Brain IschemiaRIPCAGENCT02177981
Impact of Remote Ischemic Preconditioning Preceding Coronary Artery Bypass Grafting on Inducing nEuroprotection
A study testing Remote ischemic preconditioning in people with Brain Ischemia and Postoperative Confusion, run by University of Zagreb at 1 site in Croatia.
Trial summary
Coronary artery disease (CAD) is the leading cause of death worldwide. Patients with severe CAD are often treated with coronary artery bypass grafting (CABG). Novel treatment strategies need to be pursued to respond to the continuous increase in the risk profile of contemporary CABG patients. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Brain Ischemia, Postoperative Confusion
- What is being tested?
- Remote ischemic preconditioning
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 70 participants
- Where
- 1 siteCroatia
- Study dates
- Mar 2014to Mar 2016
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult patients with multi-vessel coronary artery disease undergoing primary, elective on-pump CABG
- Written informed consent
Who cannot join
- Prior stroke, transient ischemic attack or reversible ischemic neurologic deficit
- Stenosis of the internal carotid artery (>50%)
- Significant peripheral arterial disease affecting the upper limbs
- Acute coronary syndrome within 30 days prior to surgery
- Inability to provide consent
- Postoperative exclusion criteria will be limited to contraindications to follow-up MRI (such as pacemaker dependence)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized, Double-Blind, Controlled Clinical Trial: Impact of Remote Ischemic Preconditioning Preceding Coronary Artery Bypass Grafting on Inducing Neuroprotection
Coronary artery disease (CAD) is the leading cause of death worldwide. Patients with severe CAD are often treated with coronary artery bypass grafting (CABG). Novel treatment strategies need to be pursued to respond to the continuous increase in the risk profile of contemporary CABG patients. Surgical myocardial revascularization is commonly performed with the use of cardiopulmonary bypass (CPB). Neurological impairment following CABG may take on the form of a new-onset motor deficit or postoperative cognitive dysfunction. The former is rare, but potentially devastating. Conversely, declines in attention, memory and fine motor skills can frequently be documented.
Ischemic preconditioning is a phenomenon of an endogenous protective response to organ ischemia, which is triggered by brief cycles of nonlethal ischemia and reperfusion in tissues known to be more resistant to ischemic insults. In clinical practice remote ischemic preconditioning (RIPC) is achieved by inflicting short periods of ischemia with intermittent restitution of flow to the upper extremity. This intervention has been shown to be effective in the reduction of myocardial injury in cardiac surgical patients. The hypothesis tested in this research proposal is that RIPC will decrease the extent of postoperative neurological injury following CABG.
Read more
In this research project, 70 patients scheduled for an elective CABG will be recruited at a single center. They will be randomly allocated to either undergo RIPC (intervention arm) or a sham procedure (control arm). Inflating a blood pressure cuff to 200 mmHg for 5 min will induce RIPC, thereby inducing a brief period of ischemia. This will be followed by a 5-minute arm reperfusion. In total, three cycles of arm ischemia and reperfusion will be induced in this fashion.
All patients will undergo pre- and post-procedural magnetic resonance imaging (MRI) of the brain, as well as neurocognitive testing. The array of MRI tools that will be used for the quantification of brain injury will include fluid attenuated inversion recovery, diffusion weighted and susceptibility weighted imaging, coupled with resting state functional MRI.
The investigators aim to determine whether RIPC can reduce the adverse impact of CPB on neurological outcome as evaluated by MRI detectable brain ischemia and neurocognition.
Read the detailed description
Coronary artery bypass grafting (CABG) is very effective in the management of complex coronary artery disease (CAD). Cardiopulmonary bypass (CPB) is commonly employed to achieve a still and bloodless field, which facilitates the creation of technically impeccable coronary anastomoses. Multiple adverse effects that stem from exposure of blood to a non-endothelial surface contrast the clear benefit of CPB. Neurological damage remains one of the most dreaded complications following CABG. While the incidence of new focal motor deficits is low, postoperative neurocognitive dysfunction (POCD) is seen commonly. The increasing risk profile of contemporary CABG patients makes neuroprotective strategies progressively more important.
Ischemic preconditioning is an endogenous protective response triggered by brief episodes of nonlethal ischemia and reperfusion. In clinical practice remote ischemic preconditioning (RIPC) is achieved by inducing short periods of ischemia of the upper extremity, followed by restitution of flow. This non-pharmacological strategy for inducing ischemic tolerance is cost-free and non-invasive, with potentially wide clinical applicability.
The "Impact of Remote Ischemic Preconditioning preceding Coronary Artery bypass Grafting on inducing nEuroprotection (RIPCAGE) trial" will recruit 70 patients scheduled for elective CABG at a single academic center. The hypothesis tested in this research proposal is that RIPC will decrease the extent of postoperative neuronal damage and lead to a reduction in POCD among CABG patients. Specifically, the investigators aim to determine whether RIPC can reduce magnetic resonance imaging (MRI) detectable brain damage and attenuate the neurocognitive decline universally seen in patients after CABG.
The primary composite outcome will consist of a composite of new ischemic lesions on brain MRI and POCD.
The secondary endpoints will be the following:
- Brain connectivity profiles on resting-state functional MRI (rs-fMRI).
- Pooled ischemic volumes of new diffusion-weighted imaging (DWI) hyperintensity.
- Percent declines of components in individual neurocognitive tests.
Patients will be randomly allocated in a 1:1 ratio to either receive RIPC or no intervention (control group). In the intervention arm, transient upper extremity ischemia will be induced after induction of anesthesia by inflating a blood pressure cuff to 200 mmHg for 5 min, followed by a 5 min cuff deflation. This sequence will be repeated 3 times. Patients in the control group will also have a blood pressure cuff placed, but it will not be inflated. All patients will undergo preoperative neurocognitive testing coupled with baseline brain MRI. The neurocognitive evaluation will consist of the Montreal Cognitive Assessment (MoCA) test and the Trail Making Test (TMT). Decreased cognitive function for each test will be defined as an individual decrease of at least 1 standard deviation of the group baseline mean for that test. POCD will be defined as a decrease in two or more tests. The patients will have a repeat neurocognitive evaluation prior to discharge from hospital.
Standard MRI sequences will be performed in all patients. DWI will be utilized for volumetric analysis of brain tissue exhibiting stigmata of ischemic injury. The timing of apparent diffusion coefficient quantification will be standardized to postoperative day 7, as it normalizes over time. Additional MRI sequences will include susceptibility weighted imaging (SWI) and diffusion tensor imaging (DTI). Resting state functional MRI will be performed in order to investigate the coordination of activity across brain networks. Pre- and postprocedural rs-fMRI data will be subsequently compared with each other. Disruption in the connectivity of neural circuits induced by the operation will be thereby be objectivized.
Patients will be followed for a total of 3 months, during which time all adverse events will be recorded and adjudicated by an independent clinical events committee.
- Conditions
- Brain Ischemia, Postoperative Confusion
- Being tested
- Remote ischemic preconditioning, Control
- Keywords
- Remote Ischemic Preconditioning, Coronary Artery Bypass Grafting, Diffusion Weighted Magnetic Resonance Imaging, Resting State Functional Magnetic Resonance Imaging, Postoperative Cognitive Dysfunction
- Medical subject headings
- Brain Ischemia, Postoperative Cognitive Complications
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Remote ischemic preconditioningProcedure or surgery
A blood pressure cuff will be placed on the left arm and three cycles of 5 min ischemia followed by 5 min reperfusion will be applied.
ControlProcedure or surgery
The cuff will be placed around the arm but not inflated.
| Study group | Role | What they receive |
|---|---|---|
| Remote ischemic preconditioning | Active comparator | A blood pressure cuff will be placed on the left arm and three cycles of 5 min ischemia followed by 5 min reperfusion will be applied. Receives: Procedure: Remote ischemic preconditioning |
| Control | Sham comparator | The cuff will be placed around the arm but not inflated. Receives: Procedure: Control |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite structural and functional neurological outcome
New ischemic lesions on brain MRI and postoperative neurocognitive dysfunction
Measured: 7 days
Secondary outcomes (3)
Brain connectivity profiles
Changes between pre- and postoperative resting state functional MRI expressed as continuous variables and subsequently compared among the intervention and control arms
Measured: 7 days
Peri-operative brain injury
Volumetric quantification of areas of new diffusion-weighted imaging hyperintensity in individual patients
Measured: 7 days
Postoperative neurocognitive decline
Percent declines in individual neurocognitive tests
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jun 2014 (estimated)
- Study startMar 2014
- Primary completionOct 2015
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Brain IschemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 70 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Zagreb
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Hospital Centre Zagreb
- Responsible party
- Principal investigator, Hrvoje Gasparovic, MD, PhD, University of Zagreb
- Investigators
- Hrvoje Gašparović, MD, PhD, Study chair, University of Zagreb
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02177981
- Sponsor's protocol ID
- 57./3./1.
- Acronym
- RIPCAGE
- Status last verified
- Apr 2018
- First submitted
- 7 Apr 2014
- Last updated
- 25 Apr 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
Gasparovic H, Kopjar T, Rados M, Anticevic A, Rados M, Malojcic B, Ivancan V, Fabijanic T, Cikes M, Milicic D, Gasparovic V, Biocina B. Impact of remote ischemic preconditioning preceding coronary artery bypass grafting on inducing neuroprotection (RIPCAGE): study protocol for a randomized controlled trial. Trials. 2014 Oct 27;15:414. doi: 10.1186/1745-6215-15-414.
PubMed 25348157
Study at a glance
From the registry record, last updated by the sponsor on 25 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-Blind, Controlled Clinical Trial: Impact of Remote Ischemic Preconditioning Preceding Coronary Artery Bypass Grafting on Inducing Neuroprotection
- ClinicalTrials.gov ID
- NCT02177981
- Acronym / sponsor ID
- RIPCAGE / 57./3./1.
- Conditions
- Brain Ischemia, Postoperative Confusion
- Keywords
- Remote Ischemic Preconditioning, Coronary Artery Bypass Grafting, Diffusion Weighted Magnetic Resonance Imaging, Resting State Functional Magnetic Resonance Imaging, Postoperative Cognitive Dysfunction
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 70 participants (actual)
- Lead sponsor
- University of ZagrebUniversity, hospital or other
- Collaborators
- Clinical Hospital Centre Zagreb
- Study start
- Mar 2014
- Primary completion
- Oct 2015 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 30 Jun 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Coronary artery disease (CAD) is the leading cause of death worldwide. Patients with severe CAD are often treated with coronary artery bypass grafting (CABG). Novel treatment strategies need to be pursued to respond to the continuous increase in the risk profile of contemporary CABG patients. Surgical myocardial revascularization is commonly performed with the use of cardiopulmonary bypass (CPB). Neurological impairment following CABG may take on the form of a new-onset motor deficit or postoperative cognitive dysfunction. The former is rare, but potentially devastating. Conversely, declines in attention, memory and fine motor skills can frequently be documented.
Ischemic preconditioning is a phenomenon of an endogenous protective response to organ ischemia, which is triggered by brief cycles of nonlethal ischemia and reperfusion in tissues known to be more resistant to ischemic insults. In clinical practice remote ischemic preconditioning (RIPC) is achieved by inflicting short periods of ischemia with intermittent restitution of flow to the upper extremity. This intervention has been shown to be effective in the reduction of myocardial injury in cardiac surgical patients. The hypothesis tested in this research proposal is that RIPC will decrease the extent of postoperative neurological injury following CABG.
In this research project, 70 patients scheduled for an elective CABG will be recruited at a single center. They will be randomly allocated to either undergo RIPC (intervention arm) or a sham procedure (control arm). Inflating a blood pressure cuff to 200 mmHg for 5 min will induce RIPC, thereby inducing a brief period of ischemia. This will be followed by a 5-minute arm reperfusion. In total, three cycles of arm ischemia and reperfusion will be induced in this fashion.
All patients will undergo pre- and post-procedural magnetic resonance imaging (MRI) of the brain, as well as neurocognitive testing. The array of MRI tools that will be used for the quantification of brain injury will include fluid attenuated inversion recovery, diffusion weighted and susceptibility weighted imaging, coupled with resting state functional MRI.
The investigators aim to determine whether RIPC can reduce the adverse impact of CPB on neurological outcome as evaluated by MRI detectable brain ischemia and neurocognition.
Detailed description
Coronary artery bypass grafting (CABG) is very effective in the management of complex coronary artery disease (CAD). Cardiopulmonary bypass (CPB) is commonly employed to achieve a still and bloodless field, which facilitates the creation of technically impeccable coronary anastomoses. Multiple adverse effects that stem from exposure of blood to a non-endothelial surface contrast the clear benefit of CPB. Neurological damage remains one of the most dreaded complications following CABG. While the incidence of new focal motor deficits is low, postoperative neurocognitive dysfunction (POCD) is seen commonly. The increasing risk profile of contemporary CABG patients makes neuroprotective strategies progressively more important.
Ischemic preconditioning is an endogenous protective response triggered by brief episodes of nonlethal ischemia and reperfusion. In clinical practice remote ischemic preconditioning (RIPC) is achieved by inducing short periods of ischemia of the upper extremity, followed by restitution of flow. This non-pharmacological strategy for inducing ischemic tolerance is cost-free and non-invasive, with potentially wide clinical applicability.
The "Impact of Remote Ischemic Preconditioning preceding Coronary Artery bypass Grafting on inducing nEuroprotection (RIPCAGE) trial" will recruit 70 patients scheduled for elective CABG at a single academic center. The hypothesis tested in this research proposal is that RIPC will decrease the extent of postoperative neuronal damage and lead to a reduction in POCD among CABG patients. Specifically, the investigators aim to determine whether RIPC can reduce magnetic resonance imaging (MRI) detectable brain damage and attenuate the neurocognitive decline universally seen in patients after CABG.
The primary composite outcome will consist of a composite of new ischemic lesions on brain MRI and POCD.
The secondary endpoints will be the following:
- Brain connectivity profiles on resting-state functional MRI (rs-fMRI).
- Pooled ischemic volumes of new diffusion-weighted imaging (DWI) hyperintensity.
- Percent declines of components in individual neurocognitive tests.
Patients will be randomly allocated in a 1:1 ratio to either receive RIPC or no intervention (control group). In the intervention arm, transient upper extremity ischemia will be induced after induction of anesthesia by inflating a blood pressure cuff to 200 mmHg for 5 min, followed by a 5 min cuff deflation. This sequence will be repeated 3 times. Patients in the control group will also have a blood pressure cuff placed, but it will not be inflated. All patients will undergo preoperative neurocognitive testing coupled with baseline brain MRI. The neurocognitive evaluation will consist of the Montreal Cognitive Assessment (MoCA) test and the Trail Making Test (TMT). Decreased cognitive function for each test will be defined as an individual decrease of at least 1 standard deviation of the group baseline mean for that test. POCD will be defined as a decrease in two or more tests. The patients will have a repeat neurocognitive evaluation prior to discharge from hospital.
Standard MRI sequences will be performed in all patients. DWI will be utilized for volumetric analysis of brain tissue exhibiting stigmata of ischemic injury. The timing of apparent diffusion coefficient quantification will be standardized to postoperative day 7, as it normalizes over time. Additional MRI sequences will include susceptibility weighted imaging (SWI) and diffusion tensor imaging (DTI). Resting state functional MRI will be performed in order to investigate the coordination of activity across brain networks. Pre- and postprocedural rs-fMRI data will be subsequently compared with each other. Disruption in the connectivity of neural circuits induced by the operation will be thereby be objectivized.
Patients will be followed for a total of 3 months, during which time all adverse events will be recorded and adjudicated by an independent clinical events committee.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Remote ischemic preconditioning | Active comparator | Procedure: Remote ischemic preconditioningA blood pressure cuff will be placed on the left arm and three cycles of 5 min ischemia followed by 5 min reperfusion will be applied. |
| Control | Sham comparator | Procedure: ControlThe cuff will be placed around the arm but not inflated. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Adult patients with multi-vessel coronary artery disease undergoing primary, elective on-pump CABG
- Written informed consent
Key exclusion criteria (6 listed)
- Prior stroke, transient ischemic attack or reversible ischemic neurologic deficit
- Stenosis of the internal carotid artery (>50%)
- Significant peripheral arterial disease affecting the upper limbs
- Acute coronary syndrome within 30 days prior to surgery
- Inability to provide consent
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Remote ischemic preconditioningA blood pressure cuff will be placed on the left arm and three cycles of 5 min ischemia followed by 5 min reperfusion will be applied. | Procedure or surgery | Remote ischemic preconditioning |
| ControlThe cuff will be placed around the arm but not inflated. | Procedure or surgery | Control |
Primary outcome
Composite structural and functional neurological outcome
Time frame: 7 days
New ischemic lesions on brain MRI and postoperative neurocognitive dysfunction
3 secondary outcomes
Brain connectivity profiles
Time frame: 7 days
Peri-operative brain injury
Time frame: 7 days
Postoperative neurocognitive decline
Time frame: 7 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Apr 2018.
- Derived from this study: PubMed 25348157Gasparovic H, Kopjar T, Rados M, Anticevic A, Rados M, Malojcic B, Ivancan V, Fabijanic T, Cikes M, Milicic D, Gasparovic V, Biocina B. Impact of remote ischemic preconditioning preceding coronary artery bypass grafting on inducing neuroprotection (RIPCAGE): study protocol for a randomized controlled trial. Trials. 2014 Oct 27;15:414. doi: 10.1186/1745-6215-15-414.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hrvoje Gašparović, MD, PhD study chair
University of Zagreb
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Remote ischemic preconditioning in people with Brain Ischemia and Postoperative Confusion, run by University of Zagreb at 1 site in Croatia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Croatia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Composite structural and functional neurological outcome (time frame: 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02177981, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Apr 2018.