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Editorial |
Bnai Zion Medical Center Haifa, 31048, Israel
Address all correspondence and requests for reprints to: Dr. Gabriel Dickstein, Division of Endocrinology, Bnai Zion Medical Center, 47 Golomb Street, P.O. Box 4940, Haifa, Israel.
In this issue of the JCEM, Widmer et al. (1) examine cortisol response to high (250 µg) and low (1 µg) doses of 1–24ß ACTH at different severities of stress. Their findings show (see Fig. 1A in Ref. 1), that, under the most severely stressful conditions, basal cortisol levels are similar to those achieved in response to either ACTH dose challenge in a nonstressful situation. Actually, this is what we want a stimulation test to do: to find out whether, on demand, the adrenals will be able to produce the cortisol levels needed—those actually found even under severe stress.
However, this study also demonstrates that under stressful conditions the ability of the adrenal glands to secrete cortisol in response to acute ACTH stimulation is upgraded, and that this increased ability is dose dependent, that is, much higher in response to the 250-µg than to the 1-µg challenge.
If the patient is under maximal stress, and the adrenals can produce and secrete much higher amounts of cortisol, then why don’t they do so? As the authors suggest, the limiting factor is probably the level of pituitary ACTH secretion under stress, which does not reach heights found after the 250-µg synthetic ACTH stimulation test. Even the 1-µg ACTH stimulation test, added to the already elevated endogenous ACTH, is enough to cause significant additional cortisol rise.
The main question is whether this additional possible rise in cortisol, namely the increment from baseline (
) in serum cortisol concentration, has any clinical significance. This is an issue causing much recent debate in the literature. In the study of Widmer et al. (see Table 3 in Ref. 1), about 40% of patients did not achieve the "target" cortisol cutoff of more than 9 µg/dl (250 nmol/liter), yet they suffered no adverse clinical consequences without glucocorticoid treatment. This calls for a complete rethinking of the term "relative adrenal insufficiency."
It has long been known that the single parameter defining normalcy of the hypothalamic-pituitary-adrenal system in an ACTH test is that of a cortisol level higher than a threshold level (2), usually 18 or 20 µg/dl. As Aron (3) most aptly described it, "Criteria involving minimum increments in cortisol lack validity; a stressed patient may be maximally stimulated at baseline." May and Carey (4) showed not only that an incremental cortisol rise is not a useful parameter, but it is negatively correlated with basal cortisol level. Previous research results have demonstrated that if an adrenal stimulation test is performed in the morning and again in the evening, on the same subjects (on different days), evening basal cortisol levels will be lower than the morning ones, cortisol increments will be higher, yet the stimulated cortisol levels will be similar. This is true regardless of whether the stimulation is achieved by using ACTH (5), insulin hypoglycemia (6), or CRH (7).
The ill-defined concept of "relative adrenal insufficiency" has gained increasing acceptance with attempts to improve the outcome of patients in severely stressful situations, mainly septic shock. The term is based primarily on an inability of the severely stressed adrenals to further produce cortisol of more than 9 µg/dl (250 nmol/liter) after an ACTH stimulation test, irrespective of the basal cortisol level. The concept was introduced into the literature mainly through the intensive work of Annane and colleagues (8, 9), who showed that treating such patients with stress doses of hydrocortisone would significantly improve the outcome. Although the basal cortisol levels were not provided in the initial publication (8), they appeared in a subsequent publication (see Table 2 in Ref.9). In addition to the low cortisol in the "nonresponders" to ACTH group, the basal cortisol level (in severe stress) was –24 ± 35 µg/dl (660 ± 966 nmol/liter) (mean ± SD) for the placebo-treated group and 18 ± 12 µg/dl (500 ± 330 nmol/liter) for the corticosteroid-treated group. Given that the mean is not really high, and the SD is very large, these data tell us that the group is very heterogeneous and clearly includes a sizable number of cases of real adrenal insufficiency. Indeed, these cases may have been the ones that responded to treatment.
In a recent review, Melby’s group (10) also found no clear-cut, agreed-upon definition of "relative adrenal insufficiency" and found only limited evidence that using his diagnosis for treatment purposes can be expected to reduce morbidity and mortality. In an effort to clarify this term, Pizarro et al. (11) defined absolute adrenal insufficiency in pediatric septic shock as baseline (stress) cortisol of less than 20 µg/dl (550 nmol/liter) with increment of less than 9 µg/dl and relative adrenal insufficiency as baseline (stress) cortisol more than 20 µg/dl with an increment less than 9 µg/dl. However, using these criteria, in the apparent absence of glucocorticoid treatment (no such treatment was mentioned in the study), they did not find a direct correlation of this adrenal insufficiency and mortality. Kozyra et al. (12) suggest, based on three studies, that using the low-dose ACTH test may improve the evaluation of adrenal insufficiency in critically ill patients. However, the entity of "relative adrenal insufficiency" is vague and its reasoning insufficient. The data from the study of Widmer et al. (1) actually suggests that use of the low-dose ACTH stimulation test may only increase the number of overdiagnosed patients.
Might there be another explanation as to why patients with septic shock will respond to glucocorticoid treatment? A few decades ago, high-dose glucocorticoid treatment for septic shock was tried and was not found to improve the outcome. Actually, increased mortality was noted in patients with overwhelming infection (13). In a recent study, Keh et al. (14) treated a group of 40 patients with septic shock with different modalities of about 240 mg of hydrocortisone daily, regardless of endogenous cortisol levels. These levels were measured nonetheless and were found to be about 30 µg/dl (828 nmol/liter). After treatment, cortisol levels were about 120 µg/dl (3300 nmol/liter)—much higher than one would expect even under the most severe stress. This treatment was found to result in the restoration of hemodynamic stability and modulation of the immunological response to stress, through antiinflammatory effects.
Therefore, it seems that glucocorticoid treatment, even with relatively modest doses, may have beneficial effects on septic shock—but most likely through pharmacological means rather than physiological ones. The past failure of much higher doses of glucocorticoids to improve survival is probably attributable to the fact that the known ill effects of high-dose glucocorticoid treatment outweighed the positive effects of such treatment. In a recent meta-analysis (15) a consistent and beneficial effect of glucocorticoid treatment on survival and shock in sepsis was identified, regardless of adrenal function. In addition to the lower dose of glucocorticoid administered, the longer duration (5–7 d) was found to be an important factor, in contrast to the higher-dose, shorter-duration regimens used in the past.
In summary, in normals the ACTH test (low or high dose) correctly predicts the cortisol levels that will be reached under severe stress. However, these levels do not represent the maximal adrenal reserve that can be produced by exogenous ACTH challenge in situations of extreme stress. Under such conditions, a higher ACTH dose will cause a more profound cortisol response. Nevertheless, the importance of this additional ability to secrete cortisol is doubtful. In the current study, inability to reach cortisol of greater than 9 µg/dl did not worsen clinical outcome. This is also the conclusion that one should reach if taking a critical view of the many studies published to date.
Received May 27, 2005.
Accepted June 6, 2005.
References
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