Markers of type I and III collagen turnover as indicators of growth velocity in very low birth weight infants.

Monitoring postnatal growth in very low birth weight (VLBW) infants is complicated by the difficulty of obtaining reliable measurements. A need thus exists for safe and reliable indicators of such infants' short-term growth velocity. We set out to study whether markers of type I collagen synthesis [amino-terminal propeptide of type I procollagen (PINP)] or degradation [via the matrix metalloproteinase pathway, carboxyl-terminal telopeptide of type I collagen (ICTP)] or of type III collagen synthesis [amino-terminal propeptide of type III procollagen (PIIINP)] could serve as such indicators. PINP, ICTP, and PIIINP were measured for 48 VLBW infants (mean birth weight, 923 g; range, 540-1485 g; mean gestational age, 27.6 wk; range, 23.7-32.7 wk) at the age of 1, 2, 4, and 8 wk. At each time point, these were compared with concurrent growth velocity rigorously assessed by frequent lower leg (knemometry) and weight measurements. PINP showed a significant positive correlation with lower leg growth velocity at 1, 2, and 4 wk and with weight growth velocity at 2, 4, and 8 wk. PIIINP showed a significant positive correlation with lower leg growth at 1, 2, and 8 wk and with weight growth at 2 and 8 wk. The ICTP/PINP ratio, reflecting type I collagen degradation in relation to its synthesis, showed close negative correlations with lower leg growth at 1 wk (r = -0.46; P = 0.003), 2 wk (r = -0.51; P = 0.002), and 4 wk (r = -0.56; P = 0.001) and with weight growth at 2 wk (r = -0.39; P = 0.018), 4 wk (r = -0.59; P = 0.0003), and 8 wk (r = -0.53; P = 0.005). A high ICTP/PINP ratio was an accurate predictor of impaired growth; a high ICTP/PINP ratio was a more rapid and at least as sensitive and specific indicator of slow growth as weight gain. We conclude that PINP, PIIINP, and the ICTP/PINP ratio all reflect postnatal growth velocity in VLBW infants. The most robust of these indicators is the ICTP/PINP ratio, which may thus serve as a clinical tool in assessing short-term growth of these infants.

Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life.

OBJECTIVE: To find a dose of fluconazole for very low birth weight infants during an outbreak of Candida parapsilosis. METHODS: Twelve premature infants (mean gestational age, 27.4 weeks; mean birth weight, 912 gm) receiving fluconazole prophylactically from the first day of life were enrolled in an open phase I-II pharmacokinetics, safety, and tolerance trial. Up to 5 doses of 6 mg/kg were administered intravenously every 72 hours during the first 2 weeks of life. Pharmacokinetic characteristics of fluconazole were determined after the first, third, and fifth doses. RESULTS: The mean peak and trough concentrations after the 3 doses were 5.5 and 2.6 micrograms/ml, 12.8 and 4.3 micrograms/ml, and 10.0 and 2.9 micrograms/ml (p = 0.0002 and p = 0.07), respectively. The mean fluconazole half-lives were 88.6 hours (n = 7), 67.5 hours (n = 9), and 55.2 hours (n = 4; p = 0.3). The mean total clearance corrected for weight (CL/kg) was 0.18 ml/min/kg (n = 7), 0.33 ml/min/kg (n = 7), and 0.52 ml/min/kg (n = 4; p = 0.02), and the mean volume of distribution 1.18 L/kg (n = 7), 1.84 L/kg (n = 7), and 2.25 L/kg (n = 4; p = 0.05). Weight-corrected clearance increased with postnatal age (r = 0.61; p = 0.007). CONCLUSIONS: With the used fluconazole dose (6 mg/kg every 3 days), the mean serum peak and trough concentrations increased during the first week but decreased during the second week. After the first week we suggest a dose of 6 mg/kg every 2 days, or even daily.

Neonatal Candida parapsilosis outbreak with a high case fatality rate.

A Candida parapsilosis outbreak of 58 cases in a neonatal intensive care unit lasted for 55 months. Patients infected by or colonized with C. parapsilosis were mainly very low birth weight infants (birth weight < 1500 g). Their mean birth weight was 817 g and their mean gestational age was 28 weeks. Statistical analysis including logistic regression confirmed that prematurity was the main risk factor. The analysis also suggested that C. parapsilosis infection (or colonization) was associated with a poor prognosis. In infants with gestational age < 29 weeks the risk for death in C. parapsilosis-infected patients was 16-fold greater than in those with no C. parapsilosis infection. The case fatality rate of C. parapsilosis patients was higher than that of the controls (9 of 23 vs. 1 of 40; P < 0.0001). The outbreak was most likely a result of cross-infection because C. parapsilosis could be isolated only from the patients and from the hands of four nurses immediately after they had cared for a colonized patient. Cessation of the outbreak was temporally associated with long term parenteral fluconazole (6 mg/kg/day) prophylaxis.

Diagnosis of fatal infantile defects of the mitochondrial respiratory chain: age dependence and postmortem analysis of enzyme activities.

We studied two diagnostic aspects of fatal infantile defects of the mitochondrial respiratory chain: the age dependence of muscle mitochondrial enzyme activities and the reliability of diagnosis from autopsy samples. In morphologically normal quadriceps muscle samples of 46 children between the ages of 3 days and 15 years, activities of complex I plus III (NADH:cytochrome c oxidoreductase) and complex II plus III (succinate:cytochrome c oxidoreductase) increased 2-fold during the first three years of life, while that of complex II (succinate dehydrogenase), complex IV (cytochrome c oxidase), and citrate synthase did not show significant correlation with age. We suggest that these changes are related to age and stress the importance of strictly age-matched controls when diagnosing a mitochondrial disease of early childhood. The value of autopsy samples in diagnostic studies was evaluated by comparing mitochondrial enzyme activities in quadriceps muscle from autopsies and from surgical biopsies. In quadriceps muscle mitochondria, all the enzyme activities studied remained stable for at least 3 h after death. Using age-matched controls and autopsy samples, we diagnosed a respiratory chain enzyme deficiency in two infants, and the defects were confirmed in cultured skin fibroblasts.

Intraindividual variability of infant whole-body plethysmographic measurements: effects of age and disease.

The intraindividual variability of whole-body plethysmographic measurements was studied in a large series of consecutive infants (N = 144), divided into two groups: a group of infants born very prematurely (PM, N = 63), with (N = 28) or without (N = 35) a history of bronchopulmonary dysplasia (BPD), and a group of infants with persistent respiratory symptoms (PRS, N = 81), i.e., wheezing (N = 53) or cough (N = 28). The intraindividual variability was determined within each test and between tests, separated by a 10-min interval. In both study groups, the between-test variability was significantly larger than that within tests. Expressed as the median coefficient of variation (CV), the between-test repeatabilities in the PRS group were 8.0% for thoracic gas volume (TGV), 17.5% for airway resistance (Raw), and 18.4% for specific airway conductance (sGaw), and in the PM group, 8.9% for TGV, 20.4% for Raw, and 20.7% for sGaw. However, the individual range of CVs was large, ranging from 3 to 19% for TGV and from 5 to 55% for sGaw. With respect to TGV, the difference between the groups was statistically significant (P = 0.03). In infants with a history of BPD, there was also a significant negative age dependency in CVs of sGaw (r = -0.50, P = 0. 009), showing larger variation among younger individuals. The presenting symptom (wheezing or cough) in the PRS group did not influence the measurement variability significantly, and neither did the degree of bronchial obstruction. We conclude that on a group basis, the repeatability of infant body plethysmographic measurements may be satisfactory for scientific studies demonstrating pharmacodynamic effects; however, the intraindividual measurement variability should be reported for each test conditions and for infant groups in each study. Due to the large range in individual variation and the influence of age and disease processes on the variation, for an individual child there is only questionable benefit from a given measurement, unless the intrasubject, between-test variability is assessed individually before interventions, such as a bronchodilation test.

Maturation of mismatch negativity in infants.

The mismatch negativity (MMN) is a pre-attentive change-specific component of the event-related brain potentials (ERPs). During the last decade this response has been intensively studied in adults, but investigations in children and especially in infants are still rare. Recent studies, however, have shown that MMN is also elicited in infants in response to changes in pure tones as well as in phonemes. The present study compared MMN in pre-term infants (conceptional age at the time of recording, 30-35 weeks), full-term newborns and full-term 3-month-old infants. Stimuli were Klatt-synthesized Finnish vowels /y/ and /i/. Previous studies have reported larger MMN amplitudes in school-age children compared with those obtained in adults. According to the results, however, the infant MMN amplitude seems to resemble that of adults. No significant differences in MMN amplitudes were found between the three age groups either. The mean MMN latency, however, decreased significantly with age, although in 3-month-old infants it was not much longer than in a previous study conducted in adults with the same stimuli.

Plasma immunoreactive beta-endorphin and cortisol in the newborn infant after elective caesarean section and after spontaneous labour.

The effect of the mode of delivery on the plasma concentration of immunoreactive beta-endorphin (irbeta-E) and cortisol was studied in 27 newborn infants, 10 delivered by caesarean section and 17 by spontaneous vaginal labour. After elective caesarean section, the mean plasma concentration of cortisol rose from 227 +/- 27 nmol/l (S.E.) at birth to 705 +/- 90 nmol/l at the age of 2 h, indicating a significant increase in cortisol secretion, and the mean irbeta-E remained high, being 111 +/- 24 ng/l at birth and 117 +/- 21 ng/l at the age of 2 h. After spontaneous labour, the plasma cortisol level was already high at birth, 735 +/- 78 nmol/l, and remained so to the age of 2 h, 659 +/- 43 nmol/l, whereas the plasma irbeta-E decreased from 181 +/- 29 at birth to 64 +/- 7 ng/l at the age of 2 h. All newborns were in a good condition except one in whom transitory tachypnea developed during the follow-up. In this newborn the plasma level of irbeta-E increased greatly: from 210 ng/l to 705 ng/l. These results show that, irrespective of the route, the delivery is stressfull to the newborn infant. In newborns delivered by caesarean section the stress response comes after birth. Additional stress such as respiratory difficulties seems to increase the secretion of beta-endorphin.

Total parenteral nutrition-associated cholestasis in surgical neonates may be reversed by intravenous cholecystokinin: a preliminary report.

Neonatal infants who require total parenteral nutrition (TPN) after major operations are susceptible to total parenteral nutrition-associated cholestasis (TPNAC). A therapeutic dilemma ensues if cholestasis does not resolve after the institution of full enteral nutrition. The authors report the reversal of TPN-associated cholestasis by intravenous cholecystokinin in eight infants who had undergone major surgery during the neonatal period. The indications for surgery were necrotizing enterocolitis in three patients, midgut volvulus in one, gastroschisis in one, diaphragmatic hernia in one, necrosis of the stomach in one, and cardiac anomaly in one. Four of the infants were premature. Median duration of TPN was 25 days (range, 20 to 150 days). Seven patients were weaned from TPN before treatment with cholecystokinin was instituted Mean duration of pretreatment full enteral nutrition in these seven patients was 35 days (range, 20 to 55 days). One girl with short gut syndrome tolerated only 10% of her caloric needs via the enteral route. All patients had alcoholic stools, conjugated hyperbilirubinemia, no excretion of Technetium-labeled HIDA to the biliary tree or duodenum (six patients), and significantly elevated liver enzyme values. In three patients, echography showed biliary sludge or stones in the gall bladder. Porcine cholecystokinin (2 IDU/kg) was administered intravenously for 3 to 5 days. If the stool color did not normalize, cholecystokinin injections were repeated using a larger dose (4 IDU/kg). In seven patients, including the girl with short gut syndrome, the clinical jaundice and conjugated hyperbilirubinemia completely resolved within 1 to six weeks. No biliary sludge or stones were seen in the posttreatment echography in any of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgical treatment of intractable cholestasis associated with total parenteral nutrition in premature infants.

We report surgical reversal of intractable total parenteral nutrition (TPN)-associated cholestasis refractory to conservative treatment in 9 premature infants. Indications for TPN were poorly tolerated enteral feedings in all patients. Five patients had undergone gastrointestinal operations; in addition, 7 of the 9 patients had had bacterial sepsis. The median duration of TPN was 28 days (range, 20 to 50 days). The median duration of preoperative full enteral nutrition after weaning from TPN was 34 days (range, 16 to 95 days). All patients had progressive conjugated hyperbilirubinemia, no excretion of Tc-labeled HIDA to the biliary tree and duodenum, and markedly elevated liver enzyme values. Intraoperative cholangiography showed normal biliary anatomy in all cases; in addition, 2 patients had gallbladder stones. Bile was hyperviscous in all patients and contained biliary sludge in 4. The biliary tree was irrigated and the liver biopsied in all patients. The gallbladder was removed from 2 patients who had stones in the gallbladder. Liver histology was consistent with TPN-associated cholestasis in all cases, and in addition, 4 cases showed significant destruction of intrahepatic bile ducts. One patient died 2 weeks postoperatively from intracerebral hemorrhage. Jaundice completely resolved in other patients within 2 weeks. HIDA-biligraphy performed 1 to 2 months postoperatively showed normal excretion of the radioactive marker to the biliary tree and duodenum in all cases. The functional abnormality in bile excretion and bile duct motility in TPN-associated cholestasis may be reversed by irrigation of the biliary tree. Surgical intervention should be considered when cholestasis is progressive and refractory to medical management.

Hemodynamic significance of vasopressin in the newborn infant.

In 21 normal deliveries, high concentrations of arginine vasopressin in cord arterial blood were associated with higher blood pressure and lower skin temperatures, indicating peripheral vasoconstriction. Following cesarean section after the onset of labor, cord AVP concentrations and blood pressures were lower than after normal delivery, but higher than after elective cesarean section. Maternal AVP concentrations at delivery were normal, as were plasma AVP concentrations in all infants three days after delivery. We conclude that the massive release of vasopressin is associated with normal delivery, and with peripheral vasoconstriction. These findings reflect favorable hemodynamic adaptation to the hypoxia and stress of delivery, intended to redistribute cardiac output to vital organs.

Vasopressin, ACTH and neonatal haemodynamics.

In 21 normal deliveries, high concentrations of AVP and ACTH in cord blood were associated with higher blood pressure and lower skin temperature, indicating peripheral vasoconstriction. Following Caesarean section after the onset of labour (n = 8), cord AVP concentrations and blood pressures were lower than after normal delivery but higher than after elective Caesarean section (n = 9). Maternal AVP concentrations at delivery were normal, as were plasma AVP concentrations in all infants 3 days after delivery. The relationship between vasopressin, a potential ACTH releasing factor, and ACTH was interesting. We conclude that the massive release of vasopressin is associated with normal delivery, elevated ACTH values and with peripheral vasoconstriction. These findings reflect favourable adaptation to hypoxia and stress of delivery, intended to redistribute cardiac output to vital organs and may provide for physiological adjustments necessary for extrauterine life.

The effects of acute and chronic perinatal stress on plasma vasopressin concentration and renin activity at birth.

The effects of acute and chronic intrauterine stress on plasma vasopressin (AVP) concentration and renin activity (PRA) in the cord blood of 36 newborn infants were studied. AVP concentrations in the umbilical artery were significantly higher than those in the umbilical vein in all infants, except in those delivered by elective cesarean section after normal pregnancy. AVP concentrations in the umbilical arterial blood after normal term pregnancy and vaginal delivery (779 pg/ml, log mean) were higher than those in the cord blood of infants delivered vaginally after maternal hypertensive disease (198 pg/ml). Compared to the values of the latter group, the AVP values were significantly lower (39 pg/ml) in infants delivered by cesarean section without labor because of severe growth retardation and decreased heart rate variability. The group of normal term infants delivered by elective cesarean section after normal pregnancy had the lowest AVP concentrations (13 pg/ml). PRA in the umbilical arterial blood was not different from that in the umbilical venous blood. The highest mean level of PRA (14.5 ng/ml/h) was observed in premature infants delivered by cesarean section because of fetal growth retardation and pathological heart rate variability, and the lowest mean level in term infants delivered by elective cesarean section (3.4 ng/ml/h). PRA was significantly increased in term infants delivered vaginally after normal pregnancy (7.8 ng/ml/h) or after hypertensive pregnancy (11.7 ng/ml/h) in comparison to that of term infants delivered by elective cesarean section.(ABSTRACT TRUNCATED AT 250 WORDS)

Fetal and neonatal prostacyclin and thromboxane in relation to mode of delivery.

To study whether prostacyclin and thromboxane A2 might play a role in neonatal adaption pieces of the umbilical arteries of infants born vaginally (n = 18) or by elective caesarean section (n = 11) were superfused in vitro and the release of 6-keto-PGF1a (hydration product of prostacyclin) and thromboxane B2 (metabolite of thromboxane A2) measured by radioimmunoassay. In addition, the capacity of fetal platelets to produce thromboxane A2 and the neonatal urinary concentrations of 6-keto-PGF1a were measured. Infants born by caesarean section had lower diastolic blood pressure, higher heart rate, and smaller differences between rectal and skin temperature compared with infants born vaginally during the first two hours of life. The only difference encountered in the prostanoids between the groups was reduced urinary excretion of 6-keto-PGF1a in infants born by caesarean section, whose release of 6-keto-PGF1a by the umbilical artery was positively correlated with heart rate, respiration frequency, and dermal temperature. Thus prostacyclin may be a regulatory determinant, particularly in infants born by caesarean section.

Analysis of neonatal heart rate variability by a microprocessor-based on-line system.

The effects of different rejection logic limits on the results of analysis of neonatal heart rate variability from electrocardiograms by a microprocessor-based system were studied on fourteen infants after normal labor and on ten infants after elective cesarean section. In addition to the infant's movements and crying, two further main sources of error in the calculation of variability indices were detected: premature beats and problems in the shape of QRS complexes in a neonatal electrocardiogram. No noteworthy problem was observed in the calculation of the interval index (II), which describes the long term variability of heart rate. In the calculation of the differential indices (DI), which describe the short term component of heart rate, distorted QRS complexes created very high DIs when the rejection logic was ten beats per minute (bpm). When stricter rejection limits were used (five bpm), the DI values even in these cases fell within the normal range. The DI values calculated using a rejection limit of five bpm were always lower than those calculated using a rejection limit of ten bpm, but the reference values of neonatal II and DI after normal labor were similar to those presented previously using a rejection limit of ten bpm. In conclusion, the neonatal electrocardiogram appears to be a noisy signal, comparable with the abdominal fetal electrocardiogram, and strict rejection limits are useful in processing it for indices of variability.

Fatal outcome of two siblings with idiopathic arterial calcification of infancy diagnosed in utero.

Idiopathic arterial calcification of infancy (IACI) is a rare condition characterized by extensive arterial calcification and stenoses of large and medium-sized arteries. Its complications include severe cardiac failure diagnosed in utero as hydrops fetalis or postnatally as respiratory failure combined with cardiomegaly. Two newborn male siblings with IACI are described. In utero, echocardiography revealed poor ventricular function and hyperechogenic foci in arterial walls. Both had fatal outcome during the newborn period. At autopsy, medial calcifications in the walls of great arteries, in coronary arteries, in glomeruli, and in subendocardium were detected. In addition, an inflammatory process in the shoulder joint was determined to be large periarticular tissue calcifications. Because of an autosomal recessive inheritance pattern of IACI, fetal echocardiography is recommended in future pregnancies of all affected families.

Inositol supplementation in respiratory distress syndrome.

According to preliminary results inositol (INO) is an important nutrient to immature preterm infants (J Pediatr 1987; 110:604). However, it is absent in nutrition of critically ill very low birth weight infants. In a present randomized double blind trial INO or glucose (70-100 mg/kg/day) was given to altogether 230 preterm infants (gestation 24 to 31 w, mean 27.8 w, mean BW 1,106 g) with RDS during 5 neonatal days. Two more courses during the first month were given, if the infant remained respirator-dependent and did not tolerate breast milk. INO-supplemented infants tended to have a milder respiratory course during the first week than those on glucose. The surviving INO-treated infants had a lower incidence of bronchopulmonary dysplasia (BPD) than the controls (p less than 0.01). No infant receiving INO had severe retinopathy (gr 4), whereas of the surviving placebo treated infants 8.8% became blind (p less than 0.005). Inositol promotes endothelial cell growth, enhances glucocorticoid-mediated lung epithelial cell differentiation, and may serve as an antioxidant. INO should be seriously considered as a nutrient during compromised neonatal transition of very low birth weight infants.

Effect of surfactant substitution on lung effluent phospholipids in respiratory distress syndrome: evaluation of surfactant phospholipid turnover, pool size, and the relationship to severity of respiratory failure.

The turnover and pool size of surfactant has been studied in animals, but there is little similar information in humans. In the present investigation lung effluent phospholipids were studied in 29 small preterm infants with severe RDS. Thirteen were treated with mechanical ventilation, and 16 additionally received natural human surfactant. The first dose (60 mg surfactant/kg body wt) was given between 2 and 10 h of age, and the surfactant was given again if there was an insufficient response. Together 260 aspirates, recovered during routine suctioning of the airways, were analyzed for phospholipids. Phosphatidylglycerol, present only in exogenous surfactant, was used as a specific marker to estimate the apparent pool size and the half-life of surfactant phospholipid. In addition, the saturated phosphatidylcholine/sphingomyelin ratios were correlated with the ventilatory index (mean airway pressure X fractional inspiratory oxygen/arterial oxygen tension). There was a linear correlation between the ventilatory index and the saturated phosphatidylcholine/sphingomyelin (r approximately -0.70) but no consistent correlation between the ventilatory index and the amount of phospholipids in the aspirate. The saturated phosphatidylcholine/sphingomyelin ratio increased during the surfactant-induced remission of respiratory failure, decreased during the recovery. The control infants tended to have lower saturated phosphatidylcholine/sphingomyelin ratios during the first week than the surfactant-treated infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Age dependence of human plasma renin substrate.

Renin substrate (angiotensinogen) was measured with an assay employing exhaustive incubation of plasma with purified human kidney renin and radioimmunoassay of the angiotensin I (AI) generated. Plasma renin substrate concentration was higher at the age of 3 days (females: 2028 +/- 551, males: 1951 +/- 565 micrograms AI/l, mean +/- SD) than in age group 0-15 years (females: 1513 +/- 555, males: 1263 +/- 392 micrograms AI/l). Plasma renin substrate concentration at the age over 15 years (females: 1780 +/- 464, males 1752 +/- 321 micrograms AI/l) was higher than in children 0-15 years. Expectedly, high concentrations of plasma renin substrate were found in pregnant women at term (4127 +/- 1961 micrograms AI/l).