Remote Ischemic Conditioning to Reduce Ischemia-Reperfusion Injury after Cardiac Arrest

In this episode Zack and Joe talk with a true pioneer in resuscitation and the science of cardiac arrest management. Graham Nichol, from the University of Washington, joined us at Sharp Memorial Hospital for an amazing discussion about “Remote Ischemic Conditioning” and its role in prevention of ischemia-reperfusion injury resulting from cardiac arrest. Is this VooDoo or a real phenomenon? Listen to this episode to find out…

Some Definitions:

“Ischemia-Reperfusion” injury: prolonged ischemia to the brain and heart often occur after circulatory arrest. Immediate CPR minimizes this phenomenon but many of our patients who arrest in the pre-hospital setting don’t receive immediate bystander CPR, resulting in prolonged ischemia. CPR reintroduces blood flow and oxygen to the previously ischemic tissues. This hyperoxic ‘reperfusion’ is known to be a main contributor to infarct size in both the heart and brain causing poor neurologic outcomes after arrest. Minimizing this reperfusion injury is major focus of resuscitative science right now.
“Ischemic Conditioning”: purposeful application of ischemia and reperfusion, off and on, to the tissues.
- “Pre-conditioning” = applying this therapy BEFORE circulatory arrest
- “Peri-conditioning” = applying this therapy either DURING circulatory arrest
- “Post-conditioning” = applying this therapy AFTER circulatory arrest
“Targeted” vs. “Remote” Ischemic Conditioning:
“Targeted” ischemic conditioning: application of conditioning directly to the specific target organ (ie the heart or the brain). This can be done in one of two ways:
- systemic ischemic conditioning.
  - In a pig model of cardiac arrest, Demetris Yannapoulos and Keith Lurie applied brief periods of ischemic post-conditioning via “Stutter CPR” (3-4 cycles of 20 seconds of CPR with 20 second pauses) after prolonged “no flow” arrest – upwards of 20 minutes without CPR – and found normal LV function and elimination of ischemic insult to the brain using this technique. They discussed this controversial topic with Weingart on the emcrit podcast Episode 69.
- Local conditioning: applying ischemic conditioning directly to the target organ
  - Many studies have shown effectiveness of local ischemic conditioning during PCI for acute MI. After restoration of vessel patency, reperfusion was interrupted by cycles of 1 min of coronary balloon reocclusion. Here is a good summary:
    - Staat Post-Conditioning the Human Heart 2005

“Remote“ ischemic conditioning: application of ischemic conditioning to a REMOTE area of the body (ie the limb) to reduce the degree of injury to the heart and brain that results from cardiac arrest (ischemia) followed by reperfusion (chest compressions, ROSC, or ECMO) by applying the ‘remote’ ischemia-reperfusion by using a blood pressure cuff on a limb.

How it Works:

*courtesy of the Lancet Vol 374; Oct 2009

Several theories exist to explain the benefit of ischemic conditioning. I’ll break it down in two ways:

1.) Simple explanation: “good humors” are released from the ischemic limb and protect against cell death/apoptosis in the heart and brain.

2.) Complex hypothesis:

1.) RIC induces a cascade of intracellular kinases and modifies mitochondrial function within the cell by opening ATP-sensitive potassium channels and closing the mitochondrial permeability transition pore. 2.) RIC causes release and transport of micro-RNA-144 from the ischemic limb. Amongst other effects, miRNA-144 effevely down-regulates protein expression involved in apoptosis, autophagy, and survival signaling. Supernerds, if you really want more on this:

Przyklenk Basic Res Cardiol 2014 RIC microRNA

role of mitochondria in protection of the heart by preconditioning Halestrap 2007

How its Done:

On any limb, inflate a simple blood pressure cuff to a pressure above the systolic blood pressure. 200 mmHg is a good starting point. If you are using a manual cuff, Graham recommends clamping a Kelly on the tubing to prevent deflation of the cuff too soon.
Keep the cuff inflated for 5 min and then deflate for 5 min.
Do 3-4 cycles of this, and you’re done.

The Evidence:

Xu Crit Care Med 2015 Conditioning in Rat Model of Cardiac Arrest – In rats, better myocardial and cerebral function with longer duration of survival occurred when RIC was applied prior to arrest (preconditioning), at the time of arrest, or after arrest (arrest) when compared to controls (no conditioning). This take-home from this study was that the conditioning did not have to occur before the arrest; benefit was seen if conditioning were applied intra-arrest or post-arrest. Application: RIC appears to be beneficial even if done after ROSC.
Sloth Eur Heart J 2013 Long Term RIC – In humans, RIC before PCI improved long term clinical outcomes in patients with STEMI.
Rentoukas RIC JACC CV Intervention 2010 – Remote Ischemic PERI-conditioning (applying the RIC at the time of revascularization in the cath lab) was cardioprotective.
Przyklenk Basic Res Cardiol 2014 RIC microRNA – An explanation of the proposed mechanism of RIC at the cellular level; Good Humors
Lancet Botker Ischemic Conditioning Trial – This is a great review paper on remote ischemic preconditioning.

Graham Nichol MD, MPH, FACP

nichol@uw.edu

@grahamnichol

Current Positions:

Professor of Medicine, Division of General Internal Medicine at the University of Washington in Seattle
Director, UW Medical Center/Harborview Medical Center for Pre-hospital Emergency Care
Medical Director, University of Washington Clinical Trial Center
Leonard A Cobb Medic One Foundation Endowed Chair in Prehospital Emergency Care
Medical Director, Resuscitation Outcome Consortium Clinical Trial Center

Professional Endeavors:

American Heart Association’s Basic Life Support Subcommittee and Advanced Life Support Subcommittee
chair of the Basic Life Support Subcommittee and received the American Heart Association Award of Merit
chair of the Basic Life Support Subcommittee and received the American Heart Association Award of Merit
Co-founded and co-directed the Resuscitation Science Symposium (ReSS) of the American Heart Association
National Institutes of Health (NIH) reviewer and a grantee
chair of the epidemiology panel for the National Heart Lung and Blood Institute-sponsored PULSE conference and PULSE leadership group
co-principal investigator of the Resuscitation Outcomes Consortium (ROC) Data Coordinating Center
co-investigator of the Australian Resuscitation Outcomes Consortium

TrackBacks

More with Graham Nichol

Graham is an avid cyclist and attributes his ability to ride more than 100 miles and climb more than 10,000 feet in a day to his off-label use of remote ischemic conditioning! Here, he and a friend are about to begin the long ride up Carson Pass to finish the Death Ride.

Upcoming Events

CastleFest: April 14-16, 2015

CCUS Montreal: May 1-3, 2015

SMACC Chicago 2015: June 23-26, 2015

Recording EDECMO 18 EDECMO World Headquarters San Diego, CA — Recording EDECMO 18
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EDECMO 18 – Remote Ischemic Conditioning – with Graham Nichol

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