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Original Studies |
Departments of Pediatrics (R.K., S.E., J.T., P.K.), Pharmacology and Clinical Pharmacology (J.K.), Clinical Chemistry (K.I.), and Physiology (J.T.), University of Turku, FIN-20520 Turku, Finland
Address correspondence and requests for reprints to: Riikka Karlsson, Medicity Research Laboratory, Tykistökatu 6 A, FIN-20520 Turku, Finland. E-mail: riikka.karlsson{at}utu.fi
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Abstract |
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One patient had normal responses both in the ACTH test and in the CRH test when the limit of 360 nmol/L was used as a sign of proper cortisol secretion. In four cases the patients’ cortisol secretion would have been regarded as normal by the low-dose ACTH test, whereas the CRH test did not show an adequate cortisol response.
In conclusion, the ACTH test did not reliably indicate HPA-axis suppression after a short (<2 weeks) course of dexamethasone therapy in this study. Therefore, whether the infant is or will be under acute stress after short glucocorticoid treatment, ensuring adequate cortisol secretion with the CRH test should be considered.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Insulin-induced hypoglycemia (IIH) has been regarded as the "gold standard" test when investigating HPA-axis function. However, this test has serious side effects related to hypoglycemia. Deaths have been reported among children when using IIH, and it is, therefore, contraindicated in the very young (5). The short ACTH tests (low-dose and standard dose ACTH tests) are safe and easy to perform. Because only minimal amounts of blood are needed, they are very useful tests in small preterm infants. The short ACTH test mainly examines primary adrenal suppression and is also an approved way to test secondary adrenal suppression because chronic deprivation of ACTH may cause adrenal cortex atrophy. Recently, there has been concern about the reliability of the standard ACTH test because it may overestimate the adrenal responsiveness with its pharmacological dose of ACTH (250 µg/1.73 m2). The low-dose ACTH test (1 µg/1.73 m2) was, therefore, introduced for adults and is believed to be more sensitive than the standard test (6, 7, 8, 9). However, recent reports claim that both tests are equal in sensitivity and neither is able to reliably detect subtle degrees of secondary adrenal insufficiency (10, 11).
In clinical practice, the low-dose ACTH test results usually fit well with the clinical condition of the infant. Nevertheless, there are, in some cases, clear discrepancies between an adequate cortisol response received with exogenous ACTH and the clinical condition of the infant. These infants are generally hypotensive and ill without any signs of infection or other identifiable cause. This study was designed to investigate whether the HPA-axis suppression in infants during different phases of dexamethasone treatment can be more reliably detected with the CRH stimulation test than with the low-dose ACTH test. The CRH test was chosen as the reference test because it also reveals pituitary hypofunction and can be performed safely in children and small infants (12, 13). Human CRH was chosen over ovine CRH because ovine CRH has a longer half-life causing prolonged stimulation of the pituitary and adrenal glands. It might also be more immunoactive than human CRH (14).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). All subjects
were inpatients in the neonatal intensive care unit of the Turku
University Central Hospital. The mean birth weight of the infants was
1600 g (SD, 820 g), and the median gestational
age was 30 weeks, 3 days (range: 26 weeks, 2 days to 41 weeks, 5 days).
The infants received dexamethasone therapy to prevent and treat chronic
lung disease. HPA-axis function in these infants was first tested with
the low-dose ACTH test, and the CRH test was performed the next day. In
the low-dose ACTH test, the subjects were given 1 µg/1.73
m2 synthetic ACTH (Synacthen;
Ciba-Geigy, Stein, Switzerland) as an iv bolus. In the CRH
test, the subjects were given 1 µg/kg synthetic human CRH
(Corticorelin; Ferring Pharmaceuticals Ltd., Kiel,
Germany) as an iv bolus. This dose was based on a previous study in
which it caused good ACTH and cortisol responses in preterm infants
(13). In the low-dose ACTH test, blood samples were taken
before dosing and 30 min after dosing to measure serum cortisol
concentration. These time points were based on our previous study where
cortisol concentration in infants after dosing of 1 µg/1.73
m2 ACTH was measured at the following time
points: 30, 40, 60, and 120 min; the maximal level was detected at 30
min (15). For the CRH test, blood samples were taken
before dosing and 15 and 60 min after dosing. The concentration of
plasma ACTH was measured from the samples taken at 0 and 15 min, and
the serum cortisol concentration was measured from the samples taken at
0 and 60 min. In the CRH test, ACTH concentrations over 9 pmol/L at 15
min were considered to reflect proper ACTH secretion (16, 17). In the CRH and the ACTH test, the lower limit for proper
cortisol secretion was considered to be 360 nmol/L
(18, 19, 20). The number of samples was restricted to a
minimum to avoid iatrogenic anemia.
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Serum cortisol concentration was measured with heterogeneous competitive enzyme immunoassay on Immuno 1 analyzer (Technicon; Bayer Corp., Middletown, VA). The interassay coefficients of variation were 11.1% and 6.4% at serum concentrations of 83 nmol/L and 482 nmol/L, respectively. The lower limit of detection of cortisol concentration was 20 nmol/L. The plasma ACTH concentration was determined by immunoradiometric assay using a commercial kit (Nichols Institute Diagnostics; San Juan Capistano, CA). The interassay coefficients of variation for ACTH were 8.7% and 13.2% at ACTH concentrations of 8.8 pmol/L and 79 pmol/L, respectively. The lower limit of detection of ACTH was 1.2 pmol/L. The data were statistically analyzed using paired and nonpaired t tests; P values less than 0.05 were considered statistically significant.
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Results |
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). The remaining 16 patients
had only a weak ACTH response in the CRH test (Fig. 1A). One of the 18
patients had a good cortisol response at 60 min in the CRH test,
whereas in the ACTH test 5 patients had cortisol concentrations
exceeding the 360 nmol/L limit (Fig. 1B). Two of those patients who had
cortisol concentrations over 360 nmol/L in the ACTH test also had ACTH
concentration over 9 pmol/L in the CRH test (Fig. 1C). The mean basal
cortisol concentration of all patients was similar in both tests (Fig. 1B).
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) had normal HPA-axis function
according to both the CRH and ACTH tests if the limit of 360 nmol/L was
followed as a sign of proper cortisol secretion, whereas four patients
would have had normal HPA-axis function using the ACTH test alone
(patients 1, 2, 3, and 4; Table 1). If 560 nmol/L was considered as the
correct lower limit of proper cortisol secretion, none of the patients
would have passed the CRH test and only one patient would have passed
the ACTH test (patient 14; Table 1). |
Discussion |
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In recent literature, there has been much debate regarding the correct lower limit of cortisol concentration that constitutes a normal response for both infants and adults in the ACTH and CRH tests (21, 22). The widely used limit of 560 nmol/L for adults and children in the ACTH test may be too high for neonates because their basal cortisol secretion is lower than older children and adults (23). Wilson et al. (18) suggest that an ACTH-stimulated cortisol concentration of more than 360 nmol/L indicates a normal adrenal response in infants. However, this level of cortisol response may not be high enough for stressed preterm infants because extremely high basal and CRH-stimulated ACTH and cortisol concentrations have been measured in fatally ill, low birth weight infants (13). As of yet, data do not exist regarding the optimal lower limit of cortisol secretion in CRH test in infants. We chose the limit of 360 nmol/L to reflect proper cortisol secretion in the CRH test, because in two earlier studies this was detected as the lower limit of response to exogenous CRH in healthy children (19, 20). In adults, CRH-stimulated ACTH concentrations of 9–11 pmol/L have been shown to elicit a near maximum release of cortisol from the adrenals (17). In very low birth weight infants without any glucocorticoid treatment, human CRH has induced an average ACTH concentration of 11.9 pmol/L at 15 min with a dose of 1 µg/kg (13), which was also used in this study. The average cortisol concentrations were 647 nmol/L and 578 nmol/L at 30 min and 60 min, respectively (13). This indicates that the pituitary gland is physiologically mature at an early gestational age and that the function of the HPA-axis is comparable with healthy 6- to 15-yr-old children (24).
There were only two infants in this study (patients 10 and 12; Table 1)
whose ACTH secretion properly responded to exogenous CRH at 15 min
after dosing (Fig. 1). The first infant (patient 12) passed both the
CRH and ACTH tests if the lower limit of 360 nmol/L was used,
indicating that a 64-day recovery time was long enough after
dexamethasone therapy. The second infant (patient 10) had received an
early course of postnatal dexamethasone treatment. His pituitary had
normal ACTH secretion levels, but his adrenal cortex continued to be
suppressed as he failed both tests. This may indicate fast recovery of
the pituitary after glucocorticoid therapy, as also suggested in other
studies (25).
The ACTH test is designed to evaluate primary adrenal suppression.
Nevertheless, it may also diagnose secondary hypophyseal or pituitary
suppression lasting over 8–12 days (26). During this
time, the zona fasciculata of the adrenal cortex involutes under the
deprivation of the tropic effect of ACTH. Therefore, an ACTH test
performed after dexamethasone therapy lasting less than 2 weeks may
show proper adrenal function despite the depression of the pituitary
gland. This might explain why the four patients who had only 2–3 days
of dexamethasone treatment (patients 1, 2, 3, and 4; Table 1) had a
proper cortisol response in the ACTH test while they failed the CRH
test both in terms of ACTH and cortisol secretion. The deficiency of
endogenous ACTH release may also be partial; the adrenal cortex may
respond normally to the ACTH stimulation test, whereas in severe stress
the patient fails to adequately raise his cortisol concentration
(27, 28).
The CRH test detects pituitary and/or adrenal suppression. Assessment of the entire HPA-axis would require performing an IIH or metyrapone test in conjunction with the CRH test. In adults the function of the hypothalamus can be assessed by these two tests, but not in infants (5). Earlier adult studies indicate that long-term glucocorticoid therapy leads to the suppression of endogenous cortisol production due to inhibition of ACTH synthesis and secretion in the pituitary and to secondary adrenal suppression (29, 30). This study shows that the site of suppression after short glucocorticoid treatment is also at the pituitary level in preterm infants, confirming earlier findings from Rizvi et al. (2), who examined the HPA-axis function of preterm infants after 7 days of dexamethasone treatment.
In the low-dose ACTH test the peak cortisol concentrations are reached earlier than in the standard dose ACTH test in preterm infants (15), therefore, the 30-min time point was chosen to measure cortisol concentration in this study. In the CRH test, the peak ACTH concentration has been achieved at 15 min after dosing and the peak cortisol concentration has been measured between 30 and 60 min (13, 31, 32). Based on this, we chose to measure the cortisol concentration at 60 min after dosing, which might have caused us to miss the exact peak value in some cases.
In conclusion, the ACTH test cannot reliably detect the HPA-axis suppression after a short course of dexamethasone therapy. When the infant is having surgery, or if other potential stress factors are present after a short glucocorticoid treatment, evaluation of adequate cortisol secretion with CRH test should be considered.
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Footnotes |
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Received April 8, 2000.
Accepted August 27, 2000.
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References |
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