Octreotide-induced hypoxemia and pulmonary hypertension in premature neonates.

The authors report 2 cases of premature neonates who had enterocutaneous fistula complicating necrotizing enterocolitis. Pulmonary hypertension developed after administration of a somatostatin analogue, octreotide, to enhance resolution of the fistula. The authors discuss the mechanism of the occurrence of this complication and recommend caution of its use in high-risk premature neonates.

Pharmacokinetics of betamethasone in twin and singleton pregnancy.

OBJECTIVE: The aims of the study were to compare the pharmacokinetics of betamethasone in singleton pregnancy with the pharmacokinetics in twin pregnancy and to assess the adrenal suppression produced by betamethasone. STUDY DESIGN: We measured serial betamethasone and cortisol levels in 30 singleton and 21 twin pregnancies after the first dose of betamethasone and calculated the pharmacokinetic parameters for betamethasone including volume of distribution, half-life, and clearance. We also measured cord and maternal blood levels of betamethasone at the birth of infants of 13 singleton and 9 twin pregnancies. RESULTS: The half-life of betamethasone in mothers with twin pregnancies was significantly shorter than that in mothers with singleton pregnancies (7.2 +/-2.4 versus 9.0 +/- 2.7 hours; P <.017). Clearance of betamethasone in the twin pregnancies appeared greater than in singleton pregnancies (8.4 +/- 6.4 versus 5.7+/- 3.1 L/h; P =.06) but did not reach statistical significance. Volume of distribution was similar in the two groups. Because the time between the last dose of betamethasone and birth varied widely (range, 2-158 hours), mothers with a longer interval after treatment tended to have a higher cord-to-maternal betamethasone ratio than did mothers with a shorter interval in both twin and singleton pregnancies. This finding indicated delayed fetal clearance, but the correlation was weak (R (2) = 0.29 for twins and 0.08 for singletons). CONCLUSION: The shorter half-life of betamethasone in twin pregnancy than in singleton pregnancy may cause the level of betamethasone to be subtherapeutic for lung maturation in twin pregnancy.

Objective ranking of fibrosis in standard histologic sections of human neonatal liver: applicability to alpha1-antitrypsin deficiency.

BACKGROUND: The etiologic heterogeneity of fibrotic liver disease has resulted in the formulation of diverse, often disease-specific, classification systems for biopsy assessment, based on tissue morphology and staining. Their qualitative nature and observer dependency remain a concern, and no classification exists for several significant conditions--for example, alpha1-antitrypsin deficiency (alpha1-ATD). The authors propose a disease- and morphology-independent numeric ranking system to objectively quantify fibrosis in a standard histologic section, based on its content of protein amino acids. This PNC system is applied to two cases of alpha1-ATD liver fibrosis. METHODS: High-performance liquid chromatography separation of the 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC)-labeled acid hydrolysate of an individual needle biopsy section, followed by the calculation of specific amino acid ratios to eliminate confounding variables. RESULTS: As required by the PNC system, three numeric values were identified per tissue section, one increasing (P quotient), one decreasing (N quotient), one constant (C quotient) as fibrosis progresses, assessed by calibration against Knodell-staged samples. Generated for the alpha1-ATD sections, these three coordinates numerically referenced the degree of fibrosis in a manner that in each case was consistent with the histologic evaluation, the laboratory values, and the clinical course. CONCLUSIONS: Numeric, objective referencing of the degree of fibrosis in routine liver biopsy sections, based on the PNC system, is technically possible.

Functional residual capacity and pulmonary mechanics in premature infants receiving a 12-day dexamethasone course.

The objective of this paper is to determine the effects of a 12-day dexamethasone course of the pulmonary function of preterm infants. The design consisted of a consecutive sample of eligible patients, before-after trial. The Regional referral center neonatal ICU was the setting. The patients were 13 preterm infants, 545-1315 g, requiring mechanical ventilation. The following was used: Intravenous dexamethasone for a 12-day tapering course beginning at 0.5 mg/kg every 12 hr. Main outcome measures were as follows: Measurements of functional residual capacity (FRC), compliance, resistance, arterial blood gases and alveolar-arterial differences, level of ventilatory assistance, weight, length. All measures of pulmonary function demonstrated significant improvement by Day 12 of treatment. Most improvement occurred in the first 6 days of treatment, in association with increased lung volume.

A program to reduce discharge delays in a neonatal intensive care unit.

Our hypothesis was that a program designed to identify the causes of discharge delays would reduce the length of stay in our neonatal intensive care unit. We reviewed every admission from January, 1994, to December, 1995. A discharge delay was defined as any delay not related to illness after the infant was cleared for release. Discharge delays were divided into the following categories: primary healthcare team, organizational, discharge planning, family, monitor related, and other. Potential discharge delays were identified daily according to established criteria. Actual discharge delays were reviewed monthly at a staff meeting attended by representatives of a multidisciplinary team. We identified 116 discharge delays, which accounted for 480 patient days. Eighty-three discharge delays accounted for 302 patient days in 1994, and 33 discharge delays for 178 patient days in 1995. Discharge delays ranged from 1 to 34 days, with an average of 4.1 days added per patient. Infants with discharge delays had a case mix index of 9.32. The average case mix index for the neonatal intensive care unit was 6.25 during 1994 and 5.18 during 1995, an average of 5.71 for the review period. Forty-four percent of infants who had discharge delays had private insurance, 55% had Medicaid, and 1% had self-payment arrangements. Eighty-eight of 116 discharge delays were caused by circumstances beyond the control of the primary care team. An additional 25 of 116 discharge delays were the result of our policy requiring 48 hours free of apnea-bradycardia alarms before discharge. Discharge delays for 1994 cost $226,298 ($749/day). For 1995, discharge delays cost $41,553 ($233/day) for a total cost of $262,431. Total savings in 1995 versus 1994 was $184,745 ($516/day). Despite the low birth weight and relatively severe illnesses of the infants, we believe that a focused team approach and monitoring for potential discharge delays can result in considerable reduction in hospital stay and cost.

Specific cognitive abilities in 2-year-old children with subependymal and mild intraventricular hemorrhage.

Subependymal and mild intraventricular hemorrhages (S/IVH) are likely to affect the subcortical and frontal cortex regions of the brain in premature infants. Damage to the subcortical and frontal areas has been associated with poorer performance in certain abilities, including visual attention, memory for location, and ability to change response set. This study investigated whether S/IVH, occurring at birth, affect these abilities in young children. Two-year-old premature children with S/ IVH, premature children with normal neonatal head ultrasound scans, and full term children with normal births were evaluated on a series of tasks. These tasks were a habituation/novelty preference task (visual attention), Piaget's invisible displacement task (memory for location), an object discrimination reversal task (ability to change response set), and the Bayley Scales of Infant Development (traditional infant test). Premature children with hemorrhage performed significantly less well on the task of ability to remember the last location of a hidden object and on the task of ability to reverse response set. Both groups of premature children performed.

Effects of increased red cell mass on subclinical tissue acidosis in hyaline membrane disease.

AIM: To determine whether there are subclinical deficits in oxygen delivery in ventilated premature neonates. METHOD: Ventilated premature neonates weighing less than 1500 g, who were transfused for anaemia or who were given colloids for clotting abnormalities (or oedema), were haemodynamically monitored during the first week of life. Calf muscle surface pH (pH) was measured in conjunction with peripheral limb blood flow by occlusion plethysmography. RESULTS: Packed red blood cell transfusions corrected a subclinical regional tissue acidosis (low tpH) without affecting arterial pH or limb blood flow. This observation also correlated with an increase in regional oxygen delivery. The data were also suggestive of a pattern of pathological, supply dependent, oxygen delivery and are similar to other observations made in adults with adult respiratory distress syndrome. CONCLUSIONS: Packed red blood cells increase regional oxygen delivery and tissue surface pH. In contrast, colloid infusion provided no substantial cardiovascular or metabolic benefit to these patients and should be avoided when oxygen delivery is at issue and when there may be leaky pulmonary capillaries.

Computed radiography in neonatal and pediatric intensive care units: a comparison of 2.5 K x 2 K soft-copy images vs digital hard-copy film.

OBJECTIVE: The goal of the study was to determine whether soft-copy images on high-resolution monitors (2.5 K x 2 K) are suitable for primary interpretation of images from pediatric and neonatal intensive care units. The hypotheses were that hard and soft images yield similar diagnostic information, and that both residents and faculty radiologists can use monitors effectively. Previous reports have produced conflicting results; the need for larger sample sizes has been emphasized. MATERIALS AND METHODS: One thousand one hundred and four images produced by computed radiography using the Kodak Ectascan Imagelink system were prospectively analyzed by two pediatric radiologists, one reading hard copy and the other soft copy of the same images. Bias was controlled by equal distribution of modalities between observers and by daily alternation of modality. Hard- and soft-copy observations of presence or absence of nine specific tubes and nine specific diagnostic findings were compared. Interobserver differences between pediatric radiologists and radiology residents were studied on additional images. The kappa statistic was used to evaluate the level of agreement for all observations. RESULTS: There was excellent agreement between hard and soft copy interpretation for each tube and diagnostic finding (kappa values 0.93-1.0) and excellent interobserver agreement between two pediatric radiologists (kappa values 0.84-1.0). The level of agreement between radiology residents and pediatric radiologist was excellent for the most objective findings. All results were statistically significant (p < 0.001). CONCLUSION: High resolution soft-copy images are suitable for primary interpretation in patients in pediatric and neonatal intensive care units.

Voiding after neonatal circumcision.

OBJECTIVE: To determine whether it is necessary to delay discharge of newly circumcised male neonates to observe voiding. SUBJECTS AND METHODS: A prospective study was conducted in 1992 and 1993 of 51 healthy male, newly circumcised neonates between 0 and 10 days of age. The neonates were observed for the time of first voiding after circumcision was performed. RESULTS: All neonates voided after circumcision at a mean age of 5.3 +/- 2.5 hours, and there were no complications noted in the study population. CONCLUSION: Healthy male infants who are circumcised without obvious complications can be expected to void, and it is unnecessary to delay hospital discharge to make this observation.

Glutathione metabolism in newborns: evidence for glutathione deficiency in plasma, bronchoalveolar lavage fluid, and lymphocytes in prematures.

Respiratory distress in premature newborns is associated with deficiency of surfactant in the bronchoalveolar lining fluid; this may be influenced by a local deficiency of antioxidants. Severe L-buthionine-S,R-sulfoximine-induced depletion of glutathione (GSH, a major antioxidant) in rodents is associated with lung type 2 cell lamellar body damage and decreased concentrations in lung and bronchoalveolar lavage fluid (BALF) of phosphatidyl choline (a major component of surfactant). At birth, prematurely born newborns (30-34 weeks) had lower peripheral venous plasma GSH concentrations than term (> 36 weeks) babies; these levels decreased further with increasing prematurity (< 27 weeks, with respiratory distress). On day 2, the peripheral venous plasma GSH concentrations reached a nadir, and the lowest levels were found in the most premature newborns. Lymphocyte GSH concentrations were lowest on day 2 and day 7, and in prematures (< 27 weeks, with respiratory distress) remained below adult lymphocyte GSH levels for at least 4 weeks. At birth, prematures (< 27 weeks, with respiratory distress) had a central plasma arterio-venous (A-V) GSH gradient across the lung (an estimate of lung uptake of GSH) of 0.72 +/- 0.15 (mean +/- SD) mumol/L; on day 2, the A-V gradient did not change significantly (0.49 +/- 0.09 mumol/L). At birth, these prematures had markedly decreased BALF GSH concentrations (compared with adult levels), and they were not significantly changed during the first 4 weeks of life. These results suggest that GSH deficiency is present in prematures and that it increases with the degree of prematurity. At birth, GSH deficiency will compromise the lungs' defense against oxidative stress injury. Oxidative stress is likely to increase if hyperoxic treatment is given for respiratory distress in these infants.

L-2-oxothiazolidine-4-carboxylate, a cysteine precursor, stimulates growth and normalizes tissue glutathione concentrations in rats fed a sulfur amino acid-deficient diet.

The efficiency of L-2-oxothiazolidine-4-carboxylate, a cysteine precursor, in stimulating glutathione synthesis and growth was evaluated in growing rats. Animals were fed a sulfur amino acid-deficient diet (0.25% L-methionine and no cysteine) supplemented with L-2-oxothiazolidine-4-carboxylate (0.35%) for 3 wk and compared with age-matched animals receiving the sulfur amino acid-deficient diet alone. Rats fed the sulfur amino acid-deficient diet had lower glutathione concentrations in bronchoalveolar lining fluid, lung, lymphocytes, and liver than rats fed a sulfur amino acid-deficient diet supplemented with L-2-oxothiazolidine-4-carboxylate. Rats fed the supplemented diet had normal tissue and bronchoalveolar lining fluid glutathione levels. Central venous plasma glutathione concentrations, mostly reflecting liver excretion, were less affected by L-2-oxothiazolidine-4-carboxylate supplementation. Rats fed L-2-oxothiazolidine-4-carboxylate supplementation had normal weight gain compared with a much lower weight gain in animals fed the sulfur amino acid-deficient diet alone. Thus, L-2-oxothiazolidine-4-carboxylate increased tissue glutathione concentrations and stimulated growth in rats. The lung glutathione status of the rats was reflected by glutathione concentrations in lymphocytes and the bronchoalveolar lining fluid, but not by the central venous plasma glutathione concentrations.

Ventilation-perfusion relationships in preterm infants after surfactant treatment.

Arterial-alveolar partial pressure differences for oxygen, carbon dioxide, and nitrogen were measured before and after surfactant replacement therapy on 15 occasions in 14 ventilator-dependent preterm infants with hyaline membrane disease (HMD). Eight treatments resulted in a significant improvement in arterial partial pressure of oxygen (PaO2) 2 hr after treatment; 7 did not. Neither group showed any significant change in arterial-alveolar partial pressure differences for oxygen, nitrogen, and carbon dioxide. This observation suggests that if surfactant replacement therapy produces an improvement in PaO2 it does so by recruitment of atelectatic alveoli with a balanced ventilation/perfusion ratio rather than by redistribution of ventilation within already ventilated alveoli.

Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency.

A 45-month-old girl with 5-oxoprolinuria (pyroglutamic aciduria), hemolysis, and marked glutathione depletion caused by deficiency of glutathione synthetase was followed before and during treatment with ascorbate or N-acetylcysteine. High doses of ascorbate (0.7 mmol/kg per day) or N-acetylcysteine (6 mmol/kg per day) were given for 1 to 2 weeks without any obvious deleterious side effects. Ascorbate markedly increased lymphocyte (4-fold) and plasma (8-fold) levels of glutathione. N-Acetylcysteine also increased lymphocyte (3.5-fold) and plasma (6-fold) levels of glutathione. After these treatments were discontinued, lymphocyte and plasma glutathione levels decreased rapidly to pretreatment levels. Ascorbate treatment was extended for 1 year, and lymphocyte (4-fold) and plasma (2- to 5-fold) glutathione levels remained elevated above baseline. In parallel, the hematocrit increased from 25.4% to 32.6%, and the reticulocyte count decreased from 11% to 4%. The results demonstrate that ascorbate and N-acetylcysteine can decrease erythrocyte turnover in patients with hereditary glutathione deficiency by increasing glutathione levels.

Control of inspiratory timing in newborn infants.

In order to determine if inspiratory time in preterm infants was influenced by lung volume, two studies were carried out. In the first investigation, carbon dioxide was used to stimulate tidal volume to a level three to six times normal. The anticipated decrease in inspiratory time at increased tidal volumes was not found. These preterm infants behaved in a similar fashion to vagotomized animals studied in the same way by Clark and von Euler. In the second investigation, Hering-Breuer activity was measured in relation to lung volume changes occurring with growth, measured in a body plethysmograph. Although thoracic gas volume correlated well with age and weight, inspiratory slowing with airway occlusion was found to be independent of both age and lung volume. These investigations suggest that neurologic factors have a significant influence on the inspiratory time in newborn human infants.

Characteristics associated with successful weaning in ventilator-dependent preterm infants.

Eighteen ventilator-dependent preterm infants with hyaline membrane disease were studied for 24 hours before and after an attempt at extubation. All were treated with theophylline prior to weaning and achieved average levels of 8.9 +/- 1.7 micrograms/ml (49 +/- 9 mumol/liter) in 13 successfully weaned infants and 8.4 +/- 1.1 micrograms/ml (47 +/- 6 mumol/liter) in 5 infants not extubated, p > 0.05. Infants successfully weaned were significantly (p < 0.01) older, more mature (29 +/- 1 versus 26 +/- 2 weeks' gestational age) and heavier (1107 +/- 236 versus 1016 +/- 256 gm) than infants not successfully extubated. Infants successfully weaned differed only in developing a greater maximal inspiratory force (33.8 +/- 12.3 versus 23.3 +/- 15.0 cm H2O) and higher compliance (1.1 +/- 0.3 versus 0.7 +/- 0.3) during the preweaning treatment period. These results indicate that maturity and size play a significant role in the ability to wean a preterm infant from the ventilator successfully, that maximal inspiratory force and compliance are higher in preterm infants who can be successfully extubated, and that methylxanthines do not uniformly improve pulmonary function in all potentially extubatable preterm infants.

Ascorbic acid prevents oxidative stress in glutathione-deficient mice: effects on lung type 2 cell lamellar bodies, lung surfactant, and skeletal muscle.

Glutathione deficiency in adult mice leads to lung type 2 cell lamellar body and mitochondrial damage; as reported here, these effects are associated with marked decrease of the levels of phosphatidylcholine (the main component of lung surfactant) in the lung and the bronchoalveolar lining fluid. Severe mitochondrial damage was also found in skeletal muscle. Treatment with ascorbate (1-2 mmol per kg of body weight per day), which led to greatly increased (approximately 2-fold) levels of lung and muscle mitochondrial glutathione, prevented damage to lamellar bodies and mitochondria as well as the decline of phosphatidylcholine levels in lung and alveolar lining fluid. The findings indicate that glutathione deficiency leads to depletion of lung surfactant and that this can be prevented with ascorbate. Administration of ascorbate spares glutathione and prevents cellular damage. Lamellar body degeneration in glutathione deficiency appears to be associated with oxidative damage to the perilamellar membrane, which contains the enzymes required for phosphatidylcholine synthesis. It is notable that although severe glutathione deficiency is lethal to newborn rats, which apparently do not synthesize ascorbate, adult mice are better able to survive such a deficiency because they can synthesize ascorbate. The present studies, which suggest that high doses of ascorbate may be of therapeutic value, emphasize that ascorbate and glutathione have actions in common and that they function together in a physiologically significant antioxidant system.

Hand preference, prematurity and developmental outcome at school age.

Information was obtained on the hand preference of 88 premature and 80 matched full-term children at 7-8 years old. These children were also evaluated for neurologic status, IQ, attention-deficit hyperactivity disorder, and learning disabilities. Although the difference on hand preference was not significant, 12% more of the premature children than the full-term children were left- or mixed-handed. Results showed that, among premature children, there is an association between non-right-handedness and cognitive and behavioral deficits and that left-handed children show relative clumsiness with the non-preferred hand.

Educational status and school-related abilities of very low birth weight premature children.

Eighty-eight premature children with birth weights less than or equal to 1500 g were evaluated at ages between 7 and 8 years old to determine their academic status in comparison with those of a matched full-term group. Results showed that a much higher proportion of the premature children required special educational interventions (48%) than either the full-term children (15%) or the New York State public elementary school population (10%). More than half of the premature children who received educational intervention were neurologically impaired or had below normal intelligence. The entire group of premature children differed significantly from the matched full-term group on IQ score and on tests of verbal ability, school achievement, and auditory memory. Lower socioeconomic status children performed significantly less well on each type of these measures and on a measure of attention than children of the higher socioeconomic status group. There was an interaction of prematurity and social class on Full Scale IQ, verbal tests, academic achievement, and attention, with lower socioeconomic status premature children scoring lowest on these measures. The subset of premature children normal in both IQ and neurologic status did not differ significantly from a matched normal full-term group on any cognitive measures other than arithmetic ability, but they continued to have significantly lower academic achievement scores.

Inhibition of glutathione synthesis in the newborn rat: a model for endogenously produced oxidative stress.

A model for oxidative stress is described in which glutathione (GSH) synthesis is selectively blocked in newborn rats by administration of L-buthionine-(S,R)-sulfoximine (BSO). In this model, the normal endogenous physiological formation of reactive oxygen species is largely unopposed, and therefore oxidative tissue damage occurs; because GSH is used for reduction of dehydroascorbate, tissue ascorbate levels decrease. In lung there are decreased numbers of lamellar bodies and decrease of intraalveolar surfactant. Proximal renal tubular, hepatic, and brain damage also occur. A diastereoisomer of BSO that does not inhibit GSH synthesis, L-buthionine-R-sulfoximine, does not produce toxicity; this control experiment renders it unlikely that the observed effects of BSO are produced by the sulfoximine moiety itself. There is correlation between the decrease of mitochondrial GSH levels and mitochondrial and cell damage. Oxidative stress as evaluated by mitochondrial damage and mortality can be prevented by treatment with GSH esters or ascorbate. There is apparent linkage between the antioxidant actions of GSH and ascorbate. This model, which may readily be applied to evaluation of the efficacy of other compounds in preventing oxidative stress, offers an approach to study of other effects of GSH deficiency (e.g., on lipid metabolism, hematopoiesis), and closely resembles oxidative stress that occurs in certain human newborns and in other clinical states.

Glutathione deficiency leads to mitochondrial damage in brain.

Glutathione deficiency induced in newborn rats by giving buthionine sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase, led to markedly decreased cerebral cortex glutathione levels and striking enlargement and degeneration of the mitochondria. These effects were prevented by giving glutathione monoethyl ester, which relieved the glutathione deficiency, but such effects were not prevented by giving glutathione, indicating that glutathione is not appreciably taken up by the cerebral cortex. Some of the oxygen used by mitochondria is known to be converted to hydrogen peroxide. We suggest that in glutathione deficiency, hydrogen peroxide accumulates and damages mitochondria. Glutathione, thus, has an essential function in mitochondria under normal physiological conditions. Observations on turnover and utilization of brain glutathione in newborn, preweaning, and adult rats show that (i) some glutathione turns over rapidly (t 1/2, approximately 30 min in adults, approximately 8 min in newborns), (ii) several pools of glutathione probably exist, and (iii) brain utilizes plasma glutathione, probably by gamma-glutamyl transpeptidase-initiated pathways that account for some, but not all, of the turnover; thus, there is recovery or transport of cysteine moieties. These studies provide an animal model for the human diseases involving glutathione deficiency and are relevant to oxidative phenomena that occur in the newborn.