Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants.

OBJECTIVE: To investigate pharmacokinetics and pharmacodynamics of rectally administered acetaminophen (INN, paracetamol) in term neonates directly after birth. METHODS: In this prospective clinical trial, term neonates wtih painful conditions or who were undergoing painful procedures received multiple-dose acetaminophen. Serum concentrations were determined serially with an HPLC method, and pharmacokinetic analysis was performed. Pain assessment was performed by means of a validated pain score. RESULTS: Ten consecutive term neonates received four rectal doses of acetaminophen, 20 mg/kg body weight, every 6 hours. Mean peak serum concentrations (+/-SD) during multiple-dose administration were 10.79 +/- 6.39 mg/L, 15.34 +/- 5.21 mg/L, and 6.24 +/- 3.64 mg/L for the entire group, boys, and girls, respectively. There was a significant difference between the boys and the girls (P = .01). No serum concentrations associated with toxicity (>120 mg/L) were found. Median time to peak serum concentration was 1.5 hours after the first dose and 15 hours for multiple doses. Mean (+/-SD) half-life was 2.7 +/- 1.4 hours in eight patients. There was no correlation between dose and serum concentration or between pain score and serum concentration. There was a significant inverse relationship between the preceding pain score and peak serum concentrations. CONCLUSIONS: In term neonates, multiple rectal doses of acetaminophen, 20 mg/kg body weight, led to widely varying serum concentrations but did not result in therapeutic concentrations in all infants. Boys had higher peak concentrations. Because accumulation was not found, a dose of 30 mg/kg followed by doses of 20 mg/kg at 6- to 8-hour administration intervals are appropriate to reach therapeutic concentrations. A concentration-effect relationship could not be determined.

Erythrocyte and plasma cholesterol ester long-chain polyunsaturated fatty acids of low-birth-weight babies fed preterm formula with and without ribonucleotides: comparison with human milk.

We investigated whether a regular formula for premature infants (pre) supplemented with ribonucleotides (pre+RN) raises erythrocyte and plasma cholesterol ester (CE) long-chain polyunsaturated fatty acids (LCPUFAs) of low-birth-weight babies (< or = 2.50 kg) compared with their breast-fed counterparts. From days 11 to 42, 31 babies received the pre formula and 37 received pre+RN. Eleven breast-fed babies served as a reference group. Erythrocytes and CE fatty acids were determined on days 11, 21, and 42. There were no differences in the courses of erythrocytes and CE fatty acids between pre formula-fed and pre+RN-fed babies. On day 42, formula-fed babies had lower erythrocytes and CE n-3 and n-6 LCPUFAs compared with breast-fed babies. Subdivision into gestational age- and body weight-matched subgroups gave similar results. RN supplementation does not augment the erythrocyte and CE LCPUFA status of formula-fed babies.

Fat absorption in neonates: comparison of long-chain-fatty-acid and triglyceride compositions of formula, feces, and blood.

We studied malabsorption of fat in neonates who were fed either a lard-modified formula (n = 22, gestational age, 33.6 +/- 3.9 wk) or an unmodified formula (n = 14, gestational age, 34.1 +/- 3.7 wk). In both groups fecal lipid consisted almost completely (greater than 90%) of free fatty acids, whose composition was highly correlated with the corresponding formula's fatty acid composition [r = 0.96 (lard modified) and r = 0.99 (standard)]. Both groups had similar relative amounts and compositions of fecal cholesterol esters and triglycerides. Plasma and, to a lesser extent, erythrocyte membrane long-chain-fatty-acid compositions correlated with those of the corresponding formulas. We suggest that the extensive intestinal hydrolysis and limited absorption of dietary lipids is, at least partly, due to lipolysis in the colon. Appearance of triglycerides in the colon may be due to a rapid small-intestinal passage in relation to small-intestinal lipolysis.

Incidence of forearm and hand ischaemia related to radial artery cannulation in newborn infants.

We report the incidence of transient and permanent ischaemia of the forearm and hand caused by radial artery cannulation in a series of 98 newborn infants. Birth weight ranged from 550 to 3920 g (median 1600 g) and gestational age ranged from 26 to 40 weeks (median 31 weeks). In 4 of the 98 infants transient ischaemia of the forearm and/or hand occurred. In three infants the onset of ischaemia was probably related to thrombo-embolic events and in one infant to inadequate palmar collateral circulation. Permanent ischaemic damage with tissue loss did not occur in any infant. It is concluded that permanent ischaemic damage to the forearm and/or the hand with tissue loss, attributable to radial artery cannulation, is seldom encountered in newborn infants. In minimizing the risk of ischaemia, careful assessment of palmar collateral circulation prior to cannulation and of all factors predisposing to the onset of ischaemia is essential. Immediate removal of the catheter at the earliest signs of ischaemia, is essential to prevent ensuing tissue loss.

Determination of low isotopic enrichment of L-[1-13C]valine by gas chromatography/combustion/isotope ratio mass spectrometry: a robust method for measuring protein fractional synthetic rates in vivo.

A method was developed for measuring protein fractional synthetic rates using the N-methoxycarbonylmethyl ester (MCM) derivative of L-[1-13C]valine and on-line gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). The derivatization procedure can be performed rapidly and GC separation of valine from the other branched-chain amino acids, leucine and isoleucine, is easily obtained. A good linear relationship was observed between the increment of the 13C/12C isotope ratio in CO2 gas derived from the combustion of derivatized valine and the tracer mole ratio of L-[1-13C]valine to unlabelled valine. The limit of quantitation was at an L-[1-13C]valine tracer mole ratio of 0.0002. The method was used to measure the isotopic enrichment of L-[1-13C]valine in standard mixtures and in skeletal muscle of six growing piglets infused with L-[1-13C]valine (2 mg kg-1 h-1 for 6 h). After infusion of L-[1-13C]valine the mean tracer mole ratio in plasma of L-[1-13C]valine at the isotopic steady state was 0.0740 +/- 0.0056 (GC/MS, mean +/- SEM) and the mean tracer mole ratio of valine in muscle protein fraction at 6 h was 0.000236 +/- 0.000038 (GC/C/IRMS). The resulting mean protein fractional synthetic rate in piglet skeletal muscle was 0.052 +/- 0.007% h-1, which is in good agreement with literature data obtained with alternative, more elaborate techniques. By this method protein fractional synthetic rates can be measured at low isotopic enrichment levels using L-[1-13C]valine, the MCM derivative and on-line GC/C/IRMS.

Does supplementation of formula with evening primrose and fish oils augment long chain polyunsaturated fatty acid status of low birthweight infants to that of breast-fed counterparts?

We investigated whether formulae with evening primrose and fish oils raise long chain polyunsaturated fatty acids (LCPUFA) in plasma cholesterol esters (CE), erythrocytes (RBC) and platelets (PLT) to levels encountered in breast-fed infants. Low birthweight infants (< or =2500 g) received LCP1 formula (n = 16; 0.31% 18:3 omega6, 0.17% 20:5 omega3 and 0.20% 22:6 omega3) or LCP2 formula (n = 13; 0.32% 18:3 omega6, 0.34% 20:5 omega3 and 0.43% 22:6 omega3). Fatty acids were measured days 10+/-2, 20+/-3 and 42+/-3. The formulae raised CE, RBC and PLT 20:5 omega3 and 22:6 omega3 dose-dependently (P<0.01), to exceed levels of breast-fed babies (n = 18) day 42 (P<0.05). CE, RBC and PLT 20:3 omega6 was comparable with, and CE, RBC, PLT 20:4 omega6 were below, that of breast-fed infants (P<0.05). Dietary 20:5 omega3 and 22:6 omega3 related with CE, RBC and PLT 20:5 omega3 and 22:6 omega3 (n = 47; P< or =0.01). Dietary 20:5 omega3 and LCPUFA omega3 related inversely with CE, RBC and PLT 20:4 omega6 and LCPUFA omega6 (P< or =0.002). LCP1 and LCP2 fed infants had similar LCPUFA omega6 status day 42. Added 18:3 omega6 does not correct 20:4 omega6 to that of breast-fed infants, but improves 20:3 omega6 status. Fish oil dose-dependently raises 20:5 omega3 and 22:6 omega3, but decreases 20:4 omega6 and other LCPUFA omega6.

Development of low-birthweight infants at 19 months of age correlates with early intake and status of long-chain polyunsaturated fatty acids.

We investigated the influence of early nutrition with and without long-chain polyunsaturated fatty acids (LCP) on later development of < or = 2500 g newborns receiving preterm formula without LCP (n=75), preterm formula with 18:3omega6 and LCPomega3 (at two doses; n=26) or their mother's own milk (n=27). All diets were given from birth to day 42. Erythrocytes (RBC) fatty-acid compositions were determined on day 42. Bayley's mental development (MDI) and psychomotor development (PDI) indices were assessed at 19 months. Multivariate regression analysis revealed that PDI was most strongly related to RBC 22:6omega3 in the cohort of 101 infants who received formula. The most consistent correlations were between development and early LCPomega3 intake, and between development and parameters of RBC LCPomega3 status day 42, in infants who received formula with 18:3omega6 and LCPomega3. Development of formula-fed low-birthweight infants seems positively influenced by early dietary LCPomega3.

N-methyladrenaline: age-dependent urinary excretion, perinatal organ content and relation with 'classical' catecholamines.

Using high performance liquid chromatography with electrochemical detection we determined free dopamine, noradrenaline, adrenaline and N-methyladrenaline in: (1) urines from newborns (n = 32), children (n = 45) and adults (n = 19) and (2) adrenals, organ of Zuckerkandl, dorsal roots and perirenal brown adipose tissue from deceased fetuses (n = 2), very premature (n = 6) and term (n = 2) newborns and infants (n = 2). Data from children and adults showed that contributions of adrenaline and N-methyladrenaline to the sum of urinary free catecholamines increase with age. Relative amounts of adrenaline and N-methyladrenaline increased in both adrenal and extra adrenal chromaffin tissues from late gestation up to several months of postnatal life. Increase of adrenal N-methyladrenaline content follows endocrine maturation of the medulla, phenylethanolamine-N-methyltransferase induction and subsequent adrenaline synthesis. Relative amounts of N-methyladrenaline in extra adrenal chromaffin tissue increase in a period that is associated with its regression. Further investigations are necessary to elucidate the function and possible clinical chemical usefulness of N-methyladrenaline.

Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates.

AIM: To investigate the pharmacokinetics, metabolism, and dose-response relation of a single rectal dose of paracetamol in preterm infants in two different age groups. METHODS: Preterm infants stratified by gestational age groups 28-32 weeks (group 1) and 32-36 weeks (group 2) undergoing painful procedures were included in this study. Pain was assessed using a modified facies pain score. RESULTS: Twenty one infants in group 1 and seven in group 2 were given a single rectal dose of 20 mg/kg body weight. Therapeutic concentrations were reached in 16/21 and 1/7 infants in groups 1 and 2, respectively. Peak serum concentrations were significantly higher in group 1. Median time to reach peak concentrations was similar in the two groups. As serum concentration was still in the therapeutic range for some infants in group 1, elimination half life (T1/2) could not be determined in all infants: T1/2 was 11.0 +/- 5.7 in 11 infants in group 1 and 4.8 +/- 1.2 hours in group 2. Urinary excretion was mainly as paracetamol sulphate. The glucuronide:sulphate ratio was 0.12 +/- 0.09 (group 1) and 0.28 +/- 0.35 (group 2). The pain score did not correlate with therapeutic concentrations. CONCLUSIONS: A 20 mg/kg single dose of paracetamol can be safely given to preterm infants in whom sulphation is the major pathway of excretion. Multiple doses in 28-32 week old neonates would require an interval of more than 8 hours to prevent progressively increasing serum concentrations.

Spontaneous motility in preterm, small-for-gestational age infants. I. Quantitative aspects.

The developmental course of the quantitative aspects of early spontaneous motility was studied longitudinally in fourteen intrauterine growth-retarded infants, with a birth weight below the 5th percentile, in relation to perinatal variables, brain ultrasound findings and neurological outcome. Quantitative motility was studied during the preterm period until term age, from 1 h videotape recordings, using Prechtl's classification of different spontaneous movement patterns. Comparison to a low-risk reference group, consisting of preterm, appropriate-for-gestational age infants, showed that significant differences were inconsistent and obviously by chance, with the possible exception of a decreased rate of startles from the 2nd to the 6th postnatal weeks. A trend of increasing duration of GMs was present with increasing postnatal age. There were hardly any correlations between perinatal variables and quantitative motility, and if present the correlations were weak. Such correlations were found between the reduction of heart-rate variability on cardiotocography and the rate of startles and twitches during the first week and furthermore between the neonatal blood glucose level and the rate of isolated arm movements and total motility during the first week. This study demonstrates that intrauterine growth retardation has little or no influence on the quantitative aspects of spontaneous motility postnatally during the preterm period.

Spontaneous motility in preterm, small-for-gestational age infants. II. Qualitative aspects.

In order to document in detail the developmental course of qualitative aspects of early spontaneous motility in intrauterine growth-retarded infants, sequential videotape recordings were made in 19 preterm infants with a birth weight below the 5th percentile. The quality of general movements (GMs) was studied longitudinally during the preterm and postterm period until approximately 20 weeks corrected age, using Prechtl's method of quality assessment. An abnormal quality of GMs was present in 15 out of 19 infants. Compared to a low-risk group, consisting of appropriate-for-gestational age preterm infants, the proportion of infants with normal findings on brain scans who had an abnormal quality of GMs was high. The presence of 'abrupt chaotic' GMs was related to late fetal heart-rate decelerations and ischaemic alterations of the placenta. The quality of GMs normalized before or during the third month postterm in most infants with abnormal GMs. In four infants, the GMs did not normalize during the study period. The quality of fidgety movements was, in particular, a marker for neurological outcome at 24 months. This study demonstrates that intrauterine growth retardation may cause prolonged, but in most cases transient brain dysfunction; the qualitative assessment of GMs may help to identify infants at increased risk for neurodevelopmental abnormalities.

Skin blood flow changes during apneic spells in preterm infants.

Changes in skin blood flow during apneic spells were determined in 18 preterm infants using a diode laser Doppler flow meter without light conducting fibres. Heart rate, nasal air flow, impedance pneumography, skin and incubator temperature and laser Doppler skin blood flow were recorded simultaneously in each infant. During 212 apneic spells with a duration of 11.6 +/- 7.5 s (mean +/- S.D.) (range 6.0-48.0 s), the laser Doppler skin blood flow was measured. In all children except one, the majority of the apneic spells was associated with a decrease in skin blood flow. During 155 apneic spells (73%) skin blood flow decreased significantly P less than 0.025), the maximum decrease being 16.7 +/- 14.8%, 28.5 +/- 23.9% and 18.9 +/- 16.1% (mean +/- S.D.) for central, obstructive and mixed apneic spells, respectively. The decrease in skin blood flow started immediately after the beginning of apneic spells in 71%, the rest started with a mean delay of 3.4 s (range 0.1-7.0 s). No relation was found between the decrease in skin blood flow and the duration of the apneic spells. Thirty-four percent of the apneic spells were accompanied by bradycardia. In apneic spells accompanied by bradycardia the decrease in skin blood flow was not related to the fall in heart rate.

Effects of rectally administered paracetamol on infants delivered by vacuum extraction.

OBJECTIVE: To evaluate whether paracetamol (20 mg/kg rectally) relieves pain in infants delivered by vacuum extraction, and improves clinical condition. METHODS: Prospective, randomised, double-blind, placebo-controlled study. Infants delivered by vacuum extraction were randomised either to the study group (n=61) and given paracetamol or to the control group (n=61) receiving placebo. Pain assessment was performed by a validated pain score and by scoring the clinical condition. Both scores and clinical symptoms in these groups were compared with symptoms in a reference group (n=66) with uncomplicated pregnancy and delivery in vertex position without vacuum extraction. RESULTS: Pain score did not differ between groups; clinical condition in the study group improved only after the first dose. There was a significant difference (P<0.05) in objective clinical symptoms in the vacuum extraction groups, compared to the reference group. CONCLUSION: One dose of paracetamol given to neonates delivered by vacuum extraction significantly improved their clinical condition, but did not result in a significant change in objective pain scores. Subsequent doses of paracetamol did not show any effect on the clinical symptoms or appearance of the neonates studied.

Transcutaneous PO2 and PCO2 during surfactant therapy in newborn infants with idiopathic respiratory distress syndrome.

We conclude that surfactant treatment in newborn infants with IRDS results in decrease in TcPO2 and an increase in TcPO2 within minutes. The surfactant treatment procedure used in this study was not associated with hypoxemia. During surfactant treatment monitoring of TcPO2 and TcPCO2 is absolutely necessary.

Large volume instillation of surfactant during extracorporeal life support improves lung function in lung lavaged rabbits.

The sometimes limited effect of surfactant therapy in neonates might be explained in part by an non homogeneous distribution of the surfactant after endotracheal instillation. This distribution can be improved significantly by increasing the fluid volume. The aim of this study was to evaluate the effect of two methods for gas exchange during a large volume instillation of surfactant on the outcome of this treatment in lung lavaged rabbits. In the control group (n = 6) gas exchange was maintained with continuous positive pressure ventilation (CV), whereas in the other group gas exchange was established with extracorporeal life support (ECLS) (n = 6) and intermittent sighs. Five hours after surfactant administration, an identical weaning procedure was started in both groups. The authors found significantly higher PaO2 values in the ECLS group than in the control group in the normocarbia state. All animals in the ECLS group could be weaned to room air maintaining normal blood gases, whereas all the animals in the control group died in the course of weaning. The ventilator efficiency index was significantly higher during the weaning period in the ECLS group, indicating better lung function, than in the control group. The authors conclude that a large volume instillation of surfactant is feasible by applying ECLS and intermittent sighs. Additional studies are needed to elucidate if this combined treatment will be an improvement over current surfactant therapy.

Retrograde flow detection in the radial artery as a means to assess palmar collateral circulation in newborn infants.

The aim of this clinical study was to determine whether Doppler ultrasound can be used in newborn infants to assess the adequacy of palmar collateral circulation. Retrograde flow in the radial artery, distal to the site of manual occlusion of the vessel, was studied by Doppler technique. Forty-seven newborn infants, who underwent percutaneous radial artery cannulation were studied. Prior to cannulation palmar collateral circulation was tested in each infant, using the timed Allen test and was considered to be adequate. Pulsatile retrograde flow could be demonstrated in 11 out of 47 infants, but not in 36 of the 47 studied. During the period of cannulation none of the infants showed any sign of vascular insufficiency of the hand. It can be concluded that in newborn infants, the detection of pulsatile retrograde flow in the radial artery, using a Doppler flow meter, does not appear to have advantages over the Allen test as an indicator of adequate palmar collateral circulation.

[Risks of diazepam in newborn infants]. / Risico's van diazepam bij pasgeborenen.

In children there is a good effect of diazepam on convulsions after intravenous or rectal administration. This is not the case in neonates. We describe a newborn to whom diazepam was given because of a convulsion and who exhibited serious side effects: coma, hypotonia and feeding difficulties. We point out the risks of using diazepam in neonates.

[Marked variations in phototherapy policy for neonatal jaundice in Dutch centers]. / Grote verschillen in fototherapiebeleid in Nederlandse centra bij icterus neonatorum.

OBJECTIVE: To determine what guidelines are used in Dutch hospitals in the management of neonatal hyperbilirubinaemia. DESIGN: Descriptive. MATERIAL AND METHOD: Paediatricians in 63 hospitals were sent a standard guideline diagram of phototherapy management and asked to describe how their management differed. The 10 neonatal intensive care units in the Netherlands were asked to send their phototherapy guidelines in more detail. RESULTS: Thirty-four hospitals (54%) and the 10 neonatal centres (100%) responded. The data obtained showed no general agreement; several different guidelines were used, notably with respect to the serum bilirubin concentration levels and the number of postnatal hours. CONCLUSION: We recommend that consensus should be reached on the use of phototherapy. A more restricted use of phototherapy probably would save costs without loss of quality.

[Obstructive disorders of the urinary tract in the unborn child]. / Obstructieve afwijkingen aan de urinewegen van het ongeboren kind.

The history of a patient with signs of urinary tract obstruction in utero is presented. After this presentation pathophysiologic, diagnostic and therapeutic aspects of prenatal detected obstructive malformations of the urinary tract are discussed. Obstructions of the fetal urinary tract may cause damage to the developing renal parenchyma, impairment of the normal lung development and fetal growth retardation. The seriousness of obstruction and the time of appearance during pregnancy determine the severity of the damage to the unborn child. Optimum management in case of prenatal detected obstructive uropathies needs good information about renal function of the fetus, the presence of other structural defects or chromosomal abnormalities and also the maturity and state of development of the lungs. Besides careful ultrasonography of the fetus invasive methods of investigation may be necessary. In case of fetal obstructive uropathy intrauterine decompression or extrauterine decompression after an induced premature delivery can be considered. However a good renal function and the absence of other severe structural or chromosomal malformations are necessary. When the gestational age has come to 32 to 34 weeks and the lungs are mature enough decompression of the urinary tract after an induced premature delivery can be done. When pregnancy is less than 32 weeks of gestational age and the lungs are immature intrauterine decompression is possible. The most used technique of intrauterine decompression so far is insertion of a percutaneous amniotic-bladder catheter. Antenatal detected obstructive abnormalities of the fetal urinary tract need optimum perinatal care besides good information and support of the parents.

First contact incidence of psychotic disorders among native Dutch and Moroccan immigrants in the Netherlands: influence of diagnostic bias.

BACKGROUND: Several studies have reported increased incidence rates of psychotic disorders among immigrant groups. Surprisingly, the cross-cultural validity of the diagnostic instruments that were used was never tested. AIMS: To examine whether the incidence rates of psychotic disorders including schizophrenia among Moroccan immigrants to the Netherlands remain increased when a cultural sensitive diagnostic interview is used. METHOD: We compared first contact incidence with a standard and a cultural sensitive version of a diagnostic interview. RESULTS: Age and gender adjusted relative risk for psychotic disorders and schizophrenia among Moroccans compared to native Dutch was 7.9 (95% CI 4.7-13.5) and 7.8 (95% CI 4.0-15.2) respectively based on the standard diagnostic interview and 4.2 (95% CI 2.3-7.9) and 1.5 (0.5-4.3) respectively based on the cultural sensitive version the diagnostic interview. CONCLUSION: First contact incidence of schizophrenia among Moroccans was no longer significantly higher than among ethnic Dutch people when a cultural sensitive diagnostic procedure was applied.