doi: 10.1161/circulationaha.106.679167
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(Circulation. 2007;116:I-98 – I-105.)
© 2007 American Heart Association, Inc.
Myocardial Protection, Perioperative Management, and Vascular Biology |
Remote Ischemic Preconditioning Reduces Myocardial and Renal Injury After Elective Abdominal Aortic Aneurysm Repair
A Randomized Controlled Trial
From the Cardiovascular Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Correspondence to Michael E. Gaunt, FRCS, Cambridge Cardiovascular Unit, Level 7, Box 201, Cambridge University Hospitals NHS Trust, Long Road, Cambridge, CB2 2QQ, UK. E-mail meg34{at}cam.ac.uk
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Abstract |
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Background— Myocardial and renal injury commonly contribute to perioperative morbidity and mortality after abdominal aortic aneurysm repair. Remote ischemic preconditioning (RIPC) is a phenomenon whereby brief periods of ischemia followed by reperfusion in one organ provide systemic protection from prolonged ischemia. To investigate whether remote preconditioning reduces the incidence of myocardial and renal injury in patients undergoing elective open abdominal aortic aneurysm repair, we performed a randomized trial.
Method and Results— Eighty-two patients were randomized to abdominal aortic aneurysm repair with RIPC or conventional abdominal aortic aneurysm repair (control). Two cycles of intermittent crossclamping of the common iliac artery with 10 minutes ischemia followed by 10 minutes reperfusion served as the RIPC stimulus. Myocardial injury was assessed by cardiac troponin I (>0.40 ng/mL), myocardial infarction by the American College of Cardiology/American Heart Association definition and renal injury by serum creatinine (>177 µmol/L) according to American Heart Association guidelines for risk stratification in major vascular surgery. The groups were well matched for baseline characteristics. RIPC reduced the incidence of myocardial injury by 27% (39% versus 12% [95% CI: 8.8% to 45%]; P=0.005), myocardial infarction by 22% (27% versus 5% [95% CI: 7.3% to 38%]; P=0.006), and renal impairment by 23% (30% versus 7%; [95% CI: 6.4 to 39]; P=0.009). Multivariable analysis revealed the protective effect of RIPC on myocardial injury (OR: 0.22, 95% CI: 0.07 to 0.67; P=0.008), myocardial infarction (OR: 0.18, 95% CI: 0.04 to 0.75; P=0.006) and renal impairment were independent of other covariables.
Conclusions— In patients undergoing elective open abdominal aortic aneurysm repair, RIPC reduces the incidence of postoperative myocardial injury, myocardial infarction, and renal impairment.
Key Words: aortic • aneurysm • ischemia • reperfusion • preconditioning
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Introduction |
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After elective abdominal aortic aneurysm (AAA) repair, the most common cause of both early and late mortality is cardiac-related.1 Although preoperative coronary angiography reveals significant coronary artery disease in up to 70% of patients undergoing AAA surgery,2 large randomized, controlled trials have failed to show benefits of preoperative prophylactic coronary revascularization.3 The mechanism(s) of myocardial injury remain unclear and evidence exists that most cardiovascular events in vascular surgery patients are the result of nonhemodynamically significant stenoses.4
Irrespective of the mechanism, patients undergoing AAA repair remain at high risk for cardiovascular events.5 Subclinical myocardial injury after major vascular surgery, detected by a rise in cardiac troponin, is common and is associated with increased mortality.6–11 Recent reports suggest a rise in cardiac troponin I in 30% of elective AAA repairs.12,13 Because prophylactic coronary revascularization has been unsuccessful, there remains a need to identify alternative strategies to protect the myocardium during the perioperative period in these high-risk patients.
Ischemic preconditioning is a phenomenon, whereby a brief period of ischemia followed by reperfusion before a prolonged ischemic event can provide protection from cellular injury. The initial ischemic event activates numerous signal transduction pathways, which serve to maintain myocyte contractility and function (reviewed in 14). Conventional preconditioning has been performed by applying stimuli directly to the myocardium. More recently, it has been described that ischemia at a site distant to the heart may confer the same cytoprotection through circulating or neural mediators released from distant organs exposed to ischemia.15 This technique of remote preconditioning offers the potential advantage of systemic benefit to other organs at risk of ischemic injury during surgery. Renal injury, a consequence of hemodynamic changes after application of the aortic crossclamp and ischemia–reperfusion injury after its release, is also a common cause of morbidity and mortality after elective AAA repair.1,16 Acute renal failure develops in nearly 10% of patients after elective open AAA repair17 and is an independent predictor of death.1
Remote ischemic preconditioning offers a simple procedure with the potential to provide widespread and systemic protection from major organ injury in patients undergoing major vascular surgery. Accordingly, we sought to evaluate the clinical use of remote preconditioning in providing myocardial and renal protection after elective open AAA repair in a randomized trial.
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Methods |
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To investigate the potential of remote ischemic preconditioning on myocardial and renal protection after elective open AAA repair, we conducted a randomized double-blind study comparing AAA repair with remote ischemic preconditioning (RIPC) versus conventional AAA repair (control) (ISRCTN 48315424). The trial was approved by the Cambridge Research Ethics Committee and all patients gave informed written consent. Patients were randomized by a computer-generated list in randomly sequenced blocks of 5, 6, 8, or 12 concealed using numbered, sealed, opaque envelopes. Treatment allocation was revealed by the operating surgeon by opening the top envelope on the morning of surgery. Patients and data collectors not present in the operating room were blinded to assignment of patients and the results were compared and analyzed blind in 2 groups labeled A and B.
Patients
Patients referred for primary elective open AAA repair were invited to participate in the study at the time of scheduling for operation. Potential participants were excluded if they were >90 years of age, required concomitant procedures other than AAA repair, had experienced an acute coronary syndrome or myocardial infraction within 3 months, were unable to give informed consent, or were taking sulfonylurea oral hypoglycemic agents or nicorandil drug therapy because these agents have been shown to effect preconditioning.18,19
Treatment and Procedures
Preoperatively, patients with cardiac symptoms were assessed by a cardiologist and referred for noninvasive stress testing (exercise tolerance test or myocardial perfusion imaging) as clinically mandated. Patients with unfavorable results or changes in symptoms were referred for coronary angiography. Subsequently, revascularized patients were eligible for enrollment. ß-blockers were prescribed in the absence of contraindications preoperatively.
Operative and anesthetic techniques were standardized for the purpose of this trial. All patients were induced with intravenous propofol, atracurium, and remifentanil followed by maintenance with inhaled desflurane. The operative procedure was conducted by one of three experienced attending vascular surgeons. All patients received systemic heparinization and supplemental intravenous ß-blockade in the absence of contraindications, titrated toward a target heart rate of 50 to 60 beats/minute, thus also maintaining a regulated intraoperative blood pressure. In the RIPC group, sequential crossclamping of the common iliac arteries with 10 minutes ischemia followed by 10 minutes reperfusion served as the remote preconditioning stimulus. Sequential crossclamping minimized repeat clamping of a single iliac artery, thus reducing the potential for trash foot. To prevent prolongation of total operating time by the RIPC stimulus, a standardized surgical approach was used whereby the iliac vessels were dissected before the neck of the aneurysm. The right iliac vessel was crossclamped for 10 minutes followed by reperfusion during which time the left iliac was prepared. The crossclamp was then placed to the left iliac vessel for 10 minutes and subsequently released, providing a total of 20 minutes of lower limb ischemia. During this time, the remainder of the operative dissection was carried out until the surgeon was prepared to crossclamp the aorta before opening the aneurysm sac.
Postoperatively, all patients received patient-controlled intravenous morphine and/or bupivacaine and fentanyl epidural analgesia. Patients with evidence of myocardial injury or infarction were subsequently managed conventionally using antiplatelet agents, ß-blockers, and angiotensin-converting enzyme inhibitors in the absence of any contraindications.
Outcomes
The primary outcome measure was myocardial injury defined as an increase in serum cardiac troponin I (TnI) greater than 0.40 ng/mL (Dade Behring Dimension cTnI assay, Milton Keynes, UK). Secondary outcomes included myocardial infarction (MI), renal impairment, and death. Myocardial infarction was defined as TnI rise >1.5 ng/mL with at least one of the following: typical ischemic symptoms, electrocardiographic changes indicative of ischemia, or new pathological Q-waves according to the revised American College of Cardiology/American Heart Association guidelines. Twelve-lead electrocardiograms were performed each morning after surgery, 2-hourly until extubation, and as clinically mandated. Impaired renal function was defined as peak serum creatinine level of >177 µmol/L (2.0 mg/dL) according to guidelines for risk stratification in patients undergoing major vascular surgery and noncardiac surgery.5 Blood specimens were taken preoperatively and on the morning of postoperative days 1, 3, and 7.
Statistical Methods
The sample size was calculated on an estimated 35% incidence of TnI elevation over the 7-day period in control subjects according to a previously published study reporting a 30% incidence in patients undergoing elective AAA repair over a 3-day period.12 To detect an absolute reduction of 25% at 5% significance and 80% power, the study required randomization of 82 patients (GraphPad Statmate 2.00, San Diego, Calif). Data were analyzed on an intention-to-treat basis. Descriptive variables are presented as means with SD or medians with interquartile ranges and compared with the t test or Mann-Whitney U test, respectively. Categorical data are expressed as frequency and percentage and compared with 
2 or Fisher’s exact test where appropriate. Area under the concentration–time curve (AUC) was calculated by the trapezoidal method for each patient and compared using the Mann-Whitney U test. Estimations are presented with 95% CIs. The CIs for differences in AUC were obtained using Bootstrapping (bias-corrected and accelerated estimates with 1000 replications). Conventional levels of significance (0.05) were applied throughout. Forward stepwise logistic regression was performed to identify risk factors for myocardial injury and renal impairment. Statistical analysis was undertaken using SPSS for windows version 11.0 (Chicago, Ill) and S Plus version 6 (Seattle, Wash).
Statement of Responsibility
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the article as written.
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Results |
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Between February 2003 and December 2005, all patients referred for elective open AAA repair at Addenbrooke’s Hospital (Cambridge, UK) were invited to participate in our trial. Eight patients declined invitation, 10 were excluded (8 undergoing concomitant procedures, 2 unable to provide informed consent as a result of language) and 82 randomized after informed written consent. In total, 41 patients were randomized to undergo open AAA repair with RIPC and 41 patients control (conventional open AAA repair) (Figure 1). All patients received the intended treatment, completed the study protocol, and were included in the analysis. Twenty-three patients (28%) were referred for noninvasive stress testing after cardiology consultation. Of these, 4 patients subsequently required angiography, all of whom underwent revascularization by percutaneous coronary intervention before randomization (one RIPC versus 3 control). Fourteen patients had previous revascularization, of which these 4 were the only within 6 months of AAA surgery.
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Baseline characteristics (Table 1) and operative characteristics (Table 2) were similar in both groups. Patients were risk-stratified using the prospectively validated POSSUM (physiological operative severity score for the enumeration of mortality and morbidity) risk stratification scoring system20 to ensure operative risk between groups was similar. There was no statistically significant difference with regards to aneurysm size, POSSUM risk score, aortic crossclamp time, or total operative time. Furthermore, perioperative administration of blood and intravenous fluid infusion was comparable between groups, eliminating the potentially confounding effects of differences in circulating volume on TnI and creatinine concentrations. No patient experienced distal atheroemboli as a result of iliac crossclamping. Patients who received remote preconditioning had a significantly reduced stay in the intensive care unit, but no difference in the length of stay in the hospital (Table 2). There was no difference in mortality between the 2 groups either in-hospital or at discharge (Table 3).
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Myocardial Injury and Infarction
Twenty-one of the 82 patients (26%) had a TnI rise postoperatively. Of these events, 17 occurred on postoperative day 1 (81%) and 4 (19%) on day 3, indicating that the majority of myocardial ischemia occurred within the first 24 hours postoperatively (Table 4). Furthermore, peak TnI levels occurred on days 1 (55%) and 3 (30%). Thirteen (16%) patients met the criteria for MI of which 5 died in the hospital as a direct consequence (Table 3). All patients experiencing a MI had elevated TnI and diagnostic electrocardiograms without chest pain.
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Remote preconditioning reduced the absolute risk of myocardial injury by 27% (39% versus 12% [95% CI: 8.8% to 45%]; P=0.005) and MI by 22% (27% versus 5%; [95% CI: 7.3% to 38%] P=0.006) (Table 3). Furthermore, mean TnI AUC was significantly lower in remote preconditioned patients compared with conventional AAA repair (0.38±1.3 versus 24±87, 95% CI: 7.5 to 76; P<0.001) (Figure 2A).
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Univariable analysis identified RIPC, previous MI, antiplatelet drug therapy, and renal impairment as predictors of myocardial injury (Table 5). Multivariable analysis, however, revealed the protective effect of RIPC was independent of other covariables (OR: 0.22, 95% CI: 0.07 to 0.67; P=0.008) (Table 4). The adjusted relative risk of MI (OR: 0.18, 95% CI: 0.04 to 0.75; P=0.006) was also reduced in patients who received RIPC. When patients with previous MI were excluded, RIPC reduced the incidence of myocardial injury by 23% (32% versus 9.1% [95% CI: 3.1% to 39%]; P=0.02) and MI by 18% (21% versus 3.1% [95% CI: 1.8% to 37%]; P=0.02), further confirming that the protective benefits of RIPC were independent of previous MI.
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Renal Impairment
Renal impairment was present in 3 patients before surgery (Table 1). Baseline serum creatinine levels (Table 1) and the incidence of suprarenal aortic crossclamping did not differ between the 2 groups (Table 2). Fifteen of the 81 patients (19%) had a peak serum creatinine >177 µmol/L in the postoperative period. Of these events, 11 occurred on postoperative day 1 (74%) and 4 (26%) on day 3, indicating that the majority of renal injury occurred in concert with myocardial injury within the first 24 hours postoperatively (Table 4). No patient required postoperative hemodialysis.
The absolute risk of renal impairment was reduced by 23% (30% versus 7% [95% CI: 6.4 to 39]; P=0.009) in the RIPC group (Table 3). In addition, mean creatinine AUC was significantly lower in patients who received RIPC compared with conventional AAA repair (696±188 versus 1034±718, 95% CI: 148 to 665; P=0.05) (Figure 2B).
Multivariable analysis revealed the reduced risk of renal impairment by RIPC (OR: 0.26, 95% CI: 0.06 to 1.05; P=0.06) was independent of other covariables (Table 6). Suprarenal aortic crossclamping (OR: 5.8, 95% CI: 1.3 to 25; P=0.02) and baseline serum creatinine (OR: 1.0033 per 10 µmol/L; 95% CI: 1.0023 to 1.066; P=0.04) were also independent predictors of postoperative renal impairment (Table 6).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this randomized, controlled trial, we investigated the use of a simple operative maneuver to confer remote ischemic preconditioning in patients undergoing elective open AAA repair. We observed that myocardial injury, assessed by cardiac troponin, after this procedure is common and is reduced by remote preconditioning. Furthermore, remote preconditioning reduced the risk of perioperative MI, renal impairment, and length of intensive care unit stay.
Local ischemic preconditioning was first described in a canine model of MI, in which brief periods of ischemia paradoxically resulted in reduced infarct size.21 Direct surgical preconditioning has been demonstrated in the context of coronary artery bypass surgery, hepatectomy, and lobectomy (reviewed in 22). More recently, attention has been turned to the potential systemic benefits of brief periods of ischemia, so-called remote ischemic preconditioning. Such a technique avoids the direct induction of ischemia to potentially vulnerable target organs. In animal models, preconditioning of rat mesenteric or renal arteries15 and pig lower limb reduced cardiac and pulmonary injury.23 In humans, it has been shown previously that remote preconditioning reduces inflammatory cell activation and endothelial dysfunction.24,25 More recently, Cheung and colleagues described the first clinical application of remote preconditioning in humans.26 In this randomized, controlled trial, the authors induced remote preconditioning by 4 5-minute cycles of lower limb ischemia/reperfusion using a blood pressure cuff in children undergoing cardiac surgery. In their study, remote preconditioning reduced myocardial injury, postoperative inotropic requirements, and airway resistance. In concert with the findings from our study, these randomized, controlled trial data suggest that remote preconditioning is a rational therapeutic strategy to reduce ischemic injury in vulnerable organs in humans.
Importantly, it has been shown that even small elevations in cardiac troponin concentration are associated with increased morbidity and mortality.27 Magnetic resonance studies strongly correlate troponin elevation with new myocardial hyperenhancement indicative of cell death.28 Immediately after aortic aneurysm surgery, Godet and colleagues reported that a troponin level >0.54 ng/mL in the first 3 postoperative days was associated with an increased risk of cardiac complications.6 Similarly, levels of >1.5 ng/mL were associated with a 6-fold increase in 6-month mortality and a 27-fold increased risk of MI.7 At a mean of 32 months, a raised TnI >0.6 ng/mL within 3 days of surgery was associated with a 2.15-fold increase in mortality and this rose to 3.75- fold when a TnI cutoff of 1.5 ng/mL was used.29 At 4 years, elevated TnI was associated with increased all-cause mortality.9 The results of these studies along with others indicate that even small serum rises in these markers have important clinical consequences in patients undergoing vascular surgery. In the face of large randomized trials refuting routine coronary artery revascularization,3 alternative techniques to protect the myocardium in these high-risk patients could provide a useful strategy to reduce perioperative morbidity and mortality. Remote preconditioning may offer a relatively simple means of reducing myocardial injury and infarction after major surgery. In AAA repair, the iliac arteries represent the ideal target for the induction of remote preconditioning because they require dissection and crossclamping routinely as part of the operation. Furthermore, the target in the lower limb, skeletal muscle, is more resistant to ischemia than visceral organs. In contrast to aortic crossclamping, alternating single iliac arteries reduces the risk of sudden increased afterload and the potential of AAA rupture.
Long-term antiplatelet therapy greatly reduces the risk of MI in patients at high risk of vascular disease. In our study, there was a trend toward greater preoperative antiplatelet therapy in the conventional AAA repair group compared with patients who received remote preconditioning. These findings raise an interesting paradox. It is possible that these data reflect a greater incidence or severity of underlying coronary artery disease in the conventional repair group. Alternatively, the reduced incidence and magnitude of myocardial injury in the remote preconditioning group may suggest an even greater benefit of remote preconditioning had the groups been better matched for antiplatelet therapy. In light of previous studies reporting underuse of cardiac medical therapy among patients undergoing AAA repair,30 it is also possible that the increased incidence of antiplatelet therapy simply represents secondary prevention for the higher absolute incidence of MI in the conventional treatment group. Nevertheless, multivariable logistic regression was able to exclude the potentially confounding effect of antiplatelet therapy on myocardial injury. Similarly, multivariable logistic regression as well as subgroup analysis excluding patients with previous MI confirmed the protective effects of preconditioning on myocardial injury were independent of other covariables.
Our study highlights another potential benefit of remote preconditioning. In contrast to direct preconditioning, remote preconditioning has the ability to provide a widespread and systemic benefit. Although the primary end point of our study was detecting a difference in myocardial injury, remote preconditioning also reduced the incidence of renal impairment after surgery. Ischemic renal impairment is a serious and common complication of AAA surgery17 and an independent predictor of both early31 and late death in epidemiological studies.32 These findings suggest that other organs at risk of injury during operation such as the kidney may also benefit from remote preconditioning.
Renal dysfunction decreases the clearance of cardiac troponins, thus possibly interfering with their prognostic value.33 In our study, patients in the control group exhibited higher TnI and creatinine concentrations postoperatively despite being matched at baseline. Although this may be confounding, we believe it is unlikely to be the cause of finding higher TnI. In keeping with previous reports,8,10 multivariable logistic regression analysis suggested that the protective effect of remote preconditioning on myocardial injury (TnI elevation) was independent of the serum creatinine. Furthermore, considerable evidence has emerged showing that even in the presence of acute34 or chronic renal dysfunction cardiac, troponins offer prognostic information for both MI and death in vascular surgery patients.9,29 Nevertheless, this finding remains a potential limitation of the study and further studies powered toward detecting differences in renal function using more sensitive markers of renal injury are warranted.
The exact mechanism by which remote preconditioning confers its protective effects is unclear. Previous studies have highlighted that the pathophysiology of perioperative MI differs from nonsurgical MI. In particular, that the mechanism of injury in these patients is prolonged stress induced ST depression-type ischemia attributable to increased heart rate, blood pressure, sympathetic discharge, and procoagulant activity during emergence from anesthesia as opposed to plaque rupture and coronary thrombosis in nonsurgical MI.35 In our study, the beneficial effects of preconditioning were predominant 24 hours after surgery. This temporal relationship suggests the protective effects were the results of early phase preconditioning (involving numerous mediators, triggers, and signaling pathways including adenosine, bradykinin, opiates, kinases, and ATP-dependent potassium channels [reviewed in 14]) effects on prolonged stress-induced ischemia. Further studies investigating the exact mechanism of protection in these patients are currently underway.
In conclusion, we have demonstrated that intermittent lower limb ischemia as a remote ischemic preconditioning stimulus significantly reduces myocardial injury after elective open AAA repair. This simple operative maneuver may be considered in all patients undergoing open AAA repair. Although this study was not powered toward MI or renal impairment, our data strongly indicate that remote preconditioning may additionally confer these benefits, thus justifying the need for large clinical trials investigating the use of remote preconditioning after major surgery.
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Acknowledgments |
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Source of Funding
This work was funded by Cambridge University Hospitals NHS Foundation Trust.
Disclosures
None.
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Footnotes |
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Presented at the American Heart Association Scientific Sessions, Chicago, Ill, November 12–15, 2006.
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References |
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