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Remote Ischaemic Preconditioning

Several years ago while in Galway I first came across the concept of remote ischaemic preconditioning (RIPC). This is the concept that subjecting one part of the body to a brief period of ischaemia (eg 3 cycles of 5 minutes of an arm tourniquet above systolic pressure, followed by 5 minute deflations) can protect the rest of the body from subsequent ischaemic insults.

In the past couple of years there has been an explosion of interest in this fascinating idea and some truly exciting results from initial trials (see examples below). However, as with most new areas subsequent studies have not been quite as impressive as initial results. This seems to follow the pattern of most new findings in medicine: “It’s amazing!” followed by discovery of some setback or complication, leading to “It’s awful / useless!”, and finally “It’s OK if used in the right way for the right patients”.

The background to the discovery of ischaemic preconditioning comes from interventional cardiologists, who noted that patients who had “stuttering” myocardial infarctions seemed to do better than those who just had a single large MI.

Further work on anaesthetised dogs by Murry in the mid 1980s showed that 4 episodes of 5 minutes of coronary artery ligation before a 40 minute ligation reduced infarct size to a quarter of the size seen in the control group.

http://circ.ahajournals.org/content/74/5/1124.abstract

The ischaemia seems to produce 2 periods of protection, an early window out to 6 hours and a late window out to around 72 hours.

Since then studies have emerged showing that a protective effect occurs even if the organ rendered initially ischaemic is not the organ which suffers the final insult – in fact it appears that arm or leg ischaemia can protect the heart, lungs and kidneys. This is termed remote ischaemic preconditioning. What I like about this technique is that most attempts to protect the heart so far have been drug based and very one dimensional, relying on say beta blockers or statins to target a certain receptor. This technique harnesses an intrinsic protective mechanism, rather than on us trying to pick a single mediator to convey benefit, the ischaemic insult releases a range of known and unknown protective substances. It would be very difficult to replicate this complex soup with a drug. In addition  this is almost risk free and should avoid the nasty surprises such as the finding of increased stroke and mortality found in the POISE trial which has halted the enthusiasm for beta blockers.

The study which first kicked off interest in this area was from 2007 by Hausenloy et al. 57 CABG patients were randomising to RIPC via an arm tourniquet and were found to have a 43% reduction in post operative troponin release.http://www.sciencedirect.com/science/article/pii/S0140673607612963

Also in 2007 a RCT by Ziad in 82 patients having open AAA repair showed that 2 cycles of 10 minutes of common iliac artery clamping prior to aortic crossclamping reduced MI from 27% to 5% and renal impairment from 30% to 7% compared to control.

http://circ.ahajournals.org/content/116/11_suppl/I-98.short

A recent meta-analysis of RIPC for CABG incorporating 10 studies and 693 patients showed a reduction in troponin release, however the studies with better blinding showed a smaller effect size, suggesting the benefit may be lower than original trials suggested.

Another meta-analysis of 17 cardiac and vascular trials showed a reduction in markers of myocardial injury, a reduction in MI (7.9% vs 13%) and (for AAA repair) a reduction in renal injury. There was no evidence of publication bias.

http://www.ncbi.nlm.nih.gov/pubmed/22294530

RIPC also appears to have some effect in preventing contrast nephropathy in 100 patients with renal impairment having coronary angiography, with renal injury rates of 40% in control vs 12% in RIPC. This has implications for ICU patients requiring contrast CT scans.

http://circ.ahajournals.org/content/early/2012/06/25/CIRCULATIONAHA.112.096370.short

Finally, a study just out in Anesthesiology looked at 62 patients having elective infrarenal AAA repair and found an improved a/A ratio and improved markers in intestinal injury in the RIPC group compared with control

http://europepmc.org/abstract/MED/23353795/reload=0;jsessionid=K8cOgeieWh27t1SMmKZ5.2

Of interest, a dose finding study is currently underway in Australia and NZ looking at defining the optimum “dose” of RIPC for best benefit.

There are some other interesting implications of RIPC. There has been a recent trend to orthopaedic surgeons doing knee replacements without tourniquets. Could this “improvement” in fact lead to worsening post-op outcomes due the loss of protection from myocardial ischaemia in the highest risk 72 hours post operatively, the “late” RIPC protection time?

In summary RIPC offers the latest hope in achieving the holy grail of anaesthesia- reducing post operative cardiovascular complications. The biggest advantage of RIPC over previous attempts, such as beta blockers, widespread preoperative revascularisation and regional techniques is simplicity and lack of harm. It’s hard to envisage anything bad coming from some brief cycles of tourniquet inflation and as the Lancet summarised it, it might mean “an arm and a leg can save the heart”.

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