Edema, hypoproteinemia, and zinc deficiency in low-birth-weight infants.

Three premature infants with zinc deficiency who had an unusual presentation with generalized edema and hypoproteinemia between 5 and 9 weeks of age are described. The infants were fed their own mother's milk, supplemented with a proprietary formula after the first 2 to 3 weeks of life. None of the infants had diarrhea, liver disease, or urinary protein loss. Treatment with oral zinc supplements led to rapid resolution of the edema, with an increase in values for serum proteins, alkaline phosphatase, and zinc. There was no recurrence of symptoms following discontinuation of zinc therapy 1 month later. At 1-year follow-up, all infants were doing well and had normal growth and development. As zinc plays a critical role in nucleic acid and protein synthesis, it is postulated that dietary zinc deficiency in the phase of rapid postnatal growth precipitated edema and hypoproteinemia in these infants. Zinc deficiency should be included in the list of causes of generalized edema in the low-birth-weight infant.

Metabolic fuel and hormone responses to fasting in newborn infants.

To examine why newborn infants frequently cannot maintain adequate levels of plasma glucose in the interval between delivery and the time they are first fed, circulating metabolic fuel and regulatory hormone concentrations were determined in 44 healthy infants at the end of an eight-hour postnatal fast. Plasma glucose fell below 40 mg/100 ml prior to eight hours in four of 24 term-appropriate-for-gestational-age (AGA), two of nine preterm-AGA, five of six term-small-for-gestational-age (SGA), and three of five preterm-SGA infants. Fuel and hormone patterns in the premature and SGA infants were not different from those found in term-AGA infants. Results in these neonates differed in two areas from the response to fasting seen later in life. In fasted term-AGA infants, ketones were low (beta-hydroxybutyrate 0.29 +/- 0.04 mM/liter) despite elevated concentrations of fatty acid precursors (1.4 +/- 0.07 mM/liter), and the group of infants studied failed to demonstrate the increase in plasma ketones with lower glucose levels (r = ".23, P = .07) which is found in older children. Levels of glucose precursors were two to three times higher in term-AGA infants (lactate 2.9 +/- 0.2 mM/liter; alanine 0.48 +/- 0.02 mM/liter) than levels found beyond the neonatal period and, in contrast to older children and adults, were not diminished in infants with lower plasma glucose (lactate, r = -.28, P less than .035; alanine, r = -33, P less than .02). These differences between the responses to postnatal fasting and those seen beyond the neonatal period suggest that the capacity for both hepatic ketone synthesis and gluconeogenesis is not fully developed at birth.

Follow-up studies of very low birth weight infants (1,250 grams or less) born and treated within a perinatal center.

The growth and development of inborn very low birth weight infants was evaluated in 50 of 60 survivors from 132 babies weighing less than or equal to 1,250 gm born July 1974 to December 1977. Mean +/- SE birth weight and gestation was 1,066 +/- 19.3 gm and 29.5 +/- 0.3 weeks, respectively, with 13 infants small-for-gestational age. Of the survivors, 26% weighed less than or equal to 1,000 gm. Male to female ratio was 1:1.4. Apgar scores less than or equal to 5 at five minutes occurred in 16% of the infants. Respiratory distress syndrome occurred in 56%, but only 10% (5/50) required mechanical ventilation. At 1 year, 46% small for gestational age (SGA) and 8% appropriate for gestational age (AGA) infants were less than the third percentile for weight. Major neurologic abnormality occurred in three infants (6%), one of whom is also blind. Grade V retrolental fibroplasia occurred in two others. Severe developmental delay (development quotient < 80, Gesell) occurred in these five infants and two other neurologically normal babies. Of 15 infants weighing less than or equal to 1,000 gm, two had major handicaps. Eight percent of the AGA infants and 30% of the SGA infants had major handicaps. These data indicate that infants born and treated in a perinatal center have a decreased incidence of asphyxia and severe respiratory distress syndrome and that the incidence of major handicaps is reduced, especially in the appropriate for gestational age baby.

Retrolental fibroplasia and blood transfusion in very low-birth-weight infants.

The relative contribution of transfusions of adult blood to the development of retrolental fibroplasia (RLF) in very low-birth-weight infants was examined. Five years of experience with the expanded use of replacement and exchange transfusions in 90 infants with birth weight less than or equal to 1,250 gm was reviewed. Twenty percent of the infants developed cicatricial RLF. Exchange transfusion was not related to development of cicatricial RLF. The incidence of RLF in infants receiving greater or equal to 130 ml of packed red blood cells per kilogram of birth weight as replacement blood transfusion (RBT) was significantly higher (42.9%) than that in infants receiving 61 to 131 ml of packed red blood cells per kilogram (15.4%) and infants receiving less than or equal to 60 ml of packed red blood cells per kilogram (0%), P less than .001. The need for RBT, however, was strongly correlated (r = .85, P less than .001) with increasing duration of O2 therapy. When O2 therapy was controlled for, the association between RBT and RLF did not achieve statistical significance (P = .07). The association between RBT and RLF remained significant when adjusted for duration of therapy in fractional inspired oxygen (FIO2) greater than 0.4. Further detailed studies of large numbers of susceptible infants are warranted to assess the magnitude of the contribution of transfusions of adult blood to development of RLF.

Alteration of brain cell membrane function following cocaine exposure in the fetal guinea pig.

The effect of cocaine on brain cell membrane structure and function was studied in the fetal guinea pig. We tested the hypothesis that cocaine, a potent vasoconstrictor, would result in brain cell membrane dysfunction as determined by altered activity of Na+,K(+)-ATPase and the appearance of products of membrane lipid peroxidation (conjugated dienes (CD) and fluorescent compounds (FC)). A total of 14 pregnant guinea pigs were studied at term (60 days). One hour prior to delivery, the pregnant guinea pigs were divided into 3 groups as follows: cocaine, 30 mg/kg i.p., saline placebo i.p., or 7% FiO2 for 1 h. Following cocaine, brain Na+,K(+)-ATPase activity decreased (mean +/- S.D., 25.6 +/- 9.2 vs. 54.6 +/- 3.4 mumol Pi/mg protein/h, cocaine vs. control, respectively, P < 0.01) and was similar to the hypoxia group (21.9 +/- 2.8 mumol Pi/mg protein/h). The products of lipid peroxidation did not change significantly following cocaine whereas hypoxia resulted in a rise in CD from 0 to 0.175 +/- 0.015 mumol/g brain, control vs. hypoxia, (P < 0.01), and FC from 1.13 +/- 0.15 to 1.88 +/- 0.13 micrograms quinine sulfate/g brain, control vs. hypoxia, (P < 0.01). These data show that acute fetal cocaine exposure, unlike hypoxia alone, results in a significant decrease in Na+,(K+)-ATPase activity without a significant increase in the products of lipid peroxidation, suggesting the mechanism by which cocaine affects brain cell membrane integrity is distinct from hypoxia. Inhibition of the enzyme activity may be due to a direct action of cocaine on the enzyme or due to enzyme regulation by cocaine-induced alterations in neurotransmitters.

Sequential pulmonary function measurements in very low-birth weight infants during the first week of life.

Sequential lung function was measured in 12 very low-birth weight infants (less than or equal to 1,250 g) within 14 hours of birth, and at daily intervals thereafter for the first week of life, using an esophageal balloon and pneumotachograph system. All infants were clinically free of respiratory distress syndrome and radiographically showed no evidence of atelectasis or pulmonary edema. The alveolar-arterial oxygen tension gradient was high at birth and remained elevated over the period during which arterial blood gases were monitored. Increases of lung compliance and tidal volume between the first day and the end of the first week of life were not significant. Day-to-day determinations of lung compliance revealed an individual and group variability without a definite pattern. Lung resistance measurements indicated no clear trend for the group as a whole, but inspiratory resistance was generally lower than expiratory resistance. Possible causes, in addition to technical factors, that may account for the variability in the pulmonary mechanics of these small infants include an instability of lung volume and uneven distribution of pleural pressure due to chest wall distortion, differences in sleep-state, and alteration in the distribution of body fluids, resulting in a change in lung water. Any or all of these mechanisms may result in an unstable lung, even in an apparently clinically stable very low-birth weight infant.

Liver disease associated with pregnancy.

Pregnancy is associated with altered liver function, particularly in serum enzymes. Anabolic steroids are responsible to some degree in mediating the physiologic and biochemical changes that occur during an uncomplicated pregnancy. However, several liver disorders are unique to pregnancy and include intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, and hepatic dysfunction associated with pre-eclampsia and eclampsia. It is imperative for the clinician to diagnose these liver disorders in a timely manner and to institute appropriate management as maternal and fetal outcome are affected in an adverse manner if these conditions are left untreated.

Coagulase-negative Staphylococcus bacteremia--a rising threat in the newborn infant.

Based on a three year surveillance in the neonatal intensive and transitional care nurseries (NICU) at the Hospital of the University of Pennsylvania (HUP), an analysis of all cases of nosocomial bacteremia was made. From January 1982 to September 1984, a total of 57 nosocomial bacteremic episodes were identified. This gave a rate of 3.6 episodes per 100 NICU admissions or 6.5 per 1000 live hospital births. While coagulase-negative staphylococci (CNS) accounted for approximately 40 percent of all positive blood cultures, it was responsible for 73 and 66 percent of the nosocomial bacteremias in 1982 and 1983, respectively. In 1984, coagulase-negative staphylococcus was the responsible pathogen for 92 percent of all nosocomial bacteremic episodes. Of 139 infants weighing less than or equal to 1250 g at birth, 30 (22 percent) developed CNS bacteremia. The risk of coagulase-negative staphylococcus bacteremia was associated with low birth weight, respiratory distress, prolonged hyperalimentation, and multiple supportive measures. Infants were treated with vancomycin hydrochloride, as most of the CNS were resistant to methicillin and/or gentamicin. There were no deaths related to coagulase-negative staphylococcal septicemia.

The effect of early feeding on plasma glucose levels in SGA infants.

Plasma glucose levels were measured during the first day of life in 24 small-for-gestational-age (SGA) infants who began formula feedings within two hours of birth. In contrast to the high incidence of low blood sugar seen previously in fasted SGA infants, no infant had a plasma glucose below 30 mg/dl; after the first feeding, no values below 40 mg/dl occurred. Mean plasma glucose levels were lower in infants born to mothers with preeclampsia (57.2 +/- 2 vs 69.7 +/- 2.3 mg/dl, p less than .005). The results indicate that hypoglycemia (plasma glucose less than 40 mg/dl) can be easily avoided in SGA infants simply by providing adequate calories without delay after delivery.

Respiratory complications of metatropic dwarfism.

Two infants with clinical and radiologic features of metatropic dwarfism presented in the neonatal period with episodes of cyanosis. Diagnostic studies to determine the etiology of these spells, including electrocardiogram, electroencephalogram, arterial blood gases, and metabolic and sepsis studies, were unremarkable. Chest roentgenograms revealed the characteristic long, narrow thoracic cage with no evidence of parenchymal disease. Cervical spine stability evaluation, pulmonary function studies, and chest impedance monitoring with qualitative air flow thermistor studies and transcutaneous oxygen monitoring were carried out. Both patients demonstrated a significant increase in resistance of the respiratory system following passive maneuvering of the head from a neutral position, suggestive of hypopharyngeal air flow obstruction. Obstructive sleep apnea resulting in cyanosis was documented in both patients. All other studies failed to yield a cause for the episodes of cyanosis. Our investigation failed to alter the clinical course which resulted in respiratory arrest and death by 7 months of age. A table is presented for the differentiation of skeletal dysplasias presenting in the perinatal period.

Response of the newborn cerebral circulation to cocaine.

Cocaine abuse by pregnant women is often associated with neurological injury in the newborn. To explore a vascular-related mechanism of injury, we investigated the effect of cocaine on the cerebral circulation in newborn pigs. During normoxic conditions, cocaine administration (1.5 mg/kg i.v.), resulting in peak plasma cocaine levels on the order of 10(-6) M, decreased cerebral blood flow (CBF) by 14%, as measured by the tracer microsphere method. To elicit the mechanisms by which cocaine decreased CBF, closed cranial windows were placed and the diameter of pial arterioles was measured by intravital microscopy while cocaine (10(-6) M) was applied onto the cortical surface. Topically applied cocaine decreased pial arteriolar diameter by 9%. Vasoconstriction induced by topically applied cocaine was blocked by tetrodotoxin (10(-7) M, Na+ channel blocker), whereas phentolamine (10(-5) M, noradrenergic receptor blocker) had no effect on the arteriolar response to cocaine, which suggested that cocaine effected constriction by an anesthetic and not a sympathomimetic mechanism. To evaluate this hypothesis further, cerebral vessels in the right hemibrain were sympathetically denervated while those in the left hemibrain remained innervated. During normoxia, cocaine (1.5 mg/kg i.v.) decreased CBF equally in both hemibrains, confirming the non-sympathomimetic mechanism. During asphyxia, cocaine administration attenuated cerebral hyperemia in both hemibrains, but in innervated more than in denervated, indicating that anesthetic and sympathomimetic vasoconstriction occurred during asphyxia. We conclude that cocaine constricts the immature cerebrovasculature and decreases CBF by an anesthetic mechanism during normoxic conditions and by both sympathomimetic and anesthetic mechanisms during asphyxia.

Comparison of reflex modification procedures and auditory brainstem response in high-risk neonates.

This study compared the results of reflex modification (RM)--an objective technique for assessing brainstem sensorineural processing--with those of auditory brainstem response (ABR) for a group of high-risk infants at comparable postconceptional ages. For the RM procedure, an eyeblink-eliciting tap to the glabella was presented either alone or accompanied by a brief 90dB SPL tone. 37 high-risk infants were tested with both RM and ABR at a mean postconceptional age of 37.3 weeks. Seven had an increased brainstem conduction time ('failed ABR') and eight did not exhibit significant reflex augmentation ('failed RM'), seven of whom also failed the ABR. These data provide evidence that sensory stimuli which affect the neural mechanisms responsible for the organization of the startle response and auditory processing share essential neural components.

Inhibition of the eyeblink reflex in the human infant.

In human adults the eyeblink elicited by a given stimulus can be inhibited if that stimulus is preceded by another stimulus at an appropriate lead interval. In the present work, pairs of eyeblink-eliciting stimuli separated by 300-1200 msec were presented to sleeping preterm and full-term infants as well as to adults. Preterm infants did not exhibit reliable inhibition at any interval. Full-term infants did so, but they required longer interstimulus intervals than were needed for inhibition in the adult subjects. Results imply that the neural systems that mediate reflex inhibition are functional at birth, but that they are relatively slow to act.

Reflex augmentation of a tap-elicited eyeblink: the effects of tone frequency and tap intensity.

The amplitude of the human eyeblink elicited by a mild tap between the eyebrows can be increased if a brief tone is presented simultaneously with the tap. In two experiments we examined how this reflex augmentation effect varies with changes in the frequency characteristics of the tone and with changes in the intensity of the tap. We also examined how these effects change in the course of development. For newborn infants and for adults, fixed intensity tones with frequencies of either 1, 2, or 4 kHz produced equivalent amounts of reflex augmentation. Furthermore, while blink amplitude was an increasing function of tap intensity in both populations, the amount of reflex augmentation engendered by a simultaneously presented tone was independent of the intensity of the tap.

The blink reflex: maturation and modification in the neonate.

The onset and development of the delayed blink response, elicited by a tap to the glabella, and its modification by an acoustic stimulus (tone), were studied longitudinally in 36 healthy preterm and 43 term infants. Blink amplitude increased with gestational age. By term postconceptional age, the responses of the preterm infants to tap alone, and to both tap and tone, were not significantly different from those of the term infants. These results suggest that neurological development, as reflected by the blink reflex and its modification, proceeds in an orderly, sequential fashion and that the mechanisms affecting these brainstem processes are not altered by environmental influences.

Ethanol, morphine and barbiturate alter the hemodynamic and cerebral response to cocaine in newborn pigs.

Newborns delivered to cocaine-abusing mothers are often exposed to other concurrently consumed illicit drugs, which may alter the hemodynamic and cerebral response to cocaine. This study examined the interaction of ethanol, morphine or barbiturate with cocaine on mean arterial pressure (MAP), cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in newborn pigs. CBF, CMRO2 and cerebral O2 extraction (CEO2) were measured before and 4 and 10 min after cocaine (1.5 mg/kg i.v.) was administered in piglets that were awake, or pretreated with morphine, ethanol or pentobarbital. In awake piglets, cocaine increased CMRO2 and CEO2 while it had no significant effect on CBF. Conversely, in morphine- and ethanol-pretreated piglets, cocaine decreased CMRO2, decreased CBF and had not effect on CEO2. In awake piglets, cocaine increased MAP, whereas in morphine- or ethanol-pretreated piglets, cocaine decreased MAP. In the pentobarbital group, cocaine had no effect. These data demonstrate that other drugs of abuse alter the hemodynamic and cerebral effects of cocaine in the immature animal and may contribute to the central nervous system abnormalities in 'crack babies'.

Altered brainstem sensory processing as assessed by reflex modification procedures in infants at risk for apnea.

Reflex modification procedures were used to test sensory processing in premature infants to examine the relationship between respiratory abnormalities and brainstem neuronal function. A total of 73 premature infants at risk for apnea and/or infants receiving methylxanthine therapy was given a 12-h pneumocardiogram and reflex modification test at a comparable postconceptional age, before discharge. Reflex modification was tested using a controlled eyeblink-eliciting tap to the glabella presented either alone or with a 1 kHz 90-dB SPL tone. The amplitude of the glabellar tap eyeblink and acoustically modified blink were lower in infants discharged on cardiac/apnea monitors (n = 36) than in the unmonitored group (1.44 and 1.59 volts versus 2.15 and 2.39 V, p less than 0.005, respectively). At follow-up, 12 monitored infants had clinically significant apnea after discharge. The records of this subgroup of infants revealed a significantly lower augmentation of the glabellar eyeblink response when compared to all infants screened for respiratory abnormalities and to the other monitored babies (p less than 0.01). The data suggest that abnormalities of the ventilatory pattern and occurrence of clinical apnea in preterm infants may in some measure be related to acoustic sensory processing, implying an alteration of brainstem neuronal function and organization.

Reflex modification audiometry: assessment of acoustic sensory processing in the term neonate.

Behavioral and physiological work in animals and adult humans have established the sensitivity of various procedures and allowed delineation of the neuroanatomical pathways involved in sensory processing. Herein we used the glabellar reflex and reflex modification procedures to assess acoustic sensory processing capabilities in the term newborn infant. The eyeblink-eliciting device consisted of a miniature solenoid which could deliver a controlled tap. A photoreflective densitometer attached to a TDH-39 earphone assessed the eyeblinks. A total of 98 term infants was studied to determine how a response to a reflex-eliciting event (tap) was modified (either augmented or inhibited) by a mild exteroceptive stimulus (tone) which was presented at an appropriate lead interval. Ninety adult subjects were given identical testing procedures and their data were compared to that of the infants. The results of this study showed that newborn infants reliably exhibited an eyeblink response after a tap to the glabella. With fixed intensity tones, frequencies from 1 to 4 kHz produced equivalent amounts of reflex augmentation in infants and adult subjects. Blink amplitude increased as a function of increased tap and tone intensity in both infants and adults. State change was shown to affect the amplitude of the reflexive eyeblink, but not the augmentation effect. However, neonates failed to show inhibition to either acoustic lactile stimuli at an interstimulus interval that produced significant inhibition in the adult. These data indicate that reflex modification procedures provide an objective assessment of acoustic sensory processing in the term neonate.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and effect of cocaine on cerebral blood flow in the newborn.

The present study investigated the effect of cocaine (COC) on cerebral circulation (CBF) and oxidative metabolism (CMRO2) in the newborn piglet and aimed to relate pharmacokinetics of cocaine to cerebrovascular effects. COC decreased CBF and CMRO2 from 75 to 64 and 4.27 to 3.91 ml/min/100 g, respectively, at 4 min with reduced flow to all brain regions (p < 0.05) which returned to baseline by 10 min. COC was rapidly metabolized with a t1/2 of 43 min and peak plasma concentration of 1,172 ng/ml. Norcocaine (NOR) appeared in plasma and CSF within 3 min of cocaine administration and remained elevated for the duration of the study along with COC in the CSF. These data show that the timing of the peak plasma COC level is associated with maximal decreased CBF. Further, the stable elevated level of COC and NOR in the CSF suggests that biotransformation does not occur in the brain. As a result, accumulation of these drugs may occur in the brain with successive COC use and affect the developing CNS in a deleterious manner.