INTRODUCTION — The role of glucocorticoid therapy in patients with septic shock has evolved since the 1990s. The rationale for glucocorticoid administration, assessing adrenal reserve, and indications for glucocorticoid therapy are discussed in this topic review. Other aspects of the management of sepsis and septic shock are reviewed separately. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Evaluation and management of suspected sepsis and septic shock in adults".)
RATIONALE — The rationale for glucocorticoid administration in patients with sepsis and septic shock is based upon data which suggest that critical illness induces a state of absolute or relative adrenal insufficiency that may contribute to shock. The purpose of administering glucocorticoids to patients with sepsis is to restore balance to the altered hypothalamic-pituitary-adrenal (HPA) axis with the goal of improving clinically meaningful outcomes such as mortality.
Mechanisms of adrenal insufficiency in sepsis — There are several mechanisms through which critical illness affects cortisol levels and function including HPA activation (resulting in increased levels of circulating cortisol), HPA impairment (resulting in adrenocortical hyporesponsiveness), and glucocorticoid resistance.
●Activation of the HPA axis – Normal serum cortisol levels range between 5 and 24 mcg/dL, with significant variability depending upon the time of day [1]. In patients who are critically ill, diurnal variation is lost and serum cortisol increases, reaching levels as high as 40 to 50 mcg/dL (figure 1) [2-6]. Cortisol metabolism and function may also be considerably altered by other aspects of critical illness including reduced cortisol breakdown [6], reduced binding of cortisol to cortisol binding globulin (CBG) and albumin [7,8], increased glucocorticoid receptor affinity for cortisol, and peripheral conversion of precursors to cortisol [9,10].
●Impairment of the HPA axis – Among critically ill patients, several factors are known to impair the HPA axis including head injury, central nervous system depressants, pituitary infarction, adrenal hemorrhage, infections, malignancy, previous glucocorticoid therapy, and several drugs like ketoconazole, phenytoin, and etomidate [11-13].
However, the clinical importance of HPA impairment is uncertain. As an example, a randomized trial that compared etomidate with ketamine for rapid sequence induction found that, despite an impaired response to adrenocorticotropic hormone (ACTH), etomidate was not associated with worse clinical outcomes [14].
●Glucocorticoid resistance – Glucocorticoid resistance has also been proposed as a possible mechanism at play in patients with sepsis and septic shock. One study reported that compared with healthy controls, septic patients demonstrated higher expression levels of the beta-isoform of the glucocorticoid receptor, an isoform which is associated with steroid resistance [15]. However, functional differences were not observed. Other mechanisms of glucocorticoid resistance are discussed separately. (See "Mechanisms and clinical implications of glucocorticoid resistance in asthma", section on 'Mechanisms of glucocorticoid resistance'.)
Critical illness-related corticosteroid insufficiency — It is thought that absolute adrenal insufficiency is rare among critically ill patients, with an incidence estimated to be ≤3 percent [16]. However, the term relative adrenal insufficiency (ie, suboptimal cortisol production for total body demands) has been coined to take into account the high prevalence of HPA dysfunction in those who are critically ill. This condition has also been termed "critical illness-related corticosteroid insufficiency (CIRCI)" [17]. However, there is no consensus about the diagnostic criteria of CIRCI. In addition, there exists considerable disagreement over what cortisol level is "normal" or "appropriate" in septic shock, what constitutes an adequate response to ACTH, and what dose of synthetic ACTH should be used for stimulation testing. We believe that it is uncertain whether "relative adrenal insufficiency" is a true diagnostic entity, since a clear definition is lacking and the cortisol assays that are available at most clinical laboratories are unreliable in the critically ill patient.
Should adrenal reserve be assessed? — In general, most clinicians do not rely on laboratory testing to select glucocorticoid replacement therapy in patients with septic shock. This is because laboratory assays of plasma cortisol concentration and response to ACTH stimulation are unreliable in critically ill patients. In addition, in major randomized trials, baseline cortisol levels and the ACTH stimulation test have failed to consistently identify patients with septic shock who benefit from glucocorticoid use (see 'Efficacy' below). With this caveat in mind, for clinicians who wish to assess adrenal reserve in critically ill patients, international guidelines from the Society of Critical Care Medicine and European Society of Intensive Care Medicine [17] endorse the use of a change in baseline cortisol at 60 min of <9 mcg/dL after cosyntropin (250 mcg; ie, high-dose ACTH stimulation) administration and a random plasma cortisol of ≤10 mcg/dL as indicators of likely adrenal insufficiency in critically ill patients.
Studies describing the diagnostic and prognostic performance of these tests in critically ill patients are discussed below.
●Random serum cortisol – Total serum cortisol levels vary widely in patients with septic shock [5,18-23]. There is no robust relationship between serum cortisol levels and mortality in patients with septic shock [19,21,24-31]. One prospective study of 101 patients with sepsis reported that the best predictor of adrenal insufficiency (as measured by an overnight ACTH stimulation test) was baseline random cortisol level of ≤10 microg/dL or a change of cortisol of <9 microg/dL [24].
●Free cortisol – In critically ill patients there is a shift from inactive protein-bound cortisol to physiologically active free cortisol. It has been proposed that free cortisol more accurately reflects HPA axis activation in critically ill patients [32]. However, standard assays for plasma cortisol measure total (free + bound) plasma cortisol and free cortisol assays are not available at most clinical centers [33]. Thus, most experts agree that standard assays underestimate HPA axis activity in this population.
Supporting free cortisol as a more accurate measurement of adrenal insufficiency in critically ill patients are the following:
•One prospective study reported that critically ill patients had free cortisol levels that were 7 to 10 times higher than healthy volunteers compared with total serum cortisol concentrations that were only two to three times higher [32]. However, this study was limited by the lack of inclusion of patients with septic shock and the omission of data describing hemodynamic instability at the time of plasma cortisol sampling.
•In another prospective study, baseline free cortisol levels reflected the severity of illness more closely than total cortisol levels [34]; free cortisol levels were 186 nmol/L in patients with septic shock, 29 nmol/L in patients with sepsis, and 13 nmol/L in healthy controls while total cortisol levels were 880 nmol/L in patients with septic shock, 417 nmol/L in patients with sepsis, and 352 nmol/L in healthy controls.
Further complicating matters, one study suggested that plasma levels of cortisol (free or total) had only moderate correlation with tissue availability of the hormone, suggesting that during critical illness, blood levels of cortisol poorly reflect the amount of hormone available to target tissues [35].
●ACTH stimulation tests — The ACTH (cosyntropin) stimulation test requires that a baseline serum cortisol be drawn, synthetic ACTH (cosyntropin) be administered intravenously, and serum cortisol levels then be drawn 30 and 60 minutes later.
Despite extensive investigation, ACTH stimulation tests are thought to be unreliable in critically ill patients for several reasons:
•Some critically ill individuals have spontaneous increases in their serum cortisol of ≥9 mcg/dL WITHOUT cosyntropin stimulation [36]. Thus, this threshold may not be clinically helpful.
•ACTH stimulation tests may give inconsistent results in the same individuals if performed on more than one occasion [19,37].
•Standard immunoassays appear to correlate poorly with the reference standard (mass spectrometry) in septic shock with one study reporting that approximately 27 percent of ACTH stimulation test samples were incorrectly classified by immunoassays compared with mass spectrometry measurements [38].
•Etomidate, which suppresses the HPA axis [14,39], if used for intubating patients with septic shock, can interfere with the results of ACTH stimulation.
Studies using high-dose ACTH stimulation (250 mcg cosyntropin) have yielded variable results in septic shock [19,22,31,40,41]. For example, one prospective cohort study of 189 patients with septic shock reported that a baseline serum cortisol level >34 mcg/dL and a maximum increase in cortisol of ≤9 mcg/dL were identified as risk factors for death [41]. Similarly, another retrospective cohort study of 477 patients with severe sepsis or septic shock reported that nonsurvivors had a higher baseline cortisol level (30 versus 24 mcg/dL) and a smaller cortisol increase (6 versus 11 mcg/dL) than survivors [42]. In contrast, another study found that patients with either a baseline cortisol level <15 mcg/dL or a cortisol increase ≤9 mcg/dL had a higher mortality, longer duration of shock, or shorter survival time.
Low-dose (1 mcg) ACTH stimulation testing has been compared with high-dose ACTH stimulation testing in patients with septic shock. In a prospective cohort study of 59 patients with septic shock, adrenal insufficiency (defined as post-cosyntropin serum cortisol of <18 mcg/dL) was detected in more patients by low-dose ACTH testing than high-dose ACTH testing (22 versus 8 percent) [43]. Low-dose testing was superior compared with high-dose testing at identifying steroid responders (ie, patients able to maintain a mean arterial blood pressure >65 mmHg without norepinephrine infusion within 24 hours) from non-responders. In another retrospective study, non-responders to the low-dose test had a lower survival rate than responders to both tests (27 versus 47 percent) [44]. Low-dose testing identified a subgroup of patients in septic shock with inadequate adrenal reserve who had a worse outcome and would have been missed by the high-dose test; in addition, non-responders of either low- or high-dose stimulation were less likely to survive than responders. While these studies suggest that low-dose stimulation testing may predict death, further studies are needed to validate these findings.
ACTH stimulation testing for non-critically-ill patients is discussed separately. (See "Diagnosis of adrenal insufficiency in adults", section on 'ACTH stimulation tests'.)
GLUCOCORTICOID THERAPY — The major challenge associated with the administration of glucocorticoids to patients with sepsis is to select those who are likely to benefit.
Patient selection — When considering patients with sepsis and septic shock for glucocorticoid therapy, we generally use the following guidelines:
●For adult patients with septic shock, we suggest not routinely using intravenous glucocorticoid therapy as part of initial therapy.
●We use glucocorticoid therapy on a case-by-case basis in patients with refractory shock (defined as a systolic blood pressure <90 mmHg for more than one hour following both adequate fluid resuscitation and vasopressor administration).
●When the decision is made to use glucocorticoid therapy, we suggest hydrocortisone alone (<400 mg per day in divided doses) rather than combined therapy with fludrocortisone. However, addition of fludrocortisone (50 mcg via gastric tube once daily) is a reasonable alternative based upon some trials that showed a mortality benefit [45,46].
This approach is based upon randomized trials and meta-analyses that have consistently demonstrated that while glucocorticoid therapy leads to faster resolution of shock, there appears to be minimal or no effect on mortality; in addition, benefit is more likely to be seen in those who are severely ill rather than those with mild illness [45-52]. Our recommendation is, in principle, consistent with that of other experts who state that either option of administering or not administering corticosteroids is reasonable [53].
Efficacy — In the 1980s, three randomized studies of high-dose glucocorticoids (eg, 30 mg/kg of methylprednisolone) showed no mortality benefit (at 14 days) in critically ill patients [54-56]. In the 1990s, three small trials showed that compared with placebo, low-dose hydrocortisone (eg, 200 to 400 mg per day) in patients with septic shock resulted in faster shock reversal (ie, faster pressor withdrawal) [57-59]. These trials prompted larger randomized trials, most of which have confirmed faster resolution of shock with no or minimal mortality benefit.
Studies that showed benefit — Two major randomized trials demonstrated faster resolution of shock together with a mortality benefit from the administration of both hydrocortisone and fludrocortisone.
●French trial – In the 2002 French study, 300 patients were randomly assigned to receive placebo or hydrocortisone (50 mg intravenously every six hours) plus fludrocortisone (50 mcg enterally once a day) for vasopressor-dependent septic shock [45]. Treatment began within eight hours of the onset of septic shock and continued for seven days. Hydrocortisone/fludrocortisone administration decreased 28-day mortality (55 versus 61 percent) and resulted in faster shock reversal (57 versus 40 percent). These benefits were maintained among patients with inadequate adrenal reserve (maximum increase in serum cortisol of <9 mcg/dL on a high dose ACTH test) while no benefit was demonstrated in those who had an adequate adrenal reserve. The trial was criticized for its high placebo-group mortality [60-62].
●Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHHS) – The same group published another trial in 2018. In this multicenter trial, 1241 patients with severe septic shock (mixed surgical and medical patients) on vasopressors, most of whom were mechanically ventilated, were randomized to receive placebo or hydrocortisone (200 mg per day in four divided doses) plus fludrocortisone (50 micrograms via nasogastric tube daily) for seven days without tapering [46]. Hydrocortisone/fludrocortisone administration decreased 90-day mortality (43 versus 49 percent) and 180-day mortality (47 versus 53 percent), and increased vasopressor-free days (17 versus 15 days). Also improved by hydrocortisone/fludrocortisone administration were ICU discharge (35 versus 41 percent), hospital discharge (39 versus 45 percent), and organ failure-free days (14 versus 12 days). There was no increase in the rates of superinfection or neurologic sequelae but corticosteroids resulted in an increase in the rate of hyperglycemia (89 versus 83 percent).
Differences between these two trials [45,46] and those that did not show a mortality benefit (see 'Studies that showed no mortality benefit' below) may be explained by the following:
●Sicker patients – Both the initial French trial and APROCCHHS were comprised of a sicker group of patients as evidenced by the high simplified acute physiology II scores (SAPS II), greater need for higher doses of vasopressors at the time of enrollment, and higher mortality risk. (See "Predictive scoring systems in the intensive care unit".)
●Different sepsis sources – Sources of infections may have also been different. For example, APROCCHSS had fewer patients with abdominal infection following surgery and had more patients with lung infections than trials that showed benefit.
●Addition of mineralocorticoid – Both studies included the addition of fludrocortisone to hydrocortisone as opposed to hydrocortisone alone. While one retrospective study suggested benefit [63], the biologic plausibility of additional mineralocorticoid to hydrocortisone, which is thought to have sufficient mineralocorticoid effect, is unclear. Differences among the agents are discussed separately. (See 'Type (hydrocortisone preferred)' below.)
Studies that showed no mortality benefit — Several major randomized trials demonstrated faster resolution of shock without a mortality benefit from the administration of hydrocortisone.
●Corticosteroid Therapy of Septic Shock (CORTICUS) – In this 2008 trial of 499 patients with septic shock (regardless of pressor dependency) hydrocortisone (50 mg) or placebo was administered intravenously every six hours for five days [47]. While hydrocortisone administration resulted in a faster reversal of shock (3.3 versus 5.8 days), hydrocortisone did not improve 28-day mortality (35 versus 32 percent in the placebo group). Outcomes were similar in the two pre-defined subgroups: patients with inadequate adrenal reserve and patients with adequate adrenal reserve. Hydrocortisone also resulted in an increased incidence of new infection that did not reach statistical significance (odds ratio 1.27, 95% CI 0.96-1.68). The trial was criticized for the lower than expected placebo-group mortality (32 percent versus the anticipated 50 percent).
●Hydrocortisone for the prevention of septic shock (HYPRESS) – In this 2016 trial, 353 patients who had severe sepsis but without septic shock were randomized to receive hydrocortisone or placebo [48].The definition of severe sepsis was based upon the older definition of sepsis but comprised of patients with evidence of infection, at least two indices of the systemic inflammatory response syndrome criteria (table 1 and table 2) and evidence of organ dysfunction present for no longer than 48 hours. Approximately half of patients had hospital-acquired sepsis. Compared with placebo, an infusion of hydrocortisone 200 mg daily for five days followed by tapering until day 11 had no significant effect on progression to septic shock or mortality. Hydrocortisone was associated with an increased rate of hyperglycemia (91 versus 82 percent) and a nonsignificant increase in the rate of infections (22 versus 17 percent) and muscle weakness (31 versus 24 percent). Criticisms of this trial included the exclusion of patients with septic shock and the inadequate assessment of CIRCI. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Definitions'.)
●Effect of Early Vasopressin versus Norepinephrine on Kidney Failure in Patients with Septic Shock (Vanish) – In this 2016 trial that compared vasopressin with norepinephrine in patients with septic shock, when compared with placebo, the addition of hydrocortisone to either vasopressor did not result in a mortality benefit (28-day mortality 33 versus 29 percent for vasopressin group and 29 versus 26 percent for norepinephrine group) or have an effect on the rate of kidney failure [64].
●Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) – In this 2018 multicenter trial, 3800 patients (medical and surgical) who were mechanically ventilated and on vasopressors for at least four hours for septic shock were randomized to receive placebo or a continuous intravenous infusion of hydrocortisone (200 mg per day for seven days, death, or discharge from the ICU, whichever came first) [49]. Corticotropin testing was not used to attempt to diagnose CIRCI. Hydrocortisone resulted in a faster resolution of shock (three versus four days), shorter duration of initial mechanical ventilation (six versus seven days), lower incidence of blood transfusion (37 versus 42 percent), and possibly, number of days alive outside of the ICU (58 versus 56 days). However, hydrocortisone administration did not improve 28- or 90-day mortality, overall number of mechanical ventilation-free days, rate of recurrent shock, or rate of renal replacement therapy. Hydrocortisone infusion did not increase the risk of new onset bacteremia or fungemia but patients did have higher rates of hyperglycemia and hypernatremia. A post-hoc analysis of this trial that applied updated Sepsis-3 or Sepsis-2 inclusion criteria to the study population still reported no mortality benefit from hydrocortisone [65].
Meta-analyses — While older meta-analyses suggested that glucocorticoid therapy may benefit patients with septic shock [66-71], newer meta-analyses that included all the major randomized trials listed above (see 'Studies that showed benefit' above and 'Studies that showed no mortality benefit' above) have reported that systemic corticosteroids confer no or minimal mortality benefit but do shorten the duration of shock [50,51,72-74]. As examples:
●In a 2018 meta-analysis of 22 trials that included 7297 patients, compared with placebo, corticosteroids did not improve short-term or long-term mortality (relative risk [RR] 0.98, 95% CI 0.89-1.08 and RR 0.96, 95% CI 0.91-1.02, respectively) [50]. Adverse events were greater in the group that received corticosteroids (hypernatremia, hyperglycemia) with substantial heterogeneity but the duration of shock was shorter (mean difference [MD] -1.52 days; 95% CI -1.72 to -1.32 days) as was the duration of mechanical ventilation (MD -1.38 days; 95% CI -1.96 to -0.80 days) and duration of ICU stay (MD -0.75 days; 95% CI; -1.34 to -0.17 days).
●A second meta-analysis of 42 trials including 10,194 patients, showed similar results [51]. While higher rates of shock reversal were reported compared with placebo (RR 1.26; 95% CI 1.12 to 1.42), corticosteroids resulted in minimal or no reduction in the risk of death (RR 0.93; 95% CI, 0.84-1.03, 1.8 percent absolute risk reduction at 28 days; RR 0.94; 95% CI 0.89-1.00, 2.2 percent risk reduction at 60 days). Also reported was a possible reduction in the length of hospital stay (-0.73 days; 95% CI -2.06 to 0.60), and a slight increase in the risk of hypernatremia (RR 1.64; 95% CI 1.32-2.03), hyperglycemia (1.16; 95% CI 1.08-1.24), and neuromuscular weakness (1.21; 95% CI 1.01-1.52).
ADMINISTRATION
Type (hydrocortisone preferred) — While older studies used methylprednisolone, most major, well-conducted randomized trials used hydrocortisone as the glucocorticoid of choice in patients with sepsis and septic shock. Although some trials added fludrocortisone, we do not typically add fludrocortisone because we believe that hydrocortisone alone has sufficient mineralocorticoid effect and absorption of the enterally administered drug is questionable in situations of compromised splanchnic perfusion [75]. Our decision to forego fludrocortisone is supported by others [17] and a trial (the Corticosteroids and Intensive Insulin Therapy for Septic Shock [COIITSS] trial) that randomly assigned 509 patients with septic shock to receive either hydrocortisone plus fludrocortisone or hydrocortisone alone [76]. There was no difference in any of the clinical outcomes. Nonetheless, some experts add fludrocortisone to hydrocortisone since two randomized trials demonstrated benefit in sick patients with septic shock (the French study and Activated Protein C and Corticosteroids for Human Septic Shock [APROCCHSS]) [45,46]. (See 'Studies that showed benefit' above.)
Compared with hydrocortisone, other pharmacologic glucocorticoids bind cortisol-binding globulin (CBG) poorly, resulting in greater amounts of free, physiologically active glucocorticoid and greater potency at any given dose. The different preparations vary widely in anti-inflammatory and mineralocorticoid potency (table 3). Thus, if administering another glucocorticoid, the clinician should be familiar with the potency of that agent relative to hydrocortisone.
Dose — We typically administer 200 to 300 mg per day of hydrocortisone intravenously in divided doses (50 mg every six hours or 100 mg every eight hours). This is consistent with guidelines set out by the Society of Critical Care Medicine (SCCM) and European Society of Critical Care Medicine (EISCM) who recommend <400 mg/day of hydrocortisone [17]. Most studies evaluating the effect of glucocorticoids in septic shock used hydrocortisone in divided doses rather than an infusion. Although one small prospective study showed less variability in blood glucose levels with continuous hydrocortisone infusions, the clinical benefit, from a mortality and shock reversal standpoint, remains unknown [77].
Dosing for methylprednisone is less well studied, but one suggested regimen is 40 to 60 mg daily intravenously in divided doses for a similar time period.
Fludrocortisone is administered as 0.05 mg once daily for 5 to 7 days (in combination with IV hydrocortisone or equivalent) [45,46,78].
Duration — We typically administer five to seven days of therapy and have a tapered approach to withdrawal that is guided by the clinical response (eg, taper quickly following vasopressor withdrawal). Close observation of those patients whose steroid therapy is stopped without being tapered is warranted. This practice is consistent with SCCM/EISCM guidelines who recommend <400 mg/day for ≥3 days [17]. There is no specific tapering regimen, and they vary widely.
There is no consensus regarding the optimal duration of treatment with, or withdrawal of, glucocorticoids. No large study has compared fixed-duration regimens to clinically-guided regimens, or tapering to abrupt cessation. However, in one small clinical study, abrupt cessation was associated with rebound of hemodynamic abnormalities and increased inflammatory markers [79]. In contrast, in another retrospective study reinitiation of vasopressor therapy was more common among patients in whom glucocorticoids were tapered compared with patients in whom glucocorticoid therapy was stopped abruptly [80].
Fludrocortisone is generally not tapered.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in children and adults".)
SUMMARY AND RECOMMENDATIONS
●Critical illness-related adrenal insufficiency – It is thought that absolute adrenal insufficiency is rare among critically ill patients. (See 'Rationale' above.)
•Definition – While relative adrenal insufficiency (ie, critical illness-related corticosteroid insufficiency [CIRCI]) may be more common, a clear definition of CIRCI is lacking, so the incidence is unknown. (See 'Critical illness-related corticosteroid insufficiency' above.)
•Mechanism – There are several mechanisms through which critical illness effects cortisol levels and function including activation and impairment of the hypothalamic-pituitary-adrenal (HPA) axis resulting in increased levels of circulating cortisol and adrenocortical hyporesponsiveness, respectively, and glucocorticoid resistance. (See 'Mechanisms of adrenal insufficiency in sepsis' above.)
•Laboratory testing – In general, most clinicians do not rely on laboratory testing to select glucocorticoid therapy in patients with septic shock because laboratory assays of plasma cortisol and adrenocorticotropic hormone (ACTH) stimulation testing are unreliable in critically ill patients and because testing has failed to consistently predict those who benefit from glucocorticoid use. With this caveat in mind, for clinicians who wish to assess adrenal reserve in critically ill patients, international guidelines endorse the use of a change in baseline cortisol at 60 min of <9 mcg/dL after 250 mcg intravenously of cosyntropin (250 mcg; ie, high-dose ACTH stimulation) administration and a random plasma cortisol of <10 mcg/dL as indicators of likely adrenal insufficiency. (See 'Should adrenal reserve be assessed?' above.)
●Our approach – We generally use the following guidelines when considering patients with sepsis and septic shock for glucocorticoid therapy (see 'Glucocorticoid therapy' above):
•Recommendations
-For adult patients with sepsis and septic shock, we suggest not routinely using intravenous glucocorticoid therapy as part of initial therapy (Grade 2B).
-We use glucocorticoid therapy on a case-by-case basis in patients with refractory shock (defined as a systolic blood pressure <90 mmHg for more than one hour following both adequate fluid resuscitation and vasopressor administration).
•Efficacy data to support the approach – This approach is based upon randomized trials and meta-analyses that have consistently demonstrated that while glucocorticoid therapy leads to faster resolution of shock, there appears to be minimal or no effect on mortality; in addition, benefit is more likely to be seen in those who are severely ill rather than those with mild illness.
•Adverse effects – Potential adverse effects associated with the administration of steroids in this population include hypernatremia, hyperglycemia, and neuromuscular weakness. The risk of superinfection does not appear to be consistently elevated among studies.
●Administration – When the decision is made to use glucocorticoid therapy, we suggest hydrocortisone alone (<400 mg per day in divided doses) rather than combined therapy with fludrocortisone (Grade 2C). However, addition of fludrocortisone (50 mcg via gastric tube once daily) is a reasonable alternative based upon two trials that showed a mortality benefit. We typically administer five to seven days of therapy and use a tapered approach to withdrawal that is guided by the clinical response. Close observation of patients whose steroid therapy is stopped without being tapered is warranted. (See 'Administration' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jordi Mancebo, MD, who contributed to an earlier version of this topic review.
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