Abstract

The purpose of this study was to test, whether the late phase of remote ischaemic preconditioning (L-RIPC) improves myocardial protection in coronary artery bypass grafting (CABG) with cold-crystalloid cardioplegia and whether preoperative tramadol modifies myocardial ischaemia–reperfusion injury using the same group of patients in a single-blinded randomized controlled study. One hundred and one adult patients were randomly assigned to either the L-RIPC, control or tramadol group. L-RIPC consisted of three five-minute cycles of upper limb ischaemia and three five-minute pauses using blood pressure cuff inflation 18 hours prior to the operation. Patients in the tramadol group received 200 mg tramadol retard at 19:00 hours, the day before the operation and at 06:00 hours. Serum troponin I levels were measured at eight, 16 and 24 hours after surgery. Myocardial samples for inducible and endothelial nitric oxide synthases (iNOS, eNOS) estimation were drawn twice: before and after cannulation for cardiopulmonary bypass from the auricle of the right atrium. We found that L-RIPC can reduce injury beyond the myocardial protection provided by cold-crystalloid cardioplegia, and tramadol worsened myocardial injury after CABG. Expressions of iNOS were increased in the control (significantly) and L-RIPC groups and dampened in the tramadol group.

1. Introduction

Remote ischaemic preconditioning (RIPC) is a phenomenon in which brief ischaemia of one organ or tissue confers protection to another organ against a sustained ischaemia–reperfusion injury insult. First discovered in animal models [1], RIPC results in reduced myocardial injury and lower postoperative troponin levels. It has been rapidly translated to small-scale proof-of-concept clinical trials using various settings and stimuli: elective coronary angioplasty (upper limb ischaemia) [2], paediatric cardiac surgery (upper limb ischaemia) [3] and coronary artery bypass grafting (CABG) (lower limb ischaemia) [4]. Myocardial protection has been interpreted as an effect of early-phase ischaemic preconditioning [5] with signal transduction from the remote tissue to the target organ by a neural pathway [6] and/or by circulating substances [7]. In addition to the early phase of remote ischaemic preconditioning, RIPC also elicits a late phase starting after 18 hours and lasting up to three days [8]. The late-phase effects of RIPC (L-RIPC) have not yet been studied in a clinical trial. Therefore, we first tested whether brief limb ischaemia applied 18 hours before elective cardiac surgery reduces myocardial injury.

Myocardial injury after ischaemia–reperfusion insult can also be modified by various pharmacological stimuli. Animal studies showed that opioids can act as a trigger for both phases of ischaemic preconditioning [9], and serotonin augments [10] or attenuates [11] this phenomenon depending on the concentration. In animal experiments, tramadol, which has opioid and serotonin effects, showed some myocardial cytoprotective effects [12]. Therefore, we tested whether preoperative tramadol could modify ischaemia–reperfusion injury in the same group of patients. We also measured perioperative myocardial inducible and endothelial nitric oxide synthases (iNOS, eNOS) mRNA expression because nitric oxide (NO) is considered to be a trigger and mediator of late phase of ischaemic preconditioning [13]. The primary outcome measured was postoperative plasma troponin I levels.

2. Materials and methods

This trial was planned in accordance with a checklist of Consort Statement (revision 2002). After they provided informed consent, 120 consecutive patients referred for elective CABG with or without concomitant aortic valve replacement (AVR) were recruited in a tertiary university hospital. The study was approved by the Institutional Ethics Committee and carried out between May 2008 and May 2009. Exclusion criteria included unstable angina, recent myocardial infarction (up to seven days), a left ventricular ejection fraction (LVEF) <30%, severe renal (creatinine >220 mmol/l), liver (bilirubin >30 mmol/l) or pulmonary (corticoid therapy) disease, recent systemic infection and an age more than 80 years. The consenting patients were randomized to receive either the L-RIPC, control or tramadol protocol by a cardiologist the day before surgery. The surgery team, evaluators and data analysts were blinded to group assignment.

2.1. Protocols for late remote ischaemic preconditioning (L-RIPC) and preoperative tramadol

L-RIPC was applied the day before surgery at 14:00 hours (18 hours before starting the operation). L-RIPC consisted of three five-minute cycles of upper limb ischaemia and three five-minute pauses using a blood pressure cuff inflated to 40 mmHg more than the patients actual blood pressure. The patients in the tramadol group took tramadol sandoz retard 200 mg per os at 19:00 hours, the day before operation and then at 06:00 hours.

2.2. Operative procedure

Anaesthesia was induced with boluses of diazepam (0.13 mg/kg), sufentanil (0.7 mg/kg) and pancuronium (0.02 mg/kg), and anaesthesia was maintained with the same agents: diazepam (0.17 mg/kg/h), sufentanil (0.5–1 μg/kg/h) and pancuronium (0.02 mg/kg/h). For CABG, the left, and eventually, the right internal mammary artery and saphenous vein grafts were secured. Standard non-pulsatile cardiopulmonary bypass (CPB) was used with a membrane oxygenator (Capiox RX 25, Terumo Europe, Leuven, Belgium), cardiotomy suction and a left-sided shunt. CPB was started after a bolus of heparin (3 mg/kg, ACT >400 seconds), venous return was vacuum augmented (up to 60 mmHg), pump flow was 2.4–3 l/min/m2 and the nasopharyngeal temperature was 33–34 °C. Peripheral anastomoses were constructed on the stopped myocardium using antegrade cold-crystalloid cardioplegia (St. Thomas solution, Ardeapharma, Sevetin, Czech Republic) and repeated every 20 minutes until completion. Proximal anastomoses were then performed on the beating heart using a partial aortic clamp.

2.3. Serum troponin I measurement

Blood samples were taken preoperatively and eight, 16, and 24 hours postoperatively, collected in heparin tubes and processed immediately. Troponin I was measured with the Abbott AxSYM (Abbott Lab, Longford, Ireland) cTnI ADV microparticle enzyme immunoassay. The 99th percentile value in 550 healthy volunteers has been determined to be 0.04 μg/l, and a coefficient of variation of lower than 10% was achieved for the levels 0.27–4.00 μg/l. The diagnostic cut-off for this assay indicating significant myocardial injury is 0.40 μg/l.

2.4. iNOS and eNOS quantification

Myocardial samples for relative iNOS and eNOS estimation were drawn twice: before venous cannulation for CPB from the auricle of the right atrium and after stopping the CPB from the edge of the cannula ostium (both c. 3×3 mm).

The myocardial samples were collected into RNAlater solution (Ambion, Austin, TX, USA), left at 4 °C for several days and then frozen at –80 °C.

The reverse transcription step of real-time polymerase chain reaction (RT)-PCR was carried out using a Superscript VILO cDNA Synthesis Kit (Invitrogen, Carlsbad, CA, USA) and the qPCR step was performed with TaqMan Gene Expression Master Mix (Applied Biosystems, Foster City, CA, USA) on an ABI Prism 7000 PCR cycler (Applied Biosystems). The validated PCR primers and TaqMan probes used were as follows: eNOS (assay ID: Hs00167257m1, Fam-MGB), iNOS (assay ID: Hs00167166m1, Fam-MGB), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (TaqMan endogenous control, VIC-MGB) purchased from Applied Biosystems. The samples were analysed in duplicate for each of the NOS genes. The relative expression of the NOS genes was calculated using the ΔCT method (2−(Ct NOS−Ct GAPDH)) as described earlier. Values were expressed after multiplication by a coefficient of 1000.

2.5. Statistical analysis

After consent had been obtained for participation in the clinical trial, the patients were randomly assigned to L-RIPC treatment, tramadol treatment or the control group. A computer-generated table of random numbers was used for randomization. The analysis was per-protocol. A sample size of at least 10 patients in every group was determined on the basis of previous studies [4]. Continuous data are presented as the median and 5th–95th percentile. Categorical variables are expressed as percentages of categories (%). Comparison of continuous parameters among treatment groups was computed using the Kruskal–Wallis test followed by post-hoc comparison using the mean rank test. The Wilcoxon paired test was adopted to analyse the significance of time-related changes within the treatment groups. The statistical significance of differences in category percentages was computed using the χ2-test. All values of P<0.05 were regarded as statistically significant. Analyses were performed using Statistical 9 (StatSoft CR, Prague, Czech Republic) and SPSS 18 statistical software (SPSS Inc, Chicago, IL, USA).

3. Results

Fig. 1 depicts the trial profile of 120 patients screened for eligibility in this study. Fourteen patients were excluded: nine had an additive EuroSCORE of more than 8, three had renal insufficiency and two had pulmonary disease. In total, 106 patients were approached for consent and 101 were randomized to receive either the L-RIPC (n=33), control (n=34) or tramadol protocol (n=33). One patient in the L-RIPC group (bleeding complication), one patient in the control group (perioperative myocardial infarction and revision due to venous graft torsion) and two patients in the tramadol group (cerebral infarct, incomplete data) were excluded. There was no difference in the baseline characteristics (Table 1 ) between the three groups. Concomitant AVRs were performed in five patients (15%) in the L-RIPC group and six patients (19%) in the tramadol group, as compared with only three patients (9%) in the control group. We did not perform the correction for the difference in AVRs, because the bypass and aortic clamp times were not statistically different between the groups. The time between the L-RIPC stimuli and the aortic cross-clamp was 18±2 hours. There were side effects in two patients in the tramadol group (one experienced nausea and the other experienced leg myoclonus).

Fig. 1.

Trial profile. p., patient; L-RIPC, late remote ischaemic preconditioning group; control, control group; excl., excluded; tramadol, tramadol group.

Fig. 1.

Trial profile. p., patient; L-RIPC, late remote ischaemic preconditioning group; control, control group; excl., excluded; tramadol, tramadol group.

Table 1

Patient characteristics and operation data

 L-RIPC Control Tramadol P-value 
 n=32 n=34 n=31  
Age (years) 67 (57–79) 71 (57–80) 68 (53–79) 0.861 
 Female  8 (25%) 11 (32%)  7 (22%) 0.551 
 Male 24 (75%) 23 (68%) 24 (78%) 0.505 
 BMI 27 (22–34) 26 (20–31) 27 (33–23) 0.638 
 NYHA class  2 (1–3)  2 (1–3)  2 (0–3) 0.891 
 CCS class  2 (0–3)  1 (0–2)  2 (0–3) 0.854 
EuroSCORE (add.)  5 (1–6)  5 (2–8)  4 (1–10) 0.297 
 Previous MI 17 (53%) 16 (47%) 11 (36%) 0.203 
 Peripheral vascular disease  5 (16%)  3 (9%)  4 (13%) 0.816 
 Hypertension 28 (87%) 29 (85%) 26 (84%) 0.783 
 Hypercholesterolaemia 18 (56%) 19 (55%) 21 (68%) 0.890 
 Diabetes  9 (28%) 12 (35%)  8 (26%) 0.462 
LVEF (tot.) 55 (30–63) 53 (30–65) 54 (30–60) 0.890 
 30–40%  1 (3%)  3 (9%)  4 (13%) 0.057 
 40–50% 19 (59%) 18 (53%) 18 (58%) 0.912 
 >50% 12 (38%) 13 (38%)  9 (29%) 0.876 
Drug history     
 Angiotensin-converting enzyne inhibitors 18 (56%) 16 (47%) 16 (52%) 0.808 
 Nitrates  7 (22%)  9 (26%) 10 (32%) 0.528 
 Statins 24 (75%) 25 (73%) 20 (65%) 0.0883 
 Insulin  1 (3%)  4 (12%)  4 (13%) 0.059 
 Sulphonylurea  4 (13%)  6 (18%)  3 (10%) 0.678 
Operation characteristics     
 Bypass time (min) 80 (60–100) 87 (50–125) 82 (50–100) 0.316 
 Aortic clamp time (min) 45 (33–68) 51 (29–96) 49 (28–68) 0.471 
 Venous revascularization >1 80% 81% 68% 0.419 
 Arterious revascularization >0 83% 81% 81% 0.925 
 Concomitant AVR  5 (15%)  3 (9%)  6 (19%) 0.055 
 L-RIPC Control Tramadol P-value 
 n=32 n=34 n=31  
Age (years) 67 (57–79) 71 (57–80) 68 (53–79) 0.861 
 Female  8 (25%) 11 (32%)  7 (22%) 0.551 
 Male 24 (75%) 23 (68%) 24 (78%) 0.505 
 BMI 27 (22–34) 26 (20–31) 27 (33–23) 0.638 
 NYHA class  2 (1–3)  2 (1–3)  2 (0–3) 0.891 
 CCS class  2 (0–3)  1 (0–2)  2 (0–3) 0.854 
EuroSCORE (add.)  5 (1–6)  5 (2–8)  4 (1–10) 0.297 
 Previous MI 17 (53%) 16 (47%) 11 (36%) 0.203 
 Peripheral vascular disease  5 (16%)  3 (9%)  4 (13%) 0.816 
 Hypertension 28 (87%) 29 (85%) 26 (84%) 0.783 
 Hypercholesterolaemia 18 (56%) 19 (55%) 21 (68%) 0.890 
 Diabetes  9 (28%) 12 (35%)  8 (26%) 0.462 
LVEF (tot.) 55 (30–63) 53 (30–65) 54 (30–60) 0.890 
 30–40%  1 (3%)  3 (9%)  4 (13%) 0.057 
 40–50% 19 (59%) 18 (53%) 18 (58%) 0.912 
 >50% 12 (38%) 13 (38%)  9 (29%) 0.876 
Drug history     
 Angiotensin-converting enzyne inhibitors 18 (56%) 16 (47%) 16 (52%) 0.808 
 Nitrates  7 (22%)  9 (26%) 10 (32%) 0.528 
 Statins 24 (75%) 25 (73%) 20 (65%) 0.0883 
 Insulin  1 (3%)  4 (12%)  4 (13%) 0.059 
 Sulphonylurea  4 (13%)  6 (18%)  3 (10%) 0.678 
Operation characteristics     
 Bypass time (min) 80 (60–100) 87 (50–125) 82 (50–100) 0.316 
 Aortic clamp time (min) 45 (33–68) 51 (29–96) 49 (28–68) 0.471 
 Venous revascularization >1 80% 81% 68% 0.419 
 Arterious revascularization >0 83% 81% 81% 0.925 
 Concomitant AVR  5 (15%)  3 (9%)  6 (19%) 0.055 

The data are presented as number (%) or mean with 5th–95th percentile. P, statistical differences between the groups are not significant for patient and operation data characteristics (the lower of the two values is presented). L-RIPC, late remote ischaemic preconditioning; BMI, body mass index; NYHA, New York Heart Association classification of heart failure; CCS, Canadian Cardiovascular Society classification for angina pectoris; EuroSCORE, perioperative risk score for the cardiac operation; LVEF, left ventricle ejection fraction; AVR, aortic valve replacement; MI, myocardial infarction.

L-RIPC reduced the postoperative troponin I level (μg/l) significantly after 8 hours [2.54 (1.01–3.89) with L-RIPC vs. 2.90 (1.60–6.32) for the controls, P=0.043] (Table 2 ). In contrast, preoperative tramadol increased postoperative troponin I levels significantly at all three time intervals: after 8 hours [3.97 (2.22–8.23) with tramadol vs. 2.90 (1.60–6.32) for the controls, P<0.018], after 16 hours [2.69 (1.64–8.01) vs. 1.62 (0.89–5.12), P<0.001] and after 24 hours [1.73 (0.72–4.85) vs. 0.88 (0.55–4.32), P<0.03]. In the control group, there was a small, significant increase in iNOS expression: [0.27 (0.07–1.07) preoperatively vs. 0.34 (0.11–1.09) postbypass, P<0.033]. L-RIPC increased iNOS and eNOS expression, but not significantly. In contrast, preoperative tramadol dampened these responses (Table 3 ).

Table 2

Serum levels of troponin I

 Control1 Tramadol2 L-RIPC3 
  P1,2 P1-3 
Troponin I (μg/l)    
 Before op. 0.02 (0.01–0.13) 0.02 (0.02–0.02) 0.323 0.02 (0.02–0.08) 0.749 
 After 8 hours 2.90 (1.60–6.32) 3.97 (2.22–8.23) <0.018* 2.54 (1.01–3.89) <0.043* 
 After 16 hours 1.62 (0.89–5.12)  2.69 (1.64–8.01) <0.001* 1.29 (0.83–2.80) 0.099 
 After 24 hours 0.88 (0.55–4.32)  1.73 (0.72–4.85) <0.0030.85 (0.48–2.52) 0.316 
 Control1 Tramadol2 L-RIPC3 
  P1,2 P1-3 
Troponin I (μg/l)    
 Before op. 0.02 (0.01–0.13) 0.02 (0.02–0.02) 0.323 0.02 (0.02–0.08) 0.749 
 After 8 hours 2.90 (1.60–6.32) 3.97 (2.22–8.23) <0.018* 2.54 (1.01–3.89) <0.043* 
 After 16 hours 1.62 (0.89–5.12)  2.69 (1.64–8.01) <0.001* 1.29 (0.83–2.80) 0.099 
 After 24 hours 0.88 (0.55–4.32)  1.73 (0.72–4.85) <0.0030.85 (0.48–2.52) 0.316 

1,2,3Statistically significant differences are indicated by an asterisk (*). L-RIPC, late remote ischaemic preconditioning, data are presented as median and 5th–95th percentile.

Table 3

iNOS and eNOS quantification

 Control group  Tramadol group  L-RIPC group  P1 
 P2 P2 P2  
iNOS (×1000)     
 Before CPB  0.27 (0.07; 1.07)  0.35 (0.08; 0.89)  0.29 (0.11; 0.75) 0.643 
 After CPB  0.34 (0.11; 1.09) 0.033*  0.37 (0.06; 0.77) 0.737  0.32 (0.10; 1.41) 0.212 0.808 
eNOS (×1000)     
 Before CPB 22.39 (14.41; 46.13) 25.33 (10.68; 45.75) 25.27 (14.56; 46.40) 0.380 
 After CPB 24.29 (16.92; 44.97) 0.427 25.52 (10.64; 41.11) 0.833 30.42 (14.14; 49.55) 0.162 0.557 
 Control group  Tramadol group  L-RIPC group  P1 
 P2 P2 P2  
iNOS (×1000)     
 Before CPB  0.27 (0.07; 1.07)  0.35 (0.08; 0.89)  0.29 (0.11; 0.75) 0.643 
 After CPB  0.34 (0.11; 1.09) 0.033*  0.37 (0.06; 0.77) 0.737  0.32 (0.10; 1.41) 0.212 0.808 
eNOS (×1000)     
 Before CPB 22.39 (14.41; 46.13) 25.33 (10.68; 45.75) 25.27 (14.56; 46.40) 0.380 
 After CPB 24.29 (16.92; 44.97) 0.427 25.52 (10.64; 41.11) 0.833 30.42 (14.14; 49.55) 0.162 0.557 

The data are presented as median and 5th–95th percentile. 1Comparisons of continuous parameters among treatment groups were computed using the Kruskal–Wallis test. 2The Wilcoxon paired test was used to assess the significance of time-related changes within treatment groups. Statistically significant differences are indicated by an asterisk (*). L-RIPC, late remote ischaemic preconditioning; iNOS, inducible nitric oxide synthases; eNOS, endothelial nitric oxide synthases; CPB, cardiopulmonary bypass.

4. Discussion

In this clinical study, we demonstrate that L-RIPC induced by applying brief ischaemia and reperfusion to the forearm with a blood pressure cuff 18 hours before CABG can reduce injury beyond the myocardial protection provided by cold-crystalloid cardioplegia. This increased protection was shown by a significant reduction in serum troponin I release at 8 hours postoperatively. We speculate that L-RIPC has a weaker effect than early RIPC [4], because after 16 hours postoperatively, troponin I levels displayed a non-significant decrease. The exact mechanism by which L-RIPC protects the heart is not yet known. Animal studies have suggested that the protection might be mediated via either a neuronal pathway [6] or humoral mediators, such as bradykinin, adenosine, opioids or NO [13]. For this reason, we also measured iNOS and eNOS expression in our clinical trial. We found, for the first time, that CPB with cold-crystalloid cardioplegia elicits iNOS expression, but L-RIPC did not augment iNOS. Therefore, we speculate that L-RIPC is either a weak signal for additional iNOS expression or that the cardioprotective mechanism in humans is mediated via a different pathway.

We also tested whether preoperative tramadol could modify ischaemia–reperfusion injury using the same group of patients. In our study, preoperative tramadol increased postoperative troponin I levels significantly at all three time intervals up to 24 hours. Tramadol exerts its analgesic and antinociceptive effects via opiatergic, noradrenergic and serotoninergic systems. In experiments with Langerdorff-perfused, isolated rat hearts, tramadol has shown some cardioprotective effects. It was thought that these effect might be mediated through opioid receptors, noradrenalin re-uptake or NO [12]. In our study, we did not confirm this result; instead, we observed the exacerbation of myocardial injury as evidenced by serum troponin I elevation. We hypothesize that this exacerbation may stem from tramadols serotoninergic effect. Excessive serotoninergic activity (serotonin syndrome) may be associated with coronary ischaemia, as demonstrated by multiple reports of myocardial infarction associated with antidepressant serotonin re-uptake inhibitors [14]. We used relatively large doses of tramadol (2×200 mg) that elicited temporary signs of serotonin syndrome (leg clonus and nausea) in two patients. Paradoxically, serotonin dilates normal coronary arteries, while constricting diseased ones. Endothelial 5-HT1 receptors release NO, while atherosclerotic vessels may not have this protective effect, resulting in unopposed 5-HT2 receptor-mediated vasoconstriction [15].

In conclusion, we demonstrate for the first time that L-RIPC induced by applying brief ischaemia and reperfusion 18 hours before CABG can reduce injury above the myocardial protection provided by cold-crystalloid cardioplegia. In contrast, we found that tramadol, a frequently used analgesic, can worsen myocardial injury after surgical coronary revascularization. We also found that CPB with standard cold-crystalloid cardioplegia elicits weak expression of iNOS that is likely to be a component of the postoperative defensive response. From a clinical point of view, we must keep in mind that there are still many unknown interventions that can positively impact or negatively interfere with the postoperative course of our patients.

Funding: This work was supported by a grant from the Internal Grant Agency, Ministry of Health, No. NR/9194–3.

We thank Ladislav Dusek and Jiri Jarkovsky from the Institute of Biostatistics and Analysis, Masaryk University, Brno for consultation and statistical analyses.

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