Abstract
Remote ischemic conditioning (RIC) is a powerful innate response to transient subcritical ischemia that protects against severe ischemic insults at distant sites. We have previously shown the safety and feasibility of limb RIC in aneurysmal subarachnoid hemorrhage (aSAH) patients, along with changes in neurovascular and cerebral metabolism. In this study, we aim to detect the potential effect of an established lower-limb conditioning protocol on clinical outcomes of aSAH patients. Neurologic outcome (modified Rankin Scale (mRS)) of patients enrolled in a prospective trial (RIPC-SAH) was measured. A matching algorithm was applied to identify control patients with aSAH from an institutional departmental database. RIC patients underwent four lower-limb conditioning sessions, consisting of four 5-min cycles per session over nonconsecutive days. Good functional outcome was defined as mRS of 0 to 2. The study population consisted of 21 RIC patients and 61 matched controls. There was no significant intergroup difference in age, gender, aneurysm location, clipping vs coiling, Fisher grades, Hunt and Hess grades, or vasospasm. RIC was independently associated with good outcome (OR 5.17; 95 % confidence interval (CI) 1.21–25.02). RIC also showed a trend toward lower incidence of stroke (28.6 vs. 47.5 %) and death (4.8 vs. 19.7 %). Lower-limb RIC following aSAH appears to have a positive effect in the functional outcomes of patients with aSAH. While this effect is consistent with prior preclinical studies, future trials are necessary to conclusively evaluate the effects of RIC for aSAH.
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References
Koch S, Gonzalez N. Preconditioning the human brain: proving the principle in subarachnoid hemorrhage. Stroke. 2013;44:1748–53. doi:10.1161/STROKEAHA.111.000773.
Zhao H-G, Li W-B, Li Q-J, Chen X-L, Liu H-Q, Feng R-F, et al. Limb ischemic preconditioning attenuates apoptosis of pyramidal neurons in the CA1 hippocampus induced by cerebral ischemia-reperfusion in rats. Sheng Li Xue Bao. 2004;56:407–12.
Jin RL, Li WB, Li QJ, Zhang M, Man XH, Sun XC, et al. The role of extracellular signal-regulated kinases in the neuroprotection of limb ischernic preconditioning. Neurosci Res. 2006;55:65–73. doi:10.1016/j.neures.2006.01.006.
Dave KR, Saul I, Prado R, Busto R, Perez-Pinzon MA. Remote organ ischemic preconditioning protect brain from ischemic damage following asphyxial cardiac arrest. Neurosci Lett. 2006;404:170–5. doi:10.1016/j.neulet.2006.05.037.
Ren C, Gao X, Steinberg GK, Zhao H. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience. 2008;151:1099–103. doi:10.1016/j.neuroscience.2007.11.056.
Bilgin-Freiert A, Dusick JR, Stein NR, Etchepare M, Vespa P, Gonzalez NR. Muscle microdialysis to confirm sublethal ischemia in the induction of remote ischemic preconditioning. Trans Stroke Res. 2012;3:266–72. doi:10.1007/s12975-012-0153-1.
Gonzalez NR, Hamilton R, Bilgin-Freiert A, Dusick J, Vespa P, Hu X, et al. Cerebral hemodynamic and metabolic effects of remote ischemic preconditioning in patients with subarachnoid hemorrhage. Acta Neurochir Suppl. 2013;115:193–8. doi:10.1007/978-3-7091-1192-5_36.
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;75:590–8. doi:10.1227/NEU.0000000000000514.
Koch S, Katsnelson M, Dong C, Perez-Pinzon M. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke. 2011;42:1387–91. doi:10.1161/STROKEAHA.110.605840.
Koch S, Sacco RL, Perez-Pinzon MA. Preconditioning the brain: moving on to the next frontier of neurotherapeutics. Stroke. 2012;43:1455–7. doi:10.1161/STROKEAHA.111.646919.
Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, et al. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology. 2012;79:1853–61. doi:10.1212/WNL.0b013e318271f76a.
Walsh SR, Nouraei SA, Tang TY, Sadat U, Carpenter RH, Gaunt ME. Remote ischemic preconditioning for cerebral and cardiac protection during carotid endarterectomy: results from a pilot randomized clinical trial. Vasc Endovasc Surg. 2010;44:434–9. doi:10.1177/1538574410369709.
Teunissen LL, Rinkel GJ, Algra A, van Gijn J. Risk factors for subarachnoid hemorrhage: a systematic review. Stroke. 1996;27:544–9. doi:10.1161/01.STR.27.3.544.
Claassen J, Bernardini GL, Kreiter K, Bates J, Du YE, Copeland D, et al. Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke. 2001;32:2012–20. doi:10.1161/hs0901.095677.
Molyneux A. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002;360:1267–74. doi:10.1016/S0140-6736(02)11314-6.
Gonzalez NR, Boscardin WJ, Glenn T, Vinuela F, Martin NA. Vasospasm probability index: a combination of transcranial Doppler velocities, cerebral blood flow, and clinical risk factors to predict cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2007;107:1101–12. doi:10.3171/JNS-07/12/1101.
Oskouian RJ, Martin NA, Lee JH, Glenn TC, Guthrie D, Gonzalez NR, et al. Multimodal quantitation of the effects of endovascular therapy for vasospasm on cerebral blood flow, transcranial Doppler ultrasonographic velocities, and cerebral artery diameters. Neurosurgery. 2002;51:30–43. doi:10.1097/00006123-200207000-00005.
Weisscher N, Vermeulen M, Roos YB, De Haan RJ. What should be defined as good outcome in stroke trials; a modified Rankin score of 0–1 or 0–2? J Neurol. 2008;255:867–74. doi:10.1007/s00415-008-0796-8.
Duncan PW, Jorgensen HS, Wade DT. Outcome measures in acute stroke trials: a systematic review and some recommendations to improve practice. Stroke. 2000;31:1429–38. doi:10.1161/01.STR.31.6.1429.
Kelsey JL, Whittemore AS, Evans AS, Thompson WD. Methods in observational epidemiology. New York: Oxford University Press; 1996.
Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997;28:660–4.
Cahill J, Zhang JH. Subarachnoid hemorrhage: is it time for a new direction? Stroke. 2009;40:S86–7. doi:10.1161/STROKEAHA.108.533315.
Dezfulian C, Garrett M, Gonzalez NR. Clinical application of preconditioning and postconditioning to achieve neuroprotection. Trans Stroke Res. 2012;4:19–24. doi:10.1007/s12975-012-0224-3.
Duckwiler G. Balloon angioplasty and intra-arterial papaverine for vasospasm. J Stroke Cerebrovasc Dis. 1997;6:261–3.
Vespa PM, Nuwer MR, Juhász C, Alexander M, Nenov V, Martin N, et al. Early detection of vasospasm after acute subarachnoid hemorrhage using continuous EEG ICU monitoring. Electroencephalogr Clin Neurophysiol. 1997;103:607–15.
Vespa PM. Acute presentation and early intensive care of acute aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 1997;6:230–4.
Vespa PM, Nenov V, Nuwer MR. Continuous EEG monitoring in the intensive care unit: early findings and clinical efficacy. J Clin Neurophysiol. 1999;16:1–13.
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The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. This research involved human participants. This study was conducted with Institutional Review Board approval, and participants gave informed consent before taking part. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).
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This work is supported by the Ruth and Raymond Stotter Endowed Chair in Neurosurgery and the National Institutes of Health National Institute of Neurological Disorders and Stroke award K23NS079477.
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Laiwalla, A.N., Ooi, Y.C., Liou, R. et al. Matched Cohort Analysis of the Effects of Limb Remote Ischemic Conditioning in Patients with Aneurysmal Subarachnoid Hemorrhage. Transl. Stroke Res. 7, 42–48 (2016). https://doi.org/10.1007/s12975-015-0437-3
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DOI: https://doi.org/10.1007/s12975-015-0437-3