Investigation of urine proteome of preterm newborns with respiratory pathologies.

A serious problem during intensive care and nursing of premature infants is the invasiveness of many examination methods. Urine is an excellent source of potential biomarkers due to the safety of the collection procedure. The purpose of this study was to determine the features specific for the urine proteome of preterm newborns and their changes under respiratory pathologies of infectious and non-infectious origin. The urine proteome of 37 preterm neonates with respiratory diseases and 10 full-term newborns as a control group were investigated using the LC-MS/MS method. The total number of identified proteins and unique peptides was 813 and 3672 respectively. In order to further specify the defined infant-specific dataset these proteins were compared with urine proteome of healthy adults (11 men and 11 pregnant women) resulting in 94 proteins found only in infants. Pairwise analysis performed for label-free proteomic data revealed 36 proteins which reliably distinguished newborns with respiratory disorders of infectious genesis from those with non-infectious pathologies, including: proteins involved in cell adhesion (CDH-2,-5,-11, NCAM1, TRY1, DSG2), metabolism (LAMP1, AGRN, TPP1, GPX3, APOD, CUBN, IDH1), regulation of enzymatic activity (SERPINA4, VASN, GAPDH), inflammatory and stress response (CD55, CD 93, NGAL, HP, TNFR, LCN2, AGT, S100P, SERPINA1/C1/B1/F1).

Developmental pattern of urinary bile acid profile in preterm infants.

BACKGROUND: Bile acid metabolism in preterm infants is yet to be fully characterized. We compared the developmental pattern of urinary bile acid profiles in ten infants born at gestational ages from 25 to 33 weeks with previous data from full-term infants from birth to about 7 months of age. METHODS: Gas chromatography-mass spectrometry was performed on serial samples. RESULTS: Total urinary bile acid concentrations gradually increased until 1 to 2 months of age. After this peak of excretion (30 to 60 micromol/mmol creatinine), total urinary bile acid concentrations gradually decreased to less than 20 micromol/mmol creatinine. The percentage of usual bile acids (mainly cholic acid) relative to total urinary total bile acids gradually deceased from approximately 30% at birth to less than 15% at 7 months of age. On the other hand, 1beta-hydroxylated bile acids (mainly 1beta,3alpha,7alpha,12alpha-tetrahydroxy-5beta-cholan-24-oic acid) relative to total urinary bile acids were increased gradually from 60% at birth to reach 70% to 80% at 1 month of age. The percentage of 1beta-hydroxylated bile acids relative to total urinary bile acids then remained stable at a high percentage (70% to 90%) until the age of 7 months. CONCLUSION: Physiological cholestasis in preterm infants persists longer than in full-term infants. Moreover, as large amounts of cholic and 1beta,3alpha,7alpha,12alpha-tetrahydroxy-5beta-cholan-24-oic acids were detected in urine from preterm infants during this study, the 25-hydroxylation pathway may be particularly important for bile acid synthesis in early preterm infants.

Correlation between plasma and urinary caffeine levels in preterm infants.

BACKGROUND: We hypothesize that urine levels might be reliable to assess the therapeutic range of caffeine. OBJECTIVES: We correlated plasma and urinary levels of caffeine in preterm infants treated with this drug for apnea of prematurity. METHODS: Infants (n=56) were given a loading dose of caffeine citrate (10 mg/kg, per os) and 24 h later a maintenance dose (2 mg/kg, per os, once a day). Plasma and urinary levels of caffeine were determined 24 h after the loading dose (before administration of the maintenance dose) and then weekly. RESULTS: Plasma and urinary levels correlate at all examined ages: 29 weeks (r=0.92, P<0.001), 30 weeks (r=0.97, P<0.001), 31 weeks (r=0.82, P<0.001), 32 weeks (r=0.92, P<0.001), 33 weeks (r=0.87, P<0.001), 34 weeks (r=0.81, P<0.001). CONCLUSION: Urinary levels of caffeine might be a useful means to assess therapeutic ranges.

Randomized, controlled trial of oral creatine supplementation (not effective) for apnea of prematurity.

BACKGROUND: Hypoxic ventilatory depression in mice and muscle fatigue in adult humans are improved by creatine supplementation (CS). Because these issues may be operative in apnea of prematurity (AOP), we hypothesized that CS reduces episodes of hypoxemia and bradycardia in infants with AOP. METHODS: Infants were eligible for this double-blind, controlled trial if gestational age was <32 weeks and AOP was severe enough to require treatment with caffeine. If they had > or = 1 desaturation (pulse oximeter saturation [SpO2] < or = 80%) or bradycardia (heart rate < or = two thirds of baseline) per hour in an initial 6-hour recording, they were randomized to a 2-week course of oral CS (200 mg/kg per day) or placebo (P). Infants then underwent 2 additional 6-hour recordings of breathing movements, nasal airflow, heart rate, pulse oximeter saturation (SpO2) and pulse waveforms after 7 and 14 days of treatment. Urinary creatine excretion was measured also. Recordings were analyzed for the frequency of bradycardia and desaturation, the primary outcome parameter, as well as for apnea (> or =10 seconds), baseline heart and respiratory rate, and SpO2. RESULTS: Of 38 infants enrolled, 34 completed the study (17 in each group). Median (range) gestational age at birth was 27 (25-30) vs 27 (25-30) weeks, and at study 29 (26-36) vs 29 (27-33) weeks. Oral CS was well tolerated; no side effects were noted. Urinary creatine excretion was low in the P group (median: 27 mmol/mol of creatinine; range: 18-102) and increased in the CS group (6949 mmol/mol of creatinine; range: 1427-11807). CS, however, had no effect on the combined rate of bradycardia and desaturation (P: 2.7 per hour [range: 0.2-10.3]; CS: 4.1 per hour [range: 0.6-12.1]), nor was there any decrease in apnea rate (P: 1.7 per hour [range: 0-4.5]; CS: 2.2 per hour [range: 0.2-5.1]). CONCLUSION: Despite a significant increase in creatine excretion, suggesting good enteral absorption, CS did not, in the dose and for the duration given in this study, improve symptoms of AOP in these infants.

Central apnoea and endogenous prostaglandins in neonates.

AIM: Central apnoeas without an identifiable precipitating cause frequently occur in the neonatal period. Serious apnoeas should be treated with ventilation-enhancing methylxanthines. Drugs such as opioids or prostaglandins (PGE2) are known to induce apnoea. PGE2 is an endogenous hormone that plays an important role in the regulation of neural activity and a relationship between PGE2 and central apnoeas has been postulated. METHODS: In order to test the hypothesis that the incidence of central apnoeas in preterm infants is related to endogenous PGE concentration, we measured the urinary concentration of PGE2 and PGE-M and determined the number of central apnoeas >10 s/12 h in overnight polygraphy in 18 preterm infants with apnoeas, bradycardias and desaturations, and 18 normal controls. RESULTS: We found 80.6 (SE 6.9) central apnoeas in the study group, and 52.9 (SE 4.1) in the control group (p = 0.002). Urinary PGE2 concentration was 25.9 (SE 6.1) ng/h/1.73 m2 in the control, 31.2 (SE 15.8) ng/h/1.73 m2 in the study group (p = n.s.), PGE-M concentration was 486 (SE 35) ng/h/1.73 m2 in the control and 1132 (SE 131) ng/h/1.73 m2 in the study group (p < 0.0001). There was a significant correlation between the number of central apnoeas and the PGE-M concentration in the study group (r = 0.68, p < 0.0001). CONCLUSION: Our results suggest a relationship between PGE and the respiratory system and open potential therapeutic options for the treatment of central apnoeas in neonates.

Deficient sympatho-adrenal activity-a cause of apnoea? Urinary excretion of catecholamines and their metabolites in preterm infants.

Catecholamines (CA) and the CA metabolites 4-hydroxy-3-methoxyphenyl-glycol (HMPG) and 4-hydroxy-3-methoxymandelic acid (VMA) have been determined in 8 preterm infants with recurrent apnoea and in 6 infants with the same birth weight total CA, HMPG or VMA excretion was found during the second, fifth and twelfth day, except for adrenaline, which was higher in the low-apnoeic group during one day.

Urinary biogenic amines in idiopathic apnea of prematurity.

Urinary biogenic amines were measured in 22 preterm infants of less than 36 weeks' gestational age. Fifteen of these infants had idiopathic apnea. Although levels of urinary dopa were not significantly different, dopamine, norepinephrine and epinephrine were all significantly lower in the infants with apena. It is proposed that apnea of prematurity may be related to an immaturity of catecholamine-producing pathways, leading to inadequate physiologic responses to hypoxia, with resulting accentuation of central respiratory depression. Alternatively, urinary biogenic amines may be a reflection of some unrelated process occurring elsewhere in the body or a depletion of catechol stores resulting from the apnea itself.