The role of propofol for remote ischaemic preconditioning in the setting of cardiac surgery – a Cochrane systematic review^†

Editor—The concept of remote ischaemic preconditioning (RIPC) is an easy, readily available and inexpensive strategy to increase resistance to myocardial ischaemia/reperfusion injury. Within the past decade, RIPC has been translated from experimental studies with promising results to proof-of-principle randomized controlled trials (RCTs) in the setting of cardiac surgery. Despite some beneficial effects in terms of reduced myocardial injury as expressed by blood markers,¹ most RCTs failed to show a benefit of RIPC on short or long-term clinical outcome in patients undergoing cardiac surgery.^2,3 In this context, use of the i.v. anaesthetic propofol has been repeatedly discussed as potential confounding factor that significantly interferes and inhibits RIPC’s cardioprotective effects.^4,5 We recently performed a Cochrane Systematic Review¹ to evaluate the benefits and harms of RIPC in patients undergoing coronary artery bypass grafting, with or without valve surgery. However, the potential influence of volatile anaesthetics compared with propofol anaesthesia was only part of a subgroup analysis and has not been fully evaluated yet. There is still a need to either confirm or exclude propofol as a confounding factor.

A total of seven studies^2,3,6–10 contributed data to the subgroup analysis using either volatile anaesthetics or propofol. Included trials span more than ten years of progress in cardiac surgical techniques. One study³ used a mixed approach for their anaesthetic management, but provided a separate analysis of propofol and volatile anaesthetics. Overall, the Cochrane Review analysed data on up to 210 participants in the volatile anaesthesia group and on 1640 participants in the propofol anaesthesia group. This already demonstrates a noteworthy imbalance in favour of propofol in previous studies. A composite endpoint (of all-cause mortality, nonfatal myocardial infarction and/or any new stroke assessed 30 days after surgery) and biomarkers for cardiac damage were assessed (Table 1). The Cochrane Review found, on average, no difference in treatment effect between subgroups when RIPC or no RIPC is applied before cardiac surgery. In detail, no treatment effect on the composite endpoint or on the amount of cardiac troponin T or I released after cardiac surgery (measured at 48 h, 72 h or as area under the curve (AUC) after 72 h) could be substantiated.

However, the present analysis shows that a final conclusion on the role of propofol in the context of RIPC cannot be made. Propofol can neither be confirmed nor ruled out as a confounding factor as a result of several limitations: 1) The analysis is based only on a limited number of studies that were not intended to address the research question of this meta-analysis, and the number of patients included in the volatile anaesthesia group is limited (more than seven times as many patients in the propofol group). 2) For the group of patients receiving volatile anaesthetics, there was a high variance in data availability regarding assessed outcome measures (e.g. for the seven outcomes assessed, only one to three studies provided data for each analysis) (Table 1). 3) The efficacy of cardioprotective strategies is confounded by a large variety of factors such as co-morbidities or co-medications. It is virtually impossible to control for these biasing factors.

The translation of RIPC into the clinical setting of cardiac surgery followed an impressive number of experimental studies demonstrating a significant cardioprotective effect after RIPC. While individual risk patterns might influence the potential benefit to be elicited by RIPC, all patients undergoing cardioplegic arrest for cardiac surgery suffer from ischaemia-reperfusion injury when the blood vessels are cross-clamped and reperfused. Restoration of blood flow after weaning from bypass triggers an inflammatory response with release of reactive oxygen and nitrogen species, which further contributes to the development of organ dysfunction during the postoperative course. The cardioprotective effects of RIPC are thought to be facilitated via complex neural (involving sensory afferent nerves and the vagus nerve) and humoural mechanisms.^11,12 Although the underlying mechanisms have been extensively investigated, the exact pathways of signalling involved in RIPC remain unclear. Suspected mediators are nitrites, microRNA, and other chemokines.¹³ As a detailed presentation of the underlying cellular and physiological mechanisms go beyond the scope of this letter, the authors refer to a detailed review on the topic.¹⁴ Within the myocardium, the effect is supposedly mediated via the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways. This preserves mitochondrial function and myocardial performance in ischaemia-reperfusion.¹⁵ To date, it remains unknown if propofol or volatile anaesthetics might influence these pathways differently, thereby limiting the effects of RIPC.¹² However, Heusch⁵ has summarized the possible underlying mechanisms regarding propofol concluding that propofol might impair the sensory fibre activation and also interfere with the γ-aminobutyric acid–mediated central nervous control of cardiac vagal nerves, both needed to provoke cardioprotection by RIPC.

Given the described failure of clinical translation, future trials will need to focus on the underlying reasons why studies failed to show a clinically significant effect of RIPC. One method could be to adopt a multi-organ approach to cardioprotection, as recently recommended by the European Society of Cardiology Working Group on Cellular Biology of the Heart.¹³ This is of particular relevance because postoperative dysfunction of other organs is well-known as a determinant of postoperative outcome. It will also be mandatory for future trials to consider the effects of anaesthetics as a confounding factor and avoid propofol as part of the anaesthetic management. There is a need for better, well-designed, adequately powered clinical trials that make cardioprotective effects in the setting of cardiac surgery evident –measured not only as surrogate endpoints but also as improved clinical outcome.

Declaration of interests

C.B. and A.G. have no conflicts of interest. C.S. is an investigator of the RIPHeart Study, which investigates the effects of remote ischaemic preconditioning in cardiac surgery patients. The RIPHeart trial contributed published and unpublished data to this review. We independently judged eligibility and risk of bias (performed by C.B. and A.G.).

References

Author notes