High-mobility group box-1 protein in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia and steroid therapy.

OBJECTIVE: High-mobility group box-1 (HMGB1) is a potent inflammatory mediator and contributes to acute lung injury in adults. The role of HMGB1 in neonatal lung injury and the development of bronchopulmonary dysplasia (BPD) is unknown. We studied the association between HMGB1 levels in tracheal aspirates (TAs) and adverse outcomes (BPD/death) in ventilated premature infants (VPIs) and modulation of HMGB1 levels with dexamethasone (Dex) use. STUDY DESIGN: Infants born before 32 weeks gestation and requiring mechanical ventilation were enrolled. Serial TA samples were collected on days 1, 3, 5 and 7 and HMGB1 levels were measured. HMGB1 levels in TA samples were compared between infants with no BPD and infants who developed BPD or died. HMGB1 TA levels were also compared before and after using Dex. RESULT: In all, 24 infants (gestational age 26.4+/-1.9 weeks, birth weight 859+/-200 g) had no BPD, 60 infants (gestational age 25.4+/-1.8 weeks, birth weight 749+/-156 g) developed BPD or died before 36 weeks postmenstrual age. Mean HMGB1 level in first week of life was significantly lower in infants with no BPD (27.3+/-16.5 ng mg(-1)) compared with those who developed BPD or died (45.1+/-30.9 ng mg(-1), P=0.004). In total, 29 VPIs received Dex. There was no significant change in HMGB1 levels with steroid therapy (before 47.0+/-43.9, after 60.1.5+/-58.8, P=0.3). CONCLUSION: Our data suggest that higher HMGB1 levels in TA are associated with the development of BPD or death in VPI. Dex use had no effect on HMGB1 levels.

Angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone.

OBJECTIVES: To study the association between angiopoietin 2 (Ang2) concentrations in tracheal aspirates (TAs) and adverse outcome (bronchopulmonary dysplasia (BPD)/death) in ventilated premature infants (VPIs) and modulation of Ang2 concentrations with dexamethasone (Dex) use. STUDY DESIGN: Serial TA samples were collected on days 1, 3, 5 and 7, and Ang2 concentrations were measured. Ang2 TA concentrations were compared prior to and after 48 to 72 h of using Dex. RESULT: A total of 151 TA samples were collected from 60 VPIs. BPD was defined as the oxygen requirement at 36 weeks postmenstrual age (PMA). Twelve infants (mean+/-s.d.) (gestational age (GA) 26.5+/-2.1 weeks, birth weight (BW) 913+/-230 g) had no BPD, 32 infants (GA 25.8+/-1.4 weeks, BW 768+/-157 g) developed BPD and 16 infants (GA 24.5+/-1.1 weeks, BW 710+/-143 g) died before 36 weeks PMA. Ang2 concentrations were significantly lower in infants with no BPD (median, 25th and 75th percentile) (157, 16 and 218 pg mg(-1)) compared with those who developed BPD (234, 138 and 338 pg mg(-1), P=0.03) or BPD and/or death (234, 157 and 347 pg mg(-1), P=0.017), in the first week of life. Twenty-six VPIs (BW 719+/-136 g, GA 25.1+/-1.3 weeks) received 27 courses of Dex. Ang2 concentrations before starting Dex were 202, 137 and 278 pg mg(-1) and significantly decreased to 144, 0 and 224 pg mg(-1) after therapy (P=0.007). CONCLUSIONS: Higher Ang2 concentrations in TAs are associated with the development of BPD or death in VPIs. Dex use suppressed Ang2 concentrations.

Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis.

BACKGROUND: Extremely low birth weight (ELBW) infants are at increased risk for invasive candidiasis and associated morbidity and mortality. The use of fluconazole prophylaxis in this population has raised a benefit versus risk concern among clinicians. OBJECTIVES: To evaluate the effectiveness and safety of fluconazole prophylaxis in ELBW infants. STUDY DESIGN: ELBW infants (BW

Work of breathing using high-flow nasal cannula in preterm infants.

OBJECTIVE: To compare the work of breathing (WOB) in premature neonates supported with high-flow nasal cannula (HFNC) and nasal continuous positive airway pressure (NCPAP). STUDY DESIGN: Eighteen preterm neonates <2.0 kg on HFNC or NCPAP support were studied in a random order. A ventilator was used to deliver 6 cm H2O of NCPAP with nasal prongs. High-flow nasal cannula delivered with Vapotherm (VAPO) at 3, 4 and 5 l/min was used. Tidal ventilation was obtained using respiratory inductance plethysmography calibrated with face-mask pneumotachography. An esophageal balloon estimated pleural pressure from which changes in end distending pressure were calculated. Inspiratory, elastic and resistive WOB and respiratory parameters were calculated. RESULTS: No differences were found in the WOB for all settings. Changes in end distending pressure did not vary significantly over all device settings except VAPO at 5 l/min. CONCLUSION: In these preterm infants with mild respiratory illness, HFNC provided support comparable to NCPAP.

Work of breathing during constant- and variable-flow nasal continuous positive airway pressure in preterm neonates.

BACKGROUND: Constant-flow nasal continuous positive airway pressure (NCPAP) often is used in preterm neonates to recruit and maintain lung volume. Physical model studies indicate that a variable-flow NCPAP device provides more stable volume recruitment with less imposed work of breathing (WOB). Although superior lung recruitment with variable-flow NCPAP has been demonstrated in preterm neonates, corroborating WOB data are lacking. OBJECTIVE: To measure and compare WOB associated with the use of variable-flow versus constant-flow NCPAP in preterm neonates. METHODS: Twenty-four preterm infants who were receiving constant-flow NCPAP (means, SD) and had birth weight of 1024 +/- 253 g, gestational age of 28 +/- 1.7 weeks, age of 14 +/- 13 days, and FIO(2) of 0.3 +/- 0.1 were studied. Variable-flow and constant-flow NCPAP were applied in random order. We measured changes in lung volume and tidal ventilation (V(T)) by DC-coupled/calibrated respiratory inductance plethysmography as well as esophageal pressures at NCPAP of 8, 6, 4, and 0 cm H(2)O. Inspiratory WOB (WOB(I)) and lung compliance were calculated from the esophageal pressure and V(T) data using standard methods. WOB was divided by V(T) to standardize the results. RESULTS: WOB(I) decreased at all CPAP levels with variable-flow NCPAP, with a maximal decrease at 4 cm H(2)O. WOB(I) increased at all CPAP levels with constant-flow CPAP. Lung compliance increased at all NCPAP levels with variable-flow, with a relative decrease at 8 cm H(2)O, whereas it increased only at 8 cm H(2)O with constant-flow NCPAP. Compared with constant-flow NCPAP, WOB(I) was 13% to 29% lower with variable-flow NCPAP. CONCLUSION: WOB(I) is decreased with variable-flow NCPAP compared with constant-flow NCPAP. The increase in WOB(I) with constant-flow NCPAP indicates the presence of appreciable imposed WOB with this device. Our study, performed in neonates with little lung disease, indicates the possibility of lung overdistention at CPAP of 6 to 8 cm H(2)O with the variable-flow device. Further study is necessary to determine the efficacy of variable-flow NCPAP in neonates with significant lung disease and its use over extended periods of time.continuous-flow and variable-flow NCPAP, work of breathing, premature neonates, lung compliance.

Lung recruitment and breathing pattern during variable versus continuous flow nasal continuous positive airway pressure in premature infants: an evaluation of three devices.

OBJECTIVE: To determine whether lung volume changes and breathing pattern parameters differ among 3 devices for delivery of nasal continuous positive airway pressure (CPAP) in premature infants. METHODS: Thirty-two premature infants receiving nasal CPAP for apnea or mild respiratory distress were enrolled. Birth weight was (mean +/- standard deviation) 1081 +/- 316 g, gestational age 29 +/- 2 weeks, age at study 13 +/- 12 days, and fraction of inspired oxygen (FIO(2)) at study.29 +/-.1. Three devices, applied in random order, were studied in each infant: continuous flow nasal CPAP via CPAP prongs, continuous flow nasal CPAP via modified nasal cannula, and variable flow nasal CPAP. After lung recruitment to standardize volume history, changes in lung volume (DeltaV(L)) were assessed at nasal CPAP of 8, 6, 4, and 0 cm H(2)O using calibrated direct current-coupled respiratory inductance plethysmography. RESULTS: DeltaV(L) was significantly greater overall with the variable flow device compared with both the nasal cannula and CPAP prongs. However, DeltaV(L) was not different between the cannula and the prongs. Respiratory rate, tidal volume, thoraco-abdominal asynchrony, and FIO(2) were greater with the modified cannula than for either of the other 2 devices. CONCLUSION: Compared with 2 continuous flow devices, the variable flow nasal CPAP device leads to greater lung recruitment. Although a nasal cannula is able to recruit lung volume, it does so at the cost of increased respiratory effort and FIO(2).

Thyroxine screening values in premature infants.

OBJECTIVES: Premature infants often have low thyroxine levels when compared to fullterm infants. We sought to determine gestational age specific normal ranges for thyroxine screening results for premature infants in neonatal intensive care units. METHODS: Thyroid screening results for infants less than 38 weeks gestation admitted to two NICUs were examined. For each sample the thyroxine Z-score was computed using parameters from fullterm infants. The mean thyroxine Z-score was calculated for each gestational age for days of life 1, 2, 3-7, 8-14, 15-21, 22-28, and 29-60. RESULTS: There were 1144 specimens obtained from 543 premature infants. The mean thyroxine Z-score was below 0 for almost every gestational age and days-of-life category. The mean thyroxine Z-score increased with gestational age, but did not rise with increasing postpartum age. CONCLUSION: The data show that normal thyroxine Z-scores for premature infants are lower than for fullterm infants and remain low at least as long as the infants remain ill.

Thyroid screening for early discharged infants.

OBJECTIVE: As neonatal discharge before 24 hours of life becomes commonplace, the rejection of congenital hypothyroidism (CH) screening specimens obtained too early has created the need for numerous additional tests. We sought to determine whether the specimens obtained before 24 hours could be used safely. METHODS: During a 31-day period we measured thyrotropin in all thyroid-screening specimens that had been obtained before 24 hours. We also examined the early specimens from every infant diagnosed in New Jersey with CH during 1993 or 1994. RESULTS: Among the 663 specimens, those obtained at or before 12 hours and those from infants with birth weights less than 2500 g had too many low thyroxine results to be useful. Among the 515 specimens obtained at more than 12 to 24 hours from newborns weighing 2500 g or more, 37 (7%) had low thyroxine levels and 12 (2.3%) had thyrotropin levels of 20 microIU/mL (mU/L) or higher. Four hundred seventy-one of the 515 infants had subsequent specimens obtained at more than 24 hours, and none of the results were abnormal. There was no child weighing more than or equal to 2500 g who was diagnosed with CH in 1993 and 1994 whose specimen obtained at 24 hours or less was normal. CONCLUSIONS: Accepting specimens obtained at more than 12 to 24 hours from infants weighing 2500 g or more would have resulted in more than the usual number of false-positive results but no false-negative results. This would have decreased the requests for additional specimens by more than 90%.

Effect of dose formulation on isoniazid absorption in two young children.

In an 8-month-old infant with tuberculous meningitis treatment with isoniazid was unsuccessful and was associated with lower than expected plasma concentrations of isoniazid (measured concentration 0.1 microgram/mL). The infant had received isoniazid as a crushed tablet admixed with apple sauce. Oral administration of the parenteral solution of isoniazid (Nydrazid, Squibb) mixed in apple juice produced a higher isoniazid concentration (2.9 micrograms/mL) and the child improved clinically. Pharmacokinetic studies in two subjects were performed following intramuscular injection of isoniazid and oral administration of (1) an isoniazid tablet crushed and mixed with apple sauce, (2) parenteral isoniazid solution mixed with apple juice, and (3) a commercially available syrup containing isoniazid and pyridoxine (P-I-N Forte, Lannett). Of the three oral preparations, the syrup produced the highest peak concentrations (8.3 and 6.9 micrograms/mL). The crushed tablets in apple sauce produced the lowest peak concentrations (1.4 and 2.4 micrograms/mL). Administration of crushed isoniazid tablets with food may be associated with impaired gastrointestinal absorption, lower than expected isoniazid concentrations, and treatment failure.

Digoxin toxicity in a premature infant: treatment with Fab fragments of digoxin-specific antibodies.

The first use of Fab fragments to treat digoxin toxicity in a premature infant with renal failure, 18 h after the onset of severe arrhythmias, is reported with dramatic results. The development of digoxin toxicity in the context of accepted therapeutic dosing to treat heart failure due to a cerebral arteriovenous malformation is discussed.