EDECMO 18 – Remote Ischemic Conditioning – with Graham Nichol

ischemia

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:

 “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

*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:

  1. 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.
  2. Keep the cuff inflated for 5 min and then deflate for 5 min.
  3. Do 3-4 cycles of this, and you’re done.

 

The Evidence:

  1.  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.
  2. Sloth Eur Heart J 2013 Long Term RIC – In humans, RIC before PCI improved long term clinical outcomes in patients with STEMI.
  3. Rentoukas RIC JACC CV Intervention 2010 – Remote Ischemic PERI-conditioning (applying the RIC at the time of revascularization in the cath lab) was cardioprotective.
  4. Przyklenk Basic Res Cardiol 2014 RIC microRNA – An explanation of the proposed mechanism of RIC at the cellular level; Good Humors
  5. Lancet Botker Ischemic Conditioning Trial – This is a great review paper on remote ischemic preconditioning.

Graham Nichol MD, MPH, FACP

Graham Nichol MD, MPH

Graham Nichol MD, MPH

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

LITFL Reviews Episode 164

LITFL Reviews Episode 164


 

More with Graham Nichol

Death Ride

Death Ride

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

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CCUS Montreal: May 1-3, 2015

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SMACC Chicago 2015: June 23-26, 2015

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Recording EDECMO 18  EDECMO World Headquarters San Diego, CA

Recording EDECMO 18
EDECMO World Headquarters
San Diego, CA


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Comments

  1. Matt McClure says:

    I am curious if you could point me towards some resources discussing the role of propool on the mitochondria? This is highly interesting and as someone who is actively researching mitochondrial roles in IPC I have used propofol in animal studies to maintain sedation and am wondering if I’ve lost some data due to it. What are you using for sedation in post arrests? Benzo drips? Thank you for the continued additions to the wealth of knowledge that is FOAM!

    Matt

    • Matt,

      I’d recommend you reach out to Graham directly: nichol@uw.edu on this stuff.

      Indeed I’ve turned to using Fentanyl/versed gtt’s in any case where ischemia may be an issue. I still use propofol, but not in cases where an ischemic tissue is the crux of matter (ie MI, CVA, etc)

      ~Joe

  2. Gary Grist RN CCP says:

    Remote ischemic conditioning? May I offer an alternative explanation besides the generation of “good humours”? An ischemic arm or leg will become hypoxic when a tourniquet is applied. When the tourniquet is released, the limb acts as an ‘oxygen sink’ that removes a lot of oxygen (and calcium) from the general circulation, lowering the amount of oxygen available to cause damage to the vital organs. Of course a severely ischemic limb may also become damaged over time, but this is not immediately life threatening. The same effect can be obtained by hemodiluting the patient with calcium free crystalloid before or at the beginning of ECPR. If the patient has been core cooled with IV crystalloid or by a cool ECPR pump prime he will not need much oxygen. The hemodilution reduces the amount of excess oxygen available to damage ischemic reperfusion areas. A good target Hct is 25-30%. When the ECPR pump is started the oxygenator should be ventilated with room air only. The goal is to get the blood flow high, but the oxygen delivery relatively low. The reason that the blood flow needs to be high (CI of 2-2.5 L/min/M2), even though the patient is cool, is to remove excess CO2 trapped in the tissues. This trapped CO2 changes the intracellular pH and makes protective enzymes like antioxidants ineffective until the normal intracellular pH can be restored. Removing excess tissue CO2 helps to do this. Here is an article that describes this concept. (BTW, dantrolene will prevent the formation of the MPTP. So every patient should get a dose.)

    Grist G. Extracorporeal membrane oxygenation (ECMO) or extracorporeal cardiopulmonary resuscitation (ECPR): A critical life or death choice. Progress in Pediatric Cardiology; 2008 January; 24(2):113-116.

    • Gary, several good points made. Specific to your questions about the mechanism of RIC, I asked Dr. Nichol to give his thoughts on this forum. Stay tuned. Your paper will be a nice addition to the literature section of our site as well. Thanks for sharing.

      Would you recommend adding Dantrolene to the prime? What else?

      Our current protocols are to use 100% O2 (not air as you recommend) as the initial “blend.” That’s only for the first hour or so until the pt gets to the ICU and the perfusionists get involved. We’ve long considered lowering the initial O2 but have yet to make that move. Thanks, again, for the comments.

      ~Joe

    • Jason Bowman says:

      Gary, I love your theory on how RIC works. I’ve heard several good theories on what’s actually happening (NO, adenosine or even TSG-6 release) but this is the first theory I’ve heard that answers the reason why the results of RIC can’t be fully replicated when we administer the agents that are supposedly inducing RIC. Do you know of anyone that has proven this theory, maybe by measuring SVO2 and Ca++ during RIC and seeing a drop in those levels after removing the tourniquet? Also, I’m interested to hear, how do you explain the benefit of doing several short periods of ischemia? With your theory, would I be wrong to think one long period would be more beneficial? Thanks!

      I’m curious about the oxygen, does the evidence against providing 100% O2 via the airway to cardiac arrests not translate into ECMO? Would 21% be the lower limit of O2 via ECMO or does it need to be higher to maintain O2? Sorry for my limited knowledge of ECMO.

      • Gary Grist RN CCP says:

        “Gary, I love your theory on how RIC works. I’ve heard several good theories on what’s actually happening (NO, adenosine or even TSG-6 release) but this is the first theory I’ve heard that answers the reason why the results of RIC can’t be fully replicated when we administer the agents that are supposedly inducing RIC. Do you know of anyone that has proven this theory, maybe by measuring SVO2 and Ca++ during RIC and seeing a drop in those levels after removing the tourniquet?
        Also, I’m interested to hear, how do you explain the benefit of doing several short periods of ischemia? With your theory, would I be wrong to think one long period would be more beneficial? Thanks!
        I’m curious about the oxygen, does the evidence against providing 100% O2 via the airway to cardiac arrests not translate into ECMO? Would 21% be the lower limit of O2 via ECMO or does it need to be higher to maintain O2? Sorry for my limited knowledge of ECMO.”

        Jason, unfortunately this comment venue does not allow for extended discussion. The concept of reperfusion injury is well known, including the effects of excess oxygen and calcium. There are a couple of references below relating to the effect of oxygen and calcium on reperfusion injury. But they do not really explain what is going on. If you want specifics you can contact me at garygrist@comcast.net and I will send you some detailed material. Basically you are asking the wrong questions. So they are difficult to answer. This is what I can say. Most clinicians (ECMO and critical care personnel) emphasize the goal of improving oxygen delivery in shock patients. Sometimes this works, other times it doesn’t. Increasing oxygenation by improving the Fick variables (hemodynamics, cardiac output, oxygen carrying capacity, oxygen consumption, etc.) is only half of the physiology. There is another side that assesses gas exchange and capillary perfusion at the systemic microvascular level. It is at this level where reperfusion injury is manifest and it is at this level where it must be corrected. When these aspects are understood, the clinician can sometimes save the patient or at least know the reason why the treatments didn’t work. The issue of reperfusion injury is not related exotic substances like NO, adenosine or TSG-6 release. It is much simpler than that. 1. Hypoxic/ischemic tissues become acidotic. 2. Protective molecules are deactivated by the intracellular acidosis. 3. Reoxygenation and recalcification at this critical stage will kill the patient. 4. If properly used, the ECMO pump can be used to correct the intracellular pH and reactivate protective molecules without over oxygenating or recalcification. 5. This can prevent or reduce reperfusion injury. If we give protective molecules like antioxidants to a patient before correcting intracellular pH, they not work. One of the tricky things to understand is intracellular acidosis. Most of the time, this cannot be assessed using ABGs. So when you stabilize a patient and get a good ABG, you might think progress is being made when in reality death is imminent. I know this sounds crazy, but I cannot adequately explain the concept in this short response.

        Becker LB, New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovascular Research 61 (2004);461 470

        Wang C, Nguyen HN, Maguire JL, Perry DC Role of intracellular calcium stores in cell death from oxygen-glucose deprivation in a neuronal cell line. J Cereb Blood Flow Metab. 2002 Feb;22(2):206-14.

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  1. […] is ischemic conditioning? How might it be used in managing a cardiac arrest patient? Find on on the ED ECMO podcast. […]

  2. […] discussions on this topic, check out this post over at A Medic’s Medicine and this episode of the ED ECMO podcast.) […]

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