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Remote Ischemic Conditioning

Number: 0814



Policy

Aetna considers remote ischemic conditioning experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness has not been established:

  • Cardiac, cognitive, pulmonary and renal protection during cardiac surgery (e.g., percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)), endovascular aneurysm repair, spinal surgery, or stroke
  • Enhancement of renal function after kidney transplantation
  • Treatment of aneurysmal subarachnoid hemorrhage
  • Treatment of myocardial infarction
  • Treatment of primary graft dysfunction following lung transplantation
  • Treatment of spinal cord injury
  • Treatment of tourniquet-related ischemic damage in orthopedic surgery
  • Treatment of traumatic brain injury
Background

Coronary heart disease (CHD) is the leading cause of death in the United States.  Its major pathophysiological manifestation is acute myocardial ischemia reperfusion injury.  Innovative treatment strategies for protecting the myocardium against the detrimental effects of this form of injury are needed to improve clinical outcomes in patients with CHD.  In this regard, harnessing the endogenous protection elicited by the heart's ability to “condition” itself, has recently emerged as a powerful new strategy for limiting myocardial injury, preserving left ventricular systolic function and potentially improving morbidity and mortality in patients with CHD.  “Conditioning” the heart to tolerate the effects of acute ischemia reperfusion injury can be initiated through the application of several different mechanical and pharmacological strategies.  Inducing brief non-lethal episodes of ischemia and reperfusion to the heart either prior to, during, or even after an episode of sustained lethal myocardial ischemia has the capacity to markedly reduce myocardial injury.  Interestingly, similar levels of cardio-protection can be achieved by applying the brief episodes of non-lethal ischemia and reperfusion to an organ or tissue remote from the heart, thus obviating the need to “condition” the heart directly.  This phenomenon has been termed remote ischemic conditioning (RIC), and it can offer widespread systemic protection to other organs which are susceptible to acute ischemia reperfusion injury such as the brain, liver, intestine or kidney (Hausenloy and Yellon, 2009).

Remote ischemic conditioning is a novel technique of protection against ischemia-reperfusion injury.  It entails the use of a blood pressure (BP) cuff to generate intermittent episodes of ischemia in the arm or leg via repeated brief periods of inflation.  The objective is to promote innate protective responses, which reduce injury to the heart tissue during an evolving myocardial infarction (MI).  Protective effects on heart tissue have been reported when RIC is applied prior to (pre-conditioning), during (per-conditioning), or following (post-conditioning) a sustained myocardial ischemic event, when the conditioning occurs at a site distant from the heart, usually the upper arm (RIC).  Protective effects appear in 2 stages: (i) an early effect that appears within minutes of the ischemic conditioning, and (ii) a delayed protective effect occurs within a few days of the induced ischemic conditioning.  Although the mechanism underlying this protection is not fully understood, ischemic conditioning suppresses subsequent leukocyte activation and inflammatory response to tissue injury (Saxena et al, 2010). 

Initial clinical studies reporting beneficial effects of “conditioning” the heart to tolerate acute ischemia reperfusion injury have been encouraging, however, larger multi-center randomized studies are needed to ascertain if these “conditioning” strategies are able to impact on clinical outcomes.

Hoole and colleagues (2009a) tested the hypothesis that remote ischemic pre-conditioning (RIPC) would protect the left ventricle (LV) from ischemic dysfunction.  A total of 42 patients with single-vessel coronary disease and normal LV function were prospectively recruited: 20 patients had repeated conductance catheter assessment of LV function during serial coronary occlusions with/without RIPC; and a further 22 patients underwent serial dobutamine stress echocardiography and tissue Doppler analysis with/without RIPC.  Remote ischemic pre-conditioning was induced by 3 cycles of 5-min inflations of a BP cuff around the upper arm.  This approach did not reduce the degree of ischemic LV dysfunction during coronary balloon occlusion (Tau, ms: 59.2 (2.8) versus 62.8 (2.8), p = 0.15) and there was evidence of cumulative LV dysfunction despite RIPC [ejection fraction (EF), %: 54.3 (5.8) versus 44.9 (3.7), p = 0.03].  Remote ischemic pre-conditioning did not improve contractile recovery during reperfusion (EF, %: 51.7 (3.6) versus 51.5 (5.7), p = 0.88 and Tau, ms: 55.6 (2.8) versus 56.0 (2.0), p = 0.85).  A neutral effect of RIPC on LV function was confirmed by tissue Doppler analysis of ischemic segments at peak dobutamine (V(s), cm s(-1) control: 8.2 (0.4) versus RIPC 8.1 (0.4), p = 0.43) and in recovery.  The authors concluded that RIPC does not attenuate ischemic LV dysfunction in humans.

In a prospective, randomized control trial (RCT), Hoole et al (2009b) evaluated the ability of RIPC to attenuate cardiac troponin I (cTnI) release after elective percutaneous coronary intervention (ePCI).  A total of 242 consecutive patients undergoing ePCI with undetectable pre-procedural cTnI were recruited.  Subjects were randomized to receive RIPC (induced by 3 cycles of  5-min inflations of a BP cuff to 200 mmHg around the upper arm, followed by 5-min intervals of reperfusion) or control (an uninflated cuff around the arm) before arrival in the catheter laboratory.  The primary outcome was cTnI at 24 hrs after ePCI.  Secondary outcomes included renal dysfunction and major adverse cardiac and cerebral event rate at 6 months.  The median cTnI at 24 hrs after PCI was lower in the RIPC compared with the control group (0.06 versus 0.16 ng/ml; p = 0.040).  After RIPC, cTnI was less than 0.04 ng/ml in 44 patients (42 %) compared with 24 in the control group (24 %; p = 0.01).  Subjects who received RIPC experienced less chest discomfort (p = 0.0006) and ECG ST-segment deviation (p = 0.005) than control subjects.  At 6 months, the major adverse cardiac and cerebral event rate was lower in the RIPC group (4 versus 13 events; p = 0.018).  The authors concluded that RIPC reduces ischemic chest discomfort during ePCI, attenuates procedure-related cTnI release, and appears to reduce subsequent cardiovascular events.

Hoole and associates (2009c) hypothesized that a RIPC stimulus would reduce coronary microvascular resistance (R(p)) and improve coronary blood flow during ePCI.  These researchers prospectively recruited 54 patients with multi-vessel disease (MVD; n = 32) or single-vessel disease (SVD) awaiting ePCI.  Patients with MVD had non-target vessel (NTV) index of micro-circulatory resistance (IMR) determined, before and after target vessel PCI (cardiac RIPC).  The effect of arm RIPC on serial R(p) was assessed in patients with SVD.  Target vessel balloon occlusion did not alter the NTV IMR: 16.5 (12.4) baseline versus 17.6 (11.6) post-cardiac RIPC, p = 0.65 or hyperaemic transit time.  Arm RIPC did not alter R(p) in patients with SVD: R(p), mm Hg.cm(-1).s( -1): 3.5 (1.9) baseline versus 4.1 (3.0) post-arm RIPC, p = 0.19 and coronary flow velocity remained constant.  The authors concluded that RIPC stimuli during ePCI do not affect coronary microvascular resistance or coronary flow in humans.

In a RCT, Walsh and associates (2009) examined if RIPC has the ability to reduce renal and cardiac damage following endovascular aneurysm repair (EVAR).  A total of 40 patients (all men; mean age of 76 +/- 7 years) with abdominal aortic aneurysms averaging 6.3 +/- 0.8 cm in diameter were enrolled in the trial.  Eighteen patients (mean age of 74 years, range of 72 to 81) were randomized to RIPC and completed the full RIPC protocol; there were no withdrawals.  Twenty-two patients (mean age of 76 years, range of 66 to 80) were assigned to the control group.  Remote ischemic pre-conditioning was induced using sequential lower limb ischemia.  Serum and urinary markers of renal and cardiac injury were compared between the groups.  Urinary retinol binding protein (RBP) levels increased 10-fold from a median of 235 micromol/L to 2,356 micromol/L at 24 hrs (p = 0.0001).  There was a lower increase in the RIPC group, from 167 micromol/L to 413 micromol/L at 24 hrs (p = 0.04).  The median urinary albumin:creatinine ratio was significantly lower in the RIPC group at 24 hrs (5 versus 8.8, p = 0.06).  There were no differences in the rates of renal impairment or major adverse cardiac events.  The authors concluded that RIPC reduces urinary biomarkers of renal injury in patients undergoing elective EVAR.  They noted that this small pilot trial was unable to detect an effect on clinical endpoints; further trials are needed.

In a single-center, single-blinded RCT, Venugopal et al (2009) examined if RIPC is cardio-protective in coronary artery bypass grafting (CABG) patients receiving cold-blood cardioplegia.  Adults patients (18 to 80 years) undergoing elective CABG surgery with or without concomitant aortic valve surgery with cold-blood cardioplegia were enrolled.  Patients with diabetes, renal failure (serum creatinine greater than 130 mmol/L), hepatic or pulmonary disease, unstable angina or MI within the past 4 weeks were excluded.  Participants were randomized to receive either RIPC (n = 23) or control (n = 22) after anesthesia.  Remote ischemic pre-conditioning comprised 3 cycles of  5-min right forearm ischemia, induced by inflating a BP cuff on the upper arm to 200 mmHg, with an intervening 5-min reperfusion.  The control group had a deflated cuff placed on the upper arm for 30 mins.  Serum troponin T was measured pre-operatively and at 6, 12, 24, 48 and 72 hrs after surgery and the area under the curve (AUC at 72 hrs) calculated.  Remote ischemic pre-conditioning reduced absolute serum troponin T release by 42.4 % (mean (S.D.) AUC at 72 hrs: 31.53 (24.04) microg/L 72 hrs in controls versus 18.16 (6.67) microg/L 72 hrs in RIPC; 95 % confidence interval [CI]: 2.4 to 24.3; p = 0.019).  The authors concluded that RIPC induced by brief ischemia and reperfusion of the arm reduces myocardial injury in CABG surgery patients undergoing cold-blood cardioplegia.

Ali et al (2010) examined the role of RIPC on myocardium, against ischemia reperfusion injury in patients undergoing CABG surgery by measuring creatine kinase-myocardial band (CK-MB) levels.  A total of 100 patients with double and triple vessels coronary artery disease were randomized in 2 groups of 50 each.  Protocol of RIPC consisted of 3 cycles of 5-min fore-arm ischemia, induced by a BP cuff inflated to 200 mmHg, with an intervening 5 mins of reperfusion, during which the cuff was deflated.  Patients in the control group were not subjected to limb ischemia.  The protocol of induced ischemia was completed before placing patients on extra-corporeal bypass circuit.  At the end of surgery, serum CK-MB levels were measured and compared at 8, 16, 24 and 48 hrs from both the groups.  Remote ischemic pre-conditioning significantly reduced CK-MB levels at 8, 16, 24 and 48 hrs after surgery with p-values of 0.026, 0.021, 0.052 and 0.003, respectively.  There was mean reduction of 3 International Units/L in CK-MB levels, in patients who underwent RIPC protocol prior to CABG surgery, compared to control group.  The authors concluded that these findings showed a significant reduction of enzyme marker CK-MB in patients subjected to RIPC prior to CABG surgery.  This suggests lesser degree of myocardial damage compared to control group in CABG patients.

Hong et al (2010) noted that in several recent clinical trials on cardiac surgery patients, RIPC showed a powerful myocardial protective effect.  However the effect of RIPC has not been studied in patients undergoing off-pump CABG surgery.  These investigators evaluated if RIPC could induce myocardial protection in off-pump CABG surgery patients.  Patients undergoing elective off-pump CABG surgery were randomly allocated to the RIPC (n = 65) or control group (n = 65).  After induction of anesthesia, RIPC was induced by 4 cycles of 5-min ischemia and reperfusion on the upper limb using a pneumatic cuff.  Anesthesia was maintained with sevoflurane, remifentanil and vecuronium.  Myocardial injury was assessed by troponin I before surgery and 1, 6, 12, 24, 48 and 72 hrs after surgery.  There were no statistical differences in troponin I levels between RIPC and control groups (p = 0.172).  Although RIPC reduced the total amount of troponin I (area under the curve of troponin increase) by 26 %, it did not reach statistical significance (RIPC group 53.2 +/- 72.9 hrs x ng/ml versus control group 67.4 +/- 97.7 hrs x ng/ml, p = 0.281).  In this study, RIPC by upper limb ischemia reduced the post-operative myocardial enzyme elevation in off-pump CABG surgery patients, but this did not reach statistical significance.  The authors concluded that further study with a larger number of patients are needed to fully evaluate the clinical effect of RIPC in off-pump CABG surgery patients.

Botker et al (2010) tested the hypothesis that RIPC during evolving ST-elevation MI (STEMI), and done before primary PCI (pPCI), increases myocardial salvage.  A total of 333 consecutive adult patients with a suspected first acute MI were randomly assigned in a 1:1 ratio to receive pPCI with (n = 166) versus without (n = 167) remote conditioning (intermittent arm ischemia through 4 cycles of 5-min inflation and 5-min deflation of a BP cuff).  Patients received remote conditioning during transport to hospital, and pPCI in hospital.  The primary end point was myocardial salvage index at 30 days after pPCI, measured by myocardial perfusion imaging as the proportion of the area at risk (AAR) salvaged by treatment; analysis was per protocol.  A total of 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index.  Median salvage index was 0.75 (inter-quartile range of 0.50 to 0.93, n = 73) in the remote conditioning group versus 0.55 (0.35 to 0.88, n = 69) in the control group, with median difference of 0.10 (95 % CI: 0.01 to 0.22; p = 0.0333); mean salvage index was 0.69 (standard deviation [SD] 0.27) versus 0.57 (0.26), with mean difference of 0.12 (95 % CI: 0.01 to 0.21; p = 0.0333).  Major adverse coronary events were death (n = 3 per group), re-infarction (n = 1 per group), and heart failure (n = 3 per group).  The authors concluded that ischemic conditioning before hospital admission increases myocardial salvage, and has a favorable safety profile.  They stated that these findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes.

Munk et al (2010) evaluated the short-term effects of RIC on LV function.  Patients with a first STEMI were randomized to RIC (4 cycles of 5-min upper-limb ischemia) during transfer to pPCI (n = 123) versus pPCI alone (n = 119).  Ejection fraction, LV volumes, (2D and 3D echocardiography and myocardial perfusion imaging), and speckle-tracking global longitudinal strain were compared between treatment groups.  There was no significant difference in LV function at day 1 (EF-2D, 0.51 +/- 0.10 versus 0.49 +/- 0.10; p = 0.22) and after 30 days (EF-2D, 0.54 +/- 0.08 versus 0.53 +/- 0.10) between the RIC and the pPCI-alone groups.  In patients with extensive AAR greater than or equal to 35 % of LV (n = 53), EF after 30 days was higher after RIC than after pPCI alone (EF-2D, 0.51 +/- 0.07 versus 0.46 +/- 0.09; p = 0.05).  In patients with anterior infarction (n = 97), RIC preserved LV function on day 1 (EF-2D, 0.51 +/- 0.11 versus 0.46 +/- 0.11; p = 0.03) and persistently after 30 days (EF-2D, 0.55 +/- 0.08 versus 0.50 +/- 0.11; p = 0.04; EF-myocardial perfusion imaging, 0.55 +/- 0.10 versus 0.49 +/- 0.12; p = 0.02).  These patients had similar AAR, whereas RIC reduced infarct size from 16 % to 7 % of LV (p = 0.01).  The authors concluded that although no significant overall effect was observed, RIC seemed to result in modest improvement in LV function in high-risk patients prone to develop large myocardial infarcts.  They stated that these results need to be confirmed in larger trials.

Venugopal and colleagues (2010) examined the effect of RIPC on acute kidney injury in non-diabetic patients undergoing CABG surgery.  A total of 78 consenting selected subjects were included in this study -- RIPC consisted of 3 cycles of 5-min right forearm ischemia, induced by inflating a BP cuff on the upper arm to 200 mmHg, with an intervening 5 mins of reperfusion, during which time the cuff was deflated.  The control consisted of placing an uninflated cuff on the arm for 30 mins.  Major outcomes assessed were acute kidney injury (AKI) measured using Acute Kidney Injury Network (AKIN) criteria, duration of hospital stay, in-hospital and 30-day mortality.  Numbers of participants with AKI stages 1, 2, and 3 were 1 (3 %), 3 (8 %), and 0 in the intervention group compared with 10 (25 %), 0, and 0 in the control group, respectively (p = 0.005).  The decrease in AKI was independent of the effect of concomitant aortic valve replacement and cross-clamp times, which were distributed unevenly between the 2 groups.  The limitations of this study were: (i) retrospective analysis of data, and (ii) more patients in the RIPC group underwent concomitant aortic valve replacement with CABG; although the authors had corrected statistically for this imbalance, it remains an important confounding variable.  The authors concluded that RIPC induced using transient forearm ischemia decreased the incidence of AKI in non-diabetic patients undergoing elective CABG surgery in this retrospective analysis.  Moreover, they stated that a large prospective clinical trial is needed to study this effect and clinical outcomes in patients undergoing cardiac surgery.

Hu and colleagues (2010) examined if a large clinical trial testing the effect of RIPC on neurological outcome in patients undergoing spine surgery is warranted.  A total of 40 adult cervical spondylotic myelopathy patients undergoing elective decompression surgery were randomly assigned to either the RIPC group (n = 20) or the control group (n = 20).  Limb RIPC consisted of 3 cycles of 5-min upper right limb ischemia with intervening 5-min periods of reperfusion.  Neuron-specific enolase and S-100B levels were measured in serum at set time points.  Median nerve somatosensory-evoked potentials (SEPs) were also recorded.  Neurological recovery rate was evaluated using a Japanese Orthopedic Association scale.  Remote ischemic pre-conditioning significantly reduced serum S-100B release at 6 hrs and 1 day after surgery, and reduced neuron-specific enolase release at 6 hrs, and then at 1, 3, and 5 days after surgery.  No differences were observed in SEP measurements or the incidence of SEP changes during surgery between the control and RIPC groups.  Recovery rate at 7 days, and at 1 and 3 months after surgery was higher in the RIPC group than in the control group (p < 0.05).  The authors concluded that these findings for markers of neuronal ischemic injury and rate of recovery suggest that a clinical trial with sufficient statistical power to detect an effect of RIPC on the incidence of neurological complications (e.g., paresis, palsy, etc) due to spinal cord ischemia-reperfusion injury after spine surgery is warranted.

Bein and Meybohm (2010) stated that recent demographical developments challenge anesthesiologists with an increasing number of elderly patients with cardiovascular co-morbidities undergoing major surgery.  Interventions that are capable to increase tissue tolerance against ischemia are of paramount importance.  In this context, conditioning is defined as a mechanism that fosters tissue by specific adaptive processes to develop tolerance against a subsequent ischemia.  Dependent upon the temporal relationship between the intervention and the index ischemia, pre-conditioning is differentiated from post-conditioning.  Ischemia induced in tissue remote from the target organ is called remote pre-conditioning.  Both brief periods of ischemia as well as volatile anesthetics and opioids are able to trigger conditioning.  On a cellular level, ATP-dependent potassium channels and the mitochondrial permeability transition pore are thought to be key effectors.  Effective conditioning has been demonstrated for various tissues in animal experiments.  Clinical trials in patients undergoing cardiac surgery have provided evidence for organ protection by conditioning.  The authors stated that large scale multi-center randomized trials, however, are still needed.

In the position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology on “Post-conditioning and protection from reperfusion injury”, Ovize et al (2010) noted that ischemic post-conditioning (brief periods of ischemia alternating with brief periods of reflow applied at the onset of reperfusion following sustained ischemia) effectively reduces size of MI  in all species tested so far, including humans.  Ischemic post-conditioning is a simple and safe maneuver, but because reperfusion injury is initiated within minutes of reflow, post-conditioning must be applied at the onset of reperfusion.  The mechanisms of protection by post-conditioning include: formation and release of several autacoids and cytokines; maintained acidosis during early reperfusion; activation of protein kinases; preservation of mitochondrial function, most strikingly the attenuation of opening of the mitochondrial permeability transition pore (MPTP).  Exogenous recruitment of some of the identified signaling steps can induce cardio-protection when applied at the time of reperfusion in animal experiments, but more recently cardio-protection was also observed in a proof-of-concept clinical trial.  Indeed, studies in patients with an acute MI showed a reduction of infarct size and improved LV function when they underwent ischemic post-conditioning or pharmacological inhibition of MPTP opening during interventional reperfusion.  The authors stated that further animal studies and large-scale human studies are needed to determine whether patients with different co-morbidities and co-medications respond equally to protection by post-conditioning.  Also, the underlying mechanisms must be better understood to develop new therapeutic strategies to be applied at reperfusion with the ultimate aim of limiting the burden of ischemic heart disease and potentially providing protection for other organs at risk of reperfusion injury, such as brain and kidney.

In a health technology assessment on RIC, the Canadian Agency for Drugs and Technologies in Health (CADTH, 2010) identified 1 systematic review and meta-analysis that included 4 RCTs and 8 additional RCTs that met the inclusion criteria.  Remote ischemic conditioning has been studied mostly in a pre-operative setting when the risk of experiencing an ischemic event is high.  Only 2 studies were found that applied remote conditioning induced with limb ischemia in patients experiencing an acute MI.  Mostly surrogate outcomes were measured.  In the pre-conditioning studies, only 2 studies reported morbidity outcomes.  The cardiac remote ischemic pre-conditioning in coronary stenting (CRISP Stent) study (Hoole et al, 2009b) showed that RIPC patients had statistically significantly less chest pain during stenting, and that the rate of major adverse cardiac and cerebral events were statistically significant lower at 6 months.  The study by Walsh et al (2009) showed no statistically significant differences in cardiac outcomes between groups.  Similarly, a per-conditioning study (Bøtker et al, 2010) reported no statistically significant differences in cardiac outcomes between groups.  The CADTH concluded that more studies measuring short-term as well as long-term morbidity and mortality are needed to ascertain the clinical effectiveness of remote conditioning in any clinical setting.

Ingenix Health Technology Pipeline's review on RIC (2010) stated that this approach has the potential for broad organ protection and is under investigation for diverse indications such as cognitive protection during CABG, renal or pulmonary protection during bypass surgery, and effects on survival after organ transplantation.  Many clinical studies are underway to determine whether RIC provides myocardial protection in various circumstances, including CABG and PCI.

Lavi and Lavi (2011) noted that ischemic pre-conditioning was demonstrated in animals more than 20 years ago, and subsequent studies in humans showed a dramatic protective effect on the heart.  This method did not translate into clinical practice partially due to difficulty in application of conditioning.  At the same time, multiple drugs were assessed, but none proved to be beneficial in large-scale studies for myocardial protection.  Although multi-center RCTs are still lacking, it was recently demonstrated in reasonable sized studies that in patients undergoing PCI or suffering from myocardial infarction, RIC has beneficial protective effect.  The authors noted that with more studies one may see translation into clinical practice in the near future.

The American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines' report on "Coronary artery bypass graft surgery" (Hillis et al, 2011) noted that (i) remote ischemic pre-conditioning strategies using peripheral-extremity occlusion/reperfusion might be considered to attenuate the adverse consequences of myocardial re-perfusion injury (Class IIb Recommendation; Level of Evidence: B [recommendation's usefulness/efficacy less well-established; greater conflicting evidence from single randomized trial or non-randomized studies]); and (ii) the effectiveness of post-conditioning strategies to attenuate the adverse consequences of myocardial re-perfusion injury is uncertain (Class IIb Recommendation; Level of Evidence: C [recommendation's usefulness/efficacy less well-established; only diverging expert opinion, case studies, or standard of care]).

Hahn and colleagues (2012) examined if remote ischemic per-conditioning may provide neuroprotection in a clinically relevant rat model of acute ischemic stroke.  Remote ischemic conditioning by transient limb ischemia was used in a rat transient middle cerebral artery occlusion model of acute stroke.  A total of 39 P60 rats were randomly allocated to receive pre-conditioning, per-conditioning, or sham conditioning.  Cerebral ischemia was maintained for 120 mins followed by reperfusion.  The resulting infarct size at 24 hours was quantified using computerized image analysis of 2-3-5-triphenyl tetrazolium chloride-stained brain sections.  Compared with control, both pre- and per-conditioning significantly reduced brain infarct size with the more clinically relevant per-conditioning stimulus being superior to pre-conditioning.  The authors concluded that remote per-conditioning by transient limb ischemia is a facile, clinically relevant stimulus that provides potent neuroprotection in a model of regional brain ischemia-reperfusion injury.  They stated that further studies are needed to better- understand the mechanisms and biology of this response before translation to RCTs of remote per-conditioning for acute ischemic stroke.

Veighey and Macallister (2012) stated that ischemia-reperfusion injury is a composite of damage accumulated during reduced perfusion of an organ or tissue and the additional insult sustained during reperfusion.  Such injury occurs in a wide variety of clinically important syndromes, such as ischemic heart disease and stroke, which are responsible for a high degree of morbidity and mortality worldwide.  Basic research has identified a number of interventions that stimulate innate resistance of tissues to ischemia-reperfusion injury.  These researchers summarized the experimental and clinical trial data under-pinning one of these "conditioning" strategies, the phenomenon of remote ischemic pre-conditioning.

Brevoord et al (2012) performed a systematic review and meta-analysis to investigate whether RIC reduces mortality, major adverse cardiovascular events, length of stay in hospital and in the intensive care unit and biomarker release in patients who suffer from or are at risk for ischemia re-perfusion injury.  Medline, EMBASE and Cochrane databases were searched for RCTs comparing RIC, regardless of timing, with no conditioning.  Two investigators independently selected suitable trials, assessed trial quality and extracted data.  A total of 23 studies in patients undergoing cardiac surgery (15 studies), PCI (4 studies) and vascular surgery (4 studies), comprising in total 1,878 patients, were included in this review.  Compared to no conditioning, RIC did not reduce mortality (odds ratio 1.22 [95 % CI: 0.48 to 3.07]) or major adverse cardiovascular events (0.65 [0.38 to 1.14]).  However, the incidence of MI was reduced with RIC (0.50 [0.31 to 0.82]), as was peak troponin release (standardized mean difference -0.28 [-0.47 to 0.09]).  The authors concluded that there is no evidence that RIC reduces mortality associated with ischemic events; nor does it reduce major adverse cardiovascular events.  However, RIC did reduce the incidence of peri-procedural MI, as well as the release of troponin.

Alreja and colleagues (2012) evaluated the effect of RIPC on the incidence of myocardial and renal injury in patients undergoing cardiovascular interventions as measured by biomarkers.  Clinical data were pooled to evaluate the usefulness of RIPC to benefit clinical outcomes.  Systematic review and meta-analysis of prospective RCTs of patients undergoing cardiovascular interventions who received RIPC versus control were performed.  Two independent reviewers selected articles from MEDLINE, EMBASE, SCOPUS, Cochrane, ISI Web of Science, and BIREME, and through hand search of relevant reviews and meeting abstracts upon agreement.  Surrogate markers of myocardial (troponin T or I and CK-MB) and renal (serum creatinine) injury for primary outcomes were abstracted.  Final pooled analysis from 17 clinical trials showed significant heterogeneity of results and no relevant publication bias.  Patients receiving RIPC had lower levels of markers of myocardial injury in the first few days after surgery (standardized mean difference [SMD], 0.54; 95 % CI: -1.01 to -0.08; p = 0.01) with highly heterogeneous results (I2 = 93 %).  A lower incidence of peri-operative MI (7.9 % RIPC versus 13.9 % placebo; risk ratio [RR], 0.56; 95 % CI: 0.37 to 0.84; p = 0.005; I2 = 0 %) was also noted.  In patients undergoing abdominal aortic aneurysm repair, RIPC when compared to control also decreased renal injury (SMD, 0.28; 95 % CI: -0.49 to -0.08; p = 0.007; I2 = 51 %).  The authors concluded that RIPC appears to be associated with a favorable effect on serological markers of myocardial and renal injury during cardiovascular interventions.  Moreover, they stated that larger trials should be conducted to substantiate this initial impression.

Yetgin et al (2012) stated that although RIC by transient limb ischemia in PCI and CABG has shown favorable effects on myocardial (ischemia-reperfusion) injury, recent trials provided inconsistent results.  These investigators assessed the effect of RIC in PCI or CABG.  Medline/Embase/conference reports were searched for randomized RIC trials and were included if they reported on biomarkers of myocardial injury (CK-MB/troponin T/I), after which, standardized mean differences (SMDs) were calculated (Hedges g statistic).  Meta-analysis of 4 studies on PCI, involving 557 patients, indicated reduced biomarkers for myocardial injury with RIC compared to control (random effects model: SMD, -0.21; 95 % CI: -0.66 to 0.24).  Analysis of primary PCI studies, involving 314 patients, indicated a highly significant positive effect of RIC on myocardial injury (SMD, -0.55; 95 % CI: -0.77 to -0.32).  The 13 CABG studies taken together, involving 891 patients, indicated a significant effect of RIC on myocardial injury (SMD, -0.34; 95 % CI: -0.59 to -0.08).  The statistical tests indicated moderate-to-high heterogeneity across the studies (Q-statistic: PCI, p = 0.0006, I(2) = 83 %; CABG, p < 0.0001, I(2) = 69 %).  The authors concluded that in patients undergoing PCI or CABG, RIC with transient episodes of limb ischemia is associated with lower biomarkers of myocardial injury compared to control, but this effect failed to reach statistical significance in the overall PCI analysis.

Young et al (2012) stated that the effectiveness of RIPC in high-risk cardiac surgery is uncertain.  In a pilot study, 96 adults undergoing high-risk cardiac surgery were randomized to RIPC (3 cycles of 5 mins of upper-limb ischemia induced by inflating a BP cuff to 200 mmHg with 5 mins of re-perfusion) or control.  Main end-points were plasma high-sensitivity troponin T (hsTNT) levels at 6 and 12 hrs, worst post-operative AKI based on RIFLE criteria, and noradrenaline duration.  High-sensitivity TNT levels were log-normally distributed and higher with RIPC than control at 6-hr post cross-clamp removal [810 ng/ml (inter-quartile range [IQR] 527 to 1,724) versus 634 ng/ml (429 to 1,012); ratio of means 1.41 (99.17 % CI: 0.92 to 2.17); p = 0.04] and 12 hrs [742 ng/ml (IQR 427 to 1,700) versus 514 ng/ml (IQR 356 to 833); ratio of means 1.56 (99.17 % CI: 0.97 to 2.53); p = 0.01].  After adjustment for baseline confounders, the ratio of means of hsTNT at 6 hrs was 1.23 (99.17 % CI: 0.88 to 1.72; p = 0.10) and at 12 hrs was 1.30 (99.17 % CI: 0.92 to 1.84; p = 0.05).  In the RIPC group, 35/48 (72.9 %) had no AKI, 5/48 (10.4 %) had AKI risk, and 8/48 (16.7 %) had either renal injury or failure compared to the control group where 34/48 (70.8 %) had no AKI, 7/48 (14.6 %) had AKI risk, and 7/48 (14.6 %) had renal injury or failure (Chi-squared 0.41; 2 degrees of freedom; p = 0.82).  Remote ischemic pre-conditioning increased post-operative duration of noradrenaline support [21 hrs (IQR 7 to 45) versus 9 hrs (IQR 3 to 19); ratio of means 1.70 (99.17 % CI: 0.86 to 3.34); p = 0.04].  The authors concluded that RIPC does not reduce hsTNT, AKI, or intensive care unit (ICU)-support requirements in high-risk cardiac surgery.

Lomivorotov et al (2012) examined if RIPC reduces myocardial injury in CABG patients.  A total of 80 patients were assigned to RIPC or control treatment.  Ischemic preconditioning was induced by 3 cycles (5 mins each) of upper limb ischemia and re-perfusion after anesthesia induction.  Hemodynamic and markers of myocardial damage were analyzed pre-operatively and over 48 hrs post-operatively.  The cardiac index was higher immediately after RIPC in the main group.  There were no differences in other hemodynamic, troponin I and CK-MB concentrations at any time point between groups.  The authors concluded that short-term RIPC improved hemodynamics and did not reduce myocardial injury after CABG.  Moreover, they stated that further studies of high-risk patients are needed to fully evaluate the clinical effect of RIPC.

Ovize et al (2013) provided a critical summary of the progress toward, opportunities for, and caveats to, the successful clinical translation of RIPC and RIC, the 2 conditioning strategies considered to have the broadest applicability for real-world patient care.  In the majority of phase II studies published to date, post-conditioning evoked an approximately 35 % reduction of infarct size in ST-segment-elevation MI patients.  Essential criteria for the successful implementation of post-conditioning include the appropriate choice of patients (i.e., those with large risk regions and negligible collateral flow), timely application of the post-conditioning stimulus (immediately on re-perfusion), together with proper choice of end-points (infarct size, with concomitant assessment of risk region).  Remote conditioning has been applied in planned ischemic events (including cardiac surgery and ePCI) and in ST-segment-elevation MI patients during hospital transport.  Controversies with regard to effectiveness have emerged, particularly among surgical trials.  These disparate outcomes in all likelihood reflect the remarkable heterogeneity within and among studies, together with a deficit in the understanding of the impact of these variations on the infarct-sparing effect of remote conditioning.  The author concluded that ongoing phase III trials will provide critical insight into the future role of RIPC and RIC as clinically relevant cardio-protective strategies.

Liu and colleagues (2013) stated that ischemic conditioning, the application of a mild ischemic stimulus to an ischemia-sensitive structure like the heart or brain either before (pre-conditioning) or after (post-conditioning) its exposure to a lethal ischemic insult, is known to switch on endogenous protective mechanisms.  However, most studies of its neuro-protective effect in the central nervous system (CNS) have focused on ischemic damage or related conditions like hypoxia, while its potential in treating other neural diseases remains uncertain.  In particular, the recent discovery of RIPC whereby mild ischemia applied to a region remote from the target after the main ischemic insult also confers protection offers an attractive paradigm to study its potential in other types of neural injury.  Retinal ganglion cells damaged by optic nerve transection undergo extensive cell death.  However, application of a series of mild ischemic/re-perfusion cycles to the hind-limb (limb RIPC) at 10 mins or 6 hrs after optic nerve cut was found to promote ganglion cell survival at 7 days post-injury, with the 10-min post-conditioning still exerting protection at 14 days post-injury.  Concomitant with the increased ganglion cell survival, 51 % more ganglion cells expressed the small heat shock protein HSP27, when RIPC was performed at 10 mins post-injury, as compared to the sham conditioning group.  The authors concluded that these findings high-lighted the potential of using RIPC as a non-invasive neuro-protective strategy in different CNS disorders like spinal cord injury and traumatic brain injury.

In a phase I clinical trial, Gonzalez et al (2014) evaluated the feasibility and safety of RIC for aneurysmal subarachnoid hemorrhage (aSAH).  Consecutive patients hospitalized for treatment of an aSAH who met the inclusion/exclusion criteria were approached for consent.  Enrolled patients received up to 4 RIC sessions on non-consecutive days.  Primary end-points were (i) the development of a symptomatic deep venous thrombosis (DVT), bruising or injury to the limb and, (ii) request to stop by the patient or surrogate.  The secondary end-points were the development of new neurological deficits or cerebral infarct, demonstrated by brain imaging after enrollment, and neurological deficit and condition at follow-up.  A total of 20 patients were enrolled and underwent 76 RIC sessions, 75 of which were completed successfully.  One session was discontinued when the patient became confused.  No patient developed a DVT or injury to the pre-conditioned limb.  No patient developed delayed ischemic neurological deficit during their enrollment.  At follow-up, median modified Rankin Scale was 1 and Glasgow Outcome Score was 5.  The authors concluded that the RIC procedure was well-tolerated and did not cause any injury.  They stated that RIC for aSAH warrants investigation in a subsequent pivotal clinical trial.

In a RCT, Wu and colleagues (2014) examined if RIC can attenuate ischemic reperfusion injury (IRI) in recipients after kidney transplantation using donation after cardiac death.  A total of 48 recipients referred for kidney transplantation were recruited.  The paired recipients who received the kidneys from the same donor were randomly assigned (1received RIC and the other did not).  Remote ischemic conditioning was induced by three 5-min cycles of brief repetitive ischemia and re-perfusion by clamping the exposed external iliac artery.  Blood samples were withdrawn at hour 2, hour 12, days 1 to 7, day 14, and day 30 to measure serum creatinine level and estimated glomerular filtration rate (GFR) after transplantation.  Urine samples were collected at hours 2, 12, 24, and 48 to measure urine neutrophil gelatinase-associated lipocalin after transplantation.  Renal tissues were obtained at 30 mins for histologic changes after transplantation.  There were no significant differences in clinical characteristics of the recipients and donors between RIC and control groups.  The serum creatinine level was lower in the RIC group compared with that of the control group (12 hrs, days 1 to 14, p < 0.05; other p > 0.05); the estimated GFR was higher in the RIC group compared with that of the control group (12 hrs, days 1 to 14, p < 0.05; other p > 0.05); urine neutrophil gelatinase-associated lipocalin, an early marker of IRI, was lower in the RIC group at hours 2, 12, 24, and 48 (2 hrs, 48 hrs, p > 0.05; 12 hrs, 24 hrs, p < 0.05) compared with that of the control group.  The graft pathology showed no differences between RIC and control groups.  The authors concluded that RIC enhanced the early recovery of renal function in recipients after kidney transplantation.  They stated that these findings provided a novel potential approach to attenuate transplantation-associated IRI.

In a pilot study, Lin and colleagues (2014) stated that primary graft dysfunction (PGD) remains a significant problem after lung transplantation.  Data from animal and clinical studies suggested that RIC may reduce ischemia-reperfusion injury in solid organ transplantation.  A RCT of 60 patients undergoing bilateral sequential lung transplantation assessed the utility of RIC in attenuating PGD.  Treated recipients underwent 3 cycles of lower limb ischemic conditioning before allograft reperfusion.  The primary outcome measure was a comparison of the partial pressure of arterial oxygen/fraction of inspired oxygen ratio (P/F ratio) between treatment groups.  No adverse effects of tourniquet application were observed.  The mean lowest P/F ratio during the first 24 hours after transplantation was 271.3 mm Hg in the treatment arm versus 256.1 mm Hg in the control arm (p = 0.46).  Primary graft dysfunction grade and severity and the rate of acute rejection also showed a tendency to favor the treatment arm.  Sub-group analysis demonstrated a significant benefit of treatment in patients with a primary diagnosis of restrictive lung disease, a group at high risk for the development of PGD.  Remote ischemic conditioning was not accompanied by systemic release of high-molecular-weight group.  Levels of cytokines, high-molecular-weight group, and endogenous secretory receptor for advanced glycation end products peaked within 2 hours after reperfusion and likely reflected donor organ quality rather than an effect of RIC.  The authors concluded that RIC did not significantly improve P/F ratios or PGD in this RCT.  However, encouraging results in this small study warrant a large multi-center trial of RIC in lung transplantation.

Leung et al (2015) evaluate the effectiveness of RIC on organ protection after hemorrhagic shock/resuscitation (S/R) in a murine model. C57Bl/6 mice were subjected to S/R with or without hind-limb RIC. Serum levels of alanine aminotransferase and tumor necrosis factor (TNF)-alpha, and liver TNF-alpha and interleukin (IL)-1β mRNA were evaluated. In some experiments, lung protein leakage, cytokines, and myeloperoxidase activity were investigated. Plasma from mice subjected to RIC was microinjected into zebrafish, and neutrophil migration was assessed after tailfin transection or copper sulfate treatment. In mice subjected to S/R, RIPC, remote ischemic "PRE"conditioning, and remote ischemic "POST"conditioning each significantly reduced serum alanine aminotransferase and liver mRNA expression of TNF-alpha and iIL-1β and improved liver histology compared with control S/R mice. Lung injury and inflammation were also significantly reduced in mice treated with RIPC. Zebrafish injected with plasma or dialyzed plasma (fraction greater than14 kDa) from ischemic conditioned mice had reduced neutrophil migration toward sites of injury compared with zebrafish injected with control plasma. The authors concluded that RIC protected against S/R-induced organ injury, in part, through a humoral factor(s), which alters neutrophil function. They stated that the beneficial effects of RIC, performed during the S/R phase of care, suggested a role for its application early in the post-trauma period.

In a multi-center trial, Zarbock et al (2015) examined if RIPC reduces the rate and severity of AKI in patients undergoing cardiac surgery. A total of 240 patients at high risk for AKI, as identified by a Cleveland Clinic Foundation score of 6 or higher, were enrolled in this study. These researchers randomized them to receive RIPC or sham RIPC (control). All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle. Patients received either RIPC (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham RIPC (control), both via BP cuff inflation. The primary end-point was the rate of AKI defined by Kidney Disease: Improving Global Outcomes criteria within the first 72 hours after cardiac surgery. Secondary end-points included use of renal replacement therapy, duration of ICU stay, occurrence of MI and stroke, in-hospital and 30-day mortality, and change in AKI biomarkers. Acute kidney injury was significantly reduced with RIPC (45 of 120 patients [37.5 %]) compared with control (63 of 120 patients [52.5 %]; absolute risk reduction, 15 %; 95 % CI: 2.56 % to 27.44 %; p = 0.02). Fewer patients receiving RIPC received renal replacement therapy (7 [5.8 %] versus 19 [15.8 %]; absolute risk reduction, 10 %; 95 % CI: 2.25 % to 17.75 %; p = 0.01), and RIPC reduced ICU stay (3 days [IQR of 2 to 5]) versus 4 days (IQR of 2 to 7) (p = 0.04). There was no significant effect of RIPC on MI, stroke, or mortality. Remote ischemic pre-conditioning significantly attenuated the release of urinary insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery (RIPC, 0.36 versus control, 0.97 ng/mL2/1000; difference, 0.61; 95 % CI: 0.27 to 0.86; p < 0.001). No adverse events were reported with RIPC. The authors concluded that among high-risk patients undergoing cardiac surgery, RIPC compared with no-RIPC significantly reduced the rate of AKI and use of renal replacement therapy. Moreover, they stated that the observed reduction in the rate of AKI and the need for renal replacement warrants further investigation. These investigators stated that “future studies will need to address the optimal methods for remote ischemic preconditioning and whether benefits are consistent across patients with various risks for acute kidney injury, such as those with pre-existing chronic kidney disease or with lower Cleveland Clinic Foundation score”.

In an editorial that accompanied the afore-mentioned study, Pan and Sheikh-Hamad stated that “Further studies are needed to determine whether a longer duration of limb ischemia or earlier induction of RIPC covers better renoprotection …. Before RIPC is adopted for clinical use, the potential risks and adverse effects must be considered carefully …. Clinicians should be mindful of potential harms before adopting this approach widely”.

In a meta-analysis, Zuo and colleagues (2015) examined the renoprotective role of RIC in patients undergoing PCI. PubMed, Web of Science, and Cochrane Library were searched from inception to December 31, 2014 to identify eligible RCTs. Pooled RR, mean, SD and 95 % CI were used to assess the effect by fixed- or random-effect models. Heterogeneity was assessed by the Cochran Q and I 2 statistics. A total of 9 trials were included in this study. Remote ischemic conditioning decreased the AKI incidence in patients undergoing PCI compared with control individuals (p < 0.001; RR, 0.53; 95 % CI: 0.39 to 0.71; p for heterogeneity = 0.15; heterogeneity χ2 = 13.38; I2 = 33 %). Besides, limb conditioning attenuated AKI (p = 0.001; RR, 0.57; 95 % CI: 0.41 to 0.81; p for heterogeneity = 0.13; heterogeneity χ2 = 12.48; I2 = 36 %). Remote post-conditioning may reduce the AKI incidence (p = 0.03; RR, 0.65; 95 % CI: 0.44 to 0.97; p for heterogeneity = 0.15; heterogeneity χ2 = 5.36; I2 = 44 %); remote pre-conditioning could also play a renoprotective role (p < 0.001; RR, 0.42; 95 % CI: 0.27 to 0.65; P for heterogeneity = 0.31; heterogeneity χ2 = 5.98; I2 = 16 %). The authors concluded that RIC may not only confer cardioprotection, but also reduce the incidence of AKI in patients undergoing PCI, ultimately leading to better clinical outcomes. They stated that RIC may potentially be a powerful approach conferring protection in patients undergoing PCI in future clinical practice; more large-scale trials are needed to obtain a more reliable conclusion.

Hausenloy, et al. (2015) conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham
conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. Results We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the
high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. The investigators concluded that remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery.

Enhancement of Renal Function after Kidney Transplantation:

In a RCT, Wu and colleagues (2014) examined if RIC can attenuate IRI in recipients after kidney transplantation (KT) using donation after cardiac death. A total of 48 recipients referred for KT were recruited. The paired recipients who received the kidneys from the same donor were randomly assigned (1 received RIC and the other did not). Remote ischemic conditioning was induced by three 5-min cycles of brief repetitive ischemia and re-perfusion by clamping the exposed external iliac artery. Blood samples were withdrawn at hour 2, hour 12, days 1 to 7, day 14, and day 30 to measure serum creatinine (sCr) level and estimated GFR after KT. Urine samples were collected at hours 2, 12, 24, and 48 to measure urine neutrophil gelatinase-associated lipocalin after KT. Renal tissues were obtained at 30 minutes for histologic changes after KT. There were no significant differences in clinical characteristics of the recipients and donors between RIC and control groups. The sCr level was lower in the RIC group compared with that of the control group (12 h, days 1 to 14, p < 0.05; other p > 0.05); the estimated GFR was higher in the RIC group compared with that of the control group (12 hours, days 1 to 14, p < 0.05; other p > 0.05); urine neutrophil gelatinase-associated lipocalin, an early marker of IRI, was lower in the RIC group at hours 2, 12, 24, and 48 (2 hours, 48 hours, p > 0.05; 12 hours, 24 hours, p < 0.05) compared with that of the control group. The graft pathology showed no differences between RIC and control groups. The authors concluded that RIC enhanced the early recovery of renal function in recipients after KT. They stated that these findings provided a novel potential approach to attenuate transplantation-associated IRI.

Kim and co-workers (2014) examined if remote ischemic post-conditioning (RiPoC) could improve initial graft function in living donor KT. Patients undergoing living donor KT were randomly assigned to either RiPoC (n = 30) or control group (n = 30). Immediately after re-perfusion in the RiPoC group, 3 cycles of ischemia and re-perfusion, lasting 5 minutes each, were performed on one upper limb. Renal function was assessed before surgery, 2 hours after surgery, and at 12-hr intervals for 96 hours post-surgery by measuring sCr and the estimated GFR (eGFR). Urine output and urine creatinine were assessed until post-operative day 7, and hospital stay and complication rates were compared. The time for sCr to reach 50 % of its pre-operative level was significantly shorter in the RiPoC group than in the control group [12 (12 to 24) hours for RiPoC versus 24 (21 to 36) hours for the control, p = 0.005]. The number of patients whose sCr was reduced by 50 % within 24 hours was significantly greater in the RiPoC group than in the control group [n = 26 (87 %) in RiPoC versus n = 18 (60 %) in control, p = 0.020]. However, there were no differences in sCr and eGFR thereafter, the incidence of graft dysfunction or complication rates between groups. The authors concluded that RiPoC appeared to hasten the recovery of graft function within 24 hours; but did not affect the graft function thereafter. Moreover, they noted that considering most recipients had immediate graft function, further studies with deceased donors or studies powered to detect a smaller difference are needed.

Krogstrup and colleagues (2015) stated that delayed graft function due to IRI is a frequent complication in deceased donor KT. Experimental evidence indicates that RIC provides systemic protection against IRI in various tissues. These researchers stated that “Remote ischemic conditioning in renal transplantation-effect on immediate and extended kidney graft function” (the CONTEXT study) is an investigator initiated, multi-center, RCT investigating whether RIC of the leg of the recipient improves short- and long-term graft function following deceased donor KT. The study will include 200 KT recipients of organ donation after brain death and 20 KT recipients of organ donation after circulatory death. Participants are randomized in a 1:1 design to RIC or sham-RIC (control). Remote ischemic conditioning consists of 4 cycles of 5-min occlusion of the thigh by a tourniquet inflated to 250 mm Hg, separated by 5 minutes of deflation. Primary end-point is the time to a 50 % reduction from the baseline sCr, estimated from the changes of plasma creatinine values 30 days post-transplant or 30 days after the last performed dialysis post-transplant. Secondary end-points are need of dialysis post-transplant, measured GFR and eGFR at 3 and 12 months after transplantation, patient and renal graft survival, number of rejection episodes in the first year, and changes in biomarkers of AKI and inflammation in plasma, urine and graft tissue. The authors noted that this study is approved by the local ethical committees and national data security agencies; results are expected to be published in 2016.

In a double-blind RCT, Nicholson and associates (2015) determined the safety and effectiveness of RIC in live donor KT. A total of 80 patients undergoing live donor KT were randomly assigned in a 1:1 ratio to either RIC or to a control group. Remote ischemic conditioning consisted of cycles of lower limb ischemia induced by an arterial tourniquet cuff placed around the patient's thigh. In the RIC treatment group, the cuff was inflated to 200 mm Hg or systolic pressure +25 mm Hg for 4 cycles of 5 minutes ischemia followed by 5 minutes re-perfusion. In the control group, the BP cuff was inflated to 25 mm Hg. Patients and medical staff were blinded to treatment allocation. The primary end-point was renal function measured by eGFR at 1 and 3 months post-transplant. Donor and recipient demographics were similar in both groups (p < 0.05). There were no significant differences in eGFR at 1 month (control 52 ± 14 versus RC 54 ± 17 ml/min; p = 0.686) or 3 months (control 50 ± 14 versus RC 49 ± 18 ml/min; p = 0.678) between the control and RIC treatment groups. The authors concluded that the RIC technique did not cause any serious adverse effects; RIC, using the protocol described here, did not improve renal function after live donor KT.

Tourniquet-Related Ischemic Damage in Orthopedic Surgery:

Halladin and colleagues (2014) stated that ischemia of the extremity from the use of a tourniquet and the subsequent re-perfusion contributes to the release of reactive oxygen species. This release may result in injury to remote organs. These investigators performed a qualitative systematic review exploring the interventions used to prevent tourniquet-related oxidative damage in adults undergoing orthopedic surgery, and the possible relationship between biochemical oxidative stress markers and post-operative clinical outcomes. A total of 17 RCTs were included in the qualitative synthesis. Most trials were of low methodological quality and only 2 studies reported post-operative clinical outcomes: 9 studies tested anesthetics (propofol, dexmedetomidine, ketamine, and spinal anesthesia); 4 studies tested anti-oxidants (N-acetyl-cysteine, vitamin C, and mannitol); and 4 studies tested ischemic pre-conditioning. A total of 15 studies showed a significant reduction in biochemical oxidative stress markers. The authors concluded that propofol and ischemic pre-conditioning, in particular, appeared to show some benefit at reducing oxidative stress following operations under tourniquet. They stated that the correlation between a reduction in oxidative stress and post-operative clinical outcomes should be further investigated in the future.

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015:
There are no specific codes for remote ischemic conditioning:
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive) :
I20.0 - I25.9 Ischemic heart diseases
I60.00 - I60.9 Nontraumatic subarachnoid hemorrhage
I63.30 - I63.9 Cerebral infarction [stroke]
I66.01 - I66.9 Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction
T86.818 Other complications of lung transplant [primary graft dysfunction]
Z94.0 Kidney transplant status [enhancement of renal function]


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