Remote Ischemic Preconditioning in Subarachnoid Hemorrhage

Phase I prospective clinical study to evaluate: the tolerance of clinical subjects with
Subarachnoid Hemorrhage (SAH) to the maneuvers involved in the generation of Remote Ischemic
Preconditioning (RIPC), the immediate and delayed hemodynamic effects of the RIPC in the
cerebral vasculature, in terms of Transcranial Doppler (TCD) velocities, pulsatility index
variations, Cerebral Blood Flow (CBF) measures, and cerebral arterial flow measurements
using Magnetic Resonance Imaging with flow measurement capabilities (MRI NOVA). As a
secondary goal, we will be valuating the impact of RIPC in the incidence of vasospasm,
delayed neurological deficits, development of ischemic lesions in MRI and clinical outcome.

Patient Enrollment: Patients who are admitted to the University of California Los Angeles
(UCLA) Ronald Reagan Medical Center with a diagnosis of aneurysmal subarachnoid hemorrhage
will be considered for inclusion in this study. As is standard of care for this condition,
following admission patients' aneurysms are generally treated by one of two methods,
surgical clipping or endovascular coiling. Following this definitive treatment of the
aneurysm, generally performed emergently in the first 24 to 48 hours following hemorrhage,
patients will be consented and enrolled in the study. No patients with unprotected
(untreated) aneurysms will be enrolled. Patients with a known history of lower limb vascular
disease or lower limb vascular bypass surgery will be excluded.

Remote Ischemic Preconditioning (RIPC) Procedure: Following enrollment, patients will
receive four rounds of lower limb remote ischemic preconditioning, starting at the earliest
post-hemorrhage day possible following definitive treatment of their aneurysm. The remote
ischemic preconditioning will typically take place on post-hemorrhage day 2, 3, 6 and 9.
Each cycle of RIPC will consist of four 5-minute cycles of lower limb ischemia following by
5-minute periods of reperfusion. A large blood pressure cuff will be wrapped around the
upper thigh of one leg. The cuff will be inflated to a pressure 20 mm Hg greater than the
systolic arterial blood pressure measured by the patient's arterial line or upper limb blood
pressure cuff. The adequate level of inflation will be confirmed by the absence of pulse in
the ipsilateral pedal artery as detected by Doppler. The cuff will remain inflated for 5
minutes. The cuff will then be deflated and the limb will be allowed to re-perfuse for at
least 5 minutes. After the cuff is deflated, the same procedure will then be repeated three
times for a total of four cycles.

Evaluation of Tolerance to the RIPC Maneuvers: The patient will be continuously monitored
for pain and discomfort during the RIPC session. If the patient pain is more than 6 in the
traditional 1-10 scale or if the patient expresses their desire to stop the maneuver, the
procedure will be stopped, and the data regarding number and duration of the maneuvers will
be recorded. A down-escalation of the treatment will be proposed, by reducing the number of
cuff inflations to 3 or 2, as tolerated.

Hemodynamic evaluation of the effect of RIPC Maneuvers: Transcranial Doppler (TCD)
measurements will be performed during the RIPC session. TCD and Cerebral Blood Flow (CBF)
measurements will be performed at 24 hours and 72 hours after treatment.

Cerebral arterial flow magnetic resonance imaging (MRI NOVA) will be measured the first day
after treatment and 72 hours after treatment in patients suitable for transport to the MRI
scan per Intensive Care Unit (ICU) clinical team criteria.

Clinical assessments of the patients will be performed daily and at discharge from the ICU

Treatment of subarachnoid hemorrhage (SAH) and Vasospasm: Aside from the RIPC procedures,
all other treatment and monitoring of the patients will be as is standard of care for the
treatment of patients with subarachnoid hemorrhage in our hospital. Patients will undergo
neurological monitoring in the intensive care unit. Monitoring for cerebral vasospasm,
including transcranial Doppler studies, angiograms, cerebral blood flow studies, Computed
Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans and regular neurological
examination will be performed as standard. Likewise, prophylaxis and treatment for vasospasm
or any other complications of subarachnoid hemorrhage will be performed as usual, as is the
standard of care. Apart from the rounds of RIPC, in no way will the monitoring and treatment
of these patients differ from patients not enrolled in this study.

Data Collection: Patients' clinical data will be collected in a password-protected study
computer database. General patient demographics, past medical history, history of present
illness, Hunt & Hess grade, admission Glasgow coma score, modified Rankin score, size and
location of aneurysm, dates of subarachnoid hemorrhage and aneurysm treatment, type of
aneurysm treatment, transcranial Doppler study values, cerebral blood flow measurements, and
results of clinical examinations will all be noted and recorded in the study database.
Additionally, clinical imaging studies performed (including CT scans, MRI scans and cerebral
angiograms) will be reviewed and their findings noted. Specifically, size and location of
aneurysm, extent and location of subarachnoid hemorrhage, Fisher grade, and presence and
size of ischemic brain lesions will be noted. Clinical complications and outcomes will be
recorded, including occurrence of angiographic vasospasm and delayed neurological deficit
and condition at discharge and follow-up (Glasgow outcome score and modified Rankin score).
Any complications associated with the RIPC procedure will be noted and reported
appropriately.

Inclusion Criteria:

- Diagnosis of recent aneurysmal subarachnoid hemorrhage.

- Definitive treatment of the aneurysm by surgical clipping or endovascular coiling has
been completed.

Exclusion Criteria:

- Patients with unprotected (untreated) cerebral aneurysms.

- Patients with a known history of lower limb vascular disease, lower limb vascular
bypass surgery and/or peripheral neuropathy.