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Objective: To determine whether tight glycemic control of neonatal hyperglycemia changes neurodevelopment, growth, and metabolism at school age., Study Design: Children born very low birth weight and randomized as hyperglycemic neonates to a trial of tight vs standard glycemic control were assessed at 7 years corrected age, including Wechsler Intelligence Scale for Children Fourth Edition, Movement Assessment Battery for Children 2, visual and neurologic examinations, growth measures, dual X-ray absorptiometry, and frequently sampled intravenous glucose tolerance test. The primary outcome was survival without neurodevelopmental impairment at age 7 years. Outcomes were compared using linear regression, adjusted for sex, small for gestational age, birth plurality, and the clustering of twins. Data are reported as number (%) or mean (SD)., Results: Of the 88 infants randomized, 11 (13%) had died and 57 (74% of eligible children) were assessed at corrected age 7 years. Survival without neurodevelopmental impairment occurred in 25 of 68 children (37%), with no significant difference between tight (14 of 35; 40%) and standard (11 of 33; 33%) glycemic control groups (P = .60). Children in the tight group were shorter than those in the standard group (121.3 [6.3] cm vs 125.1 [5.4] cm; P < .05), but had similar weight and head circumference. Children in the tight group had greater height-adjusted lean mass (18.7 [0.3] vs 17.6 [0.2] kg; P < .01) and lower fasting glucose concentrations (84.6 [6.30] vs 90.0 [5.6] mg⋅dL -1 ; P < .05), but no other differences in measures of body composition or insulin-glucose metabolism., Conclusion: Tight glycemic control for neonatal hyperglycemia does not change survival without neurodevelopmental impairment, but reduces height, increases height-adjusted lean mass, and reduces fasting blood glucose concentrations at school age., Trial Registration: ACTRN: 12606000270516., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To validate established neonatal neutrophil reference ranges (RRs) and determine the utility of serial measurements of neutrophil values in the first 24 hours to predict the absence of neonatal early-onset sepsis (EOS)., Study Design: Retrospective study of 2073 admissions to the neonatal intensive care unit (2009-2011). Neonates were classified as blood culture-positive, proven EOS (n = 9), blood culture-negative but clinically suspect EOS (n = 292), and not infected (n = 1292). Neutrophil values from 745 not-infected neonates without perinatal complications were selected to validate RR distributions. Positive and negative predictive values were calculated; area under receiver operating characteristic curves (AUCs) were constructed to predict the presence or absence of EOS. Neutrophil value scores were established to determine whether serial neutrophil values predict the absence of EOS., Results: Seventy-seven percent of admissions to the neonatal intensive care unit were evaluated for EOS: 9 (0.56%) had proven EOS with positive blood culture ≤ 37 hours; 18% had clinically suspect EOS. Neutropenia occurred in preterm neonates, and nonspecific neutrophilia was common in uninfected neonates. The distribution of neutrophil values differed significantly between study groups. The specificity for absolute total immature neutrophils and immature to total neutrophil proportions was 91% and 94%, respectively, with negative predictive value of 99% for proven and 78% for proven plus suspect EOS. Absolute total immature neutrophils and immature to total neutrophil proportions had the best predictability for EOS >6 hours postnatal with an AUC ∼ 0.8. Neutrophil value scores predicted the absence of EOS with AUC of 0.9 and 0.81 for proven and proven plus suspect EOS, respectively., Conclusion: Age-dependent neutrophil RRs remain valid. Serial neutrophil values at 0, 12, and 24 hours plus blood culture and clinical evaluation can be used to discontinue antimicrobial therapy at 36-48 hours., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objectives: To estimate the cord blood levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in preterm infants and to study the relationship of these levels to pregnancy-induced hypertension (PIH) and absolute neutrophil counts., Study Design: G-CSF and GM-CSF levels in the cord blood of preterm neonates (n = 74) either with or without maternal PIH were estimated by enzyme-linked immunosorbent assay., Results: Infants in the PIH group had lower white blood cell, absolute neutrophil, absolute lymphocyte, and monocyte counts. The levels of G-CSF in cord blood were significantly lower in infants whose mothers had PIH (P =.04) and in infants with neutropenia (P =. 01). G-CSF levels were positively correlated with both absolute neutrophil count (P =.02) and total white blood cell count (P =.01). GM-CSF was undetectable in all subjects. According to logistic regression with neutropenia as the dependent variable, only maternal PIH (P <.001), gestational age (P <.001), and G-CSF (P =.01) were independently related., Conclusion: In this study maternal PIH and low gestational age were significantly associated with neutropenia in premature infants. Low G-CSF levels may contribute to the neutropenia that is commonly seen in infants born to mothers with PIH.

To evaluate the ability of a loading dose of chloramphenicol succinate to rapidly, achieve adequate serum concentrations of chloramphenicol, we compared two intravenously administered dosages of chloramphenicol succinate given to initiate treatment. Thirteen premature neonates received an initial dose of 12.5 mg/kg; 26 received a loading dose of 20 mg/kg. Capillary blood samples were obtained at two, four, and 12 hours after the first dose. After the dose of 12.5 mg/kg, 45% of the neonates did not achieve serum concentrations greater than 10 mg/L. After the loading dose of 20 mg/kg, all neonates achieved concentrations greater than 10 mg/L. The peak chloramphenicol concentrations after the 12.5 mg/kg dose was 8.8 +/- 11.2 mg/L (+/- SEM) and after the 20 mg/kg loading dose, 15.9 +/- 0.7 mg/L. The disposition of chloramphenicol was age dependent. Chloramphenicol concentration peaked at four hours in neonates less than or equal to 2 days postnatal age and at two hours in neonates 3 to 55 days postnatal age. Chloramphenicol succinate concentrations were greater in younger than in older neonates at both two and four hours after the dose. We conclude that a loading dose is appropriate when using chloramphenicol succinate in neonates.

Fasting values of branched-chain amino acids (valine, leucine, and isoleucine) were measured by column chromatography in the sera of 27 normal infants and children, 15 days to 9 years of age, 14 children with documented ketotic hypoglycemia one to 7 years of age, and in 14 sera from six infants, 15 days to 2 years of age, with documented hyperinsulinism. In normal children and those with ketotic hypoglycemia, each individual branched-chain amino acid and their sum were significantly negatively correlated with blood sugar values ranging between 11 and 92 mg/dl (P < 0.001). In infants with hyperinsulinism, branched-chain amino acid concentrations were significantly lower (P < 0.001) without correlation with blood sugar values ranging between 13 and 51 mg/dl, and plasma insulin concentrations (9 to 85 microU/ML). In all the children the sum of branched-chain amino acids was positively correlated with blood beta OH butyrate concentrations measured at the same time (r = 0.75, P < 0.001). The association of low blood sugar and low branched-chain amino acid concentrations during fasting seems characteristic of hyperinsulinism, and the measurement of branched-chain amino acids in these infants offers a physiologic indicator of the diagnosis of hyperinsulinism.

The distribution of normal cell counts (the reference range) has been determined previously for circulating neutrophils in infants from birth to 28 days of age. We have determined the reference ranges for the absolute peripheral blood lymphocyte, monocyte, and eosinophil counts obtained from 393 infants in this same cohort. Furthermore, white blood cell counts were obtained from three groups of infants with perinatal complications previously shown to be associated with abnormal neutrophil values (ABO incompatibility, n = 82; maternal hypertension, n = 68; neonatal sepsis, n = 140) and compared with the derived reference ranges; significant alterations in the distribution of cell counts were found in each of these groups at different times. Our data provide reference ranges for lymphocyte, monocyte, and eosinophil counts in the neonatal period and evidence of the effect of specific perinatal events on these cell counts.

Determination of the erythrocyte sedimentation rate in capillary blood can be of value in identifying neonates with infection. The normal values for the method described here range from 1 mm/l hour at 12 hours of age to 17 mm/l hour at 14 days of age. Most noninfected neonates with moderate to severe RDS or with other serious illness had values well within the normal range. Infected patients had marked elevations, and the majority of values returned to normal with clinical improvement. Coombs-positive ABO hemolytic disease was also responsible for elevated values. In about half of the infected patients the rise was not seen until 24 to 48 hours after clinical symptoms first appeared. The ESR can be useful in the nursery as a preliminary step in the laboratory evaluation of the sick neonate. Serial determinations may be of aid in identifying the infected infant when the results of bacteriologic cultures are obscured by antibiotic therapy.

The concentration (activity) of ionized calcium in serum [Ca-++] was measured in nine patients with symptomatic hypocalcemia of diverse etiology. In all nine patients the [Ca-++] was smaller than or equal to 2.50 mg/dl. No significant correlation was found between the [Ca-++] and serum levels of either total calcium or phosphate. Use of the McLean-Hastings nomogram failed to reveal any significant statistical correlation between the predicted [Ca-++] values and those actually measured. These data indicate that: (1) symptomatic hypocalcemia occurs when levels of ionized calcium in serum fall near or below a critical threshold concentration of 2.50 mg/dl and (2) the [Ca-++] must be measured directly to confirm the clinical impression of hypocalcemia.

To re-evaluate the usefulness of the IgM fluorescent treponemal antibody absorption test in the diagnosis of congenital syphilis, three groups of infants were investigated. Group 1 infants showed that the test was always negative in normal neonates born to seronegative mothers. From Group 2 infants we determined the standardization of the test using commercially prepared conjugate to allow the maximum exclusion of false positive and negative results. Studies on Group 3 neonates confirmed that the standardized test was extremely successful in determining whether or not an asymptomatic infant was infected with Treponema pallidum. Finally it was shown that the standardization of the test varies with different commercially prepared conjugates. From the investigation it was concluded that the IgM FTA test, if suitably standardized, was a highly successful method for diagnosing congenital syphilis, especially in asymptomatic neonates.

Free thyroxine concentrations were determined by radioimmunoassay in 96 infants within an intensive care nursery and in 32 healthy term infants. Sera for free T4 levels were drawn simultaneously with the filter paper specimens for T4 obtained to screen these infants for congenital hypothyroidism. The mean free T4 level in 20 adults was 1.38 +/- 0.03 ng/dl (mean +/- SEM). The mean in the ICN infants was 3.48 +/- 0.18 ng/dl and in healthy term infants, 4.24 +/- 0.23 ng/dl. Like T4, free T4 correlated positively with increasing gestational age and birth weight, and was lower in infants with RDS. Although 66% of the ICN infants had T4 levels below the statistically selected screening level (fifth percentile), all of these infants had free T4 levels greater than 0.8 ng/dl. Two additional infants with untreated congenital hypothyroidism has free T4 levels of 0.3 and 0.4 ng/dl. The measurement of free T4 appears to be an accurate indicator of thyroid function in these infants.

Five patients, age 3 weeks to 11 years, presented with supraventricular tachycardia that remained uncontrolled following adequate digitalization. Four of these patients underwent invasive electrophysiologic studies to determine the mechanism of the arrhythmias. Of these four patients, three had concealed Wolff-Parkinson-White syndrome, and one patient had evidence of dual A-V nodal pathways. Propranolol was added to the medical treatment and was administered orally in doses ranging from 7 to 14 mg/kg/day (average 9 mg/kg/day). All five children remain free of their tachycardia except for one patient who occasionally has supraventricular tachycardia with febrile illnesses. No adverse reactions to these high doses of propranolol were encountered.

Thirty-three prospectively studied neonates born to mothers using methadone plus other drugs developed significant thrombocytosis by the second week of life compared to platelet counts performed during the first week. This increase persisted for over 16 weeks, with a further short-lived significant peak at 10 weeks of age. Platelet counts exceeding 1,000,000/mm3 were found in seven infants. Thrombocytosis was not related to withdrawal symptoms or treatment (phenobarbital or paregoric). No thrombocytosis was found in 36 normal control infants up to eight weeks of life. Twenty-eight of the study group infants were evaluated for circulating platelet aggregates. Thirteen patients had a normal aggregate index and a mean platelet count of 468,000/mm3; 15 patients had increased aggregates and mean platelet count of 754,000/mm3. The risk for increased circulating platelet aggregates correlated directly with an increase in platelet count. Thrombocytosis and increased circulating platelet aggregates may be factors in the pathogenesis of the focal infarcts, and subarachnoid and germinal plate hemorrhages, described at autopsy in infants of addicted mothers.

Neutrophil granulocyte function was assessed in 17 well term infants, 14 stressed infants, and eight infants with group B streptococcal infection. Chemiluminescence production elicited by opsonized zymosan or by a wild strain of type III group B streptococci, as well as phagocytosis and killing of streptococci, were measured. Chemiluminescence production by PMNs of term neonates in response to opsonized zymosan or group B streptococci was equal to that of adult controls. In contrast, six of nine stressed or infected neonates had depressed CL responses upon zymosan challenge. When opsonized type III group B streptococci were used to elicit CL, seven of ten stressed or infected infants had markedly depressed responses. Phagocytosis, as determined by a radiolabeled bacterial uptake technique, was normal in the healthy and stressed neonates. Depressed CL production by the PMNs of stressed or infected neonates was associated with impaired intracellular bactericidal activity, however. These studies indicate that stressed or infected neonates have impaired leukocyte metabolic activation that may be associated with depressed bactericidal activity. Such impairment may contribute to the morbidity and mortality observed in serious neonatal infections.

Little information is available regarding appropriate plasma levels of anticonvulsant drugs in neonates. We determined the plasma levels of phenobarbital and diphenylhydantoin following initial administration and during maintenance therapy in 59 neonates with seizures. Following intravenous administration of 15 to 20 mg/kg, levels of 20.7 +/- 4.4 microgram/ml were achieved for phenobarbital and levels of 14.5 +/- 3 microgram/ml for DPH. Maintenance doses of 5 mg/kg of phenobarbital resulted in initial drug accumulation followed by more rapid elimination of the drug with increasing duration of exposure. Therapeutic plasma levels of DPH could not be achieved by oral administration in the neonate.

The leukocyte left shift is commonly used as an adjunct to the early diagnosis of bacterial infection. Many different methods have been employed for its quantification, such as the absolute band count, band/seg ratio, band/total neutrophil ratio, and immature/total neutrophil ratio. We examined blood and bone marrow samples in groups of noninfected and infected neonatal dogs and human beings in order to determine which method most clearly reflects an increased call upon marrow neutrophil reserves and which correlates best with the presence and severity of infection. We found that the neutrophil ratios were more frequently abnormal during neonatal sepsis than was the the absolute band count. All subjects, canine and human, in whom the immature/total neutrophil ratio exceeded 0.800 were found to have depletion of the marrow neutrophil reserves, and those with the most profound depletion died. This study supports the concept that an elevated immature/total neutrophil ratio can aid in the diagnosis of bacterial infection in the newborn infant and suggests that the degree of elevation may serve as a method for detecting subjects at high risk for depletion of the marrow neutrophil reserves and death from sepsis.

To determine if there are significant changes in cerebral blood flow velocity and vascular resistance in neonates with polycythemia and hyperviscosity, 11 such infants were studied before and after partial exchange transfusion with Plasmanate. Seven matched control infants were also studied. Blood flow velocity of the anterior cerebral artery was measured with a bidirectional continuous waveform Doppler velocimeter. Blood flow and vascular resistance were calculated from the velocity tracings, using the area under the velocity curve and the Pulsatility Index. Reduction in hematocrit and viscosity produced significant increases in blood flow velocity and a reduction in vascular resistance. The postexchange values were similar to those of the control group. These results indicate that infants with polycythemia and hyperviscosity have decreased cerebral blood flow velocity and increased vascular resistance which normalize after partial Plasmanate exchange transfusion.

Serum concentrations of the adrenal androgen, dehydroepiandrosterone sulfate, were measured by radioimmunoassay in normal infants and children, in sick premature and full-term newborn infants, and in patients undergoing evaluation of the hypothalamic-pituitary-gonadal and -adrenal systems. Premature infants had significantly greater (p less than 0.001) levels of DHAS (263 +/- 40)[SE]migrong/dl) than did full-term infants (58.9 +/- 5.2) during the first ten days of life; further increments occurred in stressed "sick" infants. A gradual age- and maturity-related rise in serum concentrations of DHAS was observed during childhood with the earliest increase occurring prior to the onset of pubertal production of gonadal steroids. Serum levels of DHAS rose following administration of ACTH and were increased in patients with congenital adrenal hyperplasia, in whom rapid decrements followed treatment with dexamethasone. hCG or LH-RH treatment did not alter DHAS concentrations. These data suggest that direct secretion of DHAS by the adrenal gland and/or peripheral sulfation of DHA, rather than gonadal secretion, accounts for the majority of DHAS production. The involvement of adrenal androgens in the pubertal maturation of the reproductive endocrine system thus may be evaluated by quantitation of serum DHAS.

We evaluated two reagent strips, Dextrostix and Chemstrip-BG, and the reflectance meter technique, Stat-tek Photometer, in the screening of blood sugar values in newborn infants at high risk and compared them with laboratory glucose determination using an automatic analyzer (glucose oxidase method). The visual inspection provided by the Chemstrip-BG was the best screening method and correlated best with laboratory blood sugar concentrations, with a correlation coefficient of 0.885. This value was statistically better than for Dextrostix (r = 0.797) and Stat-tek (r = 0.777). When we compared the blood sugar values less than 50 mg/dl, the correlation coefficient for Stat-tek was 0.670, which was not statistically different than for Dextrostix (r = 0.502); Chemstrip-BG correlated best with true glucose values (r = 0.843). We believe that Chemstrip-BG is more accurate and technically easier to perform than either Dextrostix or Stat-tek.

A previously unrecognized hypochromic anemia associated with marked normoblastemia during the newborn period is reported. One male and two female siblings and a first cousin had a hypochromic anemia and marked normoblastemia (300 to 900 normoblast index per 100 white blood cells) at birth. Globin chain synthesis studies on peripheral blood of the proband at birth indicated the presence of alpha-thalassemia trait with possible reduced gamma chain synthesis. Studies of globin chain synthesis on the father, two older affected siblings of the proband, and the proband at 1.5 years of age revealed alpha-thalassemia trait. The data suggest this complex alpha-thalassemia-like condition as a new syndrome associated with marked neonatal normoblastemia.

We studied the effect of hypotension and of electrode temperature (41 degrees C to 44 degrees C) on the relation of skin surface PCO2 (Roche prototype) to arterial PCO2 in 24 sick neonates of 690 to 3,500 gm with systolic blood pressures of 5 to 70 mm Hg. PsCO2 closely correlated with PaCO2. The standard error of estimating PaCO2 from PsCO2 was 3.02 torr at 44 degrees C, 3.20 torr at 43 degrees C, and 3.57 torr at 41 degrees C. The pH (6.89 to 7.61), body temperature (33.5 to 38.1 degrees C), hematocrit (0.28 to 0.65), scleredema, or treatment with tolazoline did not affect the relation of PsCO2 to PaCO2. PsCO2 grossly exceeded the predicted value at systolic blood pressures below 15 mm Hg, irrespective of electrode temperature.

We evaluated the effect of muscle paralysis on gas exchange and incidence of pneumothorax in 35 severely ill infants on mechanical ventilation. Pancuronium (0.1 mg/kg) was given repeatedly until spontaneous respirations ceased in infants with inadequate gas exchange with FIO2 greater than 0.60, or peak inspiratory pressure greater than 30 cm H2O, or who were breathing out of phase with the respirator. Of 27 infants who had an alveolar-arterial oxygen gradient greater than 300 torr before paralysis, AaDO2 improved by greater than 100 torr within one hour of paralysis in only two infants; it worsened in two infants within the same period. By six hours postparalysis, 12 of 27 infants had improved, five of whom had had a worsening AaDO2 before administration of pancuronium. Changes in oxygenation were unrelated to changes in arterial carbon dioxide tension in most infants. Peak transpulmonary pressures after paralysis were lower than during spontaneous breathing, and may explain the low incidence of pneumothorax (3 of 35) during paralysis. Since those who improved could not be distinguished by birth weight, gestational age, or diagnosis, pancuronium might be worthy of trial in a mechanically ventilated infant with severe lung disease who is at risk for pneumothorax.

The criteria used for partial plasma exchange transfusion in 32 of 42 polycythemic newborn infants with capillary hematocrits greater than or equal to 70% were a venous hematocrit greater than 65% and two or more clinical "symptoms," or a venous hematocrit greater than or equal to 70%. Coagulation tests performed on 20 infants before and after the partial plasma exchange transfusion were normal for age. Low platelet counts found in six of the 32 patients were associated with venous hematocrits of greater than or equal to 70%. In three patients the platelet counts (less than 100,000/microliters) increased to greater than or equal to 130,000/microliters after three days. In 20 of 32 infants in whom partial plasma exchange transfusions were performed, peripheral venous hematocrits prior to the exchange were 8.5% higher than umbilical venous hematocrits. Following treatment the venous hematocrits (umbilical and peripheral) did not show a statistically significant difference. Thus, the study revealed coagulation findings normal for age, thrombocytopenia in 20% of polycythemic infants, hemoconcentration, and a sluggish peripheral venous circulation.

Serum bile acid patterns were determined in 31 infants ranging in age from 4 days to 24 weeks. Fifteen infants with extrahepatic biliary atresia had a mean concentration of serum bile acids of 90 microng/ml +/- 47 SD;; 16 infants with neonatal hepatitis had a mean concentration of 60 +/- 35.5 SD. The chenodeoxycholate/cholate ratio was greater than one in 13 infants (87%) with atresia and in 10 infants (66%) with neonatal hepatitis. Except for the tendency of a higher total concentration of serum bile acids in infants with atresia, a single serum bile acid value does not differentiate neonatal hepatitis from extrahepatic biliary atresia. The high proportion of chenodeoxycholate in extrahepatic atresia is different from the pattern in other types of cholestatic disease and may reflect an underlying hepatitis.

The normal range of red blood cell osmotic fragility and autohemolysis was determined in venous blood of 32 healthy newborn infants. With these normal ranges as a reference, the diagnosis of hereditary spherocytosis was definitely possible in five newborn infants by demonstration of increased osmotic fragility of fresh and incubated red blood cells, moderately increased autohemolysis, and partial reduction of autohemolysis by the addition of glucose. Most previously studied newborn infants with hereditary spherocytosis have had atypical hyperbilirubinemia. Inconstant signs are anemia, reticulocytosis, erythroblastosis, spherocytes in the blood smear, and increased mean corpuscular hemoglobin concentration. In newborn infants with atypical hyperbilirubinemia in whom blood group incompatibilities are excluded, studies for hereditary spherocytosis should be done.

Reference ranges for absolute total neutrophils/mm3, absolute immature neutrophils/mm3, and the fraction of immature to total neutrophils (I:T proportion) during the first 28 days of life are developed from 585 peripheral blood counts obtained from 304 normal neonates and 320 counts obtained from 130 neonates with perinatal complications demonstrated to have no statistically significant effect on neutrophil dynamics. Perinatal factors other than bacterial disease which significantly alter neutrophil dynamics include maternal hypertension, maternal fever prior to delivery, hemolytic disease, and periventricular hemorrhage. The predictive value of these reference ranges in identifying bacterial disease in the first week of age varies with the neutrophil factor evaluated and the clinical setting. Neutropenia in the presence of respiratory distress in the first 72 hours had an 84% likelihood of signifying bacterial disease, whereas neutropenia in the presence of asphyxia had a 68% likelihood of signifying bacterial disease. An abnormal I:T proportion had an accuracy of 82% and 61%, respectively, in the same clinical settings. Elevations of either immature or total neutrophils were less specific. Interpretation of abnormal neutrophil factors must include consideration of both infectious and noninfectious perinatal events.