Remote Ischemic Preconditioning in Subarachnoid Hemorrhage
Remote Ischemic Preconditioning in Subarachnoid Hemorrhage
Rupture of brain aneurysms is a common cause of death and disability, accounting for as many
 as 10% of stroke cases in the United States. While much of the resulting injury to the
 nervous system is caused by the initial bleeding from the aneurysm, many of these patients
 develop cerebral vasospasm, pathological constriction of the blood vessels supplying the
 brain, several days following hemorrhage. As many as a third of patients can suffer a
 resulting neurological deficit and stroke, presumably caused by the decreased blood flow to
 the brain (ischemia). This delayed brain injury accounts for a significant percentage of poor
 outcomes following aneurysm rupture. Studies have shown that remote ischemia to many organs
 can precondition other tissues (including the brain) to be more tolerant to decreases in
 blood flow. This "remote ischemic preconditioning" has the promise of protecting the brain
 from ischemic injury. Whereas in other forms of stroke the onset of ischemia cannot be
 predicted in the general population, following aneurysm rupture the investigators know which
 patients are likely to develop vasospasm and when. Therefore, ischemic preconditioning
 following aneurysm rupture may help prevent some of the ischemic injury caused by vasospasm.
 Remote ischemic preconditioning by transient limb ischemia (produced by inflation of a blood
 pressure cuff on the arm or leg) has been shown to minimize injury to other organs, most
 notably the heart. Remote ischemic preconditioning of the brain following aneurysm rupture
 has not yet been investigated.
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.