Jens Möller

Enhanced Interleukin-6 and Interleukin-8 Synthesis in Term and Preterm Infants

There is growing evidence that sepsis-related complications in neonates are crucially mediated by the action of proinflammatory cytokines. It has previously been demonstrated that elevated IL-6 and IL-8 levels can predict brain damage and chronic lung disease in preterm infants. However, it is the current view that neonates have a reduced capability to produce proinflammatory cytokines. To clarify this issue, we analyzed the inflammatory response in term and preterm infants directly at the single cell level by flow cytometry. Endotoxin challenge was performed under defined conditions on monocytes obtained from 50 healthy adults and 119 neonates, which consist of 45 term infants, 63 preterm infants (26.1–36.7 wk of gestational age), and 11 preterm infants with proven infection (24.6–29.9 wk). Our results challenge the existing view of an immature inflammatory response by demonstrating that term infants and preterm infants display a higher percentage of IL-6– and IL-8–positive cells than adults. After preincubation with dexamethasone the number of cytokine-positive cells decreased in all groups, but the number of IL-8–positive cells remained higher in term and preterm infants >32 wk compared with adults. These observations demonstrate not only a well-developed but also an enhanced inflammatory response in term and preterm infants. Under consideration of several detrimental effects of IL-6 and IL-8, our data may have major implications on the pathophysiology of inflammatory-triggered neonatal diseases.

Comparison of vancomycin and teicoplanin for prophylaxis of sepsis with coagulase negative staphylococci (CONS) in very low birth weight (VLBW) infants.

A prospective randomized study was performed to evaluate the efficacy of a low dose (5 mg/kg/day bid) vancomycin compared with a low dose (5 mg/kg/day once daily) teicoplanin therapy to prevent CONS sepsis in VLBW-infants. All infants received this therapy after their 4th day of life or after an eventual therapy of early onset sepsis as long as an i.v. line was in place or 1500 g body weight. Twenty-seven infants were treated with vancomycin (birth weight 1103 +/- 286 g, gest. age 28.8 +/- 1.9 weeks), 28 with teicoplanin (birth weight 1133 +/- 226 g, gest. age 29.04 +/- 2.2 weeks). The infants were observed for clinical and laboratory signs of sepsis. On day 4 of therapy and every 3rd day during therapy serum creatinine levels, tracheal aspirates, stool cultures and vancomycin/teicoplanin peak and trough levels were obtained. We could not detect any case of blood culture positive sepsis and 1 case of suspected sepsis (neg. blood cultures) in both groups, as compared with a former CONS sepsis rate of 24% in our institutions VLBW infants without antibiotic prophylaxis. Nine patients in the vancomycin and five in the teicoplanin group had tracheal colonization with CONS. In both groups peak and trough levels of antibiotics were in the bactericidal range. Serum creatinine was not normal in both groups. We conclude that teicoplanin is preventing CONS sepsis as well is vancomycin. The minimal inhibitory concentrations of both antibiotics against grampositive isolates in units using this strategy have to be observed carefully to detect emerging resistance.

ARDS im Kindesalter Ergebnisse einer Umfrage in deutschen Kinderkliniken und gemeinsame Empfehlungen der „Arbeitsgemeinschaft ARDS im Kindesalter“ zur Beatmungstherapie

Zusammenfassung Das Acute respiratory distress syndrome (ARDS) ist auch in der pädiatrischen Intensivmedizin angesichts der hohen Letalität eine therapeutische Herausforderung. 1992 haben sich deshalb etwa 50 deutsche Kinderkliniken in einer informellen Arbeitsgemeinschaft zusammengeschlossen, deren Ziel die Erarbeitung gemeinsamer therapeutischer Strategien ist. Um Daten über Epidemiologie, Risikofaktoren und Verlauf zu gewinnen, führten wir 1993 anhand eines standardisierten Fragebogens für die Jahre von 1991–1993 eine prospektive und retrospektive Erhebung in deutschen Kinderkliniken durch. 112 Kinder wurden gemeldet. Die Inzidenz entsprach 7 Fällen auf 1 000 pädiatrische Intensivpatienten. Die Hälfte der Kinder war jünger als 2 Jahre alt. In 43 % der Fälle entwickelte sich das ARDS aus einer pulmonalen, in 39 % aus einer systemischen Grundkrankheit, 18 % ließen sich nicht in diese Kategorien klassifizieren. Die Letalität lag bei 46 % ohne Zusammenhang mit Alter, Geschlecht oder auslösender Ursache. Die Anzahl der begleitenden Organversagen hatte dagegen einen signifikanten Einfluß auf die Prognose. Die Übersicht über die Behandlungsmaßnahmen zeigte, daß einheitliche therapeutische Strategien derzeit nicht existieren und andererseits eine Reihe bisher ungeprüfter Therapieverfahren eingesetzt wurde. Die in dieser Untersuchung gewonnenen Informationen stellen eine wichtige Grundlage für die Planung prospektiver multizentrischer Studien beim ARDS im Kindesalter dar. Die vorgestellten Empfehlungen zur Beatmungsgtherapie wurden unter diesem Gesichtspunkt erstellt.Summary Acute respiratory distress syndrome (ARDS) is a therapeutic challenge in pediatric intensive care in view of its high mortality. In 1992, about 50 German pediatric intensive care unit doctors founded a working group with the aim of collaborating in clinical research. The objectives of both a prospective and retrospective survey conducted in German pediatric intensive care units in 1993 was to accumulate data on the epidemiology, risk factors and natural history in a large group of pediatric ARDS patients. 112 patients were reported, an incidence of 7 cases per 1 000 admissions to pediatric intensive care units. Half of the children were less than 2 years old. In 43 % of the cases, ARDS was associated with a pulmonary, in 39 % with a underlying systemic disease. Mortality was 46 % and independent of age, sex and triggering event. The number of associated organ failures, however, strongly influenced mortality. The analysis of treatment modalities employed in the patients revealed a lack of uniform therapeutic strategies. On the other hand, the patients were exposed to interventions not yet supported by controlled trials. The data gathered in this survey provide the basis for the design of prospective multicenter studies urgently needed to evaluate innovative treatment modalities in pediatric ARDS. Recommendations on ventilatory management and patient monitoring are included for this purpose.

Steigende Inzidenz der bronchopulmonalen Dysplasie : Eine 8-Jahres-Retrospektive mit Analyse der Risikofaktoren

ZusammenfassungHintergrundZur Analyse von Häufigkeit und Risikofaktoren der bronchopulmonalen Dysplasie (BPD) auf dem Hintergrund der sich ändernden Bedingungen der perinatalen Medizin untersuchten wir retrospektiv die Verläufe Frühgeborener, die in der Zeit von Januar 1985–Dezember 1992 an unserer Klinik betreut wurden.Material und MethodenWährend des 1. Lebenstags beatmungsbedürftige Frühgeborene eines Geburtsgewichts von < 1751 g wurden in die retrospektive Studie einbezogen. Die BPD wurde definiert als Beatmungsnotwendigkeit bzw. Sauerstoffbedarf von > 30 % am 28. Lebenstag. Kinder mit BPD wurden mit einer Kontrollgruppe (Geburtsgewicht < 1751 g) verglichen, wobei die Auswahl nach Geburtsjahrgängen und Geburtsgewicht erfolgte. Die Risikofaktoren wurden mittels logistischer Regressionsanalyse berechnet.ErgebnisseVon insgesamt 274 Kindern wurde bei 76 (28 %) eine BPD diagnostiziert, 150 überlebten ohne BPD, während 48 Kinder verstarben. Risikofaktoren für die BPD stellten bei einer signifikant steigenden Überlebensrate und sinkenden BPD-Inzidenz in der logistischen Regressionsanalyse ein niedriges Gestationsalter sowie Geburtsgewicht, vaginale Geburt, hoher Sauerstoffbedarf, geringe Gewichtsabnahme während der 1. Lebenswoche und fehlende Surfactanttherapie dar.SchlußfolgerungWir fanden eine verbesserte Überlebensrate beatmungsbedürftiger Frühgeborener bei Reduktion der BPD-Häufigkeit im Untersuchungszeitraum. Die Kenntnis der BPD-Risikofaktoren sollte in präventive Konzepte umgesetzt werden.SummaryBackgroundBPD still remains a serious complication in very prematurely born infants. In order to assess the incidence and risk factors we analyzed the data of preterm infants (birth weight ≤ 1751 g) born between January 1985 and December 1992.Patients and MethodsPreterm infants requiring intubation on day 1 were enrolled retrospectively. BPD was defined as need for artificial ventilation or oxygen dependency (FiO2 > 0.3) on day 28. Infants with BPD were compared with matched controls in order to identify risk factors using a logistic regression analysis.ResultsA total of 274 infants were enrolled, 76 (28 %) of whom developed BPD, 48 died and 150 survived without BPD. A significant increase in survival and decreasing rate of BPD could be observed during the study period. Low gestational age and birth weight, vaginal delivery, high oxygen requirements and low body weight loss during week 1 were significantly associated with BPD. Administration of natural surfactant was associated with a reduced risk for BPD only in very preterm infants (GA ≤ 28 weeks).ConclusionsImproved outcome in preterm infants with RDS could be demonstrated in terms of increased survival with reduced risk for BPD. Knowledge of risk factors should be translated into preventive concepts.

CHARACTERIZATION OF TRACHEAL ASPIRATES (TA) FROM NEWBORNS WITH SEVERE RESPIRATORY FAILURE 1577

Introduction: In order to characterize differences in the pathophysiology of RDS in preterm infants compared with ARDS-like disease in newborns, we prospectively obtained TA (tracheal aspirates) from newborns requiring mechanical ventilation. Subjects and methods: TA were obtained within 48 h of intubation in 17 infants < 32 weeks of gestation(group 1; mean GA 29 ± 2.5 (SD) wks) and 14 newborns (group 2; mean GA 38 ± 3.2 (SD) wks). TA were cytocentrifuged and the cells were differentiated morphologically and immunocytologically (CD62L and CD11b). Total protein (TP), α2 -macroglobulin (α2-MG) and elastase-al-proteinase inhibitor complex (E-α1-PI) were analyzed and compared with controls requiring mechanical ventilation without underlying pulmonary diseases. Results: In both groups neutrophils and macrophages were found in TA, polymorphonuclear cells were positive for CD 62L and CD 11b. The table summarizes the results of the biochemical variables (mean ± SD): Conclusions: We demonstrated evidence for significant leukocyte endothelium-interactions as a consequence of granulocyte activation in the early course of both RDS and ARDS-like disease. Furthermore, significantly increased E-α1-PI concentrations in newborns ≥ 32 weeks suggest inflammatory mechanisms in ARDS-like disease. We conclude TA analyses might be helpful differentiating between both types of neonatal respiratory failure.

EARLY VERSUS LATE SURFACTANT TREATMENT: A RANDOMIZED CONTROLLED TRIAL† 1506

Background: Controversy still exits with respect to timing of surfactant administration in preterm infants at risk for or with manifest RDS. We therefore aimed to investigate in a multicenter trial whether early ( 2h following birth) surfactant administration would be superior. Subjects and methods: All infants with a gestational age from 27-32 weeks were enrolled stratified by center after prenatal parental informed consent. Early treatment with surfactant (100 mg/kg b.w. Alveofact® i.t.) was given to infants requiring intubation following birth, late treatment was given with an identical dosage to infants on mechanical ventilation with a FiO2 >0.4 between hours 2-6 following birth. The primary end point was the time on mechanical ventilation, secondary endpoints included mortality, BPD (28 days FiO2 >0.21 or mechanical ventilation), IVH >III/PVL. Sample size calculation revealed a total of 200 infants would have to be included to (α=0.05; β=0.80).Results: 236 infants were enrolled, 146 needed intubation and mechanical ventilation. Table 1 gives an overview on most relevant study data (intent-to-treat analysis).

IMPACT OF DIFFERENT SURFACTANT PREPARATIONS ON CD 62 L - EXPRESSION ON ACTIVATED NEUTROPHILS AND MONOCYTES † 2070

Introduction: The potential role of polymorphonuclear neutrophils(PMN) and macrophages in the pathogenesis of acute respiratory distress syndrome (ARDS) develops as a result of CD 62 L (L-selectin) mediated inflammatory-cell endothelial injury. Surfactant (SF) replacement therapy is gaining increased use in term infants and adults with ARDS. We therefore wanted to determine the effect of SF on CD 62-L expression of PMN and monocytes. Material and methods: Heparinized whole blood (5 ml) from healthy adult volunteers was incubated for 1 hour with 10-6 mol/ml N-formylmethionyl-leucylphenylalanin (fMLP) together with bovine SF(Alveofact®; Fa. Thomae, F.R.G.) and synthetic SF (Exosurf®, Wellcome, USA) (1,2 mg/ml). Elastase-α1 - proteinase inhibitor complex(E-PI) as a result of PMN-activation was determined by chemoluminescence immunoassay. Analyses of PMN and monocytes population as well as CD 62 L expression were performed on a FACScan flow cytometer (Becton Dickinson, F.R.G.). CD 62 L were expressed as percentage of positive stained cells.Results: After incubation with natural SF and fMLP decreased E-PI levels from 30% compared with E-PI levels after incubation with fMLP alone. Increased levels of E-PI of 90% after incubation with synthetic surfactant were found: Table Conclusion: In contrast to synthetic SF natural SF is able to inhibit PMN activation in vitro. After incubation with SF CD 62 L-expression is decreased, depending on the preparation used. From our data we conclude that SF treatment can influence inflammatory cell-mediated endothelial cell injury in the early stage of acute lung injury.

PENETRATION OF VANCOMYCIN TO CEREBROSPINAL FLUID (CSF) IN CHILDHOOD 270

Background: There are only scanty data on vancomycin(va) distribution to cerebrospinal fluid (CSF) in childhood. In order to characterize CSF distribution of va after intravenous administration, we prospectively investigated children with temporary external CSF-drainage. Subjects: In 7 children (age 1 month - 10 years), plasma and CSF-samples were taken simultaneously and va concentrations were measured(μg/ml; polarization fluorescence immunoassay; Abbott, Munich, F.R.G.).Interventions: Children were treated with i.v. va at doses in the range of 2 × 5 m/kg b.w. to 2 × 10 mg/kg b.w. per day, administered by within 60 minutes. Blood was drawn 1 h after the end of the infusions period, simultaneously CSF was aspirated from the drainage. Results: Median trough CSF va concentrations were 2.16μg/ml, mean corresponding plasma concentrations 2.72 μg/ml (n = 12 each), median peak CSF concentrations 2.5 μg/ml, median peak plasma concentrations 14.5 μg/ml (n = 4 each). All CSF cultures were sterile. Conclusion: Due to the outlined pharmacocinetic data, va may be considered for perioperative prophylaxis of CSF shunt infections.Table

TERATOGENIC EFFECTS IN A CASE OF MATERNAL TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Acute lymphoblastic leukaemia (ALL) was diagnosed in a 36-year-old and treated with cytarabin, daunorubicin, doxorubicin and cytarabin, thioguanin, respectively, in an unrecognized pregnancy at conception and at about 35-37 days p.c., Amniocentesis at 16 weeks of gestation revealed a normal female karyotype.At delivery, brachycephaly, hypoplasia of supraorbital bony structures and hypotelorism were seen. Hypoplastic nasal root, bilateral choanal atresia and micrognathia caused hypoplasia of naso- and oropharynx. There was also bilateral aplasia of the radius and hypoplasia of the first ray of the hands. Internally, an atrial septal defect II could be demonstrated. The malformations detected are in accord with the timing of teratogenesis. Neurodevelopment is normal at the age of 8 months. Experience with the use of cytotoxic drugs in pregnancy has so far been limited to folate antagonists.