We appreciate the interest of Lagier et al. in our article.1 The authors highlighted in their letter the work of Montaigne et al.,2 who have recently published on the circadian rhythm in relation to ischemia reperfusion injury in a single-center retrospective propensity-matched cohort study addressing this subject on 596 (matched-pairs) patients undergoing aortic valve replacement with or without coronary artery bypass grafting, together with a single-center randomized study in 88 patients undergoing isolated aortic valve replacement, in which the perioperative myocardial injury has been assessed with the geometric mean of perioperative cardiac troponin T release. Together with these reported studies these authors also reported in the same article on an ex vivo analysis of the human myocardium that showed an intrinsic morning afternoon variation concomitant with a circadian variation of Rev-Erbα. An accompanying comment noticed that gene-expression analysis, mainly performed in rodents, had shown in the early 2000s a rhythmic expression of clock genes in the heart3 ; whether or not clock genes modulate cell death directly and whether they affect ischemia reperfusion injury remained to be established, even after the publication of Montaigne.4
For answering the question of Lagier et al. we had to reexamine our dataset, as this question had not been addressed in our study protocol. To begin, it was expected that the chosen randomization strategy should have done its work and that distribution of morning versus afternoon operation timing over the 3 treatment groups should be about equal. Indeed, analyzing the time of randomization in the intention-to-treat population, randomization being done just after induction of anesthesia as we have described, we found that the distribution of the “morning” patients was as follows: xenon group, n = 106 (66%); sevoflurane group, n = 109 (66%); total intravenous anesthesia group, n = 107 (65%). For the “afternoon” patients this was as follows: xenon group, n = 55 (34%); sevoflurane group, n = 56 (34%); total intravenous anesthesia group, n = 59 (35%). Thus, the found noninferiority for xenon to sevoflurane and the found superiority of xenon over total intravenous anesthesia on cardiac troponin I release in low-risk, on-pump coronary artery bypass graft surgery patients are not confounded by an imbalance in randomization allocation in the daytime.
Furthermore, to investigate whether for on-pump, low-risk isolated coronary artery bypass graft (CABG) surgery, a circadian rhythm in the patients undergoing this operation might exist, we again reexamined our intention-to-treat dataset. It must be noted first of all, that our study was not designed for answering this question, which makes statistical analysis improper. Thus, only descriptive data are provided. The mean overall 24-h cardiac troponin I release, ng/ml (95% CI), was for morning (n = 322) versus afternoon (n = 169) patients: 3.05 (2.26 to 3.85) versus 2.33 (1.85 to 2.80), medians being 1.38 versus 1.15 ng/ml, suggesting that some circadian variation indeed might exist in patients undergoing isolated CABG surgery as well.
The mean xenon group 24-h cardiac troponin I release, ng/ml (95% CI), for morning (n = 106) versus afternoon (n = 55) patients was 2.36 (1.68 to 3.05) versus 2.32 (1.34 to 3.31), medians being 1.23 versus 1.11 ng/ml. The mean sevoflurane group 24-h cardiac troponin I release for morning (n = 109) versus afternoon (n = 55) patients was 2.91 (1.96 to 3.86) versus 2.15 (1.47 vs. 2.82), medians being 1.42 versus 1.11 ng/ml. The mean total intravenous anesthesia group 24-h cardiac troponin I release for morning (n = 107) versus afternoon (n = 59) patients was 3.89 (1.78 to 6.00) versus 2.49 (1.66 to 3.33), medians being 1.49 versus 1.42 ng/ml. Thus, in all groups we also found a higher 24-h post-CABG-surgery cardiac troponin I release value (both mean and median) in the morning patients.
We agree with Lagier et al. that for reporting on outcome of future cardiac surgery clinical trials, adding information about the time of day the surgery is performed seems to be of value.
Competing Interests
The following authors received grants, personal fees, or nonfinancial support from Air Liquide Santé International (Jouy-en-Josas, Paris, France) to conduct the Xenon-CABG study: Drs. Hofland, Ouattara, and Bein. The following authors received grants, personal fees (e.g., lecture fees), or nonfinancial support from Air Liquide Santé International for activities other than the work for the Xenon-CABG study: Drs. Hofland and Outtara. Dr. Bein reports personal fees from Abbvie (Wiesbaden, Germany), CSL Behring (Marburg, Germany), GE Healthcare (München, Germany), Pulsion Medical Systems (Feldkirchen, Germany), MSD (Graz, Austria), CNSystems (Graz, Austria), Edwards Life Sciences (Untersleißheim, Germany), 3M (Neuss, Germany), Orion Pharma (Hamburg, Germany), The Medicines Company (München, Germany), TEVA Ratiopharm (Ulm, Germany), and MASIMO (Puchheim, Germany) for activities outside the work for the Xenon-CABG study. Ms. Schaller was an employee of Air Liquide Santé International during the study.
References
Appendix: Xenon-CABG Study Group
Jan Hofland, M.D., Inge de Liefde, M.D. (Sector Cardiothoracic Anesthesiology, Thorax Center, Rotterdam, The Netherlands); Alexandre Ouattara, M.D. (Service d’Anesthésie-Réanimation II, Center Hospitalier Universitaire de Bordeaux, Bordeaux, France); Jean-Luc Fellahi, M.D. (Louis Pradel University Hospital, Lyon, France and Department of Anesthesiology and Intensive Care Medicine and Inserm U1060, Faculty of Medicine, Claude Bernard Lyon 1 University, Lyon, France); Berthold Bein, M.D., Matthias Gruenewald, M.D. (Klinik für Anästhesiologie und Operative Intensivmedizin, UniversitätsKlinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany); Jean Hazebroucq, M.D. (Air Liquide Santé International, Jouy-en-Josas, France); Claude Ecoffey, M.D. (Department of Anesthesia, Hôpital Pontchaillou, Center Hospitalier Universitaire de Rennes, Rennes, France); Pierre Joseph, M.D. (Department of Anesthesia and Intensive Care, Hôpital Cardiovasculaire et Pneumologique Louis Pradel, Bron, France); Matthias Heringlake, M.D. (Department of Anesthesiology and Intensive Care Medicine, University of Lübeck, Lübeck, Germany); Annick Steib, M.D. (Service d’Anesthésie Réanimation Chirurgicale, Hôpitaux Universitaire de Strasbourg, Strasbourg, France); Mark Coburn, M.D. (Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany); Julien Amour, M.D. (Department of Anesthesia and Intensive Care, Institut de Cardiologie - Chirurgie Cardiaque, Hôpital Pitié Salpetrière, Paris, France); Bertrand Rozec, M.D. (Service d’Anesthésie et Réanimation Chirurgicale, Hôpital G&R Laënnec, Center Hospitalier Universitaire de Nantes, Nantes, France); Patrick Meybohm, M.D. (Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany); Benedikt Preckel, Ph.D. (Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands); Jean-Luc Hanouz, M.D. (Service d’Anesthésie et Réanimation Chirurgicale, Center Hospitalier Universitaire de Caen, Caen, France); Luigi Tritapepe, M.D. (Department of Anesthesia and Intensive Care, Policlinico “Umberto I,” “La Sapienza,” University of Rome, Rome, Italy); Peter Tonner, M.D. (Department of Anesthesiology and Intensive Care, Klinikum Links der Weser gGmbH, Bremen, Germany); Hamina Benhaoua, M.D. (Chirurgie Cardiovasculaire - Service de Réanimation, Center Hospitalier Regional Universitaire, Hospitalier de Rangueil, Toulouse, France); Jan Patrick Roesner, M.D. (Clinic for Anesthesia and Critical Care Medicine, University Hospital of Rostock, Rostock, Germany), Rob Tenbrinck, M.D., Ad JJC Bogers, M.D., Bert G Mik, M.D. (Departments of Anesthesiology and Cardiothoracic Surgery, Thorax Center, Rotterdam, The Netherlands); Alain Coiffic, M.D. (Service d’Anesthésie-Réanimation II, Center Hospitalier Universitaire de Bordeaux, Bordeaux, France); Jochen Renner, M.D., Markus Steinfath, M.D., Helga Francksen, M.D., Ole Broch, M.D., Assad Haneya, M.D. (Klinik für Anästhesiologie und Operative Intensivmedizin, UniversitätsKlinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany); Manuella Schaller, M.Sc. (Air Liquide Santé International, Jouy-en-Josas, France); Patrick Guinet, M.D., Lauren Daviet, M.D., Corinne Brianchon, M.D., Sebastien Rosier, M.D. (Department of Anesthesia, Hôpital Pontchaillou, Rennes, France); Jean-Jacques Lehot, M.D. (Department of Anesthesia and Intensive Care, Hôpital Cardiovasculaire et Pneumologique Louis Pradel, Bron, France); Hauke Paarmann, M.D., Julika Schön, M.D., Thorsten Hanke, M.D., Joachym Ettel, M.D., Silke Olsson (Department of Anesthesiology and Intensive Care Medicine, University of Lübeck, Lübeck, Germany); Stefan Klotz, M.D. (Department of Cardiac and Thoracic Vascular Surgery, University of Lübeck, Lübeck, Germany); Amir Samet, M.D., Giedrius Laurinenas, M.D., Adrien Thibaud, M.D., Mircea Cristinar, M.D., Olivier Collanges, M.D., François Levy, M.D. (Service d’Anesthésie Réanimation Chirurgicale, Hôpitaux Universitaire de Strasbourg, Strasbourg, France); Rolf Rossaint, M.D., Ana Stevanovic, M.D., Gereon Schaelte, M.D., and Christian Stoppe, M.D. (Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany); Nora Ait Hamou, M.D., Sarah Hariri, M.D., Astrid Quessard, M.D., Aude Carillion, M.D. (Department of Anesthesia and Intensive Care, Institut de Cardiologie - Chirurgie Cardiaque, Hôpital Pitié Salpetrière, Paris, France); Hélène Morin, M.D., Jacqueline Silleran, M.D., David Robert, M.D., and Anne-Sophie Crouzet, B.S.N. (Service d’Anesthésie et Réanimation Chirurgicale, Hôpital G&R Laënnec, Center Hospitalier Universitaire de Nantes, Nantes, France); Kai Zacharowski, M.D., Christian Reyher, M.D., Sonja Iken, M.D. (Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany); Nina C. Weber, Ph.D., Marcus Hollmann, Ph.D., Susanne Eberl, M.D. (Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands); Giovanni Carriero, M.D., Daria Collacchi, M.D., Alessandra Di Persio M.D. (Department of Anesthesia and Intensive Care, Policlinico “Umberto I,” “La Sapienza,” University of Rome, Rome, Italy); Olivier Fourcade, M.D. (Chirurgie Cardiovasculaire - Service de Réanimation, Center Hospitalier Regional Universitaire, Hospitalier de Rangueil, Toulouse, France); Stefan Bergt, M.D., Angela Alms, M.D. (Clinic for Anesthesia and Critical Care Medicine, University Hospital of Rostock, Rostock, Germany).
