the 1-μg `low dose' acth test for assessment of adrenal function in geriatric patients

Archives of Gerontology and Geriatrics

27 (1998) 99–104

The 1-mg ‘low dose’ ACTH test for assessment ofadrenal function in geriatric patients

Jacob Feldman a, Menachem S. Shapiro b, Marrk Niven b,Eli Weiss c, Abraham Yaretsky a,*

a Department of Geriatric Medicine, Meir General Hospital, Sapir Medical Center,Kfar-Saba 44281, Israel

b Endocrine Unit, Sapir Medical Center, Kfar-Saba 44281, Israelc Clinical Laboratories, Sapir Medical Center, Kfar-Saba 44281, Israel

Received 15 April 1998; accepted 16 April 1998

Abstract

A commonly utilized dynamic test for evaluation of the hypothalamic-pituitary-adrenal(HPA) axis in the geriatric patient is the standard 250-mg ACTH stimulation test. However,there are significant potential drawbacks associated with this study. In contrast, administra-tion of 1 mg of ACTH has been shown to be very sensitive for detecting abnormalities in theHPA axis. We therefore assessed the responses of two groups of patients (aged 80–95 years)with no evidence of HPA disease using either the 1 or 250 mg dose of ACTH (Synacthen).Twenty six patients received 1 mg of ACTH (Synacthen). Seventeen others received astandard 250 mg dose. Patients were randomly chosen. There were no significant differencesin age or sex between the two groups. Plasma cortisol was measured at 30 and 60 min afterintravenous administration of either dose of ACTH. No significant statistical differenceswere noted in plasma cortisol responses to 1 or 250 mg of ACTH. We conclude that the 1mg ‘low dose’ ACTH stimulation test can substitute for the standard 250 mg test. Clinicaljudgment must be used in conjunction with these tests in formulating therapeutic decisions.© 1998 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Geriatric; Low dose ACTH; Adrenal function

* Corresponding author. Tel.: +97 29 7471003; fax: +97 29 455522.

0167-4943/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved.

PII S0167-4943(98)00103-4

J. Feldman et al. / Arch. Gerontol. Geriatr. 27 (1998) 99–104100

1. Introduction

The hypothalamic-pituitary-adrenal (HPA) axis is intact in elderly patients asassessed by classic dynamic hormonal studies such as the insulin tolerance test(ITT), standard short ACTH stimulation test (SAT) using 250 mg of syntheticACTH, administration of metyrapone and the corticotrophin releasing hormone(CRH) stimulation test (Grinspoon and Biller, 1994). Responses in elderly sub-jects elicited by these studies are comparable to those seen in younger individuals(Seeman and Robbins, 1994).

ITT, although potentially hazardous, is the ‘gold standard’ for evaluation ofHPA function (Jones et al., 1994). SAT, an innocuous test, commonly replacesITT because of the reportedly good correlation between the two studies (Lind-holm et al., 1978; Stewart et al., 1988). Yet, there is growing dissatisfaction withSAT because it is not adequately sensitive as a screening test to detect thepresence of hypothalamic–pituitary dysfunction (Borst et al., 1982; Hurel et al.,1996; Orme et al., 1996; Streeten et al., 1996).

A new modification of SAT using 1 mg instead of the conventional 250 mgdose of ACTH is now being championed as the substitute for ITT (Dickstein etal., 1991; Tourdjeman et al., 1995; Oelkers, 1996; Rasmusson et al., 1996). Nostudy has been carried out to date investigating this ‘low dose’ 1 mg ACTH testin an exclusively geriatric population. The availability of a safe alternative toITT in the geriatric population would be most useful in evaluation of the HPAaxis in these patients.

We have performed both the standard 250 mg test (SAT) and the 1 mg ‘lowdose’ ACTH test in a group of geriatric patients and present the data in thiscommunication.

2. Patients and methods

We evaluated 43 patients, divided into two groups, admitted with an acuteillness to a general geriatric unit. The first group (Group A) consisted of 26patients, 11 women and 15 men, aged 80–91 years (mean9S.D.: 83.993). HPAfunction was examined with the low dose ACTH test. A second group (GroupB) consisting of 17 patients, 11 men and six women, aged 80–95 years (mean9S.D.:85.493.8), received the standard SAT. Authorization was received from theSapir Medical Center Helsinki Committee and patients gave informed consent toparticipate in the study.

An indwelling catheter was inserted in the anticubital fossa. After 30 min,ACTH (Synacthen, Ciba-Geigy, Basel, Switzerland) was administered as an i.v.bolus. The 1-mg dose was prepared immediately before use by adding 250 mg ofsynacthen to 50 ml of 0.9% (w/v) NaCl in a plastic infusion bag. Then, 0.2 mlof this solution was added to 1.8 ml of NaCl. Blood for plasma cortisol wasdrawn before injection, 30 and 60 min after injection of ACTH.

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Table 1Mean9S.D. cortisol values in two groups of ‘very old’ patients receiving an injection of Synacthen

Cortisol (nmol/l)Time (min)

Group A (1 mg) P Group B (250 mg)

586925147491360 0.06930 0.015 92993207419162

7849232 0.17 1034935760

Group A received 1 mg and Group B received 250 mg.

2.1. Assay method

Plasma cortisol was measured with a standard commercial kit (Clinical Assays,MN, USA).

2.2. Statistics

The two tailed t-test and paired t-test were used for statistical analysis of thedata, carried out by the statistical SPSS-PC program.

3. Results

The results are summarized in Tables 1 and 2. The mean9S.D. basal cortisol inGroup A receiving the 1-mg dose was 4749136 nmol/l in comparison to 5859251in group B with SAT (P=0.069). The 30 and 60 min values in Group A were7419162 and 7849232. Comparable 30 and 60 min values in Group B were9299320 (P=0.015) and 10349357 (P=0.17).

The mean9S.D. increment of cortisol from the basal state to 30 min was2739116 nmol/l in group A versus 3429204 in Group B (P=0.212) (Table 2).

The responses to 250 mg of Synacthen at 30 and 60 min were greater than theresponses elicited following 1 mg. However these differences were not statisticallysignificant (Tables 1 and 2).

Table 2Changes in cortisol values (9S.D.) in two groups of ‘very old’ patients receiving an injection ofSynacthen

Time Cortisol increment (nmol/l)

Group A (1 mg) P Group B (250 mg)

0.21227391160�30 342920441915730�60 0.176 1059135

Group A received 1 mg and Group B received 250 mg.

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4. Discussion

Screening tests for HPA dysfunction are performed for two goals: (a) establishingthe presence or absence of a disease process and subsequent performance of otherdiagnostic studies, (b) assessing the need for steroid therapy. When HPA dysfunc-tion is detected, steroid supplementation is usually given in the presence of overt oranticipated stress to avoid adrenal insufficiency.

When confronted with the possibility of an abnormal HPA axis in the elderlysubject a dynamic endocrine study will be required. Which test should be chosen?Untoward side-effects, which are especially undesirable in the elderly patient, canbe encountered when using the standard tests (Grinspoon and Biller, 1994). The1-mg ACTH test may be ideal in this setting.

The 1-mg ACTH test has been shown to correlate significantly with the ITT inthe presence of documented HPA disease (Oelkers, 1996; Rasmusson et al., 1996).The 30-min cortisol response to ACTH has been preferred over the 60-min valuefor it demonstrates the best correlation to peak cortisol responses elicited with ITT(Lindholm and Kehlet, 1987). A recent editorial has commented on the potentialfor this dynamic test to substitute for ITT (Clayton, 1996).

The 1-mg dose is considered to be a ‘physiological’ stimulus in contrast to the250-mg dose of the standard SAT. In fact, the 1-mg dose elicits a near maximal tomaximal adrenal output and has been claimed to be more sensitive than the 250-mgdose (Tourdjeman et al., 1995; Oelkers, 1996; Rasmusson et al., 1996). The adrenalgland appears to maintain normal sensitivity to the standard SAT for at least 3months following the onset of diminished secretion of ACTH (Hurel et al., 1996)and it is acknowledged that the standard SAT should not be performed in thisperiod (Lindholm and Kehlet, 1987). Rarely, however, normal responsiveness to thestandard SAT may be elicited for over a year in the patient with proven abnormalHPA function (Soule et al., 1996). The 1-mg ACTH dose may prove capable indetecting corticotropin deficiency in these circumstances (Tourdjeman et al., 1995).

We have evaluated twenty six patients above age 80 years with administration of1 mg of ACTH during their initial admission to an acute geriatric unit. There wasno past history of hypothalamic pituitary disease in any of the patients. The cortisolresponse to 1 mg was comparable to that noted with 250 mg at both 30 and 60 min,with no statistical difference between the doses. The mean9S.D. minimal incre-ment in plasma cortisol was also comparable between the two doses with nostatistical differences.

Peak normal cortisol responses to 1 mg ACTH at 30 min reported in theliterature, which supposedly exclude the need to perform ITT for detection of HPAdysfunction, range from 500 to 550 nmol/l (Tourdjeman et al., 1995; Oelkers, 1996;Rasmusson et al., 1996). What is the true ‘cut off’ point dividing normal fromabnormal? If we choose the 500 nmol/l value for our ‘cut off’ point, all of thepatients in group A show normal responses. If we choose the 550 nmol/l value,there are two subjects in Group A with low 30-min cortisol values and one of theGroup B subjects.

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We can demand a yet higher ‘cut off’ point. Patel et al. (1991) suggested that thenormal cortisol response to the standard SAT in sick patients within 24 h of acutehospital admission should exceed 600 nmol/l. Applying this more stringent criterionto both the 250-mg test and the 1-mg test, one of the patients in group B and fourin group A had subnormal values. Accordingly, five patients potentially hadpreviously unsuspected HPA dysfunction.

Some authorities list still another criteria for normal responsiveness to SAT—arise of plasma cortisol of at least 193–276 nmol/l (Streeten, 1996). Other authorsreject use of the cortisol increment as a reliable parameter (Grinspoon and Biller,1994; Levy, 1996). If we, for discussion, require the presence of both a 30-minplasma cortisol of 600 nmol/l and a minimal increment of 193 nmol/l followingSynacthen, we then have a further six patients with subnormal responses. Whatdoes this mean practically for the practising physician? Significantly, none of thesepatients proved to have clinical evidence of HPA dysfunction and did not requiresupplemental steroid replacement during their acute medical episode.

A recent commentary aired the concept that tests of adrenocortical function mayindeed be too sensitive in patient management (Levy, 1996). Accordingly, acceptedpeak ‘normal’ values of cortisol following dynamic tests used to exclude the needfor steroid coverage may indeed be too high.

When considering the interpretation of the 1-mg ACTH test in the patient withsuspected HPA dysfunction, other reservations should be considered. Rarely, apatient with proven HPA dysfunction may respond to both the standard SAT andITT and still be clinically adrenal insufficient (Tsatsoulis et al., 1988). The patientsdescribed with this clinical picture were purported to have endogenous corti-cotrophin releasing hormone insufficiency. One might not expect the 1-mg test tofare better than the standard tests in diagnosing these patients. Even moredisturbing is the report that patients with primary adrenal insufficiency have alsobeen misdiagnosed with the standard SAT (Trump et al., 1989). The role of the1-mg test will have to be determined in similar patients. The clinical picture of thepatient, and not the tests, must be the over riding factor when considering steroidreplacement therapy (Clayton, 1996).

In conclusion, we have compared the results of ACTH testing with 1 and 250 mgin two groups of patients over 80 years of age. Responses were not significantlydifferent to the two doses. Depending on the ‘cut off’ point, up to eight patientshad subnormal responses. Despite these results, none of them developed signs ofadrenal insufficiency during the acute medical episode. Thus, the 1-mg ‘low dose’test appears to be a reliable and safe test for evaluating the presence of HPAdysfunction in the ‘very’ elderly population, replacing the standard test utilizing thelarger 250 mg dose.

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