Wolfgang Göpel

Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial.

BACKGROUND Surfactant is usually given to mechanically ventilated preterm infants via an endotracheal tube to treat respiratory distress syndrome. We tested a new method of surfactant application to spontaneously breathing preterm infants to avoid mechanical ventilation. METHOD In a parallel-group, randomised controlled trial, 220 preterm infants with a gestational age between 26 and 28 weeks and a birthweight less than 1·5 kg were enrolled in 12 German neonatal intensive care units. Infants were independently randomised in a 1:1 ratio with variable block sizes, to standard treatment or intervention, and randomisation was stratified according to centre and multiple birth status. Masking was not possible. Infants were stabilised with continuous positive airway pressure and received rescue intubation if necessary. In the intervention group, infants received surfactant treatment during spontaneous breathing via a thin catheter inserted into the trachea by laryngoscopy if they needed a fraction of inspired oxygen more than 0·30. The primary endpoint was need for any mechanical ventilation, or being not ventilated but having a partial pressure of carbon dioxide more than 65 mm Hg (8·6 kPa) or a fraction of inspired oxygen more than 0·60, or both, for more than 2 h between 25 h and 72 h of age. Analysis was by intention to treat. This study is registered, number ISRCTN05025922. FINDINGS 108 infants were assigned to the intervention group and 112 infants to the standard treatment group. All infants were analysed. On day 2 or 3 after birth, 30 (28%) infants in the intervention group were mechanically ventilated versus 51 (46%) in the standard treatment group (number needed to treat 6, 95% CI 3-20, absolute risk reduction 0·18, 95% CI 0·30-0·05, p=0·008). 36 (33%) infants in the intervention group were mechanically ventilated during their stay in the hospital compared with 82 (73%) in the standard treatment group (number needed to treat: 3, 95% CI 2-4, p<0·0001). The intervention group had significantly fewer median days on mechanical ventilation, (0 days. IQR 0-3 vs 2 days, 0-5) and a lower need for oxygen therapy at 28 days (30 infants [30%] vs 49 infants [45%], p=0·032) compared with the standard treatment group. We recorded no differences between groups for mortality (seven deaths in the intervention group vs five in the standard treatment group) and serious adverse events (21 vs 28). INTERPRETATION The application of surfactant via a thin catheter to spontaneously breathing preterm infants receiving continuous positive airway pressure reduces the need for mechanical ventilation. FUNDING German Ministry of Research and Technology, University of Lübeck, and Chiesi Pharmaceuticals.

Immature anti-inflammatory response in neonates

The inflammatory response plays a major role in the induction of several neonatal diseases. We hypothesize that an imbalance between the pro‐ and anti‐inflammatory response is crucial for the previously shown enhanced production of proinflammatory cytokines in term and preterm infants during infection. To test this hypothesis, we compared the capacity to produce the main anti‐inflammatory cytokines IL‐10 and TGF‐β in term infants, preterm infants and adults at different levels of synthesis by quantitative real time reverse‐transcribed PCR, flow cytometry, as well as enzyme‐linked immunoassay. Term and preterm infants showed a profoundly diminished IL‐10 mRNA‐expression and IL‐10 production after stimulation. In addition, the amount of TGF‐β‐positive lymphocytes was significantly less in neonates than adults. Furthermore, there was a considerably lower inhibition of production of IL‐1α, IL‐6, IL‐8 and TNF‐α by the use of recombinant IL‐10 in term and preterm infants compared with adults. These results demonstrate not only a diminished anti‐inflammatory capacity but also a reduced response to anti‐inflammatory stimuli in term and preterm infants. From these data we conclude that neonates display an immature compensatory anti‐inflammatory response syndrome (CARS) which may predispose preterm infants to harmful effects of proinflammatory cytokines resulting in severe organ sequelae during infection.

Mutations of Genes Involved in the Innate Immune System as Predictors of Sepsis in Very Low Birth Weight Infants

Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the −159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannose-binding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture–proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n =15) and the IL6-174G allele (n =121) had a significantly higher rate of blood culture–proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p = 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7–6.0; p < 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0–3.9; p = 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0–10.4; p = 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5%versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p = 0.033).

Selection pressure for the factor-V-Leiden mutation and embryo implantation

The factor-V-Leiden mutation is seen in high frequencies in white people, despite its contribution to second-trimester abortion, preterm birth, and deep-vein thrombosis. The reason for its high frequency is not known. We investigated 102 mother-child pairs who had had successful in-vitro fertilisation by intracytoplasmic sperm injection as a model for human implantation. In 90% (9 of 10) of mother-child pairs who carried factor-V-Leiden mutation, the first embryo transfer was successful, compared with 49% (45 of 92) in factor-V-Leiden negative pairs (p=0.018, Fishers exact test). Furthermore, the median number of unsuccessful transfers was lower in pairs who were positive for the mutation (0, range 0-2) than those who were negative (1, 0-8) (p=0.02, Mann Whitney U test) suggesting that improved implantation rate is an important genetic advantage of the factor-V-Leiden mutation.

Surfactant without intubation in preterm infants with respiratory distress: first multi-center data.

BACKGROUND Recently in a report of a single center a method has been described to apply surfactant via a thin endotracheal catheter to very low birth weight infants spontaneously breathing with nasal continuous positive airway pressure. We now analyzed available multicenter data. PATIENTS AND METHODS In a multicenter study investigating genetic risk factors, clinical and outcome data and data of antenatal and postnatal treatment of infants with a birth weight below 1,500 g were prospectively recorded. The measures of infants treated with the new method of surfactant application were compared to those of infants who received standard care. The analysis was restricted to infants with a gestational age below 31 weeks (n=1,541). RESULTS 319 infants were treated with the new method and 1,222 with standard care. The need for mechanical ventilation during the first 72 h (29% vs. 53%, p<0.001), the rate of bronchopulmonary dysplasia defined as oxygen at 36 weeks of postmenstrual age (10.9 % vs. 17.5%, p=0.004) and the rate of death or bronchopulmonary dysplasia were significantly lower in the treatment group than in the standard care group. Surfactant, theophyllin, caffeine and doxapram were significantly more often and analgetics, catecholamines and dexamethasone were significantly less frequently used in the treatment group. CONCLUSIONS A new method of surfactant application was associated with a lower prevalence of mechanical ventilation and better pulmonary outcome. A prospective controlled trial is required to determine whether this approach is superior to standard care.

Genetic Polymorphisms of Hemostasis Genes and Primary Outcome of Very Low Birth Weight Infants

BACKGROUND. Recent investigations have reported an influence of thrombophilic mutations and antithrombotic risk factors with development of intraventricular hemorrhage. It was our objective for this study to investigate the impact of genetic polymorphisms of hemostasis genes on the primary outcome measures of sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and periventricular leukomalacia in a large cohort of very low birth weight infants. METHODS. There were 586 very low birth weight infants enrolled prospectively in a multicenter trial between September 2003 and July 2005, and an additional 595 very low birth weight infants, who had been recruited in a previous prospective trial, were studied. DNA samples were taken by buccal swab, and genotypes of factor V Leiden mutation, prothrombin G20210A mutation, the factor VII-323 del/ins polymorphism, and the factor XIII-Val34Leu polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. RESULTS. In contrast to data published previously, the frequency of intraventricular hemorrhage or periventricular leukomalacia was not significantly influenced by any of the genetic variants tested. Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate and a longer period of hospital care compared with noncarriers. The factor VII-323 del/ins polymorphism was found to be a potential protective factor against bronchopulmonary dysplasia. CONCLUSIONS. We could not confirm previously reported associations of hemostasis gene variants and development of intraventricular hemorrhage in very low birth weight infants. To better understand gene-disease associations in very low birth weight infants, the prospective development of large-scale cohorts with well-defined phenotypes and corresponding DNA samples is essential.

Low prevalence of large intraventricular haemorrhage in very low birthweight infants carrying the factor V Leiden or prothrombin G20210A mutation

The influence of genetic factors that increase coagulation on the extension of intraventricular haemorrhage (IVH) in very low birthweight infants has not been studied previously. This study investigated the frequency and effect of the factor V Leiden and prothrombin G20210A mutations in a population‐based cohort of 305 preterm infants with a birthweight below 1500 g. The overall prevalence of IVH was similar in infants with (n=43) and without (n=262) prothrombotic mutations (18.6% vs 16.4%, respectively). However, infants with prothrombotic mutations had a significantly reduced risk of developing extension to IVH grade II or more [p=0.023, odds ratio (OR) 0.11,95% confidence interval (CI) 0.02‐0.5]. The carrier state of a factor V Leiden or prothrombin G20210A mutation was still predictive for a low rate of IVH grade II‐IV if possible confounding variables were included in a multivariate regression model (OR 0.12; 95%CI: 0.017–0.86).

Maturational Changes of Lymphocyte Surface Antigens in Human Blood: Comparison between Fetuses, Neonates and Adults

The objective of this study was to investigate the maturational changes of lymphocyte surface antigens during ontogeny from fetuses to adults using the proven whole blood lysis technique. Two-color flow cytometric analysis of lymphocyte surface markers was performed on 20 fetal blood samples obtained by cordocentesis, 70 cord blood and 30 adult blood samples. The leukocyte count and all T-cell subsets were highest in neonates compared to fetuses and declined into adulthood. In contrast, the percentage of CD2+ T cells (fetal blood 57% versus adult blood 82%; p ≤ 0.001), CD3+ T cells (fetal blood 52% versus adult blood 77%; p ≤ 0.001), CD4+ T cells (fetal blood 39% versus adult blood 50%; p ≤ 0.05) and CD8+ T cells (fetal blood 15% versus adult blood 24%; p ≤ 0.001) showed a significant increase from fetuses to adults. The absolute and relative amounts of B cells were highest in fetuses (fetal blood 547 × 106/l, 18%) followed by a steady decline to adulthood (adult blood 243 × 106/l, 13%; p ≤ 0.001). The discordance between the absolute and relative size of lymphocyte subpopulations emphasizes the consideration of both variables in the assessment of lymphocyte maturation. The presented data may contribute to a better knowledge of the maturation of the immune system.

Less invasive surfactant administration is associated with improved pulmonary outcomes in spontaneously breathing preterm infants

Providing less invasive surfactant administration (LISA) to spontaneously breathing preterm infants has been reported to reduce mechanical ventilation and bronchopulmonary dysplasia (BPD) in randomised controlled trials. This large cohort study compared these outcome measures between LISA‐treated infants and controls.

Prothrombotic mutations as a risk factor for preterm birth

radiopharmaceutical the syringe was applied firmly and perpendicular to the skin surface. Patients were warned about a hissing sound that is heard as soon as the trigger button is activated. We have now used this device for SLN localisation in 12 cases: six patients with breast carcinoma, two patients with limb malignant melanoma, and four volunteers. In eleven patients the SLN could be identified without any difficulty on lymphoscintigraphy. In one patient there was spillage of the radiopharmaceutical due to application of inadequate pressure on the syringe before activating the trigger button. This resulted in a contamination artefact. This patient received another conventional subdermal injection after skin decontamination and the SLN was localised successfully. Of eight patients who underwent SLN biopsy, three showed SLN involvement with metastatic tumour (two melanoma patients and one breast-cancer patient in whom the SLN was the only node involved). To assess the depth of penetration of the injectate, patent blue dye was injected with the needlefree device (figure, B). It was evident that most of the blue dye was in the dermal and subcutaneous plane. Careful analysis of the time-activity curve of dynamic acquisition showed slower particle kinetics compared with the conventional injection technique. A r e g i o n - o f - i n t e r e s t analysis shows that the area of dispersion of the tracer was also higher than was achieved by the conventional technique; however, image quality was not affected.