PEDIATRICS Vol. 105 No. 2 February 2000, pp. 320-324

Links Between Early Adrenal Function and Respiratory Outcome in Preterm Infants: Airway Inflammation and Patent Ductus Arteriosus

Kristi L. Watterberg, MD^*, Susan M. Scott, MD, Conra Backstrom, RN, Kathleen L. Gifford, RN^*, and Kristen L. Cook, BS^*

From the Departments of Pediatrics ^* Pennsylvania State University College of Medicine, and the Milton S. Hershey Medical Center, Hershey, Pennsylvania; and  University of New Mexico School of Medicine, Albuquerque, New Mexico.

	ABSTRACT

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Objective.  To investigate the relationship of cortisol concentrations during the first week of life to patent ductus arteriosus (PDA), markers of lung inflammation, and respiratory outcome in very low birth weight infants.

Methods.  Newborns <1500 g birth weight were prospectively enrolled at 2 centers. Serum cortisol was measured 3 times during days 2 to 7 of life. Tracheal lavage was performed on intubated infants and analyzed for interleukin-1, -6, and -8, and for total protein, albumin, and -1 protease inhibitor. Infants receiving prenatal glucocorticoids were excluded.

Results.  We obtained 337 cortisol values from 125 infants. Infants treated for PDA had lower cortisol values after day 2. One hundred thirty-three tracheal fluid samples were obtained on matching days from 71 intubated infants. Cortisol correlated inversely with tracheal interleukins and proteins. Lower cortisol values during the second half of the week correlated with longer duration of supplemental oxygen therapy and with subsequent development of chronic lung disease at 28 days and at 36 weeks.

Conclusion.  Infants with lower cortisol values in the first week of life had an increased incidence of PDA, increased lung inflammation, and an increased incidence of chronic lung disease. These findings suggest that early adrenal insufficiency may underlie the previously observed association of increased lung inflammation and PDA with adverse respiratory outcome in this population.  Key words:  very low birth weight infant, chronic lung disease (bronchopulmonary dysplasia), cortisol, adrenocortical function, patent ductus arteriosus.

Increased lung inflammation and patent ductus arteriosus (PDA) have both been associated with the development of bronchopulmonary dysplasia (BPD) or chronic lung disease (CLD), in the small preterm infant^1-4; however, the question of why some infants manifest these abnormalities while others do not remains unanswered. Adrenal function may be linked to both of these entities. Cortisol is central to the ability of the body to attenuate its response to inflammation and is a potent inhibitor of inflammatory edema.^5-8 Both animal and human studies have shown that adrenal insufficiency can lead to increased inflammatory response to injury,^6-8 and that glucocorticoids can affect patency of the ductus arteriosus.^9-12

The normal physiologic response to stress includes increased secretion of cortisol.⁵ In conflict with this expectation, however, sick preterm infants frequently do not have elevated serum cortisol concentrations when compared with well infants of the same gestational age.^13-15 Additionally, we have documented lower cortisol concentrations in preterm newborns receiving inotropic support,¹⁵ suggesting inadequate adrenal function in those infants. Very low birth weight infants who subsequently develop CLD have been reported to have decreased basal cortisol concentrations¹⁶ and a decreased response to adrenocorticotrophic hormone¹⁷ during the first week of life, when compared with infants matched for gestation or birth weight who recover without CLD, supporting a relationship between inadequate adrenal function early in life and adverse respiratory outcome.

We hypothesized that early adrenal insufficiency might result in increased lung inflammation, pulmonary edema, and ductal patency, leading to the development of CLD. To investigate this hypothesis, we evaluated the relationship of cortisol concentrations to markers of inflammation and protein leak in the lung, to PDA, and to respiratory outcome in these infants.

	METHODS

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Population

All appropriate-for-gestational age newborn infants <1500 g birth weight in the Neonatal Intensive Care Units at Pennsylvania State University Children's Hospital (PA) and Children's Hospital of New Mexico (NM) were eligible for this prospective study of cortisol, lung inflammation, and respiratory outcome, approved by both institutional review boards, with the following exclusions: weight not appropriate for gestation,¹⁸ congenital sepsis (positive blood or cerebrospinal fluid culture), major congenital anomaly, or major surgical procedure. Patients were enrolled after parental consent was obtained.

Because prenatal administration of glucocorticoids may affect both neonatal cortisol concentrations and postnatal morbidities,¹⁹ all values from infants exposed to prenatal steroids were excluded from analysis. Patients were enrolled in the study between March 1992 and March 1995, a time when few infants at either institution were treated with antenatal steroids. Enrollment was primarily completed before the December 1994 Committee Opinion of the American College of Obstetrics and Gynecology regarding administration of prenatal steroids.²⁰ In this group of infants, therefore, the relationship of cortisol concentrations to other clinical and laboratory measures can be examined without the confounding effects of prenatal steroids, an opportunity no longer available.

Infants were coded as being treated for a PDA if they received indomethacin treatment or underwent surgical ligation during the first 30 days of life. No infant underwent surgical ligation in the first week of life. Because CLD has been defined at both 28 postnatal days and at 36 weeks' postconceptional age, we evaluated outcome at both of these time points. CLD (28 days) was defined as a requirement for increased fraction of inspired oxygen (FIO₂) at 28 days of life to maintain an oxygen saturation >90% by pulse oximeter, and CLD (36 weeks) as a requirement for increased FIO₂ at 36 weeks' postconceptional age. Increased FIO₂ was defined as >0.25 FIO₂ in NM, to adjust for the effect of altitude (~1 mile) on barometric pressure.

Clinical Procedures

To evaluate cortisol concentrations throughout time, blood samples were obtained in the afternoon 3 times during the first week of life: on a) day 2; b) day 3 or 4; and c) day 5, 6, or 7 (where day of birth = day of life 0). All clinical care was provided at the discretion of the attending physicians, who were unaware of the results of these analyses. Tracheal fluid samples were obtained from intubated infants only, using the following protocol: 0.5 mL/kg of normal saline was instilled into the endotracheal tube, followed by 5 to 10 positive pressure breaths. Fluid was then suctioned through a catheter distal to the endotracheal tube tip. This procedure was performed 3 times, after which the suction catheter was rinsed with 0.5 mL of normal saline. Fluid was centrifuged to remove debris, then diluted with 3 mL of normal saline and frozen at 70°C until analysis.

Laboratory Analysis

Each substance was analyzed in one laboratory (cortisol in NM, all others in PA). Cortisol assays were performed by radioimmunoassay (Diagnostic Products Corp, Los Angeles), an assay with <1% cross-reactivity with other naturally occurring steroids. Intraassay and interassay variabilities were 5% and 7.5%, respectively. Interleukin-1, -6, and -8 were analyzed by enzyme-linked immunosorbent assay (ELISA), using Quantikine kits (R & D Systems, Minneapolis, MN). Lower limits of sensitivity were 0.3 pg/mL for interleukin-1, 0.3 pg/mL for interleukin-6, and 3.0 pg/mL for interleukin-8. Total protein concentrations were measured with the Micro BCA protein assay kit (Pierce, Rockford, IL), with a lower limit of sensitivity of ~1 µg/mL.

Albumin and -1 protease inhibitor (-1 antitrypsin) were analyzed by ELISA, using standards from Sigma Chemical (St Louis, MO), and antibodies from Cappel/Organon Teknika Corporation (Durham, NC). Briefly, 0.1 mL of standard or sample, diluted with coating buffer, was added to each well of a microtiter plate, incubated 1 hour at 37°C, washed, and blocked with phosphate-buffered saline/Tween. Then, 0.1 mL of primary antibody in a 1:10 000 dilution was added to each well and washed. After that, 0.1 mL of a 1:2500 dilution of secondary antibody (horseradish peroxidase-bound) was added, incubated, washed, and developed with 0.1 mL of substrate (0-phenylenediamine dihydrochloride, Sigma Chemical). The reaction was stopped with 0.05 mL of 2N H₂SO₄ and read at 490 nm. Lower limit of sensitivity was 10 ng/mL for both assays.

Secretory component of immunoglobulin A (SC) was used as a reference for tracheal fluid because its concentration in epithelial lining fluid has been shown to be independent of capillary leak.²¹ Concentrations were determined by ELISA as follows: microtiter plates were coated with 0.2 mL of a 1:2000 dilution of rabbit anti-human secretory component (Dako Corp, Carpinteria, CA), incubated overnight at 4°C, washed, and blocked. SC standard (The Binding Site, Inc, San Diego, CA) or sample (0.1 mL of a 1:10 dilution) was added to each well, incubated 1 hour, and washed. Secondary antibody, 0.1 mL of a 1:400 dilution (human anti-rabbit horseradish peroxidase-conjugated SC from Dako), was added and incubated for 1 hour. After washing, 0.1 mL of substrate (0-phenylenediamine dihydrochloride, Sigma Chemical) was added and developed for 30 minutes, after which the reaction was stopped with 0.05 mL of 2N H₂SO₄ and read at 490 nm. The lower limit of sensitivity was 1.0 ng/mL. Intraassay variability was 4.3% and interassay variability was 4.7%.

Statistical Analysis

Population data were compared by unpaired Student's t test. We have previously reported that basal cortisol concentrations are inversely correlated with gestational age.¹⁵ For that reason, and because the incidence of adverse outcomes also correlates inversely with gestational age,²² gestation was included in all multivariate analyses of these measures. Concentrations of cortisol and tracheal lavage measures were not normally distributed; therefore, log transformation was performed, yielding normally distributed data for analysis. Cortisol concentrations are expressed in nanomoles/liter (27.6 = µg/dL).

The relationships of cortisol concentrations to tracheal fluid measures were analyzed by multiple regression, using cortisol, gestational age, study center, day of life, and surfactant administration as initial independent factors, with stepwise removal of nonsignificant factors. The relationship of cortisol to the presence of a PDA was similarly assessed, using logistic regression, with initial independent factors including cortisol, gestational age, study center, and surfactant administration. Because we hypothesized a causal relationship between cortisol concentrations and all 3 outcomes (tracheal lavage measures, PDA, and CLD), these factors were not combined together into a multiple regression with respiratory outcome as the dependent variable. Instead, the relationship of cortisol to each of these variables and to respiratory outcome was evaluated separately, with gestational age as an independent continuous variable in the analyses. To further assess the relationship of cortisol values to respiratory outcome, we performed a regression analysis using cortisol values and gestational age as independent variables, with the postconceptional age at which each infant stopped receiving supplemental oxygen as the dependent variable.

	RESULTS

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One hundred twenty-five infants were enrolled in the study (68 in PA, 57 in NM). Patient characteristics and clinical outcomes are shown in Table 1. As stated in "Methods," infants exposed to prenatal glucocorticoids were excluded. More patients were treated for PDA at the NM center than the PA center (58% vs 37%, P = .02). Other characteristics and outcomes were similar at the 2 centers.

A total of 337 cortisol values were obtained. Analysis with paired t test showed that cortisol values were higher on day 2 than on days 3 to 4 or days 5 to 7 (n = 99 paired values for day 2 vs days 3 to 4, P = .01; n = 101 for day 2 vs days 5 to 7, P = .002). Values on days 3 to 4 were similar to those on days 5 to 7 (n = 108, P = .76). Cortisol values through the week are illustrated in Fig 1, grouped by respiratory outcome at 36 weeks postconception. Patients who subsequently developed CLD had significantly lower cortisol values during the second half of the week. This was also true when data were analyzed for CLD at 28 days. Geometric means for CLD versus no CLD at 28 days were as follows: day 2, 195 nmol/L (n = 51) versus 211 nmol/L (n = 37) (P = .11); days 3 to 4, 125 nmol/L (n = 52) versus 168 nmol/L (n = 39) (P = .09); days 5 to 7, 133 nmol/L (n = 67) versus 169 nmol/L (n = 43) (P = .03).

View larger version (10K): [in this window] [in a new window]   Fig. 1.   Serum cortisol concentrations (log cortisol in nmol/L, mean ± SEM) in survivors who developed chronic lung disease at 36 weeks after conception (CLD, ) versus those who recovered without CLD (). Values are significantly different at days 5 to 7 (P = .04). Gestational age was included as an independent factor in these analyses.

Regression analysis showed a significant inverse relationship between cortisol values and the postconceptional age at which each infant stopped receiving supplemental oxygen. This inverse relationship was significant for values obtained on days 3 to 4 (F = 5.84, P = .04 for cortisol, P = .03 for gestational age) and on days 5 to 7 (F = 8.38, P = .014 for cortisol, P = .002 for gestational age).

Figure 2 illustrates the differences seen in cortisol concentrations through the week in infants with and without PDA. On day 2, cortisol concentrations were similar; however, after that, the values were significantly different between the 2 groups. The differences between these patient groups seemed to be attributable to a decline in cortisol concentrations in those infants with PDA during the week. Paired t tests showed that values did not change significantly through the week in infants without PDA; however, in infants with PDA, cortisol values decreased significantly after day 2 (P < .001, day 2 vs days 3-4; P = .001, day 2 vs days 5-7). In a logistic regression analysis with gestational age and surfactant administration, the presence of a PDA was significantly associated with adverse respiratory outcome, both at 28 days (P < .001) and at 36 weeks postconception (P < .01).

View larger version (12K): [in this window] [in a new window]   Fig. 2.   Serum cortisol concentrations (log cortisol in nmol/L, mean ± SEM) in patients treated for patent ductus arteriosus () versus those not treated (). Values are significantly different between groups on days 3 to 4 (P = .002) and 5 to 7 (P < .001). Gestational age was a cofactor in this analysis.

To assess whether indomethacin therapy may have affected cortisol concentrations in patients with PDA, we first compared cortisol values between centers, because the time of PDA treatment differed significantly between the centers. The median day of life (25th to 75th percentile) for indomethacin therapy at Penn State University was 4 days (2-6 days), whereas at the University of New Mexico it was 2 days (1-3 days). Cortisol concentrations in patients with PDA were similar at both centers throughout the week. Secondly, we compared cortisol concentrations from those patients with PDA who had not received indomethacin with values obtained from patients during or after indomethacin therapy, and found that cortisol values were not significantly different between those groups. The geometric means for treated versus not yet treated infants were 97 nmol/L (n = 39) versus 118 nmol/L (n = 9) on days 3 to 4, and 112 nmol/L (n = 51) versus 88 nmol/L (n = 9) on days 5 to 7.

Forty-four intubated infants in PA and 27 in NM had a total of 133 tracheal lavage and serum cortisol samples obtained on matching days during the first week of life. All tracheal fluid values were referenced to secretory component concentration, to adjust for dilutional differences.²¹ Secretory component concentrations (n = 129) were different between centers (P < .01), but were not significantly related to cortisol values (P = .34), gestation (P = .87), surfactant administration (P = .61), or day of life (P = .61).

The relationship of cortisol concentration to each tracheal fluid measure was first evaluated for all matched values during the week. In this analysis, cortisol showed a significant inverse relationship with interleukin-6 (n = 122, r = .1967, P < .03), total protein (n = 113, r = .2553, P < .02), albumin (n = 123, r = .2243, P = .003), and -1 protease inhibitor (n = 72, r = .2830, P = .003). Fewer samples were available for -1 protease inhibitor because of small sample volumes. Because day of life was a significant factor for both cortisol and several tracheal fluid measures, and because the majority of data points at the end of the week were obtained from infants who developed CLD, data were separately analyzed for the first half of the week, using only 1 value per patient. In this analysis, cortisol concentrations correlated inversely with interleukin-1 (n = 61, r = .2771, P < .02), interleukin-8 (n = 63, r = .3135, P < .02), total protein (n = 56, r = .2795, P < .05), and albumin (n = 61, r = .1982, P < .05). Figure 3 illustrates the inverse relationship between cortisol and interleukin-8.

View larger version (14K): [in this window] [in a new window]   Fig. 3.   Serum cortisol concentrations (log cortisol in nmol/L, mean ± SEM) are shown plotted against tracheal fluid concentrations of interleukin-8. One value is included per patient, from the first lavage performed during the first 4 days of life (n = 63, r = .3135, P < .02).

	DISCUSSION

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In this study, we demonstrated for the first time, to our knowledge, that lower serum cortisol concentrations in very low birth weight infants correlated with 2 factors previously linked to adverse respiratory outcome in premature infants: increased lung inflammation and the presence of a PDA. We found that cortisol concentrations decreased during the course of the first week of life in infants with PDA. Whereas such a decline could be appropriate for well infants, or for those whose acute lung disease is resolving, patients with PDA were smaller, sicker, and had a higher incidence of adverse respiratory outcome. Lower cortisol values were also associated with evidence of increased lung inflammation and protein leak and with adverse respiratory outcome in this study population. All these presumably stressful factors might be expected to result in higher, rather than lower, serum cortisol concentrations.

These lower cortisol values cannot be attributed to gestational age, because premature infants do not have lower basal cortisol concentrations than term infants.^13-15,23 Lower serum protein concentrations do not account for the lower cortisol values seen. Although premature infants generally have lower albumin concentrations, cortisol is bound primarily to cortisol binding globulin. Cortisol binding globulin values in premature infants are lower than the adult normal range,^15,23,24 but have no relationship to cortisol concentrations²⁴ and do not result in lower free plasma cortisol levels.²³ Certainly, other factors we are not aware of may have contributed to lower cortisol concentrations; however, any adverse event should increase rather than decrease cortisol secretion, as a response to stress.

Single plasma cortisol concentrations may be of limited usefulness in evaluating adrenal function; however, statistical comparisons of values between groups can provide useful information about population differences. Further, single values may be more useful in preterm infants than in other populations. First, infants do not exhibit the diurnal variation in cortisol concentrations seen in older individuals.^15,25 In addition, a recent study found decreased variability throughout time in cortisol concentrations in small premature infants, and suggested that a single cortisol value is representative of plasma cortisol concentration throughout a prolonged period of time in these infants.²⁶

None of these infants were exposed to prenatal glucocorticoids, which can suppress postnatal cortisol values.¹⁹ Because this study was conducted before general use of prenatal glucocorticoids at either institution, these data provide a now unique opportunity to study the relationship of adrenal function to biochemical and clinical outcome measures. Future studies in this area can compare these data with values found in infants exposed to prenatal glucocorticoids.

Previous studies of the cause of CLD have generally focused on external agents of lung injury, such as oxygen or barotrauma.¹ However, infants with apparently similar exposures to such injurious agents may have quite different respiratory outcomes; thus, it seemed reasonable to consider that differences in outcome may result from differences in the individual infants' responses to lung injury. We and many other investigators have previously described early postnatal increases in measures of lung inflammation in infants who go on to develop BPD.^1,27 Recently, increased markers of inflammation have even been found prenatally in infants who develop BPD.²⁸ Additionally, pulmonary edema and increased pulmonary epithelial permeability have been described in these infants.^1,29 In this study, we found that lower cortisol concentrations correlated with higher tracheal fluid concentrations of interleukin-1, -6, and -8, as well as with tracheal fluid proteins. These findings are consistent with the central role that glucocorticoids play in dampening the inflammatory response to injury, as well as inhibiting microvascular permeability and inflammatory edema.^5-8

We are not aware of previous studies evaluating the relationship of endogenous cortisol concentrations to the presence of PDA. However, animal studies have documented that glucocorticoid administration decreases the sensitivity of ductal tissue to the dilating influence of prostaglandin E₂.^9,10 Because cortisol suppresses the activity of phospholipase A₂,^5,6 it may also decrease prostaglandin production. Several clinical studies have found a decreased incidence of PDA in newborns after exposure to prenatal steroids.¹¹ Additionally, a recent randomized study of dexamethasone therapy beginning on the first day of life found a decreased incidence of PDA in the dexamethasone-treated infants, compared with controls.¹² These studies are consistent with the theoretical basis for our observation; that is, that increased endogenous cortisol production in the premature infant may promote ductal constriction, resulting in a decreased incidence of PDA.

In this study, then, we showed that lower cortisol values in the first week of life correlated with increased lung inflammation and microvascular protein leak, increased incidence of PDA, and subsequent development of CLD in very low birth weight infants. In addition, infants who had lower cortisol concentrations remained on supplemental oxygen for longer times. These findings suggest that early adrenal insufficiency may in part explain the previously observed association of increased lung inflammation and PDA with adverse respiratory outcome in this population. By leading to an increased incidence of PDA and by permitting increased lung inflammation and protein leak, early adrenal insufficiency may play an integral part in the multifactorial etiology of CLD in the premature infant. Inadequate adrenal function may also explain, at least in part, why less mature infants have more CLD, because the ability to secrete cortisol in response to adrenocorticotrophic hormone stimulation increases through gestation.¹⁷

Whether this relationship is causal is certainly an unanswered question, as is the question of whether supplementation with cortisol would benefit these infants. High-dose steroid therapy beginning in the first week of life has been reported to decrease the incidence of CLD.^12,30 Unfortunately, high doses of glucocorticoids have multiple side effects, and may result in adverse long-term outcomes.^12,31,32 In view of these findings, investigation of the safety and therapeutic efficacy of early supplementation with lower, more physiologic doses of glucocorticoid seems appropriate.

	ACKNOWLEDGMENTS

This work was supported by Grant MCJ 420627 from the Maternal and Child Health Program (Title V, Social Security Act), Health Resources and Services Administration, Department of Health and Human Services; and by Grant NIH 5 M01RR00997-14.18 from the General Clinical Research Center of the University of New Mexico, Program DRR.

	FOOTNOTES

Received for publication Mar 11, 1999; accepted Jul 8, 1999.

Reprint requests to (K.L.W.) 18 Cedar Hill Road NE, Albuquerque, NM 87122. E-mail: klw9{at}psu.edu

	ABBREVIATIONS

PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; CLD, chronic lung disease; PA, Pennsylvania State University Children's Hospital study site; NM, Children's Hospital of New Mexico study site; FIO₂, fraction of inspired oxygen; ELISA, enzyme-linked immunosorbent assay; SC, secretory component of immunoglobulin A.

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