Continuous Fentanyl Infusion in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia: Background, Aims, and Study Protocol for Time-Concentration Profiles.

Therapeutic hypothermia (TH) is the standard of care for newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE). Discomfort and pain during treatment are common and may affect the therapeutic efficacy of TH. Opioid sedation and analgesia (SA) are generally used in clinical practice, and fentanyl is one of the most frequently administered drugs. However, although fentanyl's pharmacokinetics (PKs) may be altered by hypothermic treatment, the PK behavior of this opioid drug in cooled newborns with HIE has been poorly investigated. The aim of this phase 1 study protocol (Trial ID: FentanylTH; EUDRACT number: 2020-000836-23) is to evaluate the fentanyl time-concentration profiles of full-term newborns with HIE who have been treated with TH. Newborns undergoing TH receive a standard fentanyl regimen (2 mcg/Kg of fentanyl as a loading dose, followed by a continuous infusion-1 mcg/kg/h-during the 72 h of TH and subsequent rewarming). Fentanyl plasma concentrations before bolus administration, at the end of the loading dose, and 24-48-72-96 h after infusion are measured. The median, maximum, and minimum plasma concentrations, together with drug clearance, are determined. This study will explore the fentanyl time-concentration profiles of cooled, full-term newborns with HIE, thereby helping to optimize the fentanyl SA dosing regimen during TH.

Antibiotic Exposure, Common Morbidities and Main Intestinal Microbial Groups in Very Preterm Neonates: A Pilot Study.

Prematurity exposes newborns to increased risks of infections and it is associated with critical morbidities. Preterm infants often require antibiotic therapies that can affect the correct establishment of gut microbiota. The aim of this study was to investigate targeted intestinal bacteria in preterm neonates with common morbidities and receiving antibiotic treatments of variable duration. Stool samples were collected after birth, at 15, 30 and 90 days of life. qPCR quantification of selected microbial groups (Bifidobacterium spp., Bacteroides fragilis group, Enterobacteriaceae, Clostridium cluster I and total bacteria) was performed and correlation between their levels, the duration of antibiotic treatment and different clinical conditions was studied. An increasing trend over time was observed for all microbial groups, especially for Bifdobacterium spp. Prolonged exposure to antibiotics in the first weeks of life affected Clostridium and B. fragilis levels, but these changes no longer persisted at 90 days of life. Variations of bacterial counts were associated with the length of hospital stay, feeding and mechanical ventilation. Late-onset sepsis and patent ductus arteriosus reduced the counts of Bifidobacterium, whereas B. fragilis was influenced by compromised respiratory conditions. This study can be a start point for the identification of microbial biomarkers associated with some common morbidities and tailored strategies for a healthy microbial development.

Fentanyl analgesia in asphyxiated newborns treated with therapeutic hypothermia.

INTRODUCTION: Therapeutic hypothermia is the standard care for asphyxiated newborns. Discomfort and pain during treatment are common and may affect therapeutic efficacy of hypothermia. Opioid analgosedation is commonly used in the clinical setting, but its effects in the cooled newborns is poorly investigated. OBJECTIVE: The aim of this study was to assess the safety of fentanyl analgosedation during therapeutic hypothermia, by evaluating severe adverse effects and possible correlation with the neurodevelopmental outcome. METHODS: We analyzed asphyxiated newborns treated with hypothermia receiving fentanyl intravenous infusion (years 2013-2018). Severe neurodevelopmental outcome was defined as cerebral palsy or Griffith's developmental quotient <70 or major sensorineural deficit. Severe brain lesions were defined as cortical or/and basal ganglia extensive involvement. RESULTS: Fentanyl cumulative dose was variable (61.7 ± 18.5 µg/kg; range 34.3-120.3 µg/kg) among 45 enrolled patients. Respiratory depression was recorded in 13.3% cases of 30 spontaneously breathing patients. Severe brain lesions and severe neurodevelopmental disability were found in 24.4 and 11.1% of all included cases, respectively. Higher cumulative fentanyl dose was not associated with poor outcome. CONCLUSIONS: Fentanyl treatment during therapeutic hypothermia does not negatively affect the neurodevelopmental outcome, thus on the contrary, it may contribute to ameliorate neuroprotection in the asphyxiated cooled newborns.

Heart failure caused by VGAM: a lesson for diagnosis and treatment from a case and literature review.

We describe the case of a neonate with signs of heart failure. Echocardiography showed a structural normal heart shape with left ventricular dysfunction. At 2 months of age, a vein of Galen arteriovenous malformation was diagnosed through a brain magnetic resonance imaging. Embolization therapy was accomplished and a clinical and neurological follow-up was started. This clinical case highlights how important it is considering an intracranial cause in the differential diagnosis of neonatal congestive heart failure (CHF). We performed a narrative minireview of the literature about treatments and outcome of this malformation in association to CHF, to point out how complex the diagnosis of vein of Galen aneurysmal malformation (VGAM) may be and how an early diagnosis is important for its management.

Red blood cell transfusions alter splanchnic oxygenation response to enteral feeding in preterm infants: an observational pilot study.

BACKGROUND: Preterm infants often require red blood cell (RBC) transfusions, which may impair splanchnic hemodynamics, thus predisposing to necrotizing enterocolitis (NEC). The aim of this study was to evaluate whether RBC transfusions alter splanchnic oxygenation patterns in response to enteral feeding in this population. MATERIALS AND METHODS: Preterm neonates (gestational age < 32 weeks and/or birth weight < 1500 g) requiring RBC transfusions for anemia underwent a 12-hour Near Infrared Spectroscopy monitoring of splanchnic (SrSO2 ) and cerebral (CrSO2 ) oxygenation, including the transfusion period, one feed before and one after. Splanchnic-cerebral oxygenation ratio (SCOR) was also calculated. Patterns of CrSO2 , SrSO2 , and SCOR changes from baseline (Δ) in response to feed before and after transfusion were analyzed. RESULTS: Twenty neonates were enrolled; none of them developed any gastrointestinal complication within 48 hours after transfusion. Pre-transfusion ΔSrSO2 and ΔSCOR increased significantly in response to feeding; on the contrary, a significant post-prandial decrease of ΔSrSO2 and ΔSCOR occurred after transfusion (p < 0.05). No difference in pre- and post-transfusion ΔCrSO2 patterns was observed. CONCLUSIONS: In preterm infants, RBC transfusions may alter splanchnic oxygenation response to enteral feeds. Whether these changes are involved in the pathogenesis of transfusion-associated NEC has to be evaluated in further larger trials.

Changes of intestinal microbiota in early life.

There is an increasing evidence that the intestinal microbiota plays a pivotal role in the maturation of the immune system and in the prevention of diseases occurring during the neonatal period, childhood, and adulthood. A number of nonphysiological conditions during the perinatal period (i.e. caesarean section, prolonged hospitalization, formula feeding, low gestational age) may negatively affect the normal development of the microbiota, leading to decreased amounts of lactobacilli and bifidobacteria and increased amounts of Clostridia. In addition, perinatal antibiotics can cause intestinal dysbiosis that has been associated with short- and long-term diseases. For example, prolonged early empiric antibiotics increase the risk of necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in preterm neonates, whereas the administration of intrapartum antibiotic prophylaxis (IAP) has been associated with inflammatory bowel diseases, obesity, and atopic conditions, such as eczema and wheezing. Promoting breastfeeding, reducing the length of hospital stay, and reducing unnecessary antibiotic therapies are useful strategies to counterbalance unintended effects of these conditions.

Risk factors for group B streptococcus early-onset disease: an Italian, area-based, case-control study.

Purpose: Intrapartum antibiotic prophylaxis (IAP) prevents group B streptococcus (GBS) early-onset disease (EOD). No European study evaluates the relative impact of risk factors (RFs) for EOD after a screening-based strategy and widespread IAP use We aimed to evaluate the risks of EOD in an Italian region where a screening-based strategy for preventing EOD was implemented.Materials and methods: Cases of EOD born at or above 35 weeks' gestation were reviewed and matched with controls.Results: There were 109 cases of EOD among 532,154 live births. Most cases had negative GBS prenatal screening (56/91, 61.5%) and were unexposed to IAP (86/109, 78.9%). At multivariate analysis, GBS bacteriuria (OR = 6.99), positive prenatal screening (OR = 13.7) and maternal intrapartum fever (OR = 188.3) were associated with an increased risk of EOD, whereas intrapartum beta-lactam antibiotics were associated with a decreased risk of EOD (≥4 h: OR = 0.008; <4 h: OR = 0.04). Neonates born to nonfebrile, GBS positive pregnant women, receiving beta-lactam antibiotics had very low probability of EOD, particularly if IAP was adequate.Conclusions: GBS positive prenatal screening, GBS bacteriuria and intrapartum fever are associated with EOD. Intrapartum beta-lactam antibiotics reduce the probability of EOD in neonates born to nonfebrile mothers.

Serial clinical observation for management of newborns at risk of early-onset sepsis.

PURPOSE OF REVIEW: Current management approaches for asymptomatic neonates at risk of early onset sepsis remain controversial. Strategies based entirely on clinical observation (SCO, serial clinical observation) have gained consensus. RECENT FINDINGS: We briefly compare different strategies for managing asymptomatic newborns suggested in four high-income countries. Then this review details the existing differences in carrying out the SCO in the United Kingdom, the USA, and Italy; the experiences from the studies performed using the SCO; and open questions regarding this strategy. Advantages and limitations of SCO are also discussed. There is a need to assess which symptoms at birth are more predictive of early onset sepsis and therefore require immediate interventions versus those symptoms that can be monitored and re-evaluated. SUMMARY: SCO strategy may require changes in the processes of newborn care at birthing centers. Nonetheless, SCO is safe and is associated with fewer laboratory evaluations and unnecessary antibiotics. Thoughtful and thorough practices related to the care of all newborns will benefit any birthing centre. VIDEO ABSTRACT: http://links.lww.com/MOP/A40.

Intrapartum beta-lactam antibiotics for preventing group B streptococcal early-onset disease: can we abandon the concept of 'inadequate' intrapartum antibiotic prophylaxis?

Introduction: Neonatal sepsis remains a serious and potentially fatal illness. Intrapartum antibiotic prophylaxis (IAP) prevents group B streptococcal (GBS) early-onset sepsis. The optimal duration of IAP (adequate IAP) to reduce vertical transmission of GBS has been debated. Understanding the mechanism of action of IAP may help in minimizing neonatal evaluation and unnecessary antibiotic use.Areas covered: In recent years, several studies on pharmacokinetics and clinical use of IAP have been published. Although penicillin and ampicillin are the most preferred antibiotics, the clinical efficacy of non-beta-lactam antibiotics, including clindamycin and vancomycin, used in cases of penicillin anaphylaxis-associated allergy, remains debatable. This is a narrative review of the literature regarding the impact of 'inadequate' IAP on the clinical management of women and newborns.Expert opinion: Recent evidence suggests that 'inadequate' IAP with beta-lactams is more effective in preventing vertical transmission of GBS than previously thought. Newborns exposed to intrapartum beta-lactams and who are asymptomatic at birth are likely uninfected, irrespective of IAP duration before delivery. Hence, we may abandon the concept of 'inadequate' IAP with beta-lactams in early-onset GBS sepsis, relying primarily on clinical signs observed at birth for managing IAP-exposed neonates.

Epidemiology and complications of late-onset sepsis: an Italian area-based study.

BACKGROUND: Most studies regarding late-onset sepsis (LOS) address selected populations (i.e., neonates with low birth weight or extremely preterm neonates). Studying all age groups is more suitable to assess the burden of single pathogens and their clinical relevance. METHODS: This is a retrospective regional study involving paediatric departments and NICUs in Emilia-Romagna (Italy). Regional laboratory databases were searched from 2009 to 2012. Records of infants (aged 4 to 90 days) with a positive blood or cerebrospinal fluid (CSF) culture were retrospectively reviewed and analysed according to acquisition mode (whether hospital- or community-acquired). RESULTS: During the study period, there were 146,682 live births (LBs), with 296 patients experiencing 331 episodes of LOS (incidence rate: 2.3/1000 LBs). Brain lesions upon discharge from the hospital were found in 12.3% (40/296) of cases, with death occurring in 7.1% (23/296; 0.14/1000 LBs). With respect to full-term neonates, extremely preterm or extremely low birth weight neonates had very high risk of LOS and related mortality (> 100- and > 800-fold higher respectively). Hospital-acquired LOS (n = 209) was significantly associated with very low birth weight, extremely preterm birth, pneumonia, mechanical ventilation, and death (p< 0.01). At multivariate logistic regression analysis, catecholamine support (OR = 3.2), central venous line before LOS (OR = 14.9), and meningitis (OR = 44.7) were associated with brain lesions or death in hospital-acquired LOS (area under the ROC curve 0.81, H-L p = 0.41). Commonly identified pathogens included coagulase-negative staphylococci (CoNS n = 71, 21.4%), Escherichia coli (n = 50, 15.1%), Staphylococcus aureus (n = 41, 12.4%) and Enterobacteriaceae (n = 41, 12.4%). Group B streptococcus was the predominant cause of meningitis (16 of 38 cases, 42%). Most pathogens were sensitive to first line antibiotics. CONCLUSIONS: This study provides the first Italian data regarding late-onset sepsis (LOS) in all gestational age groups. Compared to full-term neonates, very high rates of LOS and mortality occurred in neonates with a lower birth weight and gestational age. Group B streptococcus was the leading cause of meningitis. Excluding CoNS, the predominant pathogens were Escherichia coli and Staphylococcus aureus. Neonates with hospital-acquired LOS had a worse outcome. Antibiotic associations, recommended for empirical treatment of hospital- or community-acquired LOS, were adequate.

Group B Streptococcus early-onset disease and observation of well-appearing newborns.

BACKGROUND: International guidelines lack a substantial consensus regarding management of asymptomatic full-term and late preterm neonates at risk for early-onset disease (EOS). Large cohorts of newborns are suitable to increase the understanding of the safety and efficacy of a given strategy. METHODS: This is a prospective, area-based, cohort study involving regional birth facilities of Emilia-Romagna (Italy). We compared cases of EOS (at or above 35 weeks' gestation) registered in 2003-2009 (baseline period: 266,646 LBs) and in 2010-2016, after introduction of a new strategy (serial physical examinations, SPEs) for managing asymptomatic neonates at risk for EOS (intervention period: 265,508 LBs). RESULTS: There were 108 cases of EOS (baseline period, n = 60; intervention period, n = 48). Twenty-two (20.4%) remained asymptomatic through the first 72 hours of life, whereas 86 (79.6%) developed symptoms, in most cases (52/86, 60.5%) at birth or within 6 hours. The median age at presentation was significantly earlier in the intrapartum antibiotic prophylaxis (IAP)-exposed than in the IAP-unexposed neonates (0 hours, IQR 0.0000-0.0000 vs 6 hours, IQR 0.0000-15.0000, p<0.001). High number of neonates (n = 531) asymptomatic at birth, exposed to intrapartum fever, should be treated empirically for each newborn who subsequently develops sepsis. IAP exposed neonates increased (12% vs 33%, p = 0.01), age at presentation decreased (median 6 vs 1 hours, p = 0.01), whereas meningitis, mechanical ventilation and mortality did not change in baseline vs intervention period. After implementing the SPEs, no cases had adverse outcomes due to the strategy, and no cases developed severe disease after 6 hours of life. CONCLUSIONS: Infants with EOS exposed to IAP developed symptoms at birth in almost all cases, and those who appeared well at birth had a very low chance of having EOS. The risk of EOS in neonates (asymptomatic at birth) exposed to intrapartum fever was low. Although definite conclusions on causation are lacking, our data support SPEs of asymptomatic newborns at risk for EOS. SPEs seems a safe and effective alternative to laboratory screening and empirical antibiotic therapy.

Strategies for preventing early-onset sepsis and for managing neonates at-risk: wide variability across six Western countries.

Objective: Group B streptococcus (GBS) early-onset sepsis (EOS) has declined after widespread intrapartum antibiotic prophylaxis. However, strategies for preventing EOS may differ across countries. The analysis of their strategies allows to compare the effectiveness of prevention in different countries and suggests opportunities for improvement. Methods: We compared six western countries. Prevention strategies, incidence rates of EOS and approaches for managing neonates at-risk were analysed. Countries were selected because of availability of recommendations for prevention and sufficient epidemiological data for comparison. Results: Five of six countries recommend antenatal vagino-rectal screening. The decline of GBS cases is relevant in most countries, particularly in those with a screening-based strategy, which have reached incidence rates from 0.1 to 0.3/1000 live births and zero or close to zero mortality in full-term newborns. The recommendation for managing asymptomatic neonates at risk for EOS varies according to gestational age and ranges from observation only to laboratory testing plus empirical antibiotics. Chorioamnionitis (suspected or confirmed) is the main indication for carry out laboratory testing and for administering empirical antibiotics. Conclusions: Wide variations exists in preventing EOS. They depend on national epidemiology of GBS infections, compliance, cost, and feasibility of the strategy. The extreme variability of approaches for managing neonates at risk for EOS reflects the even greater uncertainty regarding this issue, and may explain the persisting, great use of resources to prevent a disease that has become very rare nowadays.

Secondary prevention of early-onset sepsis: a less invasive Italian approach for managing neonates at risk.

Strategies to prevent early-onset sepsis (EOS) have led to a substantial decline in many countries. However, one of the most controversial topics in neonatology is the management of asymptomatic full-term and late preterm neonates at risk for EOS, and guidelines lack substantial consensus regarding this issue. A strategy for managing neonates, entirely based on serial physical examinations, has been developed in two Italian regions. This strategy seems safe, while reducing laboratory tests and unnecessary antibiotics. In the current commentary we provide area-based data concerning the prevention of EOS in 2 northern Italian regions, and we detail the results of their strategy for managing healthy-appearing newborns at risk for EOS.