Neonatal bilirubin production estimated from "end-tidal" carbon monoxide concentration.

The relationship between the pulmonary excretion rate of carbon monoxide (VECO) and the concentration of CO, in a sample of breath, drawn through a nasopharyngeal catheter at end-expiration, was assessed in 25 studies of nine preterm and 14 term infants. The VECO and this approximate end-tidal sample of CO (ETCO) correlated significantly over a wide range of CO elimination rates: VECO = 10.45 ETCO + 2.25 (n = 25, r = 0.95). The ETCO correctly predicted elevations in VECO greater than 2 SD of the mean VECO for normal infants (13.9 +/- 3.5 microliter/kg/h), with 90% sensitivity and 73% specificity (p less than 0.01). Three subjects with Rh isoimmune hemolytic disease were easily identified by the ETCO as well as the VECO. The ETCO is a simple, noninvasive measurement for rapidly identifying infants with significant hemolytic disease.

Pulmonary excretion of carbon monoxide in the human infant as an index of bilirubin production. IIc. Evidence for the possible association of cord blood erythropoietin levels and postnatal bilirubin production in infants of mothers with abnormalities of gestational glucose metabolism.

A total of 20 infants who had levels of erythropoietin (Ep), the major hormone regulating erythropoiesis, measured in their cord blood also had determinations of the pulmonary excretion rate of CO (VECO) performed, as an index of total bilirubin production. They were either infants of normal mothers or those of mothers with diabetes, gestational diabetes, and missed abnormalities of gestational glucose metabolism. The mean VECO (13.0 +/- 3.5 mu 1/kg/hr) and the mean Ep (20.0 +/- 9.7 SD mU/ml) of the infants with normal mothers (n = 9) were not different from the means previously established by our laboratories (13.9 +/- 3.5 SD mu 1/kg/hr, n = 20; and 23.7 +/- 12.8 SD mU/ml, n = 30, respectively); they were significantly lower than those of the infants of the abnormal mothers in this study. The 5 infants who had a cord blood Ep level greater than 50 mU/ml had a higher mean VECO, 27.8 +/- 7.1 mu 1/kg/hr, compared with 17.2 +/- 4.9 SD mu 1/kg/hr, of the six infants with cord blood Ep levels that were within 2 SD of the previously established normal mean cord blood Ep level (p less than .025). These data suggest that increased cord blood Ep levels and postnatal bilirubin production in infants whose mothers had abnormalities of gestational glucose metabolism are associated phenomena. Since polycythemia did not occur in these infants, ineffective erythropoiesis or mild, compensated hemolysis remains a likely cause of the increased total bilirubin production. In some cases, perinatal hypoxic stress may have affected the Ep response.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of end-tidal carbon monoxide to correct end-tidal hydrogen in neonates.

We evaluated the usefulness of end-tidal CO (ETCO) as an internal standard for reducing the error in end-tidal H2 (ETH2) measurements due to contamination of repeated breath samples with nonalveolar gas. Triplicate end-tidal samples were drawn from 12 healthy premature infants in small (less than 1 cc) increments through a posterior nasopharyngeal catheter at end-expiration, determined from the infant's chest wall movement. CO and H2 determinations were made on each sample by a reduction gas detector capable of determining CO and H2 concentrations to +/- 0.001 and 0.010 ppm, respectively. Respiratory breath samples were corrected for ambient CO and H2 concentrations. Since the alveolar gas fraction has the highest CO concentration of all tidal gases, the end-tidal sample with the highest CO peak was assumed to be most representative of uncontaminated alveolar gas. The other samples were "corrected" using a factor that was the ratio of the patient's highest CO peak to the given sample's CO value. The use of ETCO to correct ETH2 from samples deliberately contaminated with ambient air can significantly reduce the variability of ETH2 values. However, such correction is probably not necessary when comparing groups of infants using a standard collection technique. For individual infants, correction may reveal more marked short-term fluctuations in true alveolar H2 concentration.

Breath hydrogen analysis: a review of the methodologies and clinical applications.

Hydrogen gas (H2) is a product of the fermentation of dietary carbohydrate (CHO) by bacteria in the lumen of the gastrointestinal tract in man. Thus, H2 is actually an exogenously produced gas, which either is passed as flatus, or diffuses into the body and is exhaled. In the adult, a fairly constant fraction is expired, providing a reliable indicator of total colonic H2 production. Breath H2 analysis currently represents a useful clinical means of testing adults and older children for the malabsorption of CHO. Noninvasive and easy procedures for the collection of expired air have encouraged their increasingly widespread use in pediatrics. Evidence to date suggests that breath H2 analysis may provide the best available method for estimating semiquantitatively the degree of CHO malabsorption. The association of the results of breath H2 analysis with other clinical measures of CHO digestion and absorption is expected, but discrepancies can also be anticipated based on the nature of this particular trace gas method. The interpretation of the results of breath H2 analysis in neonates and young infants remains especially problematic because of confounding variables which are difficult to control and are measured infrequently.

Developmental changes in bilirubin production in the rat.

Total bilirubin production and relative rates of early labeling of bilirubin (ELB) were determined in rats during postnatal development. Total production was estimated by measuring endogenous rate of excretion of carbon monoxide (VeCO), while ELB was determined by measuring the incorporation of glycine-2-14C and delta-aminolevulinic acid-5-14C(delta-ALA-5-14C) into expired 14CO over a 30-h period after isotope injection. VeCO was considerably higher in 1- and 4-day-old rat pups than in adults, but fell rapidly toward adult values by 9 days of age. 14CO excretion from both isotopic precursors of bilirubin was significantly greater in suckling animals than in postweanling and young adult animals when expressed as a percent of the administered radioactivity. The activity of hepatic heme oxygenase showed a similar pattern of postnatal change to 14CO excretion from both glycine-2-14C and delta-ALA-5-14C. However, phenobarbital administration to young weanling animals significantly increased 14CO excretion from glycine-2-14C, but did not result in a change in the activity of hepatic heme oxygenase. The activity of hepatic heme oxygenase does not always reflect in vivo ELB.

Maternal beta-adrenergic tocolysis and neonatal bilirubin production.

The potential for beta-adrenergic drugs to increase total bilirubin formation via cyclic adenosine monophosphate-mediated stimulation of hepatic microsomal heme oxygenase in the human neonate was evaluated. The pulmonary excretion rate of endogenously produced carbon monoxide (VeCO), an index of total bilirubin formation (TBF), was measured in 18 preterm neonates whose mothers received beta-adrenergic drugs for tocolysis and in 18 preterm neonates whose mothers were untreated. The mean VeCO of the neonates in the former group (17.2 +/- 7.3 microL/kg/hr) was the same as that in the latter group (17.4 +/- 6.2 microL/kg/hr); both values were elevated when compared with the mean VeCO of 20 term newborns (13.9 +/- 3.5 microL/kg/hr). Our findings indicate that TBF is not significantly increased in neonates whose mothers received beta-adrenergic drugs before delivery.

Paired determinations of blood carboxyhemoglobin concentration and carbon monoxide excretion rate in term and preterm infants.

Paired determinations of COHb and VeCO were performed on 30 term infants (38 to 42 weeks' gestation) and 26 preterm infants (28 to 37 weeks' gestation) during the first week of life. All subjects were breathing room air at the time of the study. Values of COHb were corrected for RAco by linear regression of COHb (percent saturation) vs RAco (ppm). Regression coefficients for term and preterm infants with no history of pulmonary impairment were nearly identical (COHb = 0.175 RAco + 0.45, r = 0.77, n = 25 for term infants; COHb = 0.168 RAco + 0.51, r = 0.82, n = 9 for preterm infants) and agreed well with theoretical values. For the group of term infants, linear regression of Veco (microliter/kg/hr) vs. COHbc, where COHbc = COHb - 0.17 RAco, resulted in VEco = 23.4 COHbc + 4.02, r = 0.75, n = 30. The corresponding relationship for preterm infants with no history of pulmonary impairment was VEco = 24.7 COHbc + 3.85, r = 0.61, n = 13. For a subpopulation of preterm infants with a history of pulmonary dysfunction, the correlation decreased significantly, with VEco = 4.34 COHbc + 17.6, r = 0.097, n = 11. These results demonstrate that (1) COHbc is a reasonable index of VEco and consequently of the heme catabolic rate in both term and preterm infants with no clinical history of pulmonary dysfunction and (2) inference of VEco from COHbc may be misleading in certain cases without a consideration of the factors relating these two variables.

Pulmonary excretion rates of carbon monoxide using a modified technique: differences between premature and full-term infants.

The pathophysiology of the exaggerated hyperbilirubinemia in premature infants remains unclear. The relative contribution of bilirubin production may be estimated by measuring the pulmonary excretion rate of carbon monoxide (VeCO). We found that the mean VeCO of premature infants, 16.7 +/- 5.0 microliters/kg/h, was significantly elevated (p less than 0.05) compared with the mean VeCO of full-term infants, 13.9 +/- 3.5 microliters/kg/h. Premature infants who required phototherapy had a significantly (p less than 0.05) higher mean VeCO than those who did not. The VeCO did not correlate with gestational age, implying that factors which associate frequently but variably with gestational age may have an important influence on heme catabolism.

A sensitive analytical apparatus for measuring hydrogen production rates. II. Application to studies in human infants.

We estimated hydrogen (H2) production by determining simultaneously the end-tidal concentration (ETH2) and the direct pulmonary excretion rate (VeH2) in normal-sized, healthy, term and preterm neonates between 2 days and 7 weeks of life who were receiving all their calories enterally as breast milk or a proprietary formula. We found that there was no peak or pattern in H2 production during the first 3 postprandial hours (mean VeH2 = 1.00 +/- 0.97 SD ml/kg/h; mean ETH2 = 40.3 +/- 33.1 SD ppm). Frequently, there was marked short-term variability of the ETH2 in a given infant (coefficient of variation = 13.4% +/- 18.7%). H2 production was elevated in normal neonates without signs of malabsorption. We found that VeH2 correlated with ETH2 using both nasopharyngeal catheter (r = 0.63; p less than 0.001) and nasal prong (r = 0.71; p less than 0.001) collection techniques. We conclude that breath hydrogen determinations in neonates are not readily comparable to similar studies in older patients. Longitudinal studies of individual infants may reveal changes in breath H2 excretion of sufficient magnitude to be distinguishable from moment-to-moment variations, and correlatable with certain intercurrent clinical problems affecting intestinal H2 production or pulmonary H2 excretion. However, interpretation of breath H2 determinations in human infants will be difficult.

Pulmonary excretion of carbon monoxide in the human infant as an index of bilirubin production. IV. Effects of breast-feeding and caloric intake in the first postnatal week.

Measurements of the pulmonary excretion rate of carbon monoxide (VEco) as an index of bilirubin production in the first several days of life were taken from 64 breast-fed or bottle-fed infants. Twenty-one infants (greater than or equal to 37 weeks of gestation) were breast-fed; 43 infants (28 to 42 weeks of gestation) were bottle-fed a commercially prepared formula. Information pertaining to their caloric intake during the 24-hour period preceding VEco determination was taken from 38 of the 43 infants who were bottle-fed and they were placed into three groups based on their caloric intake: (1) less than or equal to 60 kcal/kg/day (19 infants); (2) 61 to 100 kcal/kg/day (7 infants); and (3) greater than 100 kcal/kg/day (12 infants). There was no significant difference in bilirubin production between bottle-fed and breast-fed infants. No effect of caloric deprivation on bilirubin production was demonstrated. The mean VEco values were 18.5 +/- 0.9 (SE) for group 1, 17.7 +/- 1.8 (SE) for group 2, and 16.2 +/- 1.1 (SE) microliter/kg/hr for group 3.

Pulmonary excretion of carbon monoxide in the human newborn infant as an index of bilirubin production: III. Measurement of pulmonary excretion of carbon monoxide after the first postnatal week in premature infants.

Using a single pass, flow-through system, the excretion rate of endogenously produced carbon monoxide (VeCO) was measured as an index of bilirubin production in 41 Caucasian infants of various gestational ages after the first postnatal week. twenty-one were less than or equal to 32 weeks gestation. The mean slope for the 25 premature infants with multiple VeCO determinations was -0.21 +/- 0.11 (SE) microliters/kg/hour per day (P less than .025, one-tailed). Fifteen premature infants with at least three VeCO determinations during the first 30 days of life had an average decrease in total CO excreted of 1.33% per day compared to the extrapolated initial value of total CO excretion of 27.0 +/- 2.0 (SE) microliters/hour, giving a calculated maximum red cell life span of 75 days.

Pulmonary excretion of carbon monoxide in the human infant as an index of bilirubin production. I. Effects of gestational and postnatal age and some common neonatal abnormalities.

Using a single pass, flow-through system, the pulmonary excretion rate of endogenously produced carbon monoxide was measured as an index of bilirubin production in human infants with varying gestational and postnatal ages and with a variety of clinical abnormalities. No significant difference in VECO was found related to sex or gestational age. The mean VECO for a small group of Oriental infants was significantly increased. VECO decreased with increasing postnatal age. As expected, infants with hemolytic disease of the newborn had a markedly increased mean VECO. Infants with jaundice of unknown etiology also had an elevated mean VECO, implying that increased bilirubin production may be a factor contributing to the "nonphysiologic" bilirubinemias of these infants.

Determing the pulmonary excretion rate of carbon monoxide in newborn infants.

A simplified technique was devised for measurement carbon monoxide excretion rates in newborn infants. Determinations can be performed quickly and repetitively in a noninvasive manner, with a sensitivity sufficient for use even on small preterm infants. Resolution of the method is +/- 4.3 mul/h (SD); however, variations in infant respiration rate may cause much greater changes in actual excretion rate. Preliminary results with five full-term newborn agree to within 15% of previously reported data. The system will be used extensively in ongoing studies involving total bilirubin production as a function of gestational age.