How Temporary Ischemia Reduces Later Harm

Reperfusion injury is a simple enough concept: When blood flow is rapidly restored to an ischemic tissue or organ, it can aggravate damage and cause additional injury. This can happen across a range of essential organs, including the heart and lungs. It can lead to inflammation, dysfunction, necrosis and apoptosis, and is a major cause of morbidity. Effective ways to reduce or prevent reperfusion injury, however, are still wanting.

That makes the simple, safe intervention of remote conditioning—recently subjected to a successful prehospital trial on patients having acute myocardial infarctions—especially intriguing.

Ischemic conditioning isn’t a new idea. Used before things like angioplasty, it means inducing brief and repeated cycles of ischemia and reperfusion that work to protect myocardium from injury during later, longer periods of ischemia and subsequent reperfusion. Remote conditioning involves using a distant site like an arm to confer protection on an organ like the heart. We don’t know exactly how it works, but the cycles of temporary occlusion, then release effect some kind of bloodborne factor that works to preserve mitochondria and limit damage from oxygen radicals and other biochemical changes in cells.

“It’s not well understood,” says Terry Valenzuela, MD, MPH, medical director for the Tucson Fire Department, who presented on the subject at February’s EMS State of the Sciences Conference. “The bloodborne effector may be one compound, it may be two, it may be a cluster that’s produced during remote conditioning. But what it does is block the inflammatory response and changes in calcium movement, and essentially stops the things that are bad about reperfusion injury.”

A Danish study published in The Lancet in 2010 brought the intervention to the ambulance.¹ A team led by Aarhus University’s Hans Erik Bøtker, MD, PhD, split 333 consecutive adult suspected-first-AMI patients into groups that got primary percutaneous coronary intervention with and without remote conditioning first. The remote conditioning group received, during transport, four cycles of five-minute inflation of a blood-pressure cuff to 200 mmHg, followed by five minutes of deflation. The primary endpoint was myocardial salvage index 30 days later.

The results: Median salvage index for those included in follow-up was 0.75 in the remote conditioning group (0.50–0.93, n=73) and 0.55 in the control group (0.35–0.88, n=69). Their respective mean salvage index was 0.69 (SD 0.27) vs. 0.57 (SD 0.26). “Remote ischemic conditioning before hospital admission,” the authors concluded, “increases myocardial salvage and has a favorable safety profile. Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes.”

“I think it’s pretty good evidence,” says Valenzuela. “It doesn’t quite achieve statistical significance, but the area that was viable in the preconditioning group was pretty dramatic. It’s going to take a bigger study, but it certainly showed it’s worth investigating. There are really no side effects, and it’s so easy to do.”

A year earlier, in 2009, another piece in the same journal looked at bringing remote preconditioning into common practice, and concluded it “could be close to becoming a clinical technique.”² Certainly conditioning, both before and during an event, appears to have a good safety profile. It seems to work in multiple windows of opportunity. And in an EMS setting, it wouldn’t require any special equipment, training or skills. In fact, it’s based on things we should be doing anyway: obtaining fast 12-leads and rapidly getting AMI patients to PCI-capable hospitals. If there’s a caveat, it’s that it may be difficult using current BP equipment.

“It could be tough to do those five-minute sequences with standard blood pressure cuffs,” notes Valenzuela. “I’d suggest people try it with their standard cuffs and see how well they can maintain that pressure. I’m not sure, with the cuffs we have, we could implement that sequence.”

Bøtker has suggested the effectiveness of remote conditioning after onset of target-organ ischemia could also have implications for stroke treated with thrombolytics. Sepsis might be another area to investigate, as the changes seen there have some similarities to those of reperfusion injury.

For AMI, meanwhile, the time may be ripe for a U.S. prehospital trial.

“You’d have to have your IRB approve it, but I anticipate that’d be a pretty easy sell,” says Valenzuela. “The safety has been demonstrated over a lot of clinical studies. The hard part would be, when you start doing this in an EMS system, knowing you’re having a good effect in your community. It would take good collaboration with the emergency medicine docs and cardiologists.”

References

1. Bøtker 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 Feb 27; 375(9,716): 727–34.

2. Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet 2009 Oct 31; 374(9,700): 1,557–65.