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:

  • Acute coronary syndromes individuals undergoing percutaneous coronary intervention
  • 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
  • Cardioprotection in individuals with cancer undergoing chemotherapy
  • Enhancement of renal function after kidney transplantation
  • Improvement in microcirculation of surgical flaps
  • Prevention of contrast-induced acute kidney injury
  • Prevention of ischemic cerebrovascular events in high-risk persons with acute non-disabling ischemic cerebrovascular events
  • Prevention of post-stroke depression
  • Prevention of progression of white matter hyperintensities (WMHs) and amelioration of cognitive impairment in individuals with intra-cranial atherosclerotic stenosis
  • Prevention of radial artery occlusion
  • Prevention of reperfusion injury in individuals with ST-segment-elevation myocardial infarction
  • Sepsis management
  • Treatment of acute stroke individuals undergoing thrombectomy
  • Treatment of aneurysmal subarachnoid hemorrhage
  • Treatment of cerebral ischemia
  • Treatment of intra-cerebral hemorrhage
  • Treatment of myocardial infarction / heart failure
  • Treatment of peripheral arterial disease
  • Treatment of primary graft dysfunction following lung transplantation
  • Treatment of spinal cord injury
  • Treatment of Takotsubo syndrome after acute stroke
  • Treatment of tourniquet-related ischemic damage in orthopedic surgery
  • Treatment of traumatic brain injury
  • Treatment of ulcerative colitis
  • Treatment of vascular cognitive impairment.

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:
  1. an early effect that appears within minutes of the ischemic conditioning, and
  2. 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:
  1. retrospective analysis of data, and
  2. 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
  1. 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
  2. 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
  1. the development of a symptomatic deep venous thrombosis (DVT), bruising or injury to the limb and,
  2. 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 multi-center, 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 RIPC (four 5-minute inflations and deflations of a standard BP 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, non-fatal MI, coronary revascularization, or stroke, assessed 12 months after randomization.  These researchers enrolled a total of 1,612 patients (811 in the control group and 801 in the RIPC 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 RIPC group and those in the control group (212 patients [26.5 %] and 225 patients [27.7 %], respectively; hazard ratio (HR) with ischemic preconditioning, 0.95; 95 % CI: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 peri-operative 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), AKI, duration of stay in the ICU and hospital, distance on the 6-minute walk test, and quality of life.  The investigators concluded that RIPC did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery.

Acute Coronary Syndromes Patients Undergoing Percutaneous Coronary Intervention

In a systematic review and meta-analysis, Sandven and colleagues (2020) examined the efficacy of RIC as compared to no conditioning on clinical end-points in acute coronary syndromes (ACS) patients undergoing PCI.  Literature was searched up to September 13, 2019, and these investigators identified a total of 13 RCTs.  The efficacy of RIC on incidence of clinical events during follow-up was quantified by the RR with its 95 % CI, and these researchers used fixed and random effects models to synthetize the results.  Small-study effect was evaluated, and controlled for by the trim-and-fill method.  Heterogeneity between studies was examined by subgroup and meta-regression analyses.  The risk of false-positive results in meta-analysis was evaluated by trial sequential analysis (TSA).  Pooled analysis of 13 trials (7,183 patients) showed that RIC compared to no conditioning revealed a non-significant risk reduction on end-point mortality (RR = 0.81, 95 % CI: 0.56 to 1.17) during a median follow-up time of 1 year (range of 0.08 to 3.8) with low heterogeneity (I2 = 16 %).  Controlling for small-study effect showed no efficacy of RIC (adjusted RR: 1.03, 95 % CI: 0.66 to 1.59).  Pooled effect of RIC on the incidence of MI from 11 trials (6,996 patients) was non-significant too (RR = 0.85, 95 % CI: 0.62 to 1.18), with no observed heterogeneity (I2 = 0%) or small-study effect.  A similar lack of efficacy was found in end-point congestive heart failure (CHF) from 6 trials including 6,098 patients (RR = 0.71, 95 % CI: 0.44 to 1.15), with moderate heterogeneity (I2 = 30 %); TSAs showed that the pooled estimates from the cumulative meta-analyses were true negative with adequate power.  The authors concluded that evidence from this updated systematic review demonstrated no beneficial effect of RIC on the incidence of clinical end-point mortality, MI and CHF during a median follow-up of 1 year in ACS patients undergoing PCI.

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.

In a meta-analysis, Zhou and colleagues (2017a) examined if RIC could improve graft functions in KT.  PubMed, Web of Science, and Cochrane Library were comprehensively searched to identify all eligible studies by October 5, 2016.  The treatment effects were examined with RR and weighted mean difference (WMD) with the corresponding 95 % CI.  The statistical significance and heterogeneity were assessed with both Z-test and Q-test.  A total of 6 RCTs including 651 recipients, were eventually identified.  Compared to the controls, RIC could reduce the incidence of delayed graft function (DGF) after KT (random-effects model: RR = 0.89; fixed-effect model: RR = 0.84).  However, the decrease did not reveal statistical significance.  The subgroup analysis by RIC type demonstrated no significant difference among the 3 interventions in protecting renal allografts against DGF.  Furthermore, no significant difference could be observed in the incidence of acute rejection, graft loss, 50 % fall in sCr, as well as the estimated GFR and hospital stay between the RIC and Control groups.  The authors concluded that the findings of this meta-analysis suggested that RIC might exert reno-protective functions in human KT, however,  further well-designed RCTs with large sample size are needed to evaluate its clinical effectiveness.

Cheungpasitporn and colleagues (2019) stated that renal ischemia-reperfusion injury (IRI), an inevitable event during kidney transplantation procedure, can result in delayed graft function or even primary non-function.  In addition to strategies to limit IRI such as advancements in organ allocation systems and preservation of organs, and reduction in cold and warm ischemia time, RIC has attracted much attention in recent years.  With promising findings and data suggesting a potential benefit of RIC in animal kidney transplantation models, a few clinical trials have examined the use of RIC in human kidney transplantation.  Unfortunately, the findings from these investigations have been inconclusive due to a number of factors such as diverse time-points of RIC, limited sample size, and complexity of kidney transplant patients.

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.

Cardioprotection During Cardiac Surgery

Gallagher and colleagues (2015) noted that AKI is a frequent complication of cardiac surgery and usually occurs in patients with pre-existing chronic kidney disease (CKD). Remote ischemic preconditioning may mitigate the renal ischemia-reperfusion injury associated with cardiac surgery and may be a preventive strategy for post-surgical AKI.  These investigators undertook a RCT of RIPC to prevent AKI in 86 patients with CKD (estimated GFR under 60 ml/min per 1.73 m(2)) undergoing CABG surgery.  A total of 43 patients were randomized to receive standard care with or without RIPC consisting of three 5-minute cycles of forearm ischemia followed by re-perfusion.  The primary end-point was the development of AKI defined as an increase in serum creatinine concentration over 0.3 mg/dL within 48 hours of surgery.  Secondary end-points included a comparison between the study and control groups of several serum biomarkers of renal injury including cystatin-C, neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18), and urinary biomarkers including NGAL, IL-18, and kidney injury molecule-1 measured at 6, 12, and 24 hours after CABG, and the 72-hour serum troponin T concentration area under the curve as a marker of myocardial injury.  Clinical and operative characteristics were similar between the pre-conditioned and control groups; AKI developed in 12 patients in both groups within 48 hours of CABG.  There were no significant differences between the 2 groups in the concentrations of any of the serum or urinary biomarkers of renal or cardiac injury after CABG.  The authors concluded that RIPC induced by forearm ischemia-reperfusion had no effect on the frequency of AKI after CABG in patients with CKD.

Meybohm and colleagues (2015) stated that RIPC is reported to reduce biomarkers of ischemic and re-perfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains. These researchers conducted a prospective, double-blind, multi-center RCT involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol.  The trial compared upper-limb RIPC with a sham intervention.  The primary end-point was a composite of death, MI, stroke, or acute renal failure up to the time of hospital discharge.  Secondary end-points included the occurrence of any individual component of the primary end-point by day 90.  A total of 1,403 patients underwent randomization.  The full analysis set comprised 1,385 patients (692 in the RIPC group and 693 in the sham-RIPC group).  There was no significant between-group difference in the rate of the composite primary end-point (99 patients [14.3 %] in the RIPC group and 101 [14.6 %] in the sham-RIPC group, p = 0.89) or of any of the individual components: death (9 patients [1.3 %] and 4 [0.6 %], respectively; p = 0.21), MI (47 [6.8 %] and 63 [9.1 %], p = 0.12), stroke (14 [2.0 %] and 15 [2.2 %], p = 0.79), and acute renal failure (42 [6.1 %] and 35 [5.1 %], p = 0.45).  The results were similar in the per-protocol analysis.  No treatment effect was found in any subgroup analysis.  No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the ICU or the hospital, new onset of atrial fibrillation, and the incidence of post-operative delirium.  No RIPC-related adverse events were observed.  The authors concluded that upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery.

In an editorial that accompanied the afore-mentioned study, Zaugg and Lucchinetti (2015) stated that “In view of these findings, one might ask whether remote ischemic preconditioning may even be risky – specifically, in certain patients with highly unstable coronary plaques … its safety as a cardioprotective strategy should be carefully investigated in additional, adequately powered studies, specifically in patients undergoing non-surgical interventions … Unfortunately, we do not know the right dose of ischemia to deliver”.

In a RCT, Walsh and associates (2016) examined the effect of RIPC on markers of heart and kidney injury after cardiac surgery. Patients at high-risk of death within 30 days after cardiac surgery were randomly assigned to undergo RIPC or a sham procedure after induction of anesthesia.  The pre-conditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles.  The sham procedure was identical except that ischemia was not induced.  The primary outcome was peak CK-MB within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation).  The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per liter).  Patient-important outcomes were assessed up to 6 months after randomization.  These researchers randomly assigned 128 patients to RIPC and 130 to the sham therapy.  There were no significant differences in post-operative CK-MB (absolute MD of 0.15, 95 % CI: -0.07 to 0.36) or creatinine (absolute MD of 0.06, 95 % CI: -0.10 to 0.23).  Other outcomes did not differ significantly for RIPC relative to the sham therapy: for MI, RR of 1.35 (95 % CI: 0.85 to 2.17); for acute kidney injury, RR of 1.10 (95 % CI: 0.68 to 1.78); for stroke, RR of 1.02 (95 % CI: 0.34 to 3.07); and for death, RR of 1.47 (95 % CI: 0.65 to 3.31).  The authors concluded that RIPC did not reduce myocardial or kidney injury during cardiac surgery.  They stated that this type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery.

Liu and colleagues (2017) conducted a systematic review and meta-analysis to evaluate the effects of RIC on myocardial parameters and clinical outcomes in STEMI patients undergoing primary PCI.  A total of 10 eligible RCTs with 1,006 STEMI patients were identified.  Compared with controls, RIC reduced the myocardial enzyme levels (SMD =-0.86; 95 % CI: -1.44 to -0.28; p = 0.004; I2 = 94.5 %), and increased the incidence of complete ST-segment resolution [odds ratio (OR) = 1.74; 95 % CI: 1.09 to 2.77; p = 0.02; I2 = 47.9 %]; RIC patients had a lower risk of all-cause mortality (OR = 0.27; 95 % CI: 0.12 to 0.62; p = 0.002; I2 = 0.0 %) and lower major adverse cardiovascular and cerebrovascular events rate (OR = 0.45; 95 % CI: 0.27 to 0.75; p = 0.002; I2 = 0.0 %).  The authors concluded that available evidence from the present meta-analysis suggested that RIC may confer cardio-protection by reducing elevated myocardial enzymes and increasing complete ST-segment resolution (cSTR) incidence in patients after STEMI.

The authors stated that this study had several drawbacks.  First, the potential influence of cardiovascular co-morbidities and co-medications on the effect of RIC in STEMI patients could not be analyzed from the available individual patient data.  Second, the sample size of the included studies was relatively small.  Third, the criterion for cSTR was inconsistent among these studies (greater than 50 % in 4 studies, greater than 70 % in 2 studies, greater than 80 % in 1 study).  Fourth, the potential confounding effect on the pooled result could not be ruled out.  Lastly, the heterogeneity of enzymatic result was relatively high.  Although these investigators used a random-effect model to pool major adverse cardiac and cerebrovascular events (MACCE) results, the definitions varied among the included studies.  They stated that differences in early and late clinical outcomes require future investigation by large, well-designed, multi-center clinical trials with long-term follow-up.

Kidney Protection

Zhang et al (2016) stated that results from RCTs concerning kidney effect of RIC are inconsistent. These investigators searched for relevant studies in Medline, Embase, the Cochrane Library, Google Scholar and Chinese database (SinoMed), as well as relevant references from their inception to November 2015.  They performed a systematic review and meta-analysis of all eligible RCTs of RIC with kidney events.  These researchers included 37 RCTs from 2007 to 2015 involving 8,168 patients.  Pooled analyses of all RCTs showed RIC significantly reduced the incidence of investigator-defined AKI compared with control groups (RR 0.84, 95 % CI: 0.73 to 0.96, p = 0.009) (I(2) = 25 %).  However, the difference was not significant when only RIFLE (Risk, Injury, Failure, Loss, End Stage), AKIN (Acute Kidney Injury Network), or KDIGO (Kidney Disease Improving Global Outcomes) criteria were applied to the definition of AKI (RR 0.87, 95 % CI: 0.74 to 1.02, p = 0.08) (I(2) = 22 %).  In subgroup analysis, RIC showed a significant benefit on reducing investigator-defined AKI in patients following PCI (RR 0.64, 95 % CI: 0.46 to 0.87), but not after cardiac surgery (RR 0.93, 95 % CI: 0.82 to 1.06).  There was no difference for changes in the incidence of renal replacement therapy, estimated GFR or serum creatinine.  The authors concluded that RIC might be beneficial for the prevention of investigator-defined AKI; however, the effect is likely small.  Moreover, they stated that due to lack of an effect on use of renal replacement therapy, estimated GFR, RIFLE, AKIN, or KDIGO-defined AKI, and serum creatinine, the evidence for RIC is not robust.  Finally, recent large-scale RCTs of RIC focusing on patient-centered outcomes did not support the wider application of RIC.

Cardioprotection in Individuals with Cancer Undergoing Chemotherapy

Chung and colleagues (2016) stated that cancer survival continues to improve, and thus cardiovascular consequences of chemotherapy are increasingly important determinants of long-term morbidity and mortality. Conventional strategies to protect the heart from chemotherapy have important hemodynamic or myelosuppressive side effects.  Remote ischemic conditioning using intermittent limb ischemia-reperfusion reduces myocardial injury in the setting of PCI.  Anthracycline cardiotoxicity and ischemia-reperfusion injury share common biochemical pathways in cardiomyocytes.  The potential for RIC as a novel treatment to reduce sub-clinical myocyte injury in chemotherapy has never been explored and will be investigated in the Effect of Remote Ischemic Conditioning in Oncology (ERIC-ONC) trial (clinicaltrials.gov NCT 02471885).  The ERIC-ONC trial is a single-center, blinded, randomized, sham-controlled study.  These researchers aim to recruit 128 adult oncology patients undergoing anthracycline-based chemotherapy treatment, randomized in a 1:1 ratio into 2 groups:
  1. sham procedure, or
  2. RIC, comprising 4, 5-minute cycles of upper arm BP cuff inflations and deflations, immediately before each cycle of chemotherapy. 

The primary outcome measure, defining cardiac injury, will be high-sensitivity troponin-T over 6 cycles of chemotherapy and 12 months follow-up.  Secondary outcome measures will include clinical, electrical, structural, and biochemical end-points comprising major adverse cardiovascular clinical events, incidence of cardiac arrhythmia over 14 days at cycle 5/6, echocardiographic ventricular function, N-terminal pro-brain natriuretic peptide levels at 3 months follow-up, and changes in mitochondrial DNA, micro-RNA, and proteomics after chemotherapy.  The authors stated that the ERIC-ONC trial will determine the effectiveness of RIC as a novel, non-invasive, non-pharmacological, low-cost cardio-protectant in cancer patients undergoing anthracycline-based chemotherapy.

Improvement in Microcirculation of Surgical Flaps

Kolbenschlag and associates (2016) noted that surgical flaps have become safe and reliable tools in the reconstructive armamentarium. However, total flap loss rates of up to 25 % and partial flap loss rates up to 36 % have been reported in the literature, most often due to insufficient perfusion and the resulting hypoxia.  Thus, a reliable, non-invasive and effective way to improve the microcirculation of surgical flaps is desirable.  Remote ischemic conditioning is the repeated application of non-damaging cycles of ischemia and re-perfusion on an organ remote to the tissue to be conditioned.  It is known to improve microcirculation and attenuate ischemia/reperfusion injury (IRI) and has seen growing application in various fields.  While there are promising findings on the effect of RIC on surgical flaps in animal models, no such application in humans has been reported yet.  These investigators examined the effect of RIC on the microcirculation of pedicled and free surgical flaps.  A total of 30 patients undergoing free (n = 20) and pedicled (n = 10) tissue transfer were included in this study; RIC was applied on the upper extremity for 3 cycles on post-operative days (POD) 1, 5 and 12.  Blood flow (BF), tissue oxygen saturation (StO2) and relative hemoglobin content (rHb) were measured via a combination of laser Doppler and spectroscopy (O2C device) in the flap and the surrounding tissue.  The relative increase compared to baseline measurements was assessed.  Blood flow increased significantly in controls on all 3 PODs (p < 0.05 for all).  In free flaps, StO2 improved significantly on POD 1 and 12 as well as BF on PODs 5 and 12 (p < 0.05).  In pedicled flaps, BF and StO2 increases on POD12, but not significantly.  The authors concluded that RIC is a safe, cheap, fast and reliable method to improve the microcirculation of surgical flaps.  Moreover, they stated that further research is needed to ascertain if such an improvement translates to an improved flap survival.

Treatment of Myocardial Infarction / Heart Failure

Yamaguchi and colleagues (2015) stated that RIC by repeated treatment of transient limb ischemia is a clinically applicable method for protecting the heart against injury at the time of re-perfusion. In this study, these researchers examined the effects of repeated RIC on cardiac dysfunction after MI.  At 4weeks after MI, rats were separated into the un-treated (UT) group or the RIC-treated group; RIC treatment was performed by 5 cycles of 5-min of bilateral hind-limb ischemia and 5-min of re-perfusion once-daily for 4 weeks.  Despite comparable MI size, left ventricular ejection fraction (LVEF) was significantly improved in the RIC group compared with the UT group.  Furthermore, the LVEF in the RIC group was improved, although not significantly, after treatment; RIC treatment also prevented the deterioration of LV diastolic function; MI-induced LV interstitial fibrosis in the boundary region and oxidant stress were significantly attenuated by RIC treatment.  MicroRNA-29a (miR-29a), a key regulator of tissue fibrosis, was highly expressed in the exosomes and the marginal area of the RIC group.  Even in the differentiated C2C12-derived exosomes, miR-29a expression was significantly increased under hypoxic condition.  As well as miR-29a, insulin-like growth factor 1 receptor (IGF-1R) was highly expressed both in the exosomes and remote non-infarcted myocardium of the RIC group; IGF-1R expression was also increased in the C2C12-derived exosomes under hypoxic conditions.  The authors concluded that repeated RIC reduced adverse LV re-modeling and oxidative stress by MI.  Exosome-mediated intercellular communication may contribute to the beneficial effect of RIC treatment.

Botker and associates (2015) noted that heart failure (HF) is the end-stage of a variety of underlying cardiovascular diseases and carries a poor prognosis. The condition is caused by a complex interaction between many pathophysiological processes including ischemia, fibrosis, ventricular re-modeling, abnormal neuro-humoral balance and inflammation.  While traditional pharmacological treatment of HF often targets only 1 pathophysiological mechanism, RIC induces a multitude of cardio-protective effects.  In particular, the anti-ischemic, anti-remodeling and anti-inflammatory properties of RIC may be of relevance.  The authors proposed that RIC may offer a novel strategy to improve outcomes in HF.

Kristiansen et al (2016) noted that RIC reduces infarct size and may improve prognosis in patients with acute MI. To explore the potential mechanisms, these researchers examined the effects of RIC on coagulation and fibrinolysis.  This was an interventional cross-over study that included 30 healthy drug-naive males.  Participants were exposed to a sham intervention (visit 1) and to RIC (visit 2 and 3) induced by intermittent arm ischemia through 4 cycles of 5-min inflation of a BP cuff followed by 5-min deflation.  Prior to visit 3, all participants received aspirin 75 mg daily for 7 days.  Blood samples were obtained at baseline as well as 5 and 45 minutes after intervention.  Whole blood coagulation was assessed by thrombo-elastometry (ROTEM) and thrombin generation.  Fibrinolysis was evaluated by clot turbidity-lysis, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1).  No differences were found in clot initiation, clot propagation or clot strength evaluated by ROTEM (all p-values ≥ 0.98).  During aspirin treatment, clot initiation and clot propagation decreased after RIC evaluated by ROTEM EXTEM clotting time (p = 0.04) and ROTEM EXTEM maximum velocity (p = 0.03). After sham and RIC, thrombin generation declined as evaluated by reduced endogenous thrombin potential (RIC: p = 0.001) and peak (RIC: p = 0.01).  After RIC during aspirin treatment, changes in thrombin generation were inconsistent; increased peak (p = 0.04) and time to peak (p < 0.001) and a decrease in lag-time (p < 0.001).  Clot lysis time was prolonged both after sham and after RIC (p < 0.001).  After RIC, PAI-1 levels declined (p = 0.03), but t-PA levels also declined after all interventions (p-values ≤ 0.04).  The authors concluded that RIC did not have substantial effects on coagulation or fibrinolysis compared to sham; and overall, aspirin did not influence the results.

Pryds and colleagues (2017) noted that RIC protects against acute ischemia-reperfusion injury and may also have beneficial effects in patients with stable cardiovascular disease.  These investigators examined the effect of long-term RIC treatment in patients with chronic ischemic heart failure (CIHF).  In a parallel group study, 22 patients with compensated CIHF and 21 matched control subjects without HF or ischemic heart disease were evaluated by cardiac magnetic resonance imaging (MRI), cardiopulmonary exercise testing, skeletal muscle function testing, blood pressure measurement and blood sampling before and after 28 ± 4 days of once-daily RIC treatment; RIC was conducted as 4 cycles of 5-min upper arm ischemia followed by 5-min of re-perfusion.  RIC did not affect LVEF or global longitudinal strain (GLS) in patients with CIHF (p = 0.63 and p = 0.11) or matched controls (p = 0.32 and p = 0.20).  RIC improved GLS in the subgroup of patients with CIHF and with NT-proBNP plasma levels above the geometric mean of 372 ng/l (p = 0.04).  RIC did not affect peak work-load or oxygen uptake in either patients with CIHF (p = 0.26 and p = 0.59) or matched controls (p = 0.61 and p = 0.10).  However, RIC improved skeletal muscle power in both groups (p = 0.02 for both).  In patients with CIHF, RIC lowered systolic blood pressure (p < 0.01) and reduced NT-proBNP plasma levels (p = 0.02).  The authors concluded that these findings suggested that long-term RIC treatment did not improve LVEF but increases skeletal muscle function and reduced blood pressure and NT-proBNP in patients with compensated CIHF.  They stated that this should be investigated in a randomized, sham-controlled trial.

In a systematic review, Gong and Wu (2019) examined the efficacy of RIC with primary PCI versus primary PCI alone for STEMI.  These researchers carried out computerized search for trials from PubMed, Embase, CENTRAL and Cochrane Database of Systematic Reviews databases.  Trials investigating RIC plus primary PCI (group A) versus primary PCI alone (group B) were selected for analysis.  Outcome measures included myocardial enzyme levels; LVEF; MACCEs; thrombolysis in myocardial infarction (TIMI) flow grade-III; myocardial salvage index or infarct size per patients.  A total of 14 studies involving 3,165 subjects were included.  There was a significant association of myocardial edema levels, myocardial salvage index and incidence of MACCEs in group A compared with group B (myocardial edema levels: SMD = - 0.36, 95 % CI: - 0.59 to - 0.13; myocardial salvage index: MD = 0.06, 95 % CI: 0.02 to 0.10; MACCE: OR = 0.70, 95 % CI: 0.57 to 0.85).  With regard to infarct size, TIMI flow grade-III and LVEF, group A appeared to be equivalent with group B (infarct size: MD = - 1.67, 95 % CI: - 3.46 to 0.11; TIMI flow grade III: OR = 1.04, 95 % CI: 0.71 to 1.52; LVEF: MD = 0.74, 95 % CI: - 0.80 to 2.28).  The authors concluded that RIC was associated with lower myocardial edema levels, myocardial salvage index and incidence of MACCE, while non-significant beneficial effect on infarct size, TIMI flow grade-III or LVEF.  Moreover, these researchers stated that the findings of this study suggested that RIC is a promising adjunctive treatment to PCI for the prevention of re-perfusion injury in STEMI patients; however, multi-center, high-quality studies with a larger sample size, are needed to verify its clinical efficacy.

The authors stated that this study had several drawbacks.  First, the RIC protocol was not uniform -- 9 trials were performed on ischemic pre-conditioning, 4 on ischemic post-conditioning, and 1 on ischemic pre-conditioning and post-conditioning.  Compared with ischemic pre-conditioning, ischemic post-conditioning was applied after ischemia has occurred and was more clinically operable.  In view of the unpredictability of clinical myocardial ischemic events, compared with pre-conditioning, ischemic post-conditioning was more clinically operable after the onset of ischemia, so its application prospects for target organ protection were the most promising.  However, ischemic pre-conditioning provided intervention in the time window of ischemia, did not prolong treatment time, was ethically accepted by people, and had good clinical feasibility.  Future clinical trials should further verify the clinical effects of these 2 methods.  Four studies chose the lower limb for remote treatment, and 9 studies chose the upper limb.  Kolbenschlag et al (2015) conducted further studies on remote limb selection and found that the ischemic treatment of the upper and lower limbs could increase the blood flow of the skin, but the RIC of the upper limb could better trigger the protective effect.  Second, the 14 trials included in this study were mostly small and/or single-center trials with varying quality.  All RCTs in this meta-analysis used the different trial designs.  Therefore, this meta-analysis did not provide reliable results on the effects of RIC added to PCI for prevention of re-perfusion injury in STEMI patients.  In the future, relevant research needs to be further improved from the following aspects: increasing the sample size; proper random allocation and allocation of hidden programs; sufficient follow-up duration to observe the short-term and long-term effects; stratified analysis of RIC protocol, TIMI flow grade, and more comprehensive evaluation of the efficacy of RIC.  Third, due to the retrospective nature of all the included studies, bias still exists, which may impact the comparison of clinical outcomes.

Pryds and associates (2019) stated that RIC protects against acute ischemia-reperfusion injury and may have beneficial effects in patients with stable cardiovascular disease.  These investigators examined the effect of long-term RIC treatment in patients with CIHF.  In a pre-specified, post-hoc analysis of a prospective, exploratory and outcome-assessor blinded study, 21 patients with compensated CIHF and 21 matched controls HF or ischemic heart disease were treated with RIC once-daily for 28 ± 4 days.  RIC was conducted as 4 cycles of 5 mins upper arm ischemia followed by 5 mins of re-perfusion.  These researchers evaluated circulating markers of inflammation and cardiac remodeling at baseline and following long-term RIC.  RIC reduced C-reactive protein (CRP) from 1.5 (0.6 to 2.5) to 1.3 (0.6 to 2.1) mg/L following long-term RIC treatment (p = 0.02) and calprotectin from 477 (95 % CI: 380 to 600) to 434 (95 % CI: 354 to 533) ng/ml (p = 0.03) in patients with CIHF, but not in matched controls.  Overall, RIC did not affect circulating markers related to adaptive or innate immunology or cardiac remodeling in patients with CIHF.  Among patients with CIHF and N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels above the geometric mean of 372 ng/L, long-term RIC treatment reduced soluble ST2 (n = 9) from 22.0 ± 3.7 to 20.3 ± 3.9 ng/ml following long-term RIC treatment (p = 0.01).  The authors concluded that these findings suggested that long-term RIC treatment had mild anti-inflammatory effects in patients with compensated CIHF and anti-remodeling effects in those with increased NT-proBNP levels.  This should be further investigated in a randomized, sham-controlled trial.

Treatment of Intra-Cerebral Hemorrhage

Zhao and colleagues (2020) presented the study protocol for a pilot, open-label RCT to examine the safety, feasibility, and preliminary efficacy of RIC in patients with intra-cerebral hemorrhage (ICH) and to plan for a phase-II clinical trial.  This proof-of-concept, assessor-blinded trial will be conducted with patients with ICH within 24 to 48 hours of ictus.  All subjects will be randomly allocated to the intervention group and the control group with a 1:1 ratio (n = 20) and will be treated with standard managements according to the guidelines.  Subjects allocated to the intervention group will receive RIC once-daily for 7 consecutive days.  Cranial computed tomography (CT) examinations will be carried out at baseline, and on days 3, 7, and 14.  Neurological outcomes will be examined at baseline, and on days 1 to 14, 30, and 90.  The primary outcome to be tested is safety.  Secondary tested outcomes include changes of hematoma and perihematomal edema volume, incidence of hematoma expansion, functional outcomes, and frequency of AEs.  The authors stated that this study will be the 1st proof-of-concept RCT to ascertain the safety, feasibility, and preliminary efficacy of RIC in patients with ICH, results of which will provide parameters for future studies and provide insights into the treatment of ICH.

Treatment of Takotsubo Syndrome After Acute Stroke

Wang and colleagues (2020) noted that the heart protection effect of RIC has been repeatedly confirmed in animal models and observational clinical trials; however, it has never been studied in patients with Takotsubo syndrome (TTS) after acute stroke in randomized clinical trials with a higher level of evidence.  These researchers presented the protocol of proof-of-concept study to examine if RIC can reduce cardiac injury and eventually improve the heart function and clinical outcomes of TTS patients after acute stroke.  A single-center, outcome-assessor-blinded RCT will be carried out to examine the effect of RIC in TTS patients after acute stroke.  Major eligibility criteria include TTS patients diagnosed with acute stroke, which can be confirmed on CT or MRI; patients aged 18 to 75 years; patients admitted to a hospital within 48 hours after the onset of acute stroke; and patients diagnosed with Takotsubo cardiomyopathy with an InterTAK Diagnostic Score of greater than or equal to 50.  A total of 60 eligible patients will be randomly allocated into either the RIC or the control group.  The primary end-point is a composite of death from any cause and major adverse cardiac and cerebrovascular events during the in-hospital period and at the 1- and 6-month follow-up.  This study has been approved by the Medical Ethics Committee of Xuanwu Hospital, Capital Medical University ([2017] 072).  The study findings will be presented at international conferences and published in a peer-reviewed journal.

Treatment of Ulcerative Colitis

In an explorative, randomized, sham-controlled clinical trial, Godskesen and colleagues (2020) examined the clinical and anti-inflammatory effects of RIC in patients with active ulcerative colitis (UC).  These researchers enrolled 22 patients with active UC in this study.  Participants were randomly assigned 1:1 to RIC (induced in the arm through 4 cycles of 5-min inflation and 5-min deflation of a BP cuff) or sham (incomplete inflation of the BP cuff) once-daily for 10 days.  Outcome variables were measured at baseline and on day 11.  When compared with sham, RIC did not affect inflammation in the UC patients measured by fecal calprotectin, plasma CRP, Mayo Score, Mayo Endoscopic Subscore, Nancy Histological Index or inflammatory cytokines involved in UC and RIC.  The mRNA and miRNA expression profiles in the UC patients were measured by RNA sequencing and multiplexed hybridization, respectively, but were not significantly affected by RIC.  These investigators used the Langendorff heart model to evaluate activation of the organ protective mechanism induced by RIC, but could not confirm activation of the organ protective mechanism in the UC patients.

Treatment of Vascular Cognitive Impairment

Hess and colleagues (2015) stated that RIC triggers endogenous protective pathways in distant organs such as the kidney, heart and brain, and represents an exciting new paradigm in neuro-protection. Remote ischemic conditioning  involves repetitive inflation and deflation of a BP cuff on the limb.  However, the exact mechanism of signal transmission from the periphery to the brain is not known, but both humoral factors and an intact nervous system appear to have critical roles.  Early-phase clinical trials have already been conducted to test RIC in the pre-hospital setting in acute ischemic stroke, and in subarachnoid hemorrhage for the prevention of delayed cerebral ischemia.  Furthermore, 2 small RCTs in patients with symptomatic intracranial atherosclerosis have shown that RIC can reduce recurrence of stroke and have neuro-protective activity.  The authors concluded that RIC represents a highly practical and translatable therapy for acute, sub-acute, and chronic neurological diseases with an ischemic or inflammatory basis.  They reviewed the principles and mechanisms of RIC, evidence from pre-clinical models and clinical trials that RIC is beneficial in neurological disease, and how the procedure might be used in the future in disorders such as vascular cognitive impairment and traumatic brain injury.

In a prospective, randomized, controlled study, Wang and colleagues (2017) evaluated the efficacy of RIC in patients with cerebral small-vessel disease.  A total of 30 patients with cerebral small-vessel disease-related mild cognitive impairment were enrolled in this trial.  Besides routine medical treatment, participants were randomized into the experimental group (n = 14) undergoing 5 cycles consisting of ischemia followed by re-perfusion for 5 minutes on both upper limbs twice-daily for 1 year or the control group (n = 16) who were treated with sham ischemia-reperfusion cycles.  The primary outcome was the change of brain lesions, and secondary outcomes were changes of cognitive function, plasma biomarkers, and cerebral hemodynamic parameters both at baseline and at the end of 1-year follow-up.  Compared with pre-treatment, the post-treatment white matter hyper-intensities volume in the RIC group was significantly reduced (9.10 ± 7.42 versus 6.46 ± 6.05 cm3; p = 0.020), whereas no significant difference was observed in the sham-RIC group (8.99 ± 6.81 versus 8.07 ± 6.56 cm3; p = 0.085).  The reduction of white matter hyper-intensities volume in the RIC group was more substantial than that in sham group (-2.632 versus -0.935 cm3; p = 0.049).  No significant difference was found in the change of the number of lacunes between 2 groups (0 versus 0; p = 0.694).  A significant treatment difference at 1 year on visuospatial and executive ability was found between the 2 groups (0.639 versus 0.191; p = 0.048).  RIC showed greater effects compared with sham-RIC on plasma triglyceride (-0.433 versus 0.236 mmol/L; p = 0.005), total cholesterol (-0.975 versus 0.134 mmol/L; p < 0.001), low-density lipoprotein (-0.645 versus -0.029 mmol/L; p = 0.034), and homocysteine (-4.737 versus -1.679 µmol/L; p = 0.044).  Changes of the pulsation indices of MCA from the baseline to 1 year were different between the 2 groups (right: -0.075 versus 0.043; p = 0.030; left: -0.085 versus 0.043; p = 0.010).  The authors concluded that RIC appeared to be potentially effective in patients with cerebral small-vessel disease in slowing cognition decline and reducing white matter hyper-intensities.  Moreover, they stated that this study was hypothesis-generating only, and there is a need to further test it in an adequately powered future study.

The authors stated that this study had several drawbacks.  First, sample size of this study was still small (n = 14 in the RIC group), and the follow-up time (1 year) was not long enough.  Second, these researchers only focused on ischemic brain lesions on conventional MRI and did not evaluate the microstructural changes underlying these lesions.  Third, these investigators found improvement in clinical performance, cerebral circulation, and volume of WMHs induced by RIC, but they did not determine the underlying mechanisms.

Prevention of Reperfusion Injury in ST-Segment-Elevation Myocardial Infarction

Verouhis and associates (2016) stated that previous studies indicate that RIC performed before PCI reduced infarct size in patients with STEMI.  It remains unclear whether remote conditioning affords protection when performed in adjunct to primary PCI.  In a prospective, multi-center trial, these investigators examined if remote ischemic per-postconditioning (RIperpostC) initiated after admission to the catheterization laboratory attenuates myocardial infarct size in patients with anterior STEMI.  A total of 93 patients with anterior STEMI were randomized to RIperpostC or sham procedure as adjunct to primary PCI.  RIperpostC was started on arrival in the catheterization laboratory by 5-min cycles of inflation and deflation of a BP cuff around the left thigh and continued throughout the PCI procedure.  Infarct size and myocardium at risk were determined by cardiac magnetic resonance at day 4 to 7.  The primary outcome was myocardial salvage index.  There was no significant difference in myocardial salvage index between the RIperpostC and control group (median of 48.5 % and IQR 30.9 % to 60.8 % versus 49.2 % [ IQR 42.1 % to 58.8 %]). Neither did absolute infarct size in relation to left ventricular myocardial volume differ significantly (RIperpostC 20.6 % [IQR 14.1 % to 31.7%] versus control 17.9 % [IQR 13.4 % to 25.0 %]).  The RIperpostC group had larger myocardial area at risk than the control group (43.1 % (IQR 35.4 % to 49.7 %) versus 37.0 % (IQR 30.8 % to 44.1 %) of the left ventricle, p = 0.03).  Peak value and area under the curve for troponin T did not differ significantly between the study groups.  The authors concluded that RIperpostC initiated after admission to the catheterization laboratory in patients with anterior STEMI did not confer protection against reperfusion injury.

McLeod and colleagues (2017) noted that RIC is a non-invasive therapeutic strategy that uses brief cycles of BP cuff inflation and deflation to protect the myocardium against ischemia-reperfusion injury.  In a systematic review and meta-analysis, these researchers determined the impact of RIC on myocardial salvage index, infarct size, and major adverse cardiovascular events when initiated before catheterization.  Electronic searches of Medline, Embase, and Cochrane Central Register of Controlled Trials were conducted and reference lists were hand searched; RCTs comparing PCI with and without RIC for patients with ST-segment-elevation MI were included.  Two reviewers independently screened abstracts, assessed quality of the studies, and extracted data.  Data were pooled using random-effects models and reported as MD and RR with 95 % CIs.  A total of 11 articles (9 RCTs) were included with a total of 1,220 patients (RIC + PCI = 643, PCI = 577).  Studies with no events were excluded from meta-analysis.  The myocardial salvage index was higher in the RIC +P CI group compared with the PCI group (MD: 0.08; 95 % CI: 0.02 to 0.14).  Infarct size was reduced in the RIC + PCI group compared with the PCI group (MD: -2.46; 95 % CI: -4.66 to -0.26).  Major adverse cardiovascular events were lower in the RIC + PCI group (9.5 %) compared with the PCI group (17.0 %; RR: 0.57; 95 % CI: 0.40 to 0.82).  The authors concluded that RIC appeared to be a promising adjunctive treatment to PCI for the prevention of reperfusion injury in patients with ST-segment-elevation MI; however, additional high-quality research is needed before a change in practice can be considered.  They noted that ongoing multi-center clinical trials should help elucidate the effect of RIC on clinical outcomes such a hospitalization, heart failure, and mortality.

The authors stated that this systematic review and meta‐analysis had several drawbacks:
  1. only RCTs in English were evaluated for inclusion.  The majority of the included studies were small and focused on the effect of RIC on biomarker release and other surrogate indicators of organ injury as opposed to clinical outcomes.  For the included trials that did report clinical outcomes, only 2 studies extended the assessment beyond 6 months, and the number of reported events was small.  Patient follow‐up of less than 1 year may be too short to detect long‐term benefit for patients undergoing RIC as an adjunct to primary PCI,
  2. attrition bias was judged to be high in 8 (72.7 %) of the included studies because many of the randomized patients did not complete imaging investigations needed to evaluate the primary outcome (e.g., myocardial infarct size) or were subsequently excluded from the final analysis, which may have introduced selection bias.  These missing patient outcome data presented a threat to the internal and external validity of the individual trial and the summary findings,
  3. to be included in the systematic review, studies investigating the use of RIC initiated after catheterization were included only if they also used RIC before balloon inflation.  This, along with variation in cycles of RIC before PCI, may have introduced an element of heterogeneity into the treatment protocols.  Studies comparing the use of local ischemic conditioning after catheterization versus PCI alone were excluded from the review.  In addition, for all included studies, the RIC protocol had to be initiated before reperfusion (per-conditioning); therefore, randomization occurred before PCI and before a definitive decision could be made as to whether the patient had met specific inclusion criteria.  It is unknown how many cycles of RIC were completed before PCI for the included studies and whether that affects the effect of RIC for acute STEMI patients, and
  4. all studies included in this review excluded patients who presented with cardiogenic shock or who underwent PCI following STEMI complicated by cardiac arrest, a subgroup of patients who may gain maximal benefit from the RIC technique.

Sepsis Management

Joseph and colleagues (2017) examined the effects of RIC on survival in sepsis in an animal model and evaluated alterations in inflammatory biochemical profiles.  These researchers hypothesized that RIC alters inflammatory biochemical profiles resulting in decreased mortality in a septic mouse model.  In this study, 8 to 12 week C57BL/6 mice received intra-peritoneal injection of 12.5-mg/kg lipopolysaccharide (LPS).  Septic animals in the experimental group underwent RIC at 0, 2, and 6 hours after LPS by surgical exploration and alternate clamping of the femoral artery.  Six 4-min cycles of ischemia-reperfusion were performed.  Primary outcome was survival at 5-day after LPS injection.  Secondary outcome was to assess the following serum cytokine levels: interferon-γ (IFN-γ), interleukin (IL)-10, IL-1β, and tumor necrosis factor-alpha (TNFα) at the baseline before LPS injection, 0 hour after LPS injection, and at 2, 4, 24 hours after induction of sepsis (RIC was performed at 2 hours after LPS injection).  Kaplan-Meier survival analysis and log-rank test were used.  ANOVA test was used to compare cytokine measurements.  These investigators performed experiments on 44 mice: 14 sham and 30 RIC mice (10 at each time-point).  Overall survival was higher in the experimental group compared to the sham group (57 % versus 21 %; p = 0.02), with the highest survival rate observed in the 2-hour post-RIC group (70 %).  On Kaplan-Meier analysis, 2-hour post-RIC group had increased survival at 5 days after LPS (p = 0.04) with HR of 0.3 (95 % CI: 0.09 to 0.98).  In the RIC group, serum concentrations of IFN-γ, IL-10, IL-1β, and TNFα peaked at 2 hours after LPS and then decreased significantly over 24 hours (p < 0.0001) compared to the baseline.  The authors concluded that RIC improved survival in sepsis and has the potential for implementation in the clinical practice.  They stated that early implementation of RIC may play an immune-modulatory role in sepsis; further studies are needed to refine understanding of the observed survival benefits and its implications in sepsis management.

Cour and colleagues (2019) noted that septic shock is a major public health problem that is associated with up to 50 % mortality.  Unfavorable outcomes are mainly attributed to multiple organ failure (MOF) resulting from an uncontrolled inflammatory response and ischemia-reperfusion processes.  REmote ischemic COnditioning (RECO) is a promising intervention to prevent ischemia-reperfusion injury.  These investigators hypothesized that RECO would reduce the severity of septic shock-induced MOF.  RECO in septic shock patients (RECO-Sepsis study) is an ongoing, prospective, multi-center, randomized, open-label trial, examining if RECO, as an adjuvant therapy to conventional treatment in septic shock, decreases the severity of MOF as assessed by the Sequential Organ Failure Assessment (SOFA) score.  Adult patients admitted to an ICU with documented or suspected infection, lactatemia of greater than 2 mmol/L, and treated with norepinephrine for less than 12 hours are potentially eligible for the study.  Non-inclusion criteria are: having expressed the wish not to be resuscitated, contraindication for the use of a brachial cuff on both arms, intercurrent disease with an expected life expectancy of less than 24 hours, cardiac arrest, and pregnant or breast-feeding women.  After enrollment, patients are randomized (n = 180) 1:1 to receive RECO or no adjunctive intervention.  RECO consists of 4 cycles of cuff inflation to 200 mmHg for 5 mins and then deflation to 0 mmHg for another 5 mins.  RECO is performed at inclusion and repeated 12 and 24 hours later.  The primary end-point is the mean daily SOFA score up to day 4 after inclusion.  Secondary outcomes include the need for organ support, hospital length of stay (LOS), and 90-day mortality.  The authors concluded that results of this proof-of-concept trial should provide information on the efficacy of RECO in patients with septic shock.

Treatment of Peripheral Arterial Disease

In a RCT, Shahvazian and colleagues (2017) hypothesized that RIPC occurring in diabetic patients with ankle brachial index (ABI) between 0.70 and 0.90 were included with peripheral arterial disease (PAD), would make the better coronary flow resulted in the increasing ABI.  A total of 60 subjects were randomly divided into 2 groups: intervention and control groups.  The intervention group was undergoing RIPC, and the control group was tested without RIPC.  RIPC was stimulated by giving 3 cycles of 5-min ischemia followed by 5-min reperfusion of both upper arms using a BP cuff inflated to 200 mm Hg (n = 30).  This was compared with no RIPC group that consisted of placing a deflated BP cuff on the upper limbs (n = 30).  The mean of ABI level before intervention in the RIPC and control group was 0.82 ± 0.055 and 0.83 ± 0.0603 (p = 0.347), respectively, with no significant difference.  It was 0.86 ± 0.066 in the RIPC group compared with the control group of 0.83 ± 0.0603 (p = 0.046).  Thus, levels of ABI were greater after intervention in the RIPC group.  The mean of ABI level increased from 0.82 ± 0.05 to 0.86 ± 0.06 in RIPC group (p = 0.008); the intervention group showed a significant increase in ABI.  The authors concluded that RIPC through using a simple, non-invasive technique, which composed of 3cycles of 5-min ischemia of both upper arms, showed a significant increase in ABI level in diabetic patients.  The authors stated that while the mechanism of this ABI-enhancing effect is not yet fully revealed; it has indicated a promising point in the clinical trials.  These researchers noted that no trial has been initiated to examine the effect of RIPC to lower the incidence of clinically relevant consequences of ischemia-reperfusion injury; more powerful studies are needed to study this issue in the next 3 to 4 years.

Hansen and colleagues (2019) noted that PAD is a major socioeconomic challenge in the diabetes mellitus (DM) community and non-surgical treatment options are limited.  As RIC improves vascular function and attenuates ischemia-induced tissue damage, these investigators examined the efficacy of RIC on vascular and neuronal function in type 2 DM patients (T2DM) with PAD.  They enrolled 36 T2DM patients with moderately reduced toe pressure (40 to 70 mm Hg) in a randomized, double-blinded, sham-controlled trial.  Patients were allocated to 12 weeks once-daily upper arm cuff-based treatment of either RIC treatment (4 cycles of 5-min ischemia followed by 5-min re-perfusion) or similar sham-device treatment.  Primary outcome was transcutaneous tissue oxygen tension of the instep of the feet.  Secondary outcomes were aortic pulse wave velocity, toe pressure and toe-brachial index.  Tertiary outcomes were markers of peripheral and autonomic nerve function.  These researchers enrolled 36 patients (83 % men).  Patients had a mean (SD) age of 70.7 years (6.8), DM duration of 18.4 years (8.3), HbA1c (gycated hemoglobin) of 59.7 mmol/mol (11.2); 80 % had peripheral symmetrical neuropathy.  The mean difference in change of transcutaneous tissue oxygen tension from baseline between the RIC- and sham-treated groups was -0.03 mm Hg ([95 % CI: -0.1 to 0.04], p = 0.438); RIC did not elicit any change in additional outcomes; 3 patients experienced transient skin petechiae in the treated arm.  The authors concluded that long-term repeated RIC treatment had no effect on tissue oxygenation, vascular or neuronal function in patients with T2DM and moderate PAD.

Traumatic Brain Injury

Pandit and colleagues (2018) examined the role of continuous (daily) RIC on cognitive and motor function following traumatic brain injury (TBI).  These researchers subjected 24 male C57BL mice to a cortical-controlled TBI.  Two hours after TBI, the animals were randomly allocated to the RIC group (n = 12) or the sham group (n = 12); RIC was induced by non-invasive external compression of the hind limb using an occlusive band (6 4-minute cycles/24 hours) for 6 consecutive days.  Before TBI, a baseline rotarod test and novel object recognition were performed.  Post-TBI rotarod and novel object recognition tests were performed on days 1 to 5, 7, 14, and 21.  After the animals were sacrificed on day 21, brain sections were analyzed using hematoxylin and eosin and glial fibrillary acidic protein staining to evaluate the hippocampal CA1 area for neuronal injury.  Both the RIC and sham groups had lower latency to fall compared with the baseline post-TBI.  The RIC animals had a higher latency to fall compared with the sham animals at all time-points, statistically significant after day 3, until day 21 post-TBI.  Both the RIC and sham groups had lower recognition index compared with the baseline post-TBI.  The RIC animals had a significantly higher recognition index than the sham animals after day 1, until day 21 post-TBI.  Hematoxylin and eosin and glial fibrillary acidic protein staining of the brain samples of the sham group revealed that more neurons in the hippocampal CA1 area appeared shrunken with eosinophilic cytoplasm and pyknotic nuclei compared with the brain samples of the RIC group.  The authors concluded that post-injury continuous RIC resulted in improved cognitive functions and motor coordination in a mouse model of moderate TBI.  They stated that further studies are needed to determine optimum dosage and frequency of this novel therapy to maximize its beneficial effects following TBI.

Prevention of Contrast-Induced Acute Kidney Injury

In a meta-analysis, Zhou and colleagues (2017b) examined the effect of RIC on contrast-induced acute kidney injury (CI-AKI) in patients undergoing intra-vascular contrast administration.  PubMed, Embase, and Cochrane Library were comprehensively searched to identify all eligible studies by March 15, 2017; RR and WMD with the corresponding 95 % CI were used to examine the treatment effect.  The heterogeneity and statistical significance were assessed with Q-test and Z-test, respectively.  A total of 16 RCTs including 2,175 patients were eventually analyzed.  Compared with the control group, RIC could significantly decrease the incidence of CI-AKI (RR = 0.58; 95 % CI: 0.46 to 0.74; p < 0.001), which was further confirmed by the trial sequential analysis.  Subgroup analyses showed that remote ischemic pre-conditioning (RIPrC) and remote ischemic post-conditioning (RIPoC) were both obviously effective, and peri-operative hydration might enhance the efficiency of RIC.  Furthermore, RIC significantly reduced the major adverse cardiovascular events within 6 months.  The authors concluded that RIC, whether RIPrC or RIPoC, could effectively exert reno-protective role in intra-vascular contrast administration and reduce the incidence of relevant adverse events (AEs).  Moreover, they stated that well-designed RCTs with unified criteria and large sample size are needed to evaluate the exact safety and efficacy of RIC in contrast administration.

The authors stated that this study had several drawbacks.  First, the duration of measuring relevant biomarkers to define CI-AKI differed among studies, from 16 hours to 96 hours, which could directly influence the rates of CI-AKI.  Second, serum creatinine (SCr) utilized in most of the included trials was not sensitive to detect kidney injury after contrast administration, resulting in a relatively low incidence of CI-AKI.  Third, renal function was evaluated just by some short-term outcomes without a long-term follow-up.  Fourth, most of the trials included in the present analysis were associated with PCI or coronary angiography (CA), only 4 RCTs referred to other contrast-related operations.  Finally, only 3 double-blind trials were included in this analysis, the outcomes would be interfered by aware participants.

Zhan and colleagues (2020) stated that numerous trials have examined the effect of RIC in preventing contrast-induced nephropathy (CIN) in patients receiving contrast medium (CM). In a meta-analysis, these researchers validated the role of RIC in preventing CIN.  They searched the PubMed, Embase, and Web of Science databases for eligible RCTs published before April 27, 2019; 2 investigators independently extracted basic characteristics from each study; ORs with corresponding 95 % CIs were used to examine the treatment effect.  A total of 18 studies comprising 2,503 patients were included in this meta-analysis. Compared with conventional therapy, RIC significantly reduced the risk of CIN (OR = 0.43, 95 % CI: 0.33 to 0.56, p < 0.05).  Subgroup analyses showed that the protective effect of RIC was stronger in the low-osmolar contrast media group (OR = 0.32; 95 % CI: 0.23 to  0.45, p < 0.05) and the non-diabetic group (OR = 0.39; 95 % CI: 0.29 to 0.53 p < 0.05).  RIC also significantly reduced major adverse cardiovascular events within the first 6 months (OR = 0.39; p < 0.05), but the influence was not present after long-term follow-up.  The authors concluded that the findings of this meta-analysis showed that RIC could effectively reduce CIN risk and decreased the short-term incidence of relevant AEs.  Furthermore, the effects of CIN were more pronounced in non-diabetic patients and with the use of low-osmolar contrast medium.  This meta-analysis of small trials suggested a possible protective effect of RIC on CIN and favored the performance of a large randomized trial with long‐term follow‐up and use of a standard method to further examine this strategy.

The authors stated that this analysis had several drawbacks.  First, although these investigators performed sub-analyses (which included the doses of contrast administered and race of the subjects) to evaluate the stability of the results, the sample size of some of the studies included in this analysis was relatively small, especially the subgroups of diabetic patients.  Second, among the different studies, there were no standardized methods of RIC, which needs future investigation.  Third, the concomitant use of other medications such as statins, angiotensin‐converting enzyme inhibitors, and nicorandil was frequently reported in patients with CHD, which might have biased the outcome because these medications might potentially affect renal function in an unknown manner.  However, since these different medications were randomly used by patients in both the control and experimental groups, their effect on renal function might be offset; nonetheless, this aspect needs further investigation.  Fourth, some RCTs did not report specific details of randomization.  Fifth, several studies have used renal function indicators, such as eGFR and serum creatinine, as the observation index in the trials.  However, the small number of studies and different data reporting in the trials resulted in an inability to assess changes in renal function before and after CM between the 2 groups.

Prevention of Ischemic Cerebrovascular Events in High-Risk Persons with Acute Non-Disabling Ischemic Cerebrovascular Events

Liu and associates (2018) stated that acute minor ischemic stroke (AMIS) or transient ischemic attack (TIA) is a common cerebrovascular event with a considerable high recurrence.  Prior research demonstrated the effectiveness of regular long-term RIC in secondary stroke prevention in patients with intra-cranial stenosis.  These researchers hypothesized that RIC can serve as an effective adjunctive therapy to pharmacotherapy in preventing ischemic events in patients with AMIS/TIA.  In a multi-center, single-arm, open-label, phase IIa clinical trial, these investigators examined the feasibility, safety, and preliminary efficacy of daily RIC in inhibiting cerebrovascular/cardiovascular events after AMIS/TIA.  Patients with AMIS/TIA (n = 165) received RIC as an additional therapy to secondary stroke prevention regimen; RIC consisted of 5 cycles of 5-min inflation (200 mmHg) and 5-min deflation of cuffs on bilateral upper limbs twice-daily for 90 days.  The anti-platelet strategy is based on individual physician's best practice: aspirin alone, clopidogrel alone, or combination of aspirin and clopidogrel.  These researchers will evaluate the recurrence rate of ischemic stroke/TIA within 3 months as the primary outcomes.  The authors concluded that the data gathered from this study will be used to examine if a further large-scale, multicenter, randomized controlled phase-II clinical trial is needed in patients with AMIS/TIA.

Prevention of Post-Stroke Depression

Zhao and colleagues (2017) stated that post-stroke depression (PSD) is a common neuropsychiatric complication of stroke.  However, due to the high expense and side effects of pharmacotherapy and the difficult-to-achieve of psychotherapy, the prevention and treatment of PSD are still far from satisfaction.  Inflammation hypothesis is now playing an essential role in the pathophysiological mechanism of PSD, and it may be a new preventive and therapeutic target.  Remote ischemic conditioning is a non-invasive and easy-to-use physical strategy, which has been used to protect brain (including ischemic and hemorrhagic stroke), heart and many other organs in clinical trials.  The underlying mechanisms of RIC include anti-inflammation, anti-oxidative stress, immune system regulation and other potential pathways.  The authors’ hypothesis is that RIC is a novel approach to prevent PSD.  The important implications of this hypothesis are that: RIC could be widely used in clinical practice to prevent PSD if the hypothesis were confirmed by animal experiment and clinical trial; and RIC would be thoroughly explored to test its effects on other neurobehavioral disorders (e.g., cognitive impairment).

Treatment of Acute Stroke Individuals Undergoing Thrombectomy

Zhao and colleagues (2018) noted that RIC has been demonstrated to be safe and feasible for patients with acute ischemic stroke (AIS), as well as for those receiving intravenous thrombolysis.  In a pilot study, these investigators examined the safety and feasibility of RIC for AIS patients undergoing endovascular treatment (ET).  Patients with AIS who were suspected of having an emergent large-vessel occlusion in the anterior circulation and who were scheduled for ET within 6 hours of ictus were included in this trial; 4 cycles of RIC were performed before re-canalization, immediately following re-canalization, and once-daily for the subsequent 7 days.  The primary outcome was any serious RIC-related AEs.  A total of 20 subjects, aged 66.1 ± 12.1 years, were recruited.  No subject experienced serious RIC-related AEs.  The intra-cranial pressure, cranial perfusion pressure, mean arterial pressure (MAP), heart rate, MCA peak systolic flow velocity, and pulsatility index did not change significantly before, during, or after the limb ischemia (p > 0.1 for all).  Of 80 cycles, 71 (89 %) were completed before re-canalization and 80 (100 %) were completed immediately after re-canalization; 444 of 560 cycles (78 %) were completed within 7 days post-treatment.  No patients had to stop RIC because it affected routine clinical managements; 6 subjects (30 %) experienced intra-cerebral hemorrhage, which was symptomatic in 1 case (5 %).  At the 3-month follow-up, 11 subjects (55 %) had achieved functional independence, and 2 subjects (10 %) died.  The authors concluded that RIC appeared to be safe and feasible for patients with AIS undergoing ET.  Moreover, they stated that further studies are needed to confirm these results and determine the efficacy of RIC in this patient population.

The authors stated that this study had several drawback.  First, this was a single‐armed study, and data were not compared with control group.  Instead, the data of before, during, and after the limb ischemia were self‐compared, and the clinical outcomes were compared with those of previous studies.  Second, the RIC protocol used in this study was rather pragmatic, and the optimal protocol for this patient population needs further investigations.  Finally, the trend of improvement in clinical outcome was not powered to determine the efficacy of RIC in patients with AIS who were treated with ET, and this requires further urgent investigation, which is planned in the REVISE‐2, a phase-II, parallel‐group study.

In a Cochrane review, Zhao and colleagues (2018) examined the benefits and harms of RIC for preventing ischemic stroke and for treating people with ischemic stroke and those at risk for ischemic stroke.  These investigators searched the Cochrane Stroke Group Trials Register (January 16, 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (January 2018), Medline Ovid (1946 to January 2018), Embase Ovid (1974 to January 2018), Web of Science Core Collection (1950 to January 2018) and 3 Chinese databases (January 2018).  They also searched 4 ongoing trials registers, reference lists, and conference proceedings and included RCTs comparing RIC with sham RIC or medical management in people with ischemic stroke or at risk of ischemic stroke.  Two review authors independently selected studies, assessed trial quality and risk of bias, and extracted data.  These researchers used the GRADE approach to assess the quality of the evidence.  They included 7 trials, involving 735 participants; and analyzed the effects of RIC on preventing and treating ischemic stroke, respectively.  These researchers evaluated risk of bias and judged it to be low for generation of allocation sequence in 6 studies and unclear in 1 study; unclear for allocation concealment in 4 studies and low in 3 studies; high for incomplete outcome data (attrition bias) in 5 studies and low in 2 studies; high for blinding in 3 studies and low in 4 studies; low for selective reporting; and high for other sources of bias in 6 studies and low in 1 study.  The authors included 3 trials (involving 371 participants) in the analysis of the effects of RIC on ischemic stroke prevention.  In people with symptomatic intra-cerebral artery stenosis, recurrent stroke was significantly reduced by RIC (RR 0.32, 95 % CI: 0.12 to 0.83; 2 trials, 182 participants, low-quality evidence).  In people with carotid stenosis undergoing carotid stenting, there was no significant difference in the incidence of ischemic stroke between participants treated with RIC and non-RIC (RR 0.22, 95 % CI: 0.01 to 4.03; 1 trial, 189 participants, low-quality evidence); however the stroke severity (assessed by infarct volume) was significantly lower in participants treated with RIC (MD -0.17 ml, 95 % CI: -0.23 to -0.11; 1 trial, 189 participants, low-quality evidence); AEs associated with RIC were significantly higher in participants treated with RIC (RR 10.91; 95 % CI: 2.01 to 59.28; 3 trials, 371 participants, low-quality evidence), but no severe AE was attributable to RIC treatment.  No participants experienced death or cardiovascular events during the period of the studies; and no trial reported hemorrhagic stroke or improvement in neurological, phycological or cognitive impairment.  They included 4 trials (involving 364 participants) in the analysis of the effects of RIC on ischemic stroke treatment.  In acute ischemic stroke, for people receiving intravenous thrombolysis, the rate of death or dependency was significantly increased by RIC treatment compared with non-RIC treatment (RR 2.34; 95 % CI: 1.19 to 4.61; 1 trial, 285 participants, low-quality evidence).  In people with acute ischemic stroke, there was no significant difference between RIC and non-RIC for reducing stroke severity as assessed by the National Institutes of Health Stroke Scale score and the final infarct volume (SMD -0.24 ml, 95 % CI: -1.02 to 0.54; 2 trials, 175 participants, very low quality evidence).  There was no significant difference between RIC and non-RIC for improving the psychological impairment (SMD -0.37 points, 95 % CI: -1.15 to 0.41; 1 trial, 26 participants, very low quality evidence) and the cognitive impairment (SMD -0.26 points; 95 % CI: -0.72 to 0.21; 3 trials, 79 participants, low-quality evidence) in people with acute ischemic stroke and cerebral small vessel disease.  No trial reported ischemic stroke, recurrent ischemic stroke, improvement in neurological impairment, hemorrhagic stroke, cardiovascular events, and RIC associated AEs.  The authors found low-quality evidence that RIC may reduce the risk of recurrent stroke in participants with intra-cerebral artery stenosis and reduce stroke severity in participants undergoing carotid stenting, but it may increase death or dependence in participants with acute ischemic stroke who are undergoing intravenous thrombolysis.  However, there was considerable uncertainty about these conclusions because of the small number of studies and low quality of the evidence.

Treatment of Cerebral Ischemia

Wang and colleagues (2018) examined the effects of remote limb ischemic post-conditioning (RLIPostC) on synaptogenesis in an experimental stroke rat model.  Sprague-Dawley rats were subjected to left middle cerebral artery occlusion (MCAO) and were randomly divided into a control group, an RLIPostC group and a sham group.  The RLIPostC group received 3 cycles of RLIPostC treatment immediately after re-perfusion (10 minutes ischemia and 10 minutes re-perfusion in bilateral femoral artery).  The neurological function was assessed by neurological deficit scores and the foot fault test at days 7 and 14 after MCAO.  At day 14 after MCAO, the infarct volume and edema were determined by cresyl violet (CV) staining and by measuring brain water content, respectively.  Synaptogenesis was evaluated by Western blotting and immunofluorescence staining.  Results showed that RLIPostC treatment significantly promoted the recovery of behavioral function, reduced infarct volume and brain edema, and increased the expressions of SYN1, PSD95 and GAP43.  The authors concluded that these findings confirmed that RLIPostC treatment for cerebral ischemia was safe and effective.  A possible molecular mechanism of the beneficial effects of RLIPostC treatment may be the promotion of synaptogenesis.

Prevention of Progression of White Matter Hyperintensities and Ameliorating Cognitive Impairment in Individuals with Intra-Cranial Atherosclerotic Stenosis

Zhou and colleagues (2019) stated that their previous study revealed that RIC reduced the incidence of stroke or transient ischemic attack (TIA) in octo- and nonagenarians with intra-cranial atherosclerotic stenosis (ICAS).  These investigators examined if RIC would influence the progression of white matter hyperintensities (WMHs) and cognitive impairment in the same group of patients.  A total of 58 patients with ICAS were randomly assigned in a 1:1 ratio to receive standard medical treatment with RIC (n = 30) versus sham-RIC (n = 28).  The RIC protocol consisted of 5 cycles of alternating 5-min ischemia and 5-min re-perfusion applied in the bilateral upper arms twice-daily for 300 days.  The efficacy outcomes included WMHs change on T2 FLAIR sequences, estimated by the Fazekas scale and Scheltens scale, cognitive change as assessed by the MMSE and MoCA, and some clinical symptoms within 300-day follow-up.  Compared with the baseline, RIC treatment significantly reduced Fazekas and Scheltens scores at both 180-day (both p < 0.05) and 300-day (both p < 0.01) follow-ups, whereas no such reduction was observed in the control group.  In the RIC group, Fazekas scores were significantly lower at 300-day follow-up (p < 0.001) while Scheltens scores were significantly lower at both 180-day and 300-day follow-ups (both p < 0.001), as compared with the control group.  There were statistically significant between-group differences in the overall MMSE or MoCA scores, favoring RIC at 180-day and 300-day follow-ups (all p < 0.05).  The authors concluded that RIC may serve as a promising adjunctive to standard medical therapy for preventing the progression of WMHs and ameliorating cognitive impairment in very elderly patients with ICAS.  These preliminary findings need to be validated by well-designed studies.

Prevention of Radial Artery Occlusion

Liu and colleagues (2019) examined the influence of RIC on radial artery occlusion (RAO) and distinguished the risk factors for RAO.  A total of 640 consecutive patients who prospectively underwent trans-radial artery coronary angiography (TRACA) (322 patients received RIC before TRACA) were enrolled.  RIC was not performed in 318 patients.  RAO was estimated using Doppler ultrasonography (US) following the procedure.  Patients were divided into 2 groups according to the protocol of RIC: RIC and non-RIC.  The rate of RAO was significantly lower in the RIC group than in the non-RIC group.  Patients were divided into 2 groups according to the patency of radial artery: radial artery patency (RAP) and RAO.  The radial artery diameter was significantly narrower in the RAO group (2.31 ± 0.53 mm) than in the RAP group (2.59 ± 0.47 mm).  The rate of applying β-blocker was significantly higher in the RAP group (69 %) than in the RAO group (41 %).  The rate of applying trimetazidine was significantly higher in the RAP group (49.1 %) than in the RAO group (17.6 %).  The multiple logistic regression analysis using radial artery diameter, RIC, β-blocker, and trimetazidine treatments revealed that small radial artery diameter, lack of β-blockers, and RIC were independent predictors of RAO.  The authors concluded that RIC might help in improving the rate of RAO.  The multiple logistic regression analysis showed that the lack of β-blockers, RIC, and small radial artery diameter were independent predictors of RAO.  These findings need to be validated in well-designed studies.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

There are no specific codes for remote ischemic conditioning:

Other CPT codes related to the CPB:

37184 Primary percutaneous transluminal mechanical thrombectomy, noncoronary, non-intracranial, arterial or arterial bypass graft, including fluoroscopic guidance and intraprocedural pharmacological thrombolytic injection(s); initial vessel
37187 Percutaneous transluminal mechanical thrombectomy, vein(s), including intraprocedural pharmacological thrombolytic injections and fluoroscopic guidance

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive) :

A40.0 - A41.9 Sepsis
C00.0 - D09.9 Malignant and in situ neoplasms
F32.81 - F32.89 Other depressive episodes [post-stroke depression]
G31.84 Mild cognitive impairment, so stated
I20.0 - I25.9 Ischemic heart diseases
I50.1 - I50.9 Heart failure
I51.81 Takotsubo syndrome
I60.00 - I60.9 Nontraumatic subarachnoid hemorrhage
I61.0 - I61.9 Nontraumatic intracerebral hemorrhage
I63.30 - I63.9 Cerebral infarction [stroke]
I66.01 - I66.9 Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction
I67.82 Cerebral ischemia
I69.010 - I69.019 Cognitive deficits following nontraumatic subarachnoid hemorrhage
I69.110 - I69.119 Cognitive deficits following nontraumatic intracerebral hemorrhage
I69.210 - I69.219 Cognitive deficits following other nontraumatic intracranial hemorrhage
I69.310 - I69.319 Cognitive deficits following cerebral infarction
I69.810 - I69.819 Cognitive deficits following other cerebrovascular disease
I69.910 - I69.919 Cognitive deficits following unspecified cerebrovascular disease
I70.0 - I70.72 Atherosclerosis
I73.00 - I73.9 Other peripheral vascular diseases
I74.2 Embolism and thrombosis of arteries of the upper extremities [radial artery occlusion]
K51.90 Ulcerative colitis, unspecified, without complications
K51.911 - K51.919 Ulcerative colitis, unspecified, with complications
N17.9 Acute kidney failure, unspecified [acute kidney injury]
R90.82 White matter disease, unspecified [white matter hyperintensities]
T86.818 Other complications of lung transplant [primary graft dysfunction]
Z94.0 Kidney transplant status [enhancement of renal function]

The above policy is based on the following references:

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