Full steam ahead with remote ischemic conditioning for stroke.

The finding that brief periods of ischemia can protect tissues from later ischemic damage (ischemic preconditioning, IPC; 1, 2) has engendered much research into underlying mechanisms 3-5, but also a debate as to how to translate these findings to the clinic 6-11. This was a focus of the 2nd Translational Preconditioning meeting held in Miami in 2012 12 and likely to be a major focus of the 3rd meeting to be hosted by Dr. John Zhang in Los Angeles in 2014. Although preconditioning can be induced by many stimuli other than ischemia 13, 14, the finding that brief periods of tissue ischemia can induce protection in other tissues (so-called remote ischemic preconditioning, RIPC) has generated the most clinical interest. Thus, for example, brief periods of limb ischemia may protect the brain and heart from later ischemic damage 15-18. Because of relative simplicity (repeated inflation of a cuff around arm or leg) and perceived safety, this has become the stimulus of choice for examining whether preconditioning has clinical utility. This has led to a plethora of clinical trials, with Clinical Trials.gov currently listing 55 and 12 trials focused on cardio- and neuro-protection, respectively. It really is full steam ahead with RIPC and there also trials of remote ischemic per- and post-conditioning (where the cuff is inflated during 19, 20 or after the ischemic event; 21). In brain, there has been discussion over the best neurological conditions in which to test RIPC 6-11 and clinical trials have focused on a range of conditions. Thus, there are those focusing on the effects of RIPC on neurological complications following cardiac surgery (NCT01835392; NCT00877305), neurosurgery (NCT00866489, NCT 01654666, NCT01175876), subarachnoid hemorrhage (NCT01158508, NCT01110239) and ischemic stroke (NCT 00975962 – remote ischemic preconditioning; NCT01672515 – remote ischemic post-conditioning). While these trials have focused on relative short-term neuroprotection by RIPC, others have focused on the effects of RIPC on patients with underlying cerebrovascular disease, examining stroke occurrence and hemodynamic parameters (NCT01658306, NCT 01321749, NCT01570231). Data on a number of these trials have now been published. Meng et al. 22 examined the effects of twice daily RIPC for 300 days (a herculean effort) on the recurrence of stroke in patients with symptomatic atherosclerotic intracranial arterial stenosis. They found that RIPC (bilateral arm) reduced recurrent stroke from 7.9 to 5%. Hougaard et al. 20 examined the effect of remote ischemic preconditioning in ischemic stroke patients undergoing thrombolysis. They found no overall benefit on clinical outcome at 3 months but did find a reduced tissue risk of infarction. Koch and Gonzalez have been examining the effects of RIPC in relation to subarachnoid hemorrhage and have shown general safety and some biochemical evidence of efficacy 23, 24. While the clinical effects of RIPC on brain in relation to stroke are only now being investigated, there has been a much greater history of clinical trials of RIPC in the heart (for recent reviews see 25, 26). The results of those trials have been inconsistent, with no definitive proof of benefit. These inconsistent outcomes suggest there may be icebergs that brain RIPC may need to avoid. A major concern in the cardiac field has been the potential effects of anesthesia on RIPC efficacy in relation to surgery 25-27. Volatile anesthetics (e.g. isoflurane) can induce preconditioning and, therefore, patients treated with this anesthetic may not be further preconditioned with RIPC 25. There has been a particular concern over the use of propofol for cardiac surgery and whether that anesthetic blocks RIPC 28. Beta-blockers are also used in cardiac surgery and there is evidence that they may block the effects of RIPC 26. Such effects may complicate the assessment of RIPC in patients that will undergo anesthesia. In the cardiac field, there are concerns over the potential interaction of RIPC with currently approved therapies, such as cardioplegia, hypothermia and potassium chloride, which may reduce efficacy 25. With the dearth of clinically approved treatments for stroke, this is not such a concern for acute neuroprotection. Hougaard et al. 20 have examined the effect of remote perconditioning as an adjunct therapy for thrombolysis in ischemic stroke patients and found some limited evidence of protection (see above). Whether there is any interaction between RIPC and treatments designed to prevent stroke occurrence is largely unstudied. A concern in both the heart and brain field is that some patients may be already preconditioned, limiting the effect of applied RIPC. Examples of such potential preconditioning include the effects of surgical incisions 25 and underlying vascular disease. Recently, Connolly et al. 29 found that patients with pre-existing arterial peripheral vascular disease may be protected from acute ischemic stroke. This might be a result of limb hypoperfusion having similar effects to RIPC. There are still concerns about the impact of comorbid conditions on the efficacy of ischemic preconditioning and possibly RIPC. In particular, studies suggesting that aging reduces the efficacy of preconditioning 30 are a concern considering that stroke occurrence increases in the elderly. One reason for studying RIPC in subarachnoid hemorrhage is that it generally occurs in younger individuals than ischemic stroke 31. Another concern has recently been raised in the heart at the opposite end of the age spectrum. Schmidt et al. 32 found that prior RIPC increased rather than reduced myocardial injury in the isolated neonatal rabbit. This finding merits further investigation in relation to the use of RIPC for neonatal heart surgery and if ever RIPC were considered for babies at risk for cerebral hypoxia/ischemia at birth. While clinical trials on RIPC are full steam ahead, there continues to be a relative dearth of preclinical studies (~25 studies since 2006). This may be a case of waiting to see how clinical trials fare, but such preclinical studies could help to inform such trials. Greater elucidation of the mechanisms underlying RIPC may help in understanding how co-morbidities and clinical practice (e.g. anesthetics) could impact the effectiveness of RIPC. In short, this is an exciting time for research in remote ischemic preconditioning. However, definitive clinical evidence of the efficacy of this approach is still in the future and there may be a number of icebergs to avoid in pursuing that goal.