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, et al.

► To cite this version:

Alessandro Prete, Angela E Taylor, Irina Bancos, David J Smith, Mark A Foster, et al. 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”. Journal of Clinical Endocrinology and Metabolism, 2021, 106 (1), pp.e407-e408. 10.1210/clinem/dgaa719. hal-04538948

HAL Id: hal-04538948

https://hal.science/hal-04538948

Submitted on 9 Apr 2024

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# 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, et al.

► To cite this version:

Alessandro Prete, Angela E Taylor, Irina Bancos, David J Smith, Mark A Foster, et al. 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". Journal of Clinical Endocrinology and Metabolism, 2021, 106 (1), pp.e407-e408. 10.1210/clinem/dgaa719. hal-04538948

HAL Id: hal-04538948

https://hal.science/hal-04538948v1

Submitted on 9 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Letter to the Editor Response

# 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,¹,² Angela E. Taylor,¹,² Irina Bancos,¹,³ David J. Smith,¹,⁴ Mark A. Foster,⁵,⁶,⁷ Sibylle Kohler,⁸ Violet Fazal-Sanderson,⁸ John Komninos,⁸ Donna M. O'Neil,¹ Dimitra A. Vassiliadi,⁹ Christopher J. Mowatt,¹⁰ Radu Mihai,¹¹ Joanne L. Fallowfield,¹² Djillali Annane,¹³ Janet M. Lord,⁵,⁶,¹⁴ Brian G. Keevil,¹⁵ John A. H. Wass,⁸ Niki Karavitaki,¹,² and Wiebke Arlt¹,²,¹⁴

¹Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK; ²Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2GW, UK; ³Division of Endocrinology, Metabolism and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA; ⁴School of Mathematics, University of Birmingham, Birmingham, B15 2TT, UK; ⁵Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2WB, UK; ⁶NIHR Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital, Birmingham, B15 2GW, UK; ⁷Royal Centre for Defence Medicine, Queen Elizabeth Hospital, Birmingham, B15 2GW, UK; ⁸Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, OX3 7LE, UK; ⁹Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece; ¹⁰Department of Anaesthesiology, Royal Shrewsbury Hospital, The Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK; ¹¹Department of Endocrine Surgery, Churchill Hospital, Oxford, UK; ¹²Institute of Naval Medicine, Alverstoke, PO12 2DL, UK; ¹³Critical Care Department, Hôpital Raymond-Poincaré, Laboratory of Infection & Inflammation U1173 INSERM/University Paris Saclay-UVSQ, Garches, 92380, France; ¹⁴NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK; and ¹⁵Department of Clinical Biochemistry, University Hospital of South Manchester, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

**ORCiD numbers:** 0000-0002-4821-0336 (A. Prete); 0000-0002-5835-5643 (A. E. Taylor); 0000-0001-9332-2524 (I. Bancos); 0000-0001-6153-1970 (R. Mihai); 0000-0001-6805-8944 (D. Annane); 0000-0003-1030-6786 (J. M. Lord); 0000-0002-4696-0643 (N. Karavitaki); 0000-0001-5106-9719 (W. Arlt).

Received: 27 August 2020; Editorial Decision: 1 October 2020; First Published Online: 7 October 2020; Corrected and Typeset: 9 November 2020.

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
Letter to the Editor Response

# 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,¹,² Angela E. Taylor,¹,² Irina Bancos,¹,³ David J. Smith,¹,⁴ Mark A. Foster,⁵,⁶,⁷ Sibylle Kohler,⁸ Violet Fazal-Sanderson,⁸ John Komninos,⁸ Donna M. O'Neil,¹ Dimitra A. Vassiliadi,⁹ Christopher J. Mowatt,¹⁰ Radu Mihai,¹¹ Joanne L. Fallowfield,¹² Djillali Annane,¹³ Janet M. Lord,⁵,⁶,¹⁴ Brian G. Keevil,¹⁵ John A. H. Wass,⁸ Niki Karavitaki,¹,² and Wiebke Arlt¹,²,¹⁴

¹Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK; ²Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2GW, UK; ³Division of Endocrinology, Metabolism and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA; ⁴School of Mathematics, University of Birmingham, Birmingham, B15 2TT, UK; ⁵Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2WB, UK; ⁶NIHR Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital, Birmingham, B15 2GW, UK; ⁷Royal Centre for Defence Medicine, Queen Elizabeth Hospital, Birmingham, B15 2GW, UK; ⁸Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, OX3 7LE, UK; ⁹Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece; ¹⁰Department of Anaesthesiology, Royal Shrewsbury Hospital, The Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK; ¹¹Department of Endocrine Surgery, Churchill Hospital, Oxford, UK; ¹²Institute of Naval Medicine, Alverstoke, PO12 2DL, UK; ¹³Critical Care Department, Hôpital Raymond-Poincaré, Laboratory of Infection & Inflammation U1173 INSERM/University Paris Saclay-UVSQ, Garches, 92380, France; ¹⁴NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK; and ¹⁵Department of Clinical Biochemistry, University Hospital of South Manchester, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

**ORCiD numbers:** 0000-0002-4821-0336 (A. Prete); 0000-0002-5835-5643 (A. E. Taylor); 0000-0001-9332-2524 (I. Bancos); 0000-0001-6153-1970 (R. Mihai); 0000-0001-6805-8944 (D. Annane); 0000-0003-1030-6786 (J. M. Lord); 0000-0002-4696-0643 (N. Karavitaki); 0000-0001-5106-9719 (W. Arlt).

Received: 27 August 2020; Editorial Decision: 1 October 2020; First Published Online: 7 October 2020; Corrected and Typeset: 9 November 2020.

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
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 short-term 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.

## References

1. Chee YJ, Dinesh M, Lim SC. Letter to the Editor from Chee et al: "Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery." *J Clin Endocrinol Metabol.* 2020;dgaa717.

2. Prete A, Taylor AE, Bancos I, et al. Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery. *J Clin Endocrinol Metab.* 2020;105(7):2262-2274.

3. Fellows IW, Byrne AJ, Allison SP. Adrenocortical suppression with etomidate. *Lancet*. 1983;2(8340):54-55.

4. Prete A, Taylor AE, Bancos I, et al. Data from: prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery in adrenal insufficiency. *medRxiv*. Deposited February 8, 2020. https://doi.org/10.1101/2020.02.08.20021246.
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 short-term 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.

## References

1. Chee YJ, Dinesh M, Lim SC. Letter to the Editor from Chee et al: "Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery." *J Clin Endocrinol Metabol.* 2020;dgaa717.

2. Prete A, Taylor AE, Bancos I, et al. Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery. *J Clin Endocrinol Metab.* 2020;105(7):2262-2274.

3. Fellows IW, Byrne AJ, Allison SP. Adrenocortical suppression with etomidate. *Lancet.* 1983;2(8340):54-55.

4. Prete A, Taylor AE, Bancos I, et al. Data from: prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery in adrenal insufficiency. *medRxiv*. Deposited February 8, 2020. https://doi.org/10.1101/2020.02.08.20021246.