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Original Article |
Department of Pediatrics (P.C.N., C.H.L., K.C.M., T.F.F.), Department of Chemical Pathology (C.W.K.L., I.H.S.C.), and Center for Clinical Trials and Epidemiological Research (E.W.), Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
Address all correspondence and requests for reprints to: Prof. P. C. Ng, Department of Pediatrics, Level 6, Clinical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong. E-mail: pakcheungng{at}cuhk.edu.hk.
Abstract
This prospective study aims to investigate the factors that influence the human CRH (hCRH) test and to provide reference ranges for plasma corticotropin (ACTH) and serum cortisol concentrations of the stimulation test in preterm, very low birth weight (VLBW) infants.
Two hundred twenty-six hCRH tests were performed on 137 VLBW infants at d 7 and 14 of life. Plasma ACTH did not differ significantly between infants whose mothers did not receive antenatal corticosteroids (group 1) and those whose mothers received one or two doses (group 2) or more than two doses (group 3) of the drug. However, plasma ACTH levels at d 7 were found to be significantly higher in infants with severe lung disease who required intermittent positive-pressure ventilation (IPPV) or high-frequency oscillation ventilation (HFOV), compared with those who had milder pulmonary disease and did not require mechanical ventilation or needed only continuous positive airway pressure (CPAP) support (P < 0.011). A significantly higher rate of increase in plasma ACTH concentration at d 7 was also observed in infants whose mothers suffered from antepartum hemorrhage (P < 0.016).
In contrast, infants in group 2 had significantly lower serum cortisol, compared with group 1 infants (P < 0.05), whereas group 3 infants did not have serum cortisol levels significantly different from those of patients in group 1 or 2. Significant positive correlation between serum cortisol at d 7 and the time interval between the last dose of antenatal dexamethasone and delivery was also observed in group 3 infants (r > 0.33, P < 0.045). In addition, infants who required IPPV or HFOV had significantly lower serum cortisol at d 7 (P < 0.0001), but this pattern of cortisol response was reversed on d 14, with infants requiring IPPV or HFOV having significantly higher serum cortisol (P < 0.036). The reference ranges for plasma ACTH and serum cortisol concentrations of the hCRH test at d 7 and 14 were also provided for group 1 and group 2 infants.
This study demonstrates that even one or two doses of antenatal corticosteroids cause adrenal suppression in VLBW infants. Maternal antepartum hemorrhage also influences the pituitary response of preterm newborns in the first week of life. The change in the pattern of cortisol response in sick ventilated (IPPV or HFOV) infants during the first 2 wk of life suggests that a proportion of preterm infants may have inadequate adrenal response to stress in early postnatal life, but it is likely that rapid adaptation of the hypothalamic-pituitary-adrenal axis results in enhanced and more appropriate cortisol response by d 14. The percentile distribution of plasma ACTH and serum cortisol responses provides useful statistical reference data for interpretation of the hCRH test in VLBW infants and may also assist in facilitating the use of corticosteroids replacement therapy in cases with clinical manifestations suggestive of adrenal insufficiency.
MATURATION OF THE fetal hypothalamic-pituitary-adrenal (HPA) axis during late gestation is a natural and common process of primates (1). It is now known that normal development of the HPA axis is essential for regulation of intrauterine homeostasis, timely differentiation and maturation of vital organ systems, and may also influence the timing of parturition (2, 3, 4). In addition, it has been suggested that a significant proportion of critically ill very low birth weight (VLBW) infants may suffer from systemic hypotension (5, 6) or have a higher chance of developing bronchopulmonary dysplasia as a result of low circulating cortisol secondary to adrenal insufficiency and HPA axis immaturity (7, 8). Thus, it would be clinically important to know which level of circulating corticotropin (ACTH) and cortisol constitute an adequate pituitary-adrenal response in this category of patients. We have, in our previous study of preterm neonates, demonstrated that the human CRH (hCRH) test is safe, reproducible, and capable of eliciting a consistent pituitary-adrenal response similar to those of older children and adults (9). Furthermore, the hCRH test is found to be more reliable than a single random measurement of ACTH or cortisol because of episodic secretion of these hormones (10, 11). The hCRH test is also preferable to other HPA axis stimulation tests such as the insulin stress test, the metyrapone test, and the low-dose short-synacthen test, because these latter tests are either unsuitable for use in preterm infants because of their potential adverse effects, not as sensitive as the hCRH test in demonstrating a mild degree of adrenal insufficiency, or do not assess the hypothalamic-pituitary function of the axis (9, 12). To date, no reference values have been determined for the hCRH test in VLBW infants despite the frequent use of antenatal and postnatal corticosteroids. This prospective study, therefore, aims to investigate the factors that may influence the hCRH test, and also to provide statistical reference ranges of plasma ACTH and serum cortisol concentrations for the stimulation test in this category of patients during the first 2 wk of life. These values should allow a more comprehensive interpretation of the hCRH test and identify VLBW infants who are potentially at risk of adrenal insufficiency.
Subjects and Methods
Study population
One hundred thirty-seven VLBW infants were prospectively enrolled into the study. Inclusion criteria were: 1) gestational age less than 32 wk; 2) birth weight less than 1500 g; 3) no postnatal systemic or inhaled corticosteroids treatment before the hCRH test; and 4) possession of an indwelling arterial cannulae at d 7 of life. A second hCRH test would also be performed if the arterial cannulae remained in situ at d 14. Infants were excluded if they had concurrent hypoglycemia, systemic infection, necrotizing enterocolitis, or major surgery in the preceding week. The use of antenatal corticosteroids, however, did not preclude the infants from receiving the hCRH assessment, because the majority of preterm patients would have received the treatment to enhance lung maturity. Gestation assessment was by the mother’s last menstrual period, early ultrasound dating, and new Ballard Score assessment after birth (13).
Antenatal corticosteroids regime
The decision to commence antenatal dexamethasone rested entirely on the clinical judgment of the attending obstetricians. The unit policy for starting antenatal dexamethasone treatment in mothers between 24–34 wk gestation were: 1) threatened preterm labor; 2) antepartum hemorrhage; 3) preterm rupture of membranes; and 4) any condition requiring elective premature delivery. Because the effect of antenatal corticosteroids is likely to wane after 7 d (14), repeated courses would be given if the risk of imminent preterm delivery persisted or recurred after the initial treatment. Each course consisted of two doses of dexamethasone (dexamethasone sodium phosphate; Weiner Pharma, Gmbh, Rastatt, Germany), 10 mg given 12 h apart.
hCRH test and hormone assays
We chose to perform the hCRH tests on d 7 and 14 of life. The reasons for choosing this time sequence have been previously discussed (9). All tests were performed between 0800 h and 1000 h. Each vial (100 µg) of synthetic hCRH (Ferring Pharmaceuticals Ltd., Arzneimittal, Wittland, Germany) was reconstituted with the standard diluent provided, and then it was further diluted with sterile water to obtain a concentration of 2 µg/ml. Blood samples (0.5 ml) were obtained from the indwelling arterial line for measurement of the baseline (0 min) plasma ACTH and serum cortisol concentrations before hCRH (1 µg/kg) was administered by bolus iv injection. Three further sets of blood samples were taken 15, 30, and 60 min after the hCRH injection. The blood samples were immediately immersed in ice and transported to the laboratory. The plasma ACTH and serum cortisol concentrations were measured by double-antibody RIA and solid-phase RIA, respectively (9). Processing of blood samples and details of hormone measurement have also been previously described (9). The ACTH double-antibody RIA has 0% cross-reactivity with human ACTH fragments (ACTH 1–24, 11–24, 18–39, and 1–10) as well as other related hormones (
-MSH, ß-MSH, ß-lipotrophic pituitary hormone, and ß-endorphin), even when these potential cross-reactants are present at very high concentrations (1,100–22,000 pmol/liter).
Plasma ACTH concentration in picomoles per liter can be converted to picograms per milliliter by multiplying by a factor of 4.5; likewise, the conversion of serum cortisol concentration from nanomoles per liter to micrograms per deciliter can be achieved by dividing by 27.6.
Ethical approval
Ethical approval of the study was obtained from the research ethics committee of the Chinese University of Hong Kong. Informed parental consent was obtained for each case before commencement of the test.
Statistical analysis
The descriptive statistics on the demographic data were expressed as median and interquartile range. The Kruskal-Wallis test and 
2 test were used to compare the clinical characteristics of VLBW infants whose mothers did not receive any antenatal dexamethasone (group 1), and those whose mothers received one or two doses (group 2), or more than two doses (more than one course; group 3) of the medication. Spearman’s correlation was also used to assess the relation between the hormone concentrations and the clinical characteristics of the infants, including gestational age, birth weight, Apgar scores at 1 and 5 min, quantity of oxygen supplementation, and the time interval between the last dose of antenatal dexamethasone and delivery. Multilevel models, the mixed effects models (15), were used to compare the longitudinal rate of change (i.e. the slope of the curve with reference to the basal level) of plasma ACTH and serum cortisol concentrations between different groups of patients, including male vs. female, infants born by vaginal delivery vs. cesarean section, infants with no additional oxygen supplementation vs. those requiring oxygen more than 21%, gestational age less than 28 wk vs. 28 wk or more, birth weight less than 1000 g vs. 1000 g or more, infants requiring intermittent positive-pressure ventilation (IPPV) or high-frequency oscillation ventilation (HFOV) vs. those who needed only continuous positive airway pressure (CPAP) or no mechanical ventilation, and infants whose mothers suffered from antepartum hemorrhage, preeclampsia of pregnancy, or prolonged rupture of membrane (PROM) more than 24 h, as opposed to infants whose mothers did not experience such complications during the prenatal and peripartum period. Statistically significant results were further subjected to multivariate analysis. The multilevel models were also used to construct the percentiles for plasma ACTH and serum cortisol concentrations of the hCRH test at d 7 and 14 of postnatal age. Blood hormone concentrations that were 3 SD above or below the mean level for a particular time point were considered as outliners and would be excluded from the final analysis. Multilevel models are random effects models that take into account the hierarchical nature of the data, and the within- and between-subject heterogeneity (15). For longitudinal data, such models allow for measurements made at unequal intervals and with a varied number of measurements (i.e. subjects who may have one or several measurements). The models are fitted by the method of restricted iterative generalized least-squares algorithm of MLn for Windows software package, Version 2.0 (Institute of Education, University of London, London, UK). The likelihood ratio test is used to assess the statistical significance of the estimates at the 5% level. The model assumptions are checked by inspection of the standardized residuals for normality and constant variance. The percentile derived from the MLn represents the 50th percentile under the normality assumption. The other percentiles are obtained as mean ± z SD, where z = -1.88, -1.28, 1.28, and 1.88 for the 3rd, 10th, 90th, and 97th percentiles, respectively. In addition, because the absolute plasma ACTH and serum cortisol concentrations are also important in evaluating the adequacy of pituitary-adrenal response, the unpaired t test was used to assess the circulating hormone concentrations at the corresponding time points between different groups of patients. The statistical tests were performed by SPSS for Windows (Release 10.1; SPSS, Inc., Chicago, IL). The statistical analysis was performed on raw or logarithmically transformed results, where appropriate, to correct the skewness of the data.
Results
Two hundred twenty-six hCRH tests were performed on 137 preterm, VLBW infants at d 7 and 14 of postnatal age. Twelve infants missed the first hCRH test, of whom 6 were suspected of being septicemic, 1 was suspected of having necrotizing enterocolitis, and 5 did not possess an indwelling arterial line for blood sampling. These patients were, however, subsequently studied in the second test. Thirty-six infants were not tested on d 14, of whom 6 died from respiratory failure or septicemia before the second week of life, 10 sick infants were commenced on early systemic corticosteroids because of severe lung disease or persistent hypotension, 2 developed fulminant necrotizing enterocolitis, 4 were suspected of being septicemic, and 14 no longer had an indwelling arterial line when due for investigation. Of the 10 patients who required early intervention with systemic corticosteroids, 3, 6, and 1 infants belonged to groups 1, 2, and 3, respectively, and all required mechanical ventilatory support with either IPPV or HFOV at d 7 of postnatal life. Preliminary hCRH test results of the first 61 patients have been described in our previous report (16). The clinical characteristics of the study population are summarized in Table 1
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Both circulating levels and the rate of change of plasma ACTH concentrations did not differ significantly between infants whose mothers did not receive antenatal corticosteroids (group 1) and those whose mothers received one or two doses (group 2) or more than two doses (group 3) of the drug at d 7 and 14 (Fig. 1).
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Because plasma ACTH concentration did not differ significantly between group 1 and group 2 infants, the 10th, 25th, 50th, 75th, and 90th percentiles of basal (peak) ACTH responses for the combined group (groups 1 plus 2) were 3.1 (5.4), 4.1 (7.4), 5.5 (10.4), 7.5 (14.7), and 9.8 (20.0) pmol/liter at d 7; and 3.9 (6.6), 5.2 (9.0), 7.1 (12.7), 9.8 (18.0), and 13.1 (14.7) pmol/liter at d 14, respectively.
Cortisol
Compared with group 1 patients, infants in group 2 had significantly lower basal and poststimulation (15 and 60 min) serum cortisol concentrations at d 7 (P = 0.049 and P < 0.041, respectively; Fig. 2). In contrast, serum cortisol concentrations of group 3 infants did not differ significantly from those of group 1 or group 2 patients. No significant difference in serum cortisol concentrations was observed among the groups at d 14. A significantly higher basal and poststimulation (15, 30, and 60 min) serum cortisol concentrations at d 7 were observed in infants who were delivered vaginally, compared with those delivered by cesarean section (P = 0.002 and P < 0.004, respectively).
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). Similarly, infants who required oxygen supplementation also had significantly lower poststimulation (15 and 30 min) serum cortisol at d 7 of life (P = 0.031 and P = 0.005, respectively; Fig. 4). However, this pattern of response was reversed 1 wk later (d 14), when infants requiring IPPV or HFOV had significantly higher poststimulation (15 and 60 min) serum cortisol (P < 0.036; Fig. 3), and those needing oxygen supplementation also had significantly higher basal and poststimulation (15, 30, and 60 min) cortisol levels (P = 0.004 and P < 0.003, respectively; Fig. 4). Also, serum cortisol concentrations at d 7 were reanalyzed after excluding the subset of 10 sick infants treated with early corticosteroids. The exclusion of these infants did not alter the outcomes of the comparison in hormone concentrations between: 1) groups 1, 2, and 3 infants; 2) infants requiring IPPV or HFOV and those who needed only CPAP support or no mechanical ventilation; and 3) infants who required oxygen supplementation and those who did not.
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In an overall analysis involving all studied patients, the multilevel statistical model identified two major factors that significantly influenced the cortisol response. First, infants on mechanical ventilation (IPPV/HFOV) had, on average, serum cortisol concentrations that were 31% lower at d 7, whereas the levels were 25% higher by d 14. Second, infants whose mothers received one course of antenatal dexamethasone would, on average, have serum cortisol concentrations that were lower by 21% on both d 7 and 14. However, the suppressive effect of two or more courses of antenatal corticosteroids was not necessarily more severe and did not correlate significantly with the cortisol response. Because there were significant differences in serum cortisol between group 1 and group 2 patients, Table 2 represents the percentile distribution of the cortisol responses of these two groups at d 7 and 14. In addition, the percentile distribution for the relatively well infants (i.e. those requiring minimal or no ventilatory support) is also included in Table 2 for comparison. None of the blood hormone concentrations exceeded 3 SD, which required exclusion from the data set.
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Our results indicate that stressful events occurring in the perinatal and early postnatal period can greatly influence the pituitary-adrenal response in preterm infants. Highly stressed infants, born vaginally or with low Apgar scores, have exaggerated cortisol responses after birth. These findings concur with the results from previous studies (16, 17, 18, 19). In addition, our data further indicate that maternal antepartum hemorrhage is a stressful event to the fetus and can promote the release of ACTH in newborn infants. However, in contrast to the report by Bauer et al. (20), PROM (>24 h) per se did not significantly affect the HPA axis. Given that PROM is only one of many surrogate markers of chorioamnionitis and correlates rather poorly with intrauterine infection, it is not surprising that it had relatively little influence on the early neonatal HPA axis in our series.
More importantly, the change in the pattern of circulating cortisol, in relation to mechanical ventilation and oxygen supplementation, demonstrated a unique phenomenon of adaptation of the HPA axis to stress and underlying disease in early postnatal life. Although we have reported in our previous study that serum cortisol in ventilated infants did not follow the natural decreasing trend and remained elevated at d 14 (16), the relatively small sample size precluded us from drawing a definite conclusion that some of these sick preterm infants might have inadequate cortisol release in response to stress within the first week of life. In the current study, we have been able to show that preterm infants with severe respiratory distress syndrome, requiring IPPV or HFOV and oxygen supplementation at d 7, have exaggerated ACTH responses, but paradoxically significantly lower basal and poststimulation serum cortisol concentrations, compared with infants who had much milder pulmonary disease requiring only minimal (CPAP) or no mechanical ventilatory support or oxygen supplementation (Figs. 3
and 4). This pattern of hormone response was, however, reversed in the second week of life (d 14), and those infants that required IPPV or HFOV and oxygen supplementation had significantly higher serum cortisol concentrations (Figs. 3 and 4). Recent studies suggested that preterm newborns have an immature HPA axis and that the mechanisms are likely to be associated with failure of the hypothalamus in recognizing the stimulatory signal (21) or ineffective adrenal steroidogenesis secondary to immature intermediate enzymes activity of the glucocorticoid pathway (22, 23). The lack of a significant association between gestational age and plasma ACTH concentrations, and the prompt and competent ACTH response to exogenous hCRH stimulation, both indicate that the pituitary gland is likely to be physiologically mature at an early gestation (9, 16). Furthermore, preterm infants with refractory hypotension show an adequate pituitary response but severely blunted adrenal reaction to hCRH (6). Thus, it would seem likely that the change in hormone pattern of ventilated (HFOV/IPPV) infants represents a normal or exaggerated pituitary response to stress throughout the study period but ineffective steroidogenesis of the adrenal gland in the first week of life. We further postulate that the reverse in serum cortisol pattern on d 14 was attributable to successful adaptation of the adrenal glands to extrauterine life and enhanced maturation of the intermediate enzyme activity of the glucocorticoid pathway during this critical transitional period.
Significant adrenal suppression was observed on d 7 in infants whose mothers received one or two doses of antenatal dexamethasone (group 2), compared with those whose mothers did not receive the medication (group 1). However, the magnitude of suppression was relatively mild [the 50th percentile basal (0 min) serum cortisol concentration decreased from 286 nmol/liter to 221 nmol/liter, and the peak (30 min) level decreased from 513 nmol/liter to 404 nmol/liter (Table 2)], indicating that the majority of patients in group 2 had adequate circulating cortisol levels and should not suffer from overt adrenal insufficiency. Furthermore, it seems unlikely that the difference in cortisol levels between group 1 and group 2 at d 7 can be attributed to a disproportional increase in the number of infants requiring IPPV or HFOV in the former group, because: 1) intubation and ventilation are both highly stressful experiences and would be expected to result in an increase rather than a decrease in circulating cortisol levels; 2) the simultaneous increase in plasma ACTH level at d 7 suggests that cortisol suppression in ventilated infants is likely to be caused by adrenal hyporesponsiveness; 3) the reverse in the cortisol pattern of the ventilated infants at d 14 (Fig. 3) did not support the likelihood that ventilation is the primary cause responsible for adrenal suppression; and 4) there was no statistically significant difference in the number of infants requiring IPPV or HFOV between group 1 and group 2 (Table 1). In contrast, infants who received repeated courses (more than two doses) of antenatal dexamethasone (group 3) did not necessarily have more severe adrenal suppression than those who received one or two doses of the drug (Fig. 2). Although our previous report suggests that the cumulative dose of antenatal dexamethasone is negatively associated with serum cortisol concentration and might contribute to the suppression of adrenal function (24), the results of the current study further demonstrate a significant positive correlation between the serum cortisol concentrations and the time interval between the last dose of antenatal corticosteroids and delivery at d 7, indicating that the time after discontinuation of antenatal corticosteroids is also an important element attributed to the recovery of adrenal function.
Preterm VLBW infants are (by definition) atypical; and the majority of these patients are likely to have surfactant deficiency and respiratory distress necessitating mechanical ventilation and oxygen supplementation. Because there is no such entity as a so-called normal VLBW infant, there are always problems in attempting to establish reference standards for this group of patients. In addition, it is difficult to define hypocortisolism, because: 1) preterm infants with different gestations may have different normal circulating hormone levels; 2) their circulating hormone concentrations tend to change naturally with increasing postnatal age (25); and 3) the clinical manifestations of early or mild hypocortisolism could be subtle and not readily recognizable in sick preterm neonates. Taking these constraints and difficulties into account, it would not be possible to determine an accurate diagnostic cut-off value for serum cortisol using the conventional receiver operating characteristics curve. Hence, we opted to provide the percentile distribution for blood hormone concentrations that represents a statistical reference for the typical VLBW infant. Such data should allow better understanding of the pituitary-adrenal status, especially if used in conjunction with relevant clinical findings. Many factors, including maternal perinatal conditions, mode of delivery, condition of the baby at birth, severity of the underlying pulmonary illness, and mode of mechanical ventilation, might influence the hormonal response of the HPA axis (16, 19, 26). It would, therefore, not be possible or advisable to provide separate percentile charts for each of the aforementioned parameters. Therefore, in the first step of the analysis, we identified two major factors that significantly influenced the cortisol response. First, infants requiring mechanical ventilation (IPPV/HFOV) had, on average, serum cortisol concentrations that were 31% lower at d 7, whereas the levels were 25% higher by d 14. We believe that the severity of lung disease and requirement for mechanical ventilation (IPPV/HFOV) on d 7 are most likely the result of low serum cortisol (7, 27) rather than the cause of cortisol suppression. Second, infants whose mothers received one course of antenatal dexamethasone would, on average, have serum cortisol levels that were lower by one fifth. Thus, we have, in this study, demonstrated how various parameters might interact and affect the pituitary-adrenal release, so that the main variables could be adjusted to permit comparison of hormone results between patients with different clinical characteristics. In view of these findings, we have compiled the percentile distribution of plasma ACTH and serum cortisol based on the different dosages of antenatal corticosteroids received by the infants (Table 2). Because it is important to present a full spectrum of cortisol response (28), both the percentile distribution of the whole patient group (group 1/group 2), as well as those of relatively well infants (i.e. those requiring only minimal or no ventilatory support), were included for comparison. However, no meaningful data could be generated for group 3 infants, because they constituted a very heterogenous group of patients whose mothers received variable courses of antenatal corticosteroids, and the time interval between the last dose of dexamethasone and delivery also differed widely among individual infants (Table 1). To our knowledge, the current data set represents one of the largest series of hCRH tests performed on preterm infants. The percentile distribution of basal and peak serum cortisol should be useful for providing a statistical reference for predicting which particular categories of patients are most vulnerable or likely to be at risk of developing adrenal insufficiency. In clinical practice, it is the circulating cortisol level, coupled with the stress experienced by the infant, that determine whether cortisol response is sufficient in maintaining the proper function of vital body systems. Watterberg and Scott (7) suggested that a poststimulation cortisol level less than 9 µg/dl (<248 nmol/liter) at d 7 might indicate inadequate cortisol release in response to stress, and an association with increased risk of developing bronchopulmonary dysplasia. VLBW infants with peak serum cortisol concentrations in the 25th percentile or more (
270–357 nmol/liter at d 7) are thus unlikely to have adrenal insufficiency or suffer from the consequences of this complication. Better interpretation of the hCRH test in the presence of clinical manifestations suggestive of adrenal insufficiency, such as systemic hypotension refractory to volume expansion and inotropes or electrolyte disturbance, would enable corticosteroids-replacement therapy to be confidently administered without delay.
In summary, this study demonstrates that even one or two doses of antenatal corticosteroids cause adrenal suppression in newborn infants. Multiple courses, however, may not necessarily give rise to worsening of cortisol suppression, because the time interval between the last dose of antenatal corticosteroids and delivery also plays an important role in determining the activity of the HPA axis. The unique change in cortisol pattern, observed in sick ventilated (IPPV or HFOV) infants between the first and second week of life, lends support to the hypothesis that the adrenal response may be inadequate in some ill premature infants in the first week of life, but it is likely that rapid adaptation of the HPA axis, with timely maturation of intermediate enzymes of the glucocorticoid pathway, results in enhanced and more appropriate cortisol response to stress in the subsequent week. The percentile distribution of plasma ACTH and serum cortisol concentrations provides useful statistical reference data for interpretation of the hCRH test in VLBW infants and may also assist in facilitating the use of corticosteroids-replacement therapy in cases with clinical signs suggestive of adrenal insufficiency.
Acknowledgments
Footnotes
Abbreviations: CPAP, Continuous positive airway pressure; hCRH, human CRH; HFOV, high-frequency oscillation ventilation; HPA, hypothalamic-pituitary-adrenal; IPPV, intermittent positive-pressure ventilation; PROM, prolonged rupture of membrane; VLBW, very low birth weight.
Received October 5, 2001.
Accepted June 23, 2002.
References
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