Background. Many extremely low birth weight infants (<1000 g) show biochemical evidence of adrenal insufficiency in the first week of life, correlating with subsequent development of chronic lung disease (CLD).
Methods. We conducted a randomized, double-masked, placebo-controlled pilot study to test whether early treatment with low-dose hydrocortisone for 12 days (1 mg/kg/day for 9 days followed by .5 mg/kg/day for 3 days), begun before 48 hours of life, would increase the likelihood of survival without CLD.
Results. Forty patients were enrolled at two centers. Birth weight and gestation were similar for treatment and placebo groups: 732 ± 135 g versus 770 ± 135 g and 25.2 ± 1.3 weeks versus 25.4 ± 1.5 weeks. More infants treated with hydrocortisone achieved study success, defined as survival without supplemental oxygen at 36 weeks' postconception (12/20 [60%] vs 7/20 [35%]). Lower birth weight, histologic chorioamnionitis, and preeclampsia were significant risk factors, whereas study center, prenatal steroids, sex, and ethnicity were not significant. Hydrocortisone treatment decreased days on >40% oxygen, days on >25% oxygen, days on ventilator, and oxygen at discharge. Among infants exposed to chorioamnionitis, hydrocortisone treatment also was associated with increased enteral intake during the first month of life and with increased weight at 36 weeks' postconception. Five treated infants and 6 placebo infants developed sepsis; 3 in each group died.
Conclusions. First, early treatment with low-dose hydrocortisone in this population of extremely low birth weight infants increased the likelihood of survival without CLD. Second, the benefit was particularly apparent in infants with chorioamnionitis. Third, a larger multicenter trial is needed to verify the primary outcome and to better evaluate risks and benefits.
- chronic lung disease
- bronchopulmonary dysplasia
- premature infant
- adrenal function
Chronic lung disease (CLD) develops frequently in small premature infants and results in increased health care costs, prolonged hospital stays with frequent rehospitalizations, and possible deleterious effects on subsequent growth and development.1–3 Many therapeutic interventions have been tested, with few successes.4 Exogenous surfactant therapy has improved survival in this patient population, but its effect on CLD has been small or absent.4 Recently, several studies have reported that early treatment with dexamethasone can decrease the incidence of CLD;5–8 however, dexamethasone therapy has numerous adverse effects,9 and serious concerns have been raised about its effects on long-term growth and development in these patients.10,,11
The use of early glucocorticoid therapy to prevent CLD of prematurity is appealing, because inflammation seems to be important in the pathogenesis of this disease, with increased lung inflammation documented even in the first days of life.12 Many factors can act as inflammatory stimuli for these infants, including oxygen therapy, endotracheal intubation, barotrauma, and prenatal inflammation, or chorioamnionitis.13–18 At the same time that these infants are experiencing significant inflammatory stimuli, they may have a decreased ability to dampen their inflammatory responses because of inadequate cortisol secretion. Initial clinical observations, suggestive of adrenal insufficiency,19,,20have been followed by studies documenting biochemical evidence of inadequate adrenal function in many sick preterm infants, with cortisol concentrations equal to or even lower than their well counterparts or well term infants.21–25 In addition, cortisol response to adrenocorticotropic hormone (ACTH) stimulation at the end of the first week of life was found to be significantly lower in babies who subsequently developed CLD than in those who did not.26
Building on these findings, we designed a study to test the hypothesis that early therapy with low doses of hydrocortisone during the first 2 weeks of life would protect against adrenal insufficiency in sick premature infants and decrease the incidence of CLD. The secondary hypothesis to be explored was that this therapy would improve physiologic stability during the treatment period. This pilot study of 40 infants was conducted to provide a preliminary assessment of efficacy and safety and to estimate the sample size needed for a multicenter trial.
This trial was approved by the institutional review boards and conducted at two centers: patients were enrolled after parental consent at the Hershey Medical Center of Pennsylvania State University from June 1996 to May 1998, and at the Pennsylvania Hospital of the University of Pennsylvania from June 1997 to May 1998. This study was open to appropriate for gestational age infants <48 hours of age who were between 500 and 999 g birth weight and who were ventilated mechanically. Exclusion criteria included maternal diabetes, congenital sepsis, and small for gestational age infants. Small for gestational age infants were excluded because we anticipated that adrenal function might correlate better with maturity than birth weight, and we decided to eliminate that potentially confounding factor from this pilot study.
Infants were randomized at each center by constant block design, with 4 patients per block to minimize bias over time. Separate randomization tables were used for infants exposed to prenatal glucocorticoids. Hydrocortisone doses were prepared by the hospital pharmacy, and the placebo was normal saline, given as an equivalent volume. Hydrocortisone was given as hydrocortisone sodium succinate (Solu-Cortef 100 mg Plain, Upjohn, NDC 0009-0825-01), reconstituted with sterile water for injection and diluted with normal saline. The initial dose and dosing interval, 1.0 mg/kg/day (∼8–10 mg/m2/day27) given every 12 hours, was chosen based on preliminary data,28 and estimated to be ∼1 to 1½ times the normal basal endogenous production rate.29 Therapy was given for a total of 12 days: 9 days at 1.0 mg/kg/day, and a 3-day taper at a reduced dose of .5 mg/kg/day. All other care was provided at the direction of the attending physician, including the administration of any open-label glucocorticoid therapy.
Three days after completion of therapy, cortisol response to ACTH challenge was evaluated as previously described:26 1) a blood specimen was obtained for cortisol; 2) 3.5 μg/kg of 1–24 corticotropin (Cortrosyn, Organon, Inc, West Orange, NJ) was given intravenously; and 3) 30 minutes later, another blood sample was obtained for cortisol. Cortisol assays were performed in one laboratory (K.L.W.) by radioimmunoassay (GammaCoat, INCSTAR, Stillwater, MN). Crossreactivity with 11-deoxycortisol was 6.3%; crossreactivity with other naturally occurring steroids was <2%. Interassay and intraassay coefficients of variation were 9.2% and 7.0%, respectively. Values are expressed as nmol/L (÷27.6 = μg/dL). Chorioamnionitis was diagnosed by histologic examination of the placenta.
The primary outcome variable was survival without CLD, with CLD defined as oxygen dependence at 36 weeks postconceptional age. Secondary endpoints for severity of respiratory disease were days on mechanical ventilation, days on Fio2>.40, days on Fio2 >.25, and discharge on supplemental oxygen. Other outcomes evaluated included days of dexamethasone therapy, length of stay, weight and head circumference at 36 weeks postconceptional age, nosocomial sepsis (defined as a positive blood or cerebrospinal fluid culture), necrotizing enterocolitis, patent ductus arteriosus, intraventricular hemorrhage, and retinopathy of prematurity. Secondary endpoints for physiologic stability recorded daily for the first 28 days of life included: 1) total fluid intake and enteral intake; 2) serum sodium and potassium; 3) serum glucose and insulin therapy; and 4) blood pressure and inotropic support.
Baseline characteristics among groups were compared with Student'st tests and Fisher's exact tests (Table 1). The effect of hydrocortisone treatment on survival without CLD was analyzed by stepwise logistic regression that included study center and all the variables listed inTable 1 as initial cofactors. Other secondary respiratory outcomes were compared by similar analyses, using the same set of initial cofactors in linear regression for continuous data and logistic regression for ordinal data. Adverse outcomes between groups were then compared with Fisher's exact tests. Differences between treatment groups for daily continuous data were evaluated by area under the curve analysis during the first 28 days of life. Because cortisol values are not normally distributed, these data were analyzed after log transformation. Gestational age may affect cortisol values;25,,26therefore, gestational age was included as a cofactor in cortisol analyses. Because chorioamnionitis has been associated with increased cortisol concentrations, increased inflammation and adverse respiratory outcome,15–17,30 we then examined this subset of patients separately, using univariate analysis (because of the limited number of subjects in each group). The Mann-Whitney U test was applied to data that were not normally distributed.
A total of 40 infants were enrolled in the study: 26 at Hershey Medical Center and 14 at Pennsylvania Hospital. Baseline characteristics for these infants are shown in Table 1 and are similar between the treatment and placebo groups. Patients enrolled at Pennsylvania Hospital were larger (mean birth weight 811 g vs 718 g; P = .04) and more mature (mean gestational age 25.9 vs 24.9; P = .02) than those enrolled at Hershey Medical Center, and the maternal racial group was different (86% black vs 88% white at Hershey Medical Center; P< .001).
Study outcomes are shown in Table 2. The incidence of survival without oxygen dependence at 36 weeks' postconception (success) in the placebo group was 35%. A log kept at Hershey Medical Center of patients eligible for this study but not enrolled (parental refusal  and deadline for enrollment missed ) showed that 30% (3 of 10 patients) survived without oxygen dependence at 36 weeks postconception.
Multiple logistic regression using factors listed in the “Statistical Analysis” section showed that infants treated with hydrocortisone had significantly better survival without oxygen dependence at 36 weeks postconception (P = .02), with an odds ratio for success of 12.3 (95% confidence limits: 1.8–151.5). Other baseline characteristics significant in this regression included birth weight, with an odds ratio of 3.6 per 100 g birth weight (1.7–11.2), histologic chorioamnionitis, odds ratio of .06 (.004-.51), and preeclampsia, odds ratio of .06 (.002–.75). Thus, hydrocortisone therapy and increasing birth weight increased the probability of success, whereas chorioamnionitis and preeclampsia were significant adverse factors. The direction of the hydrocortisone effect was positive at both centers. At Hershey Medical Center, survival without CLD was 31% in the placebo group and 54% in the treated group; at Pennsylvania Hospital, success was 43% in the placebo group and 71% in the treated group.
As shown in Table 2, analyzed by similar multiple regressions, infants treated with hydrocortisone also had fewer days on mechanical ventilation and supplemental oxygen, and fewer were discharged with supplemental oxygen. In the subset of patients with chorioamnionitis (15 of 26 patients at Hershey, 7 of 14 patients at Pennsylvania Hospital), patients treated with hydrocortisone were significantly heavier at 36 weeks postconception (2072 vs 2815 g,P = .03). This is compatible with our finding that, in the group of infants with chorioamnionitis, patients treated with hydrocortisone had significantly greater enteral intake during the first 28 days of life (P = .01, by area under the curve analysis).
Adverse outcomes were similar between groups (P values all >.1; Table 3). Specifically, 11 infants developed sepsis during hospitalization: 5 infants treated with hydrocortisone (Candida albicans , Candida parapsilosis , Enterococcus faecalis , andStaphylococcus epidermidis ), and 6 infants treated with placebo (Pseudomonas aeruginosa  and S epidermidis ). Of these 11 episodes of sepsis, 4 occurred while patients were receiving study drug: 2 patients treated with hydrocortisone (both C albicans, 1 of whom died) and 2 treated with placebo (both P aeruginosa, both of whom died). The patient who died from C albicans sepsis was later found to have had prenatal candidal infection of the placenta and umbilical cord, but the initial blood culture result was negative, and the patient was included in all analyses.
No differences were found in the incidence of hyperglycemia (glucose >180), 32 of 539 daily observations in the placebo group and 26 of 548 observations in the treatment group, or insulin therapy, noted on 2 days in the placebo and 6 days in the treatment group. Mean blood pressures ≥50 were recorded on 60 days in the placebo group and 68 days in the treatment group; inotropic therapy was used on 54 days and 39 days, respectively. Area under the curve analysis showed that during the treatment period infants treated with hydrocortisone had less hyponatremia (P = .004) and showed a trend toward lower fluid intake (P = .07).
Of the patients, 2 were withdrawn from the study but included in the outcome analyses. One infant receiving hydrocortisone was withdrawn after 2 doses because of increased blood pressure, with systolic values reaching 79 and mean values of 50. One infant in the placebo group was withdrawn from the study after 3 doses because of clinical deterioration. One patient who was originally enrolled in the study was found subsequently on newborn screening to have an inborn error of metabolism (glutaric aciduria); that infant was withdrawn from study and not included in the analysis.
Response to ACTH stimulation is shown in Fig 1. Hydrocortisone therapy did not suppress either basal or stimulated values. However, both basal and stimulated values were lower in those infants who subsequently developed CLD. Infants who developed CLD were smaller and less mature; however, gestational age was not significant in the analysis of either basal or stimulated values. Infants exposed to chorioamnionitis had similar basal, but higher stimulated, cortisol concentrations, than infants without chorioamnionitis. Stimulated values were 618 (462–699) nmol/L (median: 25%–75%) in the infants exposed to chorioamnionitis (n = 17) versus 472 (382–589) nmol/L in those infants without chorioamnionitis (n = 16;P = .045). However, within each separate group, infants developing CLD had lower stimulated cortisol values than infants recovering without CLD. In the group of patients exposed to chorioamnionitis, those developing CLD (n = 5) had cortisol values of 444 (421–585) nmol/L versus concentrations of 676 (618–801) nmol/L in 9 infants recovering without CLD (P = .01). In patients without chorioamnionitis, those developing CLD (n = 7) had cortisol values of 434 (279–508) nmol/L versus 531 (419–658) nmol/L in 10 infants recovering without CLD (P = .03).
In this randomized study of early prophylaxis against adrenal insufficiency to prevent CLD in a population at high risk for both disorders, we found that hydrocortisone therapy significantly improved the likelihood of survival without oxygen dependence at 36 weeks postconceptional age. This effect was seen at both study centers. The incidence of successful outcome in the placebo group (35%) seems low; however, similar outcomes have been reported in similar high-risk populations. For example, calculating from data reported for 1997 by the Vermont Oxford Network of 250 newborn intensive care units, the median incidence of survival without CLD in those units was 26% for the 501 to 750 g weight group, and 54% for 751 to 1000 g weight group.31 In addition, Brozanski et al5reported a 77% incidence of CLD in a clinical trial of similar infants who remained intubated at 7 days of life. Of the 40 babies, 38 in our study were still intubated at 7 days of life. Therefore, although the incidence of survival without CLD in the placebo group was low, it does not seem to be anomalous for this high-risk population.
The beneficial effects of hydrocortisone supplementation were particularly evident in those patients exposed to chorioamnionitis, in which hydrocortisone therapy was associated not only with better respiratory outcome, but also with improved early enteral intake and increased weight at 36 weeks postconceptional age. Improved respiratory outcome with glucocorticoid supplementation might be expected in this population, because we and others have shown previously that chorioamnionitis is associated with increased lung inflammation and with the development of CLD in intubated infants.15–17 In this study, we found that the group of infants exposed to chorioamnionitis had higher cortisol values in response to ACTH stimulation, consistent with a previous finding of higher basal cortisol values in infants exposed to chorioamnionitis.30However, within the chorioamnionitis group, just as in the group without chorioamnionitis, those infants who subsequently developed CLD had significantly lower cortisol responses to ACTH than infants who recovered without CLD.
The reason that hydrocortisone therapy was associated with better enteral intake and nutritional outcome is unknown; however, this finding is consistent with a previous observation that higher endogenous cortisol concentrations were associated with increased enteral intake in premature infants.32 The number of patients in this study is small, and the finding may not be sustained in a larger study. If the effect is real, it may simply be that improved respiratory condition allowed earlier feedings. It is also possible that glucocorticoid therapy may have decreased intestinal inflammation and/or improved intestinal maturation.33,,34
The high prevalence of histologic chorioamnionitis in our treated patients may have contributed to the magnitude of the beneficial effects of hydrocortisone therapy seen in this study. When chorioamnionitis is defined as a clinical entity, the reported incidence may be lower; however, when chorioamnionitis is defined by placental histology, the incidence reported by others at this gestation is similar to the incidence found in this study.35,,36
This study was designed to evaluate potential benefits and to calculate a sample size for a larger, multicenter trial. Although we saw no apparent increase in adverse outcomes, this study was not powerful enough to rule out a type II error. This was a pilot study, and as such, does not have the power to make a negative conclusion. A larger trial is essential to evaluate possible effects on adverse outcomes, such as sepsis, or changes in epidemiology, such as a significant increase in candidal infections, before this therapy can be recommended. This is especially true in view of a previous, nonrandomized study reporting an increased incidence of candidal infections in extremely low birth weight infants who received higher doses of hydrocortisone.37 In our study, three episodes of candidal sepsis were noted in the treatment group, wheras none were seen in the placebo group.
In this study, we found evidence of decreased adrenal function in the infants who developed CLD. Those patients had both lower baseline and lower stimulated cortisol values, not explained by gestational age (Fig 1). This evidence of decreased adrenal function continuing into the third week of life suggests the need to consider continuing hydrocortisone supplementation in some infants. We and others have previously reported decreased basal or stimulated cortisol values during the first week of life in babies who subsequently developed bronchopulmonary dysplasia.24,,26 In one recent study, no such differences were seen.38 The reason or reasons for these different findings are not clear. It is possible that administration of corticotropin-releasing hormone resulted in a different response or that there is different crossreactivity with other steroid hormones in the different radioimmunoassays. Continuing evaluation of the adrenal axis in these infants may help elucidate reasons for these different findings.
The magnitude of the apparent benefit of this low-dose hydrocortisone therapy may be surprising, because it is comparable to the effects seen after much larger doses of dexamethasone are administered to these infants for treatment or prevention of CLD.5–8 However, the hypothesis underlying our study was that a high percentage of extremely low birth weight, sick infants show evidence of adrenal insufficiency early in life. If this insufficiency is alleviated with glucocorticoid replacement, higher doses may not provide substantial additional benefit. Experimentally induced adrenal insufficiency results in greatly amplified inflammation in animal models, with parallels in human disease.39–41 Although we postulated that correction of such a deficiency would decrease inflammatory lung injury, the beneficial effects of hydrocortisone seen in this trial may well have resulted from glucocorticoid effects on other organ systems, such as cardiovascular,42–44 intestinal,33or renal.45,,46
Many clinical trials of dexamethasone to treat or prevent CLD in premature infants have now been reported, commonly employing a dose of dexamethasone (.5 mg/kg/day) equivalent to 10 to 15 times the dose of hydrocortisone used in this study.5–9,47 These trials have shown a variety of respiratory benefits; however, they also have revealed a broad range of serious adverse effects, such as cardiac hypertrophy, growth delay, and sepsis.9,,47 New reports have raised additional concerns about possible deleterious effects of early dexamethasone therapy on somatic and developmental outcomes in these infants.10,,11 The results of this pilot study now justify a larger multicenter trial to test the benefits and assess the risks of low-dose hydrocortisone therapy to prevent CLD in extremely premature infants.
This study was supported by Grant MCJ-420633 from the Maternal and Child Health Bureau (Title V, Social Security Act), Health Resources and Services Administration, Department of Health and Human Services.
- Received February 15, 1999.
- Accepted May 26, 1999.
Reprint requests to (K.L.W.) Department of Pediatrics, The Milton S. Hershey Medical Center, MC H085, PO Box 850, Hershey, PA 17033-0850.E-mail:
- CLD =
- chronic lung disease •
- ACTH =
- adrenocorticotropic hormone
- Gregoire MC,
- Lefebvre F,
- Glorieux J
- Rastogi A,
- Akintorin SM,
- Bez ML,
- Morales P,
- Pildes RS
- ↵Yeh TF, Lin YJ, Hseih WS, et al. Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clinical trial. Pediatrics. 1997;100(4). URL: http://www.pediatrics.org/cgi/content/full/100/4/e3
- ↵Bancalari E. Corticosteroids and neonatal chronic lung disease. Eur J Pediatr. 1998;157:31–37. Supplement
- ↵Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics. 1998;101(5). URL: http://www.pediatrics.org/cgi/content/full/101/5/e7
- O'Shea TM,
- Kothadia JM,
- Klinepeter KL,
- et al.
- Fujimura M,
- Takeuchi T,
- Kitajima H,
- Nakayama M
- Yoon BH,
- Romero R,
- Jun JK,
- et al.
- Watterberg KL,
- Demers LM,
- Scott SM,
- Murphy S
- Colasurdo MA,
- Hanna CE,
- Gilhooly JT,
- Reynolds JW
- Ward RM,
- Kimura RE,
- Rich-Denson C
- Watterberg KL,
- Scott SM
- Watterberg KL,
- Cook K,
- Gifford KL
- ↵Watterberg KL, Scott SM, Naeye RL. Chorioamnionitis, cortisol, and acute lung disease in very low birth weight infants. Pediatrics. 1997;99(2). URL:http://www.pediatrics.org/cgi/content/full/99/2/e6
- ↵Vermont Oxford Network. Vermont Oxford Network Annual Database Summary, 1997. Burlington, VT: Vermont Oxford Network; 1998
- ↵Trahair JF, Sangild PT. Systemic and luminal influences on the perinatal development of the gut. Equine Vet J. 1997;24:40–50. Supplement
- Botas CM,
- Kurlat I,
- Young SM,
- Sola A
- Farsky SP,
- Sannomiya P,
- Garcia-Leme J
- Helbock HJ,
- Insoft RM,
- Conte FA
- Kimura T,
- Ota K,
- Shoji M,
- et al.
- Copyright © 1999 American Academy of Pediatrics