Remote Ischaemic Conditioning and Critical Care
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Remote Ischaemic Conditioning and Critical Care by Paul Young. Paul delves into the pitfalls of clinical research. Coda Podcasts.
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Remote Ischaemic Conditioning and Critical Care
- 1. the magic of remote ischaemic preconditioning
- 3. Slide on regional two ways to give a dog a heart attack
- 4. block coronary artery unblock coronary artery measure size of infarct
- 5. block coronary artery unblock coronary artery measure size of infarct Ischaemia / reperfusion cycles
- 6. Method B gives the dog a smaller heart attack
- 7. Warm-up angina Pre-infarct angina Cross clamp fibrillation
- 9. Early work
- 10. Transient renal ischaemia protects the heart!
- 12. The breakthrough
- 13. Reproducible No one knows how it works Fundamental unknowns
- 15. My Trial
- 16. Patients allocated to RIPC had higher troponin levels
- 17. Meta-analysis
- 19. 2 NEJM papers
- 20. A JAMA paper
- 21. A Lancet paper
- 22. 1. What the patient can do 2. How the patient feels 3. Whether the patient is alive 4. Does it save money all that matters
- 23. be sceptical; changes in secondary end points are hypothesis generating
- 26. 1.Heart surgery 2.PCI 3.CVA with thrombolysis or clot retrieval 4.Vascular surgery 5.Hypoxic ischaemic encephalopathy 6.Organ transplantation
- 27. STEMI
- 28. 1. Don’t believe single-centre studies 2. Always think about biological plausibility 3. Treat findings in secondary endpoints as hypothesis generating 4. Don’t be misled by surrogate endpoints
Editor's Notes
- I have been asked to speak about remote ischaemic preconditioning. I have been involved in clinician research for 5 and a half years and my first RCT investigated RIPC. So, RIPC has a special place in my heart and much of what I now believe about clinical research is a reflection of the things I learnt conducting research in this area. When I first qualified as a specialist 6 years ago I had gone through the same evolution that all other doctors go through. I had started off as a medical student. Begun working as a junior doctor who did not know anything and even had to look up the dose of paracetamol. Become a specialist trainee and learnt how to make similar decisions to people around me and then qualified as a specialist who ‘knew’ more or less how to deal with most problems in ICU. It is at this point that I started to take the path less trodden and started to the road towards being a ‘clinician-scientist’
- As a clinician scientist I have increasing come to understand that much of our practice is dogmatic. I have come to believe that those who think they ‘know’ are living in Wonderland. RIPC has helped me understand how we come to believe things and how, as human beings, we love to believe in fantastic things. Fundamentally I have come to believe that the more questions you ask, the more you will understand how we know much less than we are trained to think we do. Today I am going to use the example of RIPC to tell you a few things that I think are fundamental truths but before I do I need to tell you more about RIPC. The story really begins with ischaemic preconditioning and, as it happens, the story started 30 years ago at Duke University, North Carolina. It started with scientists comparing...
- Two ways to give a dog a heart attack. They studied a total of 12 dogs.
- For five dogs they simply occluded (click) the circumflex coronary artery for 40 minutes (click) and then measured the size of the infarct 4 days later (click). Let’s call this Method A of causing a heart attack.
- For the other 7 dogs they performed the same circumflex coronary occlusion (click) but before they did so they performed 4 cycles of 5 minutes of occlusion and 5 minutes of reperfusion of the same artery (click). Let’s call this method B.
- Paradoxically they showed that although method B involved one and half times the ischaemic time of method A, method B gave the dog an infarct of around a quarter of the size of method A. They called this ischaemic preconditioning and this study of 12 dogs has been cited nearly 9000 times since it was published 30 years ago.
- Ischaemic preconditioning is thought to explain the following clinical phenomena. Firstly, it explains why patients with coronary artery disease sometimes experience warm-up angina. Warm-up angina is when the patient with stable angina gets angina when they exercise first thing in the morning but later on in the day the same level of exercise does not induce angina. Pre-infarct angina refers to the observation that angina before and MI seems to limit the severity of the subsequent MI (although this phenomenon may also be explained by the development of collaterals) And finally, ischaemic preconditioning may have been being utilised through serendipity by cardiac surgeons since before it was ‘discovered’. Specifically, the technique of intermittent cross clamp fibrillation for coronary artery bypass graft surgery. This is an alternate to stopping the heart with cardioplegia. It works like this. Firstly the surgeon puts a cannula in the aorta and a venous cannula in. Next, they put the patient on cardiopulmonary bypass and cross clamp the aorta and fibrillate the heart. While the heart is fibrillating they perform the distal anastamosis. Next, they take off the aortic cross clamp which allow blood to flow into the coronary arteries. They defibrillate the heart and the heart starts beating. Now remember, they are still on full bypass at the this time so the heart is empty and does not eject. They put a side clamp on the aorta and perform the proximal anastamosis. They cross clamp again, fibrillate and perform the next distal anastamosis. The global myocardial ischaemia that occurs with intermittent cross clamp fibrillation reduces ischaemic myocardial injury and reduces inotrope requirements.
- Remote ischaemic precondition is the magical cousin of ischaemic preconditioning and was first described in animal models in 1993.
- The first experimental evidence of remote ischaemic preconditioning was obtained when it was shown that temporary occlusion of the circumflex coronary artery in a dog reduced myocardial infarction size from subsequent occlusion of the LAD. Now this is not that remote but in the same year, published only in abstract form was a study in rabbits...
- Here transient renal ischaemia was shown to precondition the heart to subsequent prolonged ischaemia.
- Many experiments followed demonstrating such impractical things as myocardial protection from carotid ligation and mesenteric ischaemia proconditioning the heart. In this graph dotted lines represent remote ischaemic preconditioning to protect the heart while solid lines represent other forms of interorgan protection.
- The real breakthrough for this technique came in 2003 when it was demonstrated that transient limb ischaemia proconditioned the heart and the ‘endothelial dysfunction’ induced by 20 minutes of upper limb ischaemia in humans could be prevented by episodes of transient occlusion of blood flow to the opposite arm with a blood pressure cuff. This led to remote ischaemic preconditioning that could be used in clinical practice – 3 or 4 cycles of five minutes of ischaemia and reperfusion induced with a blood pressure cuff inflated to 200mmHg. When I started designing my trial there were a few small trials about. I decided to investigate RIPC in the sickest patients because it seemed to me like these were the patients who you might expect to be most likely to benefit. I conducted one of the first double-blind trials. When I was designing the trial I learnt a few things.
- RIPC is a readily reproducible phenomenon in experimental models. Much of the basic science literature consists of measuring lots of different things in experiments with small sample sizes. As a result there are lots of significant p values and, for me at least, no unified paradigm that explains how this works. There are many fundamental unknowns. Why use the arm? Why not the leg? The leg is bigger. Why do three cycles of five minutes? Fundamentally the correct dose of therapy is undefined
- Despite nearly 1000 RIPC papers on pubmed we still don’t where to do RIPC (arm or leg), how to do it, when to do it or who to do it on.
- Anyway, getting back to my trial...we conducted our trial in 96 adults having various high risk cardiac surgical operations and found, for the first time that remote ischaemic preconditioning was associated with harm. Our primary end point was based on hsTNT levels and...
- We found that patients allocated to RIPC had higher troponin levels than patients who did not receive RIPC.
- After this unexpected finding I conducted a SR and meta-analysis. I discovered signficant heterogeneity between trials. This means that the results were not consistent from one trial to another. When we looked for potential explanations for heterogeneity we found that it could be accounted for by the presence or absence of blinding. If there was blinding the trials showed no effect (or harm); unblinded trials showed that RIPC reduced troponin.
- Since my trial there have been a number of high impact trials that have substantially advanced our understanding
- Two large-scale multicentre double-blind RCTs have shown that RIPC does not affect troponin levels or clinical end points in patients have cardiac surgery with cardiopulmonary bypass. Both of these papers were published in the NEJM last year. As a told you no one knows how remote ischaemic preconditioning works so it is perhaps no surprise that no one knows why it did not work either. The believers speculate that propofol ‘blocks’ ischaemic preconditioning but this believe is supported by very little data.
- Another high impact paper that you may have seen is this one from JAMA. In this study they looked at AKI risk in high risk cardiac surgery and showed that RIPC significantly reduce AKI. Now I have already told you that the larger NEJM papers did not confirm these findings but the interesting thing about renal failure and RIPC is that a recent meta-analysis also showed RIPC reduced AKI. However, in its primary analysis this meta-analysis showed that RIPC used ‘investigator defined AKI’ but when the same studies were analysed looking at serum creatinine levels or standardised (rather than investigator defined) definitions of AKI there was absolutely no effect whatsoever.
- The final high impact paper was again small but illustrates some important points. This study involved 329 patients undergoing CABG surgery and showed that the area under the curve for troponin was 60ng/ml (over three days) less in the RIPC group. 60ng/ml. This is a small difference in a surrogate end point. There are many examples in the ICU literature of how surrogates mislead us. Controlling blood sugar worsens outcomes, reducing ICP with decompressive craniectomy worsens outcomes.
- In the Lancet study the mortality was significantly lower in the RIPC group but many of the small number of deaths that occurred happened late and were not conceivably related to the intervention.
- If you only remember one thing about this talk it is that you should be sceptical about changes in secondary end points. These changes are hypothesis-generating.
- Now, so far, I have described remote ischaemic preconditioning as something administered BEFORE the onset of ischaemia. However, there are two distinct injuries to consider. One is the ischaemic insult; the other is the reperfusion insult. In experimental models this technique is as effective when administered after ischaemia as it is when administered before ischaemia.
- In other words this technique is really remote reperfusion preconditioning. It may even work when applied around the time of reperfusion rather than before it. So, now, we have a technique that can easily applied with a blood pressure cuff, and might be useful for any clinical scenario where there is ischaemia/reperfusion injury that can be applied with or before reperfusion occurs.
- This means that potential uses for this technique might include: 1. Heart surgery with cardiopulmonary bypass 2. Planned PCI 3. Primary PCI for STEMI 4. CVA with lysis or clot retrieval 5. Carotid endarterectomy surgery 6. Hypoxic ischaemic encephalopathy 7. Organ transplantation 8. AAA surgery
- STEMI is the most promising indication for this technique. At this stage we are at the point of small studies. The first was published in 2010. As at the end of 2015 there were 7 studies. All favour RIPC but the primary end points are surrogates and the largest trial has 519 participants. A 4,300 participant RCT with a composite end point of cardiac death OR hospitalisation for heart failure at 12 months is ongoing. This trial will be interesting. The other indications that I have mentioned are, excepting very small single centre studies, are largely unstudied at the moment.
- As I have evolved from a clinician to a clinician researcher I have learnt: 1. don’t believe single centre studies 2. always think about biological plausibility; the most ‘interesting and surprising’ findings are the least likely to be true 3. findings in secondary end points are hypothesis-generating 4. surrogate end points are very often misleading.
- Maybe remote ischaemic preconditioning we will find a therapeutic use for RIPC but, on the other hand it is very possible that unbridled enthusiasm, coupled with a multitude of small studies which feature flexible designs, small effects, an absence of universally agreed upon definitions, and a multitude of incoherent proposed mechanisms, may have all contributed to the irreproducibility of results. Like most magic the promise of RIPC might just be an illusion.