Perioperative glucocorticoid therapy in adrenal insufficiency: what is the

correct dose?

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Roberto Salvatori, MD
Johns Hopkins University
Division of Endocrinology, Diabetes and Metabolism
1830 East Monument Street #333

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Baltimore, MD 21287

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Tel (410) 955-3921
Fax (410) 367-2042
Email: salvator@jhmi.edu

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Disclosure Statement: The author has nothing to disclose

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 Few endocrinology topics are more controversial and approached more empirically than

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the perioperative glucocorticoid (GC) treatment of patients with adrenal insufficiency (AI). Since

very early reports of adrenal crisis precipitated by surgery in patients with AI (1), treatment with

“stress dose steroids” has been used routinely for surgical procedures in AI patients, despite the

paucity of rigorous studies that would address the proper dosing and timeframe of GC

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administration in the perioperative period. Additionally, despite obvious differences between

primary and secondary AI (where an intact renin-angiotensin-aldosterone system is likely to

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make the disease less dangerous), often the two diseases are approached with the same protocols.

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The Endocrine Society guidelines on treatment of primary AI acknowledged the lack of

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controlled studies, and noted that adults produce 75–100 mg/day of cortisol in response to major

surgery and 50 mg/d in response to minor surgery, and that cortisol secretion in the first 24 hours
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after surgery rarely exceeded 200 mg (2). They note that while lower doses of hydrocortisone

(HC) (25–75 mg/24 h) for surgical stress have been advocated in secondary AI, this has not been
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studied in patients with primary AI. The Society Hypopituitarism Guidelines recommend 25–75
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mg HC per 24 hours for minor or moderate surgeries, and 100 mg followed by an infusion of 200
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mg/24 hours (or 50 mg every 6 hours) for major surgeries, without specifying the exact

definition of “major” (3).

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The literature on “stress dosing” is made more confusing by the issues of GC

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administration in the severely ill patients with sepsis (not necessarily affected by AI), in whom

sickness, in addition to activating the hypothalamic-pituitary-adrenal axis, causes significant

alterations in GCs’ metabolism (4), an issue that is likely to be less relevant in non-complicated

surgical procedures. Additionally, GC administration in ICU settings may have pharmacological

effects on acute inflammatory status that is not relevant in uncomplicated surgeries (5). While in

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the absence of rigorous studies one may advocate the approach “in doubt, give more”, even

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short-term GC overdosing may have potential deleterious effects in the perioperative period on

cardiac and kidney function, glucose control, neurological status, and immune response (6).

Therefore, guiding data on the appropriate dosing would be very valuable.

In this issue of the journal, Arafah reports the results of a study aimed at determining the

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cortisol dynamics in healthy individuals and in AI patients during surgical procedures (7). In the

first part of the study, 22 healthy volunteers received dexamethasone to suppress the endogenous

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cortisol secretion, and then were administered two doses of intravenous HC 6 hours apart. The

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HC serum half-life was confirmed to be rather short (1.8-2 hours depending from the dose), but

longer (2.1-2.4 hours) after the second dose (showing some “stacking effect”). Additionally, it
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was dose-dependent (longer with higher dose). It is important to point out that the biological
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half-life of HC is much longer that the serum half-life, about 8 hours. In the second part of the

study (whose design was guided by the results of the first part) 68 AI patients (13 with primary
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and 55 with secondary AI due to organic hypothalamic or pituitary disease) were studied before
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and during a variety of elective surgical procedures that required general anesthesia (with
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exclusion of cardiac bypass surgery), all lasting longer than 1 hour. They all were asked to take

20 mg of oral HC about 2 hours prior arriving to preoperative area (and their usual
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fludrocortisone dose in primary AI), which caused them to all have a serum cortisol >12 µg/dL
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(331 nmol/L) at time of arrival. Then, just before intubation they received 25 mg of intravenous

HC repeated every 6 hours for 24 hours, followed by 15 mg every 6 hours for additional 24

hours. No patient manifested signs or symptoms suggestive of acute AI. Nadir serum cortisol

levels after the first injection were consistently above 16 µg/dL (441 nmol/L), and increased with

subsequent injections, showing that AI patients also have a stacking effect due to decreased

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clearance and increased volume distribution. Interestingly, in AI patients HC serum half-life was

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longer and clearance was lower than normal subjects, suggesting that the stress of uncomplicated

surgery may also alter cortisol dynamics. The author concluded that the described regimen is

enough to prevent adrenal crisis in AI patients undergoing surgery under general anesthesia, and

suggests that, due to stacking effects, HC administration could be reduced to every 8 hours after

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the first 24 postoperative hours.

This study is a welcome addition to the literature, but it has several limitations. The most

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important is the low number of subjects with primary AI. Primary AI patients not only lack

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aldosterone, but their degree of cortisol deficiency is often more marked than in patients with

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secondary AI, who are often able to function with minimal GC replacement. Hence, caution

should be used in applying this protocol in patients with primary AI. The second limitation lies
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in the limited information provided about the exact kinds and lengths of surgical procedures

these patients underwent, and the lack of any cardiac surgery procedure. All procedures were
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longer than 1 h, but GC requirements may depend on the kind of procedure, its duration, and
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severity. Indeed, older literature generated in rheumatoid arthritis patients on chronic GC therapy
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(and therefore with presumed central AI) suggested that the need for supplemental GC

replacement increased with the severity of the orthopedic surgery these patient underwent (under
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general anesthesia), going from 0 for “minor surgery” to 14% for “medium” and 33% for
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“major” surgeries (8). Thirdly, the lack of patients with steroid-induced AI (by far the most

common cause of HPA axis suppression) limits the applicability of this study to a broader

number of patients.

In summary, Arafah’s study advances our knowledge on cortisol dynamics and shows

that patients with AI may require less GC during perioperative period than recommended by

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many textbooks, and provides important information about GC stacking. However, I do not

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believe it is enough to guide our practice, and to make a difference in design of surgical

protocols in AI patients. This is particularly important in view of the fact that the previously

mentioned concerns about side effects of GC overdosing in the perioperative periods were not

confirmed by a recent meta-analysis (9). Well-controlled studies including large numbers of

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patients with both primary and secondary AI undergoing a broad variety of surgical procedures

are still needed.

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 References

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1) Laippy TC. Addison’s disease due to cytotoxic contraction of adrenal cortex with sudden

death 4 days after appendicitis. Ohio State MJ 1943; 39: 652-3

2) Bornstein SR, chair, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD,

Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ. Diagnosis and Treatment

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of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline J

Clin Endocrinol Metab. 2016; 101 (2): 364–389.

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3) Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH.

us
Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical

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Practice Guideline. J Clin Endocrinol Metab. 2016; 101 (11):3888-3921

4) Boonen E1, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE,

M
Vanwijngaerden YM, Spriet I, Wouters PJ, Vander Perre S, Langouche L, Vanhorebeek

I, Walker BR, Van den Berghe G. Reduced cortisol metabolism during critical illness. N
d

Engl J Med. 2013; 368 (16):1477-88.

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5) Annane D1, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for
ep

treating sepsis. Cochrane Database Syst Rev. 2015; (12): CD002243.

6) Manou-Stathopoulou V, Korbonits M, Ackland GL. Redefining the perioperative stress

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response: a narrative review. Br J Anaesth. 2019; 123 (5): 570-583.

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7) Arafah BB Peri-operative glucocorticoid therapy for patients with adrenal insufficiency:

dosing based on pharmacokinetics data. J Clin Endocrinol Metab, 2020. Jan 30. pii:

dgaa042. doi: 10.1210/clinem/dgaa042. [Epub ahead of print].

8) Lloyd EL. A rational regimen for perioperative steroid supplements and a clinical

assessment of the requirement. Ann R Coll Surg Engl. 1981; 63 (1): 54-57.

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9) Toner AJ, Ganeshanathan V, Chan MT, Ho KM, Corcoran TB. Safety of Perioperative

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa102/5770811 by Karolinska Institutet Library user on 29 February 2020

Glucocorticoids in Elective Noncardiac Surgery: A Systematic Review and Meta-

analysis. Anesthesiology. 2017; 126 (2): 234-248.

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