Jeffrey S. Gerdes

Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial

Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%). Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. Conclusions. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.

CLINICOPATHOLOGIC APPROACH TO THE DIAGNOSIS OF NEONATAL SEPSIS

Perinatally acquired bacterial neonatal sepsis is a low incidence, high risk disease with a relatively benign treatment. Accurate diagnosis is difficult because there is no definitive diagnostic test; even blood cultures have an unacceptably low sensitivity. Therefore, the clinician must accept that a number of neonates who do not have the disease will have treatment initiated for sepsis. In order to treat rapidly all infants with sepsis and to minimize therapy for those without infection, historical, clinical, and laboratory data can be used together in a management approach to achieve optimal results.

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 (≥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.

Sepsis screen in neonates with evaluation of plasma fibronectin.

Two hundred twenty neonates with suspected early onset sepsis were prospectively studied to evaluate the ability of a sepsis screen to discriminate infected from noninfected newborn infants. A positive sepsis screen consisted of positive findings in two or more of the following tests: total white blood cell count; immature/ total neutrophil ratio; C-reactive protein; micro-erythrocyte sedimentation rate; or plasma fibronectin. For proved sepsis a four-part screen excluding fibronectin yielded a sensitivity of 100%, specificity of 83%, positive predictive value of 27% and negative predictive value of 100%. In contrast the sensitivity of white blood cell count and immature/total neutrophil ratio was only 46%. Adding fibronectin to the four-part screen provided equal sensitivity and negative predictive value but decreased specificity and positive predictive value. While plasma fibronectin may play an important role in the pathogenesis of neonatal sepsis, it is not useful as a marker for infection. The screens did not identify preterm infants with late onset noso-comial sepsis. Although clinical judgment should be the primary factor in the decision to institute antibiotic therapy, a simple four-part sepsis screen provides valuable presumptive information for excluding the diagnosis of early onset neonatal sepsis.

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 childrens 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.

Effects of dexamethasone and indomethacin on elastase, α1-proteinase inhibitor, and fibronectin in bronchoalveolar lavage fluid from neonates

Elastase activity and concentrations of alpha 1-proteinase inhibitor, albumin, and fibronectin were measured in bronchoaleolar lavage (BAL) fluid from ventilated lungs in preterm neonates with lung disease before and after treatment with dexamethasone or indomethacin. Treatment with dexamethasone was associated with a significant decrease in BAL elastase activity but no change in fibronectin, albumin, or alpha 1-proteinase inhibitor concentrations. In contrast, treatment with indomethacin was associated with an increase in BAL elastase activity and fibronectin concentration, with no change in albumin or alpha 1-proteinase inhibitor concentrations. Control groups showed no changes in these BAL fluid biochemical markers during a similar time period. These data indicate that treatment with corticosteroids decreases lung inflammation as measured by BAL elastase activity. Corticosteroid treatment may not inhibit the development of pulmonary fibrosis, because fibronectin concentrations in BAL fluid were unaffected. Indomethacin treatment may augment lung inflammation and fibrosis by increasing BAL elastase activity and fibronectin concentration.

Pulmonary mechanics and energetics in preterm infants who had respiratory distress syndrome treated with synthetic surfactant

Pulmonary mechanics and energetics were determined in 32 neonates with respiratory distress syndrome, who were randomly assigned to receive treatment with an exogenous synthetic surfactant, Exosurf Neonatal, or air placebo. Pulmonary mechanics were measured before and 2 hours after surfactant (n = 13) or air placebo (n = 19) treatment, then longitudinally at 24, 48, and 72 hours after treatment, and again at 7, 14, and 28 days of age. There were no significant differences in the values for pulmonary mechanics or energetics 2 hours after the first dose of surfactant. Improvement in pulmonary mechanics was apparent 24 hours after surfactant treatment, when dynamic compliance was 36% greater than in the placebo group (p less than 0.03). Lung compliance values were also higher in surfactant-treated infants 48 and 72 hours after treatment, with a maximal increase of 64% at 7 days of age (p less than 0.03). Surfactant treatment also caused a significant decrease in total pulmonary resistance at 48 and 72 hours after initial treatment and at 14 days of age (p less than 0.04). Similarly, a decrease in flow-resistive work of breathing was demonstrated 24, 48, and 72 hours after surfactant treatment. At 28 days of age, pulmonary mechanics were not different in the two groups. We conclude that beneficial effects of surfactant on pulmonary mechanics were not apparent 2 hours after dosing but were evident 24 hours after dosing and persisted for the first 7 to 14 days of life.

Effect of HFNC flow rate, cannula size, and nares diameter on generated airway pressures: An in vitro study

Increased use of non‐invasive forms of respiratory support such as CPAP and HFNC in premature infants has generated a need for further investigation of the pulmonary effects of such therapies. In a series of in vitro tests, we measured delivered proximal airway pressures from a HFNC system while varying both the cannula flow and the ratio of nasal prong to simulated nares diameters. Neonatal and infant sized nasal prongs (3.0 and 3.7 mm O.D.) were inserted into seven sizes of simulated nares (range: 3–7 mm I.D. from anatomical measurements in 1–3 kg infants) for nasal prong‐to‐nares ratios ranging from 0.43 to 1.06. The nares were connected to an active test lung set at: TV 10 ml, 60 breaths/min, Ti 0.35 sec, compliance 1.6 ml/cm H2O and airway resistance 70 cm H2O/(L/sec), simulating a 1–3 kg infant with moderately affected lungs. A Fisher & Paykel Healthcare HFNC system with integrated pressure relief valve was set to flow rates of 1–6 L/min while cannula and airway pressures and cannula and mouth leak flows were measured during simulated mouth open, partially closed and fully closed conditions.

Tracheal lavage and plasma fibronectin: relationship to respiratory distress syndrome and development of bronchopulmonary dysplasia.

Plasma for fibronectin determinations was obtained from 39 neonates with uncomplicated respiratory distress syndrome (RDS) and from 15 infants with RDS who developed bronchopulmonary dysplasia (BPD). Tracheal lavage fibronectin and albumin concentrations were measured in 15 infants with RDS and 15 with BPD. Control plasma fibronectin values were obtained from 20 healthy preterm infants on days 1, 2, 3, 14, and 30 of life. Control tracheal lavage fibronectin and albumin concentrations were measured in 17 neonates of various gestational ages who required tracheal intubation for nonpulmonary indications. Mean plasma fibronectin concentrations from patients with RDS was 121 +/- 11 micrograms/ml on days 1, 2, and 3, versus control level of 163 +/- 12 micrograms/ml (P less than 0.01). Mean tracheal lavage fibronectin/albumin ratio was 3.8 +/- 0.6 ng per microgram of albumin on days 1 to 5 for infants with RDS, versus control level of 5.6 +/- 3.6 (P = NS). Tracheal lavage fibronectin/albumin ratio from patients with BPD was elevated at 16.3 +/- 5.0 ng fibronectin per microgram of albumin on days 14 to 21, and 23.6 +/- 7.4 on day 30 (P less than 0.05 versus control and and versus RDS days 1 to 10). Low plasma fibronectin concentrations early in RDS may contribute to the development of pulmonary capillary leak. High tracheal lavage fibronectin levels may foster the development of pulmonary fibrosis in patients with BPD.

Severe retinopathy of prematurity in infants with birth weights less than 1250 grams: Incidence and outcome of treatment with pharmacologic serum levels of vitamin E in addition to cryotherapy from 1985 to 1991

OBJECTIVE To determine the effect of vitamin E prophylaxis and treatment on the sequelae of severe (threshold) retinopathy of prematurity (ROP) in infants treated with cryotherapy at Pennsylvania Hospital from 1985 to 1991. STUDY DESIGN Beginning on day 0, all infants with birth weights < or = 1250 gm received supplements of vitamin E using standard preparations. Serum E levels of 23 to 58 mumol/L (1 to 2.5 mg/dl) were targeted for infants with immature retinal vasculature or ROP of stage 2 or less in severity, and levels of 58 to 81 mumol/L (2.5 to 3.5 mg/dl) for infants with prethreshold ROP. At diagnosis of threshold ROP, treatment with a parenteral investigational new drug preparation of alpha-tocopherol was begun to raise serum levels to the pharmacologic range (93 to 116 mumol/L or 4 to 5 mg/dl). Within 3 days of diagnosis, and at the discretion of the retinal specialist, one or both eyes were treated with cryotherapy. Visual outcome at 4 years was compared with the 42-month outcome reported for eyes in the infants randomly assigned to treatment in the 1986-1987 Multicenter Trial of Cryotherapy for ROP (CRYO-ROP). RESULTS Threshold ROP developed in 22 of 450 surviving infants (age 3 months). All were treated with pharmacologic serum levels of vitamin E; 17 infants were also treated with cryotherapy (10 in one eye and 7 in both eyes). These 17 infants, in comparison with infants in the CRYO-ROP trial (n = 187), were at least at equal risk for poor visual outcome on the basis of birth weight, gestational age, the percentage of zone 1 ROP, and mean interval from appearance of ROP to diagnosis of prethreshold ROP, which was shorter at Pennsylvania Hospital (4.1 days for the Pennsylvania Hospital group, 10.3 days for the CRYO-ROP group). However, on the basis of the mean number of days from diagnosis of prethreshold to threshold ROP (12.5 days for Pennsylvania Hospital, 10.5 days for CRYO-ROP) and the extent of extraretinal neovascularization at threshold (mean 7.9 sectors for Pennsylvania Hospital, 9.7 for CRYO-ROP), progression of retinopathy beyond the prethreshold stage had slowed and visual outcome in the eyes of infants at Pennsylvania Hospital treated with both cryotherapy and vitamin E (worse eye used for those treated with bilateral cryotherapy) was better than that reported for the treated eye of infants in the CRYO-ROP group (percentage of favorable visual acuity, 76% vs 48%, p = 0.04; percentage of normal structure posterior retinal pole, 71% vs 38%, p < or = 0.02). CONCLUSIONS In this small case series, the combination of cryotherapy with anti-oxidant prophylaxis and treatment appeared to decrease the severity and sequelae of threshold ROP. This hypothesis deserves testing in a large, randomized clinical trial.