Intensive care management after pediatric liver transplantation: a single-center experience.

A retrospective study was conducted to determine the significance of intensive care management on outcome after liver transplantation (LTx) in children. Of 195 transplants performed in 162 children, factors affecting morbidity and mortality were documented during the post-operative intensive care unit (ICU) stay. To assess the gain in experience of ICU management, we compared mean ventilation time and stay in the ICU as well as mortality, incidence of surgical complications, infections, and rejection episodes, during three different time-periods (October 1991-August 1994, September 1994-July 1996, and August 1996-February 1998). The time spent by patients in the ICU (9.7 days vs. 7.9 days vs. 4.7 days, p < 0.001) and time on ventilation (5.2 days vs. 3.1 days vs. 1.2 days, p < 0.001) were significantly reduced over the duration of the study. The overall mortality was 18.0% (n = 30) and 76.7% (n = 23) of these deaths occurred during the early post-operative period in the ICU. The incidence of severe surgical complications decreased significantly over time, and the application of intra-operative Doppler ultrasound since 1994 led to detection of 27 correctable vascular complications. The overall incidence of acute cellular rejection episodes in our center was 64.1%: 43.5% of the infectious episodes occurred in the ICU (bacterial 70.2%, viral 12.3%, and fungal 17.5%). The main side-effect from immunosuppressive drugs was arterial hypertension in 29% of the patients. We conclude that our efforts to improve intensive care management and monitoring were the key elements in reducing morbidity and mortality after pediatric LTx.

High-performance liquid chromatography-coulometric electrochemical detection of ubiquinol 10, ubiquinone 10, carotenoids, and tocopherols in neonatal plasma.

A micromethod for the rapid simultaneous determination of several lipophilic antioxidants in plasma from newborn infants is presented. Because only 5 microliters of plasma is required, the procedure lends itself for repetitive use in very immature infants at risk for developing so-called "oxygen radical diseases of the premature." The method allows continuous monitoring of antioxidants in such patients and can easily be combined with monitoring other parameters of interest in this context. Reuse of blood samples taken routinely for the determination of hematocrit and bilirubin concentration is possible, reducing the blood volume required to be taken for the oxygen radical-related studies to virtually zero.

Monitoring erythrocyte free radical resistance in neonatal blood microsamples using a peroxyl radical-mediated haemolysis test.

Inadequate resistance to oxidative stress has been implicated in several diseases of premature children. Antioxidative defences at the membrane level can be studied by measuring haemolysis induced through exposure of erythrocytes to the free radical generator AAPH (2,2'-azobis (2-amidinopropane)dihydrochloride). We developed a micromodification of this haemolysis test requiring only 15 microl of erythrocytes derived from capillary blood samples. The time needed for 50% haemolysis (T50%) was used to characterize radical resistance of erythrocytes. T50% results in adult samples were highly reproducible. T50% values in healthy term infants on the first 2 d of life were lower than in adults (p < 0.001), but increased to the same level thereafter. A correlation was found between T50% values and plasma tocopherol levels as determined in plasma of each of the capillary blood samples (p < 0.001). On the first day of life T50% results in preterm infants (n = 20) were higher than in term infants (p < 0.001). It was easy to monitor T50% results and plasma tocopherol levels in preterm infants that were not at all burdened by the sampling method, almost daily over several weeks. The micromodification presented simplifies monitoring of antioxidative defences in sick preterm infants.

Melatonin and 6-hydroxymelatonin sulfate excretion is inversely correlated with gonadal development in children.

To delineate the development of melatonin (MLT) production during childhood, we measured the excretion of MLT and 6-hydroxymelatonin sulfate (MLTS) in the urine of children (n = 134) from the 26th week of gestation until the age of 20 years. MLTS excretion showed a diphasic pattern with declining values in preterm babies with lowest values around term. After birth, the values remained low for the first 6 months of life. The highest values were reached between 4 and 7 years of age with a smooth but steady decline thereafter. A night-day difference was not detectable before the age of 6 months; the greatest night-day variations occurred at the time of the highest MLTS excretions. The MLT values showed an identical pattern but with amounts 1,000 times smaller; the ratio of MLTS to MLT increased from 40:1 in preterm babies to 900:1 in prepubertal children. In summary, the MLT/MLTS excretion exhibits the highest activity with respect to total secretory capacities as well as night-day differences at the time of gonadal quiescence during childhood. The strong inverse correlation of MLT and MLTS excretion with the hypothalamic-pituitary-gonadal activity points to a causal relationship between pineal gland activity and pubertal development.

Decreasing melatonin and 6-hydroxymelatonin sulfate excretion with advancing gestational age in preterm and term newborn male infants.

We investigated the ontogeny of melatonin synthesis during fetal maturation by measuring the melatonin (MLT) and 6-hydroxymelatonin sulfate (MLTS) excretion in the urine of male infants aged 2-7 days and gestational age 26-42 weeks. We found a negative correlation between advancing gestational age and the MLT and MLTS excretion expressed as total 24-h amount, ratio of 24-h amount to creatinine and ratio of 24-h amount to body surface area. The ratio of MLT to MLTS was found to be about ten times higher in the study group than in prepubertal children, which might reflect the immaturity of hepatic sulfation capacities. The total amount of excreted MLT and MLTS was only one-tenth the prepubertal values. No day/night differences in MLT and MLTS excretion could be detected. We conclude that the fetal pineal gland is capable of a limited melatonin synthesis from the 26th week of gestation onwards, with decreasing values reaching its nadir around term. This indicates that the amount of fetal MLT excretion is not determined by synthesizing capacities of the pineal gland but by the development of neural connections to the pineal gland.

Regulation of insulin-like growth factors and IGF-binding proteins in bone tumours.

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) are important regulators of growth and development in normal bone and bone tumours. IGFs contribute to about 50% of basal bone cell proliferation. Their mitogenic actions is either enhanced or inhibited by specific IGFBPs which are also regulated by a variety of factors. This system is further complicated by the presence of specific proteases for IGFBPs. Serine proteases are secreted by malignant bone tumours and the hydrolysis of IGFBPs increases the bioavailability of IGFs. In addition, the autocrine production of IGFs may facilitate the development of bone tumours and metastatic lesions.

Monitoring of ubiquinol-10, ubiquinone-10, carotenoids, and tocopherols in neonatal plasma microsamples using high-performance liquid chromatography with coulometric electrochemical detection.

A method for measuring the lipophilic antioxidants alpha-tocopherol, gamma-tocopherol, ubiquinol-10, ubiquinone-10, beta-cryptoxanthin, and beta-carotene in 5 or 10 microliters neonatal plasma is presented. First lipid extraction together with the internal standards gamma-tocotrienol, ubiquinone-7, ubiquinol-9, ubiquinone-9, and ethyl beta-apo-8'-carotenoate was carried out. Then the components were separated on a RPC2/C18 column. Coulometric electrochemical detection was performed using the reduction-oxidation mode (-0.60 V; -0.15 V; +0.60 V). Detection limits for all components were between 21 and 60 fmol, corresponding to 0.004 and 0.012 mumol/liter plasma; the within-day precision (coefficient of variation) was between 3 and 14% for all measured substances. Reference values are given for healthy newborn children from the second to the sixth day of life. Using the presented HPLC technique it is possible to monitor the concentrations of lipophilic antioxidants in plasma of sick immature newborn children in order to study effects of oxidative stress.

No effect of ethinylestradiol treatment on melatonin secretion in healthy pubertal girls.

The present study investigated the impact of high estrogen doses on melatonin blood concentrations in healthy young girls. Melatonin secretion was investigated in 7 girls (chronological age 13.2 +/- 0.2 years; bone age 12.8 +/- 0.2 years) before and during treatment with ethinylestradiol (EE2, daily dose 0.5 mg/d orally) aimed at the reduction of final prospective height in familial tall stature. Melatonin, LH, FSH, E2 and EE2 were measured by radioimmunoassay. In all subjects, LH and FSH were completely suppressed, but melatonin secretion, day/night plasma values as well as the area under the curve (AUC) remained unchanged under pharmacological administration of ethinylestradiol. We therefore conclude that melatonin secretion is not affected by pharmacological doses of the synthetic estrogen derivative ethinylestradiol in healthy young girls. The decrease of melatonin blood concentrations during puberty is not caused by increasing concentrations of estrogens but must be due to some other process.

Precocious puberty and decreased melatonin secretion due to a hypothalamic hamartoma.

Hypothalamic hamartomata are benign malformations of the brain consisting of heterotopic nervous tissue, and are often associated with precocious puberty and gelastic seizures in early childhood. We report for the first time the melatonin plasma values of a girl with central precocious puberty and gelastic seizures due to a hypothalamic hamartoma. The melatonin plasma levels were low for the chronological age but appropriate for the pubertal status, making a causal relationship between lowered melatonin plasma levels and precocious puberty possible.

[Gelastic epilepsy and precocious puberty in hamartoma of the hypothalamus]. / Gelastische Epilepsie und Pubertas praecox bei Hamartom des Hypothalamus.

Four cases of hypothalamic hamartoma leading to gelastic epilepsy, precocious puberty and behavioural disorders are reported. Cerebral neuroradiologic examinations revealed a tumor-like mass attached to the hypothalamus in the region of the mamillary bodies in all cases. Precocious puberty developed in the two girls at 4 and 13 months but in neither of the two boys, who both suffered behaviour disturbances in the form of aggressive outbursts. A total resection of the tumors of both boys led to histologic confirmation of hamartoma. One boy was free of seizures upon follow-up, whereas seizure frequency in the other boy was reduced, while his aggressivity increased. The cases are discussed in context of current therapeutic conceptions of gelastic epilepsy and central precocious puberty.

Intra-atrial malpositions of Silastic catheters in newborns.

The intra-atrial position of Silastic catheters placed in the center of the right atrium was assessed by two-dimensional echocardiography in 25 newborns. In 32% of the infants, the catheter tip was located in the patent foramen ovale, and in another 40% of the infants, the catheter tip was located close to the patent foramen ovale. This placement increases the risk of systemic air and fat embolism. Consequently, the tip of Silastic catheters should be placed just behind the confluence of the superior-inferior vena cava and the right atrium.

The role of arginine-vasopressin in the regulation of water metabolism in preterm infants in the first days of life.

We studied the role of arginine-vasopressin (AVP) in the regulation of fluid homeostasis in preterm infants. Group 1 was fed orally, groups 2 and 3 received fluids parenterally, and group 3 developed respiratory distress syndrome (RDS) and had to be ventilated. The infants of group 3 were not able to excrete the administered fluid, gained weight and consecutively developed hyponatremia. 1-min Apgar scores as well as log FiO2 correlated significantly with urinary AVP excretion on day 1. We conclude that nonosmotic stimuli are involved in the release of AVP and therefore disturb fluid homeostasis in severely ill infants with RDS.

There is evidence that amniotic fluid arginine vasopressin is a marker for foetal stress in rhesus erythroblastosis.

In response to different stress stimuli the foetal neurohypophysis releases arginine vasopressin (AVP). Part of the AVP is cleared from circulation by urinary excretion into the amniotic fluid (AF). Increased AF AVP levels may therefore indicate foetal stress, all the more because AF AVP solely is of foetal origin. We therefore studied AF AVP levels in 13 patients with rhesus erythroblastosis from 22 to 34 weeks of gestation. Twenty-eight patients from 14 to 34 weeks of gestation served as controls. The AVP levels were measured by RIA. Spectral absorption curves were performed and delta/E values determined at 450 nm. Mean AF AVP levels in controls were 2.39 pg/ml and were not normally distributed. There was no significant change in AF AVP levels with different gestational age. If in rhesus erythroblastosis patients the delta/E value was low (n = 7; x = 0.048 +/- 0.007 SE), the AF AVP values were not increased. If the delta/E values were within zone III (n = 6; x = 0.22 +/- 0.035 SE), indicating severe haemolysis, the AF AVP levels were significantly elevated (4.7 pg/ml +/- 0.51 SE; P = 0.001). Linear regression analysis showed a significant correlation between delta/E and AF AVP values (P = 0.05; y = 1.94 +/- 10.88 x). We conclude that there is evidence for the role of AF AVP as a marker for foetal stress in rhesus erythroblastosis.

Urinary arginine-vasopressin (AVP) excretion in cystic fibrosis (CF).

Free water handling is impaired in chronic obstructive lung disease (COLD). We studied the role of AVP in this mechanism with a sensitive urinary AVP radioimmunoassay (RIA) in 13 patients with CF. The mean age was 14.7 +/- 1.27 SE years. The control group was age and sex matched. While the 24-hour urine volume was not significant different in both groups, urine osmolality was higher in CF (788 mosmol/kg +/- 182 SE vs. 622 mosmol/kg +/- 218 SE; p = 0.05). The 24-hour urinary AVP excretion in CF patients was found to be significantly elevated (174 ng/day +/- 99 SE vs. 74 ng/day +/- 48 SE; p = 0.01). This difference becomes even greater if these values are corrected for body weight (4.4 ng/(kg X day) +/- 2.1 SE vs. 1.5 ng/(kg X day) +/- 0.9 SE; p = 0.005). Lung function studies were available in 8 patients. We used a body plethysmograph to measure FEV1 (1 sec forced expiratory volume) and MEF25 (forced expiratory flow at 25% of vital capacity) as sensitive indices of airway obstruction. There was a significant negative correlation between urinary AVP excretion and MEF25 (r = .76) and FEV1 (r = .65): the more pronounced the airway obstruction the higher the AVP excretion. We conclude that AVP plays a major role in the impaired water handling in COLD. Increased AVP secretion is already present under clinically stable conditions and is dependent on the degree of airway obstruction. In treating those patients one has to be aware of the possibility of water intoxication.

Circadian fluctuation of plasma melatonin in Prader-Willi's syndrome and obesity.

In 3 groups of 8 children and adolescents each with Prader-Willi-Labhart's Syndrome (PW-S), obese patients matched for body weight (control I), and normal weight subjects matched for pubertal stage (control II) plasma concentrations of melatonin, cortisol, growth hormone (hGH), insulin, gonadal hormones, and gonadotropins were measured every 1 to 4 hours in 24-hour-profiles. All hormones were determined by radioimmunoassay. The specific melatonin antibody was raised in rabbits. Criteria of the melatonin assay were as follows: detection limit for plasma concentrations of 13 pg/ml, intraassay and interassay variations: 8.4 and 11.2%, respectively. PW-S-patients showed cortisol fluctuations within normal limits. hGH was lower than 5 micrograms/l even during sleep, insulin ranged between 5 and 170 mU/l, and no excessively high glucose levels were found. Estradiol and testosterone were low for age and for pubertal development in all patients except in two girls. Basal LH and FSH levels were in the low normal range and showed sluggish response to LHRH. Plasma melatonin was low during the day, increased at mid-night and peaked at 3 a.m. Melatonin levels in PW-S were not significantly different from those in both control groups. We concluded that the impairment of gonadotropin secretion in patients with PW-S is not due to elevated levels of plasma melatonin.

Effects of an artificial magnetic field on serotonin N-acetyltransferase activity and melatonin content of the rat pineal gland.

In the present study the effects of artificial magnetic fields on pineal serotonin-N-acetyltransferase (NAT) activity and melatonin content in male Sprague-Dawley rats were investigated to study the secretory activity of the pineal gland. Experimental inversion of the horizontal component of the natural magnetic field, performed at night-time, led to a significant decrease of both parameters investigated. During day-time, this effect was less conspicuous. During night-time, inversion of the horizontal component is followed by a reduced pineal secretory activity for about 2 h. After 24 h exposure to the inverted horizontal component, return to the natural condition was followed by a renewed clear depression of pineal NAT activity and melatonin content, indicating that the main stimulus is not the inverted magnetic field itself but rather its change. Changing the inclination of the local magnetic field from 63 degrees to 58 degrees, 68 degrees or 78 degrees, respectively also decreased the secretory activity of the rat pineal gland.