Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient

Kwame Asare, Pharm.D.


Pharmacotherapy. 2007;27(11):1512-1528. 

In This Article


The use of high-dose glucocorticoids was generally acceptable in the 1970s and early 1980s. With regard to sepsis or shock, high doses of glucocorticoids were defined as methylprednisolone 30 mg/kg/day or more (or its equivalent) for a short duration (1-2 days).[79,80] Recently, there has been a consensus that such doses are not beneficial and may even be harmful.[80,81] Two meta-analyses[79,80] showed that use of glucocorticoids provides no overall benefit in the treatment of septic shock, with one of the meta-analyses suggesting that it may be harmful.[80] The studies included in these metaanalyses used high-dose glucocorticoids for a short period of time. In fact, one meta-analysis[79] showed no overall beneficial effect and no difference between low-dose and high-dose glucocorticoids. The authors defined low-dose glucocorticoids as less than 20 g of hydrocortisone or its equivalent. High-dose glucocorticoids have been associated with increased secondary infections,[79] increased mortality,[80] and increased occurrence of renal and hepatic dysfunction[82] in several studies.

However, two small placebo-controlled trials showed that low-dose hydrocortisone (200-300 mg/day) over a prolonged period (≥ 5 days) significantly decreased the time for vasopressor withdrawal in patients with septic shock, with little effect on mortality.[83,84] In one study, the authors compared hydrocortisone therapy and placebo in patients with septic shock, with a primary end point of shock reversal and a secondary end point of all-cause mortality.[84] The authors defined reversal of shock as systolic blood pressure of 90 mm Hg or higher for at least 24 hours without vasopressors or fluid boluses. Twenty-two patients were randomly assigned to receive hydrocortisone treatment and 19 patients received placebo. The treatment group was noted to have greater reversal of shock at 7 days (p=0.007) and at 28 days (p=0.005) after initiation of therapy. Compared with the placebo group, the median time for cessation of vasopressors was dramatically decreased in the hydrocortisone group (4 vs 13 days). There was also a nonsignificant trend in reduction of 28-day all-cause mortality in the treatment group. In a large, randomized, placebo-controlled, double-blind, parallel-group trial in 19 ICUs in France, patients with septic shock were randomly assigned to receive either placebo (149 patients) or hydrocortisone 50 mg intravenously every 6 hours plus fludrocortisone 50 μg once/day through a nasogastric tube for 7 days (151 patients).[57] Therapy was begun within 8 hours after onset of septic shock. The main outcome measure was 28-day survival in patients with adrenal insufficiency, defined as nonresponders to the ACTH stimulation test (an increase of < 9 μg/dl at 30 or 60 min after administration of the test). Vasopressor therapy was withdrawn within 28 days in 46 patients (40% of 115 nonresponders) in the placebo group and 65 patients (57% of 114 nonresponders ) in the corticosteroid group (hazard ratio 1.91, 95% confidence interval 1.29-2.84, p=0.001). There was a 30% decrease in mortality in the corticosteroid-treated patients. The adverse events rates were similar between the two groups. In addition, the study showed that in patients with septic shock who had adrenal insufficiency, one additional life can be saved at day 28 for every seven patients treated with corticosteroids. The authors concluded that low doses of hydrocortisone and fludrocortisone significantly reduced 28-day mortality and the duration of vasopressor administration in all patients with septic shock, particularly those with adrenal insufficiency, with no increase in adverse effects. For the first time, this study showed a significant reduction in 28-day mortality with the use of low-dose hydrocortisone. It must be noted that patients in this study had more severe septic shock (systolic blood pressure < 90 mm Hg while still receiving vasopressor therapy) compared with other studies (systolic blood pressure could be > 90 mm Hg).

The efficacy of low-dose corticosteroids in patients with less severe sepsis, septic shock, or late sepsis has been questioned by the soon to be published Corticosteroid Therapy in Septic Shock (CORTICUS) study.[85] This was an international, multicenter, double-blind, randomized, controlled trial of corticosteroids for the treatment of sepsis with a primary end point of 28-day all-cause mortality in nonresponders (defined as a change of ≤ 9 μg/dl in cortisol level after the high-dose ACTH stimulation test). Secondary end points included mortality in the entire population, organ failure resolution, and safety. The study was designed to enroll 800 patients in order to have enough power to detect a 10% difference in mortality. However, the study was stopped after 500 patients were enrolled because of difficulty recruiting patients. Patients in the corticosteroid arm received hydrocortisone (without fludrocortisone) 50 mg every 6 hours for 5 days with the dosage tapered over the next 6 days. All-cause mortality was similar between the two arms (34% corticosteroids vs 31% placebo). Although not statistically significant, the rates of shock reversal appeared better in the corticosteroid group. This study differs from the above-mentioned study[57] in several ways. First the patients were not as severely ill; second, corticosteroid therapy was started within 72 hours versus 8 hours; and third, fludrocortisone was not administered. Although underpowered, this study has raised questions about the use of corticosteroids in late sepsis and in less severely ill patients. In patients with septic shock, the benefits of corticosteroids, given within 24 or 48 hours, remain to be shown. Needless to say, it might be reasonable to start low-dose corticosteroid therapy as early as possible in patients with severe septic shock, especially when overwhelming inflammation predominates.[30]

Overall, the data suggest that the use of lowdose corticosteroids for a longer period of time shortens the time receiving vasopressor therapy in severely ill patients with septic shock. In addition, none of the newly published clinical trials suggests an increase in mortality in patients with septic shock after low-dose glucocorticoids (i.e., hydrocortisone 200-300 mg/day).[86] It must be emphasized that low-dose corticosteroids should not be used for the treatment of sepsis in the absence of shock,[30] although there is no contraindication to continuing maintenance therapy for other conditions.[30] Low-dose corticosteroid replacement may also be beneficial in patients with trauma, burns, and surgical and medical conditions in which there is evidence of adrenal insufficiency.[87]

Intravenous hydrocortisone, methylprednisolone, and dexamethasone are the three glucocorticoids most commonly administered to critically ill patients with adrenal insufficiency due to stress. To this author's knowledge, no comparative study of the different corticosteroids has been performed in critically ill patients; however, hydrocortisone is usually the preferred agent because it is the synthetic equivalent of cortisol, directly replacing cortisol with no metabolism required. Furthermore, it has both glucocorticoid and mineralocorticoid activities (unlike dexamethasone and methylprednisolone) and has been most extensively studied.[57,83,84,88,89] How essential the addition of a mineralocorticoid to the glucocorticoid remains controversial. Although one can argue that mineralocorticoid activity is necessary for possible absolute adrenal insufficiency, this condition is quite rare in septic shock (reported frequency of 0-3%).[10,90] Others have argued that the dose of hydrocortisone used has enough mineralocorticoid activity, and therefore fludrocortisone is not needed even when the patient has primary adrenal insufficiency.[27,55] It is estimated that 20 mg of hydrocortisone is equivalent to 0.05 mg of fludrocortisone with regard to mineralocorticoid potency, and hence, fludrocortisone is only needed when the daily hydrocortisone dose is less than 50 mg.[91]

The reader must bear in mind, however, that although most studies showed hemodynamic improvement without adding fludrocortisone,[83,84,88,92] the only study that showed a significant reduction in 28-day mortality[57] used both hydrocortisone and fludrocortisone. Whether the addition of mineralocorticoid accounted for the decrease in mortality is unclear. There has not been a comparative study between hydrocortisone alone and hydrocortisone plus fludrocortisone.[30] Hydrocortisone and prednisone are the preferred glucocorticoids in the pregnant patient with suspected or confirmed adrenal insufficiency since they are readily inactivated by the placenta. In contrast, dexamethasone readily crosses the placenta and suppresses fetal adrenal function.[93]

The recommended dosage of hydrocortisone is 200-300 mg/day in three or four divided doses of 50 mg every 6 hours or 100 mg every 8 hours, or as a 50-100-mg bolus over 30 minutes followed by a 10-mg/hour continuous infusion.[21] Although a comparative study of intermittent versus continuous infusion has not been performed, hemodynamic improvement to a similar extent has been reported with both regimens.[57,84,88,92,94] If needed, the dose of fludrocortisone supported by the literature is 0.5 mg/day,[57] with a recommended range of 0.5-2 mg/day.[30] If the ACTH stimulation test cannot be performed immediately for some reason in a patient with suspected adrenal insufficiency, it is recommended to begin equivalent doses of dexamethasone until the test can be performed. Dexamethasone does not cross-react with the cortisol assay and will not interfere with the measurement of cortisol in response to the ACTH stimulation test,[2,12] and it should be continued until the test can be performed. When the result is available, therapy may be continued in nonresponders and discontinued in responders. One group of authors observed that hemodynamic improvement often occurred within 24 hours of glucocorticoid administration in patients with septic shock.[31] As a patient improves clinically, discontinuation of the corticosteroid should be considered.[25]

An important question is whether glucocorticoids should be tapered after resolution of shock. Although use of low-dose glucocorticoids over 5-7 days is safe,[57] it is recommended, but not required, to taper at the end of therapy by halving the dose every 2-3 days.[30,83] The reader is hereby cautioned that this recommendation is not based on controlled clinical trials. When shock recurs during weaning, reestablishing the original steroid dose might be considered.[30]

While a patient is receiving glucocorticoids, hyperglycemia should be avoided by routinely monitoring blood glucose levels.[95,96,97,98] In surgical and medical ICUs, the blood glucose level should probably be maintained below 110 mg/dl[95,96] since it has been shown that tight glycemic control reduces mortality among patients with extended ICU stays.[95,96,98] Concern for hypoglycemic episodes has been the primary reason for the limited use of tight glycemic control (blood glucose levels 80-110 mg/dl) in the critically ill patient. In a recent article, the shortterm consequences of hypoglycemia (blood glucose level < 45 mg/dl) in patients in the ICU were evaluated.[99] The authors found no association between incidental hypoglycemia and mortality. This is consistent with the findings of an earlier study that investigated the association between hypoglycemia and mortality in hospitalized elderly patients.[100] A larger study is needed to confirm the conclusions of these rather small studies. However, the findings of Comparing the Effects of Two Glucose Control Regimens by Insulin in Intensive Care Unit Patients (GLUCONTROL),[101] a recent unpublished study, have regenerated the ongoing debate over the optimal range for glycemic control. This was a multicenter, international study in mixed ICU populations that compared a tight glycemic group (blood glucose level 80-110 mg/dl) with a conventional group (blood glucose level 140-180 mg/dl). The researchers had planned to enroll 3500 patients to determine if a 4% reduction in mortality could be detected. After 1100 patients were recruited, an interim analysis showed no difference in 28-day mortality (16.9% for the tight glycemic group vs 15.2% in the conventional group), neither was there a significant difference in length of stay. However, an alarming increase in hypoglycemic episodes was observed in the tight glycemic group (8.6% for tight glycemic group vs 2.4% for the conventional group). Since the GLUCONTROL study was not completed, it remains to be seen what impact it will have on clinical practice. The ongoing Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study, which plans to enroll 6100 patients in 35 ICUs to compare two protocols (81-108 vs 144-180 mg/dl), hopefully will provide some answers to this debate.


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