There is experimental evidence that volatile anaesthetics may have direct cardioprotective properties due to an effect similar to that of ischaemic preconditioning and postconditioning, reducing ischaemia–reperfusion myocardial damage.1–4 Different studies5–10 and meta-analyses11–14 have shown that intraoperative use of halogenated agent (sevoflurane or desflurane) rather than intravenous anaesthetics (propofol or midazolam) is associated with improved postoperative cardiac function,15–17 shorter stays in the ICU and hospital14–18 and decreased mortality after 1 year.19,20 However, there is variability in the results, depending on the protocol used intraoperatively.21,22 It is only when the volatile agent is administered over the course of the entire surgical procedure that the results are positive.18 It is likely that, when the drug is used this way, it exerts a preconditioning effect (from induction of anaesthesia until the start of cardiopulmonary bypass, CPB) and a postconditioning effect (after CPB, from declamping of the aorta). The mechanisms involved in postconditioning through multiple prosurvival signalling pathways have been described in detail elsewhere23 and many data suggest that onset of postconditioning does not need to occur immediately on reperfusion24 and that, after reperfusion, there is a therapeutic time window for applying cardioprotective strategies to reduce myocardial injury. Therefore, we hypothesised that the cardioprotective effect of inhaled anaesthetic agents may be enhanced if their administration is continued after anaesthesia in the early postoperative period in the ICU, as a sedative, until weaning from mechanical ventilation.
Different halogenated agents have been administered in the ICU to sedate patients, and have been shown to have advantages over intravenous sedation.25–31 Their use as a safe alternative for sedation in ICU has been recommended in guidelines.32 Currently, the AnaConDa (Anaesthetic Conserving Device; Sedana Medical, Uppsala, Sweden) allows the administration of isoflurane and sevoflurane with any ICU ventilator, thus facilitating inhaled patient sedation in the ICU.33–36
No study exists on the cardioprotective effects of sevoflurane and propofol in patients undergoing coronary artery bypass graft (CABG) surgery when its administration is continued into the early postoperative period. We therefore designed a double-blind, double-dummy, prospective, randomised and controlled (sevoflurane vs. propofol) single-centre clinical trial to evaluate cardiac troponin I (TnI) release starting 6 h after CPB and at 12, 24, 48 and 72 h postoperatively. In these patients, the increase in myocardial biomarkers at 24 h was chosen as the primary endpoint because of its association with increases in early and late mortality.37 As secondary endpoints, we also evaluated haemodynamic events and ICU and hospital lengths of stay (LOSs).
Ethical approval for this study was provided by the Ethical Committee NAC of Hospital Clínico Universitario de Valencia, Spain (Chairperson Professor Dr D.J. Magraner) on 31 May 2006.
Patients, groups, randomisation and blinding
The study was approved by the Clinical Research Ethics Committee of the hospital and written informed consent was obtained from all patients prior to their inclusion in the study. We selected patients aged 18 years or older who were scheduled for elective CABG surgery which required at least 4 h of postoperative sedation. Exclusion criteria were combined surgery, reintervention, valve dysfunction, preoperative TnI more than 0.5 ng ml−1, altered liver (serum aspartate transaminase or serum glutamate pyruvate transaminase concentration >150 IU l−1) or kidney function (serum creatinine concentration >132 μmol l−1) and history of chronic alcoholism or neurological disease.
The patients were allocated randomly into one of two groups according to the drug used during anaesthesia (before and after CPB) and in the postoperative period: the control group (propofol, P) and the study group (sevoflurane, S). Simple randomisation was carried out using a random number table generator. Numbers were distributed in sealed, opaque envelopes which were opened at the beginning of anaesthesia.
In order to prevent any bias, a strict double-blind, double-dummy design was used. A first investigator carried out the clinical preparations and adjustments of the drug infusion rates following the anaesthetic and sedation protocols. A second investigator, blinded to the assigned group, was in charge of data collection and was responsible for clinical management. Blinding was ensured by using the same clinical preparation procedure for all patients. Patients in group S received the halogenated agent through the AnaConDa, and an intravenous infusion of a 10% lipid emulsion (placebo). Those in group P received isotonic saline solution through the AnaConDa (placebo), and propofol with an intravenous infusion syringe. The syringes, infusion lines and the end-tidal anaesthetic concentration monitor were hidden from the second investigator.
In accordance with the institution's protocol, antiplatelet medication was withheld. In diabetic patients, sulphonylureas were withdrawn 2 days before surgery and replaced with insulin. The surgeon followed a standard surgical protocol and total revascularisation was achieved in all patients. CPB standard techniques with moderate hypothermia (32–34°C) were used. Myocardial protection during aortic cross-clamping was performed with multidose intermittent antegrade cold blood cardioplegia.
On the day of surgery, after arrival in the operating area, the randomisation envelope was opened and the patient was assigned to a group. All patients were premedicated with 1 mg of sublingual lorazepam 90 min before surgery. Anaesthetic induction was carried out with midazolam 0.1–0.3 mg kg−1, etomidate 0.2–0.4 mg kg−1, fentanyl 2–40 μg kg−1 and cisatracurium 0.1 mg kg−1. In group S, anaesthesia was maintained with sevoflurane, administered through the AnaConDa, using paediatric infusion pumps (model P7000, Alaris, Carefusion, Switzerland) with syringes preloaded with 50 ml of liquid sevoflurane. The infusion rate for maintaining anaesthesia was set to obtain an end-tidal sevoflurane concentration of 0.7–1.5%, adjusting the infusion rate to obtain a bispectral index (BIS) of 40–60 (with a quality signal index of >80%). In the postoperative period, the infusion rate was adjusted to obtain an end-tidal concentration of 0.5–1% in order to obtain target sedation with a target evaluated by BIS 55–65; however, a minimum BIS of 50 or a Richmond agitation–sedation scale (RASS) score of −2/−3 was accepted. In all cases, adjustment of the sevoflurane infusion rate was carried out following the dosing scheme described by our group.36
In group P, propofol was administered using the same pumps with syringes preloaded with 50 ml of propofol 1%. During the intraoperative period, maintenance was achieved with an infusion of 4–10 mg kg−1 h−1 in order to obtain a BIS of 40–60. In the postoperative period, the initial infusion rate was set at 1–4 mg kg−1 h−1, which was then modified to achieve target sedation similar to that applied in group S.
During CPB, bolus doses of midazolam 5 mg were administered when the BIS reached 50 or more in both groups. Muscle relaxation during anaesthesia was achieved with repeated bolus doses of cisatracurium when needed. We also administered a continuous infusion of remifentanil 0.25–1 μg kg−1 min−1 during anaesthesia and 0.1–0.5 μg kg−1 min−1 in the postoperative period.
In the operating room and during the postoperative period, the patient was connected to an Intellivue MP90 monitor (Philips Healthcare, The Netherlands) to record a two-lead ECG (II and V5), as well as pulse oximetry (SpO2), end-tidal carbon dioxide concentration (EtCO2) and bladder temperature. The depths of anaesthesia and sedation were assessed using a BIS monitor (Covidien, Ireland). Haemodynamic monitoring of mean arterial pressure, heart rate, cardiac index (CI), central venous pressure, global end-diastolic index, stroke volume variation, systemic vascular resistance index (SVRI) and cardiac function index was carried out with a PiCCO2 monitor (Pulsion, Munich, Germany).
Preload was kept constant throughout the study (GEDI of 600–800 ml m−2) by the adequate administration of crystalloids and colloids. Glyceryl trinitrate, dobutamine or noradrenaline was administered by continuous infusion if CI was low (<2.4 l min−1 m−2), depending on whether afterload was high, normal or low (normal SVRI 1700–2400 dyn s cm−5 m−2).
Mechanical ventilation was adjusted in assist-control mode with a tidal volume of 8–10 ml per kg body weight and respiratory frequency was adjusted to obtain an end-tidal carbon dioxide tension of 4.7–6.0 kPa during anaesthesia and the postoperative period. Postoperative inspired oxygen fraction was set at 0.5 and positive end-expiratory pressure of 5 cmH2O was set as default and increased thereafter if the PaO2/FiO2 ratio was less than 200. To prevent environmental pollution with sevoflurane, ventilators were fitted with a Scat exhaled gas scavenging system (Temel S.A., Valencia, Spain). After the first four postoperative hours, or on meeting the established criteria for starting to wean the patient from mechanical ventilation, sedation was stopped and the patient was allowed to waken. Pressure support ventilation was used for weaning.
Determination of biomarkers and other parameters
Blood samples were collected on the day before or on the day of surgery (preoperative) and in ICU starting 6 h after CPB and at 12, 24, 48 and 72 h postoperatively. Concentrations of TnI, myoglobin, creatinine kinase MB isoenzyme (CK-MB) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were determined. NT-proBNP was measured because it is a very sensitive myocardial dysfunction biomarker of prognostic value in predicting the short-term and long-term risk of acute myocardial infarction (AMI), heart failure and cardiac death.38–40
TnI, myoglobin, CK-MB and NT-proBNP determinations were measured in plasma using a sandwich enzyme immunoassay method with the biochemical analyser Dimension (Siemens Healthcare Diagnostics, Deerfield, Illinois, USA). Sensitivity of the assay is 0.04, 1, 0.5 and 10 pg ml−1, respectively.
Haemodynamic stability was evaluated intraoperatively (before starting CPB and at the end of surgery) and in the postoperative period (upon admission to ICU and 6, 12, 24, 48 and 72 h thereafter). The variables obtained with the PiCCO2 monitor and the need for inotropic and/or vasopressor drugs were recorded. Likewise, we recorded the incidence of myocardial ischaemic episodes (AMI, angina or ST-segment descent ≥1 mm for at least 1 min) and arrhythmias (ventricular fibrillation, atrial fibrillation and atrioventricular block). Diagnostic criteria for myocardial infarction after CABG were defined as described in the expert consensus document.41
LOS in ICU was evaluated from the time of admission to compliance with the criteria for patient discharge from the unit: SpO2 at least 90% on FiO2 50% or less with a face mask, haemodynamic stability without inotropic drugs, absence of arrhythmias, negligible chest drain output, diuresis more than 1 ml kg−1 h−1 and neurological stability. The hospital LOS was evaluated from the time of admission to the ICU to compliance with the criteria for patient discharge from the hospital: haemodynamic stability, absence of clinically significant arrhythmias, a surgical wound in good condition, removal of the staples and self-sufficiency for walking and eating.
The sample size was calculated to detect differences in TnI concentration at 24 h as the primary outcome. A minimum detected difference of 2 ng ml−1 between groups was considered clinically significant. Anticipated TnI values of 4 and 2 ng ml−1 24 h after the operation were taken as means for group P and group S, respectively. For both groups, a SD for TnI of 3 ng ml−1 after 24 h was used, according to the values of 80 historical recordings of TnI at 24 h in this type of patient in our institution. These values were in agreement with those from previous studies.18 For α = 0.05 and power β = 80%, the resulting sample size was found to be 36 individuals per group. However, 75 patients were recruited in order to compensate for possible dropouts during follow-up.
In the descriptive tables, continuous variables are expressed as mean ± SD, or median, minimum and maximum and interquartile range where applicable. Categorical variables are expressed as number and percentage. In the tables, the data are stratified by anaesthetic group. The Shapiro–Wilkes test was used to assess normal data distribution.
For comparisons of categorical variables between groups, the Chi-square test was used. The McNemar test was applied when comparing two categorical variables corresponding to the same variable at different time points. Comparison of continuous variables was carried out using the Student's t-test (or Mann–Whitney U-test in the case of nonnormal data distribution) for independent data. The tables were generated with the means of the differences, the corresponding 95% confidence intervals, and the P value. To assess differences in the evolution of variables in the two groups we used a generalised linear model (GLM) for repeated measurements, followed by Tukey–Kramer multiple comparisons analysis. The homogeneity of the variances was previously assessed with Levene's test. The SPSS v.17 statistical package for Microsoft Windows (SPSS Inc., Chicago, Illinois, USA) was used for analysis of the data. P values of less than 0.05 were considered to be statistically significant.
A total of 75 patients were randomised. Two were excluded because surgery was not carried out. Of the remaining 73 patients, 37 had been allocated to group P and 36 to group S. The flow diagram is shown in Fig. 1. The characteristics of the two groups were similar (Table 1). There were no deviations from protocol.
The distribution of values was not normal for any of the markers at any of the studied time points; as a result, data are presented as median and interquartile range. The concentration of TnI increased significantly postoperatively, with a peak at 24 h. TnI, myoglobin, CK-MB and NT-proBNP values were not significantly different between the study groups at any time point. The time courses of these values are shown in Fig. 2.
There were no differences for any of the haemodynamic variables between the two groups (Table 2). The incidences of arrhythmias and perioperative myocardial ischaemia/infarction were not significantly different between groups P and S: 16.2% (six patients) vs. 11.1% (four patients) (P = 0.780) and 2.7% (one patient) vs. 5.5% (two patients) (P = 0.920), respectively.
The proportion of patients who required inotropic support with dobutamine during the study period was 72.7% in group P and 54.3% in group S (P = 0.086). Levosimendan was used in five patients in group P and in one patient in group S. Noradrenaline was used in 27% of patients in group P and in 11.1% of patients in group S (P = 0.086).
ICU and hospital length of stay
LOS in ICU and hospital were 76 ± 69 vs. 71 ± 48 h and 9.6 ± 5.6 vs. 9.2 ± 4.2 days (P
= 0.771) for groups P and S, respectively.
Two patients died in the ICU during the study, both in group S. One patient died from multiorgan failure and the other died after an extensive ischaemic stroke.
This is the first double-blind, double-dummy, randomised, prospective study in CABG surgery patients in which sevoflurane or propofol was used both for anaesthesia and as a sedative drug in the early postoperative period. There were no significant differences between the groups.
The mechanisms of protection exerted by halogenated anaesthetics on myocardial ischaemia seem to be similar to the protective mechanism of repeated ischaemia events (preconditioning) and during the reperfusion period after ischaemia (postconditioning). It is well known that cardioprotection is mediated by inhibition of mitochondrial permeability transition pore opening at the very beginning of reperfusion and this effect has been demonstrated for sevoflurane.42–45 Different postconditioning mechanisms have been described for salvaging ischaemic myocardium at reperfusion using volatile anaesthetics.23
However, the published clinical results on the cardioprotective effect of sevoflurane have been controversial. Most studies describe a beneficial effect,5–9,15–17,38,46–53 with decreased concentrations of ischaemia biomarkers, improved myocardial contractility, decreased use of inotropes and lower mortality. These findings have not been confirmed by other studies.22,29,54–60 In cardiac surgery, a recent meta-analysis including nearly 700 patients comparing sevoflurane and propofol found no differences in mortality, myocardial infarction or atrial fibrillation between groups. However, with sevoflurane, a lower TnI concentration and shorter ICU and hospital LOS were found.61 In contrast, the use of propofol resulted in lower mortality when compared with sevoflurane in high-risk CABG patients.62
There are a number of possible explanations for these contradictory results, which are also applicable to the results of our study. The most important reasons for the different findings in biomarker concentrations could be related to the different patient characteristics and methods of drug administration used among the studies. Different results have been found among patients undergoing cardiac or noncardiac surgery,20,56,63 CABG, valve or combined surgery and urgent and nonurgent CABG surgery.60,62,64 Diabetic patients were excluded in several studies but included in others, and some studies excluded only diabetic patients with sulphonylurea treatment.22,56,60 It is well known that diabetes mellitus interferes with myocardial protection offered by preconditioning and postconditioning. Specifically, sulphonylureas abolish the benefits of ischaemic and pharmacological preconditioning, although newer sulphonylurea drugs may not interfere with preconditioning.65 Other factors which may interfere with the results are the anatomy of the coronary arteries, type of cardioplegia, aging and female sex, which could have a negative impact on the efficacy of myocardial protection.66–68 The significance of all these factors is not well established and may account for the differences observed in different clinical studies.
There have also been profound differences among study protocols with regard to the timing of administration of sevoflurane (interrupted or continuous) and its effect on preconditioning.22,38,42,69 The most impressive effects have been reported when sevoflurane was administered from the beginning to the end of surgery, including administration during CPB.15 However, a meta-analysis showed that there were no statistically significant differences between groups in which volatile anaesthetic agent was administered throughout the procedure or intermittently, in terms of mortality, myocardial infarction, TnI concentration or ICU LOS.13 It has been suggested that the cross-clamping time is related to the extent of the ischaemia–reperfusion injury and TnI release.70 It could therefore be possible that the lack of cardioprotection in some studies38,56 was determined by a prolonged mean cross-clamping time.20,38,56 Another factor may be that the myocardial protective effects are dose-dependent,64 with few myocardial effects below 1 Minimum Alveolar Concentration (MAC), although an endothelial protective action is maintained.71 Conflicting results were obtained in cardiac surgery patients regarding differences in myocardial biomarkers with administration of halogenated agents between 1 and 2 MAC.70 However, one study did not find additional benefit when sevoflurane was administered for preconditioning and postconditioning when compared with either intervention alone.72 Additionally, contradictory results may be related to the fact that drugs are administered to patients concomitantly. For example, opioids exert an intrinsic cardioprotective effect.73–76 In a study on CABG surgery patients without CPB, to whom higher intraoperative doses of remifentanil were administered (with lower BIS values) compared with other studies, no differences were found in the cardioprotective effects of sevoflurane and propofol.77 In our study, the presence of diabetes in nearly 50% of patients in each group, interruption of administration of the anaesthetic during the aortic cross-clamp period, doses below 1 MAC in the postoperative period and the high remifentanil doses (although the same in both groups) could have masked the protective effect of the anaesthetic.
Only one recent study has compared two regimens of sedation with propofol or sevoflurane (administered with the AnaConDa) in postoperative CABG surgery patients.78 No significant differences were found between groups, evaluated using troponin T (TnT) and NT-proBNP concentrations 12 h postoperatively. However, this study was not blinded and had other major limitations. The most important is that sevoflurane was started at the time of ICU admission, which could be considered too late from the time of onset of reperfusion, resulting possibly in a decrease in the postconditioning effect. However, almost 30% of the sample had high preoperative TnT concentrations, indicating myocardial necrosis prior to surgery. No reference to history of diabetes or sulphonylurea treatment was reported. Additionally, sevoflurane was administered below 1 MAC. All these factors could have affected the results.
Regarding the effect of the anaesthetic on patients in the ICU and hospital LOS, various studies have reported shorter stays when inhalational agents were administered.14,18 This was described in a recent meta-analysis of modern inhalational anaesthetics,14 which found that, comparing inhalational and total intravenous anaesthetic regimens, there was a difference in ICU LOS of −7 h (95% CI −11.47 to −2.73, P < 0.001) favouring inhalational anaesthetics in 1433 patients and a difference in hospital LOS of −2.26 days (95% CI −3.83 to −0.68, P < 0.005) in 1593 patients. Another meta-analysis reported no differences in postoperative mechanical ventilation time, but shorter ICU and hospital LOS.61
A first limitation of our study is that it was a single-centre study. Multicentre studies reduce the effect of the special characteristics of a single institution. Another limit of our study is the sample size. Calculations were performed based on historical recordings in agreement with previous studies and not on a specific pilot study. Consequently, different reference values for TnI concentration could produce a different sample size and may leave our study underpowered.
There are two distinct features of our study in comparison with those found in the literature. First, our study was double-blind and double-dummy. This study design clearly precluded bias in the results and excluded the effects of important confounding factors, such as the effects of different surgeons, surgical techniques and different CPB regimens (as may happen in multicentre studies). Second, we prolonged anaesthetic use into the postoperative period. In this setting, the postconditioning effect could have been stronger than in the earlier studies, where postconditioning with sevoflurane occurred only from the end of CPB to the end of surgery. Despite these characteristics, we were not able to detect differences between the two anaesthetics regarding troponin release in the first two postoperative days.
In summary, different findings in biomarker concentrations and outcomes after surgery when volatile anaesthetics are used for myocardial protection could be related to different patient characteristics and methods of administration of the drugs, as well as the dose and timing of administration and also administration of concomitant drugs. All these aspects need to be kept in mind when considering future studies to investigate the cardioprotective effects of inhalational anaesthetics. It has recently been suggested79 that other determinants such as gene expression profiles for signalling pathways analysis should be used in clinical studies.
In conclusion, in CABG surgery patients, there were no significant differences in postoperative elevations of TnI concentration when either sevoflurane or propofol was used as an anaesthetic during surgery (before and after CPB) and maintained for sedation in the immediate postoperative period (for at least 4 h). Sedation with sevoflurane through the AnaConDa was effective and without complications related to the technique.
Assistance with the study: none declared.
Financial support and sponsorship: none declared.
Conflicts of interest: none declared.
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