The surgical patient taking glucocorticoids

Authors
Amir H Hamrahian, MD
Sanziana Roman, MD
Stacey Milan, MD
Section Editors
Lynnette K Nieman, MD
Sally E Carty, MD, FACS
Deputy Editors
Kathryn A Martin, MD
Kathryn A Collins, MD, PhD, FACS
Disclosures: Amir H Hamrahian, MD Nothing to disclose. Sanziana Roman, MD Nothing to disclose. Stacey
Milan, MD Nothing to disclose. Lynnette K Nieman, MDGrant/Research/Clinical Trial Support: HRA Pharma
[Cushing's syndrome (Mifepristone)]. Sally E Carty, MD, FACS Nothing to disclose. Kathryn A Martin, MD Nothing
to disclose.Kathryn A Collins, MD, PhD, FACS Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Mar 2015. | This topic last updated: Sep 23, 2014.
INTRODUCTION Chronic glucocorticoid therapy can suppress the hypothalamic-pituitaryadrenal (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 surgeryassociated adrenal insufficiency due to sudden preoperative withdrawal of glucocorticoids.
However, numerous studies have questioned both the need for and the doses of supplemental
perioperative glucocorticoid.
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",
section on 'Surgery'.)
OVERVIEW 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], and the observation that glucocorticoids have a
permissive effect on vascular tone and blood pressure [6]. However, a number of reports, including
two randomized studies and a systematic review [7], have questioned the need for supplemental
perioperative stress dose glucocorticoids [1,8-13]. The current approach is to determine
perioperative glucocorticoid coverage based upon the patients history of glucocorticoid intake, as
well as the type and duration of surgery planned [2,14-16].
In addition to suppression of the hypothalamic-pituitary-adrenal (HPA) axis, chronic glucocorticoid
therapy may cause a number of other problems in the perioperative period:
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 [8,20]. These include:
Hyperglycemia
Hypertension
Fluid retention
Increased risk of infection (see "Major side effects of systemic glucocorticoids")
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 [21]. 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 [22].
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 [23,24].
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 [25,26]. 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 [27,28]. 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 [29], epidural anesthesia
[30], or local anesthesia. The plasma ACTH and serum cortisol responses to surgery can also be
reduced by opiate drugs [28,31].
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 and increases to
approximately 50 mg/day of cortisol during a minor surgery or illness [14]. 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 been shown to have greater cortisol responses (75 to 100mg/day), normalizing by
postoperative day 5 [25,32]. 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].
EFFECT OF EXOGENOUS GLUCOCORTICOIDS Exogenous glucocorticoids exert negative
feedback control on the hypothalamic-pituitary-adrenal (HPA) axis by suppressing corticotropinreleasing hormone (CRH) secretion and, consequently, corticotropin (ACTH) secretion. This leads
to adrenal atrophy and loss of cortisol secretory capability [33]. 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 [34-36].
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 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 [37].
Patients who have received morning doses of less than 5 mg/day of prednisone or its
equivalent, for any length of time [38,39].
Patients being treated with less than 10 mg of prednisone or its equivalent every other day
[40-42].
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 [43-45].
Monitoring of these patients for any evidence of hemodynamic instability perioperatively should be
sufficient [44,45].
Suppressed HPA axis patients In contrast, patients who should be assumed to have functional
suppression of 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 ofdexamethasone, or
80 mg/day of hydrocortisone) for more than three weeks [46].
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 mg/day or higher of prednisone (or its equivalent) have considerable variability in 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 [38,47].
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 [34,35]. 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 one week in the 6 to 12 months prior to surgery, but this is clearly
unwarranted.
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 [48]. 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
[49,50].
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) [48,51]. 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 [49]. 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 [52], 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 2grams/day for two or more weeks
[53-55]. 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 [56]. 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 [57].
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 "General principles of dermatologic therapy and
topical corticosteroid use", 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
within three months prior to surgery.

2g/day of high potency or super high potency topical corticosteroids (class I-III).
In addition, patients who appear Cushingoid or exhibit signs or symptoms of adrenal
insufficiency should have their HPA axis evaluated [58].
Intra-articular and spinal glucocorticoid injections Systemic absorption occurs after intraarticular glucocorticoid [59-62], and HPA axis suppression has been described after both intraarticular and spinal injections [63-65]. Several factors, including the dose, interval, and the number
of glucocorticoid injections, have an impact on the severity of HPA axis suppression [59,66].
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 intra-articular or spinal glucocorticoid injections within three months prior to surgery
[64], or those who appear Cushingoid on exam [62]. (See "Evaluation of the response to ACTH in
adrenal insufficiency" and "Epidemiology and clinical manifestations of Cushing's syndrome".)
EVALUATION OF HPA AXIS SUPPRESSION
Intermediate patients We suggest that all patients in the intermediate category of hypothalamicpituitary-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 [67,68].
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)
[69,70].
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 [67,68]. 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 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 [45,71,72].
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 [73]. 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 "Diagnosis 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 [1,9,45].
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 patients history of glucocorticoid intake, as
well as the type and duration of surgery.
We suggest the following approach for perioperative glucocorticoid coverage:
Nonsuppressed hypothalamic-pituitary-adrenal (HPA) axis For patients who have been
taking exogenous glucocorticoids of any dose for less than three weeks, or
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 intra-articular or spinal glucocorticoid injections
within three months prior to surgery. (See 'Intra-articular 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
(497 nmol/L) in response to ACTH, we suggest perioperative glucocorticoid coverage (table 2).
For those with a serum cortisol response >18 (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", section on 'Surgery'.)
ACKNOWLEDGMENT The authors and UpToDate would like to acknowledge Dr. Gail Welsh, Dr.
Ellen Manzullo, and Dr. Lynnette Nieman, who contributed to earlier versions of this topic review.

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