Neuroprotective Effect of Remote Ischemic Post-conditioning in Out-of-hospital Cardiac Arrest

Official title

Neuroprotective Effect of Remote Ischemic Post-conditioning in Out-of-hospital Cardiac Arrest : a Randomized Open Label Controlled Trial

Overview

Patients admitted to intensive care unit (ICU) following an out-of-hospital cardiac arrest (OHCA) have a high morbidity and mortality rate, primarily due to ischemia-reperfusion (I/R) syndrome leading to anoxic-ischemic brain injury. Despite current recommended advanced life support therapies, no specific treatment or procedure has yet been shown to improve the neurological outcome of such patients. Remote ischemic post-conditioning (RIPOST) which usually consists of applying brief and repeated cycles of ischemia alternating with reperfusion by inflating and deflating a blood pressure cuff or a pneumatic tourniquet placed around a limb, is a promising strategy to protect organs against I/R injury, including brain. Regarding cardiac arrest, pre-clinical studies have demonstrated an improvement in neurological outcome in animal subjects treated with RIPOST after cardiopulmonary resuscitation. The aim of our study is to demonstrate the benefit of early RIPOST in OHCA patients in reducing neurological injury and organ failure related to I/R syndrome.

Detailed description

The RIPOST trial is a prospective, single-center, randomized, open-label, parallel group trial.

Patients with inclusion criteria will be randomized in two parallel groups:

* Experimental group: standard of care associated to 3 RIPOST sessions : one within the 4 hours following cardiac arrest, one 12 hours after cardiac arrest and one 24 hours after cardiac arrest. A RIPOST session = four cycles of cuff inflation to 200 mmHg for five minutes and then deflation to 0 mmHg for another five minutes, using an inflatable thigh tourniquet (total duration of the session = 40 minutes). * Control group: standard of care associated to 3 sham sessions at inclusion, 24, and 48 hours after inclusion. A sham session = application of the thigh tourniquet during 40 minutes without any inflation.

Inclusion duration: 36 months

Patient participation duration: 3 months

Study duration: 39 months

Interventions

• Other Remote ischemic post conditioning sessions
  Three sessions of RIPOST (within the 4 hours following cardiac arrest and then 12 and 24 hours after cardiac arrest), as follows: four cycles of cuff inflation to 200 mmHg for 5 min and then deflation to 0 mmHg for another 5 min (40 min total duration of the intervention), using an inflatable thigh tourniquet
• Other Sham sessions
  Three sessions of a sham procedure (within the 4 hours following cardiac arrest and then 12 and 24 hours after cardiac arrest), as follows : application of a thigh tourniquet during 40 min without any inflation

Primary outcome measures

• Neurofilament light chain (NFL) blood level evolution between 6 and 72 hours after cardiac arrest occurrence [Time frame: 72 hours after out-of-hospital cardiac arrest occurrence]

Secondary outcome measures (7)

• Sepsis organ failure assessment score (SOFA) [Time frame: 72 hours after out-of-hospital cardiac arrest occurrence]
• Rate of patients with NFL peak level >500 pg/mL [Time frame: 72 hours after out-of-hospital cardiac arrest occurrence]
• Neuron-specific enolase (NSE) blood level evolution between 6 and 72 hours after cardiac arrest occurrence [Time frame: 72 hours after out-of-hospital cardiac arrest occurrence]
• S100B protein (PS100B) blood level evolution between 6 and 72 hours after cardiac arrest occurrence [Time frame: 72 hours after out-of-hospital cardiac arrest occurrence]
• ICU mortality rate from multi-organ failure and from neurological injury [Time frame: At intensive care unit (ICU) discharge, up to 28 days]
• Modified Rankin Scale (mRS) [Time frame: 90 days after out-of-hospital cardiac arrest occurrence]
• Post out-of-hospital cardiac arrest event occurrence [Time frame: 24 hours after out-of-hospital cardiac arrest occurrence]

Eligibility criteria

Inclusion criteria

• Out-of-hospital cardiac arrest with stable return of spontaneous circulation (ROSC > 20 minutes)
• Patient receiving invasive mechanical ventilation for coma (Glasgow score < 8)
• Availability of a lower limb without intravenous infusion or tension cuff positioned on it
• Randomization and application of the first session of the tested procedure within 4 hours after ROSC
• Consent of a next-of-kin or inclusion in emergency procedure

Exclusion criteria

• Age < 18 y.o or pregnancy
• Patient unable to walk without assistance, unable to support himself properly without assistance, bedridden, incontinent and requiring nursing constant attention and care (corresponding to a mRS equal to 4 or 5)
• Interval between cardiac arrest and ROSC (no flow + low flow) estimated > 60 minutes
• Unwitnessed cardiac arrest with asystole as first rhythm
• In-hospital cardiac arrest
• Refractory cardiac arrest (no ROSC considered as stable)
• Cardiac arrest from traumatic, hemorrhage, stroke or hanging supposed origin
• Mean arterial pressure < 65mmHg persisting despite appropriate vascular filling and vasopressor and/or inotropic support
• Active uncontrolled bleeding
• Contraindication or not possible to use a pneumatic tourniquet on none of the two lower limbs (amputations, intravenous infusion positioned on both lower limbs, tourniquet size incompatible with patient morphology)
• Implementation of extracorporeal arteriovenous circulation for refractory cardiac arrest or refractory cardiogenic shock before inclusion
• Patient already included in this study
• Inclusion in another interventional study which purpose is to improve prognosis after a cardiac arrest
• Judicial protection measure
• Patient without French social security

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 1 center

• Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer — Toulon

Publications

• Ho AFW, Chong J, Ong MEH, Hausenloy DJ. Remote Ischemic Conditioning in Emergency Medicine-Clinical Frontiers and Research Opportunities. Shock. 2020 Mar;53(3):269-276. doi: 10.1097/SHK.0000000000001362. PMID 32045394
• Kloner RA, Shi J, Dai W, Carreno J, Zhao L. Remote Ischemic Conditioning in Acute Myocardial Infarction and Shock States. J Cardiovasc Pharmacol Ther. 2020 Mar;25(2):103-109. doi: 10.1177/1074248419892603. Epub 2019 Dec 11. PMID 31823646
• Albrecht M, Meybohm P, Broch O, Zitta K, Hein M, Grasner JT, Renner J, Bein B, Gruenewald M. Evaluation of remote ischaemic post-conditioning in a pig model of cardiac arrest: A pilot study. Resuscitation. 2015 Aug;93:89-95. doi: 10.1016/j.resuscitation.2015.05.019. Epub 2015 Jun 4. PMID 26051813
• England TJ, Hedstrom A, O'Sullivan SE, Woodhouse L, Jackson B, Sprigg N, Bath PM. Remote Ischemic Conditioning After Stroke Trial 2: A Phase IIb Randomized Controlled Trial in Hyperacute Stroke. J Am Heart Assoc. 2019 Dec 3;8(23):e013572. doi: 10.1161/JAHA.119.013572. Epub 2019 Nov 21. PMID 31747864
• Moseby-Knappe M, Mattsson N, Nielsen N, Zetterberg H, Blennow K, Dankiewicz J, Dragancea I, Friberg H, Lilja G, Insel PS, Rylander C, Westhall E, Kjaergaard J, Wise MP, Hassager C, Kuiper MA, Stammet P, Wanscher MCJ, Wetterslev J, Erlinge D, Horn J, Pellis T, Cronberg T. Serum Neurofilament Light Chain for Prognosis of Outcome After Cardiac Arrest. JAMA Neurol. 2019 Jan 1;76(1):64-71. doi: 10.1001 PMID 30383090

Identifiers

NCT: NCT06473207 · 2023-CHITS-010 · 2023-A02457-38

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗