Neonatal sepsis definitions from randomised clinical trials.

INTRODUCTION: Neonatal sepsis is a leading cause of infant mortality worldwide with non-specific and varied presentation. We aimed to catalogue the current definitions of neonatal sepsis in published randomised controlled trials (RCTs). METHOD: A systematic search of the Embase and Cochrane databases was performed for RCTs which explicitly stated a definition for neonatal sepsis. Definitions were sub-divided into five primary criteria for infection (culture, laboratory findings, clinical signs, radiological evidence and risk factors) and stratified by qualifiers (early/late-onset and likelihood of sepsis). RESULTS: Of 668 papers screened, 80 RCTs were included and 128 individual definitions identified. The single most common definition was neonatal sepsis defined by blood culture alone (n = 35), followed by culture and clinical signs (n = 29), and then laboratory tests/clinical signs (n = 25). Blood culture featured in 83 definitions, laboratory testing featured in 48 definitions while clinical signs and radiology featured in 80 and 8 definitions, respectively. DISCUSSION: A diverse range of definitions of neonatal sepsis are used and based on microbiological culture, laboratory tests and clinical signs in contrast to adult and paediatric sepsis which use organ dysfunction. An international consensus-based definition of neonatal sepsis could allow meta-analysis and translate results to improve outcomes.

Knowledge gaps in late-onset neonatal sepsis in preterm neonates: a roadmap for future research.

Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives. IMPACT: This review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts. Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use. Methods to personalize medicine and technologies feasible for bedside clinical use are described.

Neonatal sepsis: a systematic review of core outcomes from randomised clinical trials.

BACKGROUND: The lack of a consensus definition of neonatal sepsis and a core outcome set (COS) proves a substantial impediment to research that influences policy and practice relevant to key stakeholders, patients and parents. METHODS: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the included studies, the described outcomes were extracted in accordance with the provisions of the Core Outcome Measures in Effectiveness Trials (COMET) handbook and registered. RESULTS: Among 884 abstracts identified, 90 randomised controlled trials (RCTs) were included in this review. Only 30 manuscripts explicitly stated the primary and/or secondary outcomes. A total of 88 distinct outcomes were recorded across all 90 studies included. These were then assigned to seven different domains in line with the taxonomy for classification proposed by the COMET initiative. The most frequently reported outcome was survival with 74% (n = 67) of the studies reporting an outcome within this domain. CONCLUSIONS: This systematic review constitutes one of the initial phases in the protocol for developing a COS in neonatal sepsis. The paucity of standardised outcome reporting in neonatal sepsis hinders comparison and synthesis of data. The final phase will involve a Delphi Survey to generate a COS in neonatal sepsis by consensus recommendation. IMPACT: This systematic review identified a wide variation of outcomes reported among published RCTs on the management of neonatal sepsis. The paucity of standardised outcome reporting hinders comparison and synthesis of data and future meta-analyses with conclusive recommendations on the management of neonatal sepsis are unlikely. The final phase will involve a Delphi Survey to determine a COS by consensus recommendation with input from all relevant stakeholders.

A critical appraisal of tools for delivery room assessment of the newborn infant.

Assessment of an infant's condition in the delivery room represents a prerequisite to adequately initiate medical support. In her seminal paper, Virginia Apgar described five parameters to be used for such an assessment. However, since that time maternal and neonatal care has changed; interventions were improved and infants are even more premature. Nevertheless, the Apgar score is assigned to infants worldwide but there are concerns about low interobserver reliability, especially in preterm infants. Also, resuscitative interventions may preclude the interpretation of the score, which is of concern when used as an outcome parameter in delivery room intervention studies. Within the context of these changes, we performed a critical appraisal on how to assess postnatal condition of the newborn including the clinical parameters of the Apgar score, as well as selected additional parameters and a proposed new scoring system. The development of a new scoring system that guide clinicians in assessing infants and help to decide how to support postnatal adaptation is discussed. IMPACT: This critical paper discusses the reliability of the Apgar score, as well as additional parameters, in order to improve assessment of a newborn's postnatal condition. A revised neonatal scoring system should account for infant maturity and the interventions administered. Delivery room assessment should be directed toward determining how much medical support is needed and how the infant responds to these interventions.

Delivery Room Management of Infants with Very Low Birth Weight in 3 European Countries-The Video Apgar Study.

OBJECTIVE: To assess delivery room management of infants born preterm at 4 Level III perinatal centers in 3 European countries. STUDY DESIGN: This was a prospective, multicenter observational study. Management at birth was video-recorded and evaluated (Interact version 9.6.1; Mangold-International, Arnstorf, Germany). Data were analyzed and compared within and between centers. RESULTS: The infants (n = 138) differed significantly with respect to the median (25%, 75%) birth weight (grams) (Center A: 1200 [700, 1550]; Center B: 990 [719, 1240]; Center C: 1174 [835, 1435]; Center D: 1323 [971, 1515] [B vs A, C, D: P < .05]), gestational week (Center A: 28.4 [26.3, 30.0]; Center B: 27.9 [26.7, 29.6]; Center C: 29.3 [26.4, 31.0]; Center D: 30.3 [28.0, 31.9]), Apgar scores, rates of cesarean delivery, and time spent in the delivery room. Management differed significantly for frequency and drying time, rates of electrocardiographic monitoring, suctioning or stimulation, and for fundamental interventions such as time for achieving a reliable peripheral oxygen saturation signal (seconds) (Center A: 97.6 ± 79.3; Center B: 65.1 ± 116.2; Center C: 97.1 ± 67.0; Center D: 114.4 ± 140.5; B vs A, C, D: P < .001) and time for intubation (seconds) (Center A: 48.7 ± 4.2; Center B: 49.0 ± 30.7; Center C: 69.1 ±37.9; Center D: 65.1 ± 23.8; B vs D, P < .025). Mean procedural times did not meet guideline recommendations. The sequence of interventions was similar at all centers. CONCLUSIONS: The Video Apgar Study showed great variability in and between 4 neonatal centers in Europe. The study also showed it is difficult to adhere to published guidelines for recommended times for important, basic measures such as peripheral oxygen saturation measurements and intubation.

Transmission Risk on a Neonatal Intensive Care Unit: Escherichia coli versus Klebsiella pneumoniae.

Isolation precautions required for neonatal intensive care units are part of a bundle with the aim to prevent transmission, colonization, and infection with multidrug-resistant gram-negative pathogens as neonates face an increased risk of mortality and morbidity in case of infection. The following short report describes a transmission of 3MDRGN Klebsiella pneumoniae on a neonatal intensive care unit in a university hospital in Germany. This transmission occurred even though intensified infection control measures were in place, which impressively shows the importance of surveillance, outbreak management, and awareness of contributing factors regarding outbreak situations.

Less invasive ventilation in extremely low birth weight infants from 1997 to 2011: survey versus evidence.

Evidence for target values of arterial oxygen saturation (SaO2), CO2, and pH has changed substantially over the last 20 years. A representative survey concerning treatment strategies in extremely low-birth-weight infants (ELBW) was sent to all German neonatal intensive care units (NICUs) treating ELBW infants in 1997. A follow-up survey was conducted in 2011 and sent to all NICUs in Germany, Austria, and Switzerland. During the observation period, NICUs targeting SaO2 of 80, 85, and 90 % have increased, while units aiming for 94 and 96 % decreased (all p < 0.001). Similarly, NICUs aiming for pH 7.25 or lower increased, while 7.35 or higher decreased (both p < 0.001). Furthermore, more units targeted a CO2 of 50 mmHg (7.3 kPa) or higher (p < 0.001), while fewer targeted 40 or 35 mmHg (p < 0.001). Non-invasive ventilation (NIV) was used in 80.2 % of NICUs in 2011. The most frequently used ventilation modes were synchronized intermittent mandatory ventilation (SIMV) (67.5 %) and intermittent positive pressure ventilation (IPPV) (59.7 %) in 1997 and SIMV (77.2 %) and synchronized intermittent positive pressure ventilation (SIPPV) (26.8 %) in 2011. NICUs reporting frequent or always use of IPPV decreased to 11.0 % (p < 0.001). SIMV (77.2 %) and SIPPV (26.8 %) did not change from 1997 to 2011, while high-frequency oscillation (HFO) increased from 9.1 to 19.7 % (p = 0.018). Differences between countries, level of care, and size of the NICU were minimal. CONCLUSIONS: Target values for SaO2 decreased, while CO2 and pH increased significantly during the observation period. Current values largely reflect available evidence at time of the surveys. WHAT IS KNOWN: • Evidence concerning target values of oxygen saturation, CO 2 , and pH in extremely low-birth-weight infants has grown substantially. • It is not known to which extent this knowledge is transferred into clinical practice and if treatment strategies have changed. WHAT IS NEW: • Target values for oxygen saturation in ELBW infants decreased between 1997 and 2011 while target values for CO 2 and pH increased. • Similar treatment strategies existed in different countries, hospitals of different size, or university versus nonuniversity hospitals in 2011.

Neonatal assessment in the delivery room--Trial to Evaluate a Specified Type of Apgar (TEST-Apgar).

BACKGROUND: Since an objective description is essential to determine infant's postnatal condition and efficacy of interventions, two scores were suggested in the past but weren't tested yet: The Specified-Apgar uses the 5 items of the conventional Apgar score; however describes the condition regardless of gestational age (GA) or resuscitative interventions. The Expanded-Apgar measures interventions needed to achieve this condition. We hypothesized that the combination of both (Combined-Apgar) describes postnatal condition of preterm infants better than either of the scores alone. METHODS: Scores were assessed in preterm infants below 32 completed weeks of gestation. Data were prospectively collected in 20 NICU in 12 countries. Prediction of poor outcome (death, severe/moderate BPD, IVH, CPL and ROP) was used as a surrogate parameter to compare the scores. To compare predictive value the AUC for the ROC was calculated. RESULTS: Of 2150 eligible newborns, data on 1855 infants with a mean GA of 28(6/7) ± 2(3/7) weeks were analyzed. At 1 minute, the Combined-Apgar was significantly better in predicting poor outcome than the Specified- or Expanded-Apgar alone. Of infants with a very low score at 5 or 10 minutes 81% or 100% had a poor outcome, respectively. In these infants the relative risk (RR) for perinatal mortality was 24.93 (13.16-47.20) and 31.34 (15.91-61.71), respectively. CONCLUSION: The Combined-Apgar allows a more appropriate description of infant's condition under conditions of modern neonatal care. It should be used as a tool for better comparison of group of infants and postnatal interventions. TRIAL REGISTRATION: clinicaltrials.gov Protocol Registration System (NCT00623038). Registered 14 February 2008.

Mitochondrial mutation m.1555A>G as a risk factor for failed newborn hearing screening in a large cohort of preterm infants.

BACKGROUND: The mitochondrial m.1555A>G mutation is associated with a high rate of permanent hearing loss, if aminoglycosides are given. Preterm infants have an increased risk of permanent hearing loss and are frequently treated with aminoglycoside antibiotics. METHODS: We genotyped preterm infants with a birth weight below 1500 grams who were prospectively enrolled in a large cohort study for the m.1555A>G mutation. Treatment with aminoglycoside antibiotics in combination with mitochondrial m.1555A>G mutation was tested as a predictor for failed hearing screening at discharge in a multivariate logistic regression analysis. RESULTS: 7056 infants were genotyped and analysed. Low birth weight was the most significant predictor of failed hearing screening (p = 7.3 × 10-10). 12 infants (0.2%) had the m.1555A>G-mutation. In a multivariable logistic regression analysis, the combination of aminoglycoside treatment with m.1555A>G-carrier status was associated with failed hearing screening (p = 0.0058). However, only 3 out of 10 preterm m.1555A>G-carriers who were exposed to aminoglycosides failed hearing screening. The m.1555A>G-mutation was detected in all mothers of m.1555A>G-positive children, but in none of 2993 maternal DNA-samples of m.1555A>G-negative infants. CONCLUSION: Antenatal screening for the m.1555A>G mutation by maternal genotyping of pregnant women with preterm labour might be a reasonable approach to identify infants who are at increased risk for permanent hearing loss. Additional studies are needed to estimate the relevance of cofactors like aminoglycoside plasma levels and birth weight and the amount of preterm m.1555A>G-carriers with permanent hearing loss.

Increase of caffeine and decrease of corticosteroids for extremely low-birthweight infants with respiratory failure from 1997 to 2011.

AIM: To compare treatment strategies for respiratory failure in extremely low-birthweight (ELBW) infants in Germany in 1997 to Germany, Austria and Switzerland in 2011. METHODS: A detailed questionnaire about treatment strategies for ELBW infants was sent to all German centres treating ELBW infants in 1997. A follow-up survey was conducted in 2011 in Germany, Austria and Switzerland. RESULTS: In 1997 and 2011, 63.6% and 66.2% of the hospitals responded. In 2011, the response rate was higher in Switzerland than in Germany, and in university hospitals versus nonuniversity hospitals. Treatment strategies did not differ between university and nonuniversity hospitals as well as NICUs of different sizes in 2011. Differences between Germany, Austria and Switzerland were minimal. Administration of caffeine increased significantly, whereas theophylline and doxapram declined (all p < 0.001). While the use of dexamethasone decreased and the use of hydrocortisone increased, the overall use of corticosteroids declined (all p < 0.001). Between 1997 and 2011, therapy with inhalations and mucolytics decreased (both p < 0.001), whereas the use application of diuretics did not change significantly. In mechanically ventilated infants, the application of muscle relaxants and sedation declined significantly (p = 0.009 and p < 0.001), whereas analgesia use did not change. CONCLUSION: Treatment strategies for respiratory failure in ELBW infants have changed significantly between 1997 and 2011.

Causes of delivery and outcomes of very preterm twins stratified to zygosity.

The increasing rates of preterm birth among twins implicate that solid data on associated risks and outcomes are required. Assessment of zygosity is often based on clinical criteria (evaluation of placenta; same gender, birth weight discordance as surrogate criteria for monochorionic/monozygotic twins). The aim of this study was to compare clinical versus genetic assessment of zygosity and to compare causes of preterm delivery as well as outcome data of very-low-birth-weight (VLBW; birth weight <1,500 g) twins stratified to zygosity. In a multicenter study, we selected n=176 sets of same gender twins and determined zygosity genetically. In a subgroup of 123 sets of twins, the attending physicians at the study centers were asked to document the parameter 'zygosity' (monozygotic/dizygotic) on the basis of their clinical judgment. Concordance between genetic and clinical assessment was 62.7% for monozygotic twins and 88.9% for dizygotic twins, respectively. Outcome parameters (death, BPD, ROP, NEC, IVH) were comparable in both groups. Genetically dizygotic twins were significantly more often born due to intrauterine infection (33% vs. 20% in monozygotic twins, p<.01) and antenatal antibiotics were more frequently given to mothers of dizygotic twins (62% vs. 47% in monozygotic twins, p<.01). Obstetric complications such as twin-twin-transfusion-syndrome were only seen in monozygotic twins as expected. The unexpected increase of antenatal antibiotic treatment and birth due to intrauterine infection in dizygotic twins should be confirmed in additional VLBW twin-cohorts.

Efficacy of occlusive wraps used for delivery room care.

BACKGROUND: Guidelines advise for more than 20 years to use occlusive plastic wraps for temperature management during delivery room care but data on efficacy of different types of wrap are still scarce. METHODS: A random sample of seven different types of plastic wrap was tested using prewarmed aluminium blocks. RESULTS: The most effective wrap increased the time to cool by 2°C by one-third for the core and by 100% for the surface whereas the least effective wrap led to even faster heat loss compared with no wrap at all. The least effective wrap concerning all capacities tested was made from polyurethane that contains potentially toxic and narcotic monomers. Heat and water retention did not correlate to wrap thickness. DISCUSSION: Large differences in heat and water retention capacity warrant a careful choice of the type of wrap as some might be counterproductive. Wraps containing polyurethane should not be used.

Single-centre prospective observational study on postdelivery room care.

OBJECTIVES: As quality of care in the delivery room has major impact on outcome of preterm infants, multiple guidelines have been established in recent years. There is, however, little evidence on how to proceed during postdelivery room care, the time of transfer and admission to the neonatal intensive care unit (NICU). The aim of this study was to identify processes taking place during this period with potential impact on outcome. STUDY DESIGN: Prospective observational study. SETTING: Single-centre German tertiary NICU. PATIENTS: 40 inborn preterm infants undergoing postdelivery room care. MAIN OUTCOME: Prevalence of prolonged duration of postdelivery room care, disconnections from the ventilator and positioning of preterm infants. RESULTS: Total duration of postdelivery room care and NICU admission procedures were shorter in infants transferred in a transport incubator compared with using a NICU care station from birth. Extremely low birth weight (ELBW) infants spend 8% of the time in prone position in contrast to 39% in non-ELBW. Total duration of disconnection from the ventilator was 50 s and was ten times longer in infants who had nasal CPAP compared with infants intratracheally intubated. Infants with nCPAP had longer duration of disconnection from the ventilator if body weight was >1000 g or if they were transferred in a transport incubator. CONCLUSIONS: Multiple parameters like birth weight or type of transport affect neonatal care during the postdelivery room period. Prospective studies are needed to identify and optimise parameters within this period that affect long-term outcome.

Variations of Apgar score of very low birth weight infants in different neonatal intensive care units.

OBJECTIVE: The Apgar score should be an objective method to assess the state of newborns; however, its applicability in preterm infants is hampered by large variations among different observers. The study tested whether physicians that give low scores to written case descriptions also apply lower scores to preterm infants. PATIENTS AND METHODS: Descriptions (BMJ 2004; 329: 143-4) were sent to 14 neonatal units. Physicians were asked to evaluate the Apgar (case score). From seven units Apgar scores of all very low birth weight infants (VLBW) born between January 2004 and December 2006 were obtained from charts (clinical score). RESULTS: In total, 121 physicians from 14 institutions (median 9, range 3-15) replied: 24 residents with <6-month and 28 with >6-month neonatal experience, and 69 consultants. The assessment of the case scores was very heterogeneous with large variations in respiration, muscle tone and reflexes. Clinical scores were obtained from 1000 VLBW infants. The score depended on the gestational age, with a median of 4 at 24 and 7 at 27 weeks. With one exception, centres that assigned low case scores had also low clinical scores. CONCLUSION: There is considerable variation in assigning Apgar scores. Definitions are required to apply the Apgar score to infants under clinical conditions such as preterm delivery, resuscitation or artificial ventilation.

De novo duplication of chromosome 16p in a female infant with signs of neonatal hemochromatosis.

Reported cases of "pure" duplication of the entire short arm of chromosome 16 (16p) are rare, with only 7 patients described in the literature. We report on a female infant with de novo 16p duplication localized to the short arm of chromosome 6, detected by chromosomal analysis and characterized by array CGH and fluorescence in situ hybridization. This baby girl presented with clinical symptoms characteristic of patients with duplications of the short arm of chromosome 16: psychomotor retardation, constitutional growth delay and specific dysmorphic features, including proximally placed hypoplastic thumbs. In addition, she exhibited evidence of neonatal hemochromatosis as shown by direct hyperbilirubinemia, iron overload and elevated liver enzyme levels. To our knowledge, this is the first report of signs of neonatal hemochromatosis in a patient with 16p duplication.

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.

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.