Dataset Information

Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol.

ABSTRACT:

Introduction

Cerebral small vessel disease (cSVD) accounts for 20%-25% of strokes and is the most common cause of vascular cognitive impairment (VCI). In an animal VCI model, inducing brief periods of limb ischaemia-reperfusion reduces subsequent ischaemic brain injury with remote and local protective effects, with hindlimb remote ischaemic conditioning (RIC) improving cerebral blood flow, decreasing white-matter injury and improving cognition. Small human trials suggest RIC is safe and may prevent recurrent strokes. It remains unclear what doses of chronic daily RIC are tolerable and safe, whether effects persist after treatment cessation, and what parameters are optimal for treatment response.

Methods and analysis

This prospective, open-label, randomised controlled trial (RCT) with blinded end point assessment and run-in period, will recruit 24 participants, randomised to one of two RIC intensity groups: one arm treated once daily or one arm twice daily for 30 consecutive days. RIC will consistent of 4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min followed by 5 min deflation (total 35 min). Selection criteria include: age 60-85 years, evidence of cSVD on brain CT/MRI, Montreal Cognitive Assessment (MoCA) score 13-24 and preserved basic activities of living. Outcomes will be assessed at 30 days and 90 days (60 days after ceasing treatment). The primary outcome is adherence (completing ≥80% of sessions). Secondary safety/tolerability outcomes include the per cent of sessions completed and pain/discomfort scores from patient diaries. Efficacy outcomes include changes in cerebral blood flow (per arterial spin-label MRI), white-matter hyperintensity volume, diffusion tensor imaging, MoCA and Trail-Making tests.

Ethics and dissemination

Research Ethics Board approval has been obtained. The results will provide information on feasibility, dose, adherence, tolerability and outcome measures that will help design a phase IIb RCT of RIC, with the potential to prevent VCI. Results will be disseminated through peer-reviewed publications, organisations and meetings.

Trial registration number

NCT04109963.

SUBMITTER: Ganesh A

PROVIDER: S-EPMC7559076 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol.

Ganesh Aravind A Barber Philip P Black Sandra E SE Corbett Dale D Field Thalia S TS Frayne Richard R Hachinski Vladimir V Ismail Zahinoor Z Mai Lauren M LM McCreary Cheryl R CR Sahlas Demetrios D Sharma Mukul M Swartz Richard H RH Smith Eric E EE

BMJ open 20201014 10

<h4>Introduction</h4>Cerebral small vessel disease (cSVD) accounts for 20%-25% of strokes and is the most common cause of vascular cognitive impairment (VCI). In an animal VCI model, inducing brief periods of limb ischaemia-reperfusion reduces subsequent ischaemic brain injury with remote and local protective effects, with hindlimb remote ischaemic conditioning (RIC) improving cerebral blood flow, decreasing white-matter injury and improving cognition. Small human trials suggest RIC is safe and ...[more]

PMID: 33055122

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Project description:BACKGROUND:People with vascular cognitive impairment (VCI) constitute a clinically heterogeneous group, but previous symptomatic drug trials in VCI did not take this clinical heterogeneity into account. Executive dysfunction and memory impairment are the cognitive domains that are most frequently impaired in VCI, and these impairments are likely to reflect vascular damage to specific neurotransmitter systems, which opens the possibility for targeted symptomatic treatment directed at specific neurotransmitters. OBJECTIVE:Here we describe the design of the "Symptomatic Treatment of Vascular Cognitive Impairment" (STREAM-VCI) trial. In this proof-of-concept study, we investigate whether people with VCI with executive dysfunction due to vascular damage to the monoaminergic neurotransmitter system differentially respond to a monoaminergic challenge, whereas people with VCI with memory dysfunction associated with vascular damage to the cholinergic system will in turn respond to a cholinergic challenge. METHODS:The STREAM-VCI is a single center, double blind, three-way cross-over trial among 30 people with VCI, in which subjects received a single dose of galantamine, methylphenidate, or placebo on separate occasions. The most important inclusion criteria were a diagnosis of VCI with a Mini-Mental State Examination score of ?16 and a Clinical Dementia Rating of 0.5-1.0. For each person, the challenges consisted of a single 16 mg dose of galantamine, 10 mg of methylphenidate, and placebo, in random order on three separate visits. Change in performance in executive functioning and memory was assessed directly after the challenge using standardized neuropsychological tests. We will correlate a positive response to the cholinergic and monoaminergic treatment with differences in structural and functional connectivity at baseline using structural magnetic resonance imaging (MRI), diffusion tension MRI, and resting-state functional MRI. RESULTS:The protocol of this study is approved by the Medical Ethics Committee of VU University Medical Center and the competent authority. The first participant was enrolled in April 2014. In September 2017, enrolment for the study was completed. We expect to publish the results in 2018. CONCLUSIONS:STREAM-VCI is the first study to investigate the association of a response to a cholinergic and monoaminergic treatment with structural and functional connectivity of the monoaminergic and/or cholinergic systems on MRI. We aim to predict on an individual basis which individuals show a positive response to a cholinergic and/or monoaminergic challenge in people with VCI. This may be instrumental in moving in the direction of individually-tailored pharmacological interventions based on MRI measures in people with VCI. TRIAL REGISTRATION:ClinicalTrials.gov NCT02098824; https://clinicaltrials.gov/ct2/show/NCT02098824 (Archived by WebCite at http://www.webcitation.org/6xhO7Ya1q).

Project description:BackgroundDespite advances in perioperative care, elective major vascular surgical procedures still carry a significant risk of morbidity and mortality. Remote ischaemic preconditioning (RIPC) is the temporary blocking of blood flow to vascular beds remote from those targeted by surgery. It has the potential to provide local tissue protection from further prolonged periods of ischaemia. However, the efficacy and safety of RIPC in people undergoing major vascular surgery remain unknown. This is an update of a review published in 2011. OBJECTIVES: To assess the benefits and harms of RIPC versus no RIPC in people undergoing elective major vascular and endovascular surgery.Search methodsThe Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov to 1 April 2022.Selection criteriaWe included all randomised controlled trials that evaluated the role of RIPC in reducing perioperative mortality and morbidities in people undergoing elective major vascular or endovascular surgery.Data collection and analysisWe collected data on the characteristics of the trial, methodological quality, and the remote ischaemic preconditioning stimulus used. Our primary outcome was perioperative mortality, and secondary outcomes included myocardial infarction, renal impairment, stroke, hospital stay, limb loss, and operating time or total anaesthetic time. We analysed the data using random-effects models. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with a 95% confidence interval (CI) based on an intention-to-treat analysis. In addition, we used GRADE to assess the certainty of the evidence for each outcome.Main resultsWe included 14 trials which randomised a total of 1295 participants (age range: 64.5 to 76 years; 84% male; study periods ranged from 2003 to 2019). In general, the included studies were at low to unclear risk of bias for most risk of bias domains. The certainty of evidence of main outcomes was moderate due to imprecision of results, moderate heterogeneity, or possible publication bias. We found that RIPC made no clear difference in perioperative mortality compared with no RIPC (RR 1.41, 95% CI 0.59 to 3.40; I2 = 0%; 10 studies, 965 participants; moderate-certainty evidence). Similarly, we found no clear difference between the two groups for myocardial infarction (RR 0.82, 95% CI 0.49 to 1.40; I2 = 7%; 11 studies, 1001 participants; moderate-certainty evidence), renal impairment (RR 1.07, 95% CI 0.62 to 1.86; I2 = 40%; 12 studies, 1054 participants; moderate-certainty evidence), stroke (RR 0.33, 95% CI 0.04 to 3.15; I2 = 0%; 4 studies, 392 participants; moderate-certainty evidence), limb loss (RR 0.74, 95% CI 0.05 to 10.61; I2 = 32%; 3 studies, 322 participants; low-certainty evidence), hospital stay (MD -0.94 day, 95% CI -1.95 to 0.07; I2 = 17%; 7 studies, 569 participants; moderate-certainty evidence), and operating time or total anaesthetic time (MD 5.76 minutes, 95% CI -3.25 to 14.76; I2 = 44%; 10 studies, 803 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Overall, compared with no RIPC, RIPC probably leads to little or no difference in perioperative mortality, myocardial infarction, renal impairment, stroke, hospital stay, and operating time, and may lead to little or no difference in limb loss in people undergoing elective major vascular and endovascular surgery. Adequately powered and designed randomised studies are needed, focusing in particular on the clinical endpoints and patient-centred outcomes.

Project description:BackgroundVascular surgery patients have reduced tissues` blood supply, which may lead to mitochondrial dysfunction and accumulation of acylcarnitines (ACs). It has been suggested that remote ischaemic preconditioning (RIPC) has its organ protective effect via promoting mitochondrial function. The aim of this study was to evaluate the effect of RIPC on the profile of ACs in the vascular surgery patients.MethodsThis is a randomised, sham-controlled, double-blinded, single-centre study. Patients undergoing open surgical repair of abdominal aortic aneurysm, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited non-consecutively. The RIPC protocol consisting of 4 cycles of 5 min of ischaemia, followed by 5 min of reperfusion, was applied. A blood pressure cuff was used for RIPC or a sham procedure. Blood was collected preoperatively and approximately 24 h postoperatively. The profile of ACs was analysed using the AbsoluteIDQp180 kit (Biocrates Life Sciences AG, Innsbruck, Austria).ResultsNinety-eight patients were recruited and randomised into the study groups and 45 patients from the RIPC group and 47 patients from the sham group were included in final analysis. There was a statistically significant difference between the groups regarding the changes in C3-OH (p = 0.023)-there was a decrease (- 0.007 µmol/L, ± 0.020 µmol/L, p = 0.0233) in the RIPC group and increase (0.002 µmol/L, ± 0.015 µmol/L, p = 0.481) in the sham group. Additionally, a decrease from baseline to 24 h after surgery (p < 0.05) was detected both in the sham and the RIPC group in the levels of following ACs: C2, C8, C10, C10:1, C12, C12:1, C14:1, C14:2, C16, C16:1, C18, C18:1, C18:2. In the sham group, there was an increase (p < 0.05) in the levels of C0 (carnitine) and a decrease in the level of C18:1-OH. In the RIPC group, a decrease (p < 0.05) was noted in the levels of C3-OH, C3-DC (C4-OH), C6:1, C9, C10:2.ConclusionsIt can be concluded that RIPC may have an effect on the levels of ACs and might therefore have protective effects on mitochondria in the vascular surgery patients. Further larger studies conducted on homogenous populations are needed to make more definite conclusions about the effect of RIPC on the metabolism of ACs.Trial registrationClinicalTrials.gov database, NCT02689414. Registered 24 February 2016-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02689414.

Project description:IntroductionRemote ischaemic preconditioning (RIPC) using a non-invasive pneumatic tourniquet is a potential method for reducing ischaemia-reperfusion injury. RIPC has been extensively studied in animal models and cardiac surgery, but scarcely in solid organ transplantation. RIPC could be an inexpensive and simple method to improve function of transplanted organs. Accordingly, we aim to study whether RIPC performed in brain-dead organ donors improves function and longevity of transplanted organs.Methods and analysesRIPTRANS is a multicentre, sham-controlled, parallel group, randomised superiority trial comparing RIPC intervention versus sham-intervention in brain-dead organ donors scheduled to donate at least one kidney. Recipients of the organs (kidney, liver, pancreas, heart, lungs) from a randomised donor will be included provided that they give written informed consent. The RIPC intervention is performed by inflating a thigh tourniquet to 300 mm Hg 4 times for 5 min. The intervention is done two times: first right after the declaration of brain death and second immediately before transferring the donor to the operating theatre. The sham group receives the tourniquet, but it is not inflated. The primary endpoint is delayed graft function (DGF) in kidney allografts. Secondary endpoints include short-term functional outcomes of transplanted organs, rejections and graft survival in various time points up to 20 years. We aim to show that RIPC reduces the incidence of DGF from 25% to 15%. According to this, the sample size is set to 500 kidney transplant recipients.Ethics and disseminationThis study has been approved by Helsinki University Hospital Ethics Committee and Helsinki University Hospital's Institutional Review Board. The study protocol was be presented at the European Society of Organ Transplantation congress in Copenhagen 14-15 September 2019. The study results will be submitted to an international peer-reviewed scientific journal for publication.Trial registration numberNCT03855722.

Project description:BackgroundTo date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients.MethodsSTREAM-VCI is a single-center, double-blind, three-way crossover trial. We included 30 VCI patients (Mini-Mental State Examination (MMSE) ≥ 16 and Clinical Dementia Rating score 0.5-1.0) with cerebrovascular pathology on MRI. All patients received single doses of methylphenidate (10 mg), galantamine (16 mg), and placebo in random order on three separate study visits. We used the NeuroCart®, a computerized test battery, to assess drug-sensitive cognitive effects. Predefined main outcomes, measured directly after a single dose of a study drug, were (i) change in performance on the adaptive tracker for executive functioning and (ii) performance on the Visual Verbal Learning Test-15 (VVLT-15) for memory, compared to placebo. We performed mixed model analysis of variance.ResultsThe study population had a mean age of 67 ± 8 years and MMSE 26 ± 3, and 9 (30%) were female. Methylphenidate improved performance on the adaptive tracker more than placebo (mean difference 1.40%; 95% confidence interval [CI] 0.56-2.25; p = 0.002). In addition, methylphenidate led to better memory performance on the VVLT-15 compared to placebo (mean difference in recalled words 0.59; 95% CI 0.03-1.15; p = 0.04). Galantamine did not improve performance on the adaptive tracker and led to worse performance on delayed recall of the VVLT-15 (mean difference - 0.84; 95% CI - 1.65, - 0.03; p = 0.04). Methylphenidate was well tolerated while galantamine produced gastrointestinal side effects in a considerable number of patients.ConclusionsIn this proof-of-principle study, methylphenidate is well tolerated and improves executive functioning and immediate recall in patients with VCI. Galantamine did not improve memory or executive dysfunction. Results might be influenced by the considerable amount of side effects seen.Trial registrationhttp://www.clinicaltrials.gov. Registration number: NCT02098824. Registration date: March 28, 2014.

Dataset Information

Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol.

Introduction

Methods and analysis

Ethics and dissemination

Trial registration number

Publications

Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol.

Similar Datasets

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