Safety and efficacy of remote ischemic conditioning for the treatment of intracerebral hemorrhage: A proof-of-concept randomized controlled trial

Abstract

Background Remote ischemic conditioning (RIC) can promote hematoma resolution, attenuate brain edema, and improve neurological recovery in animal models of intracerebral hemorrhage (ICH). Aims This study aimed to evaluate the safety and preliminary efficacy of RIC in patients with ICH. Methods In this multicenter, randomized, controlled trial, 40 subjects with supratentorial ICH presenting within 24-48 hours of onset were randomly assigned to receive medical therapy plus RIC for consecutive 7 days or medical therapy alone. The primary safety outcome was neurological deterioration within 7 days of enrollment, and the primary efficacy outcome was the changes of hematoma volume on CT images. Other outcomes included hematoma resolution rate at 7 d ([hematoma volume at 7 d − hematoma volume at baseline]/hematoma volume at baseline), perihematomal edema (PHE), and functional outcome at 90 days. Results The mean age was 59.3±11.7 years and hematoma volume was 13.9±4.5 mL. No subjects experienced neurological deterioration within 7 days of enrollment, and no subject died or experienced RIC-associated adverse events during the study period. At baseline, the hematoma volumes were 14.19±5.07 mL in the control group and 13.55±3.99 mL in the RIC group, and they were 8.54±3.99 mL and 6.95±2.71 mL at 7 days after enrollment, respectively, not a significant difference (p>0.05 each). The hematoma resolution rate in the RIC group (49.25±9.17%) was significantly higher than in the control group (41.92±9.14%; MD, 7.3%; 95% CI, 1.51% to 13.16%; p=0.015). The absolute PHE volume was 17.27±8.34 mL in the control group and 12.92±7.30 mL in the RIC group at 7 days after enrollment, not a significant between-group difference (p=0.087), but the relative PHE in the RIC group (1.77±0.39) was significantly lower than in the control group (2.02±0.27; MD, 0.25; 95% CI, 0.39-0.47; p=0.023). At 90-day follow-up, 13 subjects (65%) in the RIC group and 12 subjects (60%) in the control group achieved favorable functional outcomes (mRS score≤3), not a significant between-group difference (p=0.744). Conclusions Repeated daily RIC for consecutive 7 days was safe and well-tolerated in patients with ICH, and it may be able to improve hematoma resolution rate and reduce relative PHE. However, effects RIC on the absolute hematoma and PHE volume and functional outcomes in this patient population need further investigations. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03930940.

Oxidative Stress Following Intracerebral Hemorrhage: From Molecular Mechanisms to Therapeutic Targets

“…In animals with ICH, remote ischemic conditioning can attenuate brain edema by upregulating heme oxygenase-1, transferrin, and transferrin receptor ( 122 ), and promoting hematoma resolution via increasing anti-inflammatory macrophage activation ( 123 ). In a multicenter, randomized, controlled clinical trial of 40 patients with ICH, treatment with remote ischemic conditioning for seven consecutive days was safe and well tolerated, promoted the rate of hematoma resolution, and reduced perihematomal edema ( 124 ). However, functional outcomes at 90 days were not significantly different from those in the control group possibly due to the small sample ( 124 ).…”

“…In a multicenter, randomized, controlled clinical trial of 40 patients with ICH, treatment with remote ischemic conditioning for seven consecutive days was safe and well tolerated, promoted the rate of hematoma resolution, and reduced perihematomal edema ( 124 ). However, functional outcomes at 90 days were not significantly different from those in the control group possibly due to the small sample ( 124 ). A phase III randomized clinical trial with 452 participants is currently underway to evaluate the effect of remote ischemic conditioning on the clinical outcomes of patients with ICH ( Identifier: NCT04657133).…”

The Impact of Serial Remote Ischemic Conditioning on Dynamic Cerebral Autoregulation and Brain Injury Related Biomarkers

“…Remote ischemic conditioning (RIC) refers to an intervention that offers remote tissues and organs a resistance capacity to ischemia/reperfusion injury through small doses of reversible episodes of ischemia and reperfusion ( Hess et al, 2015 ; Heusch et al, 2015 ) that activate neurogenic pathways, humoral factors, and the immune system ( Anrather and Hallenbeck, 2013 ). Recent studies have demonstrated that RIC could increase cerebral perfusion, promote hematoma resolution, facilitate recovery of nerve function, and improve the clinical prognosis of patients with cerebrovascular diseases ( Meng et al, 2012 ; An et al, 2020 ; Zhao et al, 2021 ). However, the mechanism is not fully elucidated.…”

Pilot Study of Remote Ischemic Conditioning in Acute Spontaneous Intracerebral Hemorrhage

“…Our pre-clinical data provided the conceptual framework for the open-label, assessor-blinded, randomized controlled Remote Ischemic Conditioning for Intracerebral Hemorrhage (RICH-1) trial ( ClinicalTrials.gov , NCT03930940), which found a 7-day protocol of RIC was safe, well-tolerated, and accelerated hematoma resolution rate in 40 patients with supratentorial ICH ( Zhao et al, 2020 , 2021 ). Given these promising findings, the goal of this pilot study is to test the overarching hypothesis that unilateral RIC is a safe, feasible therapy to accelerate hematoma resorption and improve outcomes in ICH patients.…”