The measurement of whole body water by H2(18)O dilution in newborn pigs.

Whole body water was measured in newborn piglets by isotope dilution with H2(18)O. The results were compared with those obtained by direct analysis of whole body water made by freeze-drying. When the tracer dose of H2(18)O was given to 30 piglets by intragastric gavage, post-equilibration values measured in urine were highly variable (average equilibration error equalled 9%) and the random error of the technique in predicting body water was 13%. When the dose was given to 49 animals intravenously, the post-equilibration values in urine were less variable (equilibration error equalled 4%), the random error of the technique was 7%, and body water was overestimated by 2%. The random error was reduced to 6% if data from animals in which equilibration errors exceeded 10% were excluded. When 18O enrichment in plasma instead of urine was measured, the technique was less precise (random error 11%). The estimation of body water from H2(18)O overestimates body water by 2%. Isotope dilution with 18O is a safe, accurate and repeatable method for the estimation of whole body water, and is suitable for use in adult and newborn humans.

Efficacy of calcium glycerophosphate vs conventional mineral salts for total parenteral nutrition in low-birth-weight infants: a randomized clinical trial.

To test the efficacy of calcium glycerophosphate (CaGlyP) vs the conventional mineral salts, calcium gluconate plus KH2PO4 + K2HPO4 (CaGluc + P), in promoting mineral retention, 72-h mineral balance, biochemical status, net acid excretion, and growth were assessed in 16 low-birth-weight infants receiving total parenteral nutrition (TPN) containing approximately 1.5 mmol Ca and P.kg-1.d-1 for 5 d. Net retentions of calcium (1.2 +/- 0.2 vs 1.0 +/- 0.2 mmol.kg-1.d-1, means +/- SD) and phosphorus (1.1 +/- 0.3 vs 0.8 +/- 0.3 mmol.kg-1.d-1) from CaGluc + P vs CaGlyP, respectively, were similar, as were retentions of magnesium and sodium, urinary pH, and net acid excretion. Plasma ionized calcium, inorganic phosphorus, alkaline phosphatase, and osteocalcin were normal and not different between groups. CaGlyP is as effective as CaGluc + P in promoting mineral retention and normal mineral homeostasis. However, at intakes of less than or equal to 1.5 mmol Ca and P.kg-1.d-1 from either mineral salt, retention represented only 60% and 45%, respectively, of the predicted intrauterine accretion for calcium and phosphorus. Larger intakes permitted by the more-soluble CaGlyP may be desirable for infants receiving TPN.

The inflammatory response in candidal chorioamnionitis.

Fetal infection with Candida organisms has not commonly been reported. Umbilical cords and placentas from 23 cases of chorioamnionitis collected over a nine-year period were examined by electron microscopy and immunoperoxidase staining. Gross features, especially of the umbilical cord, were distinctive and included the pale yellow plaques pathognomonic of candidal funisitis. Histopathologically, the lesions were found to be focal and subamniotic and were often embedded in a "fibrinoid" exudate and surrounded by inflammatory cells. In some cases the exudate and inflammatory cells were deposited in dense bands. Immunoperoxidase staining showed the lesions to contain IgG, IgM, and IgA, which probably originated in dense-staining plasmacytoid and immunoblastic cells in the inflammatory infiltrates. Additional findings in two fetal cases of giant cell pneumonitis suggested that the fetus can mount a brisk inflammatory and immune response to Candida organisms as early as 18 weeks' gestation and that mucosal exposure to this antigen can result in production of IgA by the lung.

Calcium glycerophosphate as a source of calcium and phosphorus in total parenteral nutrition solutions.

Calcium glycerophosphate (CaGP) was tested as an alternative to calcium gluconate (CaGluc) and potassium mono- and dibasic phosphate (KPhos) as a source of Ca and P in total parenteral nutrition (TPN) solutions for piglets. Four-day-old piglets were infused for 7 days with a TPN solution that provided either 4.2 mmol Ca and 2.1 mmol P/kg/24 h as CaGluc and KPhos (the maximum quantities that can be provided using these sources), or 15.0 mmol Ca and 15.0 mmol P/kg/24 h as CaGP. Ca and P retentions were more than six times greater (p less than 0.01) in the piglets receiving CaGP (14.5 +/- 0.2 vs 2.2 +/- 0.3 mmol Ca/kg/24 h and 13.3 +/- 0.4 vs 2.4 +/- 0.1 mmol P/kg/24 h) (Mean +/- SEM). The ratio of Ca to fat-free dry weight, an indicator of bone mineralization, was significantly higher (p less than 0.05) in the humerus (174.8 +/- 2.2 vs 147.2 +/- 6.7) and femur (158.3 +/- 4.8 vs 130.1 +/- 7.8) in the CaGP group. This study showed that CaGP is efficiently used as a source of Ca and P in TPN solutions for piglets. The results suggest that the use of CaGP as the source of Ca and P in TPN solutions may prevent the development of the undermineralized bone seen in low-birth weight infants nourished intravenously.

Fetal inflammatory response in second trimester candidal chorioamnionitis.

Candidal chorioamnionitis is an uncommon and apparently rather indolent intrauterine infection in which the fetus is able to marshal some of the immunological forces at its disposal against an easily visualized antigen impinging on lung mucosal surfaces. In a retrospective histological study of one of the largest reported series of these cases, we have encountered one each of 13, 16 and 22 weeks gestation, respectively. Of these, the youngest at 13 weeks showed no inflammatory response or positive cells on immunoperoxidase staining for immunoglobulins and proliferating Candida colonies were evident in the lungs. The 16 and 22 week cases revealed a unique giant cell response in the terminal airways and increasing numbers of cells staining positively for immunoglobulins, predominantly IgM, but with an increased proportion of IgA positive cells in the older case. Preliminary studies with a pan-T-cell antiserum on paraffin-embedded lung tissue from these cases have been encouraging with few positive cells seen in sections from the 13-week or control cases but abundant cells in the lungs of the two older infected cases. Some aspects of the relationship of these uncommonly encountered cases to the ontogeny of human immunity are discussed.

Mixed venous oxygen saturation in the newborn. Can we and should we measure it?

Conventional measurements of oxygenation used in the critical care of sick newborn infants are limited to arterial blood. This approach fails to describe fully the physiological economy of oxygen in terms of supply (systemic oxygen transport), demand (oxygen consumption), or functional reserve (mixed venous oxygen content). The relationship between supply and demand can be described by the fractional oxygen uptake, which can be determined from arterial (SaO2) and mixed venous (Sv-O2) oxygen saturations. Fractional oxygen uptake = (SaO2 - Sv-O2)/SaO2. Review of the literature shows that conventional methods of continuous monitoring of arterial oxygen tension or content have had little measurable effect on the incidence of retinopathy of prematurity or on the survival of low birthweight infants. In hypoxic states, oxygen can be almost completely extracted by the tissues. However, a critical value for fractional oxygen extraction can be recognised which reflects a critical value for systemic oxygen transport. While the pulmonary artery is the ideal site for the measurement of mixed venous oxygen content, blood sampled from the mid-lateral site of the right atrium is higher in mean oxygen saturation by only 0.7 (SE 0.1) vol.%, indicating that the effect of incomplete mixing is very small. The difference in oxygen saturation between right atrium and pulmonary artery remains variable, and this may reflect either true variation of central venous saturation or instrument error. Because of this, central venous oxygen saturation may be of limited use for the measurement of oxygen consumption, cardiac output or fractional oxygen extraction. The level of central venous oxygen saturation as a direct measure of blood oxygen reserve is worthy of further examination.(ABSTRACT TRUNCATED AT 250 WORDS)

First day neonatal mortality since 1935: re-examination of the Cross hypothesis.

OBJECTIVES: To describe the change in first day infant mortality during 1935-87. To examine the hypothesis that excess first day mortality in the 1950s and 1960s was attributable to restricting oxygen for sick newborn infants. DESIGN: Time series analysis of first day infant mortality and stillbirth rates. SETTING: England and Wales and the United States of America. SUBJECTS: All first day infant deaths, all neonatal deaths, and all stillbirths. MAIN OUTCOME MEASURES: Rate of fall in mortality, dates of deviation of mortality from established fall, and correlation with stillbirths. RESULTS: In England and Wales first day infant mortality fell by 3.1% a year, except between 1951 (95% confidence interval 1951 to 1954) and 1980 (confidence interval less than 1 year). During these years there were 37,000 excess deaths. In the United States an annual fall of 2.7% was interrupted in 1955 (1951 to 1954) and resumed in 1980 (1978 to 1980), resulting in 195,000 excess deaths. A similar pattern was observed in stillbirth rates. CONCLUSIONS: Restriction of oxygen in sick newborn infants cannot be the sole cause of the interruption in fall of first day neonatal mortality as stillbirth rates were also affected. The timing of onset and the course of the deviation is not consistent with the oxygen restriction hypothesis. Further investigation is needed to identify a factor affecting both fetal and newborn survival between 1950 and 1980.

Energy intake and the nature of growth in low birth weight infants.

Growth is accompanied by and depends on energy storage in growing tissue. The rate of energy storage in growing low birth weight infants depends on the rate of energy intake and on the rates of energy excretion and expenditure, both of which (on a body weight basis) are much higher than in adults, and both of which increase with increments of gross energy intake. Energy-balance studies of growing low birth weight infants on gross energy intakes approximating 500 kJ X kg-1 X d-1 of mothers' milk or of infant formula indicate that the composition of extrauterine weight gain of the low birth weight infant differs from that of the fetus of similar gestation, in that the energy storage cost of growth is much higher. Attempts to increase metabolizable energy intake beyond 500 kJ X kg-1 X d-1 by energy supplementation alone do not result in proportionately increased rates of weight gain; low birth weight formulae, in which energy, protein, and mineral contents are all increased can result in large weight gains with proportionate increases in rates of protein and fat accretion.

Effect of dopamine on failure of indomethacin to close the patent ductus arteriosus.

To test the hypotheses that administering dopamine before and concurrently with indomethacin therapy would (1) increase successful ductal closure rate, (2) act by maintaining a diuresis, and (3) prevent oliguria or high serum creatinine concentrations, we conducted a randomized, controlled trial in infants whose gestational age was <36 weeks and who had hemodynamically significant ductus arteriosus. Thirty-six infants were selected to receive a continuous infusion of either placebo or dopamine at either a low dosage of 2 micrograms/kg per minute or a higher dosage of 5 micrograms/kg per minute, beginning 6 hours before the use of indomethacin and continuing until 12 hours after the third dose of indomethacin. A total of 12 patients were selected to receive placebo, 14 were selected to receive "low dopamine," and 10 were selected to receive "high dopamine." The three groups were similar in their initial characteristics. Serum creatinine concentrations, urine output, and fractional excretion of sodium were not different in the three groups after indomethacin treatment. Two patients receiving placebo required a second course of indomethacin compared with four patients in the low-dopamine group and one in the high-dopamine group. The proportion of failures of medical treatment was not statistically different among the three groups. We conclude that concomitant dopamine therapy neither decreases the failure rate in indomethacin-treated infants nor reduces the magnitude of the indomethacin-induced oliguria.

Faecal excretion of oligosaccharides and other carbohydrates in normal neonates.

Chromatographic analysis of sugars in the stools of 40 normal newborn infants has shown the presence of an oligosaccharide in 85% of samples. The oligosaccharide has been shown to contain fucose (6-deoxygalactose), glucose, and galactose and is present in normal breast milk. In addition fucose has also been found in the presence of galactose in some samples and is probably a breakdown product of milk oligosaccharides. These findings, which affect the interpretation of faecal sugar excretion, have not been described previously.

Antenatal infections with Candida species.

The clinical, pathological, and microbiological features of 18 pregnancies complicated by intrauterine infection with Candida sp. are described. Chorioamnionitis with Candida sp. can be recognised macroscopically at birth. Penetration of the umbilical cord and membranes is associated with an intense fetal inflammatory response. The infection characteristically presents in infants of very low birthweight as pneumonia or a skin infection. In nearly every case the organism can be recovered from the gastric aspirate. A case control study showed that there is a striking association between chorioamnionitis caused by Candida sp. and the presence of a foreign body (an intrauterine contraceptive device or a cervical suture) in the mother's genital tract in pregnancy. This feature in the perinatal history of an infant of short gestation who exhibits a very high neutrophil count should alert the clinician to the possible presence of chorioamnionitis due to Candida sp.

Excretion of dicarboxylic and omega-1 hydroxy fatty acids by low birth weight infants fed with medium-chain triglycerides.

The effects of feeding a commercial formula containing increased amounts of medium-chain fatty acids on the urinary excretions of C6-C10 moncarboxylic, dicarboxylic, and omega-1 hydroxy acids were studied in 13 growing preterm infants of mean birth weight 1.42 kg in a randomized double-blind cross-over clinical trial. Infants were allocated to two sequential feeding regimes of 5 days each, during the last 3 days of which urine was collected and analysed by gas-chromatography mass spectrometry. The two feeding regimes consisted of high energy and protein-containing formulas specially designed for growing low birth weight infants. In one diet the triglyceride component consisted of 46% medium-chain (C8-C10) and 54% long-chain fatty acid residues: in the other it consisted of 4% medium-chain and 96% fatty acid residues. The infants were randomized so that six infants were fed first with the medium-chain predominant formula and seven were fed first with the long-chain predominant formula. There were significant differences in the urinary excretions of octanoate, sebacate, suberate, adipate, 7-hydroxyoctanoate, and 5-hydroxyhexanoate; these substances appearing in much greater quantities in the urine during the period in which medium-chain triglycerides were predominant in the formula. The significance of this organic aciduria, which accounted for 0.7% of the dietary intake of medium-chain triglycerides, remains to be established.

Determination of the effect of pH and foetal haemoglobin fraction on haemoglobin oxygen saturation readings by the OSM3 hemoximeter.

The visible absorption spectrum of oxyhaemoglobin depends on its content of foetal haemoglobin and on the pH of the blood. These variables are known to affect oxygen saturation readings measured by the OSM3 Hemoximeter. As the hemoximeter estimates foetal haemoglobin content from the absorption spectrum of oxyhaemoglobin, this estimation is affected by pH. We quantified the effect of pH on oxyhaemoglobin reading in order to calculate a correction factor to adjust for pH. We manipulated a pool of fresh heparinized cord blood samples to produce a range of pH values from 6.99-7.53 in fully oxygenated blood with a carbon dioxide tension of 5.3 kPa. We measured oxygen saturation and percent foetal haemoglobin using an OSM3 Hemoximeter and pH with a linked blood gas analyser. The effect of pH on readings of saturation and fractional foetal haemoglobin was confirmed and a correction factor was calculated. The value of KHbF, the coefficient used in the OSM3 Hemoximeter to estimate the amount of fractional foetal haemoglobin present in a sample, was determined to be 18.3, which slightly but significantly differed (p = 0.04) from the 18.6 used by the OSM3 Hemoximeter. An equation was derived to correct the errors made by pH on the saturation measurement of oxygenated blood.

From oxygen content to pulse oximetry: completing the picture in the newborn.

In recent years clinicians caring for sick preterm infants have come to depend on pulse oximetry to avoid hyperoxia, which means assuming saturation values for critical levels of oxygen tension. This prediction is made difficult by the shape of the haemoglobin-oxygen dissociation curve at critical values for arterial pO2 and by the effects of changes in acid-base balance on p50. Combined blood gas and co-oximetry measurements can be used to determine critical limits for pulse oximetry. Fetal haemoglobin has slightly different light absorption characteristics from adult haemoglobin. To adjust for this, adult and fetal matrices are available in the OSM 3 HEMOXIMETER (Radiometer Medical A/S, Denmark) but the measurement requires an extra preliminary step to estimate fetal haemoglobin concentration. We sought to determine the importance of this extra procedure for measuring the saturation of newborn blood, and to determine whether the adult or fetal mode should be used for determining saturation for comparison with pulse oximeters. We measured the effect of the correction for fetal haemoglobin by obtaining absorbances from the co-oximeter and multiplying them by the adult and fetal matrices. We demonstrated that, at 90% saturation, failure to use the fetal correction in the presence of high levels of fetal haemoglobin result in a 4% overestimate of saturation, with resultant underestimation of the safe range for pulse oximetry. Published values for extinction coefficients for fetal and adult blood at wavelengths used by pulse oximeters are inconsistent, but it appears that fetal haemoglobin does not bias pulse oximetry readings. Determining saturation limits by co-oximetry for use with pulse oximeters in preterm infants requires the description of the haemoglobin-oxygen dissociation curve with the correction for fetal haemoglobin.

Partition of nitrogen intake and excretion in low-birth-weight infants.

Although nitrogen balance studies have been carried out in low-birth-weight infants, few have partitioned the nitrogen into its components. In this study, 72-hour balance studies were conducted in 24 low-birth-weight infants (gestational age, 30.7 +/- 1.6 weeks; birth weight 1.36 +/- 0.25 kg) fed their mothers' milk (preterm milk) or 50% preterm milk and 50% formula. Total nitrogen, nonprotein nitrogen, and whey protein intake and excretion were measured. Total nitrogen intake (preterm milk group, 452 +/- 138 mg/kg per day; preterm + formula group, 406 +/- 93 mg/kg per day), absorption (85%), and retention (71%) were not significantly different between groups. Intact and fragments of secretory IgA and lactoferrin were detected in soluble fecal extracts, and represented 25% and 9% of intake, respectively. Feeding preterm milk allows for nitrogen accretion similar to intrauterine growth rates for 5 weeks postnatally, and provides potentially functional proteins for the low-birth-weight infant.

Abnormal zinc content in human milk. Risk for development of nutritional zinc deficiency in infants.

An abnormally low concentration of zinc in mother's milk has been associated with clinical nutritional zinc deficiency in premature and term newborns. Defective mammary gland secretion of zinc was suggested as the causative factor. We investigated whether low milk zinc concentration might be reflected in an abnormality of the distribution of zinc between casein, whey, and fat components of the milk, in a reduction in the levels of milk citrate, a zinc-binding ligand, or in abnormal levels of copper and iron. Milk from mothers of four low-birth-weight infants was identified as being deficient in zinc content for the lactational stage. One infant had clinical signs of nutritional zinc deficiency. For two of the three infants with subclinical deficiencies in whom balance study data were available, the apparent zinc balance was negative (-5.7 and -6.0 mumol/kg per day). These milks were examined for content and distribution of zinc, copper, and iron, and citrate concentration. Although total zinc concentration (4.5 to 17.2 mumol/L) was below the 95% prediction interval (15.2 to 59.7 mumol/L) for the lactational stage, the distribution of zinc was normal between milk components. Levels of citrate (1.46 to 5.13 mmol/L) were also within normal limits, as were levels of copper (0.27 to 0.85 mumol/L and iron (0.41 to 1.13 mumol/L). We concluded that there was no indirect evidence of a secretory abnormality in milk zinc deficiency, but speculated that there might instead be an abnormality of zinc uptake by the mammary gland from the plasma.

Effect of the arterial oxygenation level on cardiac output, oxygen extraction, and oxygen consumption in low birth weight infants receiving mechanical ventilation.

OBJECTIVE: To investigate the effects on oxygenation of targeting the higher versus the lower end of the currently recommended range for pulse oximetry (Spo2). DESIGN: Nonrandomized crossover trial with the use of within-subject comparisons (two-tailed paired t test). SETTING: Level III neonatal intensive care unit of a university hospital. PATIENTS: Twenty infants whose lungs were mechanically ventilated (mean +/- SD: birth weight, 1192 +/- 396 gm; gestational age, 28.7 +/- 2.7 weeks; age at time of study, 42 +/- 26 hours). INTERVENTIONS: The inspired oxygen concentration was adjusted to achieve Spo2 readings of 93% to 96% versus 89% to 92% (Ohmeda pulse oximeter) or 95% to 98% versus 91% to 94% (Nellcor oximeter). MEASUREMENTS: Cardiac output was measured by echocardiography, oxygen content of arterial blood samples by cooximetry, and oxygen consumption by indirect calorimetry. RESULTS: The inspired oxygen concentrations required to achieve the Spo2 target ranges were 39.8% +/- 8.3% versus 28.7% +/- 6.1% (p < 0.001). The respective arterial oxygen contents were 18.0 +/- 2.6 ml/dl versus 16.9 +/- 2.5 ml/dl (p < 0.001). Oxygen consumption was unchanged. In the lower-oxygen condition no compensatory increase in cardiac output was detected; thus the estimated mixed venous oxygen tension decreased and the oxygen extraction ratio increased. Venous admixture increased from 15% +/- 6% to 31% +/- 9% in the lower-oxygen condition (p < 0.001). CONCLUSIONS: The "low normal" Spo2 target range allowed for less oxygen exposure. No signs of mismatch between systemic oxygen delivery and demand could be detected.

Energy cost of growth of premature infants.

The objective of this paper is to review approaches to the determination of the energy cost of growth in premature infants. Two approaches are compared: one based on the composition of weight gain, and one based on the determination of energy balance. Data are lacking on the composition of weight gained by the premature infant after birth, while the composition of fetal weight gain and its energy cost can be calculated from data on fetal body composition. These calculations show that energy storage amounts to less than 8.4 kJ/g weight gain below a body weight of 2 kg; the total energy cost of growth is less than 10.5 kJ/g. Estimates twice as high have been obtained from energy balance studies of growing premature infants and older infants. We conclude that the energy cost of growth in premature infants is still uncertain and requires further study.

Energy balance in low birth weight infants fed formula of high or low medium-chain triglyceride content.

We tested the effect on energy balance of the partial substitution of medium-chain for long-chain triglycerides in the diet of growing low birth weight infants. Fifteen infants were studied in a randomized double-blind crossover clinical trial in which each infant was fed each of two formulas, which were of equal gross energy and protein content but differed in fat composition. The high medium-chain triglyceride (MCT) formula contained medium- and long-chain triglycerides in a weight/weight ratio of 46:54; in the low MCT formula the ratio was 4:96. The hypothesis tested was that under conditions of equal gross energy intake the two diets would differ in their digestible and metabolizable energy contents and would produce differences in the infants' rates of energy expenditure and energy storage. Gross energy intakes averaged 562 and 555 kJ/kg/day (134 and 133 kcal/kg/day) with the high and low MCT formulas, respectively. With each diet, coefficients of energy digestibility (0.93) and metabolizability (0.91) were identical; the rates of energy expenditure were 262 (high MCT) and 265 (low MCT) kJ/kg/day (63 kcal/kg/day for both diets), and of energy storage were 246 (high MCT) and 239 (low MCT) kJ/kg/day (59 and 57 kcal/day). These differences were not significant. There were also no significant differences between the two diets in coefficients of nitrogen retention (mean 0.70) or in rate of weight gain (mean 21.5 gm/kg/day). The use of high MCT content in infant formula neither provided a nutritional advantage in energy digestibility or metabolizability nor resulted in an increased rate of energy expenditure or of energy storage.