Matthias Vochem

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

BACKGROUNDnSurfactant 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.nnnMETHODnIn 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.nnnFINDINGSn108 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).nnnINTERPRETATIONnThe application of surfactant via a thin catheter to spontaneously breathing preterm infants receiving continuous positive airway pressure reduces the need for mechanical ventilation.nnnFUNDINGnGerman Ministry of Research and Technology, University of Lübeck, and Chiesi Pharmaceuticals.

Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial

IMPORTANCEnTreatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA).nnnOBJECTIVEnTo test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks gestational age in extremely preterm infants.nnnDESIGN, SETTING, AND PARTICIPANTSnThe Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013.nnnINTERVENTIONnLISA via a thin catheter.nnnMAIN OUTCOMES AND MEASURESnSurvival without BPD at 36 weeks gestational age.nnnRESULTSnOf 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, -5.0% to 21.9%; P =u2009.20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P <u2009.001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P =u2009.04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P =u2009.02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P =u2009.02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2).nnnCONCLUSIONS AND RELEVANCEnLISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants.nnnTRIAL REGISTRATIONnisrctn.org Identifier: ISRCTN64011614.

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.

Risk for late-onset blood-culture proven sepsis in very-low-birth weight infants born small for gestational age: a large multicenter study from the German Neonatal Network.

Background: It was the aim of this study to assess whether very-low-birth-weight (VLBW) infants born small for gestational age (SGA; birth weight less than 10th percentile) are at increased risk for late-onset sepsis. Methods: This was a prospective, multicenter study of the German Neonatal Network including VLBW infants from 23 to < 32 weeks post menstrual age born 2009–2011. Outcomes were compared between VLBW infants born SGA (birth weight less than tenth percentile according to gestational age and gender) and non-SGA infants. The main outcome measure was at least 1 episode of late-onset sepsis defined as blood-culture–confirmed clinical sepsis occurring at ≥72 hours of age. Results: 5886 VLBW infants were included. In SGA infants (n = 692), an increased incidence of late-onset sepsis was noted compared with non-SGA infants (20.1% vs. 14.3 %, P < 0.001). This difference was only observed among infants with a gestational age of 27 to < 32 weeks and attributed to sepsis episodes with coagulase-negative staphylococci (12.8% vs. 8.3%, P < 0.001). Different treatment modalities (eg more frequent use of central venous lines) and longer duration of invasive therapies (parenteral nutrition, mechanical ventilation, hospitalization) may account for the increased sepsis risk with coagulase-negative staphylococci in our SGA cohort. In a multivariate logistic regression analysis, higher gestational age [per week; odds ratio (OR): 0.75, 95% confidence interval (CI): 0.72–0.78, P< 0.0001], treatment with antenatal steroids (OR: 0.7, 95% CI: 0.53–0.92, P = 0.01), German descendance (OR: 0.76, 95% CI: 0.63–0.91, P = 0.003) and prophylaxis with glycopeptide antibiotics (OR: 0.64, 95% CI: 0.47–0.87, P = 0.005) were shown to be protective against late-onset sepsis. In contrast, longer duration of parenteral nutrition (per day; OR: 1.016, 95% CI: 1.011–1.021, P < 0.0001) and SGA were found to be risk factors (OR: 1.31, 95% CI: 1.02–1.68, P= 0.03). Conclusions: SGA contributes to the risk of late-onset sepsis in VLBW infants. Future studies are needed to investigate the underlying pathophysiology to guide individualized preventive measures in this vulnerable subgroup.

Epidemic Microclusters of Blood-Culture Proven Sepsis in Very-Low-Birth Weight Infants: Experience of the German Neonatal Network

Introduction We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009–2010. Methods Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. Results In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01–55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% –6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient’s Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1–27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. Discussion Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care.

Polymorphisms in the Renin-Angiotensin System and Outcome of Very-Low-Birthweight Infants

Background: The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE-ins/del) and the angiotensin II type 1 receptor 1166A/C polymorphism (ATR1166A/C) were reported to be associated with several unfavorable outcome parameters in preterm infants like bronchopulmonary dysplasia, persistent ductus arteriosus and impaired insulin sensitivity. Objective: To confirm the above-mentioned associations in a large cohort of very-low-birthweight (VLBW) infants. Method: Clinical data of VLBW infants were prospectively recorded. The ACE-ins/del polymorphism and the ATR1166A/C polymorphism were determined by polymerase chain reaction in 1,209 and 1,168 infants, respectively. Results: There was no significant association between ACE-ins/del or ATR1166A/C genotype and outcome parameters (death, intraventricular hemorrhage, sepsis, bronchopulmonary dysplasia, ventilation, supplemental oxygen at discharge, postnatal treatment with insulin, surgery for intestinal perforation/necrotizing enterocolitis/retinopathy of prematurity/persistent ductus arteriosus. Conclusion: Both known functional polymorphisms of the renin-angiotensin system do not seem to be associated with the outcome of VLBW infants.

Very low birth weight infants as a model to study genetic influences on neonatal weight gain.

In a cohort of 829 preterm infants (birth weight below 1500 g) we identified 13 monozygotic, 10 same-sex dizygotic, and 12 same-sex matched singleton pairs. The difference in daily weight gain within pairs was significantly lower in monozygotic twins compared with dizygotic twins or matched singleton pairs. Our data support a strong genetic influence on postnatal growth in preterm infants. Therefore, weight gain of preterm infants may be an interesting model to study polymorphic variants of genes regulating neonatal resorption, metabolism, or energy expenditure, and their influence on weight gain in preterm infants.

Polymorphisms in FTO and MAF Genes and Birth Weight, BMI, Ponderal Index, Weight Gain in a Large Cohort of Infants with a Birth Weight below 1500 Grams

Background The FTO gene, located on chromosome 16q12.2, and the MAF gene, located on chromosome 16q22-23, were identified as genes harboring common variants with an impact on obesity predisposition. We studied the association of common variants with birth weight, gain of body weight, body mass index (BMI), Ponderal index and relevant neonatal outcomes in a large German cohort of infants with a birth weight below 1500 grams. Methods The single nucleotide polymorphisms rs9939609 (FTO gene) and rs1424233 (MAF gene) were genotyped using allelic discrimination assays in a prospective multicenter cohort study conducted in 15 neonatal intensive care units in Germany from September 2003 until January 2008. DNA samples were extracted from buccal swabs according to standard protocols. Results 1946 infants were successfully genotyped at FTO and 2149 infants at MAF. Allele frequencies were not significantly different from other European cohorts. The polymorphisms were in Hardy-Weinberg equilibrium. The polymorphisms did not show associations with birth weight, BMI and Ponderal Index at discharge, and weight gain, neither testing for a dominant, additive nor for a recessive model. Discussion Since an association of the polymorphisms with weight gain has been demonstrated in multiple populations, the lack of association in a population of preterm infants with regular tube feeding after birth and highly controlled feeding volumes provides evidence for the hypothesis that these polymorphisms affect food intake behavior and hunger rather than metabolism and energy consumption.

Less invasive surfactant administration and complications of preterm birth

In a large cohort study of the German Neonatal Network (GNN) we aimed to evaluate whether less invasive surfactant administration (LISA) strategy is associated with complications of preterm birth. Within the observational period nu2009=u20097533 very-low-birth-weight infants (VLBWI) with gestational age 22 0/7 to 28 6/7 weeks were enrolled in GNN; nu2009=u20091214 VLBWI never received surfactant, nu2009=u20092624 VLBWI were treated according to LISA procedure, nu2009=u20093695 VLBWI had surfactant via endotracheal tube (ETT). LISA was associated with a reduced risk for adverse outcome measures including mortality [odds ratio (OR) 0.66 (95% CI: 0.51–0.84), pu2009<u20090.001] bronchopulmonary dysplasia [BPD; OR 0.55 (95% CI: 0.49–0.62), pu2009<u20090.001], intracerebral hemorrhage (ICH) grade II-IV [OR 0.55 (95% CI: 0.48–0.64), pu2009<u20090.001] and retinopathy of prematurity [ROP; OR 0.62 (95% CI: 0.45–0.85), pu2009<u20090.001]. Notably, LISA was associated with an increased risk for focal intestinal perforation [FIP; OR 1.49 (95% CI: 1.14–1.95), pu2009=u20090.002]. The differences in FIP rates were primarily observed in VLBWI born <26 weeks (LISA: 10.0 vs. ETT: 7.4%, pu2009=u20090.029). Our observational data confirm that LISA is associated with improved outcome. In infants <26 weeks we noted an increased risk for FIP. Future randomized controlled trials including LISA need to integrate safety analyses for this particular subgroup.

Klinische Verläufe monozygoter und gleichgeschlechtlicher dizygoter VLBW-Frühgeborener

Fragestellung: Die Untersuchung genetischer Einflusse auf klinische Endpunkte im Kindes- und Erwachsenenalter ist komplex, da exogene Faktoren einen genetischen Einfluss uberdecken konnen. Ob ein klinischer Endpunkt fur die Untersuchung von genetischen Einflussen geeignet ist, kann durch Zwillingsuntersuchungen festgestellt werden. Zeigen monozygote Zwillinge (im Vergleich zu gleichgeschlechtlichen dizygoten Zwillingen) eine hohere Rate an Ubereinstimmungen in Bezug auf den gewahlten Endpunkt, oder ist die Differenz eines kontinuierlichen Parameters (wie der taglichen Gewichtszunahme) zwischen monozygoten Zwillingen geringer als zwischen dizygoten Zwillingen, so spricht dies fur einen messbaren genetischen Einfluss. Methodik: Multizentrischen Studie zu den Auswirkungen genetischer Polymorphismen auf den klinischen Verlauf von VLBW-Fruhgeborenen. Gleichgeschlechtliche Zwillingsparchen wurden aufgrund klinischer Kriterien und der Bestimmung von jeweils 10 polymorphen Nucleotiden zugeordnet. Paare die einen vollstandig ubereinstimmenden Genotyp fur alle Polymorphismen aufwiesen wurden als monozygot klassifiziert. Ergebnisse: Von September 2003 bis Dezember 2005 wurden 829 VLBW-Fruhgeborene in unsere Studie aufgenommen. Wir identifizierten 17 monozygote und 14 gleichgeschlechtliche dizygote Zwillingsparchen. Die Gruppen unterschieden sich nicht bezuglich des Gestationsalters und des Geburtsgewichts. Die Outcome Daten der Kinder zeigt die Tabelle. Fur die von uns untersuchten Endpunkte intraventrikulare Hamorrhagie (alle Grade), Beatmung und Surfactantgabe, wiesen monozygote Zwillinge eine hohere Rate an konkordanten Ereignissen auf. 12 monozygote und 10 dizygote Zwillingspaare wurden jeweils am selben Tag nach Hause entlassen. Auch in dieser Subgruppe bestand kein Unterschied bezuglich des Gestationsalters, des Geburtsgewicht, und der Differenz des Geburtsgewichts zwischen den Zwillingen. Bei diesen Paaren untersuchten wir die Differenz der taglichen Gewichtszunahme. Monozygote Fruhgeborene hatten eine Differenz der taglichen Gewichtszunahme von 1,53g, wahrend gleichgeschlechtliche dizygote Zwillinge eine Differenz der taglichen Gewichtszunahme von 3,08g aufwiesen (p<0,05, Mann Whitney U Test). Schlussfolgerung: Es besteht eine messbare Konkordanz der klinische Verlaufe monozygoter Zwillinge bezuglich der fruhen Atemstorung, der Entwicklung einer IVH und der postnatalen Gewichtsentwicklung. Diese Beobachtung unterstutzt die Annahme, das diese Endpunkte durch genetische Faktoren beeinflusst werden. Fruhgeborenenkollektive sind damit moglicherweise auch interessant fur die Identifizierung bzw. Bestatigung von Kandidatengenen fur schwere Erkrankungen des Erwachsenen wie das ARDS, Hirnblutungen und das metabolische Syndrom.