Does squeezing an arm really hard improve outcomes after cardiac surgery?
Remote ischemic preconditioning tested in multiple randomized trials
Cardiopulmonary bypass (CPB) for cardiac surgery induces ischemic injury throughout the body, but especially in the kidneys. Acute kidney injury occurs in up to a third of patients undergoing CPB.
Post-bypass kidney failure is believed to result from ischemia-reperfusion injury, when oxygen supply to a tissue is cut off and then restored.
Animal studies have suggested that the body could be prepped or trained to better withstand ischemic-reperfusion injury, by inducing mild ischemia in another tissue bed before the operation. The mechanism is unclear.
In the most commonly tested method, anesthesia is induced and a blood pressure cuff is inflated to occlude blood flow in one limb for five minutes or so, followed by five minutes of reperfusion, repeated for a total of three or four cycles. The surgery is then performed.
Several randomized trials have tested this maneuver, called remote ischemic preconditioning.
RenalRIPC Trial
In the RenalRIPC trial, investigators at four hospitals in Germany randomized 240 patients planned for cardiac surgery who were at high risk for acute kidney injury in 2013 and 2014 to receive remote ischemic preconditioning or sham remote ischemic preconditioning (control). Patients received RIPC after induction of anesthesia and before the initial incision.
After 30 days, acute kidney injury was significantly reduced in the remote ischemic preconditioning group (37.5% vs 52.5%, a 15% absolute risk reduction, number needed to treat of 7). The need for renal replacement therapy was also lower in the ischemic preconditioning group (5.8% vs. 15.8%, absolute risk reduction 10%, number needed to treat of 10).
Patients left the ICU one day sooner (median 3 vs 4 days). Mortality was not reduced.
Zhonghshan Trial *
* in China
Authors randomized 509 patients at high risk for AKI who were scheduled to undergo elective cardiac surgery at a single center in China to receive either RIPC or a sham procedure 24 hours before surgery.
Within 7 days of follow-up, fewer patients receiving RIPC experienced AKI (27.2% vs 35.3%, absolute risk reduction of 8%).
What might be the most interesting difference between these two trials is that in the single-center Chinese trial, no sedation or anesthesia is described for the RIPC maneuver, which occurred 24 hours before surgery (as opposed to immediately before the incision).
In other words, five hundred Chinese people apparently agreed to have their arms painfully constricted and released on and off for a period of 30 minutes, just to participate in a research trial for an unproven therapy.
This is a remarkable example of the differences between societies, which might influence the processes of clinical trials and their outcomes.
More Randomized Trials on RIPC
Other randomized trials testing remote ischemic preconditioning have not found a benefit in improving composite cardiovascular endpoints after cardiac surgery.
Smaller randomized trials likewise were conflicting:
A large meta-analysis concluded that RIPC does improve AKI by an absolute 2% after cardiac surgery (number needed to treat, 50). The benefits occurred mostly in patients receiving volatile anesthesia. Propofol is believed to inhibit the beneficial effects of RIPC.
However, that analysis included many studies from low-resource nations (China, Iran, Pakistan, Russia, Poland, etc.).
Conclusion
Remote ischemic preconditioning (e.g., occluding blood flow in an arm for three five-minute periods just prior to cardiac surgery) reduced the rate of acute kidney injury postoperatively in some randomized trials.
In a meta-analysis, the benefits of RIPC seemed to occur mainly in patients receiving volatile-only anesthesia (not propofol). Propofol has been hypothesized to attenuate any benefits of ischemic preconditioning.
RIPC has not been shown to improve cardiovascular outcomes more generally after cardiac surgery.
References
Links to the cited trials are included in the table above.
Very good post, as always!
I had mixed feelings after reading the September paper about ischemic preconditioning. On one hand I think it would be so nice if we could prevent kidney injury just by squeezing the patient’s arm before the surgery. In the other, it is clearly to good to be true.
For any intervention to work, it needs to address the dominant cause of renal failure in the context of cardiac surgery. What is the dominant cause? No one knows. Everybody has hypotheses for that. Anyway, I would guess that “lack of ischemic preconditioning” is not the dominant cause. It is also possible that post-cardiac surgery AKI has several different causes still to be found.
This is the result of not having a disease model to articulate pre-clinical and clinical research. Researchers end up trying random interventions just to see what happens.
This is more or less what I argue here:
https://thethoughtfulintensivist.substack.com/p/dont-clinical-trial-if-you-cant-formulate?r=20qrtz