This Invited Commentary accompanies the following original article:
Straarup TS, Hausenloy DJ, Rolighed Larsen JK. Cardiac troponins and volatile anaesthetics in coronary artery bypass graft surgery. A systematic review, meta-analysis and trial sequential analysis. Eur J Anaesthesiol 2016; 33:396–407.
Insanity: doing the same thing over and over again and expecting different results.
(Attributed to Albert Einstein: 1879–1955)
Scientific research aims at testing an experimental hypothesis that, depending on the results, will either be accepted or refuted. Essential in this process is that the experimental set-up can be repeated by independent research groups that, ideally, will come to the same conclusions. The question then becomes: how many times should the experiment be repeated before the scientific community accepts the conclusions to be genuine and not the result of a random chance effect?
The more successful a research question, the more researchers will be tempted to address the same question in the hope of getting their work published in a high impact factor journal and themselves into the hall of fame. One such popular research question in anaesthesiology relates to the potential cardioprotective effects of volatile anaesthetics, especially in patients undergoing on-pump coronary artery bypass surgery. The first clinical reports on the topic were published in the late 1990s and early 2000s and since then more than 30 very similar research articles have been published. This does not take into account the numerous submissions on the topic that never made it to publication because of the lack of novelty of the message.
So how much longer do we need to keep repeating that the use of a volatile anaesthetic regimen during on-pump coronary artery surgery is associated with a lower postoperative cardiac troponin release compared with an intravenous anaesthetic regimen? The answer is provided in this issue of the European Journal of Anaesthesiology. Studies specifically investigating the effects of volatile anaesthetics on cardiac troponins following on-pump coronary surgery are no longer warranted. Simonsen Straarup et al.1 performed a systematic review, meta-analysis and trial sequence analysis to investigate the relationship between the choice of anaesthetic regimen and the extent of postoperative myocardial damage, as assessed by cardiac troponins. The total data from 30 studies, which included a total of 2578 patients, showed a significantly lower postoperative cardiac troponin I in patients receiving a volatile anaesthetic regimen compared with an intravenous anaesthetic regimen (standard mean difference: −0.995 μg l−1; 95% confidence interval: −1.316 to −0.673; P < 0.001). Trial sequential analysis indicated that the required information size is 972 patients, a number that was passed in 2006. Interestingly, the same protective effect was not evident in off-pump coronary artery surgery: here the required information size is still too small to reach unequivocal conclusions.1
The message therefore seems obvious; authors must stop designing and performing this type of study; ethical committees must stop approving such trials and editors must stop publishing over and over again data that simply confirm what is already known.
Does this mean that we have the final answer with regard to the cardioprotective effects of volatile anaesthetic agent in coronary artery surgery? Unfortunately not, as several important issues remain. First, the clinical relevance of a statistically significant difference in peak postoperative troponin levels between groups is unclear. Especially after open-heart surgery, increased postoperative troponin levels are a common phenomenon, and one that does not necessarily reflect myocardial infarction. Indeed, numerous other factors can lead to peri-procedural myocardial damage. These include mechanical myocardial trauma from needles, manipulation of the heart, coronary dissection, ischaemia/reperfusion injury and others. Biomarkers alone are not enough to support the diagnosis of myocardial infarction after coronary artery bypass surgery (type 5 myocardial infarction) and the Task Force for the Redefinition of Myocardial Infarction has made this clear.2 It has suggested, by arbitrary convention, that to be considered as diagnostic of a type 5 myocardial infarction biomarker values measured during the first 72 h following coronary artery surgery must be more than five times the 99th percentile of the normal reference range and must be associated with the appearance of new pathological Q-waves or new left bundle branch block, or angiographically documented new graft or native coronary occlusion, or imaging evidence of new loss of viable myocardium.2
Type 5 myocardial infarctions apart, increased postoperative troponins have been associated with a poorer outcome.3,4 A clear concentration–response relationship however has not (yet) been demonstrated and therefore it would be extremely unwise to relate a mean difference in troponin to any clinical outcome. Those individual studies that have attempted to explore this issue have all lacked sufficient power to address the question of postoperative outcome. Although results of systematic reviews and meta-analyses suggest a lower incidence of in-hospital myocardial infarction and mortality,5 and mortality at longest survival,6 with volatile anaesthetics, interpreting the difference correctly and understanding the relevance is hampered because of the low total number of events.5,6
As a consequence, we do not yet have a final answer as to whether a volatile anaesthetic regimen improves outcomes after coronary artery surgery. The normal approach to this is to propose a large prospective randomised trial, such as the one currently being undertaken (Volatile anaesthetics to reduce mortality in cardiac surgery; https://clinicaltrials.gov/ct2/show/NCT02105610?term=NCT02105610&rank=1). Although much is expected from the results of this study, some caution seems to be indicated. Inherent to multicentre initiatives is the risk of introducing an important number of confounding factors related to different surgical, anaesthetic and institutional protocols. This is illustrated when looking at the extent of myocardial protection between the different studies that Straarup et al. included in their analysis.1 In some of these studies, the volatile anaesthetic agent was administered as a preconditioning protocol, whilst in another it was added to the cardioplegia solution and only delivered on pump, whereas in others the agent was administered throughout the entire operation. Owing to the fact that the extent of cardioprotection may vary according to the protocol used,7 interpretation of the clinical relevance of cardioprotection with volatile anaesthetics in cardiac surgery still remains a point of debate.8–10 Nevertheless, taking these uncertainties into account, the answers to our questions with regard to potential cardioprotective effects of volatile anaesthetics in coronary surgery will probably come from a large multicentre study and not from a repetition of new small individual trials.
Apart from the methodological issues discussed earlier, it should be kept in mind that the presumed mechanisms of the specific cardioprotective effects of volatile anaesthetics relate to a modulation of ischaemia/reperfusion injury. In other words, if no perioperative ischaemia/reperfusion injury is present, no specific cardioprotective effect will be observed. As a consequence, the degree of protection may depend on the extent of ischaemia/reperfusion injury and may vary among the different types of cardiac procedure. In addition, the effects in noncardiac surgery may not be obvious because of the absence of perioperative ischaemia, thanks to the application of other cardioprotective strategies.11
In conclusion, the effects of volatile anaesthetics on myocardial biomarker release after on-pump coronary artery surgery seem well established. The clinical implications, however, are less obvious and effects on hard endpoints such as morbidity and mortality remain to be established. The incidence of these endpoints in modern anaesthesia and surgery are too low to be addressed in small studies. As a consequence, these questions need to be answered by well designed large (multicentre) trials. Finally, the specific protective properties of volatile anaesthetics are only apparent in the presence of perioperative ischaemia/reperfusion injury. It is therefore pointless trying to address this question in a patient population wherein ischaemia/reperfusion injury will occur only very rarely or not at all.
Acknowledgements relating to this article
Assistance with the invited commentary: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Comment from the Editor: this Invited Commentary was checked and accepted by the editors but was not sent for external peer review. SDH is an Associate Editor of the European Journal of Anaesthesiology.
1. Simonsen Straarup T, Hausenloy DJ, Larsen Rolighed JK. Cardiac troponins and volatile anesthetics in coronary artery bypass graft surgery: a systematic review, meta-analysis and trial sequential analysis. Eur J Anaesthesiol
2. Thygesen K, Alpert JS, White HD. On behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Circulation
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11. De Hert SG. Cardioprotection by volatile anesthetics: what about noncardiac surgery? J Cardiothor Vasc Anesth