[Gaussian distribution of intelligence in VLBW preterm infants at age 5: very low correlation with very low birth weight]. / Normalverteilung der Intelligenz von VLBW-Frühgeborenen mit 5 Jahren: sehr geringe Korrelation mit sehr geringem Geburtsgewicht.

BACKGROUND: Preterm infants with very low birth weight < 1500 g (VLBW) have a higher risk of developmental disorders. In addition to the common estimation of the mean intelligence values, we studied the distribution of intelligence at preschool age in VLBW infants and the risk factors influencing this distribution. PATIENTS AND METHODS: A prospective cohort study of 277 VLBW infants < 32 weeks born in 1991-1995 and treated according to a standardized regimen in one Perinatal Center was carried out, including measurement of intelligence (Kaufman-Assessment Battery for Children) at age 5. Statistical methods employed were: explorative data analysis, correlation, chi (2)- and t-tests; the tested variables were: small for gestational age (< third percentile), perinatal acidemia (umbilical arterial pH < 7.10), perinatal hypoxia (BE < - 10), hypothermia (< 36 degrees C), hypoglycemia after the first day of life (< 30 mg / dL), bronchopulmonary dysplasia (FiO (2) > 0.21 > or = 36 weeks), intraventricular hemorrhage, ventricular dilation, periventricular leukomalacia, seizures, abnormal acoustic evoked potentials, and hyperexcitability at discharge. RESULTS: The distribution of intelligence in 137 VLBW infants < 32 weeks (60 % follow-up rate) was similar to a symmetrical Gaussian bell curve. The intelligence increased very slightly with birth weight (Pearson correlation: 0.172; p = 0.045) and was significantly lower in children with hypoglycemia after the first day of life (- 13.35; 95 % confidence interval: - 20.08 to - 6.63; p = 0.002), hyperexcitability at discharge (- 16.28; 95 % confidence interval: - 25.26 to - 7.31; p = 0.005), and bronchopulmonary dysplasia (- 7.00; 95 % confidence interval - 11.71 to - 2.29; p = 0.039). CONCLUSIONS: At preschool age, the intelligence of VLBW infants is normally distributed and correlates only slightly with the very low birth weight. Hypoglycemia after the first day of life and bronchopulmonary dysplasia are risk factors for lower intelligence. Hyperexcitability at discharge seemed to represent a promising prognostic factor for a later intelligence reduction.

Do we need new indications for ECMO in neonates pretreated with high-frequency ventilation and/or inhaled nitric oxide?

OBJECTIVE: High-frequency ventilation (HFV) and/or inhaled nitric oxide (iNO) has reduced ECMO in neonates. But, frequently, improvement with HFV/iNO is temporary and only prolongs lung injury without preventing ECMO. We tried to identify a threshold oxygenation index (OI) that predicts temporary or persistent improvement with HFV/iNO in neonatal ECMO candidates as early as possible. DESIGN: Cohort study of all neonates with OI > 40 during intermittent positive pressure ventilation between 1992 and 1997. The first treatment was HFV; at an OI > 40 during HFV, iNO was added; at an OI > 40 during HFV+iNO, ECMO was initiated. Temporary improvement was defined as secondary need for ECMO or fatal chronic lung disease without ECMO. SETTING: University hospital level III neonatal intensive care unit. MAIN RESULTS: Ten of the 34 neonates studied rapidly required ECMO despite HFV/iNO. Eleven neonates temporarily improved for 1-10 days before the OI was again > 40. Nine received ECMO, two were denied ECMO after mechanical ventilation > 14 days and died of chronic lung disease. Thirteen neonates persistently improved with HFV/iNO without ECMO. The OI before, at 24 h or 48 h of HFV/iNO did not predict temporary or persistent improvement. However, after 72 h of HFV/iNO, neonates with persistent improvement had lower OIs than those with temporary improvement [median OI 16 (4-24) vs 31 (20-40); P = 0.0004]. In all neonates with an OI > or = 25 after 72 h, HFV/iNO eventually failed (positive predictive value 100%, sensitivity 91 %, specificity 100%, positive likelihood ratio 91). CONCLUSION: For neonates pretreated with HFV/iNO, an OI > 40 is an inadequate ECMO indication. Based on our data we hypothesize that an OI > or = 25 after 72 h of HFV/ iNO is a better ECMO indication that avoids prolonged barotrauma.

[Hearing screening of high risk newborn infants]. / Hörscreening von Neugeborenen mit Risikofaktoren.

OBJECTIVE: This prospective study reports on the prevalence of hearing impairment in an at-risk neonatal intensive care unit (NICU) population. DESIGN: From 1990 to 1998, 1062 neonates were screened with the use of transitory evoked otoacoustic emissions (TEOAE) and brainstem evoked response audiometry (BERA). RESULTS: 934 infants passed the primary screen for both ears, 75 for one ear, adding up to 95%. 17 infants (1.6%) were lost to follow-up. In fourteen infants (1.3%), bilateral hearing impairment above 30 dB was confirmed. While all children with hearing impairment belonged to the group of 862 children receiving aminoglycosides, only one of them presented no other risk factors. In twelve of the hearing impaired children other anamnestic factors, i.e. dysmorphism, prenatal rubella or cytomegaly, family history of hearing loss or severe peri- and postnatal complications seem to be more probable causes of the identified hearing loss. In one of these children, delayed onset or progression of hearing loss is suspected. CONCLUSIONS: From our data, aminoglycosides are not an important risk factor for hearing impairment, when serum levels are continuously monitored, as in our cohort. After adjustment for other risk factors, birth weight between 1000 gr and 1500 gr and a gestational age between 29 and 31 weeks were no predictive markers for hearing impairment. It might be speculated that the improved medical treatment in a NICU reduces the probability of hearing impairment for those two groups. Conductive hearing loss as a possible additional cause for hearing impairment was not studied in detail, but the high percentage of malformations detected (four out of fourteen hearing impaired infants) demands further monitoring, close follow-up, adequate treatment and counselling.

Hearing screening in at-risk neonate cohort.

OBJECTIVE: This prospective study reports on the prevalence of hearing impairment in an at-risk neonatal intensive care unit (NICU) population. DESIGN: From 1990 to 1997, 942 neonates were screened with transient evoked otoacoustic emissions (TEOAE) and brainstem evoked response audiometry (BERA). RESULTS: 835 Infants passed the primary screen for both ears, 57 for one ear, adding up to 94.7%. Seventeen infants (1.9%) were lost to follow-up. In thirteen infants (1.4%), bilateral hearing impairment above 30 dB was confirmed. While all children with hearing impairment belonged to the group of 820 children receiving aminoglycosides, only one presented no other risk factors. In 11 of the hearing impaired children other anamnestic factors, i.e. dysmorphism, prenatal rubella or cytomegaly, family history of hearing loss or severe peri- and postnatal complications seem to be more probable causes of the identified hearing loss. CONCLUSIONS: From our data, aminoglycosides seem not to be an important risk factor for communication related hearing impairment, when serum levels are continuously monitored, as occurred in our cohort. After adjustment for other risk factors, birth weight between 1000 and 1500 g and a gestational age between 29 and 31 weeks were no predictive markers for hearing impairment. It might be speculated that the improved medical treatment in a Neonatal Intensive Care Unit (NICU) reduces the probability of hearing impairment for those two groups. Conductive hearing loss as a possible additional cause for hearing impairment was not studied in detail, but the high percentage of malformations detected (four out of 13 hearing impaired infants) demands further monitoring, close follow-up, counselling and adequate treatment.

A case of cow's milk allergy in the neonatal period--evidence for intrauterine sensitization?

Clinical manifestations of cow's milk allergy rarely occur in the first days after birth. We report on a newborn presenting with hemorrhagic meconium in the first hour of life followed by bloody diarrhea in the next few days. At day 14, an elevated total IgE, specific IgE to cow's milk and an eosinophilia in peripheral blood were found. Symptoms disappeared when the milk feed was changed to an extensively hydrolyzed casein-formula. Two challenges with cow's milk formula (on day 30 and at 7 months of age) were followed by recurrence of vomiting, watery diarrhea and failure to thrive. At the age of 17 months cow's milk was tolerated well. Although other pathogenetic mechanisms cannot completely be ruled out, there is strong evidence that cow's milk allergy--induced by intra-uterine sensitization--explains the symptoms in our patient. In conclusion, cow's milk allergy can occur even in the first days of life, and our clinical observation supports the concept of intra-uterine sensitization to allergens.

[Extracorporeal membrane oxygenation of the newborn infant--an example of interdisciplinary project management]. / Extrakorporale Membranoxigenierung des Neugeborenen--ein Beispiel für interdisziplinäres Projektmanagement.

In the last three years an interdisciplinary ECMO (extracorporeal membrane oxygenation) team has been set up at the Free University of Berlin in the Steglitz clinic. With this form of management, newborns only a few hours or days old who present with pulmonary failure can temporarily be managed with extracorporeal oxygenation until normal lung function is restored. The set up of this ECMO team, starting with experimental training in animal models, to the bedside clinical use is discussed. The following presentation of the first four cases managed here with ECMO aims to clarify the problems which may be encountered as well as amplifying its use as a life-saving measure.

Venovenous extracorporeal membrane oxygenation: early CT alterations following use in management of severe respiratory failure in neonates.

PURPOSE: To describe brain CT alterations occurring after neonatal venovenous extracorporeal membrane oxygenation (V-V ECMO). METHODS: CT studies were prospectively obtained after V-V ECMO in 31 neonates with severe respiratory failure. Images were scored for cerebrospinal fluid space size, hemorrhage, and regions of decreased attenuation. RESULTS: Subarachnoid space enlargement at the interhemispheric fissure, frontal, temporal, or parietal convexity occurred in 21 of the 31 patients. When subarachnoid space enlargement was asymmetric (six of the 21), it was always isolated to or greater on the right. Ventricular enlargement was demonstrated in seven of the 31. Hemorrhage occurred in seven and regions of low brain attenuation in 11 of the 31 neonates. CONCLUSIONS: Increased sagittal sinus pressure caused by internal jugular vein ligation and cannulation of the superior vena cava may contribute to subarachnoid space enlargement by decreasing cerebrospinal fluid resorption at the arachnoid villi. Reduced incidence of cerebral hemorrhage with V-V ECMO, as compared with venoarterial (V-A) ECMO, may relate to sparing of the right common carotid artery (it is ligated with V-A ECMO), and to routing of oxygenated blood to the right atrium with V-V ECMO rather than to the arterial circuit as with V-A ECMO.

Population kinetics of gentamicin in neonates.

A population kinetic analysis was carried out on sparse plasma gentamicin (GE) concentration data from 469 neonates obtained as part of a routine therapeutic drug monitoring (TDM) programme in the hospital neonatology unit. The best predictors of the kinetic parameters of the monoexponential model, volume of distribution (Vd) and clearance (CL), were the weight (WT) and gestational age (GA). Vd of the neonates was only related to WT, whereas the half-life was only related to the GA. The clinical implications of the findings are that the initial dose per WT administered to premature infants should be larger than that for term infants, because of a larger Vd per unit WT, and the intervals between maintenance doses should extended due to the prolonged half-life. Apart from these general guidelines, specific dose recommendations are also given.

[Surgical ligation of patent ductus arteriosus on the intensive care unit in small premature infants]. / Ductusligatur auf der Intensivstation bei kleinen Frühgeborenen.

This paper summarizes the experience with ligation of persistent ductus arteriosus in prematures performed in the intensive care unit during the years 1986 to 1988. Records of 35 operated prematures on artificial ventilation were analyzed retrospectively. Management and organization of the operation are described. For comparison, records were analysed of 47 prematures, also artificially ventilated, who during the years 1978 to 1986 had to be transported to an operating theatre over a distance of 3 or 10 km for the ligation.

A European multicenter randomized controlled trial of single dose surfactant therapy for idiopathic respiratory distress syndrome.

We performed a multicenter prospective randomized controlled trial to determine the efficacy and safety of the surfactant preparation, Survanta (Abbott Laboratories, Chicago, USA), for 750-1750 g infants with idiopathic respiratory distress syndrome, (IRDS) receiving assisted ventilation with 40% or more oxygen. One hundred and six eligible infants from the eight participating centers were randomly assigned between March 1986 and June 1987 to receive either surfactant (100 mg phospholipid/kg, 4 ml/kg) or air (4 ml/kg) administered into the trachea within 8 h of birth (median time of treatment 6.2 h, range 3.2-9.1 h). The study was stopped before enrollment was completed at the request of the United States Food and Drug Administration when significant differences were observed in incidence of periventricular-intraventricular hemorrhage (PIH), between the surfactant treated and control infants. Surfactant treated infants had larger average increases in the arterial-alveolar oxygen ratio, (a/A ratio) (P less than 0.0001), and larger average decreases in FiO2 (P less than 0.0001) and mean airway pressure, (MAP) (P less than 0.017) than controls over the 48 h following treatment. The magnitude of the differences between the surfactant and control groups were 0.19 (SE = 0.03) for a/A ratio, -0.28 (SE = 0.04) for FiO2 and -1.7 cm H2O (SE = 0.70) for MAP. The clinical status on days 7 and 28 after treatment was classified using four predefined ordered categories: (1) no respiratory support; (2) supplemental O2 with or without continuous positive airway pressure (CPAP); (3) intermittent mandatory ventilation; and (4) death. There were no statistically significant differences in the status categories on days 7 or 28 between surfactant and control infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnetic resonance imaging of the brain in congenital cytomegalovirus infection.

Ten children (age 2 months to 8 years) with a congenital cytomegalovirus (CMV) infection were studied by magnetic resonance imaging (MRI) using a 2.35 Tesla magnet. CMV infection was confirmed by serological investigations and virus culture in the neonatal period. Nine children had severe mental retardation and cerebral palsy, 1 patient suffered from microcephaly, ataxia and deafness. The cranial MRI examination showed the following abnormalities (N): dilated lateral ventricles (10) and subarachnoid space (8), oligo/pachygyria (8), delayed/pathological myelination (7), paraventricular cysts (6), intracerebral calcification (1). This lack of sensitivity for calcification is explainable by the basic principles of MRI. The paraventricular cystic lesions were adjacent to the occipital horns of the lateral ventricles and separated only by a thin membrane. This finding might represent a "new sign" for congenital CMV infection in MRI examinations, being characteristic but nevertheless nonspecific, like calcification in CT.

Developmental stages of human brain: an MR study.

The differentiation of the telencephalon (TC) gyri and the myelination of TC and diencephalon were analyzed quantitatively in 50 children, 32-240 weeks' postconceptional age (PCA). For this purpose, a four-stage grading system was developed by correlating magnetic resonance images from age-matched postmortem brains with subsequently prepared myelin-stained macroslices. Gyration and myelination progressed in a occipito-rostral direction. Stages 3 and 4 myelination were recognized earlier on T1-weighted images [spin echo (SE) 500/30] than on T2-weighted images (SE 3,000/120). However, long repetition time/echo time sequences yielded better contrast and allowed finer differentiation between myelinated and nonmyelinated structures. At term, the posterior limb of the internal capsule was generally myelinated (stage 2), whereas in 50% of the children, myelin appeared in the TC between 55 and 65 weeks' PCA, e.g., between 3 and 6 months postnatally. The morphological differentiation of the brain surface preceded the biochemical maturation (myelination) by an average of 12 months. Applying such a grading system to a larger population will help establish normal standards for brain maturation and a "brain age" scale during the first 4 years of life.

[Magnetic resonance in pediatric research and clinical practice. II. Studies on the development and pathology of the brain in neonates, infants and young children]. / Magnetresonanz in der pädiatrischen Forschung und Klinik. II. Teil: Untersuchungen zur Entwicklung und Pathologie des Gehirns bei Neugeborenen, Säuglingen und Kleinkindern.

We are investigating metabolism and morphological differentiation of the developing brain in neonates and children under non-invasive conditions combining MR imaging (MRI) with spectroscopy (MRS) on a high-field/small-bore (2.35 Tesla/40 cm) system. By the end of 1987, 116 neonates, infants and young children with various perinatal problems, congenital abnormalities and different neurological diseases have been examined with MRI. In addition, MRS studies were subsequently performed on 46 of these children using the same instrument and within the same session. The small, sometimes very sick and instable patients require careful monitoring and elaborate technical devices in the high magnetic field. We are presenting solutions for methodological and technical developments and adaptations, concepts for sedation and measurement protocols in various age groups and first results of the combined use of MRI and MRS to investigate the brain in neonates and infants.

Septo-optic pituitary dysplasia. Observations on three patients.

Septo-optic pituitary dysplasia is a relatively rare but pathophysiologically interesting malformation of the brain midline structures including optic chiasm and nerves, hypothalamus, neurohypophysis and septum pellucidum. The lesion develops between the 5th and 8th week of pregnancy. The cause is unknown but heredity seems unlikely. Symptoms result from hypothalamic and neurohypophyseal insufficiency of variable severity combined with reduced vision due to hypoplasia of optic nerves and chiasm. Prognosis is variable, depending on the severity of the defect as well as on the earliest time of diagnosis followed by suitable hormone substitution and specialized care of blindness. We present the clinical course in three patients and the pathological findings in one patient who died in the 14th month of life.

Theophylline serum concentration and therapeutic effect in severe acute bronchial obstruction: the optimal use of intravenously administered aminophylline.

In 20 patients with acute exacerbation of bronchial obstruction, the therapeutic effect of high (20 mg/L) and low (10 mg/L) serum concentrations of theophylline was compared in a double-blind randomized study. The theophylline dose, administered as a continuous aminophylline infusion, was individually adjusted by means of repeated measurements of serum concentrations. At 28 h after starting therapy the high concentration group showed a significantly greater improvement in pulmonary function as assessed by FEV1 (0.57 +/- 0.52 L (mean +/- SD) versus 0.1 +/- 0.18 L, p less than 0.01) and FVC (1.0 +/- 0.65 L versus 0.01 +/- 0.66 L, p less than 0.02). As a measure of the overall clinical improvement, the time during which intravenous therapy was required was also shorter in the high-dose group (61.7 +/- 25.8 h (mean +/- SD) versus 116 +/- 49.7 h, p less than 0.02). The occurrence of side effects in the two groups was not significantly different. In patients with severe acute bronchial obstruction, serum theophylline concentrations around 20 mg/L seemed to offer a definite therapeutic advantage, thus, routine serum concentration measurements and the use of accurate infusion devices for optimal dose adjustment may be justified.

[Relation of dose, serum concentration and side effects in intravenous aminophylline therapy]. / Beziehung zwischen Dosis, Serum konzentration and Nebenwirkungen bei intravenöser Aminophyllintherapie.

Routine intravenous aminophylline therapy was monitored by drug level measurements in 45 hospitalized patients with chronic obstructive bronchitis. Only 44% had theophylline serum concentrations (Cp) in the optimum range (10-20 mg/l), while in 36% of patients potentially toxic Cp values were observed. The incidence of side effects was related to theophylline serum concentration: 78% in cases with Cp greater than 30 mg/l against 24% in cases with Cp less than 20 mg/l. Theophylline toxicity occurred most frequently in elderly patients with cardiac failure, who had markedly reduced theophylline clearances. To avoid excessive drug accumulation the usual aminophylline dose should be reduced by 50% when clinical signs of cardiac failure are present. In addition, measurement of theophylline serum concentration is often necessary for optimum dosage adjustment.

[Use of antibiotics in hospitalized patients. Comparison of medical, surgical and gynecological units]. / Antibiotikaanwendung bei hospitalisierten Patienten. Vergleich von medizinischen, chirurgischen und gynäkologischen Abteilungen.

Antibiotic use was evaluated retrospectively in 1229 patients of a university hospital (Basle, Switzerland). The frequency with which antibiotics were prescribed, the indication, duration of treatment, side-effects and clinical results were compared in relation to various subspecialities. 38.1% of medical, 36.4% of surgical and 24.4% of gynecological patients received one or more antibiotic during hospitalization. The main indications for antibiotic treatment were respiratory infection (57.8%) and urinary tract infections (21%) in medical patients, prophylaxis (38%) and urinary tract infections (23%) in surgery, and urinary tract infections (43%) and adnexitis or endometritis (23%) in gynecology. Amoxycillin or penicillin G were the first-line drugs for respiratory infection, cotrimoxazole for urinary tract infection and cefalothin or cefacetrile for surgical prophylaxis. Patients with endometritis or adnexitis usually received clindamycin in combination with an aminopenicillin. Aminoglycosides were employed in only 9.5% of antibiotic courses. Information on adverse reactions in the records was scanty, only generalized exanthem (13 cases) and nausea/vomiting (2 cases) being specifically mentioned. The therapeutic result was classified by the responsible physician as cure in 50.8% or definite improvement in 16.4% of patients. However, in 118 cases (29.7%) the contribution of antibiotics to the clinical outcome could not be evaluated retrospectively.

Rapid prediction of steady-state serum theophylline concentration in patients treated with intravenous aminophylline.

In 15 acutely ill asthmatics the steady-state serum theophylline concentration was predicted by the method of Chiou et al. using two serum concentration measurements obtained 1 and 5 h after starting a continuous infusion of aminophylline. Two theophylline assays with different precision characteristics were compared. With a precise HPLC-assay the prediction was excellent: prediction error (predicted minus measured concentration) = -0.22 +/- 1.97 mg/l (mean +/- SD); r = 0.922. When the theophylline concentration was determined by a rapid enzyme immunoassay of lower precision, but convenient for clinical use, the prediction was less accurate (prediction error = 0.58 +/- 3.88, r = 0.852). However, it was still clearly superior to dosing recommendations based on the population average of theophylline clearance, even after taking into consideration the effect of smoking, congestive heart failure and cirrhosis (prediction error = 3.62 +/- 13.36, r = 0.560). As employed in this study, the method may be useful in helping the physician to choose the optimal dose in severely ill asthmatics.