Response to Letter to the Editor from Chee et al: “Prevention of Adrenal Crisis: Cortisol Response to Major Stress Compared to Stress Dose Hydrocortisone Delivery”

Response to Letter to the Editor from Chee et al: “Prevention of Adrenal Crisis: Cortisol Response to Major Stress Compared to Stress Dose Hydrocortisone Delivery” Alessandro Prete, Angela E. Taylor, Irina Bancos, David J. Smith, Mark A. Foster,Sibylle Kohler, Violet Fazal-Sanderson, John Komninos, Donna M. O’Neil, Dimitra A. Vassiliadi, Christopher J. Mowatt, Radu Mihai, Joanne L. Fallowfield, Djillali Annane, Janet M. Lord, Brian G. Keevil, John A. H. Wass, Niki Karavitaki, and Wiebke Arlt Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2GW, UK; Division of Endocrinology, Metabolism and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA; School of Mathematics, University of Birmingham, Birmingham, B15 2TT, UK; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2WB, UK; NIHR Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital, Birmingham, B15 2GW, UK; Royal Centre for Defence Medicine, Queen Elizabeth Hospital, Birmingham, B15 2GW, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, OX3 7LE, UK; Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece; Department of Anaesthesiology, Royal Shrewsbury Hospital, The Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK; Department of Endocrine Surgery, Churchill Hospital, Oxford, UK; Institute of Naval Medicine, Alverstoke, PO12 2DL, UK; Critical Care Department, Hôpital Raymond-Poincaré, Laboratory of Infection & Inflammation U1173 INSERM/University Paris Saclay-UVSQ, Garches, 92380, France; NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK; and Department of Clinical Biochemistry, University Hospital of South Manchester, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

Chee et al (1) enquired about whether we had gathered clinical data on blood pressure or intraoperative hemodynamic instability in the patients undergoing elective surgery. However, our study (2) looked at cortisol responses to major stress in patients with otherwise normal adrenal function, including healthy patients undergoing elective surgery as well as unstressed controls, soldiers exposed to deployment stress, and patients with severe sepsis. Those were compared to serum cortisol concentrations observed after 4 different modes of hydrocortisone administration in patients with primary adrenal insufficiency.
A clinical study in patients with primary adrenal insufficiency aiming to compare the effects of continuous vs intermittent hydrocortisone delivery on hemodynamic This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. parameters during elective surgery would be very challenging to execute and, in our opinion, only of theoretical benefit. There is no robust clinical evidence that shortterm administration of stress dose hydrocortisone for prevention of adrenal crisis has significant adverse effects, while the potentially fatal consequences of glucocorticoid underreplacement in a stressed patient with adrenal insufficiency, in particular when paired with inflammation, are obvious. We think safety should prevail as first and foremost principle when looking after a patient with adrenal insufficiency who is exposed to major stress and we agree with Chee et al (1) that our pharmacokinetic data indicate that continuous hydrocortisone infusion is best suited to achieve prevention of adrenal crisis in this situation.
Chee et al. rightly enquired whether etomidate, an anesthetic agent that inhibits the crucial cortisol biosynthesis enzyme CYP11B1 (3), formed part of the anesthetic regimens that the patients with normal adrenal function received during elective surgery. We apologize that this information was hidden away in the supplementary information (Suppl. Table 1, (4) and can confirm that, indeed, none of the patients received etomidate. Furthermore, acute or chronic intake of any drug known to impact on cortisol biosynthesis or metabolism during the last 6 months preceding the study procedures were exclusion criteria for study participation.

Acknowledgments
Financial Support: This work was supported by the Medical Research Council UK (program grant G0900567, to W.A.) and the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (grant reference number BRC-1215-2009, to W.A. and J.M.L.). A.P. is a Diabetes UK Sir George Alberti Research Training Fellow (grant reference number 18/0005782). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care UK. The funders of the study had no role in the: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication.

Additional Information
Correspondence and Reprint Requests: Wiebke Arlt, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK. E-mail: w.arlt@bham.ac.uk.
Disclosure Summary: All authors declare: no support from any organization for the submitted work other than that described above; no financial relationships with any organizations that might have an interest in the submitted work; no other relationships or activities that could appear to have influenced the submitted work.