Multiple studies have shown the potential benefits of volatile anesthetics over the intravenous anesthetics in cardiac surgery [
There are several opinions regarding what is the preferred volatile anesthetic. It is known that the newer drug sevoflurane has some chemical advantages over isoflurane (e.g., less solubility resulting in a faster onset and offset of action, less irritating to the airway, and being not as pungent as isoflurane; thus it can be used for inhalational induction of anesthesia [
This meta-analysis was performed according to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) and following the recommendations of the Cochrane Collaboration [
Two authors reviewed the literature and screened the abstracts independently. They selected all relevant articles in full text for detailed comprehension and further assessment of the quality and agreement of inclusion criteria. This meta-analysis focused on randomized controlled trials (RCTs). We did not restrict our selection criteria to studies developed at specific regions nor studies with very low sample size.
The participants included in this meta-analysis were adult patients (age > 18 years) who underwent cardiac surgery with either isoflurane or sevoflurane anesthesia.
The use of isoflurane for maintenance of general anesthesia was considered the intervention in this meta-analysis, and the control group consisted of sevoflurane anesthesia.
The primary outcomes in this meta-analysis were the intensive care (ICU) length of stay and hospital length of stay. Secondary outcomes included the time to extubation, S100
RCTs compared sevoflurane with isoflurane used for maintenance anesthesia in cardiac anesthesia. RCTs should recruit adult patients (age > 18 years) undergoing cardiac surgery (on-pump and off-pump).
We excluded studies that compared volatile anesthesia with nonvolatile anesthesia.
The MEDLINE/PubMed (from 1950 to Feb 2017), Google Scholar (from 1960 to Feb 2017), EMBASE (from 1980 to Feb 2017), and Cochrane library (from 1990 to Feb 2017) were searched for randomized controlled trials (RCTs) comparing the effects of isoflurane with sevoflurane anesthesia in cardiac surgery.
The terms included in the search strategy were “cardiac surgery”, “volatile anesthesia”, “isoflurane”, “sevoflurane”, “troponin”, “hospital stay”, “intensive care unit stay”, and “randomized controlled trial”. We did not restrict for language. In addition, we reviewed citations of included articles in order to ensure inclusion of relevant studies not captured in our initial literature search.
Two authors verified and extracted the data of the eligible articles. They completed a predefined database in Excel that contained all the possibly relevant variables for this meta-analysis (year of publication, sample size, mean age, anesthetic regimen, type of surgery, and the outcomes).
Two authors performed the methodological quality assessment and no disagreement arose. The quality of each study included in this meta-analysis was assessed by the Cochrane review criteria for randomized studies. The score was calculated for each study based on seven items (random sequence generation, allocation concealment, blinding of personnel who performed anesthesia, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias). Each item was scored between 2 and 0 (being 2 “positive,” 1 “unclear,” and 0 “negative”).
First, an exploratory qualitative analysis was conducted to describe the characteristics of the studies included in this meta-analysis. The meta-analysis was performed using the Review Manager 5.3 (Cochrane Collaboration, Oxford, UK) with random-effect model (DerSimonian & Laird method) [
In total sixteen RCTs were included in the meta-analysis. The trial flow diagram illustrates the number of excluded and included articles in detail (Figure
PRISMA flow chart of the selection of studies.
Sixteen potentially eligible articles were reviewed [
Characteristics of the studies included in this meta-analysis [
Study, reference | Study design | Type of cardiac surgery | Sample size | Anesthetic regimen | Outcomes | Conclusion |
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Searle et al. 1996 [ |
Multicentre, randomized, open-labelled study | CABG | Iso: 133 |
Induction with midazolam (0.1–0.3 mg/kg) and fentanyl (5–15 |
Myocardial infarction (assessed with CK-MB and ECG changes), ventricle failure, cardiac death, noncardiac death, and other hemodynamic events | Either Sev or Iso combined with fentanyl provided acceptable hemodynamic outcomes in patients with low risk who underwent elective CABG |
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Bennett and Griffin 1999 [ |
Prospective, crossover, dose-response study | CABG | Iso: 8 |
Induction with midazolam (1-2 mg), fentanyl 3 |
Hemodynamic outcomes (HR, CI, SVRI, PVRI, SAP, PAP, CVP, and PCWP). Postoperative outcomes such as time of operation, time to open eyes, time of extubation, recall, memory, PONV, and general condition were also reported | Iso and Sev used as the primary anesthetic showed no statistical difference between them at any stage of the study |
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Bennett and Griffin 2001 [ |
Prospective, crossover, dose-response study | Valvular surgery | Iso: 14 |
Induction with midazolam (1-2 mg), fentanyl 3 |
Same hemodynamic outcomes as measured in Bennett and Griffin 1999 [ |
Sev showed a tendency to lower heart rates and cardiac index compared with Iso. Nonetheless, these findings have shown no significantly difference |
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Parker et al. 2004 [ |
3-arm (isoflurane, sevoflurane, or propofol), randomized, controlled trial with patients and intensive care staff blinded to the drug allocation | CABG | Iso: 118 |
Induction with fentanyl 10 |
Time to extubation, ICU stay, and perioperative hemodynamics and perioperative drugs administered | Time to tracheal extubation was significantly longer for the target-controlled propofol group; however a significantly greater number of patients in this group required the use of a vasodilator to control intraoperative hypertension |
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Kanbak et al. 2007 [ |
Prospective and randomized study | CABG with CPB | Iso: 14 |
Before CPB: Group Iso: 1% to 1.5%; Group Sev: 1.5% to 2%; Group Des: 7% to 8% |
Plasmatic levels of S100 |
Iso was associated with better neurocognitive functions than Des or Sev after on-pump CABG. Sev seems to be associated with the worst cognitive outcome as assessed by neuropsychological tests, and prolonged brain injury as detected by high S100 |
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Delphin et al. 2007 [ |
Prospective and randomized trial | OPCAB | Iso: 50 |
Volatile agents were titrated to maintain hemodynamic variables within 20% of their baseline values. Both groups received fentanyl 5 |
Time variables after the surgery (including duration of anesthesia, duration of surgery, time to extubation, and hospital LOS). Neuropsychological scores and troponin enzyme levels after the surgery were also measured | Both Sev and Iso may be safely used as maintenance agents in OPCAB. Sev has the advantage of allowing earlier extubation and evaluation of neuropsychological tests after OPCAB |
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Venkatesh et al. 2007 [ |
Prospective and randomized trial | OPCAB | Iso: 20 |
Induction with thiopentone sodium, midazolam (0.05–0.1 mg/kg) and fentanyl citrate (4 |
Hemodynamic data (HR, MAP, PAP, CI, and others), depth of anesthesia, ischemic changes (assessed through blood CK-MB levels and ECG changes), time of awakening, and time of extubation | Both anesthetics are safe. Sev provides early awakening and extubation as compared with Iso |
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Yildirim et al. 2009 [ |
Prospective, randomized, and controlled trial | CABG with CPB | Iso: 20 |
Iso: induction: 1 |
Hemodynamic data (HR, MAP, PAP, CVP, PCWP, CO, CI, SVRI), myocardial oxidative stress status, and troponin I changes | Inhalation anesthetics preserved cardiac function in coronary surgery patients after CPB with less evidence for myocardial damage than propofol |
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Hemmerling et al. 2008 [ |
Prospective randomized double-blind trial | OPCAB | Iso: 20 |
Induction with fentanyl 3 mg/kg, followed by propofol 1-2 mg/kg. 1 MAC for each volatile agent for maintenance | Arterial blood gases, peak expiratory flow, hemodynamic data, myocardial protection (measured by blood levels of CK-MB and troponin-T), left ventricular ejection fraction, postoperative pain, and time of extubation | Both volatile agents offer the same myocardial protection but Sev was associated with a shorter time to extubation |
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Singh et al. 2011 [ |
Prospective, randomized single-blinded trial | CABG with CPB | Iso: 59 |
Induction: intravenous midazolam 2 mg, fentanyl 3–5 mg/kg, and thiopentone 3–5 mg/kg |
Hemodynamic data and S100 |
S100 |
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Ceyhan et al. 2011 [ |
Prospective and randomized trial | CABG with CPB | Iso: 20 |
Induction: etomidate 0.3 mg/kg, a bolus dose of pancuronium 0.1 mg/kg, and remifentanil 1 |
Hemodynamic data. Troponin-T, CK, and CK-MB levels | Sev provides a better myocardial protection than Iso, with lower levels of troponin-T and CK-MB observed with Sev |
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Dabrowski et al. 2010 [ |
Prospective and randomized trial | CABG with CPB and ECC | Iso: 54 |
Induction: fentanyl (0.01–0.02 mg/kg), midazolam (0.05–0.1 mg/kg), and etomidate (0.1–0.5 mg/kg) |
Hemodynamic data and S100 |
After cardiac surgery S100 |
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Ozarslan et al. 2012 [ |
Prospective and randomized trial | CABG with CPB | Iso: 10 |
Induction: etomidate 0.4 mg/kg, vecuronium bromide 0.1 mg/kg, and fentanyl, 1 |
Hemodynamic data, laboratory parameter (such as hematocrit, lactate and potassium), and microcirculatory parameters | Sev had a negative effect on the microcirculation. Iso decreased vascular density and increased flow. Des produced stable effects on the microcirculation. All inhalation agents induced transient alterations in microvascular perfusion |
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Özgök et al. 2012 [ |
Prospective and randomized trial | CABG with CPB | Iso: 20 |
Induction: intravenous bolus infusion of midazolam (0.1 mg/kg), fentanyl (15–20 m/kg), and intravenous pancuronium bromide (0.1 mg/kg) |
Hemodynamic parameters, CK-MB, troponins, lactate | No significant differences between volatile agents |
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Freiermuth et al. 2016 [ |
Prospective and randomized trial | CABG with CPB and MECC | Iso: 15 |
Induction: propofol 1-2 mg/kg, fentanyl 3–5 |
Pharmacokinetics measurements, blood troponin levels, total dose of norepinephrine during MECC, intubation time, ICU LOS, hospital LOS, and mortality within 30 days | Similar pharmacokinetics regarding wash-in and wash-out for Sev and Iso. No significantly differences in cardiovascular stability and markers of cardiac damage were found |
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Jones et al. 2016 [ |
Pragmatic randomized noninferiority comparative effectiveness clinical trial | CABG, CPB, and/or single valve repair or replacement | Iso: 233 |
Induction: fentanyl (5–10 |
ICU LOS, mortality, troponin T levels, ICU lengths of stay, duration of tracheal intubation, inotrope or vasopressor usage in the ICU, inotrope or vasopressor usage, peak postoperative serum creatinine, new-onset hemodialysis, new-onset atrial fibrillation, use of an intra-aortic balloon pump, perioperative stroke, and ICU readmission | Sev is noninferior to isoflurane on a composite outcome of prolonged ICU stay and mortality. Sev is not superior to Iso on any other of the clinically important outcomes |
Iso: isoflurane; Sev: sevoflurane; Des: desflurane; Pro: propofol; CABG: coronary artery bypass graft; CPB: cardiopulmonary bypass; ECC: extracorporeal circulation; MECC: minimized extracorporeal circulation; OPCAB: off-pump coronary artery bypass; ECG: electrocardiogram; PONV: postoperative nausea and vomiting; ICU: intensive care unit; LOS: length of stay; CK: creatine kinase; CK-MB: creatine kinase-MB; TIVA: total intravenous anesthesia;
There were no significant differences between both volatile anesthetics in terms of intensive care unit length of stay (SMD −0.07, 95% CI −0.38 to 0.24,
Forest plot comparing ICU length of stay between isoflurane and sevoflurane.
Forest plot comparing hospital length of stay between isoflurane and sevoflurane.
Forest plot comparing time of extubation between isoflurane and sevoflurane.
Forest plot comparing S100b between isoflurane and sevoflurane at the end of surgery and 24 hours after surgery.
Forest plot comparing CK-MB between isoflurane and sevoflurane at 24 hours after surgery.
Forest plot comparing postoperative troponin levels between isoflurane and sevoflurane at the end of surgery and 24 hours after surgery.
Funnel plots were conducted to assess the publication bias in this meta-analysis of included studies. As shown in Supplemental File in Supplementary Material available online at
Risk of bias for each item.
In this study, the use of isoflurane and sevoflurane was analyzed to obtain powerful conclusions regarding their outcomes in cardiac surgery. To our knowledge, this is the first meta-analysis providing a comparison between two inhaled anesthetics in patients undergoing cardiac surgery, showing that the difference was not statistically significant between the use of isoflurane and sevoflurane.
In recent years there have been several studies comparing anesthetics used in cardiac surgery because the latter represents a remarkably cause of morbidity and mortality worldwide, especially in developing countries [
The overall results of the randomized clinical trials included in this study did not show statistically significant difference between the use of isoflurane and sevoflurane in terms of the primary clinical outcomes ICU length of stay and time of extubation (SMD = −0.07; 95% CI = −0.43, 0.28;
We consider that this study follows a comprehensive retrospective analysis of the included RCTs and exhaustive assessment of the identified primary clinical outcomes. The systematic search in major databases was wide and exhaustive and the results are consistent. Quality analysis of this study did not evidence substantial publication bias. However, this meta-analysis has limitations, listed as follows. High heterogeneity was detected comparing the difference between both anesthetics for primary clinical outcomes: time of extubation and ICU length of stay (
The volatile anesthetic choice has no significant impact on postoperative outcomes of patients undergoing cardiac surgery. Other practical considerations (availability, costs, and preference) may be influential factors into the decision regarding which anesthetic to use.
The authors declare that there are no conflicts of interest regarding the publication of this paper.