The role of remote ischemic preconditioning in organ protection after cardiac surgery: a meta-analysis

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.JournalofSurgicalResearch.com

The role of remote ischemic preconditioning in organ protection after cardiac surgery: a meta-analysis Nur A.B. Haji Mohd Yasin, MB, ChB, MSc,a Peter Herbison, MSc, DSc,b Pankaj Saxena, PhD, FRACS,a,c,d,* Slavica Praporski, PhD,e and Igor E. Konstantinov, MD, PhD, FRACSe a

College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, UK Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand c School of Surgery, University of Western Australia, Perth, Australia d Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN e Royal Children’s Hospital, Murdoch Children’s Research Institute, University of Melbourne, Melbourne, Australia b

article info

abstract

Article history:

Background: Remote ischemic preconditioning (RIPC) appears to protect distant organs from

Received 3 June 2013

ischemiaereperfusion injury. We undertook meta-analysis of clinical studies to evaluate

Received in revised form

the effects of RIPC on organ protection and clinical outcomes in patients undergoing

19 August 2013

cardiac surgery.

Accepted 5 September 2013

Methods: A review of evidence for cardiac, renal, and pulmonary protection after RIPC was

Available online xxx

performed. We also did meta-regressions on RIPC variables, such as duration of ischemia, cuff pressure, and timing of application of preconditioning. Secondary outcomes included

Keywords:

length of hospital and intensive care unit stay, duration of mechanical ventilation, and

Cardiac surgery

mortality at 30 days.

Coronary artery bypass surgery

Results: Randomized control trials (n ¼ 25) were included in the study for quantitative analysis

Cardiopulmonary bypass

of cardiac (n ¼ 16), renal (n ¼ 6), and pulmonary (n ¼ 3) protection. RIPC provided statistically

Renal failure

significant cardiac protection (standardized mean difference [SMD], 0.77; 95% confidence

Congenital heart disease

interval [CI], 1.15, 0.39; Z ¼ 3.98; P < 0.0001) and on subgroup analysis, the protective effect remained consistent for all types of cardiac surgical procedures. However, there was no evidence of renal protection (SMD, 0.74; 95% CI, 0.53, 1.02; Z ¼ 1.81; P ¼ 0.07) or pulmonary protection (SMD, 0.03; 95% CI, 0.56, 0.50; Z ¼ 0.12; P ¼ 0.91). There was no statistical difference in the short-term clinical outcomes between the RIPC and control groups. Conclusions: RIPC provides cardiac protection, but there is no evidence of renal or pulmonary protection in patients undergoing cardiac surgery using cardiopulmonary bypass. Larger multicenter trials are required to define the role of RIPC in surgical practice. ª 2013 Elsevier Inc. All rights reserved.

1.

Introduction

Remote ischemic preconditioning (RIPC) is a method whereby brief intermittent periods of ischemia and reperfusion (IR) of

tissues provide protection to distant organs from subsequent periods of prolonged IR injury [1]. RIPC in patients undergoing cardiac surgery has been performed with repeated cycles of IR using a blood pressure cuff on a patient’s limb. A number of

* Corresponding author. Department of Cardiothoracic Surgery, The Alfred Hospital, Commercial Road, Prahran, Melbourne, VIC, 3181, Australia. Tel.: þ61 3 90762000. E-mail address: [email protected] (P. Saxena). 0022-4804/$ e see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2013.09.006

2

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

randomized control trials have been conducted with quite variable outcomes, and we were interested in finding out which population will gain the most benefit. We also investigated, if there is a need for varying the protocol for RIPC for different patient groups, and whether the improvements in surrogate markers actually translate into better clinical outcomes. Most of the meta-analyses published to date report on cardiac protection based on time-point measurement, such as at 12 h postintervention, whereas we believe that area under the curve (AUC) reduction in cardiac biomarkers provides better evidence of cardioprotection. We conducted a meta-analysis where cardiac protection was assessed using AUC. Additionally, we also present meta-analyses to assess the effectiveness of RIPC on protection to other organs in patients undergoing cardiac surgery.

2.

Materials and methods

We conducted a review and meta-analysis. This research was conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement [2]. The study protocol is registered with (International Prospective Register of Systematic Reviews) PROSPERO with a registration number of CRD42012003174 [3].

2.1.

Search strategy

Literature search was done on the following databases: MEDLINE, EMBASE, SCOPUS, Web of Knowledge, Cochrane, and Global Health library. The last day of the literature search was on February 5, 2013. The Medical Subject Heading (MeSH) terms or keywords searched were “ischemic preconditioning,” “myocardial ischemic preconditioning,” “remote ischaemic preconditioning,” “remote ischemic preconditioning”, “limb ischemic preconditioning,” “cardiovascular surgical procedures,” “cardiac surgical procedures,” “thoracic surgery,” “coronary artery bypass,” “heart valve prosthesis implantation,” “ventricular septal defects,” “atrial septal defects,” and “cardiopulmonary bypass.”

2.2.

Inclusion and exclusion criteria

Human randomized control trials of RIPC involving adult or pediatric cardiac surgical patients were included. Inclusion of the studies and extraction of data were done by one of the researchers. We included studies that assessed cardiac, renal, or pulmonary protection. Inclusion of a study for metaanalysis required reporting of myocardial injury biomarkers over at least 24 h postoperatively, with AUC values, incidence of postoperative acute kidney injury, or postoperative dynamic lung compliance. Postoperative myocardial injury biomarkers included troponin I, troponin T, and creatinine kinase (CK)eMB. The incidence of acute kidney injury was used to reflect renal protection. Acute Kidney Injury Network and Risk, Injury, Failure, Loss, and End-stage kidney disease criteria were used to define acute kidney injury [4,5]. Postoperative pulmonary function was assessed using dynamic lung compliance. Postoperative mortality, length of intensive care unit (ICU) and hospital stays, and ventilation period were

also analyzed from the included studies. Studies published in non-English languages were excluded.

2.3.

Data extraction

The outcome measures as defined previously were extracted during the data analysis. Authors were contacted if any additional data were needed. If not reported directly, AUC was calculated from the tabulated data or from graphs. When both were available, troponin results were chosen over CK-MB because of higher sensitivity and specificity for myocardial injury [6e8]. CK-MB was also included, if it was the only cardiac biomarker reported in the study. Included studies were appraised and their risk of bias assessed using the Cochrane risk of a bias tool [9]. A subgroup analysis of the included studies was performed for three different surgical populations: coronary artery bypass surgery (CABG), valve replacement surgery, and pediatric cardiac surgery.

2.4.

Statistical methods

Data analysis was carried out using Review Manager 5.2 (The Cochrane Collaboration, Copenhagen). Standardized mean difference (SMD) and the corresponding 95% confidence interval (CI) were calculated for continuous outcome data using a random effects model. In the case of dichotomous outcome data, risk ratios and their corresponding 95% CIs were calculated and analyzed using a random effects model. The X2 test and I2 were used to evaluate statistical heterogeneity. Meta-regression analysis (using Stata v12 [StataCorp LP, Texas]) was carried out to assess if there was a correlation between the duration of ischemia, cuff pressure, timing of intervention, limb used (upper versus lower limb), and the treatment effect. Duration of ischemia was calculated by multiplying the duration of ischemia per cycle by the number of cycles. Cuff pressure was defined as the pressure to which the blood pressure cuff was inflated. Only studies that provide exact cuff pressures were assessed. Timing of intervention was classified as to either before or after anesthetic induction, that is, “early phase” and “late phase” RIPC or both. The treatment effect was a reduction in the release of cardiac injury biomarker as reflected by the SMD. We did sensitivity analysis, if there were any studies that showed extreme positive or negative results compared with other studies.

3.

Results and discussion

3.1.

Literature search

Using the MeSH terms and keywords mentioned earlier, we retrieved 252 articles from MEDLINE, 249 articles from EMBASE, 639 articles from SCOPUS, 624 articles from Web of Knowledge, 2 from Cochrane, and 63 from Global Health Library giving a total of 1829 articles. After removing duplicates, we were left with 1429 articles. The abstract of these articles was read, and of these, only 32 articles were found to be relevant. They were all randomized controlled trials conducted on patients who underwent cardiac surgery, where at

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

least two of their study arms included RIPC and a control group. Of the 32 selected articles, seven were excluded, four of these were conference presentations, one article was excluded as it did not report cardiac injury biomarker >24 h, and two articles were non-English full-text articles. We contacted the authors of the two non-English full-text articles but did not get any response. The results of the literature search and details of the studies are included in Figure 1 and Table.

3.2.

Cardiac protectiondcardiac injury biomarker AUC

RIPC reduced the extent of myocardial injury during cardiac surgery (SMD, 0.77; 95% CI, 1.15, 0.39; Z ¼ 3.98; P < 0.0001) (Fig. 2). A total of 1001 patients were included in this analysis. The Forest plot also showed that the study by Heusch et al. [14] was strongly positive for cardiac protection. The Funnel plot of these studies did not suggest any publication bias (Fig. 3).

3.3. Subgroup analysis of cardiac protection for different types of cardiac surgical procedures The number of studies included for CABG subgroup, valve replacement subgroup, and congenital cardiac surgery subgroup were eight, four, and five, respectively. For patients who had CABG, a total of 502 patients, the evidence suggested

3

that RIPC reduced the amount of released cardiac injury biomarkers postoperatively (SMD, 0.28; 95% CI, 0.46, 0.10; Z ¼ 3.00; P ¼ 0.003). Similar results were demonstrated for the studies of the patients who underwent valve replacement, which has a population size of 252 patients (SMD, 0.95; 95% CI, 1.21, 0.68; Z ¼ 6.98; P < 0.00001). There was high heterogeneity among valve replacement studies (X2 ¼ 17.57, df ¼ 3, P ¼ 0.0005; I2 ¼ 83%). The analysis of congenital cardiac surgery studies, which has a total population of 214 patients, similarly demonstrated that RIPC provided cardiac protection (SMD, 0.75; 95% CI, 1.05, 0.46; Z ¼ 5.06; P < 0.00001). High heterogeneity was noted among the studies (X2 ¼ 34.00, df ¼ 4, P < 0.00001; I2 ¼ 88%).

3.4.

Meta-regression of RIPC protocol variables

A total of 17 studies were included in this meta-analysis that gave a total of 1051 patients. The results for duration of ischemia did not show any relationship between the two variables (coefficient, 0.92; standard error [SE], 0.73; t ¼ 1.26; P ¼ 0.226). The cuff pressure level also did not show any relationship with the effectiveness of RIPC as represented by the SMD (coefficient, 0.00; SE, 0.00; t ¼ 0.26; P ¼ 0.802). Early phase or late phase RIPC showed no relationship with the cardioprotective effect of RIPC (coefficient, 1.36; SE, 1.49; t ¼ 0.92; P ¼ 0.373). The cardioprotective effect did not vary

Fig. 1 e Flowchart of systematic review and meta-analysis.

4

Table e Details of the studies included in the meta-analysis. No.

Study (reference)

Organ protection assessed

Population (age in years)

N

Ali et al. 2010 [10]

Cardiac-CK-MB

>50, CABG

2

Cheung et al. 2006 [11]

Cardiac-TNI, pulmonary

Pediatric, congenital

37

3

Choi et al. 2011 [12]

Cardiac-CK-MB, renal

<80, valve surgery

76

4

Hausenloy et al. 2007 [13] Heusch et al. 2012 [14]

Cardiac-TNT

<80, CABG

57

Cardiac-TNI

Adult, CABG

24

6

Hong et al. 2010 [15]

Cardiac-TNI

<80, OP-CABG

7

Karuppasamy et al. 2011 [16] Kottenberg et al. 2012 [17]

Cardiac-TNI and CK-MB Cardiac-TNI

Lee et al. 2012 [18]

10

11

5

8

9

12

100

Upper limb: 200 mm Hg  3 cycles  5 min Lower limb: (15 > SBP mm Hg)  4 cycles  5 min Lower limb: 250 mm Hg  3 cycles  10 min

Upper limb: 200 mm Hg  3 cycles  5 min Upper limb: 200 mm Hg  3 cycles  5 min

130

Upper limb: 200 mm Hg  4 cycles  5 min

<85, CABG

54

>18, CABG

72

Upper limb: 200 mm Hg  3 cycles  5 min Upper limb: 200 mm Hg  3 cycles  5 min

Cardiac-TNI, pulmonary

Pediatric, VSD repair

55

Lower limb: (30 > SBP)  4 cycles  min

Li et al. 2010 [19]

Cardiac-TNI

Adult 18e65, valve surgery

53 (81)

Lower limb: 600 mm Hg  3 cycles  4 min

Lomivorotov et al. 2011 [20] Luo et al. 2011 [21]

Cardiac-TNI and CK-MB Cardiac-TNI and CK-MB

Adult, CABG

80

Pediatric [1e5], VSD repair

40 (60)

Upper limb: 200 mm Hg  3 cycles  5 min Lower limb: 200e300 mm Hg  3 cycles  5 min

Exclusion criteria

Significant renal or hepatic disease, ongoing ischemia or infarction, AMI during last 4 wk, and/or significant PVD Isolated ASD or those undergoing Fontan completion

LCAD >50%, hepatic, or pulmonary disease, acute infective endocarditis, LVEF <30%, AMI during last 3 wk, preexisting renal dysfunction, lower limb PVD, those on sulfonylurea glyburide, or nicorandil, tricuspid valve repair, and those requiring hypothermic circulatory arrest UA, LMS disease, hepatic, renal, or pulmonary disease, upper limb PVD, and/or those on sulfonylurea DM, renal failure, upper limb PVD, UA, preoperative ionotropic support, or any kind of mechanical assist device, AMI <2 wk, and/or emergency, combined, or redo surgery UA, preoperative use of inotropic agents or mechanical assist devices, LVEF <30%, major combined surgery, severe hepatic, renal, and pulmonary disease, recent MI during past 1 wk, recent sepsis, preoperative use of nicorandil, and/or PVD or amputation of an upper limb. Sulfonylurea was stopped 3 d preoperation UA, significant hepatic, renal, and pulmonary disease, PVD in upper limbs, and/or those on sulfonylureas DM, renal insufficiency, PVD affecting upper limbs, acute, or recent MI, preoperative ionotropic support or mechanical assist device, emergency surgery, coronary intervention in the past 6 wk, combined surgery, and/or those with previous cardiac operations. Those on long-term acetylsalicylic acid and/or clopidogrel Chromosomal anomaly, pneumonia, pulmonary edema, hepatic dysfunction, renal failure, hemato-oncological disorder, and/or infection. Those with subarterial VSD, muscular VSD, pulmonary stenosis, and/or infundibular hypertrophy requiring muscle resection Infective endocarditis, previous cardiac surgery, complications of diabetes, coronary artery disease, hypertension, and/or PVD affecting the lower limbs. Those on aspirin, corticosteroids, ACE-i, and statin LVEF <50%, renal failure, hepatic, and pulmonary disease, diabetes, and/or MI within last 4 wk Only patient with isolated VSD included. Those undergoing concomitant major anomalies and/or cardiac-associated infection were excluded

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

1

RIPC protocol

13

Cardiac-TNT

Adult, CABG

55

Cardiac-TNI

Pediatric (2 months to 2 years) surgery

23

15

Pedersen et al. 2012 [24]

Renal

Children 0e15, complex congenital heart disease

105

Lower limb: (40 > SBP)  4 cycles  5 min

16

Rahman et al. 2010 [25]

Cardiac-TNT, renal

Adult, CABG

160

Upper limbs: 200 mm Hg  3 cycles  5 min

17

Thielmann et al. 2010 [26]

Cardiac-TNI

Adult >18, CABG

53

Upper limbs: 200 mm Hg  3 cycles  5 min

18

Venugopal et al. 2010 [27] Venugopal et al. 2009 [28] Wagner et al. 2010 [29] Wu et al. 2011 [30]

Renal

Adult, CABG

78

Cardiac-TNT

Adult (18e80), CABG  AVR

45

Cardiac-TNI

Adult <80, CABG  AVR

66

Cardiac-TNI

Adult (18e60), MVR

50 (75)

Adult (31e72), valve surgery Adult >18, high-risk cardiac surgery

73

Upper limbs: 200 mm Hg  3 cycles  5 min Upper limbs: 200 mm Hg  3 cycles  5 min Upper limbs: (40 > SBP)  3 cycles  5 min Two groups: upper limb: 200 mm Hg  3 cycles  5 min or upper limb: 200 mm Hg  3 cycles  5 min þ lower limb: 450 mm Hg  2 cycles  10 min Upper limb: 200 mm Hg  3 cycles  5 min Upper limb: 200 mm Hg  3 cycles  5 min

60

Upper limbs: 240 mm Hg  3 cycles  5 min

120

Lower limb: 200 mm Hg  3 cycles  5 min

14

19 20 21

22

Xie et al. [31]

Cardiac-TNI

23

Young et al. [32]

Cardiac-hsTNT, renal

24

Zhou et al. 2009 [33]

Cardiac-TNI, pulmonary

Infants, VSD repair

25

Zimmerman et al. 2011 [34]

Renal

Adult (18e80), elective cardiac surgery (mixed)

96

Lower limb: 300 mm Hg  4 cycles  5 min Lower limb: (15 > SBP)  4 cycles  5 min

Emergency surgery, MI within 48 h, DM, BMI >35, concomitant noncardiac surgery, and/or severe PVD Presence of genetic syndromes, uncontrolled infection preoperatively, immunodeficiency, class I of RACHS 1 score, and/or nonapproval of parents Operations of low complexity, such as closure of ASD, AP windows, establishment of Glenn shunts, subaortic membrane resection, redirection of partial anomalous pulmonary veins, valvotomies, repair of pulmonary stenosis, and/or operations without the use of extracorporeal circulation STEMI within last 30 days, angina within 48 h, DM, pregnancy, preoperative dialysis, additional non-CABG surgery, and/or usage of radial artery DM, renal failure, upper limb PVD, UA, preoperative inotropic support, mechanical assist device, and/or AMI. Those going for emergency combined or redo surgery excluded DM and as per Hausenloy et al. 2007 [13] and Venugopal et al. 2009 [28] DM, renal failure, hepatic, and pulmonary disease, and/or UA or AMI within the past 4 weeks UA, AMI within 7 d, LVEF <30%, severe renal, liver, or pulmonary disease, and/or recent systemic infection NYHA class IV, recent respiratory infection, asthma, or cardiac surgery, hepatic, renal, or pulmonary disease, upper limb PVD, and/or those on sulfonylurea or glibenclamide

Ischemia of the limbs Upper limb PVD, those requiring deep hypothermic circulatory arrest, and/or those considered for radial artery conduit harvesting Moderate to severe pulmonary hypertension, preoperative weight >7 kg, decompensated pulmonary and heart failure, history of limb trauma, and/or systemic disease Lower limb PVD, ESRF, planned off -pump surgery, and/or inability to give informed consent

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

Lucchinetti et al. 2012 [22] Pavione et al. 2012 [23]

AMI ¼ acute myocardial injury; ASD ¼ atrial septal defect; AVR ¼ aortic valve replacement; BMI ¼ body mass index; CABG ¼ coronary artery bypass grafting; CK-MB ¼ creatine kinaseeMB; DM ¼ diabetes mellitus; ESRF ¼ end-stage renal failure; LCAD ¼ left coronary artery disease; LMS ¼ left main stem; LVEF ¼ left ventricular ejection fraction; MVR ¼ mitral valve replacement; PVD ¼ peripheral vascular disease; RACHS ¼ risk adjusted classification for congenital heart surgery; N/A ¼ not applicable; STEMI ¼ ST elevation myocardial infarction; TNT ¼ troponin T; TNI ¼ troponin I; UA ¼ unstable angina; VSD ¼ ventricular septal defect.

5

6

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

Fig. 2 e Forest plot of studies reporting on cardiac protection.

with the use of upper or lower limb (coefficient, 0.06; SE, 0.78; t ¼ 0.08; P ¼ 0.936).

3.5.

Renal protection

The total number of patients in this analysis was 637. RIPC did not confer any renal protection (SMD, 0.74; 95% CI, 0.53, 1.02; Z ¼ 1.81; P ¼ 0.07) (Fig. 4). This group of studies showed low heterogeneity (X2 ¼ 7.83, df ¼ 5, P ¼ 0.17; I2 ¼ 36%).

3.6.

Pulmonary protection

The population included 152 patients, and based on this sample, RIPC did not provide pulmonary protection (SMD, 0.03; 95% CI, 0.56, 0.50; Z ¼ 0.12; P ¼ 0.91) (Fig. 5). There was moderate heterogeneity between the studies (X2 ¼ 5.31, df ¼ 2, P ¼ 0.07; I2 ¼ 62%).

3.7.

3.9.

Length of ICU stay

A total of 12 studies that gave a sum of 793 patients reported this outcome. There was no difference in the length of ICU stay between the RIPC and controls (SMD, 0.07; 95% CI, 0.27, 0.13; Z ¼ 0.67; P ¼ 0.50).

3.10.

Length of hospital stay

A total of eight studies that gave a sum of 534 patients reported this outcome. There was no difference in the length of hospital stay between RIPC and the control group (SMD, 0.03; 95% CI, 0.17, 0.24; Z ¼ 0.31; P ¼ 0.76).

3.11.

Adverse events

There were no reports of adverse events directly caused by the application of a blood pressure cuff during RIPC.

Duration of mechanical ventilation

A total of 11 studies that gave a sum of 734 patients reported this outcome. The evidence suggested that there was no difference in the duration of postoperative ventilation between the controls and RIPC group (SMD, 0.01; 95% CI, 0.17, 0.15; Z ¼ 0.12; P ¼ 0.91). There was low heterogeneity between the studies (X2 ¼ 11.30, df ¼ 10, P ¼ 0.33; I2 ¼ 11%).

3.8.

Thirty-day mortality

Only 19 of 25 studies (total of 1373 patients) reported on mortality. The meta-analysis showed that there was no difference in early mortality between the control and RIPC groups (risk ratio, 0.50; 95% CI, 0.12, 2.05; Z ¼ 0.96; P ¼ 0.34) (Fig. 6). There is low heterogeneity (X2 ¼ 0.36, df ¼ 3, P ¼ 0.95; I2 ¼ 0%) as the incidence of mortality at 30 d for all the included studies was very low (0.5%).

Fig. 3 e Funnel plot of the cardiac protection studies excluding the study of Heusch et al. [14]. SE [ standard error; SMD [ standardized mean difference.

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

7

Fig. 4 e Forest plot of the studies that analyzed renal protection.

3.12.

Comment

3.12.1. Cardiac protection Elevated levels of troponin T, troponin I, and CK-MB are associated with long-term poor outcomes after cardiac surgery [35,36]. Bignami et al. [36] reported that troponin I was a strong predictor of long-term mortality and that every nanogram per milliliter increase in the postoperative serum concentration is associated with a 15% increase in the risk of mortality. The degree of cardiac biomarker elevation is dependent on the type of cardiac surgery [37,38]. It is known that patients undergoing valve surgery and congenital cardiac surgery have higher elevation of cardiac injury biomarkers compared with patients who undergo CABG [39]. The evidence from the present meta-analysis showed that RIPC provides myocardial protection after cardiac surgery. Subgroup analysis of the various types of cardiac surgical procedures revealed that RIPC provided cardiac protection during CABG, valve surgery, and pediatric cardiac surgery. It appears that the cardioprotective effect is more pronounced after a higher dose of preconditioning [30]. This view is further supported by a report that the degree of protection is determined by the volume of tissue exposed to the preconditioning stimulus [39]. However, our investigations did not show any correlation between the duration of ischemia, cuff pressure, and its timing, that is, early phase or late phase RIPC and the clinical outcome.

3.13.

Renal protection

Up to 30% of patients undergoing cardiac surgery may develop acute kidney injury and about 1%e2% will require dialysis [40]. Patients with postoperative acute kidney injury have

significantly higher morbidity and mortality. The risk of death can be increased by eightfold in patients requiring dialysis in this setting [41]. Lenihan et al. [42] quoted a mortality rate of 12.8% and 35.3% in patients after cardiac surgery with acute kidney injury and those requiring dialysis, respectively. A change >0.5 mg/dL in the serum creatinine level after cardiac surgery is associated with increased mortality at 30 days postoperatively [43]. A small postoperative rise in serum creatinine is also found to be associated with increased longterm mortality [44]. A common etiology of acute kidney injury in cardiac surgery population is IR injury [45]. RIPC provides organ protection by attenuating the oxidative stress induced by IR injury [46]. The evidence from our meta-analysis regarding renal protection does not suggest any significant benefit of RIPC. It is very likely that the protective effect of this intervention is not shown in the present study because of the small size of the pooled population. Four of the six studies in the meta-analysis were underpowered and the pooled effect was expectedly statistically insignificant [12,24,25,34].

3.14.

Pulmonary protection

The reported prevalence of pulmonary complications after cardiac surgery varies from 8%e79% and is attributed to a number of factors [47,48]. Pulmonary complications result from inflammatory response to cardiopulmonary bypass and IR injury. Meta-analysis of the included studies did not show any evidence that RIPC provided effective pulmonary protection as reflected by dynamic lung compliance. This might have been related to the small size of the pooled population. We would suggest that conclusions on RIPC-induced pulmonary protection should be cautiously drawn.

Fig. 5 e Forest plot of studies with measures of pulmonary protection.

8

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

Fig. 6 e Forest plot of studies with mortality as reported at 30 days.

3.15. Should RIPC be introduced to cardiac surgical practice? Application of high pressure to an artery could potentially cause plaque rupture, thrombosis, and embolization [22]. However, there is no evidence that RIPC causes any direct harm to patients through the application of high cuff pressure. The studies included in the present meta-analysis excluded patients with peripheral vascular disease. This would mean that if this intervention were to be used routinely, patient with peripheral vascular disease may need to be excluded. Which patient population benefits the most from RIPC? The meta-analysis shows that RIPC provides cardiac protection to a heterogeneous group of the patients undergoing cardiac surgery. Recent studies suggest that the RIPC may not provide further protection to patients with cyanotic heart disease as those patients are already exposed to chronic ischemia [49e51]. An important issue is determining the effective dose for this intervention. It may be that interindividual variation is large and that each patient requires individualized dose of RIPC to elicit a particular level of response consistent with organ protection. We also found that RIPC, despite being shown to provide cardiac protection, did not improve the short-term clinical outcomes, such as mortality, length of hospital stay, length of ICU stay, and ventilation period. Although no short-term benefits are seen, one can argue that the benefits would only be more apparent when it comes to long-term clinical outcomes as the intervention is shown to reduce myocardial

IR injury and these patients would have more preserved cardiac function as a result and better long-term outcomes. Midterm follow-up of few studies with patients subjected to RIPC during cardiac surgery is available. Xie et al. [31] had mean follow-up period of 20.1  1.9 months for the control group and 21.1  1.8 months for the RIPC group. They found that RIPC improved New York Heart Association (NYHA) functional class (1.07  0.37 versus 1.31  0.47; P ¼ 0.0298) and improved left ventricular ejection fraction compared with control patients (10.3  2.5 versus 12.5  3.2; P ¼ 0.0049). Follow-up for a period of 6 months found that there was no difference between the groups in terms of death, rehospitalization secondary to heart failure, renal failure, and new atrial fibrillation in another study [22].

3.16.

Study limitations

A number of exclusion criteria were used in the present study, such as diabetes, significant renal, pulmonary, or hepatic impairment, or recent myocardial infarction. The randomized studies may not reflect true clinical picture as a number of patients undergoing cardiac surgery have significant comorbidities. The demonstrated cardioprotective effect may not be applicable to all the patient populations.

4.

Conclusions

The present meta-analysis demonstrated that RIPC provides cardiac protection, but there is no evidence of renal or pulmonary protection in patients undergoing cardiac surgery

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

using standard cardiopulmonary bypass. Meta-regression demonstrated that the duration of ischemia, cuff pressure, use of upper or lower limb, and the time difference between preconditioning stimulus and ischemia did not affect outcome. There is an increasing need to define the role of RIPC in clinical practice with emerging evidence of the potential benefits demonstrated in a number of studies.

Acknowledgment This research was undertaken by Dr Nur ABHM Yasin as part of the third year of MSc in Surgical Sciences of Edinburgh Surgical Sciences Qualification.

references

[1] Przyklenk K, Bauer B, Ovize M, Kloner R, Whittaker P. Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993;87:893. [2] Moher D, Liberati A, Tetzlaff J, Altman D, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 2010;8:336. [3] Chien P, Khan K, Siassakos D. Registration of systematic reviews: PROSPERO. BJOG 2012;119:903. [4] Mehta R, Kellum J, Shah S, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. [5] Bellomo R, Kellum J, Ronco C. Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med 2007;33:409. [6] Mair J, Morandell D, Genser N, Lechleitner P, Dienstl F, Puschendorf B. Equivalent early sensitivities of myoglobin, creatine kinase MB mass, creatine kinase isoform ratios, and cardiac troponins I and T for acute myocardial infarction. Clin Chem 1995;41:1266. [7] Shyu K, Kuan P, Cheng J, Hung C. Cardiac troponin T, creatine kinase, and its isoform release after successful percutaneous transluminal coronary angioplasty with or without stenting. Am Heart J 1998;135:862. [8] Adams JE, Bodor GS, Davila-Roman VG, et al. Cardiac troponin I. A marker with high specificity for cardiac injury. Circulation 1993;88:101. [9] Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. [10] Ali N, Rizwi F, Iqbal A, Rashid A. Induced remote ischemic pre-conditioning on ischemia-reperfusion injury in patients undergoing coronary artery bypass. J Coll Physicians Surg Pak 2010;20:427. [11] Cheung M, Kharbanda R, Konstantinov I, et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 2006;47:2277. [12] Choi Y, Shim J, Kim J, et al. Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial. J Thorac Cardiovasc Surg 2011;142:148. [13] Hausenloy D, Mwamure P, 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 2007;370:575.

9

[14] Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M. STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res 2012;110:111. [15] Hong D, Mint J, Kim J, et al. The effect of remote ischaemic preconditioning on myocardial injury in patients undergoing off-pump coronary artery bypass graft surgery. Anaesth Intensive Care 2010;38:924. [16] Karuppasamy P, Chaubey S, Dew T, et al. Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation? Basic Res Cardiol 2011;106:511. [17] Kottenberg E, Thielmann M, Bergmann L, et al. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofolda clinical trial. Acta Anaesthesiol Scand 2012;56:30. [18] Lee JH, Park YH, Byon HJ, Kim HS, Kim CS, Kim JT. Effect of remote ischaemic preconditioning on ischaemic-reperfusion injury in pulmonary hypertensive infants receiving ventricular septal defect repair. Br J Anaes 2012;108:223. [19] Li L, Luo W, Huang L, et al. Remote perconditioning reduces myocardial injury in adult valve replacement: a randomized controlled trial. J Surg Res 2010;164:6. [20] Lomivorotov V, Shmyrev V, Nepomnyaschih V, et al. Remote ischaemic preconditioning does not protect the heart in patients undergoing coronary artery bypass grafting. Interact CardioVasc Thorac Surg 2012;15:18. [21] Luo W, Zhu M, Huang R, Zhang Y. A comparison of cardiac post-conditioning and remote pre-conditioning in paediatric cardiac surgery. Cardiol Young 2011;21:266. [22] 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 2012;116:296. [23] Pavione M, Carmona F, de Castro M, Carlotti APC. Late remote ischemic preconditioning in children undergoing cardiopulmonary bypass: a randomized controlled trial. J Thorac Cardiovasc Surg 2012;144:178. [24] Pedersen K, Ravn H, Povlsen J, Schmidt M, Erlandsen E, Hjortdal V. Failure of remote ischemic preconditioning to reduce the risk of postoperative acute kidney injury in children undergoing operation for complex congenital heart disease: a randomized single-center study. J Thorac Cardiovasc Surg 2012;143:576. [25] Rahman IA, Mascaro JG, Steeds RP, et al. Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment? Circulation 2010;122(11 Suppl):9. [26] Thielmann M, Kottenberg E, Boengler K, et al. Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol 2010;105:657. [27] Venugopal V, Laing C, Ludman A, Yellon D, Hausenloy D. 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 Kidney Dis 2010;56:1043. [28] Venugopal V, Hausenloy D, Ludman A, et al. Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart 2009;95:1567. [29] Wagner R, Piler P, Bedanova H, Adamek P, Grodecka L, Freiberger T. Myocardial injury is decreased by late remote ischaemic preconditioning and aggravated by tramadol in patients undergoing cardiac surgery: a randomised controlled trial. Interact CardioVasc Thorac Surg 2010;11:758.

10

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 3 ) 1 e1 0

[30] Wu Q, Gui P, Wu J, et al. Effect of limb ischemic preconditioning on myocardial injury in patients undergoing mitral valve replacement surgeryda randomized controlled trial. Circ J 2011;75:1885. [31] Xie JJ, Liao XL, Chen WG, et al. Remote ischaemic preconditioning reduces myocardial injury in patients undergoing heart valve surgery: randomised controlled trial. Heart 2012;98:384. [32] Young P, Dalley P, Garden A, et al. A pilot study investigating the effects of remote ischemic preconditioning in high-risk cardiac surgery using a randomised controlled double-blind protocol. Basic Res Cardiol 2012;107:256. [33] Zhou W, Zeng D, Chen R, et al. Limb ischemic preconditioning reduces heart and lung injury after an open heart operation in infants. Pediatr Cardiol 2010;31:22. [34] Zimmerman R, Ezeanuna P, Kane J, et al. Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. Kidney Int 2011;80:861. [35] Lehrke S, Steen H, Sievers H, et al. Cardiac troponin T for prediction of short- and long-term morbidity and mortality after elective open heart surgery. Clin Chem 2004;50:1560. [36] Bignami E, Landoni G, Crescenzi G, et al. Role of cardiac biomarkers (troponin I and CK-MB) as predictors of quality of life and long-term outcome after cardiac surgery. Ann Card Anaesth 2009;12:22. [37] Croal B, Hillis G, Gibson P, et al. Relationship between postoperative cardiac troponin I levels and outcome of cardiac surgery. Circulation 2006;114:1468. [38] Swaanenburg J, Loef B, Volmer M, et al. Creatine kinase MB, troponin I, and troponin T release patterns after coronary artery bypass grafting with or without cardiopulmonary bypass and after aortic and mitral valve surgery. Clin Chem 2001;47:584. [39] Loukogeorgakis S, Williams R, Panagiotidou A, et al. Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)channel dependent mechanism. Circulation 2007;116:1386. [40] Rosner M, Okusa M. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 2006;1:19.

[41] Chertow G, Levy E, Hammermeister K, Grover F, Daley J. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998;104:343. [42] Lenihan C, Montez-Rath M, Mora Mangano C, Chertow G, Winkelmayer W. Trends in acute kidney injury, associated use of dialysis, and mortality after cardiac surgery, 1999 to 2008. Ann Thorac Surg 2013;95:20. [43] Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 2004;15:1597. [44] Loef BG, Epema AH, Smilde TD, et al. Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 2005;16:195. [45] Yeboah E, Petrie A, Pead J. Acute renal failure and open heart surgery. BMJ 1972;1:415. [46] Hausenloy D, Yellon D. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res 2008;79:377. [47] Al-Alao B, Parissis H, McGovern E, Tolan M, Young V. Propensity analysis of outcome in coronary artery bypass graft surgery patients >75 years old. Gen Thorac Cardiovasc Surg 2012;60:217. [48] Wynne R, Botti M. Postoperative pulmonary dysfunction in adults after cardiac surgery with cardiopulmonary bypass: clinical significance and implications for practice. Am J Crit Care 2004;13:384. [49] Jones BO, Pepe S, Sheeran FL, et al. Remote ischemic preconditioning in cyanosed neonates undergoing cardiopulmonary bypass: a randomized controlled trial. J Thorac Cardiovasc Surg. pii: S0022-5223(13)00026-3. doi: 10. 1016/j.jtcvs.2013.01.003; 2013. [50] Pepe S, Liaw N, Hepponstall M, et al. Effect of remote ischemic preconditioning on phosphorylated protein signaling in children undergoing tetralogy of fallot repair: a randomized controlled trial. J Am Heart Assoc 2013;2: e000095. http://dx.doi.org/10.1161/JAHA.113.000095. [51] Konstantinov IE. Remote ischemic preconditioning in children with cyanotic heart disease: lost in translation? J Thorac Cardiovasc Surg 2013;145:613.