Perioperative Hydrocortisone Dosing in Adrenal Insufficiency

Lower doses of hydrocortisone may be safe and sufficient for patients with adrenal insufficiency who are undergoing major surgical procedures, according to a new study published in the Journal of Clinical Endocrinology & Metabolism.¹ These findings call into question the current practice of administering excessive hydrocortisone supplementation during a stressful event in this patient population.¹

Consultant360 spoke with study author Baha M. Arafah, MD, about the implications of these findings for clinical practice and future guidelines. Dr Arafah is the chief of the Division of Clinical and Molecular Endocrinology at University Hospitals Cleveland Medical Center in Ohio.

Consultant360: In your study, you wrote that recommendations for perioperative glucocorticoid therapy for patients with adrenal insufficiency were issued without supporting pharmacokinetic data. Why is this the case? Has this been a difficult area to study?

Baha M. Arafah, MD: This area has actually been quite difficult to study for a variety of reasons. One reason is that endocrinologists are often concerned about administering doses of hydrocortisone that are lower than what has been recommended over the past 50 years. However, in examining these recommendations closely, my colleagues and I realized that the recommendations have been solely based on anecdotal experiences detailed in 2 case reports from 1952 and 1953.^2,3 Another reason that this area is difficult to study is that it takes a long time to collect data on a large number of unique patients with adrenal insufficiency. My colleagues and I have studied a large number of patients very carefully, and we have been able to collect very detailed information about their condition over the years.

Furthermore, in the past, many physicians have assumed that administering generous amounts of hydrocortisone is not problematic, as it was assumed to be harmless. However, as we have recorded more and more data on this over time, our findings have indicated that administering hydrocortisone generously is not ideal, especially because it has potential adverse effects. Until now, there have not been any data to shed light on the right amount of hydrocortisone to administer in this setting, which is why we decided to approach this topic.

CON360: How was your study designed, and how did you determine that administering excessive glucocorticoid supplementation could be problematic?

Dr Arafah: We first sought to determine the amount of cortisol that would be achieved in a healthy person without adrenal insufficiency who was undergoing a surgical procedure. Subsequently, we aimed to match or come close to matching individuals who have adrenal insufficiency to this type of data in order to determine the amount of hydrocortisone that they would need to cover their adrenal function during a surgical procedure. We also examined the impact of repeated injections of hydrocortisone on the levels achieved in the blood in healthy individuals and combined the 2 sets of data to design the current protocol.

In the present study, we expanded on the findings in healthy individuals by examining the impact of administering multiple doses of steroids or hydrocortisone to patients with adrenal insufficiency. In doing so, we found that these drugs have a “stacking effect,” meaning they accumulate in the body over time when given at regular intervals, especially with higher doses.

In our study, we provided our patients with more than adequate amounts of hydrocortisone, but at doses that were much lower than has ever been done in the past. Our findings showed that lower dosing still provided adequate coverage, as they were safe and effective. We now have objective data to show that physicians have been administering hydrocortisone among patients with adrenal insufficiency in doses that surpass what is achieved naturally among people with normal adrenal function.

CON360: What do current guidelines recommend when it comes to this practice, and might your findings inform a future update of these guidelines?

Dr Arafah: The Endocrine Society addressed this in its February 2016 clinical practice guideline for the diagnosis and treatment of primary adrenal insufficiency.⁴ Unfortunately, the current recommendations for hydrocortisone stress dosing are not based on objective data. As I mentioned earlier, the origins of current recommendations were from 2 case reports published during a time when we knew very little about hydrocortisone. My hope is that our present findings will inform future guidelines for hydrocortisone dosing among patients with adrenal insufficiency who are undergoing surgical procedures.

CON360: What is the next step in terms of future research in this field? Might your findings apply to any other stressful events among patients with adrenal insufficiency, such as critical illness?

Dr Arafah: I believe so, but we need more data to prove it, and this is currently being examined in another study. We do not know the answer yet, but I think it will be the same—we will not need to give people with adrenal insufficiency huge doses of hydrocortisone to cover their adrenal function. If the findings are similar, these patients can do as well, if not better, with lower doses.

Another important area of future research is to determine the minimum possible dose of hydrocortisone that is needed to cover adrenal function among patients with adrenal insufficiency. In the present study, we found that the wisest and safest thing to do at this point in time is to match dosing based on what is achieved in healthy individuals with normal adrenal function. I think we may be able to administer even lower doses than what we administered in the present study, but this has yet to be determined in another study.

Another interesting factor that I think is often not taken into account for patients with adrenal insufficiency who are critically ill or undergoing surgery is that many of these patients are taking other medications or have other illnesses that affect the way the body metabolizes cortisol. We need to address these confounding factors when we treat patients with hydrocortisone. For example, in a study that my colleagues and I are conducting right now, we are assessing patients with liver disease who cannot metabolize hydrocortisone the way healthy people without liver disease can. Therefore, if you give them a certain dose of hydrocortisone, it is likely to remain much longer in the body compared with healthy individuals. These patients should not receive the same doses of hydrocortisone as patients with normal liver function. These factors are becoming increasingly important to address whenever we use these drugs, and we aim to address them in future studies.

CON360: What key clinical takeaway do you hope to leave with endocrinologists on this topic?

Dr Arafah: The main takeaway is that it is not necessary to give patients with adrenal insufficiency large doses of hydrocortisone. Based on the protocol that we have established, endocrinologists should be able to provide equivalent or more-than-equivalent amounts of hydrocortisone that match the levels of cortisol achieved in people with normal adrenal function. Now that we have this data, we should be questioning current recommendations for hydrocortisone use among patients with adrenal insufficiency who are undergoing surgical procedures, because these recommendations are based on very limited data.

—Christina Vogt

References:

1. Arafah BM. Perioperative glucocorticoid therapy for patients with adrenal insufficiency: dosing based on pharmacokinetic data. J Clin Endocrinol Metab. 2020;105(3). https://doi.org/10.1210/clinem/dgaa042.
2. Fraser CG, Preuss FS, Bigford WD. Adrenal atrophy and irreversible shock associated with cortisone therapy. JAMA. 1952;149(17):1542-1543. doi:10.1001/jama.1952.72930340001009.
3. Lewis L, Robinson RF, Yee J, Hacker LA, Eisen G. Fatal adrenal cortical insufficiency precipitated by surgery during prolonged continuous cortisone treatment. Ann Intern Med. 1953;31(1):116-126. doi:10.7326/0003-4819-39-1-116.
4. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. https://doi.org/10.1210/jc.2015-1710.