In the futility analysis 6 trials were ignored by the software application in the interim analyses because of low quality according to their Jadad score (<0.1%) Belhomme et al. (1999),57 De Hert et al. (2002),60 Nader et al. (2004),63 Kawamura et al. (2006),70 Amr et al. (2010)79 and Sirvinskas et al. (2015).84 The cumulative Z-score shows, that the RIS is 1072 patients, the point at which the Z-line crosses the 0.05% significance boundary for accumulated test results under due α-spending limitations. The futility boundary for the current study was achieved at 3018 patients (Fig. 4).
No trials were ignored in interim looks by the software application because of low information use (<0.1%) in the futility analysis. The required information size was estimated to be 1442 patients (Fig. 5).
The major findings of our study are that our meta-analysis shows that volatile anaesthetics, when used in elective coronary artery bypass graft surgery, reduce postoperative peak serum cardiac troponin enzyme levels by approximately 8% compared with non-volatile anaesthesia. The effect is seen in on-pump but not in off-pump bypass surgery. The novel aspect of this report is the analysis of the results of 11 OPCAB/MIDCAB studies (n = 593 study participants). However, data in this meta-analysis were not sufficiently powered to assess the influence of volatile anaesthetics on peak postoperative cTnI and cTnT.
The pooled TSA of on-pump CABG shows conclusively that no further trials evaluating surrogate markers of ischaemia are necessary, because the RIS is approximately 1000 patients and this was reached in late 2006. Thus, further investigation of this question appears unnecessary, as the current level of clinical evidence has almost attained futility. However, further investigations appear warranted for volatile anaesthetics in off-pump CABG surgery where RIS is estimated to be 1442 patients, a higher number than for on-pump CABG because of inconsistency in the findings of the available studies.
Volatile anaesthetic conditioning (VAC) has been repeatedly put forward as a means of mitigating the irreversible myocardial injury sustained by acute ischaemia and reperfusion. The anti-ischaemic effects of volatile anaesthetics were first proposed in 1976 by Bland and Lowenstein,87 who found evidence that experimental myocardial ischaemia in canine hearts was reduced by halothane. In 1997, two groups working independently of each other, first proposed the pharmacologic concept of preconditioning with the volatile anaesthetic, isoflurane.88,89 Volatile anaesthetics consistently appear to be superior to intravenous anaesthetics with regard to experimental myocardial protection but, several decades after it was first proposed, clinical VAC remains divisive. A large adequately powered prospective RCT is still required to determine whether volatile anaesthesia compared with non-volatile anaesthesia can improve clinical outcomes in patients undergoing CABG surgery. The relative reduction in peak postoperative enzyme release carries with it no immediate clinical significance; however, it remains a surrogate marker for morbidity and mortality in patients undergoing open heart surgery.90–93
The use of volatile anaesthetics in coronary stenting procedures has not been sufficiently investigated. A recent study found that sevoflurane administration during primary percutaneous coronary intervention did not reduce infarct size but there was a trend towards its reduction among patients with anterior myocardial ischaemia. Sevoflurane was associated with improvement in ST-segment resolution.48
Postoperative troponin levels increase after virtually all open heart surgery. They not only reflect myocardial infarction but also myocardial cell injury caused by reperfusion, surgical trauma, defibrillation and operation time. Lehrke et al.90 found that a cTnT concentration more than 0.46 μg l−1 48 h postoperatively was associated with a 6.7-fold higher long-term risk for subsequent cardiac death and an 11-fold higher risk for severe postoperative heart failure requiring mechanical support. In addition, Fellahi et al.92 found that a high postoperative peak cTnI (23.8 mg ml−1; range, 13.4 to 174.6) was associated with increased long-term mortality and mortality from cardiac causes.
Some researchers argue that the true VAC effect results in 30 to 40% reductions if enzyme release is plotted over time (area-under-the-curve) and that this is a better estimate of PMI because it better quantifies the extent over that particular period.94
No attempt was made to compare within-group volatile anaesthetics because the pooled data were too sparse. There could be differences between the anaesthetics used to prevent irreversible myocardial injury as some experimental results have suggested that isoflurane might be more effective than sevoflurane in this respect, This is despite differences in relative potency. More comparative trials would be needed to resolve this and other relevant issues such as the questions of dose response, timing and duration of volatile anaesthetic exposure. The result of the meta-analysis did not take into account the considerable heterogeneity associated with these factors. Conversely, experimental VAC indicates that even low doses of volatile agents can have an effect.95,96
A recent Bayesian network meta-analysis supports the hypothesis that volatile anaesthetics are superior to TIVA-based anaesthesia in improving survival after cardiac surgery, but the data could not support the theory that one volatile agent was more beneficial than another.97 The overall results of that meta-analysis are statistically fragile as there were only 68 deaths, and statistical significance was reached only by combining all volatile agents and comparing them with total intravenous anaesthesia.
The current analysis contains the potential weaknesses inherent in meta-analysis. 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 end points limit the certainty of our findings. The TSA analysis is an attempt to adjust for this using a more conservative estimate.
Interpretation of our findings should take into account the different practices with regard to anaesthesia, surgery and ICU management of CABG patients between the various institutions and the way that techniques have developed. Much has changed since 1985 in regard to surgical technique and intraoperative and postoperative care. It is probable that clinical and technical advances have reduced postoperative myocardial injury and with it the amount of total troponin released, minimising the difference between groups. This uncertainty is best resolved by a large prospective randomised trial to establish the true role of volatile anaesthetic agents in myocardial protection. We believe such a trial is warranted, and recommend that common end point definitions should be established. An important multi-centre RCT that promises to be adequately powered is currently underway.98 As for the estimate of the benefit in terms of outcome, we expect about a 10% troponin reduction, so a 2 to 3% mortality reduction does not seem improbable in the current trial. This statement is based on a reduction of 2 to 300 ng l−1 (cTnT) relative to the control group, so in conclusion, a reduction in both morbidity and mortality could surely be expected in a trial of over 1000 patients.
The result of the current analyses cannot be extrapolated from elective CABG to valve surgery or to emergency bypass surgery, since Jakobsen et al.99 found in a retrospective study of 10,535 patients, that overall mortality was reduced by volatile anaesthetics in elective surgery, but not in emergency surgery, probably because of haemodynamic instability.
The relative reduction in myocardial infarct size is less than the 50 to 60% reduction often reported in laboratory studies.100–102 This could be because of factors such as the age, comorbidity and the use of extracorporeal circulation. Guidelines have been drawn up to address the lack of animal disease models used to assess these factors.102 Although the mechanisms of action remain unclear, volatile anaesthetics act in similar ways to ischaemic pre-conditioning by activating a number of known mechanisms, including intracellular salvage kinase pathways, endothelial nitric oxide production, modulation of calcium homeostasis and prevention of mitochondrial permeability transition pore opening.100 Overall, the effects of volatile anaesthetics in pre-conditioning are triggered by multiple pathways, and this has been reviewed elsewhere.95,96,103
There is an overlap between our meta-analysis and that of Symons and Myles and their 10 included studies. Of our included studies, 15 were published in or after 2006. Also, we made a separate analysis of OPCAB/MIDCAB procedures and excluded studies with combined CABG and valve surgery, and those using halothane and enflurane. The present study is larger and more adequately powered with regard to troponin than Symons, and Myles’ 2006 analysis.
In conclusion, we have shown that a systematic review, meta-analysis and TSA of all existing clinical CABG trials point unquestionably towards a reduction in the level of serum markers of myocardial injury by volatile anaesthetics. Moreover, the total amount of existing evidence supporting our conclusion goes beyond adequacy, and further studies will be futile. This achieves the overall objective of our study-to demonstrate that clinical studies investigating the cardioprotective effect of volatile anaesthetics on serum cardiac enzymes in CABG patients are no longer warranted. This provides support for the notion that a large prospective randomised trial, investigating the effect of volatile anaesthetics on clinical outcomes, should be a priority. Meanwhile, the potential effect of volatile anaesthetics in OPCAB/MIDCAB procedures still needs to be clarified.
Assistance with the analyses: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: preliminary data was presented as a poster and an oral presentation at the annual meeting of DASAIM (Danish Association of Anaesthesiology and Intensive Care Medicine) in 2014.
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