Remote Ischemic Preconditioning Does Not Affect the Incidence of Acute Kidney Injury After Elective Abdominal Aortic Aneurysm Repair Noelle Murphy, MB, BCh, BAO,* Ajith Vijayan, MB, BCh, BAO,J Stephen Frohlich, MB, BCh, BAO,* Frank O’Farrell,† Mary Barry, MB, BCh, BAO,‡ Stephen Sheehan, MB, BCh, BAO,‡ John Boylan, MB, BCh, BAO,§ and Niamh Conlon, MB, BCh, BAO§ Objective: Open abdominal aortic aneurysm (AAA) repair is associated with a high risk of renal injury with few known strategies demonstrating a reduction in this risk. Remote ischemic preconditioning (RIPC) has been identified as having the potential to minimize organ injury following major vascular surgery. This trial investigated the potential for RIPC to attenuate renal and myocardial injury in patients undergoing elective open AAA repair. Design: Prospective, randomized double-blinded control trial. Setting: Tertiary referral hospital. Participants: Sixty-two patients undergoing elective open AAA repair. Intervention: RIPC was achieved via three 5-minute cycles of upper limb ischemia using a blood pressure cuff or control (sham cuff). Measurements: Primary outcome was the occurrence of renal injury, as measured by an increase in creatinine during the first 4 postoperative days. Secondary outcomes included urinary neutrophil-gelatinase-associated lipocalin (NGAL),

occurrence of acute kidney injury (AKI), occurrence of myocardial injury as defined by troponin rise, incidence of postoperative complications, and mortality. There was no difference in postoperative creatinine levels, NGAL levels, or the occurrence of AKI between the groups at any postoperative time point. Similarly, there was no difference in the occurrence of myocardial injury or mortality. Of note, 6 patients in the RIPC group, while no patient in the control group, experienced postoperative complications that required repeat surgical laparotomy, potentially masking any renoprotective effects of RIPC. Conclusion: RIPC did not reduce the risk of postoperative renal failure or myocardial injury in patients undergoing open AAA repair. The authors’ results do not support the introduction of this technique to routine clinical practice. & 2014 Elsevier Inc. All rights reserved.

R

of RIPC to the upper limb would attenuate increases in serum creatinine after open abdominal aortic aneurysm repair.

ENAL INJURY is an important cause of morbidity and mortality following abdominal aortic aneurysm (AAA) repair.1,2 Development of acute renal failure (ARF) is multifactorial. Risk factors include pre-existing renal impairment, aortic cross-clamping, and ischemia–reperfusion injury after clamp release. ARF develops in up to 10% of patients after elective open AAA repair and is an independent predictor of death.1,3 To date, there is no robust evidence that existing pharmacologic or other interventions used to protect the kidneys during vascular surgery are beneficial.4 Additionally, cardiac events represent a significant cause of perioperative morbidity and mortality in patients undergoing AAA surgery.1,5 Subclinical myocardial injury after major vascular surgery, detected by a rise in cardiac troponin, occurs in up to 30% of patients and is associated with increased mortality.6–11 There remains, therefore, a need to identify renoprotective and cardioproctective strategies during the perioperative period in these high-risk patients. Remote ischemic preconditioning (RIPC) has been shown in some studies to improve renal and cardiac indices following major cardiac or vascular surgery.12–18 In remote ischemic preconditioning, a series of short periods of ischemia followed by periods of reperfusion render organs more resistant against subsequent ischemic events. The mechanism for RIPC has not been elucidated; however, signalling between tissues and organs probably occurs via humoral and neural pathways19,20 Originally, preconditioning was discovered by applying ischemic stimuli directly to the organ to which the protection was being targeted; however, more recently, distant organs have been used for preconditioning; in particular, skeletal muscle. The ease by which remote ischemic preconditioning (RIPC) may be performed makes it an attractive technique to protect against systemic organ injury in patients undergoing vascular surgery. Therefore, the authors hypothesized that the application

KEY WORDS: remote ischemic preconditioning, acute kidney injury, vascular surgery, aortic aneurysm

METHODS This prospective, randomized, double-blind, single-center study was approved by the institutional research ethics committee, and written informed consent was obtained from all patients (Trial registration: ISRCTN11019960). Adult patients undergoing primary elective AAA repair were invited to participate in this study at the time of hospital admission between September 2009 and December 2012. Exclusion criteria included refusal of consent, myocardial infarction in the preceding two weeks, history of upper limb vascular insufficiency, and emergency AAA repair. Those patients with kidney disease requiring renal replacement therapy also were excluded. Anesthesia was induced by 1 of 3 senior vascular anesthesiologists with propofol, fentanyl, and rocuronium, and the trachea was intubated and the patient ventilated. Maintenance of anesthesia was with sevoflurane. Prophylactic antibiotics were administered, and normothermia was maintained using a convective air system. All patients received systemic heparin anticoagulation (75 u/kg) prior to aortic cross-clamp. Standard monitoring included continuous

From the Department of *Anaesthesia and Intensive Care Medicine, †Clinical Chemistry, ‡Vascular Surgery, and §Anaesthesia, St. Vincent’s University Hospital, Dublin, Ireland; and ‖Anaesthesia and Intensive Care Medicine, Castle Hill Hospital, Hull and East Yorkshire Hospitals NHS Trust, East Yorkshire, UK. Address reprint requests to Noelle Murphy, MB, BCh, BAO, St Vincent’s University Hospital, Department of Anaesthesia and Intensive Care Medicine, Mailing Address Dublin 4, Ireland. E-mail: murphy. [email protected] © 2014 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2014.04.018

Journal of Cardiothoracic and Vascular Anesthesia, Vol 28, No 5 (October), 2014: pp 1285–1292

1285

1286

electrocardiography and continuous recording of heart rate, arterial blood pressure, central venous pressure, pulse oximetry, end-tidal carbon dioxide concentration, and body temperature. One of 3 attending vascular surgeons conducted the operative procedure. Perioperative pain management of epidural analgesia, intrathecal opiates, continuous wound infusion catheter, or patient-controlled analgesia (PCA) was at the discretion of the individual attending anesthesiologist. Care was provided for patients in a dedicated vascular surgical high-dependency unit (HDU) for at least 48 hours postoperatively. On the morning of surgery, patients were assigned randomly, using a random number generator in a 1:1 ratio for parallel arms and using a concealed allocation approach (computer-generated codes, Microsoft Excel, Microsoft Corporation, Seattle, WA) with sealed envelopes to (1) the RIPC group or (2) the control group. Study investigators, attending anesthesiologists, and surgical staff were blinded to treatment assignments. This was achieved by a third party placing the cuff on the patient’s upper arm in the RIPC group or on a bag of saline concealed under surgical drapes in the control group. The RIPC protocol was commenced postinduction of anesthesia and after placement of a central venous line and completed prior to the application of the aortic cross-clamp. The RIPC protocol consisted of 3 cycles of upper arm ischemia. Each cycle was induced by a blood pressure cuff inflated to 100 mmHg above systolic blood pressure for 5 minutes, followed by deflation for a period of 5 minutes (reperfusion period).13,14 The primary outcome measure was renal injury defined by an increase in serum creatinine levels during the first 4 days following open AAA repair. Secondary outcome measures included urinary NGAL (NGAL TestTM Reagent Kit [ST001CA], Bioporto Diagnostics), urea, urine output, presence of acute kidney injury (using AKIN criteria and NGAL), myocardial infarction (MI), myocardial injury (as measured by troponin), length of hospital stay, and death. Post hoc analysis examined the occurrence of major adverse outcomes. AKIN criteria were calculated daily for each patient (stage I, II or III)21; AKI was defined as an abrupt (within 48 hours) increase in s-creatinine 426.5 mmol/L (0.3 mg/dL) or a relative increase in s-creatinine 450%, or a decrease in urine output to less than 0.5 mL/kg/ h for more than 6 hours. Myocardial infarction was defined as a troponin rise to greater than the upper limit of normal for the test conducted, with at least 1 of the following: Typical symptoms of ischemia, ST/T wave changes, or left bundle-branch block, new pathologic Q-waves, imaging evidence of new loss of viable myocardium or regional wall motion abnormality or identification of a new intracoronary thrombus according to the American College of Cardiology/American Heart Association guidelines. During the study period, the hospital laboratory changed from measuring troponin I (E 170, Roche Diagnostics, Mannheim, Germany) to troponin T (high sensitivity) (E170, Roche Diagnostics, Mannheim, Germany). Therefore, troponin concentrations were not compared directly between groups; the detection of a troponin level (either subunit) above the upper limit of normal, using the hospital laboratories standard reference range, was classified as troponin positive for that day. The number of troponin-positive patients between groups was then compared. Blood and urine specimens were taken preoperatively, 4 hours following extubation and on the morning of postoperative days 1 to 3 inclusive. Each morning after surgery until postoperative day 3, 12-lead ECGs were performed. The sample size was calculated to detect a 25% difference in peak postoperative creatinine levels. Suitable data for postoperative creatinine, following open AAA repair, were not available in the literature at the time of study design. Therefore, from January to August 2009, the authors recorded all creatinine values at baseline, and for the first 4 postoperative days in patients who had undergone open AAA repair in their institution (N ¼ 16). Peak creatinine level occurred on day 2 postoperatively (105.94 þ/- 44.7 mmol/L). Based on this data, to detect a 25% reduction in peak postoperative creatinine, a total of 25 patients per group were

MURPHY ET AL

required (alpha and beta of 0.05 and 0.2, respectively). Given that test creatinine values were distributed abnormally, the number of subjects was increased by 20% to compensate for the reduced power of nonparametric statistical tests to detect significant differences. Therefore, it was planned to recruit a total of 31 patients in each group. All power calculations were performed using GraphPad Statmate 2.00, Graphpad Software Inc, La Jolla, CA). Data were analyzed on an intention-to-treat basis. Descriptive variables are presented as medians and interquartile ranges. Categorical data are expressed as frequency and percentage and compared with Chi squared, Fisher’s exact test, or the Cochran-Armitage test for trend where appropriate. Multiple comparisons between groups were performed using the Kruskal-Wallis test or repeat measures ANOVA. Normality of data was tested using the D’Agostino-Pearson normality test. Conventional levels of significance (0.05) were applied throughout. A posthoc analysis of the data was undertaken to exclude patients who returned to the operating room within 3 days of the original surgery. Statistical analysis was undertaken using Prism 6 (Graphpad Software, La Jolla, CA). RESULTS

Between September 2009 and December 2012, all patients referred for elective open AAA repair at St Vincent’s University Hospital (Dublin, Ireland) were invited to participate in this trial. Two patients declined invitation and a further two patients were excluded (upper limb vascular insufficiency, leaking AAA with hemodynamic instability). In total, 62 patients presenting for open AAA repair were included in this study; 31 patients were randomized to the RIPC group, and 31 patients were randomized to the control group (conventional open AAA repair) (Fig 1). All patients received the intended treatment, completed the study protocol, and were included in the analysis. Baseline characteristics (Table 1) and operative characteristics (Table 2) were similar between groups. There were no significant differences with regard to aortic cross-clamp time, site of cross-clamp application, or graft type. Serum creatinine levels increased from baseline during the first 48 hours postoperatively, returning to their preoperative values by day 3 (Fig 2). The greatest increase occurred at postoperative day 1 in both groups. There was no significant difference between creatinine values in the RIPC or control group at any time point (Table 3). Urinary NGAL levels increased as early as 4 hours postoperatively, with peak values occurring at day 3 (Fig 2), with no significant difference in urinary NGAL concentration at any time point between groups (Table 3). Similarly, no significant differences in urea or urine output were detectable at any time point between the RIPC group and control group (Table 4). A total of 28 patients (45%) were diagnosed with AKI according to the AKIN criteria at any time point, 11 patients (35%) in the control group and 17 patients (54%) in the RIPC group. However, this difference was not statistically significant (0.12) (Table 3). When NGAL levels (using an NGAL cut-off of 4250 ng/L, as per manufacturer’s recommendations22) were used to define clinically relevant renal injury, AKI occurred in 22 patients (36%), nine patients (29%) in the control group and 13 (42%) in the RIPC group (Table 3). Twenty-five (40%) of the 62 patients had a new troponin rise postoperatively, (16 in the RIPC group and 9 in the control group (p ¼ 0.11); RIPC was not associated with a reduction in the number of patients with a troponin increase above the upper limit

1287

REMOTE ISCHEMIC PRECONDITIONING AND KIDNEY INJURY

Enrollment

Assessed for eligibility (n =66) Excluded (n = 4) Did not meeting inclusion criteria (n =2) Refused to participate (n = 2)

Analysis

Follow up

Allocation

Randomized (n = 62)

Allocated to control group (n =31)

Allocated to RIPC group (n = 31)

Received allocated intervention (n =31) Did not receive allocated intervention (n = 0)

Received allocated intervention (n =31) Did not receive allocated intervention (n =0)

Lost to follow up (n =0) Discontinued intervention (n =0)

Lost to follow up (n =0) Discontinued intervention (n =0)

Analyzed (n =31)

Analyzed (n = 31)

Excluded from analysis (n = 0)

Excluded from analysis (n = 0)

Fig 1.

Consort diagram.

of normal post-open AAA repair (Table 5). Six (10%) postoperative myocardial infarctions were diagnosed, 4 (13%) in the RIPC group and 2 (3%) in the control group (p ¼ 0.67). Six (10%) patients developed an arrhythmia in the first 3 days postoperatively, 5 (16%) in the RIPC group and 1 (3%) in the control group (p ¼ 0.2). Twenty-five (40%) patients required vasopressors postoperatively, with no difference between groups (Table 5). There were no differences in HDU length of stay, hospital length of stay or mortality between the groups. Six patients (10%) returned to the operating room (OR) within the first 3 postoperative days for surgical complications (5 repeat laparotomies, 1 lower limb fasciotomy). All 6 of these patients had been randomized to the RIPC group (p ¼ 0.029).

Seven patients (11%) required renal replacement therapy (RRT) during the first postoperative week, all in the RIPC group (p ¼ 0.01) (Table 6). Six of the 7 patients who required RRT were those who had returned to the OR within the first 3 days. Despite randomization, a large number of subjects (n ¼ 6, almost 20%) in the RIPC group had postoperative complications that required repeat surgical laparotomy and intervention, while this occurred in none of the subjects in the control group. These surgical complications in the RIPC group present a high risk of masking any influence that RIPC itself might have had on renal outcomes, as the complications experienced are strong precipitators of renal complications. It is quite unlikely that RIPC itself would have led to this difference in surgical

1288

MURPHY ET AL

Table 1. Baseline Patient Demographics

Variable

RIPC

Control

(n ¼ 31)

(n ¼ 31)

Male gender n ¼ (%) 29 (94%) 24 (77%) Median Age 75 (68-79) 69 (65-77) 27.8 (25.4-30.2) 28.2 (24.8-30.6) Median BMI (kg/m2) ASA 3 (2-3) 2 (2-3) Medical History n ¼ (%) Previous MI 7 (22%) 4 (13%) Angina 4 (13%) 5 (16%) Hypertension 20 (64%) 16 (52%) Diabetes mellitus 7 (23%) 5 (16%) History of smoking 22 (71%) 22 (67%) Hypercholesterolemia 19 (61%) 17 (55%) NYHA score 2 (1-2) 1 (1) Chronic kidney disease 6 (19%) 2 (7%) Baseline creatinine (μmol/L) 86 (77-114) 90 (79-102) Baseline NGAL (ng/mL) 14 (7-36) 14 (8.7-23) Medication n ¼ (%) Beta-blocker 10 (32%) 11 (36%) CCB 13 (41%) 5 (16%) ARB/ACE-I 17 (54%) 18 (60%) Nitrate 4 (13%) 3 (10%) Diuretics 6 (19%) 3 (10%) Antiplatelet therapy 24 (80%) 24 (80%) Warfarin 4 (13%) 1 (3%)

p Value

0.13 0.03 0.48 0.28 0.51 0.99 0.31 0.99 0.99 0.99 0.03 0.25 0.79 0.48 0.99 0.09 0.99 0.99 0.13 0.99 0.35

NOTE. Data expressed as median (IQR) unless otherwise stated. Abbreviations: ACE-I , angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blockers; ASA, American Society of Anesthesiologiests; BMI, body mass index; CCB, calcium channel blocker; IQR, interquartile range; MI, myocardial infarction; NYHA, New York Heart Association; NGAL, neutrophil gelatinase-associated lipocalin; RIPC, remote ischemic preconditioning.

complications. Therefore, the authors undertook a posthoc analysis excluding the 6 patients who had returned to the OR during the followup period. When this subset of patients was excluded, there was still no difference in primary or secondary endpoints between the RIPC and control groups (Table 7). DISCUSSION

In this randomized, controlled trial, the authors investigated the use of a blood pressure cuff to confer remote ischemic preconditioning in patients undergoing non-emergency open AAA repair. In this study, they demonstrated that acute kidney injury after this procedure is common. However, the risk of renal injury (as measured by either creatinine or NGAL) was not reduced by a remote ischemic preconditioning maneuver previously shown to be both cardioprotective and renoprotective in patients presenting for cardiac surgery.13–15 Furthermore, remote ischemic preconditioning did not reduce the risk of perioperative MI, myocardial injury, postoperative complications, mortality, or hospital length of stay. There is increasing investigation into the potential benefits of brief periods of ischemia to systemic organs at sites remote from the organ, so-called “remote ischemic preconditioning.” RIPC is achieved clinically by repeated cycles transiently rendering groups of skeletal muscle (upper or lower limb) ischemic either by direct surgical occlusion of arterial supply or indirectly using a cuff inflated above systolic blood pressure. RIPC has

undergone most clinical investigation as a means for myocardial protection during major cardiac and vascular surgery. A recent detailed meta-analysis showed the occurrence of periprocedural myocardial infarction was reduced by RIPC, as was the postprocedural peak release of troponin,17 but showed no evidence of reduced mortality associated with ischemic cardiac events and no reduction in the combined endpoint of major adverse cardiovascular events. Given that most clinical studies are small, the total number of adverse events are low, and endpoints focus on surrogate markers of cardiac ischemia or biomarkers, which have uncertain clinical relevance; a role for routine use of RIPC to reduce perioperative cardiac events currently has not been established.12,17,18,23,24 Ischemic renal impairment is a serious and common complication of AAA surgery, occurring in up to 28% of patients.25 Moreover, development of postoperative ARF is an independent predictor of both early and late death in epidemiologic studies.26,27 Despite extensive investigation, no treatments are available to reduce the occurrence of or treat this renal injury. Therefore, the potential role of RIPC in reducing renal injury following high-risk cardiovascular surgery recently has gained much interest. There is conflicting evidence supporting the renoprotective effect of RIPC post-open AAA repair. In 2007, Ali et al studied 82 patients undergoing open AAA repair. Two cycles of intermittent cross-clamping of the common iliac artery with 10 minutes of ischemia followed by 10 minutes of reperfusion served as the RIPC stimulus. They reported that RIPC significantly reduced the occurrence of acute renal impairment postoperatively, defined as an increase in serum creatinine above 177 μmol/L.12 However, when the same authors completed a followup study in open AAA patients using the same RIPC stimulus but examining the effect on a number of renal injury indices, including urinary retinol-binding protein, albumin-creatinine ratios, and estimated GFR and serum creatinine values, they failed to detect an effect.28 RIPC similarly has failed to demonstrate a reduction in AKI in patients undergoing endovascular aneurysm repair.24 In cardiac surgery, conflicting evidence also exists; 2 studies examining the effect of RIPC on postoperative renal function found a significant reduction in the incidence of AKI in the group who received RIPC.15,16 However, a similar RIPC investigation by Table 2. Operative Characteristics

Variable

RIPC

Control

p

(n ¼ 31)

(n ¼ 31)

Value

Clamp Position n ¼ (%) Infrarenal 31 (100%) 30 (97%) 40.99 Suprarenal 0 1 (3%) Graft Type n ¼ (%) Tube 23 (74%) 24 (77%) 40.99 Bifurcated 8 (26%) 7 (23%) Median blood loss (mL) 1450 (900-2100) 1800 (1150-2120) 0.8 Median cross-clamp time 68 (55-85) 59 (48-76) 0.12 (mins) Median operating time 180 (140-209) 155 (136-207) 0.23 (mins) NOTE. Data expressed as median (IQR) unless otherwise stated. Abbreviations: IQR, interquartile range; RIPC, remote ischemic preconditioning.

1289

REMOTE ISCHEMIC PRECONDITIONING AND KIDNEY INJURY

Fig 2.

Biomarkers of renal injury up to postoperative day 3. (A) Median serum creatinine (μmol/mL) and (B) median urinary NGAL ng/mL.

Choi et al failed to demonstrate a difference in novel renal biomarkers.29 Beyond a cardioprotective and renoprotective effect of RIPC in patients presenting for open AAA repair, there is also evidence that in patients presenting for open infrarenal aortic aneurysm repair, RIPC attenuates both pulmonary and intestinal injury.30 Given the theoretical benefit of RIPC as part of a renoprotective strategy in major vascular surgical patients and the conflicting evidence currently available, the authors aimed to assess the effects of RIPC on renal outcome in patients having elective AAA repair in a randomized controlled clinical trial. Although they powered the study to detect a difference in the most commonly used marker of renal damage, creatinine, they also included additional parameters reflecting subclinical renal injury (NGAL), a renal injury score (AKIN criteria), and additional renal parameters (urine output, urea) to maximize the chances of detecting any potential difference. The authors found a very high incidence of AKI as defined by AKIN criteria in patients following open AAA repair (54% and 31% in RIPC and control groups, respectively). Rates of AKI as diagnosed by NGAL 4250 ng/L were very similar (42% and 29% in RIPC and control groups, respectively). These rates of

Table 3. Renal Indices RIPC

Creatinine μmol/L Baseline Postop Day 0 Postop Day 1 Postop Day 2 Postop Day 3 NGAL (ng/mL) Baseline Postop Day 0 Postop Day 1 Postop Day 2 Postop Day 3 AKI (AKIN Diagnosis), no. (%) AKI (NGAL Diagnosis), no. (%)

Control

p Value

86 97 118 98 85

(77-114) (79-139) (88-170) (75-188) (70-183)

90 95 101 83 78

(79-102) (81-127) (82-156) (71-131) (67-121)

40.99 40.99 0.81 40.99 40.99

14 37 102 82 53 17 16

(7-36) (20-115) (28-367) (27-261) (29-176) (55%) (52%)

14 25 33 36 150 11 11

(8.7-23) (17-51) (12-113) (18-89) (48-845) (36%) (35%)

40.99 40.99 0.13 0.32 0.18 0.2 0.43

NOTE. AKI was either diagnosed using AKIN criteria or using a NGAL cut-off 4250 ng/L up to postoperative day 3. Data are expressed as median (interquartile range) unless otherwise stated. Abbreviations: AKI, acute kidney injury; AKIN, acute kidney injury network; NGAL, neutrophil gelatinase-associated lipocalin; RIPC, remote ischemic preconditioning.

renal injury are higher than previously reported; however, they used more sensitive definitions and markers of AKI and have a higher median age than in previously reported studies.3,25 Despite similar baseline creatinine values, they failed to detect a difference in this primary endpoint during the first 4 postoperative days. Similarly, NGAL levels, perhaps a more suitable marker of subclinical renal injury, were no different between groups. This study also detected high rates of troponin-diagnosed myocardial injury and a high rate of postoperative MI similar to that reported by previous authors12; RIPC had no effect on the occurrence of myocardial events. More patients in the RIPC group had postoperative complications that required a surgical intervention. It is quite unlikely that the RIPC intervention led to increased surgical complications given that the literature does not demonstrate any signals consistent with such events. This difference in surgical complications probably represents a chance finding that occurred despite randomization. Similarly, a significantly greater number of patients in the RIPC group required renal replacement therapy (Table 6). Considering the study was not powered to detect a difference in requirement for RRT, this may represent a chance finding. However, it more likely reflects the higher incidence of surgical complications in the RIPC group. Of the 7 patients who received RRT, 6 (86%) had undergone a second surgical intervention; almost all commenced RRT immediately following reoperation to address a surgical complication. Renal indices were not significantly deranged at the time of initiation, and the duration of RRT was short (median 3 days), suggesting a physician preference for early initiation of RRT also may have been a contributory factor (Table 8). Table 4. Daily Serum Urea and Volume of Urine Output (mL) RIPC

Control

Urea (mmol/L) Baseline 7.3 (5.5-9) 6.3 (5.5-7.4) Postop Day 0 7.7 (5.1-10.2) 6.9 (5.8-8.8) Postop Day 1 8 (6.5-12.3) 7.4 (5.8-11.4) Postop Day 2 7.5 (5.6-11.1) 6.3 (5.3-11.5) Postop Day 3 6.4 (5-1) 5.7 (4.7-10) Daily urine output (mL) Postop Day 0 600 (347-960) 795 (498-1295) Postop Day 1 1340 (890-1600) 1610 (1108-2315) Postop Day 2 1415 (878-2005) 1775 (1330-2495) Postop Day 3 1648 (1101-2000) 1675 (1375-2160) Abbreviation: RIPC, remote ischemic preconditioning.

p Value

40.99 40.99 40.99 40.99 40.99 40.99 0.08 0.11 0.99

1290

MURPHY ET AL

Table 5. Postoperative Cardiac Events RIPC

New troponin elevation, no. (%) Myocardial infarction, no. (%) New arrhythmia, no. (%) Postoperative vasopressors Requirement no. (%)

16 4 5 14

(51%) (13%) (16%) (45%)

Control

9 2 1 11

p Value

(29%) (6%) (3%) (35%)

0.11 0.67 0.2 0.61

NOTE. The number (%) of patients with newly elevated troponin and the number requiring vasopressors up to postoperative day 3. Abbreviation: RIPC, remote ischemic preconditioning.

Table 6. Post Operative Outcomes

LOS in HDU Hospital LOS In hospital mortality, n ¼ (%) Other Adverse Outcomes, n ¼ (%) Ischemic Colitis Massive intra-operative haemorrhage Graft leak Femoral embolectomy Return to Theatre* Cerebrovascular accident LRTI Post-operative delirium Renal replacement therapy*

RIPC

Control

p-Value

6 (4-7) 15 (12-20) 3 (10%)

4 (3-7) 14 (11-18) 1 (3%)

0.07 0.39 0.61

2 (6%) 2 (%)

0 1 (3%)

0.49 40.99

2 (6%) 1 (3%) 6 0 2 (6%) 0 7 (23%)

0 0 0 1 (3%) 0 2 (6%) 0

0.49 0.49 0.029 40.99 0.49 0.49 0.01

NOTE. Data are Expressed as Median (IQR) Unless Otherwise Stated. Abbreviations: RIPC, remote ischemic preconditioning; HDU, high dependency area; LOS, length of stay; LRTI, lower respiratory tract infection. * Within seven post-operative days.

The high incidence of surgical complications in the RIPC group and consequential high rate of RRT may have served to mask any beneficial influence that RIPC might have had on the primary endpoint. However, when a posthoc analysis was performed, excluding patients who required a second surgical

intervention, there remained no difference in primary or secondary endpoints between groups. There are several reasons that may account for conflicting evidence supporting RIPC as a means of organ protection after vascular and cardiac surgery. There is considerable variation between clinical trials as to the nature of the remote ischemic stimulus. RIPC may be achieved by impeding blood flow using either a vascular cross-clamp or an inflated cuff on either the upper limb or the lower limb; the time interval and total time of ischemia and reperfusion are similarly variable. Skeletal muscle is the ischemic target, but skeletal muscle mass varies considerably between patients and between anatomic sites. Mechanics of blood flow are complex; the ultimate aim of RIPC is to cease blood flow to skeletal muscle for a defined period of time; however, studies that rely on an inflated cuff may not achieve an adequate pressure to induce ischemia. Furthermore, there is no endpoint or biomarker to confirm that the RIPC technique was effective.31,32 Previous studies of RIPC in patients presenting for open AAA repair used an iliac cross-clamp to achieve the ischemic stimulus;12,24 in contrast to the authors’ study in which they used a blood pressure cuff on the upper limb. In 1 of these studies, there was a high complication rate associated with cross-clamping the iliac artery,28 perhaps rendering the cuff technique safer. Furthermore, studies investigating renal protection after open AAA repair all have used different definitions and markers of renal injury; thus, comparisons between studies are difficult to make. This study had a number of limitations. The number of patients involved was determined on the basis of the postoperative serum creatinine values and, thus, might have been underpowered to detect the effect of RIPC on NGAL levels or the incidence of postoperative AKI. Also, despite randomization, patients in the RIPC group were older and had higher ASA scores. As a single-center study, the authors’ findings may not be immediately generalizable to the wider population. A further limitation of this study was that sevoflurane was used to anesthetise the patients intraoperatively; sevoflurane is

Table 7. Posthoc Analysis

Creatinine (μmol/L) Baseline Postop Day 0 Postop Day 1 Postop Day 2 PostopDay 3 NGAL (ng/mL) Baseline Postop Day 0 Postop Day 1 Postop Day 2 Postop Day 3 AKI (AKIN Diagnosis), no. (%) New troponin rise

RIPC

Control

n ¼ 25

n ¼ 31

p Value

81 96 108 85 81

(76-112) (80-133) (87-153) (73-129) (64-125)

90 95 101 83 78

(79-102) (81-127) (82-156) (71-131) (67-121)

40.99 40.99 40.99 40.99 40.99

14 37 85 78 109

(7-45) (20-100) (20-100) (18-168) (43-459)

14 25 33 36 176 11 9

(8.7-23) (17-51) (12-113) (18-89) (53-923) (36%) (29%)

40.99 40.99 0.705 40.99 40.447 0.41 0.67

11 (52%)

NOTE. Patients who returned to the operating room because of surgical complications were excluded from the analysis. Data are expressed as median (interquartile range) unless otherwise stated. Abbreviations: AKI, acute kidney injury; AKIN, acute kidney injury network; NGAL, neutrophil gelatinase-associated lipocalin; RIPC, remote ischemic preconditioning.

1291

REMOTE ISCHEMIC PRECONDITIONING AND KIDNEY INJURY

Table 8. Details of Renal Replacement Therapy Postop

No. of Days

Group

Day

on RRT

Serum Urea

Creatinine

Serum pH

Average Hourly Urine Output (mL/h)

Surgical Complication

RIPC RIPC RIPC RIPC RIPC RIPC RIPC

1 1 1 1 1 3 1

2* 3 13 3 15* IHD IHD

16.2 12 17 7.9 12 17 6.3

248 229 270 140 179 415 130

7.23 7.28 7.22 7.15 7.334 N/A 7.11

10 0 15 30 10 15 10

Ischemic colitis – Laparotomy day 1 Graft leak – Laparotomy day 1 Ischemic colitis – Laparotomy day 1 Major intraop blood loss-Fasciotomy day 3 Right femoral embolectomy day 1-ACS-MOF Prolonged cross-clamp time pre-existing Graft leak – Laparotomy day 1

NOTE. Postoperative day renal replacement therapy (RRT) was commenced, length of time patients were RRT-dependent, and laboratory parameters and on the day RRT was commenced. Abbreviations: ACS, acute coronary syndrome; IHD, intermittent hemodialysis; MOF, multi-organ failure; RIPC, remote ischemic preconditioning; RRT, renal replacement therapy. *Patient died on this postoperative day.

known to confer organ protection through a preconditioning effect33,34 and potentially could have diminished the protective effect of the RIPC protocol used in this study. Finally, in this study, the upper limb was used to generate the RIPC stimulus; however, lower limbs typically have a greater muscle mass and potentially would have conferred greater end-organ protection. The lower limbs were not used in this study because peripheral

vascular disease often coexists with aortic aneurysms.35,36 Therefore, the upper limbs were chosen as a more suitable target in this study. In conclusion, the authors detected a high rate of renal and myocardial injury in patients undergoing open AAA repair. However, RIPC mediated by transient upper limb ischemia did not confer any renal or cardioprotective effects.

REFERENCES 1. Diehl JT, Cali RF, Hertzer NR, et al: Complications of abdominal aortic reconstruction. An analysis of perioperative risk factors in 557 patients. Ann Surg 197:49-56, 1983 2. Brady AR, Fowkes FG, Greenhalgh RM, et al: Risk factors for postoperative death following elective surgical repair of abdominal aortic aneurysm: Results from the UK Small Aneurysm Trial. On behalf of the UK Small Aneurysm Trial participants. Br J Surg 87: 742-749, 2000 3. Wald R, Waikar SS, Liangos O, et al: Acute renal failure after endovascular vs open repair of abdominal aortic aneurysm. J Vasc Surg 43:460-466, 2006 4. Zacharias M, Conlon NP, Herbison GP, et al: Interventions for protecting renal function in the perioperative period. Cochrane Database Syst Rev 9:CD003590, 2008 5. Eagle KA, Brundage BH, Chaitman BR, et al: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery. Circulation 93:1278-1317, 1996 6. Kim LJ, Martinez EA, Faraday N, et al: Cardiac troponin I predicts short-term mortality in vascular surgery patients. Circulation 106:2366-2371, 2002 7. Andrews N, Jenkins J, Andrews G, et al: Using postoperative cardiac Troponin-I (cTi) levels to detect myocardial ischaemia in patients undergoing vascular surgery. Cardiovasc Surg 9:254-265, 2001 8. Landesberg G, Mosseri M, Shatz V, et al: Cardiac troponin after major vascular surgery: The role of perioperative ischemia, preoperative thallium scanning, and coronary revascularization. J Am Coll Cardiol 44:569-575, 2004 9. Lee TH, Thomas EJ, Ludwig LE, et al: Troponin T as a marker for myocardial ischemia in patients undergoing major noncardiac surgery. Am J Cardiol 77:1031-1036, 1996 10. Haggart PC, Adam DJ, Ludman PF, et al: Comparison of cardiac troponin I and creatine kinase ratios in the detection of myocardial injury after aortic surgery. Br J Surg 88:1196-1200, 2001 11. Barbagallo M, Casati A, Spadini E, et al: Early increases in cardiac troponin levels after major vascular surgery is associated with

an increased frequency of delayed cardiac complications. J Clin Anesth 18:280-285, 2006 12. 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 13. 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 370:575-579, 2007 14. Venugopal V, Hausenloy DJ, Ludman A, et al: Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: A randomised controlled trial. Heart 95:1567-1571, 2009 15. Venugopal V, Laing CM, Ludman A, Yellon DM, et al: Effect of remote ischemic preconditioning on acute kidney injury in nondiabetic patients undergoing coronary artery bypass graft surgery: a secondary analysis of 2 small randomized trials. Am J Kid Dis 56:1043-1049, 2010 16. 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 17. Brevoord D, Kranke P, Kuijpers M, et al: Remote ischemic conditioning to protect against ischemia-reperfusion injury: A systematic review and meta-analysis. PloS One 7:e42179, 2012 18. Heusch G: Cardioprotection: Chances and challenges of its translation to the clinic. Lancet 381:166-175, 2013 19. Gho BC, Schoemaker RG, van den Doel MA, et al: Myocardial protection by brief ischemia in noncardiac tissue. Circulation 94: 2193-2200, 1996 20. Schulz R, Cohen MV, Behrends M, et al: Signal transduction of ischemic preconditioning. Cardiovasc Res 52:181-198, 2001 21. Bagshaw SM, George C, Bellomo R: A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 23:1569-1574, 2008 22. The NGAL Test reagent Kit ST001CA Ifu. http://ngal.com/ media/43899/st001ca_ifu_ivd.pdf. [May 13th 2013]; Available from: http://ngal.com/media/43899/st001ca_ifu_ivd.pdf.

1292

23. 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 24. Walsh SR, Boyle JR, Tang TY, et al: Remote ischemic preconditioning for renal and cardiac protection during endovascular aneurysm repair: a randomized controlled trial. J Endovasc Ther 16: 680-689, 2009 25. Godier S, Dusseaux MM, David N, et al: Intraoperative factors affecting renal outcome after open repair of suprarenal aortic aneurysms. Ann Vasc Surg 26:913-917, 2012 26. Hertzer NR, Mascha EJ, Karafa MT, et al: Open infrarenal abdominal aortic aneurysm repair: The Cleveland Clinic experience from 1989 to 1998. J Vasc Surg 35:1145-1154, 2002 27. Hertzer NR, Mascha EJ: A personal experience with factors influencing survival after elective open repair of infrarenal aortic aneurysms. J Vasc Surg 42:898-905, 2005 28. Walsh SR, Sadat U, Boyle JR, et al: Remote ischemic preconditioning for renal protection during elective open infrarenal abdominal aortic aneurysm repair: randomized controlled trial. Vasc Endovascular Surg 44:334-340, 2010 29. Choi YS, Shim JK, Kim JC, et al: Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: A randomized controlled trial. J Thorac Cardiovasc Surg 142: 148-154, 2011

MURPHY ET AL

30. Li C, Li YS, Xu M, et al: Limb remote ischemic preconditioning for intestinal and pulmonary protection during elective open infrarenal abdominal aortic aneurysm repair: A randomized controlled trial. Anesthesiology 118:842-852, 2013 31. Lim SY, Hausenloy DJ: Remote ischemic conditioning: From bench to bedside. Front Physiol 3:27, 2012 32. Kharbanda RK, Nielsen TT, Redington AN: Translation of remote ischaemic preconditioning into clinical practice. Lancet 374:1557-1565, 2009 33. Codaccioni JL, Velly LJ, Moubarik C, et al: Sevoflurane preconditioning against focal cerebral ischemia: Inhibition of apoptosis in the face of transient improvement of neurological outcome. Anesthesiology 110:1271-1278, 2009 34. Lucchinetti E, Bestmann L, Feng J, et al: Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: Lack of synergy or evidence of antagonism in cardioprotection? Anesthesiology 116:296-310, 2012 35. Galland RB, Simmons MJ, Torrie EP: Prevalence of abdominal aortic aneurysm in patients with occlusive peripheral vascular disease. Br J Surg 78:1259-1260, 1991 36. Barba A, Estallo L, Rodriguez L, et al: Detection of abdominal aortic aneurysm in patients with peripheral artery disease. Eur J Vasc Endovasc Surg 30:504-508, 2005

Remote ischemic preconditioning does not affect the incidence of acute kidney injury after elective abdominal aortic aneurysm repair.

Open abdominal aortic aneurysm (AAA) repair is associated with a high risk of renal injury with few known strategies demonstrating a reduction in this...
326KB Sizes 1 Downloads 6 Views