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CHAPTER 102: Critical Illness–Related Corticosteroid Insufficiency 983

the underlying disease. CIRCI should also be considered in patients with 20 meta-analyses have been published in an attempt to better under-
progressive ALI. Laboratory assessment may demonstrate eosinophilia stand the role of glucocorticoids in the treatment of critically ill patients.
and hypoglycemia. Hyponatremia and hyperkalemia are uncommon. The results of these studies together with our current understanding
of CIRCI allow us to make a number of general recommendations. It
DIAGNOSIS OF ADRENAL INSUFFICIENCY AND CIRCI should be appreciated that the nonstressed daily production of cortisol
(hydrocortisone) in adults is approximately 15 to 25 mg/day while the
The diagnosis of adrenal insufficiency in the critically ill is fraught with maximal stressed daily production of cortisol (hydrocortisone) is about
difficulties. Furthermore we have no test that quantifies corticosteroid 200 to 350 mg/day. Based on these data, a daily dose of hydrocorti-
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activity at the tissue level. Traditionally the diagnosis of adrenal insuf- sone (or equivalent) of 25 to 200 mg/day can be considered “low-dose,”
ficiency in the critically ill has been based on the measurement of a 200 to 350 mg/day a physiologic “stress-dose”, 351 to 1000 mg/day a
random total serum cortisol (“stress” cortisol level) or the change in “supraphysiologic” dose, and >1000 mg/day pharmacologic-dose corti-
the serum cortisol in response to 250 µg of synthetic ACTH (cosyntro- costeroid. A number of RCTs have investigated the clinical outcomes of
pin) the so-called delta cortisol. 18,40 Both of these tests have significant pharmacologic-dose, short course corticosteroid treatment in patients
limitations in the critically ill. Commercially available cortisol assays with ARDS and sepsis. Doses of methylprednisolone as high as 20
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measure the total hormone concentration rather than the biologically to 30 mg/kg body weight (10,000-40,000 mg of hydrocortisone) over
active free cortisol concentration Furthermore, the timing of cortisol 24 hours were investigated. 27,28 These studies were unable to demonstrate
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measurements may be important as large hourly variations in cortisol improved outcomes and there was a higher incidence of complications
have been reported. 41,43 In addition, the reproducibility of the ACTH in the patients who received high-dose corticosteroids. 27,28 Furthermore,
stimulation test is poor in critically ill patients. 43,44 To complicate the issue this dosing strategy is at odds with our current understanding of CIRCI.
further, the specificity, sensitivity, and performance of the commercially Ideally the dose of corticosteroid should be sufficient to downregulate
available assays are not uniform. Despite these limitations, Annane and the proinflammatory response without causing excessive immune
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colleagues have reported that a delta cortisol of less than 9 µg/dL was the paresis and interference with wound healing. Similarly, the duration of
best predictor of adrenal insufficiency (as determined by metyrapone glucocorticoid therapy should be guided by the duration of CIRCI and
testing) in patients with severe sepsis/septic shock. A cortisol of less the associated duration of systemic inflammation.
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than 10 µg/dL was also highly predictive of adrenal insufficiency (PPV of Schneider and Voerman were the first investigators (in 1991) to sug-
0.93); however, the sensitivity of the test was poor (0.19). gest that “physiologic and not pharmacologic doses of glucocorticoids
One approach to resolving the question of whether too little glucocor- [be administered] in the course of septic shock.” These authors dem-
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ticoid signal ultimately “gets through” is to examine target tissues whose onstrated reversal of shock in three of eight patients given “100 mg of
function is regulated in part by glucocorticoids. Through their inhibitory hydrocortisone intravenously followed by 100 mg every 8 hours with
effects on nuclear factor-κβ signaling pathways, glucocorticoids are the dose tapering with improvement.” The use of extended course, stress-
most potent anti-inflammatory hormones in the body and thereby serve dose corticosteroids has been evaluated in 10 RCTs in critically ill
to suppress the production and activity of proinflammatory cytokines patients with sepsis, septic shock, and ARDS (see Table 102-2). 29-31,49-54
during exposure to stress. Inadequate glucocorticoid-mediated feed- Overall, this dosing strategy has been reported to be associated with a
back inhibition of the immune response will result in excess circulating significant reduction in 28-day all-cause mortality, more rapid weaning
levels of proinflammatory mediators. Kwon and colleagues measured of vasopressor agents (septic shock), a reduction in ICU length of stay,
the levels of proinflammatory mediators in a cohort of 82 patients, most and an increase in ventilator-free days (ARDS). 27,28,33,55 It is, however,
of whom had sepsis. Thirty-six patients (43%) met the above cited important to realize that the analysis and meta-analyses of these studies
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criteria for adrenal inefficiency. The authors divided the patients with are largely influenced by the largest two studies, namely, the study by
adrenal inefficiency into two groups, namely (1) those with a low basal Annane et al and the CORTICUS study. 31,49 Both of these studies have
cortisol (basal cortisol <10 µg/dL ) and (2) those with a basal cortisol important limitations in that 24% patients received etomidate in the
>10 µg/dL and a delta cortisol <9 µg/dL. In the group of patients with Annane study while 19% received etomidate in the CORTICUS study
a low delta cortisol the serum levels of proinflammatory mediators (see implication below). Furthermore, only patients with “refractory
were markedly elevated compared to group of patients with a low basal septic shock” were enrolled into the Annane study while an overwhelm-
cortisol. In the low basal cortisol group the levels of proinflammatory ing selection bias resulted in approximately only 5% of eligible patients
mediators were similar to those of the nonadrenal insufficiency control being enrolled into the CORTICUS study. A more recent study found
patients. These data suggest that the adrenal insufficiency subgroup with no benefit from a 7-day course of 40 mg prednisolone in patients hos-
a low delta cortisol may truly have too little glucocorticoid signaling pitalized with community-acquired pneumonia. Based on the current
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while the low baseline subgroup appears to have adequate cellular gluco- data, it is not possible to make strong recommendations regarding the
corticoid activity. From a pathophysiological and therapeutic standpoint use of corticosteroids in the critically ill. The risk/benefit ratio should be
it may therefore be useful to divide adrenal inefficiency/CIRCI into two determined in each patient and a “prolonged” course (10-14 days) of low
subgroups, namely, Type I, characterized by a random (stress) cortisol dose (200 mg/day hydrocortisone or equivalent) should be considered
<10 µg/dL, and Type II, characterized by a random cortisol ≥10 µg/dL in patients with septic shock who have responded poorly to fluids and
and a delta cortisol <9 µg/dL. The practical implication of this classifi- vasopressor agents as well as patients with ARDS who have progressive
cation is that only patients with type II CIRCI may benefit from stress disease (after 48 hours) despite supportive care. Infection surveillance is
doses of corticosteroids. Additional studies are required to confirm the critical in patients treated with corticosteroids and to prevent the rebound
findings of Kwon and colleagues. phenomenon the drug should be weaned slowly (after 10-14 days)
and never stopped abruptly (see Table 102-3).
TREATMENT WITH CORTICOSTEROIDS. The use of a continuous infusion of hydrocortisone has been reported
WHO AND HOW? to result in better glycemic control with less variability of blood glucose
concentration. 57,58 This may be important, as it has been demonstrated
Over the last three decades approximately 20 randomized controlled that oscillating blood glucose is associated with greater oxidative injury
trials (RCTs) have been conducted evaluating the role of glucocorticoids than sustained hyperglycemia. 59,60 A number of reports indicate that
in patients with sepsis, severe sepsis, septic shock, and ARDS. Varying glucose variability may be an independent predictor of outcome in
doses (37.5-40,000 mg/hydrocortisone Eq/day), dosing strategies (single critically ill patients. 61-63 Nevertheless, “tight” glucose control has not
bolus/repeat boluses/continuous infusion/dose taper), and duration of been demonstrated to improve the outcome of general ICU patients
therapy (1-32 days) were used in these studies. 27,28 Similarly, approximately nor specifically in those patients being treated with glucocorticoids. 64-66

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