Cardiac troponin (cTn) elevation after either coronary artery bypass grafting (CABG) or percutaneous coronary intervention directly represents the extent of irreversible myocardial injury as documented by delayed-enhancement magnetic resonance imaging [1,2]. The prognostic significance of elevated postprocedural cTn release has been established by numerous clinical investigation following cardiac surgery [3-7] with no discernible threshold below which an elevated value for cTn would be deemed harmless and a continuous relation between minimal myocardial damage and large infarcts, characterized by complications such as heart failure or shock.
CABG is a widely used, safe and valid procedure with a low mortality rate but significant morbidity. Patients who undergo coronary artery revascularization are at risk for myocardial damage. These risks have always been present in the setting of coronary artery interventions, but they have been highlighted by the new, more sensitive biomarkers. The potential benefits gained by reducing cardiac damage led to a renewed interest in cardiac protection strategies, including pharmacological preconditioning.
Volatile anaesthetics, commonly used for general anaesthesia to induce and maintain hypnosis, analgesia and amnesia and to produce mild muscle relaxation, were found in the 1980s to reduce infarction and to improve postischaemic recovery at the cellular level, in isolated hearts and in vivo [8-11]. Several potential mechanisms for cardioprotection have been identified, and it is now well accepted that these agents act mainly through pharmacological preconditioning. New halogenated anaesthetics may represent a choice to attenuate myocardial damage when iatrogenic damage is planned. Few studies have been performed in human patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) [12-16]. CPB is one of the few controlled models of human myocardial ischaemia and it offers the opportunity to study preventive measures that, if effective, could be transferred to all ischaemic patients undergoing procedures that could trigger ischaemia and myocardial damage.
We have performed the first multicentric randomized trial to compare the effects of desflurane vs. total intravenous (i.v.) anaesthesia in CABG surgery with extracorporal circulation in terms of cTn release.
The study was carried out according to the principles of the Declaration of Helsinki. The local Ethical Committees of the hospital centres approved this study and written informed consent was obtained from all patients. Consecutive patients scheduled for elective CABG with CPB at three university hospitals (Vita Università Vita-Salute San Raffaele, Milano, La Sapienza University of Rome Umberto I Policlinic and Azienda Ospedaliera Universitaria Pisana, Cisanello Hospital, Pisa, Italy) were randomly assigned to receive volatile anaesthetics or total i.v. anaesthesia on top of an opiates-based anaesthesia.
All subjects underwent isolated CABG and were eligible if referred for isolated elective coronary bypass surgery and were >18 yr of age. Patients were excluded if they had: CABG planned with the off-pump technique; any other surgical procedure during current admission; a Q-wave myocardial infarction in the preceding 6 weeks; valve insufficiency; active congestive heart failure; previous unusual response to an anaesthetic; an experimental drug within 28 days before surgery; use of sulfonylurea, theophylline or allopurinol.
Patients in the volatile anaesthetics group received desflurane with 1.0 minimum alveolar concentration end-tidal (6%) from induction of general anaesthesia to the beginning of CPB and from the end of CPB to the end of surgery. Patients in the total i.v. anaesthesia group received propofol (Diprivan, Astra Zeneca, Brussels, Belgium) 2-3 μg mL−1 plasma level (equivalent to 2-3 h mg kg−1) via target-controlled infusion throughout the procedure since this drug represents the standard hypnotic drug in many cardiac anaesthesia units. Propofol decreases postischaemic myocardial mechanical dysfunction, infarct size and histological degeneration but has no pharmacological preconditioning effect . All patients received desflurane or propofol on top of an opiates (fentanyl)-based anaesthesia.
In the current study we tested the hypothesis that desflurane would decrease perioperative myocardial damage as measured by cTnI release when compared to total i.v. anaesthesia.
Baseline demographics and clinical characteristics have been collected as described in Table 1. All preoperative medications were routinely omitted on the day of surgery. Aspirin was stopped 1 week before surgery. Angiotensin-converting enzyme inhibitors were withdrawn on hospital admission (generally 1 day before surgery). Preoperative beta-blockers were continued postoperatively if permitted by heart rate (HR), blood pressure (BP) and cardiac index evaluation. No other drugs were continued routinely. No other drugs were given for cardiac protection. All patients were premedicated with diazepam 0.1 mg kg−1 os, morphine 0.1 mg kg−1 and scopolamine 0.25 mg intramuscularly (i.m.) and received standard monitoring. Patient monitoring included invasive radial artery BP measurement, continuous electrocardiographic leads II and V5 with ST segment monitoring, pulse oximetry, central venous pressure, capnometry and urine output. For induction of anaesthesia, all patients received an i.v. bolus of midazolam (0.2 mg kg−1), fentanyl (5-10 μg kg−1) and pancuronium (0.1 mg kg−1). Anaesthesia maintenance was obtained through repeated doses of fentanyl, pancuronium and with either halogenated anaesthetics or propofol as described above. The desflurane group received additional midazolam to maintain hypnosis during CPB. Hypnosis was monitored by a Bispectral index (BIS) monitor and level of anaesthesia was adjusted to maintain a value <40.
For all patients undergoing isolated elective CABG, a standard median sternotomy approach was used. Patients included in the study were treated by experienced cardiothoracic anaesthesiologists and surgeons experienced in both on-pump and off-pump bypass surgery. In all patients at least one internal mammary artery graft was used. Additional grafts were performed after harvesting saphenous veins.
All patients received an intraoperative infusion of tranexamic acid. No aprotinin was administered. Activated clotting time was maintained greater than 480 s for CPB, and the effect of heparin (starting dose 3 mg kg−1) was reversed with protamine sulphate in a 1 : 1 ratio.
CPB was conducted at moderate hypothermia (32-34 °C) and myocardial protection during aortic cross clamping was obtained by anterograde and/or retrograde cold blood cardioplegia.
Following surgery, patients were transferred to the intensive care unit (ICU), sedated with midazolam for 4 h and weaned from the ventilator as soon as the following parameters were achieved: haemodynamic stability; no significant dysrhythmias; no major bleeding; temperature >36 °C; adequate level of consciousness with no sign of neurologic injury; adequate pain control; pH and blood gases within normal values with FiO2 <60% and positive end-expiratory pressure (PEEP) <6. Weaning from catecholamine infusion was guided by standard haemodynamic criteria. All patients were started on aspirin within the first 24 h after surgery. Postoperative pain relief was provided to all patients by boluses of i.v. morphine. BP (systolic, mean and diastolic), HR and central venous pressure were recorded at 6 time points: before induction of anaesthesia, before and after CPB, at ICU arrival, 4 and 18 h later. A subset of 40 patients had the following haemodynamic data collected: mean pulmonary arterial pressure, pulmonary wedge pressure, cardiac index, stroke index, systemic and pulmonary vascular resistance index. New Q-waves were defined as the appearance of a Q-wave ≥ 40 ms in at least two adjacent leads or the loss of R-wave amplitude in precordial leads. Patients were eligible to transfer out of the ICU when the following criteria were met: SPO2 > 90% at an FiO2 ≤ 50% by a face mask, adequate cardiovascular stability with no haemodynamically significant arrhythmia, chest tube drainage <50 mL h−1, urine output >0.5 h mL kg−1, no i.v. inotropic or vasopressor therapy and no seizure activity. Criteria for hospital discharge were: haemodynamic and cardiac rhythm stability, the presence of clean and dry incisions, an afebrile condition, normal bowel movement, and independent ambulation and feeding.
End-point of the study
In the current study we tested the hypothesis that desflurane would reduce perioperative myocardial damage as assessed by postoperative cTnI release when compared to propofol. The study primary end-point was peak postoperative cTnI release.
All data were collected by trained observers who did not participate in patient care and who were blinded to the anaesthetic regimen used. Medical treatment and decision making in the ICU and in the main ward were performed by physicians who were blinded to the type of anaesthesia used. Caregivers were daily interviewed for the occurrence of postoperative adverse events as described above.
Measurement of cardiac biomarkers concentration: laboratory analysis
We decided to use the most recently described and preferred biomarker for myocardial damage: cTnI, which has nearly absolute myocardial tissue specificity, as well as high sensitivity, thereby reflecting even microscopic zones of myocardial necrosis. Analysis of cTnI concentration was performed preoperatively, at ICU arrival, 4 h and 18 h later. Peak cTnI analysis included daily samples as well. Blood was collected in plastic tubes with a clot activator (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ, USA) and was centrifuged (2500 g for 15 min) before analysis. cTnI was assayed with Dimension XP and (Dade-Behring Diagnostic, Paris, France) according to the manufacturer's instructions. The cTnI method is a one-step enzyme immunoassay based on the sandwich principle. For troponin I, sensitivity of the assay was 0.04 ng mL−1. Samples were frozen at 30°C and analysed by a central laboratory.
Power of the study
Sample size calculation was based on a two-sided alpha error of 0.05 and 80% power. On the basis of previous reports  investigating postoperative cTnI release after CABG, we anticipated a mean peak postoperative release of 9 ± 7 ng mL−1 in the propofol group and assumed a 3.5 ng mL−1 reduction in peak troponin concentration after treatment with halogenated anaesthetics. We calculated that we would need a sample size of 64 patients per group. We planned to randomize 150 patients to account for possible protocols deviation. The calculation of this sample size followed the suggestions of the consensus conference  that the analysis of the actual distribution of myocardial damage observed (peak values of a biomarker or area under the curve) is more appropriate than analysis of the presence or absence of events only since it is more relevant to assess the total amount of perioperative myocardial cell injury as a continuum variable. All data were analysed according to the intention-to-treat principle, beginning immediately after randomization.
The details of the randomization, created by a computer generated list in blocks of 10, were contained in a set of sealed envelops that were opened at the start of anaesthesia. All study personnel and participants were blinded to treatment assignment for the duration of the study with the exception of the cardiac anaesthesiologists, who were not involved in data collection, data entry or data analysis.
Data were stored electronically and analysed with the help of Epi Info 2002 software (CDC) and SAS software, version 8 (SAS Institute). All data analysis was carried out according to a pre-established analysis plan. Dichotomous data were compared by using two-tailed χ2-test with the Yates correction or Fisher's exact test when appropriate. 95% confidence interval (CI) estimation for the differences between independent proportions was performed with methods based on the Wilson score. Continuous measures were compared by analysis of variance (ANOVA) or the U-test when appropriate. 95% CI estimate for the mean/median difference was performed. Two-sided significance tests were used throughout. Data are presented as mean (±SD) or as median (25th and 75th percentiles) if not otherwise indicated. To analyse data on plasma troponin I levels, the area under the concentration-time curve was calculated by the trapezoidal method for each patient, and treatment-related differences in the area under the curve were then compared by t-test. No interim analyses were carried out during the course of this study.
Between February and August 2005, 150 consecutive qualifying and consenting patients were randomly assigned to receive either volatile anaesthetics (75 patients) or total i.v. anaesthesia (75 patients) (Fig. 1). The baseline demographic and clinical characteristics of the two groups are summarized in Table 1 and none of them showed statistically significant differences.
All patients showed detectable cTnI after CABG surgery, but patients in the volatile anaesthetic group had a significant reduction of myocardial damage as documented by postoperative median (interquartile) peak cTnI release, 2.5 (1.1-5.3) ng dL−1, when compared to patients receiving a total i.v. anaesthesia, 5.5 (2.3-9.5) ng dL−1 (P < 0.001). Figure 2 shows cTnI levels at different points in time. Troponin release at 4 and 18 h postoperatively showed statistically significant differences between groups. The median (interquartile) area under the curve analysis confirmed the results: 36.3 (17.9-86.6) vs. 68 (30.5-104.8) h ng mL−1 (P = 0.002). A sensitivity analysis (‘per protocol') excluding the 13 patients (6 in the total i.v. anaesthetics group and 7 in the volatile anaesthetics group) who deviated from protocol confirmed the results of the primary analysis.
No centre to centre variation was noted in peak cTnI (P = 0.3). Myocardial protection by volatile anaesthetics, documented by a lower release of cTnI, translated into clinical outcomes as shown in Table 2. Patients receiving volatile anaesthetics had reduced need for postoperative inotropic support (24/75, 32.0% vs. 31/75, 41.3%, P = 0.04), and interesting trends toward a reduction in Q-wave myocardial infarction, time on mechanical ventilation, ICU and overall hospital stay.
A post hoc power analysis with alpha error 0.05 and 70 patients per group confirmed an adequate power of ln peak cTnI.
HR, central venous pressure, BP (systolic, mean and diastolic), pulmonary artery pressure, pulmonary wedge pressure, cardiac index, systemic and pulmonary vascular resistance index, temperature and arterial blood results were similar in the two groups in all the time points (data not shown). Only the stroke volume index showed a less dramatic decrease (from 38 ± 5.9 to 32 ± 4.2 mL m−2) in the volatile anaesthetic group when compared with the total i.v. group (from 40 ± 6.1 to 29 ± 3.7 mL m−2, P = 0.02).
The most important result of this study is to indicate that patients receiving volatile anaesthetics for CABG surgery have less myocardial damage than patients receiving a standard total i.v. anaesthesia with propofol. This is documented by a significantly lower release of postoperative troponin I (as peak postoperative value, as area under the curve and at every time point) and translates into a reduced use of postoperative inotropes.
Even if a steadily increasing number of investigations demonstrating cardioprotective effects of halogenated anaesthetics exist [12-16], this is the first multicentric randomized trial to demonstrate that desflurane decreases myocardial damage after ischaemia-reperfusion injury in human beings when compared to total i.v. anaesthesia in patients undergoing off-pump coronary artery bypass grafting (OPCABG) using an established cardiac biomarker (cTnI) .
Myocardial injury, assessed by postprocedural cTn elevation, always occurs during cardiac surgery procedures. In the large majority of cases, only a small release of markers of myocardial necrosis can be detected, without electrocardiogram changes or impairment of cardiac function; however, even small cardiac biomarkers release is an expression of myocardial damage  and correlates to short- and long-term prognosis after cardiac surgery [3-7].
Patient characteristics, surgical strategies, postoperative sedation and analgesia were similar in all groups. This implies that the only difference between the groups was the choice of associated anaesthetic drug: propofol or desflurane.
It can be hypothesized that the better preservation of early cardiac function with volatile anaesthetics desflurane (evident from data on reduced postoperative troponin I, reduced need for inotropic support and less dramatic decrease of stroke volume index) may result in an improved global tissue perfusion with a better recovery from surgery. Preservation of postoperative cardiac function may be responsible for an earlier recovery as suggested by trends towards a reduction in mechanical ventilation time, ICU and hospital stay. These results are congruent with evidence that exposure to volatile anaesthetics provides myocardial protection through pharmacological preconditioning, even if the mechanisms underlying the beneficial effects of halogenated anaesthetics are not completely clear.
In 1986, Murry and colleagues  found that four cycles of 5-min left circumflex coronary artery occlusions, before a 40-min occlusion, reduced myocardial infarction by 75%. This phenomenon, named ‘ischaemic preconditioning', has been extensively investigated and represents the most powerful means of achieving cardiac protection. However, because of practical issues, the concept of ischaemic myocardial preconditioning has not been widely applied in cardiac surgery despite its potential benefit. As knowledge of the basic mechanisms involved in myocardial preconditioning improves, alternative means have been proposed for achieving the cardioprotective benefit without the induction of myocardial ischaemia. Several clinical as well as experimental studies have shown a similar effect by volatile anaesthetics in protecting the myocardium from ischaemia-reperfusion injury [8-11]. In a fashion similar to ischaemic preconditioning, volatile anaesthetics can trigger an acute cardioprotective memory effect that lasts beyond their elimination and that is called anaesthetic or pharmacological preconditioning. To protect a patient's heart against injury by possible or planned ischaemia and reperfusion, inducing preconditioning by pharmacological means seems more applicable. Volatile anaesthetics have been successfully used in patients for decades and may offer a useful role in patients with coronary artery disease undergoing surgery. Although the exact signalling pathway is not yet fully understood, volatile anaesthetics precondition the myocardium by mechanisms similar to ischaemic preconditioning but they have the distinct advantage of not requiring ischaemia to produce this effect. Volatile anaesthetics are lipophilic and can easily diffuse through cellular and subcellular membranes. They do not require ionic or covalent binding to specific receptors but can interact with lipophilic amino acids to cause conformational changes in membranes, channels and enzymes.
By conferring protection to the myocardium as well as to other tissues beyond the duration of the anaesthetic exposure during anaesthesia, anaesthetic preconditioning may offer additional benefits during the vulnerable postoperative period.
Anaesthetics also have attributes that may contribute to protection when administered after the onset of ischaemia, such as mitigation of Ca2+ overload, free radical production and neutrophil adhesion. Indeed, in some studies the administration of the inhalation anaesthetic was discontinued before ischaemia-reperfusion and resulted in reduced infarct size. Nonetheless, protective effects of inhalation anaesthetics were also reported if inhalation anaesthetics were administered exclusively during the reperfusion phase.
Because of obvious limitations, it was difficult to provide evidence for anaesthetic preconditioning in human beings. Recent evidence has shown that, when compared with i.v. anaesthetics, volatile anaesthetics produce myocardial protection in animals and in human beings during cardiac surgery without harm. Few clinical studies have been conducted in patients undergoing CABG surgery with CPB [13-15,21,22], demonstrating a reduction of cTn release and systolic dysfunction in patients treated or preconditioned with volatile anaesthetics. Belhomme and colleagues  assessed the effect of isoflurane on cTn release. Preconditioning by isoflurane reduced cTn release, but not to a statistically significant degree. According to Tomai and colleagues, isoflurane suppressed the release of this enzyme in patients with compromised left ventricular function . A limitation of these clinical studies is that the number of subjects was small.
Clinical confirmation of volatile anaesthetics properties occurred with the recent studies carried out by De Hert and colleagues on a large single centre population of CABG with CPB . The authors showed that patients undergoing coronary surgery under CPB had a lower postoperative troponin and improved left ventricular function when they received sevoflurane or desflurane in a pre- or a postconditioning protocol compared with an i.v. protocol by propofol . Preconditioning and postconditioning might involve different pathways and have additional protective effects. In their study, the authors showed that, when volatile anaesthetic is dispensed throughout the pre-, peri- and postischaemic period, the cardioprotective effects were more obvious: they showed a reduction in troponin I concentration and a decrease in hospital and ICU stay.
Only one group performed a multicentre study on the preconditioning effects of volatile anaesthetics in patients undergoing cardiac surgery. They investigated natriuretic atrial peptide concentrations  and also evidenced long-term (1 yr) benefits in terms of incidence of cardiac events . Their study is different from our experience in that they focused on less established cardiac biomarkers and their patients received only a few minutes of a different volatile anaesthetic (sevoflurane).
The low cost and very low risk of volatile anaesthetics may support their routine use in patients undergoing CABG to reduce periprocedural myocardial injury.
Anaesthesiologists treat an increasing number of patients with ischaemic heart disease undergoing non-cardiac surgery and witness the frequent occurrence of perioperative myocardial ischaemia. Currently halogenated anaesthetics are the most promising agents as cardioprotectors among anaesthetics at clinically relevant concentrations; hence, halogenated anaesthetics might be good choices in anaesthetizing patients at risk of myocardial ischaemia.
The current study mainly focused on cardiac biomarker release after cardiac surgery and did not aim to relate the choice of the anaesthetic agent to mortality because it was not sufficiently powered to address this issue. To demonstrate a reduction in mortality rate from 1.2 to 0.6%, assuming a power of 0.8 and an alpha value of 0.05, an estimated sample size of 4215 patients is needed.
This is the first multicentric randomized controlled trial (RCT) study that identifies the use of desflurane in the anaesthetic regimen as one factor that may affect myocardial damage in patients undergoing CABG as documented by cTn. Since myocardial damage, defined by cTnI release, is independently correlated to short- and long-term prognosis, these observations give further importance to our study, that could have prognostic implications as well. Patients receiving volatile anaesthetics coronary artery surgery had a reduced postoperative myocardial damage than patients receiving propofol for the same procedure. This study supports cardioprotective effects of halogenated inhalation anaesthetics and suggests that the choice of an anaesthetic with respect to myocardial reperfusion injury might be of importance also in the general surgical patient population with coronary artery disease.
The authors would like to thank Michael John, coordinator of the English courses in the Faculty of Medicine and Surgery at the Vita-Salute San Raffaele University, Milan, for his help and suggestions during the writing of this work. We are also indebted to Mariano Fichera, RN, Monica Lischio, RN, Giardina Giuseppe, RN, Marco Costantini, RN, Luigi Villani, RN, for their help in data collection and data entry. There are no financial associations that might pose a conflict of interest in connection with the submitted article. The study was conducted exclusively with departmental sources. Desflurane (Suprane) was provided free of charge by the producer (Baxter).
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