Non-cardiac surgery and volatile agents - Back to the future.

Guest editorial to the article: Cardioprotective Effect of Sevoflurane in Patients with Coronary Artery Disease Undergoing Vascular Surgery.

In this issue of the Saudi Journal of Anaesthesia, Bassuoni et al.[1] suggest that the cardioprotective properties of sevoflurane might have clinically relevant implications in non-cardiac surgery. In a relatively large randomized controlled trial comparing patients with coronary artery disease undergoing peripheral vascular surgery to receive total intravenous anesthesia (propofol) or an anesthesia plan including a volatile agent (sevoflurane), Bassuoni et al.[1] found reduced cardiac troponin release in the overall population and in the subgroup of patients experiencing perioperative ischemia.

These results are extremely important and document for the first time that the powerful cardioprotective properties of volatile agents that have been studied in vitro and in animal studies for many years could apply to the vast majority of patients undergoing surgery.

So far, they represent the only evidence-based medicine to support the statement of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on perioperative cardiovascular evaluation and care for non-cardiac surgery that, in 2007, already suggested the use of volatile anesthetics during non-cardiac surgery for the maintenance of general anesthesia in hemodynamically stable patients at risk of myocardial ischemia.

The reduced cardiac troponin release documented in this study should not be taken as a surrogate endpoint since this cardiac biomarker has proven to be strongly associated to clinically relevant outcomes: the higher the cardiac troponin release, the poorer the outcome (irrespective of the setting and of the cause of troponin release).

Were Bassuoni et al.[1] the first ones to conduct a randomized controlled trial to compare volatile agents versus total intravenous anesthesia in non-cardiac surgery? Of course not. Till 2007, there were at least 79 randomized controlled trials published in peer-reviewed journals, which included 6219 patients receiving total intravenous anesthesia or volatile agents (sevoflurane or desflurane). Unfortunately, none of these studies reported adverse cardiac events or cardiac biomarker release.[2] After 2007, there was only one randomized controlled study addressing the cardioprotective properties of volatile agents in non-cardiac anesthesia[3] and, probably due to the small sample size and to the low risk profile of the included patients, it found no beneficial cardioprotective effects of volatile agents.

Volatile agents might reduce perioperative mortality in low-risk patients undergoing coronary artery bypass grafting,[4] but their effect has not yet been confirmed in high-risk patients undergoing other cardiac surgery operations[5] or stenting procedures, and their effect should be further studied in large randomized controlled trials.

What will happen after the study of Bassuoni et al.[1] Should we start using volatile agents in all non-cardiac operations worldwide? Should we include them in guidelines and recommendations? With more than 200 million major non-cardiac surgery procedures performed yearly and approximately 4 million patients experiencing perioperative adverse cardiovascular events or mortality,[6] we are facing a major public health problem and still do not have a magic bullet to help us in reducing this burden. Volatile agents are cheap, not more expensive than total intravenous agents, out of patent, and easy to use. Even if the number needed to treat or prevent one major complication will be 10.000, we can still prevent thousands of adverse events each year.

The answer is no. What we should do is to go on and study them further.[7] Single-center trials have small sample size, limited external validity (e.g., maybe the authors have expertise with volatile agents and are still on the learning curve with the use of intravenous agents), tend to have implausible effect size, may have unequal allocation of resources (e.g., maybe the most skilled team took care of the volatile agents group), and suffer from lack of blinding, although inevitable, which could cause conscious or unconscious biases. Furthermore, clinically relevant outcomes (mortality) sometimes go in opposite directions of intermediate outcomes.[8]

Unfortunately, bureaucracy prevents us to conduct large randomized trials on simple topics like this one. To compare two standard anesthesia plans such as those proposed by Bassuoni et al.,[1] we only would need a web-based randomization and a network of colleagues willing to perform a phone call (alive or dead) to their patients 30 days after the surgical operations. One hundred and thousand patients could be randomized in a few months worldwide, and the entire scientific community and millions of patients would benefit from the results of the study for years. But we are living in a world of bureaucracy and the international policy makers are not even aware that this bureaucracy is indirectly killing thousands of patients per year.

We should therefore go back to the study of Bassuoni et al.,[1] thank them for this original and important finding, and wait for some donor to spend millions of dollars to support a large randomized trial to pay the bureaucracy and to confirm or not the extremely promising findings of this pilot study.