Perioperative Glucocorticoid Therapy in Adrenal Insufficiency

What Is the Correct Dose?

Roberto Salvatori


J Clin Endocrinol Metab. 2020;105(5) 

Few endocrinology topics are more controversial and approached more empirically than 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 time frame of GC administration in the perioperative period. Additionally, despite obvious differences between primary and secondary AI (in which an intact renin-angiotensin-aldosterone system is likely to make the disease less dangerous), often the 2 diseases are approached with the same protocols. The Endocrine Society guidelines on treatment of primary AI acknowledged the lack of controlled studies, and noted that adults produce 75 to 100 mg/day of cortisol in response to major surgery and 50 mg/day in response to minor surgery, and that cortisol secretion in the first 24 hours after surgery rarely exceeded 200 mg.[2] They note that although lower doses of hydrocortisone (HC) (25–75 mg/24 h) for surgical stress have been advocated in secondary AI, this has not been studied in patients with primary AI. The Society Hypopituitarism Guidelines recommend 25 to 75 mg HC per 24 hours for minor or moderate surgeries, and 100 mg followed by an infusion of 200 mg/24 hours (or 50 mg every 6 hours) for major surgeries, without specifying the exact definition of "major".[3]

The literature on "stress dosing" is made more confusing by the issues of GC administration in 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 noncomplicated surgical procedures. Additionally, GC administration in intensive care unit settings may have pharmacological effects on acute inflammatory status that is not relevant in uncomplicated surgeries.[5] Although in the absence of rigorous studies one may advocate the approach "in doubt, give more," even 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 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 cortisol secretion, and then were administered 2 doses of intravenous HC 6 hours apart. The HC serum half-life was confirmed to be rather short (1.8–2 hours depending on the dose), but longer (2.1–2.4 hours) after the second dose (showing some "stacking effect"). Additionally, it was dose dependent (longer with higher dose). It is important to point out that the biological 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 and 55 with secondary AI due to organic hypothalamic or pituitary disease) were studied before and during a variety of elective surgical procedures that required general anesthesia (with 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 before arriving at their preoperative area (and their usual fludrocortisone dose in primary AI), which caused them to all have a serum cortisol greater than 12 μg/dL (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 greater than 16 μg/dL (441 nmol/L) and increased with subsequent injections, showing that AI patients also have a stacking effect due to decreased clearance and increased volume distribution. Interestingly, in AI patients HC serum half-life was longer and clearance was lower than normal individuals, 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, owing to stacking effects, HC administration could be reduced to every 8 hours after the first 24 postoperative hours.

This study is a welcome addition to the literature, but it has several limitations. The most important is the low number of participants with primary AI. Primary AI patients not only lack aldosterone, but their degree of cortisol deficiency is often more marked than in patients with 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 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 longer than 1 hour, but GC requirements may depend on the kind of procedure, its duration, and severity. Indeed, older literature generated in rheumatoid arthritis patients on chronic GC therapy (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 general anesthesia), going from 0 for "minor surgery" to 14% for "medium" and 33% for "major" surgeries.[8] Thirdly, the lack of patients with steroid-induced AI (by far the most common cause of hypothalamic-pituitary-adrenal 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 many textbooks, and provides important information about GC stacking. However, I do not 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 patients both with primary and secondary AI undergoing a broad variety of surgical procedures are still needed.