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Age and Ageing Advance Access originally published online on October 25, 2007
Age and Ageing 2007 36(6):686-689; doi:10.1093/ageing/afm113
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Copyright © The Author 2007. Published by Oxford University Press on behalf of the British Geriatrics Society.

Hypothalamic–pituitary–adrenal axis reactivity and dehydroepiandrosterone sulfate plasma concentrations in the critically ill elderly

SIR—Despite a normal, or high basal cortisol, critically ill patients, particularly those with sepsis or systemic inflammatory response syndrome, may develop a relative adrenal insufficiency (RAI) [1, 2]. The identification of this so-called RAI is important since sepsis-associated adrenal insufficiency is associated with an increase in mortality, and because stress doses of hydrocortisone improve the hemodynamic status and the survival of patients with septic shock [3, 4]. RAI could also occur in other critical conditions such as trauma, acute lung injury and after surgery [5–7]. A greater uncertainty exists, however, about this pathology in elderly patients admitted to an intensive care unit (ICU).

As a consequence of prolonged life expectancy in developed countries, many patients admitted to ICUs are elderly [8, 9]. Acute illness of critically ill elderly patients should be considered in the context of a physiological organ senescence, particularly the hypothalamic–pituitary–adrenal (HPA) axis. In healthy elderly subjects, a basal HPA axis hyperactivity, higher basal cortisol and ACTH levels, and an enhanced response to stimulation are remarkable [10, 11]. By contrast, plasma concentrations of dehydroepiandrosterone (DHEA) and its metabolite sulfate (DHEAS) decrease as a result of a specific impairment of the activity of the adrenal reticularis zone [12]. In severe acute illness settings, hormonal modifications in the elderly are not, however, well investigated. This study was, therefore, designed to investigate the HPA axis reactivity and the basal plasma concentrations of DHEAS in the elderly as compared to non-elderly critically ill patients.

Methods

This prospective study in consecutive patients was performed between 1 March and 31 July 2005, in two multidisciplinary ICUs in a teaching hospital. Approval of the study was obtained from the local ethics committee, written informed consent was obtained from each patient or their surrogate.

Study population
Adrenal function was evaluated in critically ill patients with severe sepsis or septic shock. Patients were excluded if they had received steroids, etomidate, fluconazole or ketoconazole prior to cortisol measurements, if they had a past history of use of systemic or inhaled steroids, or if they had a disease of the HPA axis. Two groups of patients were studied: elderly patients aged 75 years or more [13] and non-elderly patients aged 74 years or less. Baseline patient characteristics were recorded including age, gender, cause of admission to the ICU and past medical history. The severity of illness was evaluated at inclusion using the simplified acute physiology score (SAPS II) [14]. The need for vasopressive agents, for mechanical ventilation, and for dialysis treatment was collected. Length of stay in the ICU, and ICU mortality were recorded.

Endocrine evaluation and assays
Twenty-four hours after admission to the ICU, blood samples were obtained at 8 a.m. for determination of cortisol, ACTH, and DHEAS basal plasma concentrations. Two hundred and fifty microgram of freshly prepared tetracosactrin (Synacthene, Novartis, Basel, Switzerland) was then administered intravenously, and two blood samples were withdrawn 30 and 60 min later for stimulated cortisol measurements.

Cortisol levels were determined by a fluorescence polarisation immunoassay (IMMUNOTECH a.s.-Radiova 1–102 27 PRAGUE 10), with results expressed in nmol/l. The cortisol response to Formula g tetracosactrin was defined as the difference between the basal concentration and the highest level of the 30 and 60 min samples ({Delta} max). A basal cortisol concentration of <276 nmol/l indicate absolute adrenal insufficiency, and a {Delta} max <250 nmol/l indicate RAI [4].

ACTH levels were determined by a highly specific immunoradiometric assay (Nichols Institute Diagnostics, San Clemente, California, USA) and expressed in pg/ml. DHEAS levels were determined by a chemiluminescence immunoassay (Nichols Institute Diagnostics, San Clemente, California, USA) and expressed in µg/ml.

Statistical analysis
Results were compared between the elderly and non-elderly patients. Data is presented as the mean ± standard deviation. Comparisons were performed using an independent sample t-test for parametric continuous variables, a Mann–Whitney U test for non-parametric continuous variables, and a chi-square test for categorical variables. A P-value of <0.05 was regarded as statistically significant.

Results

During the inclusion period, 52 patients were eligible, but only 36 fulfilled the inclusion criteria and were studied: 18 patients comprised each group. Characteristics of each group are shown in Table 1. Except for age, the two groups were similar, particularly for the diagnosis and severity of the illness. During their stay in the ICU, both groups showed the same morbidity as reflected by the need for mechanical ventilation, haemodialysis or vasoconstrictive agents (including their duration use) (Table 1).


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  		Table 1. Clinical characteristics, morbidity and mortality. Comparison between elderly and non-elderly critically ill patients. (SAPS II: Simplified acute physiology score)

 
The mean values of basal cortisol were not significantly different between the two groups, and neither were the mean values of stimulated cortisol (Table 2). Although cortisol maximal increment after tetracosactrin was lower in the elderly group, the difference did not reach statistical significance (Table 2). Eight patients met the criteria for RAI and were equally distributed in the two groups. The mean values of basal ACTH were similar between the two groups. By contrast, DHEAS plasma concentrations were significantly lower in the elderly patients (P = 0.05) (Table 2).


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  		Table 2. Comparison of basal cortisol, ACTH and DHEAS (dehydroepiandrosterone sulfate), stimulated cortisol and maximal cortisol increment after stimulation between elderly and non-elderly critically ill patients

 
The ICU mortality was about 22% in both groups, while length of stay in the ICU was higher in the elderly group without a significant difference (Table 1).

Discussion

In the present study, it was found that the rate of RAI in critically ill elderly patients over 75 years was not negligible, reaching 22%, not different from that in a younger population. However, maximal increase of stimulated cortisol were, although not significant, lower, and basal DHEAS measurements significantly lower in the elderly group.

The proportion of elderly patients admitted to intensive care facilities is on the increase, as a consequence of the prolonged lifespan observed in developed countries [8, 9]. An overall ICU mortality has been found to be higher in elderly populations which may be accounted for by higher severity scores and/or various underlying conditions [9, 15]. However, another explanation could be the untoward effects of the physiological senescence of organs in response to stress. There is now growing evidence that a RAI is frequent in critically ill patients, particularly in severe sepsis and septic shock [1–4], conditions during which the incidence can reach 30–65% [16, 17]. Some studies clearly show that the incidence of RAI is higher in the elderly population [18, 19]. Yet, little is known of the endocrine behaviour in the ageing population in an ICU setting. In a study on septic shock, Annane [20] reported that patients with a stimulated cortisol level below 250 nmol/l were older, although the difference in age was not significant. In addition, Beale [21] found a significant difference in the basal and stimulated cortisol measurements between the group of patients whose mean age was 75.8 years when compared to a group of young patients of 22.9 years. In a surgical ICU population, Barquist [22] found that 11% of patients of more than 55 years of age, and who had stayed more than 14 days in the ICU, had adrenal insufficiency, whereas the overall incidence was only 0.6%. In our study, there was no difference found for the basal cortisol level between elderly and non-elderly patients, yet the response to tetracosactrin stimulation was lower in the elderly, although it did not reach statistical significance. It is thus possible, yet uncertain, that the elderly critically ill have a lesser reactivity to ACTH. Some data have demonstrated that cortisol response to supramaximal and submaximal doses of tetracosactrin in elderly people is preserved, but that the response is blunted if low doses are used for the stimulation test [23]. It has been suggested that the lower reactivity in the elderly is explained by a higher basal cortisol level [23]. We also found significantly low basal DHEAS plasma levels in the elderly group indicating that age contributes to a stress-induced down-regulation of the DHEAS adrenal secretion. A decrease in DHEAS levels is observed in the elderly due to the alteration or the atrophy of the reticularis zone of the senescent adrenal gland [24], while acute or chronic illness may, additionally, inhibit DHEAS production via interleukine 6 secretion [25, 26].

We are aware that evaluation of adrenal function during critical illnesses is difficult because there are many controversies and a larger number of confounding factors. Whether a random plasma cortisol measurement and the corticotropin test adequately reflect glucocorticoid secretory capacity in such circumstances is questionable. Venkatesh et al. [27] showed, however, that 24 h mean plasma cortisol was strongly correlated with both, random plasma cortisol, and the cortisol response to corticotropin. Recent studies have stressed the interest of the dosage of plasma-free cortisol rather than total cortisol to identify patients with RAI [28]. Total plasma cortisol level is indeed influenced by the level of albumin, to which it is partially bound. Total plasma cortisol levels thus decrease in hypoalbuminemic states, a frequent occurrence in an ICU setting [28]. In our study, albuminemia in the elderly group was not significantly different from that of the younger group (Table 1).

In conclusion, the incidence of RAI in elderly ICU patients is important, but it did not seem to be influenced by age. Low DHEAS levels, however, may reflect some specific impairment of the HPA axis reactivity in the critically ill elderly.

Key points

  • Relative adrenal insufficiency is not age-dependent in ICU settings.
  • In critically ill patients, ageing may, however, alter HPA axis reactivity as shown by low DHEAS and low cortisol increment after stimulation.

Conflict of interest

None

K. Klouche*, E. Ferreira Da Mota, R. Durant, L. Amigues, P. Corne, O. Jonquet and J. J. Beraud

Lapeyronie University Hospital, Intensive Care Unit, 371, Avenue du Doyen Gaston, Giraud, 34 95, Montpellier, France

* To whom correspondence should be addressed E-mail: k-klouche{at}chu-montpellier.fr

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