Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

Effect of premedication regimen on infant pain and stress response to endotracheal intubation.

OBJECTIVE: (1) Evaluate the effect of different medications on pain and stress in neonates during nonemergent endotracheal intubation; (2) determine whether gestational age affects medication use; (3) determine whether better sedation results in a decrease in the number of attempts and/or total time for the procedure. STUDY DESIGN: Prospective observational study. Infant responses were measured using a clinical pain scale and blood glucose, a biochemical marker of acute stress. RESULT: A total of 166 infants were included, with adjusted gestational ages 24 to 44 weeks at the time of procedure. Premedication regimens included no medication ('none,' 27%), morphine (19%), morphine+midazolam (11%), fentanyl (14%), fentanyl+midazolam (19%) and midazolam alone (10%). Fentanyl+midazolam resulted in lower pain scores and less increase in blood glucose (both P<0.0001). No other regimen was different from 'none'. The most immature infants were less likely to receive premedication (P=0.023), although their pain scores and blood glucose responses were similar to more mature infants. None of the medication regimens reduced the total procedure time (P=0.55) or the number of attempts (P=0.145). CONCLUSION: Only fentanyl+midazolam significantly attenuated both the clinical pain score and the increase in blood glucose. Less mature infants had responses similar to those of more mature infants, but were less likely to receive premedication. None of the regimens decreased the time or number of attempts required for successful intubation.

Evolving blood pressure dynamics for extremely preterm infants.

OBJECTIVE: To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants. STUDY DESIGN: Prospective observational study of infants 23(0/7) to 26(6/7) weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 h. RESULT: A cohort of 367 infants had 18 709 ABP measurements recorded. ABP decreased for the first 3 h, reached a nadir at 4 to 5 h and then increased at an average rate of 0.2 mm Hg h(-1). The rise in ABP from hour 4 to 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135) or dopamine (n=92). GA-specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA. CONCLUSION: ABP increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.

Use of the Ages and Stages Questionnaire and Bayley Scales of Infant Development-II in neurodevelopmental follow-up of extremely low birth weight infants.

OBJECTIVE: For infants born with extremely low birth weight (ELBW), we examined the (1) correlation between results on the Ages and Stages Questionnaire (ASQ) and the Bayley Scales of Infant Development-II (BSID-II) at 18 to 22 months corrected age; (2) degree to which earlier ASQ assessments predict later BSID-II results; (3) impact of ASQ use on follow-up study return rates. STUDY DESIGN: ASQ data were collected at 4, 8, 12 and 18 to 22 months corrected age. The BSID-II was completed at 18 to 22 months corrected age. ASQ and BSID-II 18 to 22 month sensitivity and specificity were examined. Ability of earlier ASQs to predict later BSID-II scores was examined through linear regression analyses. RESULT: ASQ sensitivity and specificity at 18 to 22 months were 73 and 65%, respectively. Moderate correlation existed between earlier ASQ and later BSID-II results. CONCLUSION: For extremely low birth weight infant assessment, the ASQ cannot substitute for the BSID-II, but seems to improve tracking success.

Adrenal function in newborns undergoing surgery.

OBJECTIVE: To measure cortisol, adrenocorticotropic hormone (ACTH)-stimulated cortisol and ACTH values in the newborn intensive care unit-admitted newborn infants within 48 h before surgery and to describe the relationship of these values to measures of clinical illness before and after surgery. STUDY DESIGN: In this prospective observational study, we measured baseline and ACTH-stimulated cortisol concentrations within 48 h before surgery in newborn infants <44 weeks postmenstrual age and examined the relationship of these values to measures of illness severity both before and after surgery, including the score for neonatal acute physiology (SNAP) and use of vasopressors. ACTH concentrations were measured in a subset of the infants. RESULT: Twenty-five infants were enrolled and had median (25th to 75th percentile) baseline and ACTH-stimulated cortisol values of 7.1 (3.5 to 11.1) and 40.4 mcg per 100 ml (22.6 to 50.6). Preterm infants had significantly lower ACTH-stimulated cortisol values (median 21.6 vs 44.7 mcg per 100 ml). There was no correlation between any of these values and either the presurgical or postsurgical measures of illness severity, nor the increase in SNAP after surgery. Infants receiving vasopressors perioperatively had lower median ACTH-stimulated cortisol values (22.6 vs 44.7 mcg per 100 ml). CONCLUSION: Presurgical cortisol values do not predict clinical response to surgical stress as measured by severity of illness scores but lower values were associated with vasopressor therapy. Further investigation would be required to determine how cortisol values are related to outcome and whether perioperative glucocorticoid supplementation would be beneficial in this population.

Early cortisol values and long-term outcomes in extremely low birth weight infants.

OBJECTIVE: Both excess and insufficient levels of glucocorticoid in extremely low birth weight (ELBW) infants have been associated with adverse hospital outcomes, whereas excess glucocorticoid exposure has been associated with long-term adverse neurodevelopment. Our objective was to evaluate the relationship between neonatal cortisol concentrations and long-term outcomes of growth and neurodevelopment. STUDY DESIGN: As part of a multicenter randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency, cortisol concentrations were obtained at 12 to 48 h of postnatal age and at days 5 to 7 on 350 intubated ELBW infants, of whom 252 survived and returned for neurodevelopmental follow-up at 18 to 22 months corrected age. Cortisol values from each time point were divided into quartiles. Growth and neurodevelopmental outcome were compared for each quartile. RESULT: Median cortisol value was 16.0 microg per 100 ml at baseline for all infants, and 13.1 microg per 100 ml on days 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or at days 5 to 7 were not associated with impaired growth or neurodevelopment at 18 to 22 months corrected age. High cortisol values were associated with an increase in cerebral palsy, related to the increased incidence of severe intraventricular hemorrhage (IVH) and periventricular leukomalacia. CONCLUSION: Low cortisol concentrations were not predictive of adverse long-term outcomes. High cortisol concentrations, although predictive of short-term adverse outcomes such as IVH and periventricular leukomalacia, did not additionally predict adverse outcome. Further analysis into identifying factors that modulate cortisol concentrations shortly after birth could improve our ability to identify those infants who are most likely to benefit from treatment with hydrocortisone.

Relative adrenal insufficiency in the preterm and term infant.

Cortisol release in the face of illness or stress is vital for survival. Relative adrenal insufficiency occurs when a patient's cortisol response is inadequate for the degree of illness or stress. Numerous studies have documented the existence of relative adrenal insufficiency in critically ill adults, and its association with increased morbidity and mortality. There is increasing evidence that relative adrenal insufficiency may be an etiology for hemodynamic instability and hypotension in the critically ill newborn, but compared with the adult population, there is still a paucity of data in this population. Randomized controlled trials are needed to evaluate the efficacy and safety of glucocorticoids for the treatment of cardiovascular insufficiency due to relative adrenal insufficiency in ill preterm and term newborn infants.

ACTH and cortisol response to critical illness in term and late preterm newborns.

OBJECTIVE: To determine cortisol and adrenocorticotropic hormone (ACTH) responses to critical illness in term and late preterm newborns and examine the relationship of these values to measures of clinical illness, including markers of cardiovascular dysfunction. STUDY DESIGN: In this prospective observational study, we measured ACTH, baseline cortisol and ACTH-stimulated cortisol concentrations in mechanically ventilated infants >or=34 weeks gestational age and <5 postnatal days. ACTH-stimulated cortisol concentrations were also measured in a comparison group of non-critically ill, non-mechanically ventilated infants. The relationship of these values to measures of severity of illness including SNAP (score for neonatal acute physiology) scores, blood pressure and vasopressor initiation was examined. RESULT: Concentrations are presented as median (25th to 75th percentile). Baseline cortisol values in critically ill infants (n=35) were 4.6 microg per 100 ml (3.0 to 16.2); 26 (74%) of these were <15 microg per 100 ml. ACTH-stimulated cortisol values were not significantly different from the comparison group (41 microg per 100 ml (30.3 to 51.8) vs 34.2 microg per 100 ml (25.2 to 43.3)). ACTH concentrations in ill infants (n=10) were 12 pgml(-1) (5.5 to 19.2). None of baseline cortisol, stimulated cortisol and ACTH increased significantly with increasing severity of illness. Of the ill infants, 71% received vasopressor therapy for hypotension. Cortisol concentrations in these infants were similar to those infants who did not receive vasopressor therapy. CONCLUSION: The majority of these critically ill newborns had very low cortisol and ACTH values without the expected increase in response to critical illness; however, their response to exogenous ACTH was normal. These results demonstrate that the inadequate response to critical illness in these newborns does not result from adrenal dysfunction. We therefore hypothesize that this is a secondary insufficiency arising from inadequate stimulation of the adrenal gland.

Cardiac troponin T and cardiac dysfunction in extremely low-birth-weight infants.

Extremely low-birth-weight (ELBW) infants frequently manifest signs of cardiac dysfunction requiring inotropic support. It is not clear if this is due to cardiac injury, which can be monitored by measuring cardiac troponin T (cTnT). We performed a nested prospective cohort study at a university level III neonatal intensive care unit. The study included 27 infants weighing between 500 and 999 g. Exclusion criteria included evidence of sepsis, use of postnatal steroids, and cardiac anomalies. Measurements included serum cTnT and echocardiogram in the first 48 hours of life. The mean serum cTnT level of the study population was 0.52 +/- 0.38 ng/ml. It was higher in those with lower Apgar scores (0.89 +/- 0.37 if 5-minute Apgar < 4 vs 0.36 +/- 0.26 ng/ml, p < 0.001) and correlated to initial base deficit (r = -0.37, p < 0.05). Infants who required inotropic support had higher cTnT levels than those who did not (0.73 +/- 0.43 vs 0.39 +/- 0.29 ng/ml, p < 0.03). cTnT concentrations did not relate to simultaneous echocardiographic measures of cardiac function. In ELBW infants, serum cTnT levels are higher than normally seen in term infants and adults, and they are higher in infants with greater perinatal stress as well as those who show evidence of cardiac dysfunction requiring pressor support.

Impaired glucocorticoid synthesis in premature infants developing chronic lung disease.

Premature infants have higher cortisol precursor concentrations than term infants; however, many sick preterm infants have surprisingly low cortisol concentrations. Those who develop chronic lung disease (CLD) have lower cortisol values than those who recover. We hypothesized that some infants have a decreased ability to synthesize cortisol, leading to physiologic disruptions including amplified inflammatory responses, thereby resulting in CLD. We measured cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, 17-hydroxypregnenolone, dehydroepiandrosterone sulfate, and ACTH in 40 extremely low birth weight infants enrolled in a study of low-dose hydrocortisone therapy to prevent CLD. Thirty-four infants survived and 15 developed CLD. Hydrocortisone therapy did not suppress ACTH or any measured steroid value. Before study (<48 h of life), 17-OH progesterone was higher in CLD infants, as was the ratio of 17-OH progesterone to 11-deoxycortisol. On d 15-19 (> or =72 h after end of therapy), basal and stimulated cortisol concentrations were lower in CLD infants. In contrast, the basal ratio of 11-deoxycortisol to cortisol was higher in CLD infants, as were stimulated values of 17-OH progesterone and stimulated ratios of 17-OH progesterone to 11-deoxycortisol and 11-deoxycortisol to cortisol. Thus, infants who developed CLD had lower basal and stimulated cortisol values, but elevated cortisol precursors and precursor to product ratios, compared with infants who recovered. These data support the hypothesis that these immature infants have a decreased capacity to synthesize cortisol, which may lead to a relative adrenal insufficiency in the face of significant illness.

Links between early adrenal function and respiratory outcome in preterm infants: airway inflammation and patent ductus arteriosus.

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 <1,500 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-1beta, -6, and -8, and for total protein, albumin, and alpha-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.

Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants.

UNLABELLED: 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.

Chorioamnionitis, cortisol, and acute lung disease in very low birth weight infants.

OBJECTIVE: To explore the relationship between chorioamnionitis, postnatal cortisol concentrations, and acute respiratory distress in very low birth weight infants. METHODS: Appropriate for gestational age infants weighing between 501 to 1500 g at birth were enrolled into this prospective, observational study, and data regarding respiratory distress on the first day of life were recorded. Serum cortisol concentrations were measured on (a) day 2, (b) day 3 or 4, and (c) day 5, 6, or 7 of life. On day (b) or (c), 3.5 microg/kg of cosyntropin (an adrenocorticotrophic hormone analog) was given, and a repeat specimen was drawn 30 minutes later. Chorioamnionitis was diagnosed by placental examination by one author (R.L.N.). RESULTS: Forty-two infants exposed to chorioamnionitis and 37 infants not exposed were enrolled. Chorioamnionitis correlated inversely with gestational age, and was associated with decreased measures of acute respiratory support (exogenous surfactant, fraction of inspired oxygen, and ventilator support at 12 and 24 hours). Infants with chorioamnionitis had higher cortisol concentrations, both basal and stimulated. Gestational age was not significantly related to basal cortisol, but did correlate positively with stimulated values. Cortisol values from the 16 infants exposed to prenatal glucocorticoid therapy were excluded from these analyses. CONCLUSIONS: These results provide evidence that prenatal inflammation leads to adrenal stimulation, resulting in increased cortisol secretion and accelerated lung maturation. The enhanced response to cosyntropin stimulation seen in these infants may reflect an increased adrenal capacity to respond to postnatal stressors. Because of the apparent magnitude of the effect of chorioamnionitis on cortisol measures, this factor should be included in future investigations of adrenal function in very low birth weight newborns.

Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.

OBJECTIVE: The development of bronchopulmonary dysplasia (BPD) often has been attributed to injury from mechanical ventilation and supplemental oxygen. Early lung inflammation in infants with BPD has been thought to be secondary to these factors. The purpose of this study was to evaluate whether preexisting (prenatal) inflammation may be a primary causative factor in the development of BPD. METHODS: Intubated newborns of less than 2,000 g birth weight were prospectively enrolled. The presence or absence of chorioamnionitis was documented. Lung inflammation was evaluated on days 1, 2, and 4 of intubation by assaying concentrations of interleukin 1 beta (IL-1 beta), thromboxane B2, leukotriene B4, and prostaglandin E2 in tracheal lavages. Infants in whom BPD developed were compared with those in whom it did not using these measures. RESULTS: Fifty-three infants were enrolled; 41 survived. Thirty-eight had respiratory distress syndrome; 15 were intubated for other diagnoses. Infants prenatally exposed to chorioamnionitis were less likely to present with respiratory distress syndrome; however, chorioamnionitis was significantly associated with both the presence of IL-1 beta from the first day of intubation and the development of BPD. Tracheal lavage concentrations of IL-1 beta were higher in infants in whom BPD developed. Thromboxane B2 concentrations were similar on day 1 but were higher on days 2 and 4 in infants in whom BPD developed. CONCLUSIONS: In this study, intubated infants weighing less than 2,000 g at birth in whom BPD developed had increased exposure to inflammation prenatally (chorioamnionitis) and evidence of increased lung inflammation from the first postnatal day. We speculate that chorioamnionitis may accelerate lung maturation but that it also causes lung inflammation and subsequent lung injury in intubated infants, fostering the development of BPD.

Effect of gestational age, postnatal age, and illness on plasma cortisol concentrations in premature infants.

The purpose of this study was to define the pattern of postnatal plasma cortisol concentrations during the first week of life in premature infants, and to evaluate the effect of developmental and clinical factors on this pattern. We measured plasma cortisol concentrations in the morning and afternoon on d 2, 4, and 6 in 120 premature infants (gestational age 24-36 wk) and examined the effects of gestational age, postnatal age, and illness. We described an inverse relationship between gestational age and cortisol concentrations, with the youngest infants having the highest random cortisol values (F = 5.14, p = 0.0073). Illness had a significant negative effect such that the cofactors ventilatory support pattern (F = 6.62, p = 0.0016) or "use of surfactant" (F = 6.63, p = 0.001) defined a pattern where cortisol values were lower in infants that had the highest ventilatory requirements or that received surfactant compared with values from those infants who did not have these requirements. The postnatal pattern in cortisol values depended on gestational age. Ill infants more than 27 wk gestational age increased their cortisol values from d 2 to d 6 although cortisol values decreased in well infants. These patterns resulted in a nonsignificant change over time for these age groups. In contrast, cortisol values significantly decreased from d 2 to d 6 in both well and ill infants that were less than or equal to 27 wk. We conclude that plasma cortisol concentrations in the premature infant are significantly correlated with gestational age and to markers of illness.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence of early adrenal insufficiency in babies who develop bronchopulmonary dysplasia.

OBJECTIVES: To test the cortisol response to adrenocorticotrophic hormone (ACTH) in a population of very low birth weight newborns at the end of the first week of life, and to evaluate the relationship of this response to the subsequent development of bronchopulmonary dysplasia and to the total length of oxygen dependence. METHODS: Appropriate for gestational age newborns < 1500 g birth weight were enrolled prospectively. Response to ACTH stimulation was tested on days 5, 6, or 7. Baseline cortisol, stimulated cortisol, and magnitude of response were compared between babies who developed bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 28 days, and those who recovered without BPD. RESULTS: In this population, the cortisol response to ATCH increased with increasing birth weight (P < .001). Using birth weight as a cofactor, analysis of variance showed that patients who developed BPD (n = 34, BW 974 +/- 192 g, mean +/- S.D.) had significantly reduced responses to ACTH at 5 to 7 days of age compared to those who recovered (n = 25, BW 1251 +/- 194 g), P = .006. Additionally, 84% of patients who recovered without BPD, but only 26% of BPD patients, achieved a prospectively defined positive cortisol response to ACTH (> or = 9 micrograms/dL; P < .005). Supplemental oxygen was discontinued at a younger postconceptional age in babies with a positive cortisol response to ACTH (P < .01) and fewer of those babies were on supplemental oxygen at 36-week postconceptional age (P < .01). CONCLUSIONS: At the end of the first week of life, infants who subsequently developed BPD and prolonged oxygen dependence had significantly lower cortisol secretion in response to ACTH than infants who recovered without BPD. We speculate that these babies may be unable to secrete adequate amounts of cortisol in a setting of increased stress, leaving them vulnerable to continuing lung injury.

Optimal cost-effective timing of cranial ultrasound screening in low-birth-weight infants.

Our aim in this study was to determine whether delaying the initial screening cranial ultrasound on infants of low birth weight until the 2nd week of life affects clinical diagnosis and cost of patient care. Data were reviewed on all premature infants of less than 33 weeks gestation or less than 1500 g birth weight admitted to the Neonatal Intensive Care Unit between January 1989 and August 1992. Babies admitted before August 1991 were screened on day 4 or 5 with a second scan frequently performed on day 14; babies admitted after that date were screened once between days 10-14. Populations were compared for (1) proportion of ultrasound findings considered normal on final diagnosis; (2) incidence of major and minor abnormalities; (3) periventricular leukomalacia (PVL); (4) change in diagnosis from 1st to 2nd week; and (5) number of studies performed per patient. The study group was composed of 499 eligible infants. Demographic features of infants screened in the 1st vs. 2nd week of life were similar, with comparable diagnoses of major and minor intracranial hemorrhage and ventricular dilatation; however, more patients screened in the 1st week had questionable PVL diagnosed (p = 0.04). There was a significant decrease in the number of scans per patient in the group screened in the 2nd week (p < 0.004). Routine screening may be delayed until the 2nd week without compromising patient care. Widespread use of a similar screening protocol would result in significantly fewer studies being performed, with an estimated saving, in the USA, of more than $3 million annually.

Secretory leukocyte protease inhibitor and lung inflammation in developing bronchopulmonary dysplasia.

OBJECTIVE: To investigate secretory leukocyte protease inhibitor (SLPI) concentrations in tracheal lavage fluids of neonates with an endotracheal tube in place during the first month of life, and to evaluate the relationship of SLPI to neutrophil counts and elastase activity in patients in whom bronchopulmonary dysplasia (BPD) developed versus those in whom it did not. DESIGN: A prospective, inception cohort study. SETTING: University children's hospital neonatal intensive care unit. PATIENTS: Fifty-three neonates who weighed < 2000 gm at birth, and who had an endotracheal tube in place, were enrolled. Forth-one patients survived to 28 days; BPD developed in 24 but not in 17 patients. MAIN OUTCOME MEASURES: Tracheal lavage was performed on days 1, 2, 4, 7, 14, 21, and 28, and analyzed for neutrophils, elastase activity, and SLPI. Results were evaluated longitudinally for 28 days, and were compared between BPD and no-BPD groups during the first week. RESULTS: SLPI concentrations increased significantly for all patients during the study period. During the first week, SLPI concentrations were similar between BPD and no-BPD groups; neutrophil counts and elastase activity were higher in the BPD group. CONCLUSIONS: Patients in whom BPD ultimately developed had early evidence of increased pulmonary inflammation and a significantly less favorable protease-antiprotease balance. If elastase-induced injury contributes to the development of BPD, early therapy with recombinant SLPI might be beneficial by increasing the antielastase capacity of epithelial lining fluid.

Failure of cromolyn sodium to reduce the incidence of bronchopulmonary dysplasia: a pilot study. The Neonatal Cromolyn Study Group.

This prospective, randomized, blinded clinical trial was conducted to test whether therapy with cromolyn sodium might decrease the incidence or severity of bronchopulmonary dysplasia when given to newborns with respiratory distress syndrome. Cromolyn (20 mg) or placebo was aerosolized to intubated newborns with respiratory distress syndrome every 6 hours, beginning on the first day of intubation. Patients were stratified by birth weight less than 1000 g and 1000 to 2000 g; primary outcome success was defined as survival to 30 days without oxygen dependence. Of 10 patients enrolled who were less than 1000 g birth weight, there were no treatment successes, preventing outcome analysis. The study was discontinued after 28 patients of 1000 to 2000 g birth weight had been studied, at which time it had been found with 95% confidence, with a power of .80, that cromolyn sodium did not decrease by 50% the incidence of bronchopulmonary dysplasia. Severity of bronchopulmonary dysplasia was also similar, with 4 patients in the treatment group and 3 in the placebo group receiving mechanical ventilation at 30 days. Possible reasons for this study outcome include (1) a delivered dose too small to produce a clinical effect; (2) the start of therapy too late to prevent the onset of inflammation; (3) inadequate effect of cromolyn on polymorphonuclear cells in vivo; or (4) development of bronchopulmonary dysplasia through factors unaffected by the actions of cromolyn.