The development of circadian rhythmicity in neonates.

Eleven healthy, full-term babies were studied on the second day (d2) after birth and again 4 weeks (w4) later. The babies lived in natural lighting conditions and were fed every 4 h. Blood pressure, heart rate, skin (abdomen) and rectal temperatures were measured at 10-min intervals for 24 h. Behavioural states (deep sleep, light sleep, drowsy, alert, crying) were measured at the same times, and used to purify the raw data. Both the raw and purified data were assessed for circadian (24-h) rhythmicity by cosinor analysis. Circadian rhythms in heart rate and blood pressure were poorly developed at d2 and w4. By contrast, skin and rectal temperatures showed circadian rhythmicity that increased in amplitude between d2 and w4; this increase was seen in both raw and purified data. The masking effect due to sleep changed also; the depression caused by "deep sleep" became greater between d2 and w4. The results indicate that the development of circadian rhythmicity in body temperature was not secondary to that of a circadian pattern of sleep and activity, and presumably derives from a body clock that is beginning to develop independently.

[The startle reaction of the newborn infant]. / Die Startle-Reaktion des Neugeborenen.

Startle characterized by a spontaneous or reflecting motoric symptom like brisk, shortlasting and generalized contraction of limb and trunk muscles influence considerably the cardio-respirogram of neonates. The dependence of startles on behaviour, gestational age and postnatal age as well as on levels of blood glucose, calcium and magnesium in serum has been studied in 12 premature infants and in 24 full term neonates by means of polygraphic conditions. The average of 3.6 +/- 3.0 complete startles in premature infants and of 10.6 +/- 8.7 startles in full term neonates per hour non rapid eye movement-sleep, observed on second day after birth, was significantly higher than the frequency of startles in rapid eye movement-sleep measured as 0.6 +/- 0.9 and 1.9 +/- 2.1 complete startles respectively. In an age of 4 weeks there were no complete startles demonstrable in full term neonates and only 0.2 complete startles/h in non rapid eye movement sleep could be observed in premature infants. There was no correlation between frequency of startles and investigated chemical parameters in serum.

[Clotrimazol in the treatment of candida infections in premature and newborn children (author's transl)]. / Clotrimazol in der Behandlung von Soorinfektionen auf Früh- und Neugeborenenstationen

The early infancy is especially affected by moniliasis in pediatrics. The causes are: broad spread of Candida albicans in the environment of these children, a growing immunity, the immaturity of the skin and an insufficient candida-static activity of the serum. The prematures and the newborns with an irregular birth are especially endangered. This danger is increased by simultaneous antibiotic therapy. The arising mycosis can reach from the relative harmless mouth- and diaper-thrush to serious septic diseases. An effective therapy therefore is very much desired. As new efficacious medicaments the derivates of imidazol, Clotrimazol, have proved satisfactory for the treatment of mycoses. It is as Canesten marketed. The drug possesses a strong activity against numerous fungi, some protozoa, and bacteria. In this paper it is reported on own pharmacokinetic and therapeutic investigations with Clotrimazol. The substance has been very useful for the treatment of mouth- and diaper-thrush. Clotrimazol was administered as BAYb 5097 peroral and local as Canesten -solution 1% and -cream 1%. There were 171 treatments carried out. Essential side-effects were not observed.

[Erythropoietin as a marker of perinatal risk]. / Erythropoietin als Marker perinataler Risiken.

The purpose of this study was to estimate if the erythropoietin (EPO) concentration in cord arterial blood can be an indicator of a fetal risk. We studied EPO concentration measured by enzyme immonoassay in ten patient groups: (1) control group with healthy newborns (n = 72); (2) neonates born by elective caesarean section (n = 16); (3) newborns with acidosis at birth (n = 12); (4) newborns with 1-min-Apgar < 7 (n = 8); (5) preterm neonates (n = 25); (6) newborns with gestational age > or = 242 weeks (n = 19); (7) neonates born to mothers with hypertension (n = 16); (8) newborns with signs of fetal distress in CTG (n = 29); (9) neonates born to mothers with diabetes (n = 19), divided into two subgroups: diabetes White A-D (n = 8) and gestational diabetes (n = 11); (10) neonates born to mothers with diabetes White A-D and with acidosis at birth (n = 7). The geometric mean was 26.4 mU/ml in the control group. EPO levels was found significantly increased (p < 0.01) in the following groups: (3) newborns with acidosis (52 mU/ml); (6) newborns with gestational age > or = 242 weeks (63.5 mU/ml); (8) newborns with signs of fetal distress in CTG (47.1 mU/ml); (9) neonates born to mothers with diabetes White A-D (47.7 mU/ml); (10) neonates born to mothers with diabetes White A-D and with acidosis at birth (> 64 mU/ml). We came to the conclusion that the cord arterial EPO concentration indicates a chronic fetal hypoxia and a longer duration of hypoxia before birth.

[Results of neonatal hearing screening with transitory evoked otoacoustic emissions]. / Ergebnisse eines Neugeborenen-Hörscreenings mittels transitorisch evozierter otoakustischer Emissionen.

From 1. 10. 1992-31. 12. 1993 a hearing screening was performed in 994 preterm and term babies (765 healthy neonates and 229 neonates with risk factors for hearing loss) by means of transient evoked otoacoustic emissions (TEOAE). There was a bilateral absent of emissions in 4.3% of the healthy neonates and 11.8% of the risk babies. 8 from 32 healthy neonates and 10 from 22 risk babies also had a negative test result in the control investigation. 16 of these children showed in 7 cases a severe hearing impairment in expanded pedaudiological investigations. The registration of TEOAE is a recommendable method for a hearing screening in neonates.

[Hearing screening of newborn infants at risk for perinatal hearing damage]. / Hörscreening Neugeborener mit einem Risiko für perinatale Hörschäden.

630 neonates with risk factors of perinatal hearing impairment were screened of hearing loss by means of registration of transient otoacoustic emissions before discharge from the newborn nursery. Neonates were screened additionally by means of brainstem evoked response audiometry, if they had bilateral negative emissions. 810 healthy neonates were screened as control group. The investigations were carried out in incubator after the feeding of neonates. The prevalence of a bilateral negative cochlear response was 5.2% in the risk babies and 1.7% in healthy neonates. Neonates are high risk patients for hearing loss if they show craniofacial anomalies including alcohol embryofetopathy, connatal infections, or very low birth weight babies with additional risk factors. The pedaudiological control investigations of the babies with a negative bilateral cochlear response delivered in the risk group 15 cases (2.4%) with an important hearing impairment and in the healthy neonates 2 cases (0.25%) respectively. Prevalence and importance of perinatal hearing impairment explains the necessity of detection in the neonatal period.

[Intravenous administration of doxycycline vibravenös in childhood--clinical and pharmacokinetic problems]. / Zur intravenösen Verabfolgung von Doxycyclin (Vibravenös) im Kindesalter--klinische und pharmakokinetische Probleme

The paper describes special advantages of doxycycline, especially also in comparison with other tetracyclines, the possbile side-effects of the preparation, and the various ways of application-under special consideration of the pathogenetic spectrum. Pharmacokinetic examination were carried out in eight permature babies, nine new-born, eight normal babies, and in two groups of school children, comprising 7 and 8 test persons each. During these examinations, the serum levels after 1, 6, 10, and 24 hours were evaluated. The values found showed levels in the range of bacteriologic efficiency as far as premature babies and new-born - after 24 hours and with 0.6 gamma/ml - were concerned. In older babies and school children, the values had decreased, after a single application, within 24 hours to 0.2 to 0.15 gamma/ml. However, it has been possible to achieve final values of about 1.5 gamma by applying the preparation twice, i. e. 2 x 2 mg/kg body-weight, within 24 hours. The complete course of elimination of Vibravenös was determined in 8 school children by blood sample taking after 5, 10, 15, and 20 minutes as well as after 1, 3, 6 hours. The values found herein were calculated by means of computer analyses. Half-life of doxycyclin in infantile individuals is subject to rather strong variations. Therefore, a higher dose than usual so far is recommended, viz 6 MG/KG B.W. as initial dose and 3 mg/kg b.w. as maintenance dose.

[Mezlocillin in neonatal medicine]. / Mezlocillin in der Neonatalmedizin.

The acylureido penicillin mezlocillin was tested clinically and pharmacologically in neonates and young infants who received the antibiotic for prophylactic and therapeutic reasons. On the basis of blood level determinations following the administration of various dosages, we consider a dose of 200 mg/kg per day necessary for premature babies and 300-400 mg/kg per day for full-term babies. Pharmacokinetic data showed age-dependent features. The clinical results were good in 40 children treated with mezlocillin. Twenty of these children received a combination of mezlocillin and gentamicin. No child died of an infection. Therapy was not successful in three babies suffering from productive bronchopulmonary infections. Important side-effects were not observed.

[Pharmacokinetic investigations on sisomicin in children (author's transl)]. / Pharmakokinetische Untersuchungen von Sisomicin unter besonderer Berücksichtigung des frühen Kindesalters.

Sisomicin is an aminoglycoside effective against gramnegative germs. The sensitiveness of coli, proteus, pseudomonas and klebsiella ranges from 0,1 to 0,4 mcg/ml. Germs with inhibition-values of up to 1 mcg/ml are certainly Sisomicin-sensitive. The side-effects of Sisomicin resemble those of other aminoglycosides, as for instance lesions of the VIIth cranial nerve and the kidney. Since aminoglycosides have a relatively small therapeutic range between toxicity and effective minimal-concentration, investigations are important especially in children. 66 children of different age groups received Sisomicin in doses of 3 mg/kg, 2 mg/kg and 1 mg/kg, and examined pharmacokineticly. Serum-levels were measured after 30 min 1, 2, and 4h, in some cases also after 6 and 8 h. In a separate group we determined the values after 5, 10, 15, 20, 30 and 40 min. The urinary output was controlled and the content of Sisomicin in meconium determined. Based on these results we recommend an individual, Sisomicin dosage for each age group. Clinically the Sisomicin proved to be well tolerated and effective antibioticum.

Pharmacokinetics of azlocillin in neonates.

The pharmacokinetics of the acylureido-penicillin, azlocillin, were studied after intravenous or intramuscular injections in 53 premature and full-term infants with infections. Effective concentrations wer" achieved in premature babies after doses of 50 mg/kg every 12 h and in full-term infants with 100 mg/kg every 12 h. No untoward effects of azlocillin were observed. On the basis of these studies, a dosage schedule for azlocillin has been established.

[Pediatric pharmacology of azlocilin (author's transl)]. / Pädiatrisch-klinische Pharmakologie von Azlocillin.

Pharmacokinetic investigations of acylureido-penicillins azlocillin in newborns, infants and school shildren showed age dependend results. The differences were especially evident in a prolongation of the serum half-life to 2,56 hours in newborns compared to 0.94 hours in school children. On the basis of our pharmacokinetic results and of the dosages resulting from the data the antibiotic was used clinically in twenty eight patients with Pseudomonas aeruginosa infections and one patient with a Proteus mirabilis infection. The results were much better in infections of the urinary tract than in infections of the respiratory tract. This might be due to an observe bacterial presistence in spite of highly effective levels of azlocillin in bronchial secretion. The tolerance to the antibiotic was good.

Experience with amoxycillin in neonates and premature babies.

Amoxycillin, a semi-synthetic penicillin, resembles ampicillin in many respects. There is cross-resistance between the two antibiotics. Numerous Gram-positive and Gram-negative organisms are sensitive to amoxycillin at relatively low dosage. Investigations using oral amoxycillin, 50 mg/kg body weight were carried out in neonates and premature babies in the first days of life. Peak values of 38 microng/ml and 59 microng/ml at 4 1/4 hours were obtained for the neonates and premature babies respectively. The 10-hour value for the first group was 13 microng/ml and for the second 19 microng/ml. With a single dose of amoxycillin, serum levels of 0.9 microng/ml were still obtained after 24 hours. In children who received the same dose twice daily, the serum values were 6.5 microng/ml after 24 hours. The urinary excretion of amoxycillin was, on an average, 41% in 24 hours. Amoxycillin was also found in the meconoium, but the quantity in the different portions showed a large dispersion. Amoxycillin can, therefore, be recommended as an effective and well tolerated antibiotic for use in the neonatal and premature period. In general the drug should be administered 12-hourly at a dose of 50 mg/kg body weight. Only in severe illnesses is 8-hourly administration required.

[Effect of the beta-2 mimetic drug terbutaline of growth hormone secretion in prepubertal asthmatic children]. / Zum Einfluss des Beta-2-Mimetikums Terbutalin auf die Wachstumshormonsekretion präpubertärer asthmakranker Kinder.

Asthmatics display a tendency to retarded growth and hyposomia in childhood. The reasons for this are not yet clear, although the atopic disposition seems to occupy a key role. It is a known fact that stimulation of the beta-2 receptors results in inhibiting growth hormone secretion. The purpose of our study was to find out whether the beta-2 mimetic terbutalin, often used in asthma therapy, exercises a negative influence on the spontaneous release of growth hormone in children suffering from asthma. The growth hormone release was studied in 10 prepuberal children suffering from atopic asthma who received intravenous therapeutic doses of terbutalin: testing was done for a total period of 24 hours before and during administration. Terbutalin effected significant inhibition of growth hormone secretion merely during the waking phase (6.2 +/- 1.0 to 3.7 +/- 0.7 ng/ml), but not during the sleep phase (13.1 +/- 1.8 to 12.5 +/- 2.0 ng/ml) and the 24-hour period (11.0 +/- 1.0 to 9.8 +/- 1.5 ng/ml). There was also no significant influence on the average group value for the maximum growth hormone peak (40.8 +/- 9.5 to 42.7 +/- 11.0 ng/ml). These results point to a short-term inhibition of growth hormone secretion, exercised by intravenously administered terbutalin. Terbutalin does not seem to be responsible for any clinically relevant inhibition of growth and development.

[Hair cell function diagram in premature and mature newborn infants]. / Haarzellfunktionsdiagramme bei Früh- und Reifgeborenen.

BACKGROUND: The grade of maturation of the cochlear function must be taken into account when the cochlear function is investigated in premature infants and neonates. Quantitative analysis has not yet been performed. METHODS: Using the otodynamic analyzer ILO 88/92, we therefore determined haircell functional diagrams and the echo 65 dB levels in 35 healthy neonates as well as 30 healthy premature infants with a median gestational age (GA) of 32 weeks (28-35 weeks) 2-3 days post natum. Follow up investigations were performed in 10 neonates and 16 premature infants. RESULTS: The mean echo 65 dB levels were 4.88 +/- 4.22 dB for the right ears and 5.72 +/- 5.16 dB for the left ears in premature infants < or = 32 weeks of GA, 10.25 +/- 3.89 dB and 10.69 +/- 5.55 dB respectively in premature infants > 32 weeks of GA, and 16.01 +/- 4.99 and 14.90 +/- 4.41 dB respectively in neonates. There was no significant difference between neonates at day 2 and 4 post natum. In 16 premature infants the echo 65 dB levels increased from 4.92 dB for the right ears and 4.79 dB for the left ears at the second day of life to 11.72 dB and 11.73 dB respectively at the age of 4 weeks. CONCLUSION: We present therefore strong evidence for a maturation of the cochlear function in premature infants with increasing age. The individual grade of maturation of the cochlea is of relevance for the auditive stimulation of very premature infants.

[Experiences using acylureido-penicillins (azlocillin, mezlocillin) in pediatrics]. / Erfahrungen mit Acylureido-Penicillinen (Azlocillin-Mezlocillin) in der Pädiatrie.

The acylureidopenicillins azlocillin and mezlocillin cover a broad spectrum of bacteria, including gramnegative and grampositive species as well as anaerobes. Azlocillin is especially active against P. aeruginosa. Mezlocillin has a good activity against Klebsiella. Both antibiotics inhibit Hemophilus, N. meningitidis and D. pneumoniae in low concentrations. Clinical and kinetic studies were made in more than 300 pediatric patients. Elimination-constant halflife, distribution volume and area under the curve were determined to propose dosage recommendations. Concentrations of azlocillin (44) and mezlocillin (77) were measured in the bronchial secretions. Up to hour 5 after i.v. injection a wide range of concentration values were observed. Azlocillin was found in the meconium in different concentrations after a single injection into the newborn. Mezlocillin diffused into the CSF even in uninflamed meninges, 3 h after injection the mean concentrations were 5.5 mg/l. 39 patients, 35 of them infected by P. aeruginosa, were treated by azlocillin. Urinary tract infections, wound infections and dacryocystitis were cured with one exception. Less convincing were the results in complicated bronchopulmonary diseases. The clinical efficacy of mezlocillin was similar. In a group of 59 patients there were only 3 without effect and some with improvement again in complicated pulmonary diseases. Side effects worth to be mentioned were not seen. In 2 patients the azlocillin injection caused nausea. Mezlocillin led to some minor transitory elevations of the transaminases and dyspepsia in some patients.

Investigations of the rhythmic function of heart rate, blood pressure and temperature in neonates.

Over a period of 24-30 h in 10 min intervals, the systolic diastolic and mean arterial blood pressure, heart rate, rectal and skin temperature were measured simultaneously in 17 full-term babies on the 2nd day of life, and in 11 of them again at the age of 4 weeks. Each profile was analysed individually by the Cosinor method. On the 2nd day of life, a statistically significant circadian rhythm could be detected in 12 of the 17 neonates for systolic blood pressure and heart rate, in 16 for skin temperature and in all 17 neonates for rectal temperature. Summarizing the data of the 17 newborns the circadian rhythm was the most frequent component in all functions. A high portion of ultradian rhythms was observed as well. With increasing postnatal age, the variance of acrophases decreased, particularly for the temperature rhythms. This means that synchronization with the environment is beginning. Furthermore, we found an increase in the mesor of heart rate and blood pressure and an increase in amplitude of temperature.

[On the excretion of azlocillin with bronchial secretion in children (author's transl)]. / Zur Frage der Ausscheidung von Azlocillin in das Bronchialsekret im Kindesalter.

This pharmacokinetic study involved school children who were treated with 6-[(R)-2-(2-oxo-imidazolidine-1-carboxamido)-2-phenyl-acetamido]-penicillanic acid sodium walt (azlocillin, Securopen) at doses of 50 mg/kg bodyweight or 75 mg/kg body weight i.v. Kinetics of the first order were found for the concentrations measured at the same time, being proportionate to the administered dose, while there was no dose dependence for the relative distribution volume. The elimination half-life was about 55 min. In 25 children of different age who had to undergo bronchoscopy for diagnositic and therapeutic reasons, the azlocillin concentrations in the bronchial secretions were measured 1 h and 4 h after the administration of 75 mg/kg quantity of bronchial secretion was obtained, azlocillin concentrations of 30 - 240 microgram/g were found. Measurements of azlocillin concentration in the bronchial secretion and in the serum, which were made at the same time, did not show any correlation.

Amoxicillin in paediatrics, with special reference to its excretion into bronchial secretion.

Pharmacokinetic examinations with amoxicillin in neonates and prematures are reported. Good values of up to 5 mcg/ml after 24 hours were achieved with two doses of 50 mg/kg amoxicillin daily. Amoxicillin was also found in the meconium, although quantities varied greatly. Amoxicillin is recommended for the treatment of disorders of the respiratory tract because of its good absorption, tissue penetration and tolerance. Examinations to assess the excretion of amoxicillin into the bronchial secretion were therefore carried out in 88 children in different age groups. Two artificial respiration bronchoscopies were carried out with an interval of 7 days, and the bronchial secretion collected and tested for organisms and for amoxicillin concentrations. After the first bronchoscopy, patients were given amoxicillin for 7 days, in doses of 125 to 750 mg t.i.d., corresponding to 40-100 mg/kg body weight. Some very high amoxicillin values were found, especially in those groups from whom the secretion was taken 2, 3, or 4 hours after the last amoxicillin treatment. The values were widely scattered. We recommended 50-100 mg/kg for broncho-pulmonary diseases.

[Pharmakokinetic and clinical studies with azlocillin in paediatrics (author's transl)]. / Pharmakokinetische und klinische Untersuchungen mit Azlocillin in der Pädiatrie.

Azlocillin, an acylureido penicillin with bactericidal activity, is particularly effective against Pseudomonas, enterococci and Haemophilus influenzae. It is also very active against E. coli, various Proteus species and Bacteroides. Pharmacokinetic studies were carried out in 138 children of various ages (prematures, newborns, infants, schoolchildren) after administering 50-75-100 mg/kg/ body weight azlocillin via the i.v. or i.m. routes; The constant of elimination and the distribution volumes were calculated besides the serum levels. In prematures and newborns, therapeutically effective serum levels were obtained on administering 50 or 100 mg/kg body weight twice daily. Infants and older children required 100 or 75 mg/kg body weight t.i.d. Determination of azlocillin in the bronchial secretion after i.v. doses of 75 mg/kg body weight showed good elimination. Azlocillin was always identified up to the 5th hour post injectionem. Inspite of parenteral administration, azlocillin was identified in different concentrations in the meconium as well. 39 children were treated with azlocillin, 35 of whom had Pseudomonas infection. Very good results were obtained in infections of the urinary tract, wound infections, conjunctivitis, dacryocystitis and in one case of meningitis. Bronchopulmonary diseases did not take an equally good course, but in these cases the conditions had not been favourable. No serious side effects were revealed by testing several laboratory parameters.

[Oncology patients in a pediatric intensive care unit--a 7-year experience]. / Die wachsende Bedeutung der pädiatrischen Intensivstation in der Behandlung onkologischer Patienten--Erfahrungen über 7 Jahre.

BACKGROUND: As a result of improved therapeutic and diagnostic modalities the survival rate of children with neoplastic disease has increased dramatically. The consequences of these scientific advances have led to increased malignancy-related critical complications requiring the expertise of intensive care practitioners. PATIENTS: From all children admitted to the pediatric intensive care unit (PICU) of the Martin-Luther University Halle those with hematologic-oncologic condition were evaluated. RESULTS: From 4068 PICU admissions 196 (4.8%) oncologic patients were identified. Most of them were admitted for postoperative care, monitoring or intervention. 24 patients were admitted because of severe disease or treatment related complications. 14 out of 24 (58%) patients died on PICU. Mortality was significant higher in a subgroup requiring mechanical ventilation or suffering from sepsis. All patients but two with multi-organ system failure (> or = 2 organs) died. CONCLUSIONS: Children with neoplastic disease can benefit from pediatric intensive care unit (PICU) support. Successful treatment of life-threatening complications requires a close cooperation of pediatric oncology and PICU. Further studies are necessary to improve therapeutic strategies in oncology patients requiring PICU admission.