Remote Ischemic Conditioning during Myocardial Infarction

A future process & protocol for treating STEMI patients?

 

 
 
 

Terence Valenzuela, MD, MPH | From the June 2014 Issue | Tuesday, June 3, 2014


Dispatch receives a call reporting a 50-year-old man with acute onset retrosternal chest pain. He’s a heating technician on a repair call to a home in a nearby retirement community. Due to adverse weather and road conditions, you don’t arrive on scene until 20 minutes later.

The patient appears frightened and is diaphoretic. His fist is pressed over the center of his sternum—the universal sign for coronary ischemia. Your partner’s focused physical examination finds a pulse of 100, blood pressure of 95/55 and respiration rate of 24. Oxygen saturation is 89% with the patient on oxygen via a non-rebreather mask.

Crackles are audible over both lung fields from top to bottom. You perform a 12-lead ECG which shows ST-T segment elevations in leads V1–V5 and ST-T segment depressions in leads 2, 3 and AVF. (See Figure 1, p. 46.)

The patient is experiencing an anterior myocardial infarction (MI). (See Figure 2, p. 47.) The left coronary artery, whose thrombosis produced the ECG pattern, supplies 75% of muscle of the left ventricle. A loss of just 40% of the left ventricle results in cardiogenic shock and a mortality of 70%. This patient has extensive pulmonary edema and is on the verge of cardiogenic shock. He’s in dire straits.

Helicopters are grounded due to the severe weather. Your transport time to the nearest medical center able to provide emergent cardiac catheterization and intervention is 45 minutes. You administer aspirin and sublingual nitroglycerin.

The patient’s condition doesn’t improve and his extreme respiratory distress moves you to consider immediate endotracheal (ET) intubation with rapid sequence intubation. However, your patient, though afraid, is alert and cooperative; his anatomy (a short neck, one finger width from chin to neck, less than one finger width from thyroid notch to the chin-neck junction) promises a most challenging intubation with direct laryngoscopy.

On the other hand, your clinical judgment and experience predicts he could tolerate a trial of continuous positive airway pressure (CPAP) ventilation to avoid the potential complications in the performance of ET intubation in the field, including ET tube dislodgement and the requirement for continued sedation during transport. You also consider that the most important adverse consequence of a CPAP trial is delaying an inevitable intubation.

In pulmonary edema, CPAP decreases the work of breathing, cardiac preload and cardiac afterload. CPAP also improves oxygenation and eases the intense fear that accompanies severe dyspnea.

The drawbacks of CPAP are the requirement for a cooperative patient, a continued risk of aspiration, and the potential for hypotension in patients who are preload-dependent (e.g., right ventricular failure, extensive pulmonary embolism).

You coach the patient on what to expect from the CPAP mask—possible feeling of suffocation and claustrophobia caused by the required snug mask fit to face. You’re also prepared to bolus him with fluids in case he becomes hypotensive after you initiate CPAP.

Fortunately, his blood pressure holds; he tolerates the mask well and “works with” the CPAP device. After just a few minutes, the patient is more comfortable and his vital signs are: blood pressure 105/60, heart rate 100, respiratory rate 20 and oxygen saturation of 94%.

You wonder if there’s anything else you can do during the 45-minute transport to the ST elevation myocardial infarcation (STEMI) center to increase his probability of survival and minimize the damage to his heart.

You look at your manual blood pressure cuff and think about a recent continuing education discussion on remote ischemic conditioning at the STEMI center.

As you load your patient into the ambulance, you decide to share with him what you’ve learned about remote ischemic conditioning in STEMI. The patient consents so you proceed with this treatment: inflate the BP cuff to 200 mmHg for five minutes, then deflate it for five minutes. You repeat this process three more times for a total of four cycles of inflation-deflation.

Ischemia & Reperfusion Injury
Interruption of blood flow to a portion of the heart causes ischemia. Complex cellular metabolic and structural changes ensue during this interruption of blood flow. Lack of oxygen inhibits cellular oxidative phosphorylation—the metabolic pathway in which the mitochondria oxidize nutrients to form adenosine triphosphate (ATP), the “energy currency” of metabolism.

The myocytes (muscle cells in the heart) suffer a rapid decline of available ATP. Lactic acid accumulates as the mitochondria are forced to change from aerobic to anaerobic metabolism. The cell membrane “pumps” that keep some ions inside the cell and others outside fail. Potassium leaks out of the cell; sodium and calcium enter. The myocytes swell. A high concentration of calcium activates intracellular enzymes, which degrade the cell membrane. The damaged cell membrane becomes porous and the myocytes die.

Although reperfusion of the heart must occur to salvage ischemic yet still-viable myocardium, reperfusion itself causes cell damage distinct from the original ischemic coronary artery blockage. Restoration of blood flow to the heart produces within the myocytes reactive oxygen species. These are molecules or atoms of oxygen with one extra electron. They’re very unstable and reactive and cause oxidation of cell membrane constituents, proteins and DNA. Damage and dysfunction follow. Normally, there’s 10,000 times more calcium in the extracellular space around the myocytes than within them.

Meanwhile, membranes inside and on the border of the cells become more permeable, and more calcium floods into the cell. Too much calcium inside myocytes makes them contract irreversibly and opens a special pore in the mitochondria that permits the entry of water and certain small molecules that destroy the energy-producing processes inside the mitochondria.

The toxins produced by cellular necrosis flow into the extracellular space and activate inflammation mechanisms and platelets. These inflammatory mediators draw neutrophils and platelets from circulating blood into the heart muscle itself.

Activated neutrophils release toxic substances—the same substances that kill bacteria and viruses. The cascade of inflammatory mediators and procoagulants in reperfusion injury attack the cells lining the blood vessels of the heart, resulting in thrombosis and the plugging of capillaries.

In summary, restoring blood flow to an ischemic portion of the heart, as occurs in MI, causes injury to potentially viable heart cells through the interaction of multiple factors. Reperfusion injury is estimated to cause up to 50% of the final infarct size in acute MI.1

So, a logical question is whether there is an intervention that can prevent, stop, or ameliorate reperfusion injury, and if it could be started in the prehospital setting.

Ischemic Conditioning
Ischemic conditioning consists of brief and repeated cycles of nonlethal ischemia alternating with reperfusion in a selected organ or tissue. This conditioning reduces damage from later, prolonged ischemia.

Murry and Reimer first reported experiments in which the circumflex coronary arteries (LCXs) of dogs were obstructed with a balloon catheter.2 The animals underwent four cycles of five-minute LCX occlusion followed by five minutes of reperfusion. Thereafter the LCX was blocked for 40 minutes; long enough to cause irreversible infarction.

A control group of dogs underwent only the prolonged occlusion. The animals were maintained for four days, sacrificed, and the extent of infarction in the LCX vascular bed measured by histochemical techniques.

Infarct size in the experimental group of dogs that only had the prolonged occlusion was 25% of those that did receive pulsatile ischemia/reperfusion. It was found that somehow the intermittent occlusions produce a tolerance to more prolonged ischemia.

This phenomenon, termed “ischemic conditioning,” was later extended by Przyklenk in a similar experiment wherein conditioning of the left circumflex vascular bed reduced infarct size and contractile dysfunction after sustained coronary occlusion of the left anterior descending artery.3

Ischemic conditioning thus appeared to generate blood-borne factors in the circulation and protect organs distant from the tissue conditioned. This came to be known as “remote ischemic conditioning” (RIC).

Remote Ischemic Conditioning
Ischemic conditioning remained an interesting, but not clinically useful, phenomenon for many years until the discovery that ischemic conditioning of an extremity could induce protection in internal organs such as heart, brain, lung and kidney.4

Work with animal models demonstrated RIC could be induced by brief cycles of ischemia/reperfusion in limbs, and experiments showed that cardiac infarct size could be reduced.

The feasibility of RIC in humans was reported in 2002 when Kharbanda showed that RIC was possible with the use of a standard blood pressure cuff applied to an arm for timed pulses of brief ischemia/reperfusion in human volunteers by measuring changes in the cells lining blood vessels in the contralateral arm.5 (See Figure 3, p. 48.)

The mechanism(s) of ischemic conditioning has been intensively studied over the past 25 years and involves humoral, neurogenic, inflammatory and clotting factors.6

Moreover, it has been found that there are two phases to the protection: the first lasts approximately four hours after ischemic conditioning; the protective effect then fades. This initial phase is likely mediated through small trigger molecules such as adenosine, bradykinins, opioids and reactive oxygen species.

Research has shown a significant proportion of the protective effect of RIC is mediated through stabilization of the mitochondrial permeability transition pore (mPTP).7 The mPTP is blocked by ischemic conditioning, thus preserving the structure and function of the mitochondria.

The second phase of ischemic conditioning occurs 12–24 hours after conditioning and requires new transcription of DNA and protein synthesis. These changes produce distinct mediators that inhibit the expression of proinflammatory genes and enhanced expression of antiinflammatory genes. The second wave of reperfusion injury to myelocytes and vascular endothelial cells is damped down.8

These observations suggest different therapeutic “windows” for ischemic conditioning exist before the onset of ischemia (preconditioning), during ischemia (perconditioning) and after the beginning of reperfusion (postconditioning). (See Figure 4, p. 49.)

Ischemic conditioning applied before ischemia is called “preconditioning” and is well-supported by several clinical studies on elective procedures such as percutaneous coronary artery stenting and coronary artery bypass grafting.

Ischemic postconditioning is started very quickly (within a minute after reperfusion begins) and consists of cycles of reperfusion and reocclusion lasting only one minute each.9

Ischemic Perconditioning
The therapeutic intervention being considered by the paramedic for the patient described earlier is called “perconditioning.” He knows a large portion of the patient’s heart is ischemic (as indicated by the anterior ST-T elevations on his 12-lead ECG) and won’t be reperfused until he arrives at the STEMI center. He also knows that the transport time interval presents an opportunity for him to perform RIC and perhaps improve this patient’s outcome.

Perconditioning in STEMI is attractive because any EMT or paramedic with a blood pressure cuff and a wristwatch can perform it. No expensive and complicated special equipment is required. No elaborate orientation and training is required, and the procedure poses small risk of harm to patients. Best of all, the potential benefit-to-risk ratio is extremely high. (See “Remote Ischemic Conditioning Protocol,” below.)

The perconditioning phase offers the best target for EMS intervention. Is there any evidence that it would work? In an intriguing proof of concept study (designed to show that RIC can be used in the prehospital environment), Botker and others at the Aarhus University Hospital in Denmark prospectively randomized symptomatic STEMI patients (recognized by first responders in the field by 12-lead ECG) to receive either five cycles of brief ischemia/reperfusion, administered to an upper arm by blood pressure cuff, or to no ischemic conditioning.10

The conditioning was done in ambulances while patients were en route to the investigators’ medical center for emergency percutaneous coronary intervention. On arrival, patients underwent primary coronary angioplasty. A radionuclide scanning technique (single photon emission computed tomography [SPECT]) performed within eight hours of hospital arrival delineated the area of ischemic myocardium (area at risk) for each patient.

A repeat scan 30 days later revealed final infarct size. By comparing the two scans, researchers were able to determine the area of the original ischemic myocardium that progressed to infarction and the area that remained viable—the myocardial salvage index.

Of those who returned for the second SPECT scan, thus completing the study protocol, the median myocardium salvaged in ischemic conditioned patients was 75% versus 55% in the unconditioned group. The difference didn’t, however, achieve statistical significance.10

In the subgroup of patients with anterior—and therefore more serious—MIs, the investigators did identify a trend toward greater myocardial salvage and better left ventricular function in the remote ischemic conditioned patients.10

Though interesting, their results for myocardial salvage didn’t meet the customary tests for statistical significance because too few subjects randomized in the field completed the protocol through acute angioplasty to a second scan at 30 days permitting calculation of the degree of myocardial salvage in each patient.

Nevertheless, this study established the feasibility and safety of prehospital remote ischemic perconditioning in STEMI patients prior to emergency percutaneous coronary interventions.

A long-term follow-up analysis (median duration of follow-up of 3.8 years) of those completing the protocol measured the prevalence of “major adverse cardiac and cerebral events (MACCE),” presented a composite outcome consisting of all-cause mortality, MI, readmission for heart failure, and ischemic stroke/transient ischemic attack.11

MACCE occurred in 17 (13.5%) patients in the ischemic conditioned group compared with 32 (25.6%) patients in the control group, yielding a hazard ratio (the chance of an event occurring in the treatment arm divided by the chance of the event occurring in the control arm of a study) of 0.49 (95% confidence interval: 0.27–0.89, P = 0.018).

The hazard ratio for all-cause mortality alone was 0.32 (95% confidence interval: 0.12-0.88, P = 0.027).

The result suggests that remote ischemic perconditioning performed in the prehospital environment may improve long-term clinical outcomes in patients with STEMI.

A follow-up study is in progress to determine whether remote ischemic perconditioning, administered during EMS transport to hospital and before percutaneous coronary intervention, can reduce the rates of cardiovascular death and hospitalization for heart failure in patients one year after presenting with ST-elevation acute MI.12

This is a multicenter, randomized, controlled, single-blind, prospective clinical trial. The participating medical centers are located in Denmark, Spain and the United Kingdom, and will enroll approximately 2,300 patients with half receiving prehospital RIC and the other half not receiving it. The study is underway; approximately 200 subjects have been enrolled. Scheduled for completion in 2016, this study should provide scientific evidence as to whether RIC provided by EMS in the field can significantly benefit STEMI patients.

Summary
Ischemic conditioning is a unique physiologic process that has shown potential for reducing the size of MI in animal studies for more than twenty years. Early human trials have been inconclusive. However, one clinical trial is in progress that is well designed and will enroll enough subjects to potentially demonstrate significant reductions in mortality and hospitalization for congestive heart failure in STEMI patients who receive RIC in the field. Certainly, the simplicity, low cost and safety of ischemic conditioning merit continued clinical study in humans.

References
1. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121–1135.
2. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–1136.
3. Przyklenk K, Bauer B, Ovize M, et al. Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87(3):893–899.
4. Rock P, Yao Z. Ischemia reperfusion injury, preconditioning and critical illness. Curr Opin Anaesthesiol. 2002;15(2):139–146.
5. Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo.
Circulation. 2002;106(23):2881–2883.
6. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: Underlying mechanisms and clinical application. Cardiovasc Res. 2008;79(3):377–386.
7. Hausenloy DJ, Ong SB, Yellon DM. The mitochondrial permeability transition pore as a target for preconditioning and postconditioning. Basic Res Cardiol. 2009;104(2):189–202.
8. Tapuria N, Kumar Y, Habib MM, et al. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review. J Surg Res. 2008;150(2):304–330.
9. Hansen PR, Thibault H, Abdulla J. Postconditioning during primary percutaneous coronary intervention: a review and meta-analysis. Int J Cardiol. 2010;144(1):22–25.
10. Botker HE, Kharbanda R, Schmidt MR, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: A randomised trial. Lancet. 2010;375(9716):727–734.
11. Sloth AD, Schmidt MR, Munk K, et al. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J. 2014;35(3):168–175.
12. University of Aarhus. (May 13, 2013.) Effect of RIC on clinical outcomes in STEMI patients undergoing pPCI (CONDI2). ClinicalTrials.gov. Retrieved Feb. 27, 2014, from www.clinicaltrials.gov/ct2/show/NCT01857414.

Remote Ischemic Conditioning Protocol
Place a manual blood pressure (BP) cuff on the patient’s arm and inflate the cuff to 200 mmHg for five minutes; then deflate it for five minutes. Repeat three more times for a total of four cycles of inflation/deflation.

Don’t attempt to clamp the tubes of the cuff to keep it inflated because standard BP cuffs will lose significant pressure over the five-minute inflation phase. Instead, check the pressure frequently and reinflate the cuff to 200 mmHg as needed.

NOTE: The sensation of a blood pressure cuff inflated to 200 mmHg for five minutes is unpleasant and some patients may find it painful. Therefore, you must warn patients about this so that it doesn’t add to the stress of an ongoing myocardial infarction.

 

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Related Topics: Patient Care, Cardiac and Circulation, STEMI, ST-elevation myocardial infarction, remote ischemic conditioning, myocardial infarctions, myocardial infarction, coronary ischemia, blood pressure cuff, AMI, acute myocardial infarction, Jems Features

 

Terence Valenzuela, MD, MPH

Terence Valenzuela, MD, MPH, is medical director of Tucson Fire Department. He can be reached at terry@aemrc.arizona.edu.

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