Cardiovascular and cerebrovascular responses to cardio-respiratory events in preterm infants during the transitional period.

KEY POINTS: Non-invasive simultaneous multiparametric monitoring allows the in vivo evaluation of cerebral and cardiovascular haemodynamic responses to different types of recurrent episodes of intermittent hypoxia and/or bradycardia, also defined as cardio-respiratory events (CRE), in preterm neonates during postnatal transition. By decreasing left cardiac output, bradycardia further contributes to cerebral hypoxia during CRE. The presence of a haemodynamically significant patent ductus arteriosus results in a deeper impairment of cerebral oxygen status in response to CRE, whereas the brain-sparing remodelling of the fetal circulation resulting from placental insufficiency is associated with more favourable haemodynamic responses to intermittent hypoxia. During transition, the haemodynamic impact of CRE is influenced not only by the event type, but also by specific clinical features; this highlights the importance of developing individualized approaches to reduce the hypoxic burden in this delicate phase. ABSTRACT: The present observational prospective study aimed to investigate cerebral and cardiovascular haemodynamic responses to different types of cardio-respiratory events (CRE) in preterm infants during postnatal transition, as well as evaluate the impact of relevant clinical characteristics. Infants with gestational age (GA) <32 weeks and/or birth weight <1500 g were enrolled after birth. Cerebral oxygenation index (cTOI), fractional oxygen extraction (cFTOE), cardiac output (CO), cardiac contractility (iCON) and systemic vascular resistances (sVR) were simultaneously monitored over the first 72 h by near-infrared spectroscopy and electrical velocimetry. CRE were clustered into isolated bradycardia (IB), isolated desaturation (ID) and combined desaturation/bradycardia (DB). For each parameter, percentage changes from baseline (%Δ) were calculated. The impact of different CRE types and clinical variables on %Δ was evaluated with generalized estimating equations. In total, 1426 events were analysed. %ΔcTOI significantly differed among ID, IB and DB (P < 0.001), with the latter showing the greatest drop. %ΔcFTOE decreased significantly during DB (P < 0.001) and ID (P < 0.001) compared to IB. DB and IB were associated with more negative %ΔCO (P < 0.001) and more positive %ΔsVR (P < 0.001) compared to ID. A slight iCON reduction was observed during DB compared to ID (P = 0.043). Antenatal umbilical Doppler impairment, GA and the presence of a haemodynamically significant patent ductus arteriosus had a significant independent impact on %ΔcTOI, %ΔcFTOE and %ΔCO. During the transitional period, the haemodynamic responses to CRE are influenced by the event type and by specific neonatal characteristics, suggesting the importance of targeted individualized approaches for minimizing the risk of cerebral injury in the preterm population.

Cardiorespiratory Events in Infants Born Preterm during the Transitional Period.

OBJECTIVE: To investigate the features of cardiorespiratory events in infants born preterm during the transitional period, and to evaluate whether different neonatal characteristics may correlate with event type, duration, and severity. STUDY DESIGN: Infants with gestational age (GA) <32 weeks and/or birth weight <1500 g were enrolled in this observational prospective study. Heart rate (HR) and peripheral oxygen saturation (SpO2) were recorded continuously over the first 72 hours. Cardiorespiratory events of ≥10 seconds were clustered into isolated desaturation (SpO2 <85%), isolated bradycardia (HR <100 bpm or <70% of baseline), or combined desaturation/bradycardia and classified as mild, moderate, or severe. The daily incidences of isolated desaturation, isolated bradycardia, and combined desaturation and bradycardia were analyzed. The effects of relevant clinical variables on cardiorespiratory event type and severity were assessed using generalized estimating equations. RESULTS: Among the 1050 events analyzed, isolated desaturations were the most frequent (n = 625) and isolated bradycardias the least common (n = 171). The number of cardiorespiratory events increased significantly from day 1 to day 2 (P = .028). One in 5 events had severe characteristics; event severity was highest for combined desaturation and bradycardia (P < .001). Compared with other event types, the incidence of combined desaturation and bradycardia was inversely correlated with GA (P = .029) and was higher with the use of continuous positive airway pressure (P = .002). The presence of a hemodynamically significant patent ductus arteriosus was associated with the occurrence of isolated desaturations (P = .001) and with a longer duration of cardiorespiratory events (P = .003). CONCLUSIONS: Cardiorespiratory events during transition exhibit distinct types, duration, and severity. Neonatal characteristics are associated with the clinical features of these events, indicating that a tailored clinical approach may reduce the hypoxic burden in preterm infants aged 0-72 hours.

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.

Free radicals and neonatal encephalopathy: mechanisms of injury, biomarkers, and antioxidant treatment perspectives.

Neonatal encephalopathy (NE), most commonly a result of the disruption of cerebral oxygen delivery, is the leading cause of neurologic disability in term neonates. Given the key role of free radicals in brain injury development following hypoxia-ischemia-reperfusion, several oxidative biomarkers have been explored in preclinical and clinical models of NE. Among these, antioxidant enzyme activity, uric acid excretion, nitric oxide, malondialdehyde, and non-protein-bound iron have shown promising results as possible predictors of NE severity and outcome. Owing to high costs and technical complexity, however, their routine use in clinical practice is still limited. Several strategies aimed at reducing free radical production or upregulating physiological scavengers have been proposed for NE. Room-air resuscitation has proved to reduce oxidative stress following perinatal asphyxia and is now universally adopted. A number of medications endowed with antioxidant properties, such as melatonin, erythropoietin, allopurinol, or N-acetylcysteine, have also shown potential neuroprotective effects in perinatal asphyxia; nevertheless, further evidence is needed before these antioxidant approaches could be implemented as standard care.

Parechovirus infection causing sepsis-like illness in newborns: a NICU approach.

Human parechovirus (HpeV) is an important emerging infection in young infants, able to cause sepsis-like disease and meningoencephalitis, especially in newborns. Among the 19 identified genotypes, HPeV1, 3 and 6 are the most common types involved in human infections; HPeV3 is the type mainly responsible for neonatal infections and for infections involving the central nervous system. Signs and symptoms overlap with those of a bacterial infection and patients are usually treated with broad spectrum antibiotics. In the majority of cases lumbar puncture shows absence of pleocytosis, even in the presence of signs of meningitis. In these cases, cerebrospinal fluid cultures are negative for bacteria but, in the absence of diagnosis of viral infection, a full and unnecessary antibiotic cycle is often continued. Moreover, high sensitivity neuroimaging, i.e., magnetic resonance, and follow-up are often missed, thus resulting in substandard care. Availability of a real time PCR assay for HPeV RNA allows rapid and sensitive diagnosis as long as the disease is suspected. In this case study, we present cases of HPeV infections in newborns requiring neonatal intensive care admission, discuss their optimal management, and highlight the most relevant findings in the literature.

Carnitine longitudinal pattern in preterm infants <1800 g body weight: a case-control study.

BACKGROUND: The aim of this study is to investigate free carnitine (C0) and total acylcarnitine levels (AC) in preterm infants with BW < 1800 g and the relationship with neonatal and perinatal factors. METHODS: Ninety-three thousand two hundred and ninety-three newborns were screened between 2011 and 2013. Dried blood samples (DBS) were collected at 48-72 h, 14, and 30 days of age. We studied 92 consecutive preterm (BW < 1800 g) infants with low carnitine levels at 30 days of life (Group 1). As controls, we included the first 92 cases (BW < 1800 g) with normal carnitine levels (Group 2) and another 92 at or near-term newborns with BW > 1800 g (Group 3). RESULTS: Compared to 48-72 h levels, C0 and AC decreased at 14 and 30 days of life in Groups 1 and 2 (p < 0.001). In Group 2, the percentage of children with carnitine-free parenteral nutrition (PN) and BW < 1000 g was lower than in Group 1 (p < 0.001). Only in Group 2 did C0 increase at 30 days (p < 0.001). The multivariate regression analysis confirmed the influence of body weight and type of nutrition on C0 and AC. CONCLUSION: Body weight and type of nutrition influenced the carnitine longitudinal pattern.

Effect of Patent Ductus Arteriosus on Splanchnic Oxygenation at Enteral Feeding Introduction in Very Preterm Infants.

Because of its possible effect on mesenteric blood flow, the presence of a hemodynamically significant patent ductus arteriosus (PDA) is often of concern for the introduction of enteral feeds in preterm neonates. Near-infrared spectroscopy allows a continuous monitoring of splanchnic oxygenation (SrSO2) and may provide useful hemodynamic information. This observational study evaluated SrSO2 patterns in response to first feed administration in 50 preterm infants <32 weeks' gestation with different ductal status. According to their echocardiographic characteristics, the enrolled infants were divided into the following groups: pulsatile PDA with hemodynamically significant features, restrictive PDA, and no evidence of PDA. The presence of PDA, either with restrictive or hemodynamically significant characteristics, does not significantly affect SrSO2 response to enteral feeding introduction and is not associated with increased rates of gut complications. This finding may provide encouraging evidence in support of early enteral nutrition in very preterm infants with PDA.

Feed-related Splanchnic Oxygenation in Preterm Infants With Abnormal Antenatal Doppler Developing Gut Complications.

Preterm infants with antenatal absent or reversed end diastolic flow (AREDF) in umbilical arteries are at major risk for gastrointestinal (GI) complications, such as necrotizing enterocolitis, intestinal perforation and feeding intolerance. Near-infrared spectroscopy provides continuous monitoring of splanchnic oxygenation (SrSO2) and may represent a useful tool to predict GI outcomes in this high-risk population. This observational, pilot study assessed feed-related SrSO2 patterns at enteral feeding introduction and full enteral feeding (FEF) achievement in twenty AREDF infants with gestational age ≤34 weeks. Enrolled infants were divided into 2 groups according to the development versus lack of GI complications. Infants developing GI complications showed significantly lower SrSO2 and increased splanchnic oxygen extraction in response to enteral feeds at both enteral feeding introduction and FEF. The potential role of these findings in predicting GI complications in AREDF preterm infants seems promising and deserves further evaluation.

Lung ultrasound for the diagnosis of pneumonia in children with acute bronchiolitis.

BACKGROUND: Guidelines currently do not recommend the routine use of chest x-ray (CXR) in bronchiolitis. However, CXR is still performed in a high percentage of cases, mainly to diagnose or rule out pneumonia. The inappropriate use of CXR results in children exposure to ionizing radiations and increased medical costs. Lung Ultrasound (LUS) has become an emerging diagnostic tool for diagnosing pneumonia in the last decades. The purpose of this study was to assess the diagnostic accuracy and reliability of LUS for the detection of pneumonia in hospitalized children with bronchiolitis and to evaluate the agreement between LUS and CXR in diagnosing pneumonia in these patients. METHODS: We enrolled children admitted to our hospital in 2016-2017 with a diagnosis of bronchiolitis and undergone CXR because of clinical suspicion of concomitant pneumonia. LUS was performed in each child by a pediatrician blinded to the patient's clinical, laboratory and CXR findings. An exploratory analysis was done in the first 30 patients to evaluate the inter-observer agreement between a pediatrician and a radiologist who independently performed LUS. The diagnosis of pneumonia was established by an expert clinician based on the recommendations of the British Thoracic Society guidelines. RESULTS: Eighty seven children with bronchiolitis were investigated. A final diagnosis of concomitant pneumonia was made in 25 patients. Sensitivity and specificity of LUS for the diagnosis of pneumonia were 100% and 83.9% respectively, with an area under-the-curve of 0.92, while CXR showed a sensitivity of 96% and specificity of 87.1%. When only consolidation > 1 cm was considered consistent with pneumonia, the specificity of LUS increased to 98.4% and the sensitivity decreased to 80.0%, with an area under-the-curve of 0.89. Cohen's kappa between pediatrician and radiologist sonologists in the first 30 patients showed an almost perfect agreement in diagnosing pneumonia by LUS (K 0.93). CONCLUSIONS: This study shows the good accuracy of LUS in diagnosing pneumonia in children with clinical bronchiolitis. When including only consolidation size > 1 cm, specificity of LUS was higher than CXR, avoiding the need to perform CXR in these patients. Added benefit of LUS included high inter-observer agreement. TRIAL REGISTRATION: Identifier: NCT03280732 . Registered 12 September 2017 (retrospectively registered).

Vancomycin-induced red man syndrome presentation in a preterm infant.

A male infant born at 32 weeks' gestation with a birthweight of 1030 g was started on intravenous vancomycin for a femoral osteomyelitis. On day 7 of treatment, he developed an erythematous flushed rash, rapidly spreading from the head to trunk and extremities, and became markedly irritable; vancomycin infusion was promptly stopped, with subsequent skin clearance. Given the wide use of vancomycin for the treatment of neonatal infections, a good awareness of red man syndrome signs and symptoms in the neonatal population is fundamental to recognize this adverse drug reaction and manage its rare but possible life-threatening complications.

Chlorhexidine-Induced Chemical Burns in Very Low Birth Weight Infants.

Skin disinfection with chlorhexidine gluconate has not been standardized in preterm infants. We present 5 cases of chemical burns that occurred within the first 2 days of life in very low birth weight neonates after skin disinfection with aqueous and alcohol-based chlorhexidine solutions.

Splanchnic Oxygenation at First Enteral Feeding in Preterm Infants: Correlation With Feeding Intolerance.

Preterm infants are at risk of developing gastrointestinal complications such as feeding intolerance and necrotizing enterocolitis. Near-infrared spectroscopy (NIRS) provides continuous monitoring of abdominal oxygenation (ArSO2) and could help to predict gastrointestinal complications in preterm neonates. In this prospective observational study, ArSO2 patterns at first enteral feed were evaluated by NIRS in 61 clinically stable preterm infants. Splanchnic-cerebral oxygenation ratio, which is a marker of gut hypoxia, was also calculated. ArSO2 and splanchnic-cerebral oxygenation ratio were significantly lower both at baseline and after feeding administration in infants who later developed feeding intolerance (n = 23). NIRS could help the early prediction of gastrointestinal complications in high-risk preterm infants.

Immune and inflammatory response in bronchiolitis due to respiratory Syncytial Virus and Rhinovirus infections in infants.

Bronchiolitis is a common disease in infancy, mostly due to Respiratory Syncytial Virus and Rhinovirus. In addition to acute infection, viral bronchiolitis is responsible for sequelae including recurrent wheezing and asthma. The analysis of the viral characteristics and of the pathogenesis of the infection shows differences between the two viruses that may be helpful for the development of therapies and preventive strategies.

Does the Use of Pacifier Affect Gastro-Esophageal Reflux in Preterm Infants?

UNLABELLED: This crossover study showed that non-nutritive sucking, provided with a pacifier in 30 preterm infants, had no effect on acid and nonacid gastro-esophageal reflux evaluated by esophageal pH-impedance, and thus may be reasonably used in preterm neonates with symptoms of gastro-esophageal reflux. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02023216.

Influence of Intrapartum Antibiotic Prophylaxis for Group B Streptococcus on Gut Microbiota in the First Month of Life.

OBJECTIVES: The effect of intrapartum antibiotic prophylaxis (IAP) for group B Streptococcus (GBS) on bacterial colonization of the infant's gut has not been investigated extensively. We aimed to evaluate the effect of IAP on gut microbiota in healthy term infants, also exploring the influence of type of feeding. METHODS: Healthy term infants, whose mothers had been screened for GBS in late gestation, were divided into 2 groups: infants born to GBS-positive mothers who had received IAP versus controls. Neonatal fecal samples were collected at 7 and 30 days of life; DNA was extracted, and quantification of selected microbial groups (Lactobacillus spp, Bifidobacterium spp, and Bacteroides fragilis group) was performed by real-time PCR. RESULTS: A total of 84 infant-mother pairs were recruited. Bifidobacteria count was significantly lower in the IAP group at 7 days of life (median [interquartile range] 6.01 Log colony-forming unit per gram [5.51-6.98] vs 7.80 [6.61-8.26], P = 0.000). No differences in Bifidobacteria count at 30 days or in Lactobacilli and B fragilis counts at any time point were documented. Furthermore, at 7 days of life, infants who had not received IAP and were exclusively human milk-fed had higher counts of Bifidobacteria. Regardless of IAP treatment, infants fed exclusively human milk had higher Lactobacillus spp counts both at 7 and 30 days of life. CONCLUSIONS: IAP alters gut microflora by reducing the count of Bifidobacteria, which is further affected in infants receiving formula feeding. Whether these alterations could have long-term consequences on health and disease requires further investigation.

Linguistic features in children born very preterm at preschool age.

AIM: This cross-sectional study focused on the effect of very preterm (VPT) birth on language development by analysing phonological, lexical, grammatical, and pragmatic skills and assessing the role of cognitive and memory skills. METHOD: Sixty children (29 males, 31 females) born VPT (<32wks) aged 5 years were compared with 60 children with typical development. The linguistic assessment was performed by administering a battery of Italian tests for the evaluation of language; cognitive and memory skills were assessed by Raven's coloured progressive matrices and digit span subtest (Wechsler Intelligence Scale for Children [WISC-III]). RESULTS: Children born VPT showed delays in lexical (comprehension: z-score difference -1.18; 95% confidence interval [CI] -1.60 to -0.77; naming: -0.88; 95% CI -1.19 to -0.58) and pragmatic skills (comprehension: -0.76; 95% CI -1.02 to -0.49; narrative production: -0.47; 95% CI -0.72 to -0.23). Delays in phonology and grammar were less diffuse, involving productive skills (-1.09; 95% CI -1.64 to -0.54; -0.48; 95% CI -0.85 to -0.12, respectively), and were dependent by cognitive and memory skills. Lexical delays were more specific. INTERPRETATION: The linguistic profile of children born preterm is characterized by some abilities more impaired than others. This highlights the need of a linguistic assessment at the end of preschool age in order to plan a focused intervention aimed at improving lexical and pragmatic skills.

Evaluation of the effects of intrapartum antibiotic prophylaxis on newborn intestinal microbiota using a sequencing approach targeted to multi hypervariable 16S rDNA regions.

Different factors are known to influence the early gut colonization in newborns, among them the perinatal use of antibiotics. On the other hand, the effect on the baby of the administration of antibiotics to the mother during labor, referred to as intrapartum antibiotic prophylaxis (IAP), has received less attention, although routinely used in group B Streptococcus positive women to prevent the infection in newborns. In this work, the fecal microbiota of neonates born to mothers receiving IAP and of control subjects were compared taking advantage for the first time of high-throughput DNA sequencing technology. Seven different 16S rDNA hypervariable regions (V2, V3, V4, V6 + V7, V8, and V9) were amplified and sequenced using the Ion Torrent Personal Genome Machine. The results obtained showed significant differences in the microbial composition of newborns born to mothers who had received IAP, with a lower abundance of Actinobacteria and Bacteroidetes as well as an overrepresentation of Proteobacteria. Considering that the seven hypervariable regions showed different discriminant ability in the taxonomic identification, further analyses were performed on the V4 region evidencing in IAP infants a reduced microbial richness and biodiversity, as well as a lower number of bacterial families with a predominance of Enterobacteriaceae members. In addition, this analysis pointed out a significant reduction in Bifidobacterium spp. strains. The reduced abundance of these beneficial microorganisms, together with the increased amount of potentially pathogenic bacteria, may suggest that IAP infants are more exposed to gastrointestinal or generally health disorders later in age.

Nevirapine prophylaxis to prevent HIV-1 mother-to-child transmission: pharmacokinetic considerations in preterm infants.

Prophylaxis with zidovudine and 3 doses of nevirapine (NVP) is recommended for infants born to HIV-1 infected untreated mothers to prevent HIV-1 mother-to-child transmission. However little is known about NVP pharmacokinetics in neonates, mostly in preterm infants. We performed therapeutic monitoring of NVP plasma concentrations in a 32-week preterm HIV-1 exposed infant born to an infected untreated mother. With the recommended regimen, an intense NVP exposure was observed, with NVP plasma levels exceeding the target concentration by up to 40 times, suggesting that when a laboratory assessment of NVP plasma concentrations is available, it may be useful to monitor and optimize drug exposure.

Evaluation of a new protocol for retrospective diagnosis of congenital toxoplasmosis by use of Guthrie cards.

The aim of this study was to assess the diagnostic value of IgM Western blotting (WB), IgA enzyme immunoassay (EIA), and DNA amplification by real-time PCR on Guthrie cards to retrospectively establish the diagnosis of congenital toxoplasmosis (CT). To this purpose, Guthrie cards were collected from 18 infants born to mothers with primary Toxoplasma gondii infection during pregnancy. Moreover, the analytical sensitivity of T. gondii PCR was assessed by testing mock dried blood specimens set up with several known DNA dilutions. IgM WB was demonstrated to be the most sensitive method. When the results of T. gondii DNA detection and specific IgM recovery were combined, retrospective CT diagnosis by using Guthrie cards was established in 3 out of 6 infected infants (sensitivity, 50%; 95% confidence interval, 26.8% to 73.2%). No positive PCR or serologic results were found in the group of 12 uninfected infants, demonstrating the excellent specificity of the three methods (95% confidence interval, 78.1% to 99.5%). The findings of the present study suggest that, in cases of missed diagnosis of CT at birth, analysis of Guthrie cards for children with compatible clinical findings after the perinatal period, in particular the combination of recovery of specific IgM antibodies and T. gondii DNA amplification, could be helpful. Nevertheless, since suboptimal conditions of storage of dried blood specimens can seriously affect sensitivity, negative results cannot rule out CT diagnosis. In contrast, because of the excellent specificity shown by IgM serologic testing and T. gondii DNA amplification on Guthrie cards, positive results obtained by either of the two methods should be considered diagnostic.

Cardiorespiratory events with bolus versus continuous enteral feeding in healthy preterm infants.

We evaluated the effects of bolus vs continuous tube feeding on cardiorespiratory events, detected by polysomnographic monitoring, in healthy preterm infants. Continuous tube feeding resulted in a significant increase of apneas and apneas-related hypoxic episodes compared with bolus feeding.