In a lab at Duke University in 1986, scientists conducted an experiment comparing two different ways to give a dog a heart attack.
The investigators cut off the blood flow of the circumflex artery for 40 minutes in 12 dogs. For 7 of those dogs, they first initiated a “preconditioning” protocol that consisted of four 5-minute occlusions of the vessel, with 5 minutes of reperfusion in between. Five “control” dogs underwent the circumflex occlusion without any antecedent intervention.
Ischemic preconditioning, they found, “paradoxically limited infarct size to 25% of that seen in the control group (p < .001).” A race was underway to elucidate the mechanism of this effect and to determine applications in humans.
In the years that followed, small experiments suggested some benefit to ischemic preconditioning, that could even be done at “remote” sites – short bursts of cutting off circulation in an extremity, for example, might protect perfusion in heart muscle. Early studies were small, and most did not examine clinical outcomes. The exact physiological mechanisms remained a mystery.
Nearly three decades after that 12-dog experiment, two trials are now published in this week’s issue of NEJM in which investigators sought to definitively determine whether remote ischemic preconditioning improves clinical outcomes in patients undergoing cardiac surgery. Neither trial offers reason to be hopeful about this approach.
The first study was a sham-controlled trial that enrolled 1600 adults undergoing on-pump coronary artery bypass graft (CABG) surgeries at 30 centers in the United Kingdom. Participants were randomized either to a remote ischemic preconditioning arm or to a control group. In the intervention group, a blood pressure cuff on the arm was inflated to 200 mmHg for 5 minutes, then deflated for 5 minutes, repeating this cycle a total of 4 times. All participants then underwent surgery as usual, with no other part of the anesthesia or operative care standardized.
The findings were clear: there was no difference in the primary endpoint of cardiovascular death, myocardial infarction, coronary revascularization, or stroke at 12 months (26.5% in the preconditioning arm as compared with 27.7% in the control group, p=0.58).
The second trial of 1400 adults undergoing elective cardiac surgeries at 14 sites in Germany revealed comparable results. Using a similar method of remote ischemic preconditioning, the trial also found no difference in a primary composite endpoint of death, myocardial infarction, stroke, and acute renal failure, with follow up until hospital discharge or a maximum of two weeks.
In an accompanying editorial, Drs. Zaugg and Lucchinetti of the Department of Anesthesiology at the University of Alberta describe several reasons that these trials might have been negative in the face of positive preliminary data: “It is likely that remote ischemic preconditioning is less effective in infarct-remodeled, diabetic and aged hearts. Also, since cardiopulmonary bypass per se, as well as hypothermia and cardioplegia, are known to be protective, perhaps further protection is impossible to achieve. Most importantly, concomitant medications, specifically anesthetics, may interfere with remote ischemic preconditioning.”
Is there any chance this still works? The editorialists don’t think so: “The conclusions from both trials are definitive,” they write. “[R]emote ischemic preconditioning is ineffective in adult patients undergoing on-pump cardiac surgery.”
Much work still remains to improve outcomes for patients undergoing complex cardiac surgery. Despite the initial hopes, remote ischemic preconditioning doesn’t seem to help. Maybe it’s time to determine new targets – time, that is, to go back to the lab.
The authors of the first study and the editorialist are available through October 16 to answer your questions on the NEJM Group Open Forum. There is also an NEJM Quick Take video summary available.