[Developmental neurology - networked medicine and new perspectives]. / Entwicklungsneurologie ­ vernetzte Medizin und neue Perspektiven.

Developmental neurology is one of the major areas of neuropediatrics and is among other things (legally) responsible for monitoring the motor, cognitive and psychosocial development of all infants using standardized monitoring investigations. The special focus is on infants born at risk and/or due to premature birth before 32 weeks of gestation or a birth weight less than 1500 g. Early diagnosis of deviations from normal, age-related development is a prerequisite for early interventions, which may positively influence development and the long-term biopsychosocial prognosis of the patients. This article illustrates the available methods in developmental neurology with a focus on recent developments. Particular attention is paid to the predictive value of general movements (GM). The current development of markerless automated detection of spontaneous movements using conventional depth imaging cameras is demonstrated. Differences in spontaneous movements in infants at the age of 12 weeks are illustrated and discussed exemplified by three patients (healthy versus genetic syndrome versus cerebral palsy).

[Indications and concept of follow-up care of home-monitoring for premature and risk infants]. / Indikation und Nachsorgekonzept zur Heimmonitorüberwachung in der Komplexbetreuung von Früh- und Risikoneugeborenen.

The pros and cons of home monitoring especially for premature infants with continuing apneic episodes and/or chronic lung disease are an ongoing discussion. The controversy spans socio-economic requirements, medical indication as well as patient and family needs. Here, the costs of home monitoring and follow-up care on the one hand and longer hospitalization times on the other need to be considered. This article aims to create a basis for this discussion by summarizing current evidence for the indications and considerations for differential diagnoses while also outlining the established follow-up program for these patients at the Dr. v. Hauner Children's Hospital at the Ludwig-Maximilians-University Munich, Germany.

[Establishment of a Neonatal ECMO Programme on the Basis of a Special Training Programme--A 6-year Analysis]. / Etablierung neonataler ECMO bei Lungenversagen auf der Grundlage eines speziellen Trainingsprogramms--Eine 6-Jahres-Analyse.

BACKGROUND: Internationally the need for neonatal ECMO is decreasing and the Extracorporeal Life Support Organization (ELSO) recommends that centres providing neonatal ECMO should treat at least 6 children per year. METHOD: After a one-year training programme and preparation of the clinical application, neonatal ECMO was established and subsequently 41 infants [median age 1 day (1-172 days), median weight 3.25 kg (1.27-5.79 kg)] with severe respiratory failure have been treated within a 6-year period (fall 2008-fall 2014). For rescue therapy we provide inhaled nitric oxide, high-frequency oscillation and other differentiated ventilator strategies. Parallel to the clinical use of ECMO all employees have been trained in a special programme at 3-monthly intervals. RESULTS: By establishing an elaborate training programme and concentrating the treatment of critically ill newborns in one centre, the expertise of both running and preventing of neonatal ECMO due to pulmonary failure can be achieved. The diagnoses correlate to those of other centres which perform neonatal ECMO. 13 infants needed ECMO. The resulting overall survival rate was 11/12 (91.7%) infants treated with ECMO with a curative approach. All patients could be weaned from ECMO. CONCLUSION: In the context of a specialised university hospital with all treatment options for critically ill newborns and with the establishment of a specialised training programme, neonatal ECMO for pulmonary failure can achieve equally good results in comparison to those of national and international ECMO centres.

[Treatment of neonatal asphyxia with a special focus on therapeutic hypothermia]. / Behandlung der neonatalen Asphyxie unter besonderer Berücksichtigung der therapeutischen Hypothermie.

In recent years the treatment of newborns for neonatal asphyxia has experienced a lot of new developments. A major milestone were the positive results of various trials for prophylactic treatment of hypoxic-ischemic encephalopathy by moderate cooling of the child or of his head. With this paper we attempt to provide a consented guideline to aid in the treatment decision for affected newborns and thus achieve a more homogeneous treatment strategy throughout Germany.

Gestational diabetes in Turkmenistan: implementation of a screening program and first results.

PURPOSE: Data on the prevalence of gestational diabetes (GDM) is not available for Turkmenistan or any other central Asian country with large energy resources and rapidly increasing wealth and rates of obesity. We initiated a screening program to determine the prevalence of and the risk factors for GDM in Turkmenistan. METHODS: Between March 2008 and March 2011, all pregnant women presenting to the Ene-Maehri-Merkezi perinatal center in Ashgabat before week 34 of pregnancy received a glucose screening test (after 26 weeks of pregnancy; 50 g glucose). If 60-min glucose was ≥7.8 mmol/l, an oral glucose tolerance test (oGTT) (75gr) was performed. GDM was diagnosed if ≥1 glucose values were abnormal (≥5.0, ≥10.0, ≥8.0 mmol/l at 0-, 60-, 120-min, respectively). Birth weight, 30 min glucose, and APGAR (1, 5, and 10 min) were recorded for all newborns. RESULTS: Of 1,738 women, 22.7 % had a pathological screening test. 70 % of these, underwent an oGTT and of these, 39.5 % had GDM (overall prevalence 6.3 %). Age, BMI, parity, and blood pressure were associated with screening glucose (all p < 0.001). In a multivariate analysis, age, BMI, and family history for diabetes were associated with GDM. Newborns from affected mothers were heavier (3,622 ± 435 vs. 3,480 ± 464 g, p = 0.007) and developed postnatal hypoglycaemia more often (21.6 vs. 9.3 %, p = 0.001), while there was no difference in APGAR. CONCLUSIONS: GDM is a relevant problem in Turkmenistan and probably also in other central Asian countries. The prevalence is similar to other developing countries such as India or China. Risk factors are comparable to those determined in other parts of the world.

Delivery room desaturations and bradycardia in the early postnatal period of healthy term neonates - a prospective observational study.

OBJECTIVE: It has been suggested that desaturations and bradycardia precede acute life-threatening events (ALTE) and that ALTE is more common in the delivery room than later in life. However, frequency, duration and severity of desaturations in the first hours of life and additional risk factors have not readily been studied. METHODS: Term neonates (n = 100) were monitored for the first two hours after birth by pulse oximetry. The impact of maternal and perinatal factors on the frequency and severity of desaturations (<85%) and bradycardia (<80/min) was evaluated. RESULTS: Desaturations were detected in 30%, prolonged desaturations in 25% of infants. Desaturations were observed significantly more often in infants born by planned Cesarean section (pCs) compared to other modes of delivery (pCs 20/49; others 10/51; p = .029). Desaturations were also more frequent in infants diagnosed with neonatal infection (NI) or infants born to a mother with gestational diabetes (GDM), although not significantly. No bradycardia <80/min was detected. CONCLUSIONS: In our collective 4% of healthy term neonates had prolonged, clinically relevant desaturations in the first hours after birth. The mode of delivery and maternal risk factors may increase the risk for these events. However, our cohort was too small to detect any ALTE or SIDS and determine potential risk factors for these events. Our data lay ground for a large-scale prospective trial to investigate whether the mode of delivery could be an indication for general pulse oximetry monitoring of newborn in the delivery room.

Use of impregnated catheters to decrease colonization rates in neonates - A randomized controlled pilot trial.

OBJECTIVE: Nosocomial infections increase mortality and morbidity in preterm infants. Central venous line colonization is a major risk factor for the development of such infections. In adults and children, antibiotic and antimycotic impregnated catheters have been demonstrated to reduce colonization. However, recently published data showed no significant difference in bloodstream infection in neonates when an impregnated catheter was used. We investigated the effect of impregnation of percutaneously inserted micro-catheters (PICC) on colonization in preterm and sick term infants in our unit. METHODS: Neonates were randomly assigned to receive either a standard (S-PICC; n = 34) or antibiotic and antimycotic impregnated (IP-PICC; n = 37) PICC. Catheters were placed and removed according to a standard procedure and subsequently examined by roll-out culture. The primary outcome was the rate of colonization defined as >15 colony-forming-units/ml. Additional outcomes were catheter associated or systemic infections. RESULTS: The rate of colonization was lower in neonates who received an IP-PICC as compared to S-PICC (5.6% vs. 12.1% respectively; p = 0.42). However, the difference was not significant. In IP-PICC vs S-PICC, catheter related local infection (CRI) although lower was not statistically significant (2.9% vs. 6.1%; p = 0.60). We observed no difference in catheter related systemic infection (CR-SI) (0% vs. 3.1%, p = 0.48). The neonates whose catheters were colonized were predominantly of a lower gestational age (median 254/7, p = 0.05) and males (100%, p = 0.01). In addition, the median colony count in the colonized IP-PICC catheters was lower as compared to S- PICC group (53 vs 250, p = 0.06). CONCLUSIONS: The use of antibiotic and antimycotic impregnated PICC-lines in neonates tended to decrease colonization rates in neonates in our centers but this difference was not significant. Lower gestational age and male sex are risk factors for catheter colonization.

Clinically stable very low birthweight infants are at risk for recurrent tissue glucose fluctuations even after fully established enteral nutrition.

OBJECTIVE: In previous cases, we have observed occasional hypoglycaemic episodes in preterm infants after initial intensive care. In this prospective study, we determined the frequency and severity of abnormal tissue glucose (TG) in clinically stable preterm infants on full enteral nutrition. METHODS: Preterm infants born at <1000 g (n=23; G1) and birth weight 1000-1500 g (n=18; G2) were studied at a postmenstrual age of 32±2 weeks (G1) and 33±2 weeks (G2). Infants were fed two or three hourly, according to a standard bolus-nutrition protocol, and continuous subcutaneous glucose measurements were performed for 72 h. Normal glucose values were assumed at ≥2.5 mmol/L (45 mg/dL) and ≤8.3 mmol/L (150 mg/dL). Frequency, severity and duration of glucose values beyond normal values were determined. RESULTS: We observed asymptomatic low TG values in 39% of infants in G1 and in 44% in G2. High TG values were detected in 83% in G1 and 61% in G2. Infants in G1 experienced prolonged and more severe low TG episodes, and also more frequent and severe high TG episodes. In G1 and G2, 87% and 67% of the infants, respectively, showed glucose fluctuations characterised by rapid glucose increase followed by a rapid glucose drop after feeds. In more mature infants, glucose fluctuations were less pronounced and less dependent on enteral feeds. CONCLUSIONS: Clinically stable well-developing preterm infants beyond their initial period of intensive care show interstitial glucose instabilities exceeding values as low as 2.5 mmol/L and as high as 8.3 mmol/L. This novel observation may play an important role for the susceptibility of these high-risk infants for the development of the metabolic syndrome. TRIAL REGISTRATION NUMBER: German trial registration number DRKS00004590.

Methodological investigation of measuring nasopharyngeal temperature as noninvasive brain temperature analogue in the neonate.

OBJECTIVES: (a) To investigate in a newborn animal model whether nasopharyngeal temperature is more closely related to epidural brain temperature than rectal temperature and (b) to investigate in human neonates whether measurement of nasopharyngeal temperature is dependent on the measurement site and other conditions. DESIGN AND SETTING: (a) Animal experiment in newborn piglets, at an institute for surgical research. (b) Prospective study in human neonates, at a neonatal intensive care unit of a tertiary care university hospital. ANIMALS AND PATIENTS: (a) Nineteen tracheostomized ventilated newborn piglets. (b) Twenty-two spontaneously breathing human newborns nursed either in an incubator or a cot. MEASUREMENTS AND RESULTS: (a) In the piglets nasopharyngeal temperature (Tnasoph) measured at the nose-ear distance, defined as distance from the inner brim of the nostril to the tragus and inner rim of the meatus accusticus, most closely reflected epidural temperature (Tepidur) at the epidural surface (r2 = 0.89), followed by skin temperature at the temple, rectal temperature (Trectum) at 2 cm depth, and esophageal temperature (Tesoph) in the middle esophagus. Tnasoph did not significantly differ before and after tracheostomy. (b) In the newborns Tnasoph was significantly lower than Trectum. Measurements of Tnasoph at nose-ear distance within a feeding tube had a high precision and were unaffected by breathing or head turning. A nasopharyngeal probe was imaged by magnetic resonance imaging in four newborns of various body weight; its tip when inserted to a depth equal to nose-ear distance was anatomically closest to the brain base but separated from it by tissue layer 2.2 cm thick. CONCLUSIONS: Tnasoph measured at a position anatomically closest to the brain reflects epidural brain temperature more closely than Trectum. When measured at nose-ear distance it is unaffected by breathing or head turning. Measuring Tnasoph within a feeding tube and standardizing the measuring position is crucial for its use as brain temperature analogue.

[Malassezia furfur colonising the respiratory tract of mechanically ventilated neonates]. / Malassezia furfur im trachealsekret beatmeter frühgeborener.

BACKGROUND: Ventilated neonates are prone to acquire ventilator-associated pneumonia (VAP). Consequently early diagnosis of pneumonia is required. Beside bacteria, fungi are suspected as a cause of VAP. However, fungal colonisation and infection of the lung have not been studied systematically. The purpose of this study was to evaluate pulmonary fungal colonisation in ventilated neonates and premature infants. MATERIALS AND METHODS: 187 tracheal aspirates (TA) from 29 ventilated neonates (23-35 weeks gestational age) were investigated. TAs were evaluated microscopically and by culture. Data were matched with clinical signs of VAP or sepsis. RESULTS: Candida species were not detected in TA or culture. In contrast, Malassezia furfur (Mf), a lipophilic fungus, was detected from the 10th, 21st and 31st postnatal days onwards in TAs of 3 out of 17 extremely prematures (gestational age at birth < 25 weeks). The presence of Mf was associated with clinical deterioration either immediately or a few days after the first positive Mf smear. Topic steroids were more frequently applied to Mf-positive ELBW infants (p = 0.03). In vitro, natural surfactant was demonstrated to be a sufficient substrate for Mf in culture. CONCLUSION AND DISCUSSION: This is the first report on Mf lung colonisation of ELBWI during mechanical ventilation. Because Mf is generally not detected in standard cultures it appears to be an overlooked, potentially pathogenic fungus in prematures. Mf must be considered in the differential diagnosis of VAP in ELBWI exposed to topical steroids, especially when natural surfactant was administered.

Transcellular sodium transport and basolateral rubidium uptake in the isolated perfused cortical collecting duct.

The relation between transcellular Na+ absorption, intracellular Na+ concentration and Na+/K(+)-ATPase activity (the last estimated by the rubidium uptake across the basolateral cell membrane) was examined in the different cell types of the rabbit cortical collecting duct (CCD). Experiments were performed on isolated perfused CCD in which Na+ absorption was varied by perfusing the tubule with solutions containing different Na+ concentrations (nominally Na(+)-free, 30 mM and 144 mM). Experiments were terminated by shock-freezing the tubules during perfusion. Precisely 30 s before shock-freezing, the K+ in the bathing solution was exchanged for Rb+. Intracellular element concentrations, including Rb+, were determined in freeze-dried cryosections of the tubules using energy-dispersive X-ray analysis. Increasing Na+ concentration in the perfusion solution caused significant rises in intracellular Na+ concentration and Rb+ uptake of principal cells. Principal cell Na+ and Rb+ concentrations were 7.8 +/- 0.9 and 7.0 +/- 0.8 mmol/kg wet weight respectively, when the perfusion solution was Na(+)-free, 10.1 +/- 0.7 and 11.6 +/- 0.6 mmol/kg wet weight with 30 mM Na+ in the perfusion solution, and 14.5 +/- 1.5 and 14.9 +/- 0.9 mmol/kg wet weight with 144 mM Na+ in the perfusion solution. In contrast, a comparable relationship between lumen Na+ concentration, intracellular Na+ concentration and basolateral Rb+ uptake was not seen in intercalated cells. These results support the notion that principal, but not intercalated, cells are involved in transepithelial Na+ absorption. In addition, the data demonstrate that apical Na+ entry and basolateral Na+/K(+)-ATPase activity are closely coupled in principal cells of the rabbit CCD.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of ion transport by direct targeting of protein phosphatase type 1 to the Na-K-Cl cotransporter.

The specificity of major protein phosphatases is conferred via targeting subunits, each of which binds specifically to the phosphatase and targets it to the vicinity of substrate proteins. In the case of protein phosphatase 1 (PP1), an RVXFXD motif on a targeting subunit binds to a cleft in PP1c, the catalytic subunit. Here we report that a substrate of PP1, the Na-K-Cl cotransporter (NKCC1), bears this motif in its N terminus near sites of regulatory phosphorylation and that direct binding of PP1 to NKCC1 is functionally important in determining the set point for intracellular chloride regulation. NKCC1 mutants in which the motif is destroyed or improved exhibit dramatically shifted activation curves because of a change in the rate of cotransporter dephosphorylation. Furthermore, direct interaction of NKCC1 and PP1c observed by coprecipitation of the two proteins is not seen in a mutant lacking the site. This establishes a new paradigm of phosphatase specificity, one in which a substrate protein containing an RVXFXD motif binds directly to PP1c; we propose that this may be a quite general mechanism.

Sodium entry routes in principal and intercalated cells of the isolated perfused cortical collecting duct.

Transmembrane sodium transport pathways were studied in principal and intercalated cells of the isolated perfused rabbit cortical collecting duct. Intracellular electrolyte concentrations in individual collecting duct cells were measured by electron microprobe analysis during blockage of basolateral Na-K-ATPase by ouabain and simultaneous inhibition of sodium entry across the apical and/or basolateral cell membrane. In principal cells the ouabain-induced rise in cell sodium concentration could only partially be blocked by amiloride (10(-4) mol/l) in the perfusion fluid. Amiloride (10(-3) mol/l) added to the bathing solution produced a further, significant reduction of sodium influx. In principal cells the ouabain-induced increase in sodium concentration was completely prevented by amiloride in the perfusion solution in combination with omission of sodium from the peritubular bathing solution. In intercalated cells ouabain caused a less pronounced increase in sodium concentration than in principal cells. Neither amiloride in the perfusate, nor amiloride in both bathing and perfusion solution, significantly reduced the ouabain-induced rise in intercalated cell sodium concentration. These results indicate that in principal cells amiloride-sensitive sodium channels constitute the predominant pathway for sodium entry across the apical cell membrane. In addition, substantial amounts of sodium enter principal cells across the basolateral cell membrane, probably via Na-H exchange. Finally, the data suggest that in intercalated cells sodium channels and the Na-H exchange are sparse or even absent.

Effect of lung water content, manipulated by intratracheal furosemide, surfactant, or a mixture of both, on compliance and viscoelastic tissue forces in lung-lavaged newborn piglets.

OBJECTIVE: To study the impact of lung water content and its reduction by a topically applied diuretic on respiratory and lung tissue mechanics in comparison with surfactant administration in surfactant-deficient newborn piglets with lavage-induced lung injury. DESIGN: Controlled, randomized study. SETTING: Animal research facility. SUBJECTS: Newborn piglets. TREATMENT Piglets were surfactant depleted by lung lavage and, after a pretreatment period, randomly treated with intratracheal furosemide, furosemide and surfactant, or with surfactant alone. MEASUREMENTS AND MAIN RESULTS: Dynamic compliance (C(DYN)), static compliance (C(ST)), stress-adaptation pressures (P(DIFF)) and post mortem lung water content were determined. Static compliance in the furosemide-surfactant group was not significantly higher than in the surfactant group. At the end of the study, C(ST) did not differ between the three groups because C(ST) in the furosemide group had increased to values similar to those of the surfactant-containing treatment groups: C(ST) F+S: 0.73 +/- 0.2 mL/cm H2O/kg body weight (BW); C(ST) S: 0.61 +/- 0.11 mL/cm H2O/kg BW; and C(ST) F: 0.60 +/- 0.19 mL/cm H2O/kg BW). Compliance was inversely and P(DIFF) was directly correlated to lung water (LW) content (C(ST) vs. LW: r2 = .59, p = .001; C(DYN) vs. LW: r2 = .49, p = .006; P(DIFF) vs. LW: r2 = .37, p = .059), independent of the type of treatment. Changes in C(ST) and C(DYN) were inversely related to changes in P(DIFF). Intrapulmonary furosemide was more rapidly absorbed when administered to the surfactant-depleted lung alone compared with the mixture with surfactant, and intrapulmonary furosemide had a rapid systemic effect. CONCLUSION: Although the combination of surfactant with a diuretic failed to increase respiratory compliance to a significantly larger extent than surfactant alone, furosemide at the end of the study increased respiratory compliance to a level similar to surfactant-containing treatments. Lung water content and, to a lesser extent, the absence or presence of surfactant appeared to determine lung mechanics, and its impact on lung mechanics was similar to surfactant administration.

The low molecular weight heparin dalteparin for prophylaxis and therapy of thrombosis in childhood: a report on 48 cases.

UNLABELLED: We investigated the efficacy, safety and relation of dose to plasma anti-Xa activity of the low molecular weight heparin (LMWH) dalteparin in prophylaxis and therapy of arterial and venous thrombosis in pediatric patients. A total of 48 children were enrolled: 10 received dalteparin for prophylaxis (group I), 8 for reocclusion prophylaxis following successful thrombolysis (group II), 5 following failed thrombolysis (group III) and 23 for primary antithrombotic therapy (group IV). Two children were treated with dalteparin for pulmonary veno-occlusive disease (PVOD) and for primary pulmonary hypertension (PPH), respectively. OUTCOME: In group I no thrombo-embolic event occurred. In group II recanalization was maintained or improved, in group III vascular occlusion persisted under dalteparin. In group IV we saw complete recanalization in 7/23 (30%), partial recanalization in 7/23 (30%) and no recanalization in 9/23 (40%) cases. The child with PVOD had recanalization proven by lung biopsy; the clinical condition of the child with PPH also improved. Minor bleeding occurred in 2/48 (4%) children. For prophylaxis 95 +/- 52 (mean and SD) anti-Xa IU/kg BW, for therapy 129 +/- 43 (mean and SD) anti-Xa IU/kg BW proved effective. For both prophylaxis and therapy the required dose per kg BW was inversely related with age (r2 = 0.64, P = 0.017; r2 = 0.13, P = 0.013). CONCLUSION: Dalteparin proved to be an effective and well tolerated drug for prophylaxis and therapy of thrombosis in pediatric patients. Dose requirement for effective treatment was higher in younger children and decreased with age.

Percutaneous transjugular intrahepatic stent shunt for treatment of intractable varicose bleeding in paediatric patients.

UNLABELLED: Two 10-year and 11-year-old children with oesophageal and gastric varicose haemorrhage unresponsive to medical treatment and repeated endoscopic sclerotherapy underwent percutaneous transjugular intrahepatic portosystemic shunting (TIPSS). A newly developed introducing system was used. The procedure was performed to avoid the increased risk of emergency liver transplantation in children with hepatic failure. Immediately after the procedure bleeding stopped and the patient's condition improved. Ascites disappeared and liver function improved. The stent shunt was shown to be patent by angiography and Doppler ultrasound for a follow up period of more than 1 year. CONCLUSION: TIPSS may be of benefit in children with severe portal hypertension. It allows control of intractable bleeding, and stabilizes the patients preparing them for subsequent elective orthotopic liver transplantation.