- Email: [email protected]
Remote Ischemic Preconditioning in High-risk Cardiovascular Surgery Patients: A Randomized-controlled Trial
ADULT – Original Submission
Remote Ischemic Preconditioning in High-risk Cardiovascular Surgery Patients: A Randomized-controlled Trial Nicole S. Coverdale, PhD,* Andrew Hamilton, MD,* Dimitri Petsikas, MD,* R. Scott McClure, MSc, MD,† Paul Malik, MD,‡ Brian Milne, MD,§ Tarit Saha, MD,§ David Zelt, MD,* Peter Brown, MD,* and Darrin M. Payne, MSc, MD* Remote ischemic preconditioning (RIPC) may reduce biomarkers of ischemic injury after cardiovascular surgery. However, it is unclear whether RIPC has a positive impact on clinical outcomes. We performed a blinded, randomized controlled trial to determine if RIPC resulted in fewer adverse clinical outcomes after cardiac or vascular surgery. The intervention consisted of 3 cycles of RIPC on the upper limb for 5 minutes alternated with 5 minutes of rest. A sham intervention was performed on the control group. Patients were recruited who were undergoing (1) high-risk cardiac or vascular surgery or (2) cardiac or vascular surgery and were at high risk of ischemic complications. The primary end point was a composite outcome of mortality, myocardial infarction, stroke, renal failure, respiratory failure, and low cardiac output syndrome, and the secondary end points included the individual outcome parameters that made up this score, as well as troponin-I values. A total of 436 patients were randomized and analysis was performed on 215 patients in the control group and on 213 patients in the RIPC group. There were no differences in the composite outcome between the 2 groups (RIPC: 67 [32%] and control: 72 [34%], relative risk [0.94 {0.72-1.24}]) or in any of the individual components that made up the composite outcome. Additionally, we did not observe any differences between the groups in troponin-I values, the length of intensive care unit stay, or the total hospital stay. RIPC did not have a beneficial effect on clinical outcomes in patients who had cardiovascular surgery. Semin Thoracic Surg ■■:■■–■■ © 2017 Elsevier Inc. All rights reserved. Keywords: remote ischemic preconditioning, cardiovascular surgery, ischemia-reperfusion *Department of Surgery, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada † Department of Surgery, Libin Cardiovascular Institute of Alberta, Foothills Medical Center, University of Calgary, Calgary, Alberta, Canada ‡ Department of Medicine, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada § Department of Anesthesiology and Perioperative Medicine, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada This study was funded by the Southeastern Ontario Academic Medical Organization’s Innovation Fund. The authors report no conflicts of interest. Funding was provided by the Southeastern Ontario Academic and Medical Organization. Clinical trial registration: ClinicalTrials.gov: NCT01328912. Research Ethics Board approval: Queen’s University and Affiliated Teaching Hospitals #6005871, initial approval on June 8, 2011. Address reprint requests to Darrin M. Payne, MSc, MD, Department of Surgery, Kingston General Hospital, Victory 3, 76 Stuart St, Kingston, ON, Canada K7L 2V7. E-mail: [email protected]
Troponin-I values 6 hours after vascular surgery and on postoperative days 1 and 2. Central Message The application of remote ischemic preconditioning before high-risk vascular or cardiac surgery did not improve clinical outcomes as assessed with a composite end point measure. Perspective Statement Previously, remote ischemic preconditioning (RIPC) was associated with improvements in cardiac biomarkers, but it was unclear how these findings would translate to clinical outcomes. We investigated whether RIPC was associated with improved outcomes after high-risk cardiac or vascular surgery. We did not find a difference between RIPC and the control intervention. RIPC does not confer any benefit during high-risk cardiovascular surgery.
INTRODUCTION Cardiovascular surgical interventions are among the most common surgical procedures performed worldwide. These procedures are associated with a predictable array of adverse events. Perioperative complications of cardiac and vascular surgery include myocardial infarction (MI), stroke, renal failure, and death.1-5 With an aging patient population and an increasing number and degree of concomitant comorbid conditions, the risk associated with these procedures increases proportionally. Adverse events associated with cardiovascular surgical procedures can have dramatic consequences on patients and families, including pain, prolonged
1043-0679/$-see front matter © 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1053/j.semtcvs.2017.09.001
1
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY hospitalization, permanent disabilities, and loss of independence. The already overburdened health-care system suffers as well, with increased attendant costs. Thus, there is an appropriate interest in interventions that may mitigate these risks. During cardiac and vascular surgery, restoration of blood flow after bypass or clamping can induce ischemia-reperfusion injury that is defined as the death of cells not due to the ischemia itself.6,7 Remote ischemic preconditioning (RIPC) refers to the application of transient periods of reduced or absent blood supply to a distant tissue bed that is subsequently reperfused. The idea is that the initial ischemic insult will confer some degree of protection from a secondary ischemic insult.8 Over the last decade, this idea has transitioned from animal to human models, and the ischemic preconditioning is performed at a remote tissue bed (such as an arm or a leg) with the goal of inducing a protective response in target tissues and organs (such as the heart, kidneys, or brain). Although the underlying mechanism of the purported benefits of RIPC remains unclear, it has been proposed that humeral and neural signals transmitted from remote tissues impact intracellular signaling and mitochondrial functioning within target tissues, decreasing proinflammatory gene expression and function.9 Initial human studies of RIPC have shown promise as surrogate biomarkers of end organ damage are reduced during various surgical interventions.10-12 However, how such findings would translate to clinical outcomes is unclear. Recently, 2 multicenter randomized control trials examining outcomes after cardiac surgery have found no benefit of RIPC.13,14 In addition, a pilot trial examining clinical end points after vascular surgery has found no difference between RIPC and control groups.15 Previous studies have examined the impact of RIPC in high-risk cohorts, where risk was assessed based on the European System for Cardiac Operative Risk Evaluation (EuroSCORE).13,16 However, surgical risk assessment tools have inherent limitations, and it has been recognized that true risk assessment can be overestimated, possibly in some types of surgery more than others.17 We chose to examine patients deemed to be at high clinical risk, as judged by having a high-risk surgery, having a repeat surgery, or those who had substantial surgical risk factors. Considering their increased risk of ischemic complications, this cohort could potentially realize important benefits from any protective effect incurred by RIPC. We hypothesized that RIPC would improve clinical outcomes in a cohort of high-risk vascular and cardiac surgical patients. METHODS This trial (NCT01328912) was approved by the Queen’s University Health Sciences and Affiliated Hospitals Research Ethics Board. All participants provided informed consent. Participants Eligible participants were adults over the age of 18 who were undergoing either (1) cardiac or vascular surgical procedures and were at increased risk of suffering ischemia-related events, (2) preoperative screening indicating cardiovascular disease, or (3) undergoing higher-risk surgery. We considered there to be an increased risk of ischemia-related events there was preoperative
2
evidence of prior MI, unstable angina, an ejection fraction less than 40%, a prior stroke or transient ischemic attack, chronic renal insufficiency (estimated glomerular filtration rate less than 60 mL/ min), or limb claudication. Preoperative screening indicating cardiovascular disease included a positive MIBI scan or an angiogram, a cardiac computed tomography, or a magnetic resonance imaging with evidence of 1 or more coronary arteries with greater than 70% stenosis, or a carotid Doppler ultrasound showing greater than 70% stenosis, uni- or bilaterally. High-risk surgery was defined as a combined valve-coronary artery bypass graft (CABG) surgery, double valve surgery, aortic surgery, left ventricle aneurysm repair, redo surgery, or open abdominal or thoracoabdominal aneurysm repair. Participants underwent follow-up assessments at 30 days, which were performed mainly by telephone interview. Intervention This was a single-center study and the participants were randomized in a 1:1 ratio to receive the RIPC or a sham RIPC treatment (control) by a biostatistician. Randomization was done with a computer-generated scheme and opaque sealed envelopes. The patients were enrolled and assigned to intervention by a research nurse. Surgeons, anesthetists, and postoperative care providers were blind to the group assignments, and the patients were instructed not to disclose whether they had received the intervention. The intervention was initially planned to occur once the patient was inside the operating room (OR) under anesthesia. The protocol was modified such that the RIPC intervention occurred immediately before the patient was transferred to the OR. This change was made due to time constraints within the OR as well as difficulty and restrictions of line placement (arterial lines or intravenous lines) that were not available for use and threatened blinding with a blood pressure cuff cycling. The intervention was well tolerated and no significant complaints were voiced by the patients. Patients were transferred to the OR immediately following the completion of the RIPC intervention, where access and monitoring lines were placed and the operation commenced. The window of protection provided by RIPC was postulated to be approximately 2 hours18; therefore, we were well within this time frame. A blood pressure cuff was placed on the patient’s upper arm. The RIPC stimulus consisted of 3 cycles of 5 minutes of ischemia with the cuff inflated to 200 mm Hg alternated with 5 minutes of cessation of pressure. The intervention occurred in isolation with only the research nurse and the patient present, to ensure all OR staff and caregivers remained blinded. The control group received similar treatment, in terms of blood pressure cuff application and segregation, although the cuff was not inflated. All patients were instructed not to disclose whether they had received the intervention. Procedures The anesthetic protocol was performed as per the standard practices of the attending anesthetist. In general, anesthesia was induced with intravenous midazolam, opiate (fentanyl or sufentanil), propofol or etomidate, and rocuronium. Anesthesia was maintained with desflurane, sevoflurane, or propofol infusion with opiate and
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY
Outcomes The primary outcome was a composite measure that incorporated all-cause mortality, MI, stroke, respiratory failure, acute renal failure, and low cardiac output syndrome. Definitions of the major clinical end points are provided in Supplementary Appendix S1. Secondary outcomes included the individual components of the composite end point, troponin I at 6 hours, postoperative days 1 and 2, length of intensive care hospital stay, and total length of hospital stay.
type I error equal to 0.05, power equal to 0.80, and an RRR of 40%, we required 198 patients per group, which was bolstered by 10% to account for any losses to follow-up (total of 436 patients). The composite outcome and its components were compared between groups with a chi-square test. The relative risk was also calculated. Subgroup analysis was performed to examine the effect of RIPC on the composite outcome within sexes and for those less than 70 years of age vs those who were 70 years or older. Troponin-I values and length of stay were compared between the groups with a Mann-Whitney test. The same statistical analysis was performed on the subgroups of vascular surgery only and cardiac surgery only. Before the trial commencement, we also planned to perform an analysis comparing those who had general anesthesia with those who had regional anesthesia. However, this was abandoned because not enough patients received regional anesthetics. All analysis was done with SPSS 20.0.
Statistical Analysis Sample size was calculated based on previous research conducted on higher-risk patients undergoing surgery that reported outcomes between 15% and 30% for clinical major adverse cardiac or cerebrovascular event.19,20 The largest randomized trial looking at RIPC in open abdominal aneurysm repair reported myocardial injury and infarction to be 39% and 27%, respectively, and acute renal injury to be 30%,21 with a relative risk reduction (RRR) of 82% for MI, 75% for renal dysfunction, and 33% for mortality.21 Patients undergoing percutaneous coronary intervention were randomized to RIPC vs control and reported a similar composite end point of major adverse cardiac or cerebrovascular event with an RRR of 67% with RIPC-randomized patients22 We therefore assumed an event rate of 30% and an RRR of 40% with RIPC. Assuming a
RESULTS Figure 1 summarizes patient recruitment into the trial, which occurred between February 2012 and November 2015. The final analysis was performed on 215 patients in the control group and on 213 patients in the RIPC group, and recruitment ceased when we reached our target sample size. The control and the RIPC groups were well matched in terms of sex, age, body mass index, and prevalence of surgical risk factors (Table 1). Table 2 summarizes the surgical procedures performed in each group. Roughly one-third of patients in each group underwent vascular surgery, whereas twothirds underwent cardiac surgery. Of the cardiac surgeries, CABG was most commonly performed, whereas peripheral revascularization occurred most often in vascular patients. For the cardiac surgical
rocuronium administered, as required. Some patients having peripheral vascular repair or abdominal aneurysm surgery received epidural anesthesia (Supplementary Table S1). Postoperative analgesia was managed at the discretion of the attending surgeon and postoperative caregivers, and typically included combinations of intravenous and oral morphine and hydromorphone.
Figure 1. Consolidated Standards of Reporting Trials diagram.
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
3
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY Table 1. Baseline Patient Characteristics Characteristic
Control (n = 215)
RIPC (n = 213)
Male sex, no. (%) Age (y) BMI (kg/m2) Prior diagnoses, no. (%) Diabetes Dyslipidemia Hypertension Renal insufficiency* Ejection fraction <40% Current tobacco use Myocardial infarction Peripheral vascular disease Cerebrovascular accident or transient ischemic attack Chronic obstructive pulmonary disease
166 (77) 68 ± 9 28.6 ± 4.90
178 (84) 69 ± 10 28.8 ± 5.0
76 (35) 149 (69) 160 (74) 100 (47) 15 (7) 44 (20) 71 (33) 62 (29) 47 (22)
77 (36) 149 (70) 172 (81) 87 (41) 17 (8) 41 (19) 66 (31) 53 (25) 42 (20)
27 (13)
37 (17)
BMI, body mass index. *Renal insufficiency was defined as having an estimated glomerular filtration rate less than 60 mL/min.
patients, there were no differences in the cardiopulmonary bypass time or the aortic cross-clamp time between the groups. Our primary outcome, the number of composite outcomes, was not different between the groups. There were no differences between the groups in mortality, MI, stroke, respiratory failure, renal failure, or low cardiac output syndrome (Table 3). The subgroup analysis of only cardiac surgery patients did not reveal any differences (Table 4). Similarly, no differences were observed in RIPC vs control when vascular surgery patients were examined independently
Figure 2. Subgroup relative risk of the composite outcome for RIPC vs control.
(Table 5). Subgroup analysis also indicated that, within each sex and when groups were subdivided based on age, there were no differences between the control and RIPC for the composite outcome (Fig. 2). We also compared troponin-I values between groups 6 hours after the end of surgery and on postoperative days 1 and 2, and did not observe any differences between the control and RIPC when all patients were analyzed together or when cardiac and vascular patients were analyzed separately (Fig. 3A-C). Finally, there were no differences in the length of intensive care unit stay or total hospital stay between the groups.
Table 2. Operative Characteristics Surgery
Control (n = 215)
RIPC (n = 213)
Cardiac, no./total no. (%) CABG 1 graft 2 grafts 3 grafts 4+ grafts Valve CABG + valve Other Cardiopulmonary bypass time (min) Aortic cross-clamp time (min) Reoperation, no./total no. (%) Vascular, no./total no. (%) Abdominal aortic aneurysm repair Carotid endarterectomy Peripheral vasculature Other
147/215 (69) 77 4 23 27 23 20 33 17 99 ± 63
142/213 (67) 62 2 16 30 14 14 45 21 102 ± 48
77 ± 48 15/215 68/215 (31) 14
78 ± 39 13/213 71/213 (33) 18
18 28 7
16 33 4
4
DISCUSSION After CABG surgery, ischemia-reperfusion injury to the heart may occur as a result of the re-establishment of blood flow due to the procedure or due to the use of cardiopulmonary bypass. The same type of injury may affect other organs during vascular surgery, and the deleterious impact on postsurgical morbidity and mortality has been recognized for decades.23-25 Recent proof-of-concept clinical studies in humans examining biomarkers of organ damage have suggested that RIPC may have a favorable effect not only on the target organs that were ischemic but also on other organ systems.12,26 Therefore, the purpose of the present study was to determine if RIPC was protective against adverse clinical outcomes after cardiac or vascular surgery in high-risk patients. We did not observe any differences between the RIPC and the control group for our primary composite outcome or any of the individual components that made up the estimate. Our findings are in line with 2 recently published trials that examined outcomes at 90 days after cardiac surgery and at 12 months after CABG.13,14 We included only high-risk patients because they could potentially receive the most benefit from any amelioration
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY Table 3. 30-Day Outcomes and Treatment Effect Outcome
Control (n = 215)
RIPC (n = 213)
Relative Risk (95% CI)
P Value
Composite outcome, no. (%) Mortality Myocardial infarction Stroke Respiratory failure Renal failure Low cardiac output syndrome Hospital stay (days ± standard deviation) ICU stay (days ± standard deviation)
72 (34) 5 (2) 12 (6) 5 (2) 11 (5) 43 (20) 37 (17) 6.9 ± 5.6 2.3 ± 3.1
67 (32) 3 (1) 9 (4) 5 (2) 12 (6) 37 (17) 28 (13) 6.7 ± 4.8 2.5 ± 3.7
0.94 (0.72-1.24) 0.61 (0.15-2.50) 0.77 (0.33-1.76) 1.01 (0.30-3.4) 1.10 (0.50-2.44) 0.87 (0.58-1.29) 0.76 (0.49-1.20) – –
0.73 0.73 0.67 0.76 0.98 0.57 0.30 0.80 0.96
CI, confidence interval; ICU, intensive care unit.
Table 4. 30-Day Outcomes and Treatment Effect for Cardiac Surgery Patients Outcome
Control (n = 147)
RIPC (n = 142)
Relative Risk (95% CI)
P Value
Composite outcome, no. (%) Mortality Myocardial infarction Stroke Respiratory failure Renal failure Low cardiac output syndrome Hospital stay (days ± standard deviation) ICU stay (days ± standard deviation)
61 (42) 4 (3) 10 (7) 4 (3) 9 (6) 38 (26) 31 (21) 7.5 ± 5.5 3.0 ± 3.4
52 (37) 3 (2) 6 (4) 3 (2) 11 (8) 33 (23) 21 (15) 7.1 ± 4.3 2.9 ± 3.2
0.88 (0.66-1.18) 0.78 (0.18-3.41) 0.62 (0.23-1.66) 0.78 (0.18-3.41) 1.27 (0.54-2.96) 0.90 (0.60-1.35) 0.70 (0.42-1.16) – –
0.47 0.96 0.48 0.96 0.76 0.71 0.22 0.60 0.76
CI, confidence interval; ICU, intensive care unit.
Table 5. 30-Day Outcomes and Treatment Effect for Vascular Surgery Patients Outcome
Control (n = 68)
RIPC (n = 71)
Relative Risk (95% CI)
P Value
Composite outcome, no. (%) Mortality Myocardial infarction Stroke Respiratory failure Renal failure Low cardiac output syndrome Hospital stay (days ± standard deviation) ICU stay (days ± standard deviation)
11 (16) 1 (2) 2 (3) 1 (2) 2 (3) 5 (7) 6 (9) 5.6 ± 5.4 0.9 ± 1.5
15 (21) 0 (0) 3 (4) 2 (3) 1 (2) 4 (6) 7 (10) 5.8 ± 5.7 1.6 ± 4.5
1.31 (0.65-2.64) – 1.44 (0.25-8.33) 1.92 (0.18-20.64) 0.48 (0.04-5.16) 0.77 (0.22-2.73) 1.12 (0.40-3.16) – –
0.60 0.31 0.96 0.97 0.97 0.95 0.94 0.97 0.63
CI, confidence interval; ICU, intensive care unit.
in adverse clinical ischemic events. Hausenloy et al also examined a higher-risk population of patients, as judged by a preoperative EuroSCORE of 5 or higher.13 Because of the inherent difficulty in surgical risk scoring systems accurately predicting mortality and adverse events,17 we based our inclusion criteria on clinical indicators of risk. We included patients based on a planned high-risk operation, or documented evidence of comorbid ischemic or cardiovascular disease over and above that which was the primary indication for their surgery. Approximately one-third of our study population was composed of patients undergoing high-risk vascular surgery. We found no differences in either clinical outcomes or biomarkers in this subgroup. This result is in keeping with other studies that have examined RIPC in patients having abdominal aneurysm repair, carotid endarterectomy, or peripheral revascularization that have reported no differences between the intervention and the
Seminars in Thoracic and Cardiovascular Surgery
control group in terms of outcomes or biomarkers.15,27 Despite restricting our enrolment to only high-risk patients, we did not observe any differences between groups as a result of the intervention. We selected the outcomes that made up the composite end point based on previous studies that found changes in biomarkers related to the particular organ system. Although the majority of studies have focused on how RIPC affects the heart,10,28 previous studies have also documented reduced creatinine levels after RIPC during CABG12 and improved the alveolar-arterial oxygen tension ratio during abdominal aneurysm repair.11 Therefore, we included renal failure and respiratory failure as outcomes in addition to stroke and the cardiac-related outcomes of MI or low cardiac output syndrome. This is also in keeping with the designs of other similar trials that included stroke13,14 and renal failure14 as outcome measures. The mechanism through which RIPC may exert multiorgan
• Volume ■■, Number ■■
5
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY
Figure 3. Troponin-I values 6 hours after surgery and on postoperative days 1 and 2. Dots represent values that were greater than 90% of the data. The minimal detectable value for this assay was 0.01 ng/mL. (A) All participants. (B) Cardiac surgery only. (C) Vascular surgery only. POD, postoperative day. (Color version of figure is available online.)
protection remains unclear, but multiple hypotheses have been postulated. For example, a host of neural and humoral mediators have been proposed to play a role (see Hausenloy and Yellon29 for review). Also, animal and preliminary human works suggest that RIPC alters gene expression and the expression of proinflammatory and proapoptotic mediators.30-32 Additionally, recent work by Lambert et al33 reported a reduced sympathetic outflow after RIPC, which indicates that the autonomic nervous system could also play a role in the systemic effects of RIPC. Along with others,34 Lambert et al also documented improved endothelial function after RIPC.33 Improved endothelial function could be associated with better blood flow regulation, and this hypothesis is in line with the findings of Meng et al,35 who observed increased cerebral perfusion after repeated RIPC with single-photon emission computed tomography imaging and transcranial Doppler ultrasound.
6
Because of the initial promising studies in animals, proof-ofconcept clinical studies reported that RIPC reduced cardiac, renal, respiratory, and cerebral damage after RIPC in humans.10-12,26 However, the effect of RIPC on the reduction of clinical outcomes has been disappointing. It is possible that the beneficial effects of RIPC have been mitigated as the methodology has transitioned to human studies where there are multiple confounding factors unaccounted for in the animal studies (eg, cardiopulmonary bypass and cardioplegia were not performed in animal work8,36). Other differences from the initial animal work and current human trials are the way that the ischemic stimulus is applied and the amount of tissue that becomes ischemic. Interestingly, the only RIPC trial showing improved biomarkers after vascular surgery employed their ischemic stimulus directly by crossclamping the iliac artery, thereby affecting a substantially large
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY amount of tissue.21 Other studies, including ours reported here, utilized arm ischemia and have found no differences in outcomes when RIPC was performed on the upper arm with a blood pressure cuff.15 Another important distinction between our study and the initial proof-of-concept studies (which typically utilized healthy animal populations) is the occurrence of comorbidities such as diabetes and dyslipidemia. The impact that added comorbid conditions may have on the effects of RIPC is unclear. Some evidence suggests that diabetes and dyslipidemia may inhibit the effectiveness of RIPC,37,38 which is an important consideration as approximately one-third of our subjects were diabetic. The potential confounding effect of diabetes and other comorbidities highlights the possibility that the factors that make these patients high risk may prevent the RIPC intervention from being sufficiently protective. It is possible that any benefit of the intervention may not have been sufficient to overcome the risk of damage that is inherent in patients that fit our inclusion criteria, for example, those with poor cardiac or kidney function, prior surgery, or prior ischemic event. In recent decades, cardiovascular surgery is increasingly being performed on higher-risk patients; despite the increase in the number of higher-risk CABG procedures being performed, mortality has not increased concomitantly.39 These findings have likely contributed to lower-than-predicted event rates in recent randomized controlled trials.40,41 For example, Newman et al40 reported an event rate of 2.3% in each group for severe left ventricle dysfunction, which occurred if an intra-aortic balloon pump or a ventricular assist device was required. In contrast, we found that low cardiac output syndrome was evident in 17% of patients in the control group and 13% of patients in the RIPC group. Our outcome was also met if inotropes were used for greater than 24 hours so the numbers are not directly comparable. However, these numbers do support the idea that the inclusion criteria that we used truly are representative of a high-risk population where any intervention that would reduce morbidity and mortality would be very beneficial. The present study is limited by the fact that the anesthesia protocol was not standardized across patients. Evidence exists to suggest that anesthetics may impact the results of RIPC. It has been proposed that propofol may inhibit the potential cardioprotective effects of RIPC,42 whereas some volatile anesthetics have been reported to both attenuate and provide cardioprotection.42,43 We did not standardize our anesthesia protocol so that the present study would be generalizable to cardiovascular surgery where multiple anesthetics can be used over the course of 1 surgery and the protocol may vary from site to site. We followed up our patients for a total of 30 days postoperatively. Although a greater follow-up may have allowed us to detect long-term differences in outcomes, we feel that 30 days capture the perioperative risk window for which any purported benefits of RIPC are expected to occur. In conclusion, we did not observe any differences in clinical outcomes, biomarkers of ischemic damage, or lengths of hospital stay between the RIPC group and the control group after cardiovascular surgery. Therefore, we did not demonstrate any benefit of RIPC when the intervention group was compared against a control group
Seminars in Thoracic and Cardiovascular Surgery
in a population of high-risk cardiovascular surgery patients at 30 days. SUPPLEMENTARY MATERIAL Supplementary materials associated with this article can be found in the online version at https://doi.org/10.1053/j.semtcvs.2017 .09.001. REFERENCES 1. Ten Bosch J, Willigendael EM, Kruidenier LM, et al: Early and mid-term results of a prospective observational study comparing emergency endovascular aneurysm repair with open surgery in both ruptured and unruptured acute abdominal aortic aneurysms. Vascular 20:72-80, 2012 2. Brott TG, Howard G, Roubin GS, et al: Long-term results of stenting versus endarterectomy for carotid artery stenosis. N Engl J Med 374:10211031, 2016 3. Wiseman JT, Fernandes-Taylor S, Saha S, et al: Endovascular versus open revascularization for peripheral arterial disease. Ann Surg 265:424-430, 2017 4. Milojevic M, Head SJ, Parasca CA, et al: Causes of death following PCI versus CABG in complex CAD 5-year follow-up of SYNTAX. J Am Coll Cardiol 67:42-55, 2016 5. Conlon PJ, Stafford-Smith M, White WD, et al: Acute renal failure following cardiac surgery. Nephrol Dial Transplant 14:1158-1162, 1999 6. Piper HM, García-Dorado D, Ovize M: A fresh look at reperfusion injury. Cardiovasc Res 38:291-300, 1998 7. Twine CP, Ferguson S, Boyle JR: Benefits of remote ischaemic preconditioning in vascular surgery. Eur J Vasc Endovasc Surg 48:215-219, 2014 8. Przyklenk K, Bauer B, Ovize M, et al: Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893-899, 1993 9. Kharbanda RK, Nielsen TT, Redington AN: Translation of remote ischaemic preconditioning into clinical practice. Lancet 374:1557-1565, 2009 10. Hausenloy DJ, Mwamure PK, Venugopal V, et al: Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: A randomised controlled trial. Lancet 370:575579, 2007 11. Li C, Li Y-S, Xu M, et al: Limb remote ischemic preconditioning for intestinal and pulmonary protection during elective open infrarenal abdominal aortic aneurysm repair. Anesthesiology 118:842-852, 2013 12. Zimmerman RF, Ezeanuna PU, Kane JC, et al: Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. Kidney Int 80:861-867, 2011 13. Hausenloy DJ, Candilio L, Evans R, et al: Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 373:1408-1417, 2015 14. Meybohm P, Bein B, Brosteanu O, et al: A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 373:1397-1407, 2015 15. Healy D, Boyle E, McCartan D, et al: A multicenter pilot randomized controlled trial of remote ischemic preconditioning in major vascular surgery. Vasc Endovascular Surg 49:220-227, 2015 16. Walsh M, Whitlock R, Garg AX, et al: Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): A randomized controlled trial. Can Med Assoc J 188:329336, 2016 17. Siregar S, Groenwold RHH, de Heer F, et al: Performance of the original EuroSCORE. Eur J Cardiothorac Surg 41:746-754, 2012 18. Heusch G: Cardioprotection: Chances and challenges of its translation to the clinic. Lancet 381:166-175, 2013 19. Bennett-Guerrero E, Swaminathan M, Grigore AM, et al: A phase II multicenter double-blind placebo-controlled study of ethyl pyruvate in highrisk patients undergoing cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 23:324-329, 2009
• Volume ■■, Number ■■
7
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY 20. Møller CH, Perko MJ, Lund JT, et al: No major differences in 30-day outcomes in high-risk patients randomized to off-pump versus on-pump coronary bypass surgery: The best bypass surgery trial. Circulation 121:498504, 2010 21. Ali ZA, Callaghan CJ, Lim E, et al: Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: A randomized controlled trial. Circulation 116:I98-I105, 2007 (suppl 1) 22. Hoole SP, Heck PM, Sharples L, et al: Cardiac remote ischemic preconditioning in coronary stenting (CRISP stent) study. A prospective, randomized control trial. Circulation 119:820-827, 2009 23. Lang TW, Corday E, Gold H, et al: Consequences of reperfusion after coronary occlusion. Effects on hemodynamic and regional myocardial metabolic function. Am J Cardiol 33:69-81, 1974 24. Weight SC, Bell PRF, Nicholson ML: Renal ischaemia-reperfusion injury. Br J Surg 83:162-170, 1996 25. Yeung KK, Groeneveld M, Lu JJN, et al: Organ protection during aortic cross-clamping. Best Pract Res Clin Anaesthesiol 30:305-315, 2016 26. Zhao W, Meng R, Ma C, et al: Safety and efficacy of remote ischemic preconditioning in patients with severe carotid artery stenosis prior to carotid artery stenting: A proof-of-concept, randomized controlled trial. Circulation 135:1325-1335, 2017 27. Thomas KN, Cotter JD, Williams MJA, et al: Repeated episodes of remote ischemic preconditioning for the prevention of myocardial injury in vascular surgery. Vasc Endovascular Surg 50:140-146, 2016 28. Thielmann M, Kottenberg E, Kleinbongard P, et al: Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: A single-centre randomised, double-blind, controlled trial. Lancet 382:597-604, 2013 29. Hausenloy DJ, Yellon DM: Remote ischaemic preconditioning: Underlying mechanisms and clinical application. Cardiovasc Res 79:377386, 2008 30. Konstantinov IE, Arab S, Kharbanda RK, et al: The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics 19:143-150, 2004 31. Peralta C, Fernández L, Panés J, et al: Preconditioning protects against systemic disorders associated with hepatic ischemia-reperfusion through blockade of tumor necrosis factor-induced P-selectin up-regulation in the rat. Hepatology 33:100-113, 2001 32. Hussein A, Harraz A, Awadalla A, et al: Remote limb ischemic preconditioning (rIPC) activates antioxidant and antiapoptotic genes and inhibits
8
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
proinflammatory cytokine genes in renal ischemia/reperfusion injury. Gen Physiol Biophys 35:77-86, 2016 Lambert EA, Thomas CJ, Hemmes R, et al: Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning. Am J Physiol Heart Circ Physiol 311:H364H370, 2016 Manchurov V, Ryazankina N, Khmara T, et al: Remote ischemic preconditioning and endothelial function in patients with acute myocardial infarction and primary PCI. Am J Med 235:e67, 2014 Meng R, Asmaro K, Meng L, et al: Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 79:1853-1861, 2012 Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 74:11241136, 1986 Ungi I, Ungi T, Ruzsa Z, et al: Hypercholesterolemia attenuates the antiischemic effect of preconditioning during coronary angioplasty. Chest 128:1623-1628, 2005 Ishihara M, Inoue I, Kawagoe T, et al: Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction. J Am Coll Cardiol 38:1007-1011, 2001 Ferguson TB, Hammill BG, Peterson ED, et al: A decade of change— risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990-1999: A report from the STS National Database Committee and the Duke Clinical Research Institute. Ann Thorac Surg 73:480490, 2002 Newman MF, Ferguson TB, White JA, et al: Effect of adenosineregulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: The RED-CABG randomized controlled trial. JAMA 308:157-164, 2012 Alexander JH, Emery RW, Carrier M, et al: Efficacy and safety of pyridoxal 5’-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: The MEND-CABG II randomized clinical trial. JAMA 299:1777-1787, 2008 Kottenberg E, Thielmann M, Bergmann L, et al: Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol—a clinical trial. Acta Anaesthesiol Scand 56:3038, 2012 Zhou C, Liu Y, Yao Y, et al: Beta-blockers and volatile anesthetics may attenuate cardioprotection by remote preconditioning in adult cardiac surgery: A meta-analysis of 15 randomized trials. J Cardiothorac Vasc Anesth 27:305-311, 2013
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
Remote Ischemic Preconditioning in High-risk Cardiovascular Surgery Patients: A Randomized-controlled Trial Nicole S. Coverdale, PhD,* Andrew Hamilton, MD,* Dimitri Petsikas, MD,* R. Scott McClure, MSc, MD,† Paul Malik, MD,‡ Brian Milne, MD,§ Tarit Saha, MD,§ David Zelt, MD,* Peter Brown, MD,* and Darrin M. Payne, MSc, MD* Remote ischemic preconditioning (RIPC) may reduce biomarkers of ischemic injury after cardiovascular surgery. However, it is unclear whether RIPC has a positive impact on clinical outcomes. We performed a blinded, randomized controlled trial to determine if RIPC resulted in fewer adverse clinical outcomes after cardiac or vascular surgery. The intervention consisted of 3 cycles of RIPC on the upper limb for 5 minutes alternated with 5 minutes of rest. A sham intervention was performed on the control group. Patients were recruited who were undergoing (1) high-risk cardiac or vascular surgery or (2) cardiac or vascular surgery and were at high risk of ischemic complications. The primary end point was a composite outcome of mortality, myocardial infarction, stroke, renal failure, respiratory failure, and low cardiac output syndrome, and the secondary end points included the individual outcome parameters that made up this score, as well as troponin-I values. A total of 436 patients were randomized and analysis was performed on 215 patients in the control group and on 213 patients in the RIPC group. There were no differences in the composite outcome between the 2 groups (RIPC: 67 [32%] and control: 72 [34%], relative risk [0.94 {0.72-1.24}]) or in any of the individual components that made up the composite outcome. Additionally, we did not observe any differences between the groups in troponin-I values, the length of intensive care unit stay, or the total hospital stay. RIPC did not have a beneficial effect on clinical outcomes in patients who had cardiovascular surgery. Semin Thoracic Surg ■■:■■–■■ © 2017 Elsevier Inc. All rights reserved. Keywords: remote ischemic preconditioning, cardiovascular surgery, ischemia-reperfusion *Department of Surgery, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada † Department of Surgery, Libin Cardiovascular Institute of Alberta, Foothills Medical Center, University of Calgary, Calgary, Alberta, Canada ‡ Department of Medicine, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada § Department of Anesthesiology and Perioperative Medicine, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada This study was funded by the Southeastern Ontario Academic Medical Organization’s Innovation Fund. The authors report no conflicts of interest. Funding was provided by the Southeastern Ontario Academic and Medical Organization. Clinical trial registration: ClinicalTrials.gov: NCT01328912. Research Ethics Board approval: Queen’s University and Affiliated Teaching Hospitals #6005871, initial approval on June 8, 2011. Address reprint requests to Darrin M. Payne, MSc, MD, Department of Surgery, Kingston General Hospital, Victory 3, 76 Stuart St, Kingston, ON, Canada K7L 2V7. E-mail: [email protected]
Troponin-I values 6 hours after vascular surgery and on postoperative days 1 and 2. Central Message The application of remote ischemic preconditioning before high-risk vascular or cardiac surgery did not improve clinical outcomes as assessed with a composite end point measure. Perspective Statement Previously, remote ischemic preconditioning (RIPC) was associated with improvements in cardiac biomarkers, but it was unclear how these findings would translate to clinical outcomes. We investigated whether RIPC was associated with improved outcomes after high-risk cardiac or vascular surgery. We did not find a difference between RIPC and the control intervention. RIPC does not confer any benefit during high-risk cardiovascular surgery.
INTRODUCTION Cardiovascular surgical interventions are among the most common surgical procedures performed worldwide. These procedures are associated with a predictable array of adverse events. Perioperative complications of cardiac and vascular surgery include myocardial infarction (MI), stroke, renal failure, and death.1-5 With an aging patient population and an increasing number and degree of concomitant comorbid conditions, the risk associated with these procedures increases proportionally. Adverse events associated with cardiovascular surgical procedures can have dramatic consequences on patients and families, including pain, prolonged
1043-0679/$-see front matter © 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1053/j.semtcvs.2017.09.001
1
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY hospitalization, permanent disabilities, and loss of independence. The already overburdened health-care system suffers as well, with increased attendant costs. Thus, there is an appropriate interest in interventions that may mitigate these risks. During cardiac and vascular surgery, restoration of blood flow after bypass or clamping can induce ischemia-reperfusion injury that is defined as the death of cells not due to the ischemia itself.6,7 Remote ischemic preconditioning (RIPC) refers to the application of transient periods of reduced or absent blood supply to a distant tissue bed that is subsequently reperfused. The idea is that the initial ischemic insult will confer some degree of protection from a secondary ischemic insult.8 Over the last decade, this idea has transitioned from animal to human models, and the ischemic preconditioning is performed at a remote tissue bed (such as an arm or a leg) with the goal of inducing a protective response in target tissues and organs (such as the heart, kidneys, or brain). Although the underlying mechanism of the purported benefits of RIPC remains unclear, it has been proposed that humeral and neural signals transmitted from remote tissues impact intracellular signaling and mitochondrial functioning within target tissues, decreasing proinflammatory gene expression and function.9 Initial human studies of RIPC have shown promise as surrogate biomarkers of end organ damage are reduced during various surgical interventions.10-12 However, how such findings would translate to clinical outcomes is unclear. Recently, 2 multicenter randomized control trials examining outcomes after cardiac surgery have found no benefit of RIPC.13,14 In addition, a pilot trial examining clinical end points after vascular surgery has found no difference between RIPC and control groups.15 Previous studies have examined the impact of RIPC in high-risk cohorts, where risk was assessed based on the European System for Cardiac Operative Risk Evaluation (EuroSCORE).13,16 However, surgical risk assessment tools have inherent limitations, and it has been recognized that true risk assessment can be overestimated, possibly in some types of surgery more than others.17 We chose to examine patients deemed to be at high clinical risk, as judged by having a high-risk surgery, having a repeat surgery, or those who had substantial surgical risk factors. Considering their increased risk of ischemic complications, this cohort could potentially realize important benefits from any protective effect incurred by RIPC. We hypothesized that RIPC would improve clinical outcomes in a cohort of high-risk vascular and cardiac surgical patients. METHODS This trial (NCT01328912) was approved by the Queen’s University Health Sciences and Affiliated Hospitals Research Ethics Board. All participants provided informed consent. Participants Eligible participants were adults over the age of 18 who were undergoing either (1) cardiac or vascular surgical procedures and were at increased risk of suffering ischemia-related events, (2) preoperative screening indicating cardiovascular disease, or (3) undergoing higher-risk surgery. We considered there to be an increased risk of ischemia-related events there was preoperative
2
evidence of prior MI, unstable angina, an ejection fraction less than 40%, a prior stroke or transient ischemic attack, chronic renal insufficiency (estimated glomerular filtration rate less than 60 mL/ min), or limb claudication. Preoperative screening indicating cardiovascular disease included a positive MIBI scan or an angiogram, a cardiac computed tomography, or a magnetic resonance imaging with evidence of 1 or more coronary arteries with greater than 70% stenosis, or a carotid Doppler ultrasound showing greater than 70% stenosis, uni- or bilaterally. High-risk surgery was defined as a combined valve-coronary artery bypass graft (CABG) surgery, double valve surgery, aortic surgery, left ventricle aneurysm repair, redo surgery, or open abdominal or thoracoabdominal aneurysm repair. Participants underwent follow-up assessments at 30 days, which were performed mainly by telephone interview. Intervention This was a single-center study and the participants were randomized in a 1:1 ratio to receive the RIPC or a sham RIPC treatment (control) by a biostatistician. Randomization was done with a computer-generated scheme and opaque sealed envelopes. The patients were enrolled and assigned to intervention by a research nurse. Surgeons, anesthetists, and postoperative care providers were blind to the group assignments, and the patients were instructed not to disclose whether they had received the intervention. The intervention was initially planned to occur once the patient was inside the operating room (OR) under anesthesia. The protocol was modified such that the RIPC intervention occurred immediately before the patient was transferred to the OR. This change was made due to time constraints within the OR as well as difficulty and restrictions of line placement (arterial lines or intravenous lines) that were not available for use and threatened blinding with a blood pressure cuff cycling. The intervention was well tolerated and no significant complaints were voiced by the patients. Patients were transferred to the OR immediately following the completion of the RIPC intervention, where access and monitoring lines were placed and the operation commenced. The window of protection provided by RIPC was postulated to be approximately 2 hours18; therefore, we were well within this time frame. A blood pressure cuff was placed on the patient’s upper arm. The RIPC stimulus consisted of 3 cycles of 5 minutes of ischemia with the cuff inflated to 200 mm Hg alternated with 5 minutes of cessation of pressure. The intervention occurred in isolation with only the research nurse and the patient present, to ensure all OR staff and caregivers remained blinded. The control group received similar treatment, in terms of blood pressure cuff application and segregation, although the cuff was not inflated. All patients were instructed not to disclose whether they had received the intervention. Procedures The anesthetic protocol was performed as per the standard practices of the attending anesthetist. In general, anesthesia was induced with intravenous midazolam, opiate (fentanyl or sufentanil), propofol or etomidate, and rocuronium. Anesthesia was maintained with desflurane, sevoflurane, or propofol infusion with opiate and
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY
Outcomes The primary outcome was a composite measure that incorporated all-cause mortality, MI, stroke, respiratory failure, acute renal failure, and low cardiac output syndrome. Definitions of the major clinical end points are provided in Supplementary Appendix S1. Secondary outcomes included the individual components of the composite end point, troponin I at 6 hours, postoperative days 1 and 2, length of intensive care hospital stay, and total length of hospital stay.
type I error equal to 0.05, power equal to 0.80, and an RRR of 40%, we required 198 patients per group, which was bolstered by 10% to account for any losses to follow-up (total of 436 patients). The composite outcome and its components were compared between groups with a chi-square test. The relative risk was also calculated. Subgroup analysis was performed to examine the effect of RIPC on the composite outcome within sexes and for those less than 70 years of age vs those who were 70 years or older. Troponin-I values and length of stay were compared between the groups with a Mann-Whitney test. The same statistical analysis was performed on the subgroups of vascular surgery only and cardiac surgery only. Before the trial commencement, we also planned to perform an analysis comparing those who had general anesthesia with those who had regional anesthesia. However, this was abandoned because not enough patients received regional anesthetics. All analysis was done with SPSS 20.0.
Statistical Analysis Sample size was calculated based on previous research conducted on higher-risk patients undergoing surgery that reported outcomes between 15% and 30% for clinical major adverse cardiac or cerebrovascular event.19,20 The largest randomized trial looking at RIPC in open abdominal aneurysm repair reported myocardial injury and infarction to be 39% and 27%, respectively, and acute renal injury to be 30%,21 with a relative risk reduction (RRR) of 82% for MI, 75% for renal dysfunction, and 33% for mortality.21 Patients undergoing percutaneous coronary intervention were randomized to RIPC vs control and reported a similar composite end point of major adverse cardiac or cerebrovascular event with an RRR of 67% with RIPC-randomized patients22 We therefore assumed an event rate of 30% and an RRR of 40% with RIPC. Assuming a
RESULTS Figure 1 summarizes patient recruitment into the trial, which occurred between February 2012 and November 2015. The final analysis was performed on 215 patients in the control group and on 213 patients in the RIPC group, and recruitment ceased when we reached our target sample size. The control and the RIPC groups were well matched in terms of sex, age, body mass index, and prevalence of surgical risk factors (Table 1). Table 2 summarizes the surgical procedures performed in each group. Roughly one-third of patients in each group underwent vascular surgery, whereas twothirds underwent cardiac surgery. Of the cardiac surgeries, CABG was most commonly performed, whereas peripheral revascularization occurred most often in vascular patients. For the cardiac surgical
rocuronium administered, as required. Some patients having peripheral vascular repair or abdominal aneurysm surgery received epidural anesthesia (Supplementary Table S1). Postoperative analgesia was managed at the discretion of the attending surgeon and postoperative caregivers, and typically included combinations of intravenous and oral morphine and hydromorphone.
Figure 1. Consolidated Standards of Reporting Trials diagram.
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
3
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY Table 1. Baseline Patient Characteristics Characteristic
Control (n = 215)
RIPC (n = 213)
Male sex, no. (%) Age (y) BMI (kg/m2) Prior diagnoses, no. (%) Diabetes Dyslipidemia Hypertension Renal insufficiency* Ejection fraction <40% Current tobacco use Myocardial infarction Peripheral vascular disease Cerebrovascular accident or transient ischemic attack Chronic obstructive pulmonary disease
166 (77) 68 ± 9 28.6 ± 4.90
178 (84) 69 ± 10 28.8 ± 5.0
76 (35) 149 (69) 160 (74) 100 (47) 15 (7) 44 (20) 71 (33) 62 (29) 47 (22)
77 (36) 149 (70) 172 (81) 87 (41) 17 (8) 41 (19) 66 (31) 53 (25) 42 (20)
27 (13)
37 (17)
BMI, body mass index. *Renal insufficiency was defined as having an estimated glomerular filtration rate less than 60 mL/min.
patients, there were no differences in the cardiopulmonary bypass time or the aortic cross-clamp time between the groups. Our primary outcome, the number of composite outcomes, was not different between the groups. There were no differences between the groups in mortality, MI, stroke, respiratory failure, renal failure, or low cardiac output syndrome (Table 3). The subgroup analysis of only cardiac surgery patients did not reveal any differences (Table 4). Similarly, no differences were observed in RIPC vs control when vascular surgery patients were examined independently
Figure 2. Subgroup relative risk of the composite outcome for RIPC vs control.
(Table 5). Subgroup analysis also indicated that, within each sex and when groups were subdivided based on age, there were no differences between the control and RIPC for the composite outcome (Fig. 2). We also compared troponin-I values between groups 6 hours after the end of surgery and on postoperative days 1 and 2, and did not observe any differences between the control and RIPC when all patients were analyzed together or when cardiac and vascular patients were analyzed separately (Fig. 3A-C). Finally, there were no differences in the length of intensive care unit stay or total hospital stay between the groups.
Table 2. Operative Characteristics Surgery
Control (n = 215)
RIPC (n = 213)
Cardiac, no./total no. (%) CABG 1 graft 2 grafts 3 grafts 4+ grafts Valve CABG + valve Other Cardiopulmonary bypass time (min) Aortic cross-clamp time (min) Reoperation, no./total no. (%) Vascular, no./total no. (%) Abdominal aortic aneurysm repair Carotid endarterectomy Peripheral vasculature Other
147/215 (69) 77 4 23 27 23 20 33 17 99 ± 63
142/213 (67) 62 2 16 30 14 14 45 21 102 ± 48
77 ± 48 15/215 68/215 (31) 14
78 ± 39 13/213 71/213 (33) 18
18 28 7
16 33 4
4
DISCUSSION After CABG surgery, ischemia-reperfusion injury to the heart may occur as a result of the re-establishment of blood flow due to the procedure or due to the use of cardiopulmonary bypass. The same type of injury may affect other organs during vascular surgery, and the deleterious impact on postsurgical morbidity and mortality has been recognized for decades.23-25 Recent proof-of-concept clinical studies in humans examining biomarkers of organ damage have suggested that RIPC may have a favorable effect not only on the target organs that were ischemic but also on other organ systems.12,26 Therefore, the purpose of the present study was to determine if RIPC was protective against adverse clinical outcomes after cardiac or vascular surgery in high-risk patients. We did not observe any differences between the RIPC and the control group for our primary composite outcome or any of the individual components that made up the estimate. Our findings are in line with 2 recently published trials that examined outcomes at 90 days after cardiac surgery and at 12 months after CABG.13,14 We included only high-risk patients because they could potentially receive the most benefit from any amelioration
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY Table 3. 30-Day Outcomes and Treatment Effect Outcome
Control (n = 215)
RIPC (n = 213)
Relative Risk (95% CI)
P Value
Composite outcome, no. (%) Mortality Myocardial infarction Stroke Respiratory failure Renal failure Low cardiac output syndrome Hospital stay (days ± standard deviation) ICU stay (days ± standard deviation)
72 (34) 5 (2) 12 (6) 5 (2) 11 (5) 43 (20) 37 (17) 6.9 ± 5.6 2.3 ± 3.1
67 (32) 3 (1) 9 (4) 5 (2) 12 (6) 37 (17) 28 (13) 6.7 ± 4.8 2.5 ± 3.7
0.94 (0.72-1.24) 0.61 (0.15-2.50) 0.77 (0.33-1.76) 1.01 (0.30-3.4) 1.10 (0.50-2.44) 0.87 (0.58-1.29) 0.76 (0.49-1.20) – –
0.73 0.73 0.67 0.76 0.98 0.57 0.30 0.80 0.96
CI, confidence interval; ICU, intensive care unit.
Table 4. 30-Day Outcomes and Treatment Effect for Cardiac Surgery Patients Outcome
Control (n = 147)
RIPC (n = 142)
Relative Risk (95% CI)
P Value
Composite outcome, no. (%) Mortality Myocardial infarction Stroke Respiratory failure Renal failure Low cardiac output syndrome Hospital stay (days ± standard deviation) ICU stay (days ± standard deviation)
61 (42) 4 (3) 10 (7) 4 (3) 9 (6) 38 (26) 31 (21) 7.5 ± 5.5 3.0 ± 3.4
52 (37) 3 (2) 6 (4) 3 (2) 11 (8) 33 (23) 21 (15) 7.1 ± 4.3 2.9 ± 3.2
0.88 (0.66-1.18) 0.78 (0.18-3.41) 0.62 (0.23-1.66) 0.78 (0.18-3.41) 1.27 (0.54-2.96) 0.90 (0.60-1.35) 0.70 (0.42-1.16) – –
0.47 0.96 0.48 0.96 0.76 0.71 0.22 0.60 0.76
CI, confidence interval; ICU, intensive care unit.
Table 5. 30-Day Outcomes and Treatment Effect for Vascular Surgery Patients Outcome
Control (n = 68)
RIPC (n = 71)
Relative Risk (95% CI)
P Value
Composite outcome, no. (%) Mortality Myocardial infarction Stroke Respiratory failure Renal failure Low cardiac output syndrome Hospital stay (days ± standard deviation) ICU stay (days ± standard deviation)
11 (16) 1 (2) 2 (3) 1 (2) 2 (3) 5 (7) 6 (9) 5.6 ± 5.4 0.9 ± 1.5
15 (21) 0 (0) 3 (4) 2 (3) 1 (2) 4 (6) 7 (10) 5.8 ± 5.7 1.6 ± 4.5
1.31 (0.65-2.64) – 1.44 (0.25-8.33) 1.92 (0.18-20.64) 0.48 (0.04-5.16) 0.77 (0.22-2.73) 1.12 (0.40-3.16) – –
0.60 0.31 0.96 0.97 0.97 0.95 0.94 0.97 0.63
CI, confidence interval; ICU, intensive care unit.
in adverse clinical ischemic events. Hausenloy et al also examined a higher-risk population of patients, as judged by a preoperative EuroSCORE of 5 or higher.13 Because of the inherent difficulty in surgical risk scoring systems accurately predicting mortality and adverse events,17 we based our inclusion criteria on clinical indicators of risk. We included patients based on a planned high-risk operation, or documented evidence of comorbid ischemic or cardiovascular disease over and above that which was the primary indication for their surgery. Approximately one-third of our study population was composed of patients undergoing high-risk vascular surgery. We found no differences in either clinical outcomes or biomarkers in this subgroup. This result is in keeping with other studies that have examined RIPC in patients having abdominal aneurysm repair, carotid endarterectomy, or peripheral revascularization that have reported no differences between the intervention and the
Seminars in Thoracic and Cardiovascular Surgery
control group in terms of outcomes or biomarkers.15,27 Despite restricting our enrolment to only high-risk patients, we did not observe any differences between groups as a result of the intervention. We selected the outcomes that made up the composite end point based on previous studies that found changes in biomarkers related to the particular organ system. Although the majority of studies have focused on how RIPC affects the heart,10,28 previous studies have also documented reduced creatinine levels after RIPC during CABG12 and improved the alveolar-arterial oxygen tension ratio during abdominal aneurysm repair.11 Therefore, we included renal failure and respiratory failure as outcomes in addition to stroke and the cardiac-related outcomes of MI or low cardiac output syndrome. This is also in keeping with the designs of other similar trials that included stroke13,14 and renal failure14 as outcome measures. The mechanism through which RIPC may exert multiorgan
• Volume ■■, Number ■■
5
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY
Figure 3. Troponin-I values 6 hours after surgery and on postoperative days 1 and 2. Dots represent values that were greater than 90% of the data. The minimal detectable value for this assay was 0.01 ng/mL. (A) All participants. (B) Cardiac surgery only. (C) Vascular surgery only. POD, postoperative day. (Color version of figure is available online.)
protection remains unclear, but multiple hypotheses have been postulated. For example, a host of neural and humoral mediators have been proposed to play a role (see Hausenloy and Yellon29 for review). Also, animal and preliminary human works suggest that RIPC alters gene expression and the expression of proinflammatory and proapoptotic mediators.30-32 Additionally, recent work by Lambert et al33 reported a reduced sympathetic outflow after RIPC, which indicates that the autonomic nervous system could also play a role in the systemic effects of RIPC. Along with others,34 Lambert et al also documented improved endothelial function after RIPC.33 Improved endothelial function could be associated with better blood flow regulation, and this hypothesis is in line with the findings of Meng et al,35 who observed increased cerebral perfusion after repeated RIPC with single-photon emission computed tomography imaging and transcranial Doppler ultrasound.
6
Because of the initial promising studies in animals, proof-ofconcept clinical studies reported that RIPC reduced cardiac, renal, respiratory, and cerebral damage after RIPC in humans.10-12,26 However, the effect of RIPC on the reduction of clinical outcomes has been disappointing. It is possible that the beneficial effects of RIPC have been mitigated as the methodology has transitioned to human studies where there are multiple confounding factors unaccounted for in the animal studies (eg, cardiopulmonary bypass and cardioplegia were not performed in animal work8,36). Other differences from the initial animal work and current human trials are the way that the ischemic stimulus is applied and the amount of tissue that becomes ischemic. Interestingly, the only RIPC trial showing improved biomarkers after vascular surgery employed their ischemic stimulus directly by crossclamping the iliac artery, thereby affecting a substantially large
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY amount of tissue.21 Other studies, including ours reported here, utilized arm ischemia and have found no differences in outcomes when RIPC was performed on the upper arm with a blood pressure cuff.15 Another important distinction between our study and the initial proof-of-concept studies (which typically utilized healthy animal populations) is the occurrence of comorbidities such as diabetes and dyslipidemia. The impact that added comorbid conditions may have on the effects of RIPC is unclear. Some evidence suggests that diabetes and dyslipidemia may inhibit the effectiveness of RIPC,37,38 which is an important consideration as approximately one-third of our subjects were diabetic. The potential confounding effect of diabetes and other comorbidities highlights the possibility that the factors that make these patients high risk may prevent the RIPC intervention from being sufficiently protective. It is possible that any benefit of the intervention may not have been sufficient to overcome the risk of damage that is inherent in patients that fit our inclusion criteria, for example, those with poor cardiac or kidney function, prior surgery, or prior ischemic event. In recent decades, cardiovascular surgery is increasingly being performed on higher-risk patients; despite the increase in the number of higher-risk CABG procedures being performed, mortality has not increased concomitantly.39 These findings have likely contributed to lower-than-predicted event rates in recent randomized controlled trials.40,41 For example, Newman et al40 reported an event rate of 2.3% in each group for severe left ventricle dysfunction, which occurred if an intra-aortic balloon pump or a ventricular assist device was required. In contrast, we found that low cardiac output syndrome was evident in 17% of patients in the control group and 13% of patients in the RIPC group. Our outcome was also met if inotropes were used for greater than 24 hours so the numbers are not directly comparable. However, these numbers do support the idea that the inclusion criteria that we used truly are representative of a high-risk population where any intervention that would reduce morbidity and mortality would be very beneficial. The present study is limited by the fact that the anesthesia protocol was not standardized across patients. Evidence exists to suggest that anesthetics may impact the results of RIPC. It has been proposed that propofol may inhibit the potential cardioprotective effects of RIPC,42 whereas some volatile anesthetics have been reported to both attenuate and provide cardioprotection.42,43 We did not standardize our anesthesia protocol so that the present study would be generalizable to cardiovascular surgery where multiple anesthetics can be used over the course of 1 surgery and the protocol may vary from site to site. We followed up our patients for a total of 30 days postoperatively. Although a greater follow-up may have allowed us to detect long-term differences in outcomes, we feel that 30 days capture the perioperative risk window for which any purported benefits of RIPC are expected to occur. In conclusion, we did not observe any differences in clinical outcomes, biomarkers of ischemic damage, or lengths of hospital stay between the RIPC group and the control group after cardiovascular surgery. Therefore, we did not demonstrate any benefit of RIPC when the intervention group was compared against a control group
Seminars in Thoracic and Cardiovascular Surgery
in a population of high-risk cardiovascular surgery patients at 30 days. SUPPLEMENTARY MATERIAL Supplementary materials associated with this article can be found in the online version at https://doi.org/10.1053/j.semtcvs.2017 .09.001. REFERENCES 1. Ten Bosch J, Willigendael EM, Kruidenier LM, et al: Early and mid-term results of a prospective observational study comparing emergency endovascular aneurysm repair with open surgery in both ruptured and unruptured acute abdominal aortic aneurysms. Vascular 20:72-80, 2012 2. Brott TG, Howard G, Roubin GS, et al: Long-term results of stenting versus endarterectomy for carotid artery stenosis. N Engl J Med 374:10211031, 2016 3. Wiseman JT, Fernandes-Taylor S, Saha S, et al: Endovascular versus open revascularization for peripheral arterial disease. Ann Surg 265:424-430, 2017 4. Milojevic M, Head SJ, Parasca CA, et al: Causes of death following PCI versus CABG in complex CAD 5-year follow-up of SYNTAX. J Am Coll Cardiol 67:42-55, 2016 5. Conlon PJ, Stafford-Smith M, White WD, et al: Acute renal failure following cardiac surgery. Nephrol Dial Transplant 14:1158-1162, 1999 6. Piper HM, García-Dorado D, Ovize M: A fresh look at reperfusion injury. Cardiovasc Res 38:291-300, 1998 7. Twine CP, Ferguson S, Boyle JR: Benefits of remote ischaemic preconditioning in vascular surgery. Eur J Vasc Endovasc Surg 48:215-219, 2014 8. Przyklenk K, Bauer B, Ovize M, et al: Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893-899, 1993 9. Kharbanda RK, Nielsen TT, Redington AN: Translation of remote ischaemic preconditioning into clinical practice. Lancet 374:1557-1565, 2009 10. Hausenloy DJ, Mwamure PK, Venugopal V, et al: Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: A randomised controlled trial. Lancet 370:575579, 2007 11. Li C, Li Y-S, Xu M, et al: Limb remote ischemic preconditioning for intestinal and pulmonary protection during elective open infrarenal abdominal aortic aneurysm repair. Anesthesiology 118:842-852, 2013 12. Zimmerman RF, Ezeanuna PU, Kane JC, et al: Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. Kidney Int 80:861-867, 2011 13. Hausenloy DJ, Candilio L, Evans R, et al: Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 373:1408-1417, 2015 14. Meybohm P, Bein B, Brosteanu O, et al: A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 373:1397-1407, 2015 15. Healy D, Boyle E, McCartan D, et al: A multicenter pilot randomized controlled trial of remote ischemic preconditioning in major vascular surgery. Vasc Endovascular Surg 49:220-227, 2015 16. Walsh M, Whitlock R, Garg AX, et al: Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): A randomized controlled trial. Can Med Assoc J 188:329336, 2016 17. Siregar S, Groenwold RHH, de Heer F, et al: Performance of the original EuroSCORE. Eur J Cardiothorac Surg 41:746-754, 2012 18. Heusch G: Cardioprotection: Chances and challenges of its translation to the clinic. Lancet 381:166-175, 2013 19. Bennett-Guerrero E, Swaminathan M, Grigore AM, et al: A phase II multicenter double-blind placebo-controlled study of ethyl pyruvate in highrisk patients undergoing cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 23:324-329, 2009
• Volume ■■, Number ■■
7
ADULT – RIPC IN HIGH-RISK CARDIOVASCULAR SURGERY 20. Møller CH, Perko MJ, Lund JT, et al: No major differences in 30-day outcomes in high-risk patients randomized to off-pump versus on-pump coronary bypass surgery: The best bypass surgery trial. Circulation 121:498504, 2010 21. Ali ZA, Callaghan CJ, Lim E, et al: Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: A randomized controlled trial. Circulation 116:I98-I105, 2007 (suppl 1) 22. Hoole SP, Heck PM, Sharples L, et al: Cardiac remote ischemic preconditioning in coronary stenting (CRISP stent) study. A prospective, randomized control trial. Circulation 119:820-827, 2009 23. Lang TW, Corday E, Gold H, et al: Consequences of reperfusion after coronary occlusion. Effects on hemodynamic and regional myocardial metabolic function. Am J Cardiol 33:69-81, 1974 24. Weight SC, Bell PRF, Nicholson ML: Renal ischaemia-reperfusion injury. Br J Surg 83:162-170, 1996 25. Yeung KK, Groeneveld M, Lu JJN, et al: Organ protection during aortic cross-clamping. Best Pract Res Clin Anaesthesiol 30:305-315, 2016 26. Zhao W, Meng R, Ma C, et al: Safety and efficacy of remote ischemic preconditioning in patients with severe carotid artery stenosis prior to carotid artery stenting: A proof-of-concept, randomized controlled trial. Circulation 135:1325-1335, 2017 27. Thomas KN, Cotter JD, Williams MJA, et al: Repeated episodes of remote ischemic preconditioning for the prevention of myocardial injury in vascular surgery. Vasc Endovascular Surg 50:140-146, 2016 28. Thielmann M, Kottenberg E, Kleinbongard P, et al: Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: A single-centre randomised, double-blind, controlled trial. Lancet 382:597-604, 2013 29. Hausenloy DJ, Yellon DM: Remote ischaemic preconditioning: Underlying mechanisms and clinical application. Cardiovasc Res 79:377386, 2008 30. Konstantinov IE, Arab S, Kharbanda RK, et al: The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics 19:143-150, 2004 31. Peralta C, Fernández L, Panés J, et al: Preconditioning protects against systemic disorders associated with hepatic ischemia-reperfusion through blockade of tumor necrosis factor-induced P-selectin up-regulation in the rat. Hepatology 33:100-113, 2001 32. Hussein A, Harraz A, Awadalla A, et al: Remote limb ischemic preconditioning (rIPC) activates antioxidant and antiapoptotic genes and inhibits
8
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
proinflammatory cytokine genes in renal ischemia/reperfusion injury. Gen Physiol Biophys 35:77-86, 2016 Lambert EA, Thomas CJ, Hemmes R, et al: Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning. Am J Physiol Heart Circ Physiol 311:H364H370, 2016 Manchurov V, Ryazankina N, Khmara T, et al: Remote ischemic preconditioning and endothelial function in patients with acute myocardial infarction and primary PCI. Am J Med 235:e67, 2014 Meng R, Asmaro K, Meng L, et al: Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 79:1853-1861, 2012 Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 74:11241136, 1986 Ungi I, Ungi T, Ruzsa Z, et al: Hypercholesterolemia attenuates the antiischemic effect of preconditioning during coronary angioplasty. Chest 128:1623-1628, 2005 Ishihara M, Inoue I, Kawagoe T, et al: Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction. J Am Coll Cardiol 38:1007-1011, 2001 Ferguson TB, Hammill BG, Peterson ED, et al: A decade of change— risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990-1999: A report from the STS National Database Committee and the Duke Clinical Research Institute. Ann Thorac Surg 73:480490, 2002 Newman MF, Ferguson TB, White JA, et al: Effect of adenosineregulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: The RED-CABG randomized controlled trial. JAMA 308:157-164, 2012 Alexander JH, Emery RW, Carrier M, et al: Efficacy and safety of pyridoxal 5’-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: The MEND-CABG II randomized clinical trial. JAMA 299:1777-1787, 2008 Kottenberg E, Thielmann M, Bergmann L, et al: Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol—a clinical trial. Acta Anaesthesiol Scand 56:3038, 2012 Zhou C, Liu Y, Yao Y, et al: Beta-blockers and volatile anesthetics may attenuate cardioprotection by remote preconditioning in adult cardiac surgery: A meta-analysis of 15 randomized trials. J Cardiothorac Vasc Anesth 27:305-311, 2013
Seminars in Thoracic and Cardiovascular Surgery
• Volume ■■, Number ■■