The management of the surgical patient taking glucocorticoids

INTRODUCTION — Chronic glucocorticoid therapy can suppress the hypothalamic-pituitary-adrenal (HPA) axis and, during times of stress such as surgery, the adrenal glands may not respond appropriately. Protocols for "stress dose" steroids followed reports in the 1950s of possible surgery-associated adrenal insufficiency due to sudden preoperative withdrawal of glucocorticoids. However, some studies have questioned the need for supplemental perioperative glucocorticoids beyond the maintenance dose.

The management of the surgical patient on chronic glucocorticoid therapy is reviewed here. Perioperative glucocorticoid regimens for patients taking replacement glucocorticoid for primary adrenal insufficiency are addressed separately. (See "Treatment of adrenal insufficiency in adults".)

PERIOPERATIVE GLUCOCORTICOIDS — The use of stress doses of glucocorticoids, such as 300 mg/day of hydrocortisone for several days [1-3], had become a common perioperative practice for patients on glucocorticoid therapy, based upon early case reports of intraoperative adrenal crisis after abrupt withdrawal of glucocorticoids [4,5].

However, a number of studies suggest that supplemental exogenous stress glucocorticoids may not be needed to meet the demands of perioperative stress [1,6-14]. However, all studies are limited by small numbers of patients [13].

Two reports suggest that stress doses may not be needed even in patients on glucocorticoids undergoing major colorectal surgery. In a 2012 retrospective cohort study of patients with inflammatory bowel disease undergoing such surgery, administration of low-dose perioperative steroids (the equivalent of their preoperative dose given intravenously), no patients required vasopressors for hemodynamic instability or additional steroids for adrenal insufficiency [15]. In a randomized trial of similar patients undergoing major colorectal surgery, no differences in postural hypotension or adrenal insufficiency were seen between those receiving high-dose glucocorticoids (hydrocortisone 100 mg intravenously three times daily) or low-dose glucocorticoids (the equivalent of their preoperative dose given intravenously) [16].

Although these data are reassuring, our approach to glucocorticoid dosing is based upon the likelihood of hypothalamic-pituitary axis (HPA) suppression and the magnitude of the surgical stress.

Potential adverse effects of perioperative glucocorticoids — In addition to suppression of the HPA axis, perioperative glucocorticoid therapy may cause a number of other problems:

●Impaired wound healing [17]

●Increased friability of skin, superficial blood vessels, and other tissues (eg, mild pressure may cause hematoma or skin ulceration, removing adhesive tape may tear the skin, and sutures may tear the gut wall)

●Increased risk of fracture, infections, gastrointestinal hemorrhage, or ulcer [18,19]

One important reason to avoid supraphysiologic administration of glucocorticoids perioperatively, unless absolutely necessary, is that they have acute side effects that can influence surgical outcomes [7,20]. These include:

●Hyperglycemia

●Hypertension

●Fluid retention

●Increased risk of infection (see "Major side effects of systemic glucocorticoids")

Individualized approach — The current approach is to determine perioperative glucocorticoid coverage based upon the patient's history of glucocorticoid intake, as well as the type and duration of surgery planned [2,21-23].

An anesthetic agent, etomidate, should be avoided in patients at risk for adrenal suppression and adrenal crisis. This is a commonly used anesthetic induction agent known to have properties of inhibiting steroid synthesis and precipitating acute adrenal insufficiency [24]. While etomidate has many benefits in specific clinical settings, it is best avoided in patients with possible HPA suppression. If it is used, patients need to receive glucocorticoid coverage perioperatively or be closely monitored for any clinical features suggestive of adrenal insufficiency [25].

In patients with possible HPA suppression, the presence of unexplained nausea, vomiting, hypotension, orthostasis, change in mental status, hyponatremia, or hyperkalemia should prompt checking a random cortisol and, depending on the urgency of the situation, may require empiric therapy with additional corticosteroids. Additionally, postoperative stressors, such as infection, myocardial infarction, bleeding, or other complications may also prompt the administration of additional glucocorticoids.

Patients who are taking glucocorticoids should be monitored carefully for infection postoperatively because glucocorticoids may suppress the fever response.

CORTISOL SECRETION DURING STRESS — Acute physical or psychological stress activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased plasma corticotropin (ACTH) and serum cortisol concentrations. Stress exerts its effects by stimulating the hypothalamus to release ACTH secretagogues, with corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) being the most important [26,27].

Surgery is one of the most potent activators of the HPA axis. The degree of activation of the HPA axis depends on both the type of surgery performed and the anesthetic agents used during the procedure [28,29]. Plasma ACTH concentrations increase at the time of incision and during surgery, but the greatest ACTH and cortisol secretion occurs during reversal of anesthesia, extubation, and, in the immediate postoperative recovery period, primarily in response to pain [30,31]. The response is mediated by afferent nerve impulses since it can be abolished by interrupting the neural connections from the operative site, such as by sectioning the spinal cord [32], epidural anesthesia [33], or local anesthesia. The plasma ACTH and serum cortisol responses to surgery can also be reduced by opiate drugs [31,34].

There is considerable variation in the increase in cortisol secretion among individuals undergoing surgery; this variability is in part due to concomitant medication use, age, and concurrent illness.

However, in general, cortisol secretion is proportional to the degree of surgical stress:

●The normal basal secretion of cortisol from the adrenal gland is approximately 8 to 10 mg/day.

●During a minor surgery or illness, secretion of cortisol increases to approximately 50 mg/day [21]. Small, transient cortisol responses are seen with minor stress (eg, inguinal hernia repair), returning to baseline within 24 hours after uncomplicated surgery.

●Patients exposed to greater surgical stress (eg, subtotal colectomy) have greater cortisol responses (75 to 100 mg/day), normalizing by postoperative day 5 [28,35].

●The cortisol secretion rate can reach 200 to 500 mg/day with severe stress (such as major trauma), but secretion rates greater than 200 mg/day in the 24 hours after surgery are rare [2].

APPROACH BASED UPON HPA AXIS SUPPRESSION — Exogenous glucocorticoids exert negative feedback control on the hypothalamic-pituitary-adrenal (HPA) axis by suppressing corticotropin-releasing hormone (CRH) secretion and, consequently, corticotropin (ACTH) secretion. This leads to adrenal atrophy and loss of cortisol secretory capability [36].

The time course for recovery of the HPA axis after stopping glucocorticoid therapy following a prolonged treatment course is variable and depends upon a variety of factors including the dose, time of day, and duration of glucocorticoid therapy [37-39]. Drugs such as azole antifungal agents and ritonavir that inhibit cytochrome P450 3A4 enzyme pathway may result in increased serum level of glucocorticoids. Such combination may result in more pronounced suppression of HPA axis. A detailed drug history and the presence of Cushingoid features may help identify such patients. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Adverse effect of medications'.)

In patients whose glucocorticoid history is uncertain, biochemical evaluation of HPA may be considered prior to surgery or a short course of glucocorticoid therapy can be given perioperatively. (See 'Evaluation of HPA axis suppression' below.)

Nonsuppressed HPA axis — Prednisone doses of less than 5 mg/day given in the morning do not suppress the hypothalamic-pituitary-adrenal (HPA) axis. The equivalent morning doses of other glucocorticoids (eg, 4 mg/day of methylprednisolone, 0.5 mg/day of dexamethasone, or 20 mg/day of hydrocortisone) will have a similar effect (table 1). (See "Pharmacologic use of glucocorticoids".)

We suggest that the following groups of patients do not need additional perioperative glucocorticoid coverage, because they are not considered to have suppression of their HPA axis:

●Any patient who has been taking any dose of glucocorticoid for less than three weeks [40]

●Patients who have received morning doses of less than 5 mg/day of prednisone or its equivalent for any length of time [41,42]

●Patients being treated with less than 10 mg of prednisone or its equivalent every other day [43-45]

These patients can be safely maintained on their normal daily dose of glucocorticoids in the perioperative period. Furthermore, these patients do not require testing for HPA axis suppression, as the testing does not accurately predict development of adrenal crisis postoperatively [46-48]. Monitoring of these patients for any evidence of hemodynamic instability perioperatively should be sufficient [47,48].

Suppressed HPA axis patients — In contrast, patients who should be assumed to have functional suppression of hypothalamic-pituitary-adrenal (HPA) function include:

●Any patient who is currently taking more than 20 mg/day of prednisone or its equivalent (eg, 16 mg/day of methylprednisolone, 2 mg/day of dexamethasone, or 80 mg/day of hydrocortisone) for more than three weeks [49]

●Any patient on glucocorticoids who has clinical Cushing's syndrome

We suggest that these patients be treated with supplemental glucocorticoids in the perioperative period in accordance with the magnitude of the stress (table 2).

Intermediate patients (HPA suppression unknown) — Patients currently taking doses of 5 to 20 mg of prednisone (or its equivalent) for more than three weeks have considerable variability in hypothalamic-pituitary-adrenal (HPA) axis suppression that does not correlate well with age, sex, dose, or duration of therapy. This variability is probably due to differences in rates of glucocorticoid metabolism (figure 1).

Additionally, doses lower than the equivalent of 5 mg of prednisone daily taken in the evening may disrupt the normal diurnal variation and the way the patient responds to surgical stress [41,50].

We suggest that all patients in this intermediate category undergo preoperative evaluation of their HPA axis. (See 'Evaluation of HPA axis suppression' below.)

Glucocorticoid use in past year — The patient who has discontinued glucocorticoids in the year prior to surgery presents another problem. Early studies found that profound suppression of the HPA axis could take up to one year to recover fully [37,38]. This led some to recommend the administration of glucocorticoids to any patient who had been on prednisone doses of more than 5 mg/day for more than three weeks in the 6 to 12 months prior to surgery, but available evidence does not support this approach [51].

For patients who are currently off glucocorticoids but used them in the past year, we suggest the following:

●Patients who received regimens that would not be expected to suppress the HPA axis do not require testing. (See 'Nonsuppressed HPA axis' above.)

●All other patients who received regimens of either longer duration or higher doses of glucocorticoids that could have potentially suppressed the HPA axis (eg, the suppressed or intermediate "unknown" HPA suppression categories) should undergo preoperative assessment of their HPA axis beginning with a morning serum cortisol. (See 'Evaluation of HPA axis suppression' below.)

Inhaled and topical glucocorticoids — Chronic use of inhaled or high-potency, topical glucocorticoids has potential to cause HPA axis suppression, although this rarely manifests as overt adrenal insufficiency [52]. The degree of HPA axis suppression is dependent on potency, dose, duration, frequency, and timing of glucocorticoid administration.

The effect of inhaled and topical glucocorticoids on the HPA axis is illustrated by the following:

●The result of studies of inhaled glucocorticoids (IGCs) on HPA axis function in asthmatic adults are inconsistent because they have often been uncontrolled, and study subjects have received intermittent courses of oral glucocorticoids, which may also affect the HPA axis [53,54].

●Children are at higher risk of HPA suppression from IGCs. Two retrospective studies identified a number of cases of acute adrenal crisis in patients using IGCs (at doses ranging from 500 to 2000 mcg daily) [52,55]. This occurred disproportionately in children and with the use of fluticasone.

●A meta-analysis of 21 studies of urinary cortisol excretion and 13 studies of morning serum cortisol concentrations in patients taking IGCs found evidence of HPA axis suppression that was most common with IGC doses greater than 800 mcg daily but was often absent even at higher doses [53]. HPA axis suppression was seen with lower daily doses of fluticasone (750 mcg daily) than with beclomethasone, triamcinolone, or budesonide (1500 mcg daily). (See "Major side effects of inhaled glucocorticoids", section on 'Adrenal suppression'.)

●The inhaled agent, ciclesonide, may theoretically be less likely to cause biochemical evidence of adrenal suppression due to differences in pharmacokinetics. A meta-analysis of four studies using doses of 160 to 640 mcg/day did not show evidence for suppression of morning or 24-hour urinary cortisol [56], but further data are needed to confirm that HPA suppression does not occur with this agent.

●Topical corticosteroids, particularly class I agents (the strongest, eg, super potent), can cause significant HPA axis suppression using as little as 2 grams/day for two or more weeks [57-59]. In one report, temporary reversible suppression was noted in 8 of 40 patients (20 percent) with psoriasis treated with super potent, topical corticosteroids for three weeks [60]. In contrast, topical clobetasol propionate at a mean dose of 23 grams per week for six weeks did not result in significant alteration of the HPA axis in patients being treated for vitiligo [61]. Factors that predispose to HPA suppression include use of high potency corticosteroids, chronic use, application to highly permeable areas such as face or genitalia, treatment of large areas, occlusion, poor skin integrity, liver failure, and young age. Routine use of even mild corticosteroids in young children can cause HPA axis suppression. Systemic absorption is increased when there is an altered skin barrier, which is common in the conditions for which these medications are prescribed. (See "Topical corticosteroids: Use and adverse effects", section on 'Systemic'.)

We recommend evaluation of adrenal function perioperatively in patients who have been on:

●≥750 mcg daily of fluticasone (1500 mcg daily for other IGCs) for more than three weeks prior to surgery

●≥2 g/day of high potency or super high potency topical corticosteroids (class I-III) for more than three weeks prior to surgery

●In addition, patients who appear Cushingoid or exhibit signs or symptoms of adrenal insufficiency should have their HPA axis evaluated [62]

Intraarticular and spinal glucocorticoid injections — Systemic absorption occurs after intraarticular glucocorticoid [63-66], and HPA axis suppression has been described after both intraarticular and spinal injections [67-69]. Several factors, including the dose, interval, and the number of glucocorticoid injections, have an impact on the severity of HPA axis suppression [63,70].

Although the risk of perioperative adrenal crisis is likely to be low in patients with a history of previous glucocorticoid injections, we suggest HPA axis evaluation in those who have received three or more intraarticular or spinal glucocorticoid injections within three months prior to surgery [68] or those who appear Cushingoid on exam [66]. (See "Diagnosis of adrenal insufficiency in adults" and "Epidemiology and clinical manifestations of Cushing syndrome".)

EVALUATION OF HPA AXIS SUPPRESSION

Intermediate patients — We suggest that all patients in the intermediate category of hypothalamic-pituitary-adrenal (HPA) axis suppression (eg, status of HPA axis suppression is unknown) undergo preoperative evaluation of their HPA axis.

Morning serum cortisol — The measurement of morning (prior to 8 AM) serum cortisol has been described as a good screening method for evaluation of secondary adrenal insufficiency, with a good correlation with maximum cortisol achieved during insulin-induced hypoglycemia [71,72].

●In patients on chronic glucocorticoid therapy, an early morning cortisol <5 mcg/dL (138 nmol/L) 24-hour off glucocorticoid replacement dose is highly suggestive of an impaired HPA axis with the need for additional glucocorticoid intake perioperatively (table 2) [73,74].

●Patients with an early morning cortisol level >10 mcg/dL (275 nmol/L) likely do not have a significant impairment of the HPA axis and may be continued on their current glucocorticoid replacement dose on the day of surgery [71,72]. Such patients do not need additional perioperative glucocorticoid therapy.

●In patients with an early morning cortisol level between 5 to 10 mcg/dL (138 to 275 nmol/L), we suggest further evaluation with a corticotropin (ACTH) stimulation test or empiric additional perioperative glucocorticoid therapy.

ACTH stimulation tests — We suggest measurement of serum cortisol at 30 minutes after 250 mcg corticotropin (ACTH) stimulation for preoperative evaluation of the HPA axis. A cortisol level >18 mcg/dL (497 nmol/L) 30 minutes after 250 mcg ACTH stimulation predicts an adequate adrenal reserve during surgery with no need for glucocorticoid coverage perioperatively [48,75,76].

Patients with an inadequate response should receive additional glucocorticoid coverage (table 2).

The ACTH stimulation test may be normal in patients with acute (within two to four weeks) ACTH deficiency (as might occur soon after pituitary surgery) and, therefore, cannot be relied upon as an indicator of a normal HPA axis in such circumstances [77]. An insulin tolerance test or metyrapone stimulation test may be done to evaluate HPA axis in such patients. However, these tests are not practical in most clinical settings, and therefore, we suggest empiric replacement with glucocorticoids in patients with suspected acute ACTH deficiency due to recent pituitary surgery. (See "Determining the etiology of adrenal insufficiency in adults".)

A normal cortisol response during the ACTH stimulation test confirms adequate cortisol reserve during surgery and a lack of need for glucocorticoid coverage perioperatively. However, a normal clinical response to surgical stress has been reported in three studies of patients with an inadequate response to high-dose ACTH stimulation test while being maintained on their usual daily glucocorticoid dose [1,8,48].

Urgent or emergency surgery — Patients who require urgent or emergency surgery who fall into the intermediate category described above (eg, they have taken glucocorticoids but the degree of suppression of their HPA axis is unknown) should receive empiric perioperative glucocorticoid coverage. Our recommendations for specific glucocorticoid regimens are based upon the type and anticipated duration of surgery (table 2). Delaying surgery to perform evaluation of the HPA axis would be inappropriate in this setting.

SUMMARY AND RECOMMENDATIONS — The use of stress doses of glucocorticoids has become a common perioperative practice for patients on glucocorticoid therapy. However, available data suggest that these doses are excessive and unnecessary in most patients.

The current approach is to determine glucocorticoid coverage based upon the patient's history of glucocorticoid intake and likelihood of hypothalamic-pituitary-adrenal (HPA) axis suppression, as well as the type and duration of surgery.

We suggest the following approach for perioperative glucocorticoid coverage:

●Nonsuppressed HPA axis – For patients who have been taking exogenous glucocorticoids of any dose for less than three weeks, morning prednisone (<5 mg daily or its equivalent) for any duration, or less than 10 mg of prednisone or its equivalent every other day, we suggest continuing the same glucocorticoid regimen perioperatively (Grade 2C). These patients are unlikely to have a suppressed HPA axis, and neither preoperative evaluation of the HPA axis nor supraphysiologic doses of glucocorticoids are needed. (See 'Nonsuppressed HPA axis' above.)

●Suppressed HPA axis – For patients who are currently taking prednisone >20 mg/day for three weeks or more and in patients with a Cushingoid appearance, we suggest additional perioperative glucocorticoid coverage, because HPA axis suppression should be assumed to be present (Grade 2C). Our recommendations for specific glucocorticoid regimens are based upon the type and anticipated duration of surgery (table 2).

●Intermediate HPA suppression – For all other patients, the degree of HPA axis suppression is unknown, and biochemical evaluation of the HPA axis should be performed. (See 'Intermediate patients (HPA suppression unknown)' above.)

•Although the risk of perioperative adrenal crisis is likely to be low in patients with a history of previous glucocorticoid injections, we also suggest HPA axis evaluation in those who have received three or more intraarticular or spinal glucocorticoid injections within three months prior to surgery. (See 'Intraarticular and spinal glucocorticoid injections' above.)

•The approach to patients taking inhaled or topical glucocorticoids is described above. (See 'Inhaled and topical glucocorticoids' above.)

●The first step in the evaluation of the HPA axis is a morning (8 AM) serum cortisol (24-hour off glucocorticoid replacement dose).

•If the 8 AM cortisol is <5 mcg/dL (138 nmol/L), the patient is likely to have a suppressed HPA axis, and we therefore suggest additional glucocorticoid intake perioperatively (table 2) (Grade 2C).

•If the 8 AM cortisol is >10 mcg/dL (275 nmol/L), the patient likely does not have a significant impairment of the HPA axis, and the patient may be continued on his current glucocorticoid replacement dose on the day of surgery (Grade 2C).

•If 8 AM cortisol level is between 5 to 10 mcg/dL (138 to 275 nmol/L), we suggest further evaluation with a corticotropin (ACTH) stimulation test (if time permits) or empiric additional glucocorticoid therapy (table 2) (Grade 2C).

●For patients who undergo a standard 250 mcg ACTH stimulation test, if serum cortisol is <18 mcg/dL (497 nmol/L) at 30 minutes in response to ACTH, we suggest perioperative glucocorticoid coverage (table 2). For those with a serum cortisol response >18 mcg/dL (497 nmol/L), no coverage is needed (Grade 2C).

●For patients who require urgent or emergency surgery who fall into the intermediate category described above (eg, they have taken glucocorticoids but the degree of HPA axis suppression is unknown), we suggest empiric perioperative glucocorticoid coverage (Grade 2C).

●The issue of supplemental glucocorticoids for patients with known adrenal insufficiency already taking glucocorticoids is reviewed separately. (See "Treatment of adrenal insufficiency in adults".)

DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Gail Welsh, MD, Ellen Manzullo, MD, and Lynnette Nieman, MD, who contributed to earlier versions of this topic review.