Published online October 1, 2008
PEDIATRICS Vol. 122 No. 4 October 2008, pp. 873-875 (doi:10.1542/peds.2008-0516)

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COMMENTARY

Is There a "Normal" Range of Serum Cortisol Concentration for Preterm Infants?

Pak C. Ng, FRCPCH, MD

Department of Pediatrics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong

On average, I receive approximately 2 to 3 telephone calls and/or e-mails per month inquiring "What is considered to be the normal serum cortisol concentration for preterm infants?" and "What should be the serum cortisol level for consideration of glucocorticoid replacement therapy?" Surprisingly or not so surprisingly, my answer is "I am not too sure, but ...".

As circulating cortisol in early weeks of life can be significantly affected by both an intrinsic transient productive failure because of immaturity of the hypothalamic-pituitary-adrenal (HPA) axis^{1, 2} and extrinsic stressful events or antenatal drug usage,² it is, therefore, not difficult to understand why serum cortisol concentration may vary widely within this period.^{2, 3} The intrinsic production failure mainly concerns the inability of adrenal glands to produce adequate amounts of cortisol necessary for maintaining cardiovascular and biochemical homeostasis.^{1, 2} It is now known that a proportion of extremely preterm infants are transiently unable to produce enough cortisol to counteract stress,^{1, 2} thereby resulting in complications associated with adrenal insufficiency such as refractory hypotension.^4–6 In addition, other factors that can significantly influence circulating cortisol, include: the physiologic decline in serum cortisol concentration in the immediate postpartum period⁷; the effect of antenatal corticosteroids on the HPA axis.^{2, 8, 9} The degree of suppression is directly proportional to the cumulative dose of antenatal dexamethasone administered^{2, 9} and inversely proportional to the time interval between the last dose of antenatal corticosteroids and delivery²; the stress experienced by infants during delivery. Vaginal delivery and low Apgar scores have been associated with exaggerated cortisol responses after birth and higher serum concentrations²; and events associated with postnatal stress such as respiratory distress syndrome (RDS) and the requirement of mechanical ventilation, in particular, intermittent positive pressure ventilation (IPPV) and high frequency oscillatory ventilation (HFOV),² hypoglycemia, infection, etc. Thus, the interpretation of a "normal" or "adequate" cortisol response should take into account the clinical circumstances and presence or absence of features suggestive of adrenocortical insufficiency. In view of many variables that can affect the circulating cortisol level, there has been much difficulty in defining a "normal" range of cortisol in preterm infants, especially in the immediate postnatal period.

Our previous studies of very low birth weight (VLBW) infants (n = 137) administered human corticotrophin releasing hormone (hCRH) suggested that relatively well infants who did not require IPPV and HFOV demonstrated the usual physiologic decline in serum cortisol concentration in the immediate postnatal period, whereas those with moderately severe RDS and required mechanical ventilation showed comparatively lower levels at the early stage, but increasing basal and peak serum cortisol levels with increasing postnatal age.² Based on these findings² and results from other studies suggesting transient adrenocortical insufficiency,^{10, 11} we postulate that low serum cortisol concentrations could be used to predict the development of chronic lung disease (CLD). To our disappointment, the data analysis suggested that birth weight (closely associated with gestational age), severity of initial respiratory failure as reflected by the A-aDO₂ gradient and continuing ‘stress’ with persistently elevated serum cortisol concentration on day 14, were significant risk factors associated with the duration of oxygen supplementation, whereas early pituitary-adrenal response at day 7 was not an independent predictive factor.¹² In addition, the Clinical Risk Index for Babies (CRIB) score > 9 and peak serum cortisol concentration > 740 nmol/L (26.8 mg/dL) on day 14 were useful predictors of CLD.¹² Thus, the current article by Aucott et al³ and our previous study¹² indicate that high serum cortisol levels, probably represent continuing stress, are associated with neonatal morbidity, whereas low serum cortisol levels are unable to predict the development of CLD¹² or retinopathy of prematurity.¹³

Another important condition frequently associated with low serum cortisol is refractory hypotension.^{4, 5, 14, 15} This condition is characteristically encountered in extremely preterm infants and presents with severe hypotension within the first days of life that is resistant to high-dose vasopressors and volume expansion, but responds readily to physiologic or stress dose of glucocorticoids.^{4, 5, 14} Our previous study demonstrated that both basal and peak serum cortisol at day 7 were significantly and negatively correlated with the maximum and cumulative dose of vasopressors, total volume of crystalloid and duration of vasopressor treatment in the univariate analysis. More importantly, the lowest systolic, mean and diastolic blood pressures recorded in the immediate postpartum period were significantly and independently associated with these hormone levels in the multivariate regression model.⁶ The median (50th percentile) basal serum cortisol concentrations at day 7 were 198 nmol/L (7.2 µg/dL) and 311 nmol/L (11.3 µg/dL) in hypotensive infants who required vasopressors and ‘normotensive’ infants who did not require pressor support, respectively.⁶ These median levels are slightly lower than the level (13.1 µg/dL between day 5 and 7) reported in the recent study.³ In contrast, Aucott and colleagues did not find any significant association between low serum cortisol levels and the number of infants commenced on vasopressor during the first 28 days, use of open label hydrocortisone or duration of vasopressor.³ Although there are differences between these 2 studies^{3, 6} in primary objectives, patient populations and composition, methodology and data acquisition (eg, maximum and cumulative dose of different vasopressors, vasopressor use in the first 14 days, duration of vasopressor usage measured in hours and the use of the hCRH test for assessing pituitary-adrenal reserve⁶ versus vasopressor use in the first 28 days, duration of vasopressor usage measured in days and basal serum cortisol measurement³); collectively, studies on cortisol response in preterm infants^{2, 3, 6, 12, 13} suggest that both basal and peak serum cortisol concentrations are highly variable in the first 2 weeks of life, rendering it difficult to establish a normal range. In addition, the "reference standard" at one time point may not be applicable to another time point, serum cortisol may not be a good biomarker for predicting conditions associated with transient adrenocortical insufficiency such as CLD^{3, 12} because this stress hormone can be influenced by intrinsic, as well as extrinsic factors.² The data, however, must not be wrongly interpreted that infants with genuine adrenocortical insufficiency, especially associated with refractory hypotension, do not have low serum cortisol concentration.^{4, 5} The latter condition simply constitutes a very small proportion of cases ever treated with vasopressors. Complicating the issue further is the problem that low serum cortisol concentrations may signify adrenocortical insufficiency in highly stressed preterm infants⁵ but may also be evidence of well-being for nonstressed patients.² In addition, serum cortisol may be suppressed, but compensated by maternal antenatal corticosteroids which are transferred to maintain body homeostasis. Thus, the hormone level must be interpreted in association with clinical features, postnatal age, antenatal corticosteroids usage and stress experienced by the infant, and high serum cortisol concentrations, presumably a sign of continuing stress, are associated with prolonged oxygen supplementation¹² and other neonatal morbidities.³

Looking ahead, it is still important to establish a percentile range of serum cortisol in preterm infants for clinical reference. However, such data should be adjusted for important perinatal variables (noted above), focus on the category of preterm infants most at risk of adrenocortical insufficiency and should record serial cortisol values obtained at standardized time intervals during the first 14 days of life. Future research should be targeted to search for cutoff serum cortisol levels with good diagnostic utilities to identify genuine cases of refractory hypotension secondary to adrenocortical insufficiency of prematurity and also for adverse neonatal outcomes. As there are no standard guidelines on the use of systemic corticosteroids for the management of refractory hypotension, more knowledge on indications and proper use of medications are required. Currently, our neonatal unit cautiously restricts the use of the ‘stress’ dose of hydrocortisone¹⁵ for preterm infants with severe hypotension necessitating epinephrine (ie, infants already receiving dopamine and dobutamine 20 µg/kg/min). We also routinely check the serum cortisol concentration before hydrocortisone administration. If the circulating level (results available within 12 hours) is >200 nmol/L (>7.2 µg/dL [ie, >50th percentile of basal serum cortisol concentration in VLBW infants requiring vasopressor support or >25th percentile in those not requiring pressors—an arbitrary cutoff level⁶]) plus absence of response in weaning vasopressors, the attending neonatologist will consider discontinuing the hydrocortisone treatment. The latter scenarios are frequently encountered in cases with early-onset bacterial infection or severe intracranial hemorrhage (unpublished data).

As often commented in my reply to previous enquires and in Grand Rounds for neonatal trainees "I am not too sure, ... although in genuine cases we are replacing the deficient hormone for the infant, there is a possibility that in others we may be exploiting the ‘side effect’ of corticosteroids to treat his/her blood pressure because no normal range of serum cortisol is available for reference."

	FOOTNOTES

 
Accepted Feb 20, 2008.

Address correspondence to Pak C. Ng, Department of Pediatrics, Level 6, Clinical Sciences Building, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. E-mail: pakcheungng{at}cuhk.edu.hk

The author has indicated that he has no financial relationships relevant to this article to disclose.

Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.

	REFERENCES

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1. Hingre RV, Gross SJ, Hingre KS, Mayes DM, Richman RA. Adrenal steroidogenesis in very low birth weight preterm infants. J Clin Endocrinol Metab. 1994;78 (2):266 –270[Abstract]
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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