CLINICAL TRIALS MONITOR European Trial Evaluates Remote Ischemic Preconditioning in Aneurysm Treatment By Robert Kowalski, MD An Austrian neurosurgical group has Although the mechanism is not yet fully understood, remote begun a trial of applying mild restriction ischemic conditioning to an arm or leg is thought to help to blood fl ow in an upper extremity, or prevent ischemic injury in distant organs, including the heart and remote ischemic preconditioning, to brain, by releasing endogenous anti-infl ammatory mediators, evaluate impact on outcome in patients with and preventing an infl ammatory cascade that might normally unruptured aneurysms treated with surgical accompany temporary ischemia in those remote body regions. or endovascular repair. The study, Remote Previous research demonstrated promising results with this Ischemic Preconditioning for Intracranial approach in sepsis, transplant surgery, and after myocardial Aneurysm Treatment (RIPAT), is testing a infarction. The remote conditioning has been applied in upper hypothesis that ischemic brain injury related to and lower extremities. cerebral aneurysm repair procedures can be avoided by triggering a protective systemic response through mild, benign ischemia More recently, remote conditioning has been utilized in research induced elsewhere in the body. involving cerebrovascular disease and injury. A group at the University of Arizona applied the technique within one hour of The technique, which has been employed in the past several years emergency department presentation in traumatic brain injury with some success for prevention of ischemic heart injury during patients. In a paper published in March, this group reported a cardiovascular surgical procedures such as arterial stenting, has signifi cant reduction in serum levels of S-100B and NSE six hours only recently been applied in cerebrovascular disease. and one day after treatment with remote ischemic conditioning. “Remote ischemic preconditioning (RIPC) involves the Remote preconditioning also has been applied in subarachnoid administration of a subcritical ischemic stimulus to one organ hemorrhage. A group at the University of Miami in 2010 reported with the goal of protecting another (remote) organ from favorable results of a Phase IB safety and feasibility trial of limb subsequent ischemia,” said Martin Ortler, MD, MSc, principal preconditioning applied every 24 to 48 hours for 14 days after investigator of the RIPAT study and a neurosurgeon at the aneurysm rupture in a group of 33 patients. Innsbruck Medical University in Austria. “We hypothesize that pre-interventional RIPC reduces ischemic cerebral tissue damage “Although prevention of delayed cerebral ischemia after in patients undergoing elective intracranial aneurysm treatment.” subarachnoid hemorrhage would be one of the major potential applications of RIPC in the fi eld of cerebrovascular disease, Investigators in the RIPAT study, which began in November 2013, this is not our primary goal,” Prof. Ortler said. “We rather hope to enroll a total of 48 patients with unruptured intracranial use the treatment of unruptured intracranial aneurysms aneurysms in the trial, randomized to remote ischemic as an ‘experimental paradigm’ in which protection from preconditioning or a sham treatment. For subjects randomized to ischemia is highly desirable and many important variables treatment, a blood pressure cuff is applied to one arm and infl ated can be controlled very easily, since the interventions are done to 200 mmHg for fi ve minutes, three times, while the patient is electively,” said Prof Ortler. under general anesthesia prior to aneurysm repair. For patients assigned to the sham group, the pressure cuff is applied similarly, The potential for use of preconditioning in medicine is broad, but infl ated to only 10 mmHg. The study includes patients whose Prof. Ortler said. “We think that preconditioning is a simple aneurysms are microsurgically clipped, and those who undergo strategy of nature to prepare our organism for strain. Probably endovascular coiling. we employ preconditioning mechanisms every day on ourselves and on our patients,” he said. “If the concept proves right for “Patients may experience temporary ischemia with both treatment brain protection as it has for the protection of other organs, this techniques: during temporary artery occlusion of the aneurysm- would open a completely new aspect in the research of ischemia bearing vessel in microsurgical aneurysm clipping, as well as prevention.” during vessel occlusion by balloon in endovascular coiling and/or stenting,” Prof. Ortler said. Outcome will be assessed among subjects in the study groups with MRI and neuropsychological testing, as well as the modifi ed Rankin Scale (mRS) and NIH Stroke Scale (NIHSS) at the time of hospital discharge, and at six and 12 months afterward. RIPAT study investigators also are collecting an array of serum biomarkers, including S100B, NSE, GFAP, NSE, MMP9, and microparticles. These markers will be obtained at admission, after ischemic preconditioning, after aneurysm repair and at eight additional time points following the aneurysm clipping or coiling. “These biomarkers have been shown to correlate with the extent of cerebral ischemia in imaging,” said Prof. Ortler. “Microparticles were included in this panel because microparticles are a special study focus of our group and preliminary data from animal studies suggest that microparticles might be the link between peripheral ischemic preconditioning and remote end-organ effects,” he said. Martin Ortler, MD, MSc 24
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