Patients prescribed an oral and inhaled corticosteroid are at a dose related increased risk of adrenal crisis as illustrated in a recently published epidemiological case control study of 154 reported cases in the general population . The magnitude of the risk for an individual patient with oral and inhaled corticosteroids for AECOPD, however, has not yet been determined and is often neglected in common practice . A sensitive measure to assess the functional status of the HPA-axis, and thus the risk for Addisonian crises upon stress, is the low-dose ACTH-test. In this study, even short-term low-dose courses of systemic corticosteroids for the treatment of AECOPD in steroid naive patients was associated with a measurable and prolonged suppression of the HPA-axis in the majority of patients. Importantly, clinical signs and symptoms are unreliable and unable to predict an impairment of the HPA-axis. Accordingly, in patients with AECOPD receiving systemic corticosteroids the presence of adrenal insufficiency should be considered.
Physiologically, the hypothalamus secretes corticotropin releasing hormone (CRH), which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH leads to the release of cortisol through stimulation of the adrenal cortex, which in turn has a negative feedback on CRH and ACTH. Administration of exogenous corticosteroids, even in small doses for only few days, leads to a measurable suppression of the HPA-axis resulting in the inability of the adrenal cortex to secrete additional cortisol if needed . One might argue that laboratory changes in the HPA axis after short-term systemic steroid therapy are not of clinical relevance. Indeed, the absolute risk of adrenal crisis after cessation of oral and inhaled corticosteroids might be considered rare based on the literature, but is likely to be substantially underreported in clinical practice . Importantly, the manifestation and the severity of clinical signs depend on the presence of stress with its resulting increased cortisol demand. Upon major stress, even a mild adrenal insufficiency can be hazardous leading to hemodynamic instability, vasoactive-refractory shock and ultimatively death [3, 15, 18]. Consequently, in adrenal insufficiency administration of systemic corticosteroids (preferably hydrocortisone) is mandatory and potentially lifesaving. Unfortunately, symptoms of adrenal insufficiency are highly variable and only occur if the patient is experiencing more or less severe stress. Therefore, predicting or excluding the risk for adrenal insufficiency from clinical parameters, as often falsely done, is delicate and potentially dangerous. Illustratively, typical symptoms of adrenal insufficiency (e.g. weakness, low blood pressure and hypoglycemia) were completely nonspecific in this study and were, thus, unreliable predictors of adrenal insufficiency. This should be kept in mind before an absence of adrenal insufficiency is postulated based on the absence of signs and symptoms by the treating physician.
Based on our data and supported by the literature, basal cortisol levels are helpful to diagnose adrenal insufficiency in a subset of patients, i.e. if cortisol values are < 150 or > 400 nmol/l adrenal insufficiency is highly likely or can be excluded, respectively. Measurement of basal ACTH concentration did not improve the diagnostic accuracy. This is not surprising because of the pulsatile secretion of ACTH.
In asthmatic patients, the various adverse effects of oral and even inhaled corticosteroids on the HPA axis, including adrenal crisis, have been well recognized [18, 19]. In patients receiving systemic corticosteroids for acute exacerbation of COPD, the frequency and duration of adrenal suppression has not prospectively been investigated. Surprisingly, in common practice, a so called "short-term" 14 days course of systemic corticosteroids is generally considered safe and the potential consequences of adrenal suppression are often neglected . In our patients, adrenal stimulation tests revealed a suppressed adrenal response to corticotropin in 7 out of 9 patients after only one day of treatment and in 8 out of 9 patients after the 2 weeks course. Similar proportions have been reported from studies on longer-term glucocorticoid treatment . The observed gradual recovery of the suppressed adrenal response to the low-dose corticotropin test was heterogeneous among the patients lasting from a few days to up to 3 weeks after withdrawal. In individual patients, it is not possible to predict the duration of the HPA axis recovery, though, careful instruction and observation of these patients and examination for potential adrenal insufficiency should be recommended.
This study has limitations. Firstly, we have only included a small, but well defined number of patients to assess the adrenal response after steroid treatment for AECOPD. The number of performed tests is too small to recommend definitive cut-off levels for peak cortisol concentrations during acute illnesses. Secondly, our population varied in respect to the use of inhaled corticosteroids on admission, which is a known risk factor for adrenal insufficiency. However, all patients had a normal ACTH stimulation test at baseline and the inhaled medical treatment with inhaled long acting β2-agonists and corticosteroids after study inclusion was uniform. Still, the impact of inhaled corticosteroids can not be addressed with this study. Thirdly, we did not directly assess free cortisol values or albumin or cortisol binding globulin concentrations to calculate free cortisol levels. Depending on the severity and kinetic of acute disease, total and free cortisol levels may show discordant results and total cortisol levels may not adequately anticipate the free cortisol levels needed during severe peracute stress .