British Journal of Anaesthesia

BJA Advance Access originally published online on June 21, 2006
British Journal of Anaesthesia 2006 97(2):127-136; doi:10.1093/bja/ael149

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Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysis

J. A. Symons^1,* and P. S. Myles^1,2

¹ Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Monash University Melbourne, Australia
² National Health and Medical Research Council Canberra, Australia

^*Corresponding author: Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, PO Box 315, Melbourne, Victoria 3004, Australia. E-mail: j.symons{at}alfred.org.au

	Abstract

Top Abstract Introduction Materials and methods Results Discussion References

 
Previous studies have investigated the role of volatile anaesthetic agents in myocardial protection during coronary artery bypass graft (CABG) surgery, and some have identified beneficial effects. However, these studies have been too small to identify a significant effect on myocardial infarction (MI) or mortality. We undertook a systematic overview and meta-analysis of all randomized trials comparing volatile with non-volatile anaesthesia in CABG surgery. We identified 27 trials that included 2979 patients. There was no significant difference in myocardial ischaemia, MI, intensive care unit length of stay or hospital mortality between the groups (all P>0.05). Post-bypass, patients randomized to receive volatile anaesthetics had 20% higher cardiac indices (P=0.006), significantly lower troponin I serum concentrations (P=0.002) and lesser requirement for inotropic support (P=0.004) compared with those randomized to receive i.v. anaesthetics. Duration of mechanical ventilation was reduced by 2.7 h (P=0.04), and there was a 1 day decrease in hospital length of stay (P<0.001). Some of these outcomes were based on a smaller number of trials because of incomplete data, largely because the individual trials focused on one or more surrogate endpoints. We found some evidence that volatile anaesthetic agents provide myocardial protection in CABG surgery, but larger adequately powered trials with agreed, defined outcomes need to be done to fully assess a possible beneficial effect of volatile anaesthetic agents on the risk of MI and mortality.

Keywords: anaesthetics, volatile; heart, coronary artery bypass; heart, preservation; protection; meta-analysis

	Introduction

Top Abstract Introduction Materials and methods Results Discussion References

 
Myocardial ischaemia–reperfusion injury, which commonly occurs during and after coronary artery bypass grafting (CABG) surgery, can lead to marked myocardial dysfunction and, possibly, myocardial infarction (MI) and prolonged hospitalization. The concept of pharmacologically protecting the myocardium to prevent this type of injury is an attractive concept. Since 1985, when Freedman and colleagues¹⁵ reported that enflurane could improve postischaemic myocardial recovery in the isolated rat heart, there has been a body of research into the potential benefits of anaesthetic myocardial protection in both animal and human models.

Volatile anaesthetic agents may afford myocardial protection by minimizing ischaemia–reperfusion injury or by having a preconditioning effect on the myocardium (preconditioning is a treatment before an ischaemic event). The mechanisms of volatile anaesthetic protection and preconditioning have been extensively studied in vivo and in vitro. These include: opening mitochondrial K_ATP channels^{12 19 20 40 62 63} increasing mitochondrial reactive oxygen species,^{12 36 58} and activation or translocation of protein kinase C, tyrosine kinases and p38 mitogen-activated protein kinase.^{12 16 42 56} These mechanisms decrease cytosolic and mitochondrial calcium loading.⁶⁰ Volatile anaesthetic agents may also protect endothelial coronary cells by mediating nitric oxide release.⁴¹ Finally, some volatile agents suppress neutrophil activation and the neutrophil–endothelium interactions that cause myocardial dysfunction.^{24 32} For a more complete review of myocardial protection by anaesthetic agents, the reader is referred to Kato and Foëx U.²⁹

Many studies have explored various endpoints as surrogate markers of myocardial protection by volatile anaesthetic agents during CABG surgery. In all cases, these studies have been underpowered to identify a significant effect on MI or mortality. We, therefore, did a systematic overview and meta-analysis of randomized trials to better define the role of volatile agents in myocardial protection during CABG surgery.

	Materials and methods

Top Abstract Introduction Materials and methods Results Discussion References

 
We included all randomized control trials of adult cardiac patients undergoing on-pump or off-pump CABG surgery that compared volatile with non-volatile anaesthetic agent(s). Patients having valve surgery, and those who had central neuraxial blockade were excluded.

Search strategy for identification of studies
A systematic search for all relevant randomized control trials, in all languages, was conducted. Relevant trials were obtained from the following sources between January 1985 and March 2005: electronic databases (MEDLINE and EMBASE), the Cochrane Controlled Trials Register, abstracts in major journals related to anaesthesia and cardiac surgery, and reference lists of relevant randomized trials and review articles. In addition, the following medical subject headings and text words in various combinations were included in a MEDLINE electronic search: propofol, isoflurane, sevoflurane, desflurane, anaesthetics, volatile agents, inhalational, ischaemic preconditioning, protection, myocardial, cardiac surgery, coronary artery bypass surgery, human, postoperative complications, fast-track, early extubation, tracheal extubation, intensive care, morbidity and mortality. Studies which did not include both a volatile anaesthetic and a non-volatile control group were excluded. In studies which had both CABG and valve surgery in the study groups, the valve surgery data were excluded. We also recorded the temporal relationship of the administration of the volatile anaesthetic agent to the commencement of cardiac bypass, and whether the study was single-blind (patient, but not staff or researchers), double-blind (patient plus staff but not researchers) or triple-blind (patient, staff and researchers). In studies in which there was more than one volatile or non-volatile group, these groups were combined for the pooled analyses. The quality (validity) of individual trials was quantified by the Jadad scale,²⁶ using five criteria (one point each): (i) proper randomization, (ii) double blind, (iii) withdrawals documented, (iv) randomization adequately described, (v) blindness adequately described.

Outcome measures
Our outcome measures included: myocardial ischaemia in the first 24 h after surgery, MI during hospital admission, hospital mortality, cardiac index post-bypass, troponin I enzyme increase, inotrope requirement in intensive care unit (ICU) (or in the operating theatre, post-bypass, where no ICU data were available), ICU and hospital length of stay, and mechanical ventilation time. Because the definitions of myocardial ischaemia and MI varied between studies, all were accepted. The criteria for tracheal extubation and ICU discharge also varied between studies and all were accepted.

For studies where the median and range were reported, the mean and SD were estimated by using the O’Rourke method⁴⁴ whereby the median was used as the estimate of the mean, and the SD was a quarter of the range. Troponin T concentrations were converted to troponin I concentrations using a conversion factor of 2/0.65, based on the ratio of the upper limit of their respective reference ranges. Cardiac output was converted to a cardiac index by either dividing the cardiac output by the body surface area (if reported) or otherwise assuming a value of 1.7 m² (the mean value of pooled studies reporting body surface area). Variables which were not reported numerically in the original papers were estimated from the published figures.

Statistical analysis
All data were abstracted and verified by both authors independently, and differences resolved by consensus. Data were then entered into a Rev Man 3.1 (Cochrane Collaboration) database. Trials with no events in both groups for a particular endpoint were excluded from the relevant meta-analysis. The pooled OR and 95% CI were estimated for dichotomous endpoints: mortality, MI, ischaemia and inotrope use. The weighted mean difference and 95% CI were estimated for numerical variables: ICU and hospital length of stay, mechanical ventilation time, cardiac index and troponin level. We tested each endpoint for heterogeneity²³ and used random-effects models if significant (P<0.05) heterogeneity was detected; all other comparisons were done with fixed-effects models.

Subgroup analyses were done to explore a possible differential effect if the volatile agent was administered throughout the entire CABG surgery or for only a portion of the procedure. In a previous study,¹¹ one group (50 patients) received volatile agent throughout the entire procedure, the other two groups (100 patients) received volatile at ‘any time’ and therefore all data for the volatile group from this trial were included in the volatile ‘any time’ group to avoid double-counting of data in the non-volatile group.

	Results

Top Abstract Introduction Materials and methods Results Discussion References

 
Our literature search identified 43 studies, 16 of which were excluded because volatile agent was not used at all, the study population was restricted to valve surgery, no relevant outcomes were reported, the study was retrospective, or dealt with long-term outcome (list available from the authors). This left 27 studies,^{1 2 6 8}–^{11 13 17 18 21 28 31 33 35 37 39 45}–^{50 53}–^{55 59} with 2979 patients, included in the analysis. Most of the studies only reported some of the endpoints which were the focus of this review, in which case each meta-analysis included fewer patients.

The characteristics of the study populations are summarized in Table 1. There was no evidence of statistical heterogeneity for the endpoints of mortality, MI, or myocardial ischaemia (P>0.1), but there was evidence of heterogeneity for the endpoints of hospital length of stay, ICU length of stay, duration of mechanical ventilation, cardiac index, troponin level and post-bypass inotrope administration.

View this table: [in this window] [in a new window]   Table 1 Characteristics of the trials included in the meta-analysis. Blinding: single-blind (patient, but not staff or researchers); double-blind (patient plus staff but not researchers); triple-blind (patient, staff and researchers). Volatile administration: 1, pre-bypass; 2, during bypass; 3, post-bypass

 
Five trials reported an effect on mortality,^{8 10 35 45 55} 12 trials reported an effect on MI,^{8 10 11 18 28 31 35 37 45 46 50 55} and 8 trials reported an effect on myocardial ischaemia.^{1 28 35 37 39 46 50 55} There was no significant difference between volatile and non-volatile anaesthetic groups with respect to MI (Fig. 1), mortality, myocardial ischaemia or ICU length of stay (Fig. 2).

View larger version (15K): [in this window] [in a new window]   Fig 1 Myocardial infarction.

 

View larger version (15K): [in this window] [in a new window]   Fig 2 Intensive care length of stay.

 
Patients randomized to receive volatile anaesthetics had 20% higher cardiac indices (Fig. 3) (P<0.006), significantly lower troponin I serum concentrations (P<0.002) (Fig. 4), lesser requirement for inotropic support (P<0.004) (Fig. 5), shorter duration of mechanical ventilation (P<0.04) (Fig. 6) and a shorter length of hospital stay (P<0.001) (Fig. 7) compared with those randomized to receive intravenous anaesthetics.

View larger version (15K): [in this window] [in a new window]   Fig 3 Cardiac index.

 

View larger version (13K): [in this window] [in a new window]   Fig 4 Troponin I concentration.

 

View larger version (21K): [in this window] [in a new window]   Fig 5 Inotrope use.

 

View larger version (15K): [in this window] [in a new window]   Fig 6 Mechanical ventilation time.

 

View larger version (9K): [in this window] [in a new window]   Fig 7 Hospital length of stay.

 
Timing of volatile anaesthetic agent administration
The subgroup analyses of the timing of volatile anaesthetic agent administration with respect to cardiopulmonary bypass showed no statistically significant difference between those groups in which volatile anaesthetic agent was administered throughout the procedure or at intermittent periods of the procedure for the endpoints of mortality, MI, myocardial ischaemia, troponin I level or ICU length of stay (Figs 1–7).

	Discussion

Top Abstract Introduction Materials and methods Results Discussion References

 
Our systematic overview and meta-analysis has demonstrated some evidence of volatile anaesthetic agent protection in CABG surgery, with a significant increase in post-bypass cardiac index, and a reduction in troponin I levels, inotrope use, duration of mechanical ventilation and hospital length of stay (Table 2, Fig. 7). There was no significant difference in MI or hospital mortality between the volatile and non-volatile groups.

View this table: [in this window] [in a new window]   Table 2 Variables comparing volatile agent with a non-volatile agent regimen in CABG surgery. *OR, odds ratio; WMD, weighted mean difference; CI, confidence interval

 
The reduction in mechanical ventilation time in the volatile group was about 2.5 h. Although significant, this difference needs to be interpreted with caution for a number of reasons. First, there was heterogeneity in the data, perhaps reflecting the varied practices in postoperative ventilatory management in CABG patients. Second, the studies most likely used different criteria for tracheal extubation. Third, studies varied widely in their adjuvant anaesthetic drug administration(s), in particular different opioid dose administration and this is known to affect the time to patient awakening. In one study,⁴⁵ in whom all patients received low-dose (<15 µg kg^–1) fentanyl, they found no difference in extubation time between their isoflurane and sevoflurane groups, but a significantly longer extubation time in the propofol group. Volatile anaesthetic agent was administered for the entire duration of surgery in the volatile group. Myles and colleagues,³⁷ however showed that a propofol-based regimen led to a decrease in ventilation time compared with a volatile (enflurane) anaesthetic technique. Two major differences in the aforementioned studies could explain the discrepant findings: the latter study³⁷ did not administer volatile agent during bypass, and the volatile group received a higher dose of fentanyl compared with the non-volatile group (30 µg vs 15 µg). Low-dose opioid regimens reduce tracheal extubation times in CABG surgery.^{4 38} However, a specific effect of volatile anaesthetic agent administration on postoperative mechanical ventilation and tracheal extubation time has been unclear.

There was a decrease in length of hospital stay of 1 day in the volatile group. Although this result needs to be interpreted with caution in view of the heterogeneity and limited amount of data (four studies with a total of 600 patients), it does represent a potentially important outcome for patients and clinicians, as it is usually associated with a reduced number of serious complications and hospital costs. In a systematic review on fast-track cardiac anaesthesia, there was no significant difference in hospital length of stay between low-dose and high-dose opioid groups.³⁸ DeHert and colleagues¹⁰ conducted a randomized study of 320 elective CABG patients, in which 80 patients received propofol, 80 midazolam, 80 sevoflurane and 80 desflurane. All patients received a remifentanil-based anaesthetic regimen. They found a significant decrease in ICU and hospital length of stay in the volatile groups when compared with the non-volatile groups. Postoperative troponin I and inotropic support was significantly lower in the volatile group. The occurrence of atrial fibrillation, a postoperative troponin I concentration of >4 ng ml^–1, and the need for prolonged inotropic support were identified as risk factors for a prolonged ICU stay.¹⁰ They concluded that a better preservation of early postoperative myocardial function with volatile anaesthetic agents resulted in a shorter ICU and hospital length of stay. This study was notable, in that volatile anaesthetic agent was used for the entire duration of surgery. However, the study was not adequately powered to show a decrease in mortality or postoperative MI with volatile agents.

The increase in post-bypass cardiac index, and reduced troponin flux, in the volatile group in our study supports a myocardial protection effect. It has been suggested that in order for preconditioning to be effective, the volatile should be administered throughout the entire procedure.¹¹ Our subgroup analyses are equivocal, and neither support nor refute this assertion. Nevertheless, volatile myocardial protection seems to be concentration-dependent and time-dependent,^{30 43} and volatile agents preserve myocardial energy stores during ischaemia (through a decrease in afterload, contractility and heart rate), thereby allowing the myocardium to recover.⁵¹ Each of these proposed mechanisms should be detected by troponin flux, a sensitive marker of myocardial damage.^{14 34} Volatile anaesthetic agents may also prevent reperfusion injury, a concept which has been raised previously.¹¹ Other mechanisms whereby volatile agents prevent myocardial reperfusion injury include suppression of neutrophil activation and the neutrophil–endothelium interaction.^{22 24 25 32} This effect may also be concentration dependent.^{30 43} Reduction in dysrrhythmias^{3 61} and decrease in infarct size⁷ may be additional mechanisms.

Limitations of the study
There was no difference in the rates of MI between the volatile and non-volatile groups. These results would seem to weaken the proposed role of volatile anaesthetic agents in myocardial protection. However, in order to detect a clinically important (e.g. >20%) difference would require many thousands of patients to be studied, considering that postoperative MI is an uncommon event. Detection of perioperative myocardial ischaemia is probably best done with continuous Holter ST-segment monitoring,²⁷ and a uniform definition of ischaemia is used.

The heterogeneity in our data for post-bypass inotrope use is not surprising given the differences in inotrope usage and the thresholds for commencing inotropic support in various institutions. Sevoflurane may protect the myocardium against stunning,^{5 57} an effect not reported with propofol.⁵² Another explanation for decreased inotrope usage in ICU could be the result of volatile agents preserving myocardial energy stores, thereby allowing the myocardium to recover.⁵¹ Our subgroup analyses could not identify a variable effect according to the timing of volatile agent administration (before, during, and/or after bypass) nor whether any particular volatile agent, if any, has superior myocardial protection effects. More standardized protocols, including agreed, defined endpoints, need to be developed in future studies. This study has potential weaknesses inherent in meta-analyses. Being able to pool many smaller studies increases the power of the analyses, but varied clinical practices and lack of uniformity of definition and reporting of endpoints limit the certainty of our findings. The results need to be interpreted taking into account the different practices with regard to anaesthesia, surgery and ICU management of CABG patients between various institutions. This uncertainty is best dealt with by a large prospective randomized trial in order to establish the true role of volatile anaesthetic agents in myocardial protection. We believe such a trial is warranted, and recommend that common endpoint definitions should be established.

In conclusion, this systematic overview and meta-analysis has found some evidence of volatile agent protection in CABG surgery, with increased cardiac index and a reduction in mechanical ventilation time, hospital length of stay, troponin flux and inotrope use in ICU. These findings support the conduct of a large definitive trial.

	Acknowledgments

 
This research was funded by an Alfred Hospital Trust Fund Grant. P.S.M. is supported by an Australian National Health and Medical Research Council Practitioner’s Fellowship (Canberra, Australia).

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