Alterations in theophylline metabolism during the first year of life.

Maturational changes in theophylline disposition were evaluated in 52 infants (gestational age, 24 to 40 weeks; postnatal age, 2 to 69 weeks) receiving maintenance theophylline therapy. Theophylline and metabolites were measured in serum and urine at steady state, and the influence of clinical parameters on the maturational changes was analyzed by multiple stepwise linear regression. Theophylline clearance and urine metabolite pattern reached adult values at 55 weeks' postconceptional age. Serum caffeine concentrations greater than 1 microgram/ml occurred in infants up to 50 weeks' postconceptional age. Disappearance of serum caffeine concentrations and maturation of theophylline clearance were primarily related (p < 0.001) to development of the demethylation pathway to 3-methylxanthine. Postconceptional age was the major factor (p < 0.001) explaining the interpatient variability in theophylline clearance (r2 = 0.57), serum caffeine to theophylline ratio (r2 = 0.46), and urinary excretion of theophylline (r2 = 0.51), caffeine (r2 = 0.49), 1,3-methyluric acid (r2 = 0.32), 1-methyluric acid (r2 = 0.53), and 3-methylxanthine (r2 = 0.58). Our findings indicate that postconceptional age rather than postnatal age should be used as a maturational marker during theophylline therapy in infancy.

Early-onset Haemophilus sepsis in newborn infants: clinical, roentgenographic, and pathologic features.

Nine infants with early-onset Haemophilus sepsis were seen between January 1973 and July 1977. Of the five isolated strains that were typed, only one was type B. All infants had respiratory distress, metabolic acidosis, and large alveolar-arterial oxygen tension difference gradients. Eight infants weighed less than 1,500 gm and died; one infant weighed 1,701 gm and survived. Roentgenograms in six of eight showed hyaline membrane disease. Pulmonary pathologic specimens in eight infants revealed hyaline membranes in six and polymorphonuclear leukocytes in the alveolar spaces in four. In two infants, small Gram-negative bacilli were noted within proteinaceous exudates in alveolar ducts. The route and time of infection in these infants with early-onset Haemophilus sepsis are unclear. However, the possibility that the infection occurs before birth and that these infants represent septically aborted prematures is suggested by the high incidence of prematurity in infants with early-onset Haemophilus sepsis and early detection of bacteremia in three infants.

Indomethacin and its effect on renal function and urinary kallikrein excretion in premature infants with patent ductus arteriosus.

In the course of a double-blind trial of intravenous indomethacin therapy in premature infants with patent ductus arteriosus, renal function and urinary kallikrein were studied in 21 infants following one dose of either saline placebo or indomethacin. Ten infants were assigned to the control group and 11 were in the indomethacin group. Significantly lower urine output, fraction excretion of sodium, fraction excretion of chloride, and urinary kallikrein were noted by 45%, 59%, 63%, and 51%, respectively, in the indomethacin group as compared to the control group. There was a concomitant decrease in serum sodium concentration (P less than .05) at 24 hours following indomethacin therapy. No significant difference in glomerular filtration rate was seen between the control group and the indomethacin-treated infants.

Fever in full-term newborns in the first four days of life.

Over a period of 18 months, 100 full-term newborns developed an axillary or a rectal temperature greater than or equal to 37.8 C during the first four days of postnatal life. These febrile term newborns represented 1% of all full-term newborns in the normal nursery. Of the febrile newborns, 10% had culture-proven bacterial disease (BD). Fever developed in 54%, 27%, 13%, and 6% on the first, second, third, and fourth days, respectively. In 17 newborns fever developed within the first hour of life; 13 of these had mothers with fever and two others were under a radiant warmer in the birth room. Fever occurring on the third day of postnatal life had a significantly higher chance of being associated with BD than fever occurring at any other time in the first four days of postnatal life. Newborns with temperature greater than or equal to 39 C had a significantly higher incidence of BD than newborns with temperature less than 39 C. The incidence of fever among breast-fed newborns (0.98%) was similar to that of formula-fed newborns (1.01%). Of the 100 febrile newborns, 45 had other symptoms compatible with BD, and eight of these had proven BD (group B Streptococcus in five, group D Streptococcus in one, Shigella D in one, and Propionibacterium species in one). The two other febrile newborns with proven BD had no other symptoms of infection (group B Streptococcus and Escherichia coli). Mean WBC count of febrile newborns with BD was significantly lower than that of febrile newborns without BD. Only three febrile newborns had WBC count less than 5,000/cu mm and two of them had proven BD. Febrile newborns should be evaluated and treated with antibiotics when they have symptoms of infection other than fever or when the fever persists or recurs.

Early dexamethasone therapy and blood cell count in preterm infants.

OBJECTIVE: To assess the effects of early postnatal dexamethasone therapy on hematologic values in preterm infants. MATERIALS AND METHODS: We reviewed the hematologic data of 179 preterm infants who participated in a double-blind clinical trial of early postnatal dexamethasone therapy (<12 hours after birth) for the prevention of chronic lung disease. One group (86 infants) received saline and the other group (93 infants) received dexamethasone. Dexamethasone was given intravenously every 12 hours in tapering doses: 0.25 mg/kg on days 1 to 7, 0.12 mg/kg on days 8 to 14, 0.05 mg/kg on days 15 to 21, and 0.02 mg/kg on days 21 to 28. Blood samples were obtained on days 0, 3, 7, 10, 14, 21, and 28. None of the infants received prenatal steroid therapy. RESULTS: Multiple regression analysis revealed significant differences in the values versus time curves of the white blood cell, neutrophil, lymphocyte, basophil, and eosinophil counts between the two groups. The white blood cell count was significantly higher in the dexamethasone group on days 7 through 14, and this was associated with significantly higher numbers of segmented neutrophils and band forms and significantly lower numbers of lymphocytes and eosinophils. The hematocrit and platelet counts were similar in the two groups throughout most of the trial. Except for platelet count, steroid therapy did not alter the hematologic values for infants with bacteremia. CONCLUSION: Dexamethasone affects white blood cell, segmented neutrophil, lymphocyte, basophil, and eosinophil counts in neonates. This should be taken into consideration when evaluating preterm infants who are receiving dexamethasone.early dexamethasone therapy; neonatal blood count; preterm infant; respiratory distress syndrome.

Improved lung compliance following indomethacin therapy in premature infants with persistent ductus arteriosus.

In the course of a double-blind controlled study of intravenous indomethacin therapy in premature infants with patent ducts arteriosus (PDA), dynamic lung compliance (CL) was determined in 11 infants (six control, five indomethacin) who were not on assisted ventilation during the study period. The clinical, biochemical and laboratory data before the study were comparable between the groups. Following therapy with indomethacin there was a significant decrease in left atrial/aortic root ratio (LA/Ao), left ventricular end-diastolic dimension (LVEDD) on echocardiogram, and an increase in tidal volume (VT) and CL. In the control group, these variables did not change significantly. The improved lung compliance following early indomethacin closure of PDA may alter the clinical course and outcome of these premature infants.

Effect of antenatal dexamethasone on the expression of endothelial nitric oxide synthase in the lungs of postnatal pups.

Activities of endothelial nitric oxide synthase (eNOS) are developmentally regulated and its presence at birth may play a role in the transition of cardiopulmonary circulation. Antenatal dexamethasone (Dex) therapy accelerates fetal lung maturation. We speculate that Dex therapy may enhance pulmonary eNOS protein expression in the newborn. This article examines whether antenatal Dex therapy affected the expression of eNOS in the lungs of rat pups in the postnatal period. Time-dated pregnant Wistar rats were subjected to 2 doses of Dex (0.8 mg/kg, intramuscularly, daily) or equivalent volume of normal saline at the 18th and 19th gestational day and delivered naturally. The newborn pups were randomly assigned to 4 groups by age: days 1, 3, 5, and 7. After homogenization, abundance of eNOS protein in lungs was determined by Western blot analysis. There were 7 dams in each group. Mean body weights of the pups in the Dex group were lighter than those in the control at birth and remained stunted up to day 7 (5.68+/-0.47 g v 6.34+/-0.47 g, P <.01). However, there were no differences in wet lung weights and lung/body weight ratios between both groups in the study period. Abundance of eNOS protein expression decreased in both the control and Dex groups (P < .01). Pups that received antenatal Dex had 39% more in abundance of eNOS protein expression in lungs when compared to the control on day 1 (P < .05) but there were no differences between both groups from day 3 to 7. We conclude that antenatal Dex therapy enhances the abundance of eNOS protein expression in the lung at birth and could be a factor in improving respiratory functions in infants who received antenatal steroid therapy.

Early postnatal dexamethasone therapy may lessen lung inflammation in premature infants with respiratory distress syndrome on mechanical ventilation.

Early postnatal use of dexamethasone has recently been shown to be effective in improving the pulmonary status in premature infants with respiratory distress syndrome (RDS). To study the effect of dexamethasone on pulmonary inflammatory responses, we studied ten infants treated with dexamethasone and ten infants without this treatment. Serial tracheal aspirates were obtained for cell counts, neutrophil counts, total protein concentrations, and leukotriene B4 (LTB4) and 6-keto prostaglandin (PG)F(1 alpha) levels before and after starting the study. Infants in the dexamethasone-treated group required significantly lower mean airway pressures for ventilation and had lower PaCO2 values from day 3 to day 14 than infants in the control group, suggesting better pulmonary function. For infants in the dexamethasone group, the tracheal aspirates showed significantly lower cell and neutrophil counts, protein concentrations, and 6-keto-PGF(1 alpha) and LTB4 levels than in the control group. We conclude that early postnatal dexamethasone therapy may lessen lung inflammation and improve pulmonary function in infants with RDS.

Efficacy of nasal intermittent positive pressure ventilation in treating apnea of prematurity.

The efficacy of nasal intermittent positive pressure ventilation (NIPPV) in treating apnea of prematurity was evaluated. Apneic preterm infants were randomly assigned to receive either NIPPV or continuous positive airway pressure (NCPAP) for 4 hr when they failed to respond to conservative therapy. The amount of reduction in apneic spells and bradycardia in the two groups after treatment was compared. Thirty-four infants (18 with NIPPV, 16 with NCPAP) were enrolled. Their birth weights ranged from 590-1,880 g (mean, 1,021 g) and gestational ages from 25-32 weeks (mean, 27.6 weeks). The baseline characteristics were comparable in the two groups. Frequency of apnea and bradycardia was reduced during both forms of treatments. However, the infants receiving NIPPV had a greater reduction of apneic spells (P = 0.02) and a tendency to greater decrease in bradycardia (P = 0.09) than those receiving NCPAP. We conclude that NIPPV is more effective than NCPAP in reducing apnea in preterm infants. NIPPV may reduce bradycardia; however, this needs to be validated by a larger number of observations.

Prevention of chronic lung disease in preterm infants by early postnatal dexamethasone therapy.

Recent studies suggest that early dexamethasone therapy may lessen the pulmonary inflammation in preterm infants with respiratory distress syndrome (RDS). To investigate whether early (<12 hr) postnatal dexamethasone therapy would reduce the incidence of chronic lung disease (CLD), a randomized, double-blind, controlled trial was conducted in 40 infants (birth weights from 500 to 1,999 gm) who had severe RDS and required mechanical ventilation within 6 hr of birth. All infants received one dose of Survanta before they were randomly assigned to control (saline placebo) or dexamethasone-treated groups (0.5 mg/kg/d for 1 week, then tapered over 3 weeks). Sequential analysis was performed with the end point of assessment being the presence or absence of CLD on postnatal Day 28. Statistical significance favoring dexamethasone was reached when 12 consecutive pairs in which one infant had CLD and the other did not have CLD showed that ten pairs favored dexamethasone and two pairs favored control treatment. Among the survivors, 12/15 were extubated in the dexamethasone group and 9/16 in the control group at the end of study. Infants in the treated group had transient hyperglycemia and hypertension. There was no difference between the groups in mortality and in incidence of sepsis or intraventricular hemorrhage. We conclude that early postnatal dexamethasone therapy is potentially effective in the lessening of CLD in preterm infants. To substantiate our result, large randomized controlled trials are needed and warranted.

Effect of aminophylline on brain stem auditory evoked potentials in preterm infants.

To determine the neurophysiological effects of aminophylline on apnoea of prematurity, the brain stem auditory evoked potentials (BAEPs) of 30 apnoeic infants and 34 age matched controls were evaluated and compared. After six days of treatment with aminophylline, the brain stem conduction time (interpeak latency of I-V) in apnoeic infants decreased compared with controls of a similar postconceptional age. The mean latencies of the peaks and interpeaks of all waves except wave I were significantly lower in the apnoeic infants after than before receiving aminophylline. No significant differences were found in the latencies of BAEPs between the apnoeic infants who responded and those who did not respond to aminophylline treatment, however. These results suggest that aminophylline may enhance conduction along central auditory pathways and stimulate the regulatory effect on the respiratory centre of the brain stem.

Assessment of gestational age in newborns by neurosonography.

Current methods for estimating gestational age using clinical parameters can be inaccurate in prematurity. A simplified ultrasonographic system, based on cerebral sulcal development, for clinically determining fetal maturation in newborns was developed and studied in 148 newborns (92 appropriate-for-gestational-age, 54 small-for-gestational-age and 2 large-for-gestational age). This ultrasonographic sulcal method correlates better with the gestational age by dates than by the Dubowitz scoring system in the neonates less than 30 weeks' gestation. There are significant correlations between gestational age assessed by dates and by sonographic sulcal age in both appropriate-for-gestational-age (R = 0.91, P less than 0.001) and small-for-gestational-age newborns (R = 0.92, P less than 0.001). Maternal hypertension during pregnancy is a significant risk factor associated with accelerated fetal cerebral maturation in 12 neonates. Although overestimate of gestational age may occur in neonates born to mothers with hypertension, cranial ultrasonography is an accurate and convenient method of estimating gestational age in neonates.

Indomethacin therapy in premature infants of advanced postnatal age.

Indomethacin (0.3 mg/kg every eight hours IV for three doses) was administered to eight infants whose postnatal ages were eight weeks or greater and who developed patent ductus arteriosus either in the late postnatal life or in the early neonatal period but persisted. In spite of maintenance of appropriate plasma indomethacin levels, none of the infants responded with ductus closure. The present study suggests that a distinct group of infants may exist whose ductus arteriosus is prostaglandin independent and the patency of the ductus may persist.

Chest physiotherapy in preterm infants with RDS in the first 24 hours of life.

To evaluate if chest physiotherapy is beneficial to premature infants with respiratory distress syndrome (RDS) during the first 24 hours of life, 20 infants were randomly assigned to two groups; 10 infants in Group I received routine chest physiotherapy and suction, and 10 infants in Group II received suction only. The birth weight, gestational age, postnatal age, Apgar scores, blood gases, acid-base status, and ventilatory requirements prior to study were comparable between the two groups. There were no significant differences between the groups in the amount of endotracheal secretions removed, the PO2/FIO2 ratio, blood gases, and pH during the study. The incidence of patent ductus arteriosus (PDA), bronchopulmonary dysplasia (BPD), Grade I and II intraventricular hemorrhage (IVH), and mortality was comparable. However, five of 10 Group I and zero of 10 Group II infants developed Grade III or IV IVH (P less than 0.05).

The role of pulmonary inflammation in the development of pulmonary hypertension in newborn with meconium aspiration syndrome (MAS).

1. There was no clear correlation between the tracheal aspirate cytokines and the elevation of pulmonary arterial pressure in newborn piglets with MAS. The use of dexamethasone significantly suppressed tracheal aspirate cytokines but did not significantly alter pulmonary arterial pressure. Dexamethasone significantly increased the cardiac stroke volume and blood pressure. 2. Early dexamethasone therapy (< 12 hrs) for one week in infants with MAS significantly improved pulmonary ventilation and facilitated weaning from mechanical ventilation. 3. The mechanisms for the improvement in cardiopulmonary status following early dexamethasone therapy in MAS remain unclear. An overall improvement in cardiac hemodynamics, along with a significant decrease in lung inflammation may be responsible for the improvement.

Fuzzy oxygen control system for the indirect calorimeter of premature infants.

The indirect calorimetric system of measuring O2 consumption and CO2 production has been developed for energy expenditure estimation of premature infants. This apparatus requires an input room air mixing with pure oxygen to obtain a stable gas with definite oxygen concentration flowing into the hood for neonatal breath or supplemental oxygen treatments. In this paper, we propose an oxygen control system based on fuzzy control logic to automatically adjust the mixing ratio of room air to pure oxygen gas from the hospital's supply system, designed for premature infants. It is designed to reduce the risks of oxygenic toxicity and retinopathy of prematurity by lowering the overshoot of oxygen concentration. Its performance was evaluated and optimal membership functions were obtained. As a result, the system is quite robust with little effect caused by disturbance and has little or no overshoot when step changing the level of oxygen concentration in the mixed gas.

Mortality, morbidity, length and cost of hospitalization in very-low-birth-weight infants in the era of National Health Insurance in Taiwan: a medical center's experience.

The impact of implementation of the National Health Insurance on the outcome, cost, and length of hospitalization of very-low-birth-weight (VLBW) infants is not clear in Taiwan. These data are important for the planning of medical care and regionalization in this area. This study was an attempt to examine these questions. We retrospectively collected mortality, morbidity, and length and cost of hospitalization data of VLBW (BW < 1500 g) infants between March 1995 and February 1998. There were totally 162 patients enrolled. The overall mortality rate was 21.6%; the birth weight (BW)-specific mortality rate was 72%, 31%, 19%, and 3% for infants with BWs of < 750 g, 750-999 g, 1000-1249 g, and 1250-1499 g, respectively. The incidence of morbidities were: respiratory distress syndrome (74%), patent ductus arteriosus (36%), necrotizing enterocolitis (9%), sepsis (42%), intraventricular hemorrhage (15%), retinopathy of prematurity (31%), failure to pass auditory brainstem response (ABR) (34%), and chronic lung disease (17%). The average length of hospitalization was 67.2 days, and the cost per infant was 62 x 10(4) NT dollars; 108 +/- 38 days, 73 +/- 32 x 10(4) NT dollars if BW < 750 g; 94 +/- 15 days, 99 +/- 35 x 10(4) NT dollars if BW 750-999 g; 66 +/- 23 days, 64 +/- 36 x 10(4) NT dollars if BW 1000-1249 g; and 43 +/- 14 days, 39 +/- 37 x 10(4) NT dollars if BW 1250-1499 g. In conclusion, VLBW infants are associated with high mortality and morbidity rates. They have long lengths and high costs of hospitalization, and therefore deserve attention in the implementation of the National Health Insurance and regionalization.

Use of graft flow measurement and computerized tomography angiography to evaluate patency of endoscopically harvested radial artery as sequential graft in coronary artery bypass surgery.

AIM: Endoscopic radial artery (RA) graft harvesting in coronary artery bypass surgery (CABG) is attractive but concern remains regarding early graft failure. We evaluated RA graft patency via intraoperative graft flow measurements and mid-term computerized tomography angiography (CTA). METHODS: The patients who had RA harvested by endoscopic technique which was used as sequential grafts were retrospectively reviewed. Graft quality was confirmed by intraoperative transit time flow measurements. Graft stenosis was defined as stenosis >70% on CTA, 6-12 months postoperatively. RESULTS: From 2007 to 2011, 58 patients underwent endoscopic RA harvesting for sequential bypassed grafts. All received total arterialized grafts, including 22 (38%) bilateral internal thoracic arteries (ITAs), with 208 total bypassed grafts (mean: 3.59±0.52) and 128 RA bypassed grafts (mean: 2.21±0.35). Off-pump technique was performed in 43 (84%) of 51 isolated CABG patients. The pulsatility index of graft flow of the left, right ITA and sequential RA grafts with 2 or 3 targets were 1.8±0.7, 2±0.8, 1.9±0.4, and 1.7±0.7, respectively. There was no hospital mortality, and median intensive care unit and hospital stay was 2 and 8 days. Follow-up was completed in 57 patients, but 3 patients refused CTA due to lack of exertional angina. Stenosis of the left, right ITA, and RA grafts occurred in 1/54 (1.9%), 1/21 (4.8%), and 11/120 (9.2%). After a mean of 35.8±10.9 (median: 30.7) months follow-up, there was no late mortality and one documented myocardial infarction was reported. Age, diabetes, previous percutaneous coronary intervention, off-pump technique, RA target number, and graft flow or pulsatility index did not predict RA stenosis. Only RA grafts targeting the circumflex territory had an adverse impact. CONCLUSION: The RA of appropriately selected patients can be harvested safely by endoscopic technique and can be used as sequential grafts for CABG with satisfactory outcomes. Intraoperative flow measurement can assure the quality of the grafts. CTA is a valuable tool for patency follow-up.