hospital

Country where clinical trial is conducted

Denmark, 

References & Publications (2)

Gonzalez NR, Connolly M, Dusick JR, Bhakta H, Vespa P. Phase I clinical trial for the feasibility and safety of remote ischemic conditioning for aneurysmal subarachnoid hemorrhage. Neurosurgery. 2014 Nov;75(5):590-8; discussion 598. doi: 10.1227/NEU.0000000000000514. — View Citation

Hess DC, Blauenfeldt RA, Andersen G, Hougaard KD, Hoda MN, Ding Y, Ji X. Remote ischaemic conditioning-a new paradigm of self-protection in the brain. Nat Rev Neurol. 2015 Dec;11(12):698-710. doi: 10.1038/nrneurol.2015.223. Epub 2015 Nov 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical outcome after 6 months measured by modified Rankin scale score (0-6, Higher score indicates worse outcome)	Assessed by telephone interview. Patient assessor is blinded to intervention	Assessed 6 months after initial aneurysm rupture.
Secondary	Difference in Infarct growth	Assessed by MRI, measured by segmentation and calculation of infarct volume.	MRI performed 4-6 weeks after initial hemorrhage.
Secondary	Clinical outcome after 14 days measured by modified Rankin scale score (0-6, Higher score indicates worse outcome)	Assessed by clinician in charge of patient discharge.	14 days after initial hemorrhage.
Secondary	Occurrence of delayed cerebral ischemia	Neurological deterioration after aSAH where DCI is deemed most likely cause, supported by angiography/perfusion CT.	Within first 14 days after initial hemorrhage.
Secondary	Mortality after 3 months	Assessed via patient records. Assessor is blinded to intervention.	Assessed at 3 months post initial hemorrhage
Secondary	Mortality after 12 months	Assessed via patient records. Assessor is blinded to the intervention.	Assessed at 12 months post initial hemorrhage
Secondary	Presence of angiographic vasospasm on CT angiography baseline vs 8-day scan	Evaluated by a neuro-radiologist with more than 10 years of experience in intracerebral angiography. Assessor is blinded to intervention.	8-9 days post initial hemorrhage.

External Links

•   Background on Aneurysmal Subarachnoid Hemorrhage and Delayed Cerebral Ischemia