Once-daily gentamicin dosing in newborn infants.

OBJECTIVE: We developed a simplified gentamicin dosing protocol for all neonates using a loading dose and once-daily dosing that would have an equal or lower incidence of toxicity and an equal or improved effectiveness compared with a regimen with no loading dose that included use of divided daily dosing. METHODS: All neonatal intensive care unit patients with a postnatal age /=37 weeks; weight, >/=2500 g). One hundred percent of the initial and maintenance peak SDL in term protocol neonates were 5 to 12 micrograms/mL; compared with 84% of the initial and 61% of maintenance peak SDL in the term control group. One hundred percent of the initial and maintenance trough SDL were in the desired range of <2 micrograms/mL in term protocol neonates; compared with 70% of the initial and 94% of maintenance trough SDL in the term control group. No significant differences were found in any SDL in low birth weight neonates (gestational age <37 weeks or weight <2500 g and >1500 g) in the protocol compared with the control group. The very low birth weight (weight <1500 g) protocol neonates had a significantly higher mean initial trough SDL (2.3 +/- 0.7 micrograms/mL vs 1.5 +/- 0.6 micrograms/mL) and a lower incidence of initial trough SDL <2.0 micrograms/mL (30% vs 95%) than very low birth weight neonates in the control group. No differences were seen between groups in incidence of significant rise in serum creatinine or failure of hearing screen. CONCLUSION: A loading dose followed by once-daily dosing was shown to result in SDL in the safe and therapeutic range in all term neonates in this study. In low birth weight neonates, this regimen resulted in peak and trough SDL throughout therapy that were similar to those observed in the control group. Delaying the initiation of maintenance once-daily dosing until 36 to 48 hours after the loading dose would be expected to result in a higher incidence of initial trough SDL in target range for very low birth weight neonates.

Retrospective analysis of risks associated with an umbilical artery catheter system for continuous monitoring of arterial oxygen tension.

We reviewed retrospectively the incidence of complications encountered with two different umbilical artery catheters (UACs): a silicone-rubber end-hole catheter and an electrode-tipped, side-hole catheter for continuous, invasive monitoring of arterial oxygen tension (PaO2). During calendar year 1989, there were 457 admissions to the neonatal intensive care unit: 168 patients had placement of a UAC. Two of these were admitted only briefly for cardiac catheterization and were eliminated from analysis. One patient had both types of catheters placed sequentially. Thus the data on 166 patients with 51 PaO2 monitors and 116 silicone-rubber UACs were evaluated. The patients who had a PaO2 monitor UAC had a lower mean birth weight than those in the other group (1621 +/- 1043 gm vs 1972 +/- 1048 gm; p = 0.0473). The catheter life span was not different between the groups, with a range of 1 to 16 days for PaO2 monitors and 1 to 27 days for silicone-rubber UACs. Inability to withdraw blood, poor blood pressure tracing, or both conditions resulted in catheter removal for 5 of 51 PaO2 monitor UACs and 4 of 116 end-hole UACs. The incidence of these problems did not differ significantly between the two groups. There were no cases of thromboembolic complications in the patients who had a PaO2 monitor UAC, whereas two of the silicone-rubber UACs were removed because of perfusion problems in the lower limbs, which resolved with decannulation. We conclude that the use of the PaO2 monitor UAC allows for continuous, invasive monitoring of PaO2 without any significant increase in risk compared with that for the silicone-rubber end-hole UAC.

The Zavanelli maneuver for relief of abdominal dystocia associated with gastroschisis.

A patient with acute hydramnios and advanced preterm labor at 34 weeks was seen after gastroschisis had been diagnosed by second-trimester fetal ultrasonography. The fetus also had meconium peritonitis and acute ascites. The distended abdomen did not decompress spontaneously during the second stage of labor. Severe abdominal dystocia was resolved with the Zavanelli maneuver (cephalic replacement) and cesarean delivery. This is the first reported use of the Zavanelli maneuver for abdominal dystocia.

A modified newborn intensive care unit environment may shorten hospital stay.

Premature infants with birth weights from 1121 to 2000 gm were assigned randomly to two groups. Experimental group infants were placed on a microprocessor-controlled cradle that provided levels of motion and sound analogous to those of the third-trimester intrauterine environment. Periods of motion totaling 50% of the time were randomized on and off; motion speed was reduced 35% during a 12-hour night period. A uterine souffle sound was generated continuously but varied in pulse rate and volume with the motion and speed of the bed. Experimental group infants (n = 20) were placed on the cradle under a radiant warmer as soon as their condition was stable clinically. Control group infants (n = 18) were usually placed initially under a radiant warmer and transferred to an incubator when their condition was stable. Otherwise, both groups received standard newborn intensive care unit care. The mean length of hospital stay was significantly shorter for experimental group infants than for control group infants after controlling for gestational age and weight on entry to the study. Experimental group infants began nippling earlier and stopped requiring gavage feedings sooner. Experimental group infants had a decreased incidence of apnea. Blinded Brazelton Neonatal Behavioral Assessment Scale scores for the Orientation and Range of State cluster scales were significantly better for experimental group infants. A retrospective contrast group of preterm infants who met study criteria had an average length of stay similar to that of the control group infants. These data support the hypothesis that appropriate levels and kinds of stimulation may facilitate the maturation of preterm infants.

Experience with double-lumen umbilical venous catheters in the low-birth-weight neonate.

Reliable vascular access can be problematic in sick low-birth-weight neonates. Umbilical venous catheters are one form of vascular access that can be used in this population. A retrospective review of experience with umbilical venous catheters in our neonatal intensive care unit from January 1989 through December 1991 was conducted. This included 128 patients: 70 with single-lumen (Gesco Umbilicath II) and 58 with double-lumen (Becton-Dickinson Careflow) catheters. Birth weight, gestational age, catheter life span, complications, and number of punctures for peripheral intravenous lines were analyzed. The mean birth weight, gestational age, and catheter life span did not differ significantly between catheter types. The incidence of catheter-related sepsis did not differ significantly (two single-lumen, three double-lumen) and occurred only in neonates with a catheter life span greater than 10 days. The number of intravenous punctures was significantly decreased in those neonates with double-lumen umbilical venous catheters (p < 0.0001). We conclude that in sick low-birth-weight infants the use of double-lumen umbilical venous catheters entails no greater risk than the use of a single-lumen umbilical venous catheter and may reduce iatrogenic stress associated with the starting of peripheral intravenous lines.

Concomitant branching enzyme and phosphorylase deficiencies. An unusual glycogenosis with extensive neuronal polyglucosan storage.

A baby girl was born hypotonic and was respirator-dependent until death at 43 days of age. A muscle biopsy revealed PAS-positive, diastase-resistant sarcoplasmic inclusions with a vaguely fibrillar structure by electron microscopy. Biochemical studies at autopsy disclosed complete absence of branching enzyme in skeletal muscle and heart, and a deficiency of phosphorylase activity in skeletal muscle with a modest reduction in myocardium. Storage material was present in glia and perikarya of neurons, increasing in amount in the rostrocaudal direction, involving most severely the motor neurons in the brain stem and spinal cord, dorsal root ganglia and myenteric plexi. Inclusions were also present in most organs, especially liver and skeletal muscle. Ultrastructurally, the inclusions ranged from granular aggregates of membrane-bound material concentrated in the region of Golgi apparatus to large filamentous bodies similar to polyglucosan bodies. This baby differs from other patients with infantile glycogenosis IV by the severity and onset of symptoms at birth, involvement of neuronal perikarya and widespread extraneural deposits. The combined deficiencies of branching enzyme and phosphorylase may have accounted for the unique clinical and neuropathological findings.

Adhesion of percutaneously inserted Silastic central venous lines to the vein wall associated with Malassezia furfur infection.

Percutaneously inserted Silastic central venous catheters have been used for prolonged infusion of parenteral nutrition in neonates. Malassezia furfur infection has been associated with intravenous fat emulsions infused through central venous lines. In this paper, we report two premature infants whose Silastic catheters were adhered to the vein wall with associated M furfur infection.

Evidence for pituitary regulation of somatic growth, insulin-like growth factors-I and -II, and their binding proteins in the fetal rat.

We investigated pituitary regulation of late-gestation fetal growth in the spontaneous dwarf rat, a strain with an autosomal recessive mutation (gene symbol dr) in the growth hormone (GH) gene resulting in complete isolated GH deficiency. GH-normal/GH-deficient (Dr/dr) females were crossed with Dr/dr or dr/dr males, producing both GH-deficient and GH-normal fetuses within the same litter. Pups were killed within 3 h after birth to approximate the developmental state of a late-gestation fetus. The body weight of GH-deficient fetuses was inhibited by 14% in comparison to GH-normal animals, but tail length remained unaffected. The brain and lungs were the only organs whose growth appeared to be pituitary-independent. Other organs showed moderate pituitary dependence in proportion to body weight. Serum IGF-I and IGF-II were reduced by 73% and 52%, respectively, in the absence of GH. The major IGF-binding proteins (IGFBP) were analyzed by Western ligand blot. The predominant 26- to 30-kD IGFBP band normally seen in neonatal rat serum was greatly increased in GH-deficient sera, to 250% of GH-normal sera as measured by densitometry. However, addition of alpha-Hec 1 antibody to IGFBP-2, which has been used to identify IGFBP-2 as the major neonatal IGFBP, resulted in immunoprecipitation of only a small amount of the 26- to 30-kD band from the GH-deficient fetuses, suggesting the presence of an additional IGFBP. Northern analysis of GH-deficient livers did not reveal any visible increase in IGFBP-1, IGFBP-2, or IGFBP-4 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of continuous infusion of insulin-like growth factor I and II, alone and in combination with thyroxine or growth hormone, on the neonatal hypophysectomized rat.

In this study, we examined the effects of systemically administered insulin-like growth factor (IGF)-I and -II on growth of the hypophysectomized (Hx) neonatal rat. Neonatal Wistar rats were Hx or sham Hx on postnatal day (PND) 6 and implanted sc with Alzet pumps on PND 10. Recombinant human IGF-I or -II were infused between PND 10 and 18 at an average dose of 1.9 micrograms/g body weight (BW) per day. In addition, some groups received daily sc injections of recombinant human GH or thyroxine (T4) at 2.5 micrograms and 25 ng/g BW per day, respectively. Pups were sacrificed on PND 18 and serum IGF levels determined. Despite restoration of serum IGF-I levels to sham control values in the Hx pups infused with IGF-I, no significant increase in BW occurred, although some increase in individual organ growth was observed (spleen, kidney, lung). Similarly, administration of IGF-II proved ineffective as a growth promoter in the neonatal Hx rat. In contrast, GH alone stimulated BW gain (P less than 0.001). T4 proved most potent in increasing skeletal growth (50% increase over Hx controls, P less than 0.001), without increasing serum IGF-I or -II levels. IGF-I and GH were equally effective in promoting a small yet statistically significant (17% over Hx controls, P less than 0.05) increase in skeletal growth. A synergistic effect on BW was observed with combined administration of T4 plus IGF-I to the Hx pups (P less than 0.05). The effects of hormonal therapy on serum IGF binding proteins (IGFBPs) was assessed by Western ligand blots. Administration of IGF-I, but not GH, resulted in increased levels of IGFBP-3, the predominant IGFBP of the adult rat. We conclude that systemically administered IGFs in doses that result in normalization of serum levels are ineffective promoters of somatic growth in neonatal rats. While normalization of serum IGF-I levels does result in modest skeletal growth, selective organ growth and increased serum IGFBP-3, growth stimulation does not equal that seen with GH (body weight) or thyroid hormone (skeletal growth). Differences in IGFBP profiles fail to account for the increased potency of GH as a promoter of BW gain. Thus, our data do not support a major endocrine role for IGF-I or -II in neonatal growth, but are consistent with an autocrine/paracrine action of IGF in the mediation of neonatal mammalian growth.

The effects of thyroid hormone on insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) expression in the neonatal rat: prolonged high expression of IGFBP-2 in methimazole-induced congenital hypothyroidism.

In the rat a developmental switch in the serum insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) profile takes place during the first 3 postnatal weeks. The fetal expression pattern of high IGF-II and IGFBP-2 is replaced by the adult pattern of low levels of IGF-II and IGFBP-2 and high levels of IGF-I and IGFBP-3. The regulatory mechanisms mediating these changes are unknown, but may include perinatal changes in endocrine function. To study the effects of thyroid function and the perinatal thyroid secretory burst on IGF and IGFBP expression, we established a rat model of congenital hypothyroidism, leading to marked postnatal growth retardation during the perinatal period. The hypothyroid animals lacked the steep rise in serum IGF-I levels normally occurring during the third week of life, showing only a modest rise to approximately 50% of control levels. The pattern of serum IGF-II decline in hypothyroid animals was slightly different from that in controls, with lower IGF-II levels during the second week of life and a slower decline down to the very low final levels. The hypothyroid pups continued to express high levels of IGFBP-2 up to the age of 19 days, while the control animals, after a slow initial decline, showed an abrupt fall of IGFBP-2 serum levels during the third week of life. Liver IGFBP-2 mRNA levels reflected the serum changes, with elevated IGFBP-2 mRNA in hypothyroid animals. The expression of other IGFBPs did not differ from that in the control group. At the age of 18 days, serum GH levels in the hypothyroid animals were approximately one third of control GH levels, which suggests a role for GH as a possible mediator of thyroid hormone actions on the IGF system. The changes in growth parameters and in the IGF and IGFBP profile of hypothyroid pups could be abolished by thyroid hormone replacement from birth. We conclude that thyroid hormone is, directly or indirectly, essential for some of the neonatal changes in IGF and IGFBP profiles.

Pituitary regulation of postnatal small intestinal ontogeny in the rat: differential regulation of digestive hydrolase maturation by thyroxine and growth hormone.

During the third week of postnatal life, dramatic ontogenic changes occur in the morphology and enzymology of the small intestine of the infant rat, enabling the animal to make the transition from milk to solid food. To investigate the roles of T4 and GH in regulation of these changes, infant rats were hypophysectomized on day 6 of life by the transauricular technique. Hypophysectomy resulted in diminution of somatic and intestinal growth as well as abnormal maturation of the disaccharidases lactase, sucrase, and maltase when measured on day 25. Administration of either T4 or GH to hypophysectomized animals resulted in moderately increased intestinal growth, while complete restoration of small intestinal growth resulted from administration of the combination of both hormones. Although T4, GH, or the combination of hormones reduced lactase activities, T4 alone produced normal maturation of sucrase and maltase. Neither hypophysectomy nor hormone replacement affected aminooligopeptidase. The molecular structure of lactase, analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, was not altered to a major degree in hypophysectomized animals or animals that received hormone replacement, but minor alterations were evident in sucrase structure in hypophysectomy. These studies indicate that 1) T4 and GH actively participate in postnatal regulation of small intestinal ontogeny; 2) thyroid hormones act directly on developing intestinal tissues to independently produce the normal maturation of the disaccharidases by mechanisms that are not likely to involve alterations in processing of the enzyme-protein; and 3) maturation of aminooligopeptidase is not regulated by pituitary hormones, in distinct contrast to the disaccharidases.

Ontogeny of pituitary regulation of growth in the developing rat: comparison of effects of hypophysectomy and hormone replacement on somatic and organ growth, serum insulin-like growth factor-I (IGF-I) and IGF-II levels, and IGF-binding protein levels in the neonatal and juvenile rat.

We investigated pituitary regulation of growth during two critical stages of development in the rat, using hypophysectomy (Hx) with replacement of GH and/or T4. In the neonatal period (Hx on day 6), body weight and tail length were inhibited by 60% and 50%, respectively, while these parameters were inhibited by 80% and 85% by Hx in the juvenile period (Hx on day 45). Administration of T4 alone significantly increased skeletal growth (tail length) in neonatal Hx rats, while T4 alone proved ineffective in promoting somatic growth in juvenile Hx rats. GH effects were greater on body weight than on tail length at both stages of development. Replacement of both GH and T4 restored somatic growth to normal values during both time periods. The brain was the sole organ whose growth appeared to be independent of the pituitary. Hx reduced serum insulin-like growth factor-I (IGF-I) and -II in both age groups, and GH alone restored IGF-I and -II levels to the control range. The major IGF-binding proteins (IGFBPs) were analyzed by Western ligand blots. The effect of Hx on the predominant IGFBP was greater in the juvenile rat. T4 replacement in the neonate and GH replacement in the juvenile rat restored IGFBPs to control levels. We conclude that somatic growth in the rat is less pituitary dependent in the neonatal period. There are also important age-specific differences in organ response to GH and T4. Serum IGFs and their binding proteins are pituitary dependent even in infancy, and GH is their primary regulator. The neonatal Hx rat is an important model for the study of the dynamic development of the pituitary-dependent growth.

Pituitary control of growth in the neonatal rat: effects of neonatal hypophysectomy on somatic and organ growth, serum insulin-like growth factors (IGF)-I and -II levels, and expression of IGF binding proteins.

The neonatal period is a time of transition between pituitary-independent fetal growth and the pituitary-dependent growth seen in older mammals. To evaluate pituitary-dependent neonatal growth, Wistar rats were hypophysectomized (Hx) on postnatal day 6. Nineteen days post-Hx, body weight and tail length were inhibited 48% and 34%, respectively, compared with sham-Hx controls. Organ weights determined on days 10, 15, 20, 25, and 30 revealed three patterns of pituitary-dependence: 1) pituitary-independent growth in the brain and lung; 2) moderate pituitary-dependent growth in the heart, liver, kidney, and intestine; and 3) marked pituitary-dependent growth in the adrenals, spleen, and testes. Both serum insulin-like growth factor (IGF)-I and -II levels fell significantly in Hx pups by 54 h after Hx (P = 0.0005), and Northern analysis on day 15 showed a significant decrease in liver messenger RNA (mRNA) for IGF-II. Analysis of the major IGF binding proteins (BPs) was performed by Western ligand blots. Hx performed on day 6 resulted in a linear decrease in the amount of the 22k BP from day 10 to day 30. In contrast, the major neonatal BP (IGFBP-2, a 29.5k molecule) showed a biphasic response to neonatal Hx. On postnatal day 10, 4 days after Hx, a significant decrease in IGFBP-2 occurred, which persisted through day 15; by postnatal day 20 and continuing through postnatal day 30, the amount of IGFBP-2 in the serum dramatically increased. The 40 to 50k fraction of IGFBP-3 first appeared in significant quantities by postnatal day 20, and after Hx dropped to 10% of sham-control values. Similarly, Northern analysis on day 15 demonstrated a significant decrease in liver, but not brain, mRNA for IGFBP-2 after Hx, whereas on postnatal day 25, liver mRNA for IGFBP-2 was increased in Hx pups compared with sham controls. We conclude that the pituitary gland exerts significant but selective effects on neonatal growth, with the notable exception of brain growth. Serum levels of both IGF-I and IGF-II, as well as their BPs, are pituitary dependent in the neonatal period. Pituitary-dependent neonatal growth thus appears to be mediated by IGF and modulated by IGF-binding proteins. On the other hand, that portion of the persistent growth in the neonatal Hx rat that is independent of the pituitary-IGF axis may be a good model for investigation of fetal growth.

Hormonal control of growth in the infant rat: further evidence that neither thyrotropin nor thyroid hormones are transferred via milk to suckling pups.

Experiments were conducted to obtain information on the possible transfer of TSH and thyroid hormones from mother rats to their infants via milk. The mothers were thyroidectomized by surgical or chemical (tapazole) means to eliminate maternal thyroid hormones from milk while increasing its content of TSH. Their pups were either hypophysectomized (HX) or sham HX, and some pups were also chemically thyroidectomized (CTX) by tapazole injections. Surgical thyroidectomy (STX) of the mothers reduced the weight gain of HX and sham HX pups by 28% and 22%, respectively, but it did not affect tail growth in either group of pups, Their pups were either hypophysectomized (HX) or sham HX, and some pups were also chemically thyroidectomized (CTX) by tapazole injections. Surgical thyroidectomy (STX) of the mothers reduced the weight gain of HX and sham HX pups by 28% and 22%, respectively, but it did not affect tail growth in either group of pups, Their pups were either hypophysectomized (HX) or sham HX, and some pups were also chemically thyroidectomized (CTX) by tapazole injections. Surgical thyroidectomy (STX) of the mothers reduced the weight gain of HX and sham HX pups by 28% and 22%, respectively, but it did not affect tail growth in either group of pups, and it did not affect serum T4 levels in the sham HX infants. In contrast, CTX caused a pronounced inhibition of weight gain (-45%), tail growth (-45%), and serum T4 (to less than 0.5 micrograms/100 ml) in the sham HX pups. In comparison to the HX pups with euthyroid or STX mothers, the HX infants with CTX mothers also showed reduced weight gain (-57% and -40%, respectively) and tail growth (-40% and -34%, respectively). Tapazole injections into sham HX pups suckling CTX mothers further reduced weight gain, but not tail growth. Because skeletal growth in the pups is highly dependent on their thyroid status, the lack of effect of surgical TX of mothers on tail growth in their sham HX infants provides no evidence for the transfer of physiologically effective amounts of thyroid hormones from mother to infant via milk. Likewise, the failure of TX of mothers to affect the tail growth of the HX pups argues against milk TSH being of significance to the infant. However, the data obtained with the tapazole-treated mothers indicate that significant quantities of the drug are passed from mother to infant via milk.