Orthopedics

Pharmacology Update 

Current Controversies in Critical Illness-related Corticosteroid Insufficiency and Glucocorticoid Supplementation

A. Kendall Gross, PharmD; P. Shane Winstead, PharmD

Abstract

Alterations in corticosteroid activity during stress include both insufficient circulating cortisol and tissue corticosteroid resistance. Perioperative management of these patients may be accomplished by consideration of the stress caused by the surgery and administration of hydrocortisone based on the extent of the predicted degree of stress.

Supplemental glucocorticoid therapy was reviewed in this column initially in 2007.1 Since that time, a number of new additions have been added to the literature with respect to glucocorticoid therapy, particularly in the critically ill patient population. This article reviews the current controversies surrounding the pathophysiology, diagnosis, and treatment of corticosteroid insufficiency in critically ill patients.

Adrenal insufficiency, defined as a deficiency in either the production or use of glucocorticoids, can be divided into primary and secondary insufficiency. Primary insufficiency refers to the inability of the adrenal glands to produce cortisol, the principal endogenous glucocorticoid. Secondary adrenal insufficiency is a result of hypothalamic pituitary adrenal axis dysfunction and can be due to pharmacologic suppression, pituitary or hypothalamic abnormalities, physiologic stress such as surgery, or critical illness.2 Critical illness-related corticosteroid insufficiency is a form of secondary insufficiency related to the critical illness itself.3

Critical illness-related corticosteroid insufficiency is a term recommended in a consensus statement from an international task force by the American College of Critical Care Medicine to describe a clinical entity defined as inadequate glucocorticoid activity for the severity of a patient’s illness.3 This is intended to replace terminology such as relative adrenal insufficiency. Critical illness-related corticosteroid insufficiency involves both the inadequate production of glucocorticoids as well as improper use by the tissues.2,3

Cortisol, the principal endogenous glucocorticoid, is produced and subsequently released by the zona fasciculata of the adrenal glands in response to stimulation by adrenocorticotropic hormone. Adrenocorticotropic hormone is released from the anterior pituitary when stimulated by corticotropin-releasing hormone. This process originates in the hypothalamus where corticotropin-releasing hormone is stored and released in response to both circadian rhythm and other stressors. Cortisol, in turn, will have a negative feedback on the additional release of corticotropin-releasing hormone and adrenocorticotropic hormone. Collectively, this is referred to as the hypothalamic pituitary adrenal axis (Figure).

Figure: Normal hypothalamic-pituitary-adrenal axis function. Corticotropin-releasing hormone stimulates the anterior pituitary gland to release adrenocorticotropic hormone that subsequently leads to the production and release of cortisol from the adrenal cortex. Cortisol then exhibits negative feedback on the release of corticotropin-releasing from the hypothalamus.

Hormones secreted from the adrenal gland are classified into glucocorticoids, mineralocorticoids, and androgens. As previously mentioned, cortisol is the primary glucocorticoid, and its normal secretion is estimated to be between 15 and 25 mg/day; synthetic glucocorticoids include prednisone, methylprednisolone, and hydrocortisone.2 The mineralocorticoid aldosterone is also released from the adrenal gland in response to angiotensin II; its physiologic effects are related to sodium and water balance, but it may have use in the management of critical illness-related corticosteroid insufficiency.

Cortisol has numerous physiologic roles, many of which relate to its functions in the stress response.2,3 It is a potent anti-inflammatory agent, causing a reduction in immune cell function and a decreased production of proinflammatory cytokines. Cortisol increases hepatic gluconeogenesis and decreases peripheral glucose use, leading to hyperglycemia. It sensitizes patients to catecholamines and may also reduce nitric oxide-mediated vasodilation, both of which contribute to its effects in increasing blood pressure.3

A number of factors contribute to the activation of the hypothalamic pituitary adrenal axis including stress, surgery, hypoglycemia, fever, trauma, and hypotension. In addition, vasopressin and the pro-inflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-a (TNF-a) may stimulate the pituitary gland directly to release adrenocorticotropic hormone. Additionally, the sympathetic nervous system is activated, causing an…

Alterations in corticosteroid activity during stress include both insufficient circulating cortisol and tissue corticosteroid resistance. Perioperative management of these patients may be accomplished by consideration of the stress caused by the surgery and administration of hydrocortisone based on the extent of the predicted degree of stress.

Supplemental glucocorticoid therapy was reviewed in this column initially in 2007.1 Since that time, a number of new additions have been added to the literature with respect to glucocorticoid therapy, particularly in the critically ill patient population. This article reviews the current controversies surrounding the pathophysiology, diagnosis, and treatment of corticosteroid insufficiency in critically ill patients.

Adrenal insufficiency, defined as a deficiency in either the production or use of glucocorticoids, can be divided into primary and secondary insufficiency. Primary insufficiency refers to the inability of the adrenal glands to produce cortisol, the principal endogenous glucocorticoid. Secondary adrenal insufficiency is a result of hypothalamic pituitary adrenal axis dysfunction and can be due to pharmacologic suppression, pituitary or hypothalamic abnormalities, physiologic stress such as surgery, or critical illness.2 Critical illness-related corticosteroid insufficiency is a form of secondary insufficiency related to the critical illness itself.3

Critical illness-related corticosteroid insufficiency is a term recommended in a consensus statement from an international task force by the American College of Critical Care Medicine to describe a clinical entity defined as inadequate glucocorticoid activity for the severity of a patient’s illness.3 This is intended to replace terminology such as relative adrenal insufficiency. Critical illness-related corticosteroid insufficiency involves both the inadequate production of glucocorticoids as well as improper use by the tissues.2,3

Physiologic Role of Cortisol

Cortisol, the principal endogenous glucocorticoid, is produced and subsequently released by the zona fasciculata of the adrenal glands in response to stimulation by adrenocorticotropic hormone. Adrenocorticotropic hormone is released from the anterior pituitary when stimulated by corticotropin-releasing hormone. This process originates in the hypothalamus where corticotropin-releasing hormone is stored and released in response to both circadian rhythm and other stressors. Cortisol, in turn, will have a negative feedback on the additional release of corticotropin-releasing hormone and adrenocorticotropic hormone. Collectively, this is referred to as the hypothalamic pituitary adrenal axis (Figure).

Figure: Normal hypothalamic-pituitary-adrenal axis function

Figure: Normal hypothalamic-pituitary-adrenal axis function. Corticotropin-releasing hormone stimulates the anterior pituitary gland to release adrenocorticotropic hormone that subsequently leads to the production and release of cortisol from the adrenal cortex. Cortisol then exhibits negative feedback on the release of corticotropin-releasing from the hypothalamus.

Hormones secreted from the adrenal gland are classified into glucocorticoids, mineralocorticoids, and androgens. As previously mentioned, cortisol is the primary glucocorticoid, and its normal secretion is estimated to be between 15 and 25 mg/day; synthetic glucocorticoids include prednisone, methylprednisolone, and hydrocortisone.2 The mineralocorticoid aldosterone is also released from the adrenal gland in response to angiotensin II; its physiologic effects are related to sodium and water balance, but it may have use in the management of critical illness-related corticosteroid insufficiency.

Cortisol has numerous physiologic roles, many of which relate to its functions in the stress response.2,3 It is a potent anti-inflammatory agent, causing a reduction in immune cell function and a decreased production of proinflammatory cytokines. Cortisol increases hepatic gluconeogenesis and decreases peripheral glucose use, leading to hyperglycemia. It sensitizes patients to catecholamines and may also reduce nitric oxide-mediated vasodilation, both of which contribute to its effects in increasing blood pressure.3

Hypothalamic Pituitary Adrenal Axis

A number of factors contribute to the activation of the hypothalamic pituitary adrenal axis including stress, surgery, hypoglycemia, fever, trauma, and hypotension. In addition, vasopressin and the pro-inflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-a (TNF-a) may stimulate the pituitary gland directly to release adrenocorticotropic hormone. Additionally, the sympathetic nervous system is activated, causing an increased release of catecholamines. In response to stress, endogenous cortisol production may approach 200 to 350 mg/day.2

Alterations in corticosteroid activity during stress include both insufficient circulating cortisol and tissue corticosteroid resistance.3 Insufficient circulating cortisol may be related to a primary adrenal injury, as occurs in acute injury or trauma, fungal and bacterial infection, malignancy, autoimmune adrenalitis, and certain medications.

Secondary insufficiency may also occur from a transient, reversible hypothalamic pituitary adrenal axis dysfunction; this is believed to be the source of adrenal insufficiency in critical illness-related corticosteroid insufficiency.

Surgery is a well-characterized model for stress-induced adrenal dysfunction, and acute increases in cortisol and adrenocorticotropic hormone have been demonstrated in response to surgery.4-6

In another study, patients with multitrauma have been noted to have serum cortisol and adrenocorticotropic hormone levels closely correlated with those of septic patients.7 Tissue corticosteroid resistance may contribute, possibly resulting from the failure of the activated glucocorticoid receptor to repress transcription of proinflammatory cytokines. Corticosteroids are used to mitigate this process by their anti-inflammatory activity and subsequent reduction in systemic inflammation seen in patients with septic shock and acute respiratory distress syndrome.

It is also important to consider medication-related causes of glucocorticoid insufficiency and their potential contribution to critical illness-related corticosteroid insufficiency.2,3,8 A number of agents have been cited to contribute to adrenal insufficiency including etomidate, neuromuscular blocking agents, ketoconazole, rifampin, phenytoin, megestrol acetate, and corticosteroids.

Chronic corticosteroid use, as may be present in many orthopedic patients, will exert negative feedback on the hypothalamic pituitary adrenal axis and contribute to a secondary adrenal insufficiency. Treatment with corticosteroids or similar agents, such as megestrol acetate, may cause secondary insufficiency via negative feedback inhibition of the hypothalamic pituitary adrenal axis.

Etomidate, a short-acting hypnotic agent commonly used to facilitate endotracheal intubation, is a known inhibitor of 11-b hydroxylase, the enzyme responsible for the last step in steroidogenesis. Use of etomidate may inhibit cortisol production for up to 48 hours, and may be most pronounced in the elderly and debilitated patients.3 Neuromuscular blockade has also been associated with an increased risk of myopathy with steroids, and concurrent use should be avoided if possible.

Diagnosis

The predominant clinical features of critical illness-related corticosteroid insufficiency are that of an exaggerated proinflammatory response, and it is frequently characterized by persisting hypotension despite resuscitation or progressive acute lung injury.

Typically, the diagnosis of adrenal insufficiency is obtained using an adrenocorticotropic hormone stimulation test. Cosyntropin, a synthetic adrenocorticotropic hormone, is traditionally used in doses of 250 mcg. Random cortisol concentrations are obtained at baseline and at 30 or 60 minutes after administration. There are a number of definitions of adrenal insufficiency, but widely accepted diagnostic values are a baseline random cortisol concentration of <10 mcg/dL or an incremental increase after adrenocorticotropic hormone stimulation test of <9 mcg/dL.3,9,10

Some have advocated the use of a lower, physiologic dose of cosyntropin 1 mcg, suggesting that it may more accurately estimate the ability of the adrenal gland to produce cortisol in response to adrenocorticotropic hormone.10,11 The majority of studies have been done using the 250 mcg dose and it is currently recommended by the consensus guidelines.3

A number of other limitations exist to the diagnosis of adrenal insufficiency.3,12-14 First, this assay only measures the ability of the adrenal gland to secrete cortisol in response to adrenocorticotropic hormone; it neither assesses the hypothalamic pituitary adrenal axis as a whole, nor does it determine the ability of the tissues to properly use cortisol. Secondly, if the patient was receiving steroid treatment as an outpatient or during hospitalization, all corticosteroids except dexamethasone will interfere with the cortisol assay. Additionally, cortisol measurements are done using total cortisol concentrations.

Approximately 90% of cortisol is bound in the plasma to corticotropin-binding globulin in a nonstressed patient, leaving the free cortisol to act at the tissue level. In critically ill patients, it is estimated that concentrations of corticotropin-binding globulin are reduced by up to 50%, thereby increasing the amount of free cortisol in the plasma; this may be applied to other patients undergoing physiologic stress, such as surgery. The assay for free cortisol, however, is not readily available, and there is less data on the clinical interpretation of free cortisol concentrations.

Perhaps the most important factor in determining whether to use the stimulation test is that of treatment benefit. A recent study determined that septic shock patients benefited from hydrocortisone treatment regardless of their response to an adrenocorticotropic hormone stimulation test, and the guidelines recommend that it is not necessary to determine which patients will benefit from therapy.3,15 This may also be relevant to patients who are receiving glucocorticoids at baseline, as is the case with many orthopedic patients. The adrenocorticotropic hormone stimulation test is recommended in the diagnosis of adrenal insufficiency, and it may be considered in patients with unexplained hypotension postoperatively.

Management

When considering the use of corticosteroids, the clinician is faced with a number of decisions including which agent should be used, what dose and duration is appropriate, and when the course should be followed with a taper. Although corticosteroids have been demonstrated to increase ventilator-free days, hospital-free days, and improve mortality in specific patient groups, there remains a significant controversy in how to manage critical illness-related corticosteroid insufficiency.15-19

The choice of agent may be influenced by disease state, relative mineralocorticoid activity, and pharmacokinetic profile. Hydrocortisone has been extensively studied in the septic shock population15,16 whereas methylprednisolone has been used primarily in acute respiratory distress syndrome.17-19 Dexamethasone may exhibit long-term suppression of the hypothalamic pituitary adrenal axis, and is therefore not currently recommended.3 Relative potencies and mineralocorticoid effects of the corticosteroids are listed in Table 1.

Table 1: Relative Corticosteroid Potencies

Historically, supraphysiologic doses of corticosteroids were administered to counteract the underlying inflammatory processes in both critical illness-related corticosteroid insufficiency and perioperative glucocorticoid supplementation; this approach, however, was associated with an increased incidence of superinfection and other adverse effects but not an incremental benefit in anti-inflammatory activity.20-22

Both the Society of Critical Care Medicine critical illness-related corticosteroid insufficiency guidelines3 and the surviving sepsis campaign23 recommend physiologic stress doses of glucocorticoids which, for cortisol, is approximately 200 to 350 mg/day, correlating to 200 to 300 mg/day of hydrocortisone. To achieve this endpoint, hydrocortisone is frequently dosed as 50 mg intravenous every 6 hours and methylprednisolone dosing ranges from 1 to 2 mg/kg/day administered either intermittently or as a continuous infusion.

Adverse Effects

A number of adverse effects are commonly associated with corticosteroid therapy, but appropriate management may offset many of those encountered in the intensive care unit.2,3 The likelihood of adverse effects is related to the dose and duration of therapy, so patients receiving glucocorticoids at baseline may be more likely to encounter these adverse effects. The primary concern with steroids in this population is immunosuppression and the development of superinfection, and infection surveillance is of extreme importance.

The literature is conflicting on this subject, with some studies reporting no increased incidence with current dosing strategies. Conversely, one study reported an increased incidence of infection and new septic shock in patients receiving hydrocortisone.3,16 Hyperglycemia may also be prevalent but is frequently managed by inpatient insulin protocols and limiting glycemic load.

With an increasing focus on delirium, one must also consider the potential contribution of steroid-induced psychosis. Steroid therapy has been implicated as a risk factor for neuropathy and myopathy, which is most common in concurrent neuromuscular blockade; therefore, avoidance of concurrent therapy and monitoring of muscle strength and creatine phosphokinase will likely minimize this adverse event.

Overall, orthopedic patients are more likely to experience acute, self-limiting stress associated with surgery rather than protracted critical illness, thus decreasing the probability of adverse effects common in long-term therapy.

Contribution of Chronic Corticosteroid Use

In addition, some patients may be concurrently receiving glucocorticoids on an outpatient basis and will have a degree of underlying secondary adrenal insufficiency. Degree of hypothalamic pituitary adrenal axis suppression is relative to the dose and duration of prior glucocorticoid therapy, and fatalities, although uncommon, have been reported in patients undergoing surgery who have chronic glucocorticoid therapy withdrawn. Perioperative management of these patients may be accomplished by consideration of the degree of stress caused by the surgery and administration of hydrocortisone based on the extent of the predicted stress response. (Table 2).24

Table 2: Perioperative Glucocorticoid Supplementation for Patients Receiving Chronic Corticosteroids

Septic Shock

Two recent studies have been published on the use of corticosteroids in septic shock.15,16 The first, a multicenter French study published by Annane et al15 in 2002, demonstrated a benefit of hydrocortisone 200 mg/day with enteral fludrocortisone in vasopressor-refractory septic shock patients. Conversely, the 2008 CORTICUS (Corticosteroid Therapy of Septic Shock) study found that a similar population of septic shock patients failed to demonstrate a reduction in mortality with corticosteroids but had faster resolution of septic shock.16 Although initially similar in appearance, several key differences exist between these studies (Table 3).

Table 3: Differences Between Studies Using Hydrocortisone for Critical Illness-Related Corticosteroid Insufficiency Due to Septic Shock

Both studies enrolled patients who were persistently hypotensive despite vasopressor therapy, but patients in the French study were enrolled within 8 hours of septic shock onset, whereas patients in the CORTICUS study were enrolled up to 72 hours. A greater proportion of surgical patients were in the CORTICUS study, suggesting that primary site control may be more important for reversal of septic shock in surgical patients.

Additionally, dosing was slightly different; the French study administered hydrocortisone 50 mg intravenously every 6 hours for 7 days and did not taper, but the CORTICUS trial used the same dosing strategy for 5 days and tapered over 6 days. Tapering is not typically necessary for steroid treatments lasting shorter than 7 days, but there is an increased likelihood of a rebound in inflammatory mediators with abrupt discontinuation.25

Conversely, if patients have been receiving corticosteroids chronically, a taper should be considered as patients may exhibit long-term hypothalamic pituitary adrenal axis suppression. While fixed duration and symptom-driven duration of corticosteroids has been advocated, the guidelines recommend to taper slowly in patients with critical illness-related corticosteroid insufficiency.3 Therapy duration should be guided by the resolution of symptoms initially leading to the diagnosis of critical illness-related corticosteroid insufficiency.

Based on the available evidence, the critical illness-related corticosteroid insufficiency guidelines recommend that, when initiated early, hydrocortisone 200 to 300 mg per day may be beneficial in reducing mortality in septic shock patients who remain hypotensive despite adequate resuscitation and vasopressor therapy; this intervention was also recommended in the 2008 surviving sepsis campaign.23

Other Populations

Benefits of corticosteroid replacement during critical illness has been demonstrated in a number of other patient populations including acute respiratory distress syndrome, severe community-acquired pneumonia, high-risk cardiac surgery, weaning from mechanical ventilation and post-traumatic stress disorder.3,16-19,26

Methylprednisolone use is recommended in patients with early severe acute respiratory distress syndrome or in persistent acute respiratory distress syndrome prior to day 14, as one study showed no benefit in late acute respiratory distress syndrome when started after 14 days duration.17,18

Conclusion

The stress response, which can be triggered by a number of factors, including orthopedic surgery, causes an activation of the hypothalamic pituitary adrenal axis and release of cortisol from the adrenal glands.

Critical illness-related corticosteroid insufficiency is a complex entity that results in an inadequate corticosteroid response relative to a patient’s illness and is most studied in the septic shock and acute respiratory distress syndrome patient populations. These patients have an insufficient circulating cortisol as well as an impaired use of glucocorticoids at the cellular level.

Adrenocorticotropic hormone stimulation testing is not necessary to determine which septic patients will respond to therapy, but it may be beneficial in other cases of adrenal insufficiency. Corticosteroids have been cited to improve survival, oxygenation status, duration of mechanical ventilation, and intensive care unit-free days in critically ill patients.

When initiated early, hydrocortisone may improve survival in patients with septic shock who do not respond to initial resuscitation. Benefit may also be seen in patients with acute respiratory distress syndrome, severe community-acquired pneumonia, postoperative cardiac surgery patients, and in post-traumatic stress disorder; these populations should be further studied to determine the role of steroids in their management.

The Bottom Line
  • Critical illness-related corticosteroid insufficiency is a complex entity resulting from inadequate corticosteroid activity relative to the severity of a patient's illness.
  • Hydrocortisone use has been cited to reduce mortality in patients with septic shock, including surgical patient populations.
  • Patients receiving corticosteroids at baseline should be administered a perioperative glucocorticoid dose relative to the stress of the surgery; most routine orthopedic surgery is considered moderate stress.

References

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  26. Salem M, Tainsh RE Jr, Bromberg J, et al. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg. 1994; 219(4):416-425.

Authors

Drs Gross and Winstead are from Pharmacy Services, UKHealthCare and the Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky.

Drs Gross and Winstead have no relevant financial relationships to disclose.

Correspondence should be addressed to: A. Kendall Gross, PharmD, UK HealthCare, Pharmacy Services, 800 Rose St, H110, Lexington, KY 40536-0293.

DOI: 10.3928/01477447-20090728-40.

10.3928/01477447-20090728-40

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