33 Perioperative Management of Patients on Steroids Requiring Surgery

Alexandra Reiher, MD, and Rebecca S. Sippel, MD, FACS

Perioperative glucocorticoid replacement therapy can be challenging, but appropriate replacement is essential to optimize the patient's outcome. Intermittent and chronic steroid use results in decreased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, which over several weeks results in adrenal gland atrophy, eventually leading to secondary adrenal insufficiency.1 Patients with chronic lung disease, inflammatory bowel disease, rheumatoid arthritis, and solid-organ transplantations are often on steroid supplementation either intermittently or chronically. Determining which of these patients requires high-dose steroids perioperatively can be difficult. Insufficient dosing of glucocorticoids during the perioperative period can result in hypotension and even death. Excessive treatment with glucocorticoids decreases wound healing and increases susceptibility to infection, among a myriad of other complications. This chapter provides guidelines toward evaluation and treatment of secondary adrenal insufficiency during the perioperative period.

Historical Perspective

Iatrogenic adrenal insufficiency was first identified in 1952 by Fraser and colleagues.2 A patient on chronic steroids underwent surgery and subsequently developed acute adrenal crisis attributable to preoperative withdrawal from glucocorticoid therapy. A similar case was reported by Lewis and colleagues in 1953.3 A patient who had surgical repair for a flexion contracture of the right knee died a few hours after surgery. The patient had been on cortisone daily for 5 months before surgery, but his cortisone had been held the day prior to and the day of his surgery. A postmortem examination revealed diffuse atrophy and hemorrhage of the adrenal glands, confirming the diagnosis of adrenal insufficiency. The authors then published the first set of guidelines regarding perioperative glucocorticoid management. They recommended increasing glucocorticoids fourfold to avoid intraoperative hypotension and death. These recommendations are probably what has led us to overtreat most patients today. We now know that this dose is in great excess to the normal physiologic response to surgery.

Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal (HPA) axis is activated during acute physical or emotional stress. Corticotropin-releasing hormone (CRH) is secreted by the hypothalamus as a result of stimulation by serotonin. CRH secretion is inhibited by noradrenaline and cortisol. CRH secretion results in secretion of plasma ACTH from the pituitary gland, stimulating secretion of cortisol from the zona fasciculata in the adrenal glands [see Figure 1]. ACTH is also stimulated by adrenaline. Normal basal secretion of cortisol by the adrenal gland is 8 to 10 mg/day.4 A study using stable isotope dilution thermospray liquid chromatography–mass spectrometry confirmed that the average cortisol production rate per day was approximately 9.9 mg.5


Figure 1 Hypothalamic-Pituitary-Adrenal Axis

During a minor procedure or surgery, the adrenal gland produces up to 50 mg/day of cortisol.6,7 A study by Plumpton and colleagues evaluated plasma cortisol levels in patients during and after major and minor surgeries.7 In patients undergoing major surgery, cortisol levels initially fell after premedication, followed by a rapid rise during surgery and a further rise in cortisol during the early postoperative period. A similar pattern of response was seen in patients undergoing minor surgeries, but with a smaller peak. Peak values occur within 4 to 6 hours after surgery or injury and return to baseline after 24 hours.8 After major surgery, such as cardiac surgery, cortisol secretion is 75 to 100 mg on the first day and can remain elevated for 48 to 72 hours.6 Secretion rates greater than 200 mg/day within the first 24 hours of surgery are rare.

Assessing a Patient's HPA Axis

BASELINE CORTISOL LEVELS

Determining whether a patient's HPA axis is functioning is the first step to deciding if glucocorticoid supplementation is indicated during the perioperative period. Random serum cortisol levels are of little utility because of diurnal variation, but early-morning serum cortisol levels drawn between 7 and 9 am will reflect maximal secretion. Morning cortisol levels of 18 to 20 µg/dL reflect an intact adrenocortical reserve. No further testing is needed in these patients.9 A morning cortisol level below 3 µg/dL strongly suggests adrenal insufficiency, and the level should be repeated. If it remains low, physiologic steroid replacement should be initiated, and no further testing is necessary. Patients with baseline cortisol levels between 3 and 11 µg/dL benefit from an additional workup for adrenal insufficiency to clarify their adrenal function. Dynamic testing is useful in this setting to determine a patient's ability to produce cortisol in response to stress or ACTH stimulation10 [see Figure 2].


Figure 2 Algorithm for Evaluation of the Patient on Steroids

Serum cortisol reflects primarily protein-bound cortisol levels. Estrogen, which increases cortisol-binding globulin, increases total cortisol concentrations. This can lead to falsely elevated cortisol levels. Low serum albumin concentrations can cause falsely low total serum cortisol levels, even though they have normal biologically active free cortisol concentrations. Measuring serum free (unbound) cortisol levels is thus more accurate in these patients.9

INSULIN-INDUCED HYPOGLYCEMIA

The insulin-induced hypoglycemia test is considered the gold standard but is rarely used today because of the associated risks, including coma and seizures. This test involves administering intravenous (IV) insulin (0.10 to 0.15 units/kg) to a fasting patient until hypoglycemia (blood glucose < 40 mg/dL) is achieved. A normal stress response to hypoglycemia will elicit an increase in serum cortisol.9 A patient with an intact HPA axis will have a rise in cortisol to at least 18 to 20 µg/dL.11 This must be performed in a controlled setting, preferably an experienced endocrine clinic with close supervision.

ACTH STIMULATION TEST

The ACTH stimulation test is more commonly used to determine adrenal function. Synthetic ACTH (cosyntropin [Cortrosyn]) is administered intravenously in a dose of 250 µg. Baseline, 30-minute, and 60-minute cortisol levels are obtained. Normal adrenal function will produce a peak cortisol of at least 18 to 20 µg/dL and typically a delta of more than 8 to 10 µg/dL. The delta level (change from baseline) is not recommended as the sole determinant of adequate response to ACTH stimulation. An expected delta of 8 to 10 µg/dL in the setting of a peak cortisol lower than 18 µg/dL should still be considered an abnormal response.12

Performing an ACTH stimulation test in the morning yields the best results. It is important to hold exogenous steroids for 24 hours prior to the test, and longer-acting glucocorticoids, such as prednisone, should be held for 5 to 7 days. This dose of cosyntropin is supraphysiologic and can stimulate cortisol levels to the normal range in a patient with partial adrenal insufficiency. A low-dose cosyntropin stimulation test with 1 µg can be performed to better evaluate patients with partial adrenal suppression or central adrenal insufficiency but is not currently recommended because of a need for further studies to determine the efficacy of this test. Also, this low dose of cosyntropin is not commercially available, and serial dilutions are therefore required. This is both inconvenient and has the potential for inconsistent dosing.13

The ACTH stimulation test is easier to perform than the insulin tolerance test, requires less supervision, and does not carry the risks associated with inducing hypoglycemia. The ACTH stimulation test has been shown to have a close correlation with the insulin tolerance test (r=.92; p≤.0001).14 The ACTH stimulation test is the recommended test for evaluating adrenal insufficiency.

When to Suspect an Impaired HPA Axis

PATIENTS CURRENTLY ON ORAL STEROIDS

The exact time period it takes for a patient to become adrenally suppressed while treated with glucocorticoids, and the time it takes to recover adrenal function after discontinuation of steroids, is not known. When evaluating for HPA suppression, one needs to consider both the dose and the duration of previous glucocorticoid therapy. In general, any patient who has received doses equivalent to 20 mg of prednisone for more than 5 days is at risk for suppression of the HPA axis. If the glucocorticoid doses are closer to but above the physiologic range, 1 month is likely the minimal interval. For patients on chronic steroids, if the dose is equivalent to 5 mg or less of prednisone daily [see Table 1 for steroid conversions], these patients have a normal response to HPA testing and do not require additional glucocorticoid treatment perioperatively. Patients receiving between 5 and 20 mg of prednisone daily (or an equivalent dose of another steroid) should undergo further testing.15 Patients receiving alternate-day glucocorticoid treatment (a short-acting glucocorticoid given every 48 hours, in the morning) tend to have less adrenal suppression than patients taking steroids on a daily basis. These patients should be evaluated for adrenal suppression as the response is not the same between patients.13

PATIENTS USING INHALED STEROIDS

A meta-analysis by Masoli and colleagues evaluated adrenal function in patients receiving inhaled corticosteroids.16 Many studies were eliminated because of insensitive measurements for testing the HPA axis, lack of placebo control, and inclusion of patients on oral steroids. Five randomized, controlled studies were analyzed. Patients receiving therapeutic doses of inhaled fluticasone (50 to 500 µg/day) were found to have minimal abnormal responses to a cosyntropin stimulation test. Four percent of patients had an abnormal response to adrenal function testing. For each 500 µg/day increase in a patient's fluticasone dose, the odds ratio of an abnormal adrenal function test increased 1.4-fold. It is necessary to consider adrenal suppression in all patients on inhaled corticosteroids, particularly those receiving supratherapeutic doses.

PATIENTS USING TOPICAL STEROIDS

Although it is unknown what potency or dose of topical steroid can induce secondary adrenal suppression, the risk associated with topical steroids must be assessed. The following factors increase the risk of adrenal suppression: application to a large surface area of skin, long-term use, associated use of occlusive dressings, and use of high-potency (class I) glucocorticoid agents.17

PATIENTS PREVIOUSLY ON STEROIDS

Multiple studies have shown normal adrenal responses within 3 weeks of discontinuing short-term glucocorticoid therapy. It would therefore be safe to assume that recovery from suppression may be incomplete for approximately 2 months after glucocorticoid treatment. For patients who have had prolonged exposure to high doses of glucocorticoids, recovery can take up to 1 year. These patients should undergo formal testing, preferably an ACTH stimulation test, to determine adrenal responsiveness. A normal response eliminates the need for perioperative glucocorticoid supplementation.7,13 However, should such a patient develop hypotension perioperatively, there should be a low threshold to administer a dose of IV hydrocortisone. Obtaining a complete history regarding current and past use of glucocorticoids is necessary to avoid potential adrenal crisis in the perioperative period.

PATIENTS WITH KNOWN PRIMARY ADRENAL INSUFFICIENCY

Patients with primary adrenal insufficiency require both mineralocorticoid and glucocorticoid replacement therapy. The most common cause of primary adrenal insufficiency in the United States is autoimmune adrenal insufficiency, or Addison disease. A thorough review of a patient's medical history should elicit this information. These patients often have hyperpigmentation of their skin and mucosa because of elevated plasma β-lipotropin concentrations (derived from pro-opiomelanocortin) and increased synthesis of melanin by melanocytes.9 Patients with primary adrenal insufficiency typically take fludrocortisone 0.05 to 0.1 mg once daily, as well as hydrocortisone 15 mg daily divided into two to three doses (typically 10 to 15 mg in the morning and 5 to 10 mg in the evening).18 Glucocorticoid replacement must be continued in the perioperative period because of primary disease of the HPA axis. If a patient with primary adrenal insufficiency is receiving hydrocortisone in excess of 100 mg/day, mineralocorticoid supplementation can be held. Hydrocortisone has both mineralocorticoid and glucocorticoid properties at high doses. However, once the glucocorticoids are tapered to below 100 mg/day, fludrocortisone must be restarted.

Argument against Supraphysiologic Glucocorticoid Treatment in the Perioperative Period

Weighing the risks and benefits of glucocorticoid supplementation for surgery is quite difficult. The complications associated with high-dose glucocorticoids are well known, including hyperglycemia, impaired wound healing, and hypertension. In the postoperative setting, patients treated with steroids are at increased risk for decreased tissue repair rates and increased susceptibility to infections.19 Numerous studies have been performed over the past 30 years challenging the theory that patients on chronic steroids need additional steroids perioperatively. The reported incidence of perioperative adrenal insufficiency is rare, estimated at 0.01 to 0.7%.20,21

Kehlet and Binder evaluated 104 glucocorticoid-treated patients undergoing surgery without supplemental stress doses of glucocorticoids.22 Glucorticoid therapy was withheld 36 hours before surgery and restarted 24 hours after minor surgery and 72 hours after major surgery. Plasma corticosteroid doses were measured during the 24-hour postoperative period. The mean corticosteroid value 1 hour after skin incision increased significantly from baseline. This response was impaired in 39 patients undergoing major surgery (53%) compared with the control group. Seven episodes of hypotension were noted, all of which responded spontaneously or to fluid administration. All hypotensive episodes lasted less than 20 minutes. Nine patients undergoing minor surgery (30%) had an abnormal corticosteroid response. One patient undergoing minor surgery developed unexplained intraoperative hypotension. This patient had severe adrenocortical failure and responded to 50 mg of hydrocortisone along with fluid resuscitation.

A study by Udelsman and colleagues evaluated glucocorticoid replacement in the perioperative period on adrenalectomized primates.23 Primates were given glucocorticoid replacement for 4 months after adrenalectomy. The monkeys were then stratified to receive different quantities of glucocorticoid replacement for 4 days prior to surgery: subphysiologic (one tenth the normal cortisol production rate), physiologic, or supraphysiologic (10 times the normal cortisol production rate). Sham adrenalectomized placebo-treated animals served as controls. The monkeys then underwent a cholecystectomy. The subphysiologically treated group was hemodynamically unstable before, during, and after surgery and had a significantly higher mortality rate than controls. However, the physiologically replaced group had intraoperative hemodynamics and postoperative outcomes similar to those of the supraphysiologically treated and sham-operated controls. This study suggests that replacing physiologic doses of glucocorticoids is sufficient for glucocorticoid replacement for moderate surgery in primates.

The need for high-dose steroids during orthopedic surgery was evaluated by Friedman and colleagues.15 The authors performed a prospective study of 28 patients on chronic, immunosuppressive doses of glucocorticoids who were undergoing major orthopedic operations. The patients were given their baseline doses of glucocorticoids (mean dose 10 mg prednisone), with no additional stress doses of steroids. Twenty-four-hour urinary free cortisol levels were obtained perioperatively and postoperatively. No evidence of adrenocortical insufficiency was documented. Seventy-one percent of patients demonstrated increased production of endogenous corticosteroids (urinary level of free cortisol) in response to the operative stress.

These studies by Kehlet and Binder, Udelsman and colleagues, and Friedman and colleagues all independently provide clinical evidence that supraphysiologic doses of glucocorticoids in the perioperative period are likely of little benefit. The study by Kehlet and Binder provides evidence that it is necessary to continue glucocorticoids during the perioperative period as withholding glucocorticoids may result in hypotension.22 Udelsman and colleagues demonstrated that subphysiologic doses are not sufficient in the perioperative period either.23 However, continuing a patient's outpatient glucocorticoid regimen during the perioperative period may be safe for minor or moderate surgeries based on recent clinical evidence.

Why Treat Patients with Impaired Adrenal Function?

Patients with normal adrenal function have increased secretion of plasma ACTH and cortisol concentrations, urinary free cortisol, and concentrations of urinary metabolites of cortisol when faced with surgery, trauma, or critical illness. The HPA response to surgical stress has a considerable interindividual variation.19 Thus, it is necessary to cover a patient with impaired adrenal function sufficiently, but exactly how much coverage is needed is not entirely understood. The goal of treatment with glucocorticoids is to provide an amount equivalent to the normal physiologic response to surgical stress while avoiding overtreatment. To determine a proper dose replacement, one must consider the patient's adrenal status, as well as the severity and duration of surgery.

Guidelines for Dosing Glucocorticoids in the Perioperative Period

Once it is determined that a patient will require perioperative glucocorticoid replacement, the dose of glucocorticoids must be determined. Optimal dosing will mimic a normal physiologic response to surgical stress. Three factors will determine the dose of glucocorticoids required: the preoperative dose of glucocorticoid, the preoperative duration of glucocorticoid use, and the anticipated duration of surgery. Surgeries that require a longer duration or greater physiologic stress, such as cardiothoracic surgery, require a higher dose of glucocorticoid supplementation.19 IV steroids should be continued in all cases until a patient is able to tolerate enteral feeding. Should a patient develop postoperative complications and require close monitoring in the hospital, stress-dose steroids should be administered.

MINOR SURGERY

Minor surgeries, which include those lasting less than an hour, do not require additional glucocorticoid administration. Inguinal hernia repair, scheduled cardiac catheterization, and laparoscopic cholecystectomy are some examples of minor surgery. Patients should be instructed to continue their home regimen of steroids through the perioperative period, including the day of surgery. The HPA axis to minor surgery is minimal; additional steroid supplementation is not indicated.19

MODERATE SURGERY

For moderate surgeries, including nonlaparoscopic abdominal surgeries and total joint replacement, patients should receive their outpatient steroid dose preoperatively (either intravenously or by mouth). Hydrocortisone 50 mg IV should be administered intraoperatively, followed by hydrocortisone 25 mg IV twice daily for 24 to 48 hours postoperatively. Patients can return to their preoperative doses (either enterally or parenterally) on postoperative day 2 and, once tolerating oral feeding, can be continued on their outpatient glucocorticoid regimen.

MAJOR SURGERY

Major surgeries, including pancreatoduodenectomy, cardiac surgeries requiring cardiac bypass, and total proctocolectomies, require higher doses of glucocorticoids intraoperatively and postoperatively. The target glucocorticoid dosing is 100 to 150 mg of hydrocortisone per day (or another glucocorticoid in equivalent dosing) for 2 to 3 days. For example, hydrocortisone 50 mg every 8 hours for 72 hours. Stress-dose steroids can be initiated on the day of surgery, immediately prior to anesthesia induction. Once the patient is tolerating an enteral diet and is no longer in a critical condition, steroids can quickly be tapered to the outpatient regimen.

Table 2 provides an outline of recommended steroid replacement in the perioperative period based on the nature of surgery being performed. Recommendations are based on expert opinion.

Consulting a Specialist

Patients with suspected or known adrenal insufficiency attributable to pituitary disease should be followed by an endocrinologist as it is more difficult to assess the HPA axis in these patients. Endocrinologists can help with interpretation of ACTH stimulation tests that have produced confusing results. There are no clear guidelines on steroid tapering, but a slower taper should be initiated for complicated surgeries or patients with longer hospital stays postoperatively, and a specialist can help formulate the taper. A patient being treated for Cushing disease with pituitary or adrenal surgery must be followed by an endocrinologist. The endocrinologist can provide guidelines for a slow steroid taper after surgery and will likely follow the patient after hospital discharge in the clinic.

Conclusion

A patient with an intact HPA axis will mount a cortisol response to surgery or other stressors. The goal of glucocorticoid replacement in patients without an intact HPA is to mimic normal adrenal function. Most patients undergoing minor surgeries can continue their outpatient glucocorticoid regimens alone. For patients undergoing moderate or major surgeries, their adrenal function needs to be determined, and an appropriate dose of glucocorticoids should then be administered. Although adrenal insufficiency in the perioperative setting is rare, it is easily avoided with a good history regarding prior steroid use within the previous year. It is important to ask patients regarding inhaled and topical steroids as well as these can impact adrenal function. Below are a few case examples for further review:

    Case 1. A 51-year-old man with rheumatoid arthritis on prednisone 5 mg every other day chronically is undergoing a laparoscopic cholecystectomy.
    Answer. The patient should take 5 mg prednisone the morning of surgery. If his postoperative course is uncomplicated, he can resume his outpatient glucocorticoid regimen.
    Case 2. A 30-year-old woman with Crohn disease on prednisone 10 mg daily for the last 6 months is undergoing a total abdominal hysterectomy for fibroids.
    Answer. The patient should receive prednisone 10 mg daily prior to surgery followed by hydrocortisone 50 mg IV intraoperatively. Postoperatively, continue hydrocortisone 25 mg IV every 12 hours. The patient can be transitioned to either prednisone 10 mg daily on postoperative day 2 if tolerating an oral diet or continue hydrocortisone 25 mg IV every 12 hours until the patient is tolerating enteral feeding.
    Case 3. A 60-year-old man with chronic obstructive lung disease who has required frequent steroid burst over the past year is undergoing three-vessel cardiac bypass surgery.
    Answer. Although the patient is not currently on glucocorticoids, he likely has an abnormal HPA axis. Prior to surgery, it would be appropriate to perform an ACTH stimulation test.

If his peak cortisol level is only 12 µg/dL, the patient should take an outpatient dose of glucocorticoid the morning of surgery. The patient should receive 50 mg IV intraoperatively and then stress-dose steroids: hydrocortisone 150 mg IV daily for 2 to 3 days (50 mg every 8 hours). After this time period, his dose can be quickly tapered to his outpatient regimen.

If his peak cortisol level is 20 µg/dL or greater, he does not need supplemental steroids perioperatively. Should he develop hypotension, a random cortisol should be drawn, and he should receive hydrocortisone 50 mg IV followed by fluid resuscitation until his adrenal sufficiency is better established. An endocrinology consultation would be appropriate at that point for recommendations on further management.


Financial Disclosures: None Reported

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