Publications by authors named "Bettina Bohnhorst"

40 Publications

[Epidemiology and treatment of retinopathy of prematurity. The Hannover data in the Retina.net ROP registry from 2001-2017].

Ophthalmologe 2021 Nov 22. Epub 2021 Nov 22.

Universitätsklinik für Augenheilkunde, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.

Background: The Retina.net ROP registry documents data of preterm infants developing stages of retinopathy of prematurity (ROP) that need ROP treatment. The aim of this analysis was to investigate data regarding epidemiology, therapy and changes over time (15 years) in a single participating center (Hannover Medical School, MHH).

Methods: Analysis of data of infants treated for ROP at a single center over time (birth 2001-2016, ROP treatment in 2002-2017).

Results: Overall, 65 infants were treated (23 female). In 11 infants (16.9%) ROP screening was conducted externally and infants were transferred to the MHH for ROP treatment. Between 2006 and 2016, incidence of ROP requiring treatment among infants screened for the development of ROP was 4.1%. Mean gestational age was 25.7 weeks (standard deviation, SD 1.8), mean birth weight 763 g (SD 235), postmenstrual age at treatment 38.2 weeks (SD 3.2), postnatal age 12.4 weeks (SD 3.2). There was no significant change in parameters over time. ROP zone II, stage 3+ was most frequently treated (57 eyes of 31 infants). 58 infants were treated with laser (114 eyes), 7 infants were treated with anti-VEGF (bevacizumab, bilateral, 14 eyes) from 2014 onwards. Retreatment due to recurrence of ROP was necessary in one infant after initial laser coagulation. Infants with ROP requiring treatment often presented with neonatal comorbidities, ventilation in more than 90%, bronchopulmonary dysplasia, and received transfusions.

Conclusion: This is the first monocentric analysis over 15 years originating from the Retina.net ROP registry. In this cohort we see a change in ROP therapy from laser coagulation to anti-VEGF (bevacizumab) from 2014 onwards, demographic data and treatment parameters remained relatively stable over time.
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http://dx.doi.org/10.1007/s00347-021-01528-9DOI Listing
November 2021

Anatomic accuracy, physiologic characteristics, and fidelity of very low birth weight infant airway simulators.

Pediatr Res 2021 Nov 8. Epub 2021 Nov 8.

Department of Neonatology and Pediatric Intensive Care Medicine, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Medical simulation training requires realistic simulators with high fidelity. This prospective multi-center study investigated anatomic precision, physiologic characteristics, and fidelity of four commercially available very low birth weight infant simulators.

Methods: We measured airway angles and distances in the simulators Premature AirwayPaul (SIMCharacters), Premature Anne (Laerdal Medical), Premie HAL S2209 (Gaumard), and Preterm Baby (Lifecast Body Simulation) using computer tomography and compared these to human cadavers of premature stillbirths. The simulators' physiologic characteristics were tested, and highly experienced experts rated their physical and functional fidelity.

Results: The airway angles corresponded to those of the reference cadavers in three simulators. The nasal inlet to glottis distance and the mouth aperture to glottis distance were only accurate in one simulator. All simulators had airway resistances up to 20 times higher and compliances up to 19 times lower than published reference values. Fifty-six highly experienced experts gave three simulators (Premature AirwayPaul: 5.1 ± 1.0, Premature Anne 4.9 ± 1.1, Preterm Baby 5.0 ± 1.0) good overall ratings and one simulator (Premie HAL S2209: 2.8 ± 1.0) an unfavorable rating.

Conclusion: The simulator physiology deviated significantly from preterm infants' reference values concerning resistance and compliance, potentially promoting a wrong ventilation technique.

Impact: Very low birth weight infant simulators showed physiological properties far deviating from corresponding patient reference values. Only ventilation with very high peak pressure achieved tidal volumes in the simulators, as aimed at in very low birth weight infants, potentially promoting a wrong ventilation technique. Compared to very low birth weight infant cadavers, most tested simulators accurately reproduced the anatomic angular relationships, but their airway dimensions were relatively too large for the represented body. The more professional experience the experts had, the lower they rated the very low birth weight infant simulators.
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http://dx.doi.org/10.1038/s41390-021-01823-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573578PMC
November 2021

Cardiorespiratory Events Following the Second Routine Immunization in Preterm Infants: Risk Assessment and Monitoring Recommendations.

Vaccines (Basel) 2021 Aug 16;9(8). Epub 2021 Aug 16.

Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Lower Saxony, Germany.

Due to frequent cardiorespiratory events (CREs) in response to the first routine immunization (rIM), current guidelines recommend readmitting and monitoring extremely preterm infants after the second rIM, though evidence on CREs in response to the second rIM is weak. In a prospective observational study, preterm infants with an increase in CREs after the first rIM were monitored for CREs before and after the second rIM. Seventy-one infants with a median gestational age of 26.4 weeks and a median weight of 820 g at birth were investigated at a median postnatal age of 94 days. All but seven infants showed an increase in CREs after the second rIM. The frequency of hypoxemias ( < 0.0001), apneas ( = 0.0003) and cardiorespiratory events requiring tactile stimulation (CRE-ts) ( = 0.0034) increased significantly. The 25 infants (35%) presenting with CRE-ts were significantly more likely to have been continuously hospitalized since birth ( = 0.001) and to receive analeptic therapy at the first rIM ( = 0.002) or some kind of respiratory support at the first ( = 0.005) and second rIM ( < 0.0001). At a postmenstruational age of 43.5 weeks, CRE-ts ceased. Our data support the recommendation to monitor infants who fulfil the above-mentioned criteria during the second rIM up to a postmenstruational age of 44 weeks.
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http://dx.doi.org/10.3390/vaccines9080909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402520PMC
August 2021

Analysis of Sirtuin 1 and Sirtuin 3 at Enzyme and Protein Levels in Human Breast Milk during the Neonatal Period.

Metabolites 2021 May 29;11(6). Epub 2021 May 29.

Clinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.

Breast feeding is regarded as the preferred nutrition modality for children during the first few months of life. It not only furthers growth and development but also is supposed to impact later life. The first 1000 days are regarded as a critical window for development, even beyond infancy. The physiological basis underlying this beneficial effect is not clear. Sirtuins are important regulatory proteins of metabolism and are supposed to play a critical role in ageing and longevity as well as in diseases. In the present study, we developed novel methods to assay sirtuin 1 and sirtuin 3 at enzyme activity (via fluorometry) and protein levels (by Western blot) in the aqueous phase and in the cell pellet of human breast milk and assessed the impact of ongoing lactation during the neonatal period. Sirtuin activities in the aqueous phase were negatively correlated with the duration of lactation in the neonatal period. There was no correlation of sirtuin activities in the cell pellet with the duration of lactation. The amounts of sirtuin 1 and sirtuin 3 measured by Western blot were negatively correlated with the lactation period.
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http://dx.doi.org/10.3390/metabo11060348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229955PMC
May 2021

Detection of Breathing Movements of Preterm Neonates by Recording Their Abdominal Movements with a Time-of-Flight Camera.

Pharmaceutics 2021 May 14;13(5). Epub 2021 May 14.

Division of Translational Biomedical Engineering, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, 30625 Hannover, Germany.

In order to deliver an aerosolized drug in a breath-triggered manner, the initiation of the patient's inspiration needs to be detected. The best-known systems monitoring breathing patterns are based on flow sensors. However, due to their large dead space volume, flow sensors are not advisable for monitoring the breathing of (preterm) neonates. Newly-developed respiratory sensors, especially when contact-based (invasive), can be tested on (preterm) neonates only with great effort due to clinical and ethical hurdles. Therefore, a physiological model is highly desirable to validate these sensors. For developing such a system, abdominal movement data of (preterm) neonates are required. We recorded time sequences of five preterm neonates' abdominal movements with a time-of-flight camera and successfully extracted various breathing patterns and respiratory parameters. Several characteristic breathing patterns, such as forced breathing, sighing, apnea and crying, were identified from the movement data. Respiratory parameters, such as duration of inspiration and expiration, as well as respiratory rate and breathing movement over time, were also extracted. This work demonstrated that respiratory parameters of preterm neonates can be determined without contact. Therefore, such a system can be used for breathing detection to provide a trigger signal for breath-triggered drug release systems. Furthermore, based on the recorded data, a physiological abdominal movement model of preterm neonates can now be developed.
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http://dx.doi.org/10.3390/pharmaceutics13050721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156597PMC
May 2021

S100A8/A9 is the first predictive marker for neonatal sepsis.

Clin Transl Med 2021 04;11(4):e338

Department of Pediatric Pneumology, Allergology, and Neonatology, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1002/ctm2.338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021540PMC
April 2021

Detection of Serratia marcescens in neonatal intensive care units requires a rapid and comprehensive infection control response starting with the very first case.

GMS Hyg Infect Control 2021 15;16:Doc12. Epub 2021 Mar 15.

Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.

is a well-known and challenging pathogen in neonatal intensive care units. It is responsible for severe infections and can cause nosocomial outbreaks. We present the infection control response to a cluster which occurred in a tertiary neonatal intensive care unit. : The presented comprehensive and decisive hygiene management response starting with the very first case aims especially at early detection and immediate interruption of nosocomial transmission. Frequent and sensitive microbiological screening, rigorous spatial isolation of colonized infants, and reinforcing adherence to hand hygiene are essential in this response, which comprises eight measures. It prevented a full-blown outbreak.
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http://dx.doi.org/10.3205/dgkh000383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983028PMC
March 2021

Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain-A new treatment strategy for neonatal seizures?

Epilepsia 2021 01 2;62(1):269-278. Epub 2020 Nov 2.

Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.

Objectives: The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ-aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N,N-dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents. However, it is not known whether esterase activity in neonates is sufficient to hydrolyze ester prodrugs such as DIMAEB.

Methods: In the present study, we examined whether esterases in neonatal serum of healthy term infants are capable of hydrolyzing DIMAEB to bumetanide and whether this activity is different from the serum of adults. Furthermore, to extrapolate the findings to brain tissue, we performed experiments with brain tissue and serum of neonatal and adult rats.

Results: Serum from 1- to 2-day-old infants was capable of hydrolyzing DIMAEB to bumetanide at a rate similar to that of serum from adult individuals. Similarly, serum and brain tissue of neonatal rats rapidly hydrolyzed DIMAEB to bumetanide.

Significance: These data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add-on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures.
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http://dx.doi.org/10.1111/epi.16746DOI Listing
January 2021

Application of two different nasal CPAP levels for the treatment of respiratory distress syndrome in preterm infants-"The OPTTIMMAL-Trial"-Optimizing PEEP To The IMMAture Lungs: study protocol of a randomized controlled trial.

Trials 2020 Oct 1;21(1):822. Epub 2020 Oct 1.

Department of General Pediatrics and Neonatology, Center for Child and Adolescent Medicine, Justus-Liebig-University, Feulgenstraße 12, 35392, Gießen, Germany.

Background: Nasal continuous positive airway pressure (CPAP) applies positive end-expiratory pressure (PEEP) and has been shown to reduce the need for intubation and invasive mechanical ventilation in very low birth weight infants with respiratory distress syndrome. However, CPAP failure rates of 50% are reported in large randomized controlled trials. A possible explanation for these failure rates is the application of insufficient low levels of PEEP during nasal CPAP treatment to maintain adequate functional residual capacity shortly after birth. The optimum PEEP level to treat symptoms of respiratory distress in very low birth weight infants has not been assessed in clinical studies. The aim of the study is to compare two different PEEP levels during nasal CPAP treatment in preterm infants.

Methods: In this randomized multicenter trial, 216 preterm infants born at 26 + 0-29 + 6 gestational weeks will be allocated to receive a higher (6-8 cmHO) or a lower (3-5 cmHO) PEEP during neonatal resuscitation and the first 120 h of life. The PEEP level within each group will be titrated throughout the intervention based on the FiO (fraction of inspired oxygen concentration) requirements to keep oxygenation within the target range. The primary outcome is defined as the need for intubation and mechanical ventilation for > 1 h or being not ventilated but reaching one of the two pre-defined CPAP failure criteria (FiO > 0.5 for > 1 h or pCO ≥ 70 mmHg in two consecutive blood gas analyses at least 2 h apart).

Discussion: Based on available data from the literature, the optimum level of PEEP that most effectively treats respiratory distress syndrome in preterm infants is unknown, since the majority of large clinical trials applied a wide range of PEEP levels (4-8 cmHO). The rationale for our study hypothesis is that the early application of a higher PEEP level will more effectively counteract the collapsing properties of the immature and surfactant-deficient lungs and that the level of inspired oxygen may serve as a surrogate marker to guide PEEP titration. Finding the optimum noninvasive continuous distending pressure during early nasal CPAP is required to improve CPAP efficacy and as a consequence to reduce the exposure to ventilator-induced lung injury and the incidence of chronic lung disease in this vulnerable population of very preterm infants.

Trial Registration: drks.de DRKS00019940 . Registered on March 13, 2020.
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http://dx.doi.org/10.1186/s13063-020-04660-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527266PMC
October 2020

Sepsis related mortality of extremely low gestational age newborns after the introduction of colonization screening for multi-drug resistant organisms.

Antimicrob Resist Infect Control 2020 08 26;9(1):144. Epub 2020 Aug 26.

Department of Pediatrics, University of Lübeck, Lübeck, Germany.

Background: In 2013 German infection surveillance guidelines recommended weekly colonization screening for multidrug-resistant (MDRO) or highly epidemic organisms for neonatal intensive care units (NICUs) and extended hygiene measures based on screening results. It remains a matter of debate whether screening is worth the effort. We therefore aimed to evaluate sepsis related outcomes before and after the guideline update.

Methods: The German Neonatal Network (GNN) is a prospective cohort study including data from extremely preterm infants between 22 + 0 and 28 + 6 gestational weeks born in 62 German level III NICUs.

Results: Infants treated after guideline update (n = 8.903) had a lower mortality (12.5% vs. 13.8%, p = 0.036), reduced rates for clinical sepsis (31.4 vs. 42.8%, p <  0.001) and culture-proven sepsis (14.4% vs. 16.5%, p = 0.003) as compared to infants treated before update (n = 3.920). In a multivariate logistic regression analysis, nine pathogens of culture-proven sepsis were associated with sepsis-related death, e.g. Pseudomonas aeruginosa [OR 59 (19-180), p <  0.001)]. However, the guideline update had no significant effect on pathogen-specific case fatality, total sepsis-related mortality and culture-proven sepsis rates with MDRO. While the exposure of GNN infants to cefotaxime declined over time (31.1 vs. 40.1%, p <  0.001), the treatment rate with meropenem was increased (31.6 vs. 26.3%, p <  0.001).

Conclusions: The introduction of weekly screening and extended hygiene measures is associated with reduced sepsis rates, but has no effects on sepsis-related mortality and sepsis with screening-relevant pathogens. The high exposure rate to meropenem should be a target of antibiotic stewardship programs.
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http://dx.doi.org/10.1186/s13756-020-00804-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449086PMC
August 2020

Active perinatal care of preterm infants in the German Neonatal Network.

Arch Dis Child Fetal Neonatal Ed 2020 Mar 27;105(2):190-195. Epub 2019 Jun 27.

Department of Neonatology and Pediatric Intensive Care, University Hospital Carl Gustav Carus, Dresden, Germany.

Objective: To determine if survival rates of preterm infants receiving active perinatal care improve over time.

Design: The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016.

Setting: 43 German level III neonatal intensive care units (NICUs).

Patients: 8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care.

Interventions: Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (
Main Outcome Measures: Death by any cause before discharge.

Results: Total survival increased from 85.8% in 2011-2013 to 87.4% in 2014-2016. This increase was due to reduced mortality of NICUs with low survival rates in 2011-2013. Survival increased in these centres from 53% to 64% in the 22-24 weeks strata and from 73% to 84% in the 25-26 weeks strata.

Conclusions: Our data support previous reports that active perinatal care of very immature infants improves outcomes at the border of viability and survival rates at higher gestational ages. The high total number of surviving infants below 24 weeks of gestation challenges national recommendations exclusively referring to gestational age as the single criterion for providing active care. However, more data are needed before recommendations for parental counselling should be reconsidered.

Trial Registration: Approval by the local institutional review board for research in human subjects of the University of Lübeck (file number 08-022) and by the local ethic committees of all participating centres has been given.
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http://dx.doi.org/10.1136/archdischild-2018-316770DOI Listing
March 2020

Impact of maternal education on the outcome of newborns requiring surgery for congenital malformations.

PLoS One 2019 8;14(4):e0214967. Epub 2019 Apr 8.

Department of Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.

Objective: Numerous studies established a link between socioeconomic status (SES) and several dimensions of general health. This study examines the association between maternal education as a widely used indicator of SES and outcome in newborns requiring surgical correction of congenital anomalies.

Methods: Ambispective data analysis of newborns with esophageal atresia (EA), intestinal atresia (IA), congenital diaphragmatic hernia (CDH), omphalocele (OC), gastroschisis (GS) undergoing surgery between 01/2008-11/2017 accessing the clinical databases Neodat and Viewpoint. Maternal education was determined according to the validated education classification CASMIN and stratified into "low" SES and "high" SES group. Endpoints were incidence of postoperative complications, length of mechanical ventilation, and readmission to NICU.

Results: Inclusion of 169 patients with EA (n = 32), IA (n = 24), CDH (n = 47), OC (n = 19), GS (n = 47). Women of low SES (n = 67, 40%) attended fewer prenatal screenings (total, 4.6 vs. 7.9, P<0.0001; EA, 3.7 vs. 7.1, P = 0.0002; IA, 3.5 vs. 9.4, P = 0.0006; OC, 2.5 vs. 8.8, P = 0.009; GS, 4.1 vs. 7.0, P = 0.002). Low SES was associated with higher incidence of patients born small for gestational age (37% vs. 20%, P = 0.019), with additional congenital malformations (37% vs. 15%, P = 0.001), being born in a peripheral center (7% vs. 0%, P = 0.008), and with higher incidence of 5´APGAR scores <7 (23% vs. 7%, P = 0.004). Moreover, low SES was associated with higher incidence of postoperative complications (total 70% vs. 32%, P<0.0001; EA, 60% vs. 23%, P = 0.04; IA, 67% vs. 11%, P = 0.008; CDH, 83% vs. 46%, P = 0.009; GS, 74% vs. 25%, P = 0.001), and higher readmission rate to NICU (IA, 33% vs. 0%, P = 0.043; GS, 32% vs. 4%, P = 0.007).

Conclusions: Low maternal education is associated with a reduced uptake of prenatal screenings, adverse neonatal outcomes, and higher incidence of postoperative complications in newborns with congenital anomalies. Primary prevention and specific support should be provided prenatally for families with low SES to avoid adverse outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214967PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453467PMC
December 2019

[A Short Neonatologic Case Report: Salt Cod and Blue Lips].

Klin Padiatr 2018 10 6;230(6):336-338. Epub 2018 Nov 6.

Department of pediatric Cardiology and pediatric intensive care, Hanover Medical School.

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http://dx.doi.org/10.1055/a-0750-5882DOI Listing
October 2018

Influence of PCO2 Control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants.

Neonatology 2018 4;113(3):221-230. Epub 2018 Jan 4.

Division of Neonatology, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.

Background: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants.

Objectives: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes.

Methods: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression.

Results: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01).

Conclusions: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.
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http://dx.doi.org/10.1159/000485828DOI Listing
September 2019

Necrotizing enterocolitis and high intestinal iron uptake due to genetic variants.

Pediatr Res 2018 01 13;83(1-1):57-62. Epub 2017 Sep 13.

Department of Pediatrics, University of Lübeck, UKSH, Lübeck, Germany.

BackgroundIntestinal iron is a nutritional compound, which is essential for enteric microbiota. We evaluated the hypothesis that polymorphisms, which are known modifiers of intestinal iron uptake in adults, are associated with necrotizing enterocolitis (NEC) in preterm infants.MethodsPreterm infants (birth weight below 1,500 g) were studied. Single-nucleotide polymorphisms with known effects on serum iron levels (rs1800562, rs1799945, and rs855791) were determined using PCR. The effects of polymorphisms on NEC surgery were tested by Mendelian randomization. Outcome data were compared with χ-test, Fisher's exact test, t-test, and Cochran-Armitage test for trend and multiple logistic regression analysis.ResultsComplete genotyping data were available for 11,166 infants. High serum iron levels due to rs855791 genotype were associated with a significantly reduced risk of NEC surgery (odds ratio (OR) 0.265; 95% confidence interval (CI) 0.11-0.65; adjusted P=0.011). Carriers of the rs855791 A-allele not receiving prophylactic probiotics had a higher risk of NEC surgery (OR 1.12, 95% CI 1.08-1.70, nominal P=0.002). Prophylactic treatment with probiotics was associated with a reduced risk of NEC surgery in carriers of the rs855791 A-Allele. No differences were found with regard to other short- or long-term outcome data.ConclusionPolymorphisms inducing lower intestinal iron uptake like the rs855791 A-allele might be an underestimated risk factor for NEC.
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http://dx.doi.org/10.1038/pr.2017.195DOI Listing
January 2018

Comprehensive analysis of the L-arginine/L-homoarginine/nitric oxide pathway in preterm neonates: potential roles for homoarginine and asymmetric dimethylarginine in foetal growth.

Amino Acids 2017 04 4;49(4):783-794. Epub 2017 Feb 4.

Department of Neuropaediatrics, University Children's Hospital, Ruhr University, Bochum, Germany.

L-Arginine (Arg) and L-homoarginine (hArg) are precursors of nitric oxide (NO), a signalling molecule with multiple important roles in human organism. In the circulation of adults, high concentrations of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) and low concentrations of hArg emerged as cardiovascular risk factors. Yet, the importance of the Arg/hArg/NO pathway, especially of hArg and ADMA, in preterm neonates is little understood. We comprehensively investigated the Arg/hArg/NO pathway in 106 healthy preterm infants (51 boys, 55 girls) aged between 23 + 6 and 36 + 1 gestational weeks. Babies were divided into two groups: group I consisted of 31 babies with a gestational age of 23 + 6 - 29 + 6 weeks; group II comprised 75 children with a gestational age of 30 + 0 - 36 + 1 weeks. Plasma and urine concentrations of ADMA, SDMA, hArg, Arg, dimethylamine (DMA) which is the major urinary ADMA metabolite, as well as of nitrite and nitrate, the major NO metabolites, were determined by GC-MS and GC-MS/MS methods. ADMA and hArg plasma levels, but not the hArg/ADMA molar ratio, were significantly higher in group II than in group I: 895 ± 166 nM vs. 774 ± 164 nM (P = 0.001) for ADMA and 0.56 ± 0.04 µM vs. 0.48 ± 0.08 µM (P = 0.010) for hArg. There was no statistical difference between the groups with regard to urinary ADMA (12.2 ± 4.6 vs 12.8 ± 3.6 µmol/mmol creatinine; P = 0.61) and urinary SDMA. Urinary hArg, ADMA, SDMA correlated tightly with each other. Urinary excretion of DMA was slightly higher in group I compared to group II: 282 ± 44 vs. 247 ± 35 µmol/mmol creatinine (P = 0.004). The DMA/ADMA molar ratio in urine was tendentiously higher in neonates of group I compared to group II: 27 ± 13 vs. 20 ± 5 (P = 0.065). There were no differences between the groups with respect to Arg in plasma and to nitrite and nitrate in plasma and urine. In preterm neonates, ADMA and hArg biosynthesis increases with gestational age without remarkable changes in the hArg/ADMA ratio or NO biosynthesis. Our study suggests that ADMA and hArg are involved in foetal growth.
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http://dx.doi.org/10.1007/s00726-017-2382-9DOI Listing
April 2017

Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO targets: the PHELBI follow-up study.

Arch Dis Child Fetal Neonatal Ed 2017 Sep 13;102(5):F376-F382. Epub 2017 Jan 13.

Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.

Background: Tolerating higher partial pressures of carbon dioxide (PCO) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial.

Methods: Infants (n=359) between 400 and 1000 g birth weight and 23 0/7-28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO or to a control group with mildly elevated PCO targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI).

Results: There were no differences in body weight, length and head circumference between the two PCO target groups. Median Mental Developmental Index (MDI) values were 82 (60-96, high target) and 84 (58-96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57-100) and 84 (65-96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment.

Conclusions: A higher PCO target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO targets to optimise short-term outcomes is a safe option.

Trial Registration Number: ISRCTN56143743.
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http://dx.doi.org/10.1136/archdischild-2016-311581DOI Listing
September 2017

Severe methemoglobinemia caused by continuous lidocaine infusion in a term neonate.

Eur J Paediatr Neurol 2017 May 28;21(3):576-579. Epub 2016 Dec 28.

Hanover Medical School, Hanover, Germany. Electronic address:

Neonates and young infants are especially prone to develop drug-induced methemoglobinemia. Therefore, lidocaine is not licensed as local anesthetic in children below the age of 3 months. However, its systemic use is advocated for neonatal seizures. Cardiac arrhythmia has been reported as sole major side effect. Here we report a case of severe methemoglobinemia caused by continuous infusion of lidocaine in a term neonate with neonatal seizures. The increase of methemoglobin up to 13.8% was accompanied by hypoxemia and cyanosis, necessitating additional inspired oxygen and CPAP ventilation. After stopping lidocaine infusion methemoglobin levels fell and the neonate could be weaned from ventilation. Neonates treated with lidocaine for seizures must be monitored for the occurrence of methemoglobinemia.
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http://dx.doi.org/10.1016/j.ejpn.2016.12.011DOI Listing
May 2017

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial.

Lancet Respir Med 2015 Jul 15;3(7):534-43. Epub 2015 Jun 15.

Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.

Background: Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death.

Methods: In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743.

Results: Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36).

Interpretation: Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection.

Funding: Deutsche Forschungsgemeinschaft.
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http://dx.doi.org/10.1016/S2213-2600(15)00204-0DOI Listing
July 2015

Parents' Prenatal, Onward, and Postdischarge Experiences in Case of Extreme Prematurity: When to Set the Course for a Trusting Relationship between Parents and Medical Staff.

Am J Perinatol 2015 Nov 22;32(13):1191-7. Epub 2015 May 22.

Department of Pediatric Pulmonology, Allergology and Neonatology, Hanover Medical School, Hanover, Lower Saxony, Germany.

Objectives: This article aims to investigate the impact of prenatal counseling on subsequent parents' experiences during in-patient care of their infant(s) and whether feelings of parents with deceased infants are different in principle.

Study Design: A questionnaire was sent to 99 families with a child born less than 26 weeks' gestational age at Medical School Hanover 2000-2008. Statistical analysis was performed using Fisher exact t test and chi-square tests in IBM SPSS Statistics for Windows, Version 20.0.

Results: Response rate was 73%. Parents with solely surviving children significantly more often answered the questionnaire (p < 0.001). Regardless of the infants' outcome, parents who felt well involved in prenatal decision making significantly more often also felt adequately involved in postnatal treatment of their child (p = 0.006) and would again decide on life-sustaining treatment of an extremely premature infant (p = 0.007). Furthermore, they were significantly less dubious about the treatment of their baby (p = 0.013) than parents not feeling sufficiently involved. Significantly fewer parents with only surviving child(ren) decided to have another baby later than parents with at least one deceased child (p = 0.004).

Conclusion: This study stresses the impact of prenatal counseling and shows that, regardless of outcome, the course of a trusting relationship between parents and health care team is already set before birth.
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http://dx.doi.org/10.1055/s-0035-1551672DOI Listing
November 2015

Prescription of home oxygen therapy to very low birth weight infants in Germany: a nationwide survey.

Clin Pediatr (Phila) 2014 Jul 25;53(8):726-32. Epub 2014 Mar 25.

Hanover Medical School, Hanover, Germany

Objective: There is no consensus on prescription of home oxygen therapy to infants in Germany. We hypothesized that this causes considerable variability in prescribing home oxygen to infants.

Study Design: A structured questionnaire involving management of home oxygen therapy was sent to all German pediatric departments (n = 293).

Results: Response rate was 84% (247/293). SpO2 cutoff values below which oxygen therapy was considered indicated showed a wide range (80% to 94%, mean 90%). Respondents admitting >50 very low birth weight infants annually significantly more frequently prescribed home oxygen (P < .001) and aimed for SpO2 levels closer to the physiological range than those admitting less very low birth weight infants (P = .046).

Conclusion: Management of pediatric home oxygen therapy is diverse in Germany. Optimal SpO2 targets have to be further investigated by controlled studies and German guidelines should be established. Until then practice should abide by existing foreign guidelines.
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http://dx.doi.org/10.1177/0009922814528037DOI Listing
July 2014

Usefulness of abdominal ultrasound in diagnosing necrotising enterocolitis.

Arch Dis Child Fetal Neonatal Ed 2013 Sep 9;98(5):F445-50. Epub 2013 Apr 9.

Department of Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Germany.

Necrotising enterocolitis is a serious disorder in preterm infants with a mortality of up to 60%. Therefore, early and precise diagnosis and rapid initiation of proper treatment are essential. Clinically suspected diagnosis is usually confirmed by typical findings on plain abdominal radiograph, for example, pneumatosis intestinalis, portal venous gas and, in case of intestinal perforation, pneumoperitoneum. Recently, there has been growing evidence that with real-time ultrasound, intramural air and portal gas can be better detected than with x-ray. Furthermore, ultrasound is able to assess the bowel wall directly and detect bowel wall thickening or thinning, reduced peristalsis or disturbed bowel wall perfusion. Intra-abdominal fluid, both intraluminal or extraluminal is also visible. However, data regarding the diagnostic validity and prognostic value of abdominal ultrasound are limited and often focused on a single finding rather than a combination of them. Additionally, until now, ultrasound findings seem to have little influence on therapeutic decisions. Therefore, the value of abdominal ultrasound in the diagnosis of necrotising enterocolitis has to be determined by further studies until its use can be generally recommended.
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http://dx.doi.org/10.1136/archdischild-2012-302848DOI Listing
September 2013

Closed versus open endotracheal suctioning in extremely low-birth-weight neonates: a randomized, crossover trial.

Neonatology 2013 1;103(2):124-30. Epub 2012 Dec 1.

Department of Pediatric Pulmonology, Allergology and Neonatology, Hanover Medical School, Hanover, Germany.

Background: Endotracheal suctioning, which is frequently necessary in mechanically ventilated patients, might cause complications, especially in patients with compromised lung function such as extremely low-birth-weight (ELBW) neonates.

Objectives: To investigate whether closed endotracheal suctioning (CS) reduces the frequency of hypoxemia and bradycardia in ELBW neonates compared to open suctioning (OS).

Methods: In a randomized, crossover trial, 15 ventilated ELBW neonates (mean birth weight 655 g) underwent suctioning with both techniques. Data on oxygen saturation (SpO2), heart rate (HR), arterial blood pressure, arterial blood gases, duration of the suctioning procedure and recovery time were collected. Statistical analysis was done using the SPSS t test for paired samples.

Results: The mean frequency of hypoxemia <85% was significantly decreased (p = 0.012) during CS (0.5) versus OS (1.1). The mean minimum SpO2 was significantly higher (p = 0.012) during CS (87%) compared to OS (84%), and a significantly less steep drop in mean SpO2 (p = 0.007) (CS: -5%, OS: -8%) was found. Mean arterial PO2 (p = 0.035; CS: 59 mm Hg, OS: 53 mm Hg) and mean oxygenation ratio (p = 0.016; CS: 197, OS: 171) were significantly higher after CS. No significant differences were found in HR, incidence or duration of bradycardia, recovery time, arterial blood pressure, duration of suctioning, number of complications, or duration of hypoxemia.

Conclusion: CS was superior to OS on oxygenation values. To prove its overall superiority, further research is required. So, in this group of patients, CS should currently be administered on an individual basis.
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http://dx.doi.org/10.1159/000343472DOI Listing
July 2013

Epidemic microclusters of blood-culture proven sepsis in very-low-birth weight infants: experience of the German Neonatal Network.

PLoS One 2012 29;7(6):e38304. Epub 2012 Jun 29.

Department of Pediatrics at the University of Lübeck, Lübeck, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038304PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387163PMC
November 2012

Procalcitonin and valuable clinical symptoms in the early detection of neonatal late-onset bacterial infection.

Acta Paediatr 2012 Jan 29;101(1):19-25. Epub 2011 Aug 29.

Department of Paediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Germany.

Aim: To evaluate which clinical symptoms indicate proven neonatal bacterial infection (NBI) and whether measuring procalcitonin aside from C-reactive protein and interleukin 6 improves sensitivity and specificity in diagnosis.

Methods: In a prospective observational study, clinical symptoms and procalcitonin, C-reactive protein and interleukin 6 were simultaneously determined from the 4th day of life in 170 preterm and term neonates at the first time of suspicion of NBI. Proven NBI was defined as a positive culture of otherwise sterile body fluids or radiologically verified pneumonia in combination with elevated inflammatory markers.

Results: Fifty-eight (34%) patients were diagnosed with proven late-onset NBI. In case of proven NBI, odds ratio and 95% confidence intervals were 2.64 (1.06-6.54) for arterial hypotension, 5.16 (2.55-10.43) for feeding intolerance and 9.18 (4.10-20.59) for prolonged capillary refill. Sensitivity of combined determination of C-reactive protein (>10 mg/L) and interleukin 6 (>100 pg/mL) was 91.4%, specificity 80.4%, positive predictive value 70.7% and negative predictive value 94.7%. The additional determination of procalcitonin (>0.7 ng/mL) resulted in 98.3%, 65.2%, 58.8% and 98.6%, respectively.

Conclusion: Arterial hypotension, feeding intolerance and especially prolonged capillary refill indicate proven neonatal late-onset bacterial infection, even at the time of first suspicion. Additional measurement of procalcitonin does indeed improve sensitivity to nearly 100%, but is linked to a decline in specificity. Nevertheless, in the high-risk neonatal population, additional procalcitonin measurement can be recommended because all infants with NBI have to be identified.
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http://dx.doi.org/10.1111/j.1651-2227.2011.02438.xDOI Listing
January 2012

Successful treatment of vancomycin-resistant Enterococcus faecium ventriculitis with combined intravenous and intraventricular chloramphenicol in a newborn.

J Med Microbiol 2010 Nov 15;59(Pt 11):1371-1374. Epub 2010 Jul 15.

Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Vancomycin-resistant Enterococcus faecium (VRE) infection is a rare event in paediatric patients and often occurs under immunosuppression or after surgical intervention. We report what we believe to be the first paediatric case of ventriculitis due to VRE (in a 2-month-old infant) to be successfully treated with combined intravenous (i.v.) and intraventricular chloramphenicol after failure of i.v. linezolid and intraventricular gentamicin.
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http://dx.doi.org/10.1099/jmm.0.022921-0DOI Listing
November 2010

Novel CHD7 mutations contributing to the mutation spectrum in patients with CHARGE syndrome.

Eur J Med Genet 2010 Sep-Oct;53(5):280-5. Epub 2010 Jul 30.

Institute of Human Genetics, Hannover Medical School, Hannover, Germany.

CHARGE syndrome is an autosomal dominant inherited multiple malformation disorder typically characterized by coloboma, choanal atresia, hypoplastic semicircular canal, cranial nerve defects, cardiovascular malformations and ear abnormalities. Mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene are the major cause of CHARGE syndrome. Mutation analysis was performed in 18 patients with firm or tentative clinical diagnosis of CHARGE syndrome. In this study eight mutations distributed across the gene were found. Five novel mutations - one missense (c.2936T > C), one nonsense (c.8093C > A) and three frameshift mutations (c.804_805insAT, c.1757_1770del14, c.1793delA) - were identified. As far as familial data were available these mutations were found to have arisen de novo. Comparison of the clinical features of patients with the same mutation demonstrates that expression of the phenotype is highly variable. The mutation detection rate in this study was 44.4% in patients with a clinically established or suspected diagnosis of CHARGE syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2010.07.002DOI Listing
January 2011

Oral versus nasal route for placing feeding tubes: no effect on hypoxemia and bradycardia in infants with apnea of prematurity.

Neonatology 2010 16;98(2):143-9. Epub 2010 Mar 16.

Department of Pediatric Pulmonology and Neonatology, Hannover Medical School, Hannover, Germany.

Background: Raised upper airway resistance may be involved in apnea of prematurity (AOP).

Objectives: To determine the effects of an oral versus a nasal gastric tube on episodes of hypoxemia and bradycardia in infants with AOP.

Methods: In a randomized controlled cross-over trial, 32 infants (median gestational age 29 (range 24-31) weeks, postmenstrual age at study 32 (range 30-35) weeks) with the need for tube feeding and symptoms of AOP underwent a 24-hour recording of breathing movements, nasal airflow, heart rate, pulse oximeter saturation and pulse waveforms. A 5-Fr feeding tube was placed orally or nasally for 12 h each, the position selected first was randomly assigned. When the feeding tube was placed nasally, always the smaller nostril was selected. Each infant acted as his/her own control. Recordings were analyzed for the summed rate of bradycardia and desaturation (heart rate <2/3 of baseline, saturation
Results: The route of placing the feeding tube had no significant effect on the summed rate of bradycardia and desaturation (nasal route: median 1.6, CI 0.8-1.9; oral route: median 1.0, CI 0.9-1.6, p = 0.25).

Conclusion: We could not confirm an advantage of placing a feeding tube orally in these infants with AOP, as the oral route did not improve their symptoms of AOP. Possible explanations include: (i) the increase in nasal airway resistance by the 5-Fr nasogastric tube, inserted into the smaller nostril, is too small to have any effect on AOP; (ii) any benefit of the oral route is neutralized by the negative effects of an enhanced vagal stimulation, or (iii) study duration was too short to detect a difference in AOP.
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http://dx.doi.org/10.1159/000279617DOI Listing
November 2010
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