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.

Challenges in developing a consensus definition of neonatal sepsis.

Sepsis remains a leading cause of morbidity and mortality in the neonatal population, and at present, there is no unified definition of neonatal sepsis. Existing consensus sepsis definitions within paediatrics are not suited for use in the NICU and do not address sepsis in the premature population. Many neonatal research and surveillance networks have criteria for the definition of sepsis within their publications though these vary greatly and there is typically a heavy emphasis on microbiological culture. The concept of organ dysfunction as a diagnostic criterion for sepsis is rarely considered in neonatal literature, and it remains unclear how to most accurately screen neonates for organ dysfunction. Accurately defining and screening for sepsis is important for clinical management, health service design and future research. The progress made by the Sepsis-3 group provides a roadmap of how definitions and screening criteria may be developed. Similar initiatives in neonatology are likely to be more challenging and would need to account for the unique presentation of sepsis in term and premature neonates. The outputs of similar consensus work within neonatology should be twofold: a validated definition of neonatal sepsis and screening criteria to identify at-risk patients earlier in their clinical course. IMPACT: There is currently no consensus definition of neonatal sepsis and the definitions that are currently in use are varied.A consensus definition of neonatal sepsis would benefit clinicians, patients and researchers.Recent progress in adults with publication of Sepsis-3 provides guidance on how a consensus definition and screening criteria for sepsis could be produced in neonatology.We discuss common themes and potential shortcomings in sepsis definitions within neonatology.We highlight the need for a consensus definition of neonatal sepsis and the challenges that this task poses.

Gender disparities in preterm neonatal outcomes.

AIM: From birth to old age, males generally have poorer disease outcomes compared to females. Preterm infants display a marked gender disparity in disease outcomes, and the underlying mechanisms are not well delineated. Our aim was to review the literature on clinical outcomes between preterm infants of different genders and discuss the potential mechanisms underlying the differences observed. METHODS: A literature review was undertaken for experimental and clinical research related to gender differences in preterm outcomes. RESULTS: Preterm male infants appear to have consistently worse outcomes compared to females, and the aetiology of these differences, while mostly undetermined, is likely multifactorial. CONCLUSION: The male disadvantage in preterm outcomes is likely multifactorial with hormonal, genetic and immunological differences likely playing key roles. Gender is an important variable in preterm outcome and should be considered when designing clinical and experimental research.

A review of superior vena cava flow measurement in the neonate by functional echocardiography.

Neonatologists have begun using superior vena cava flow as assessed by functional echocardiography to facilitate real-time decision-making on cardiovascular care. This review aims to describe the basis of the technique, summarise the evidence for its use and compare the technique to existing clinical, biochemical and radiological techniques for assessing neonatal circulatory status. CONCLUSION: Although echocardiographic measurements of superior vena cava flow, like other measures of perfusion, are not perfect, their noninvasive nature and ability to facilitate real-time decision-making means that at present, they remain the best available methodology of monitoring central perfusion in the neonatal population.

Thyroid function testing in neonates born to women with hypothyroidism.

Our aim was to assess the utility of serum thyroxine and thyroid stimulating hormone performed at 10-14 days of life in diagnosing congenital hypothyroidism (CH) in babies born to mothers with hypothyroidism. This was a retrospective study of all babies born in a tertiary referral centre for neonatology over a 12-month period. Infants who had thyroid function testing (TFT) checked at 10-14 days of life because of maternal hypothyroidism during the period of study were included. The results of the newborn bloodspot and day 10-14 TFT were recorded along with whether or not patients were subsequently treated. Of the 319 patients included in the study, only two patients were found to have CH and in both cases the newborn blood spot had been abnormal. CONCLUSION: No extra cases of CH were detected from the thyroid test at 10-14 days and this practice should be discontinued due to the robust nature of existing newborn screening programmes. What is Known: • Congenital hypothyroidism(CH) is the commonest preventable cause of childhood intellectual impairment. • Family history of hypothyroidism has been implicated as a risk factor for CH. • CH has formed part of newborn screening since the 1970s. What is New: • There is no research recommending thyroid function testing at 10-14 days of life to detect CH in neonates born to mothers with hypothyroidism. • Thyroid function testing at 10-14 days of life does not improve diagnostic yield for CH in babies born to mothers with hypothyroidism. • Newborn blood spot remains the mainstay for accurate and timely diagnosis of CH.

Gender and sex hormone effects on neonatal innate immune function.

OBJECTIVES: Scientific evidence provides a widened view of differences in immune response between male and female neonates. The X-chromosome codes for several genes important in the innate immune response and neonatal innate immune cells express receptors for, and are inhibited by, maternal sex hormones. We hypothesized that sex differences in innate immune responses may be present in the neonatal population which may contribute to the increased susceptibility of premature males to sepsis. We aimed to examine the in vitro effect of pro-inflammatory stimuli and hormones in neutrophils and monocytes of male and female neonates, to examine the expression of X-linked genes involved in innate immunity and the miRNA profiles in these populations. METHODS: Preterm infants (n = 21) and term control (n = 19) infants were recruited from the Coombe Women and Infants University Hospital Dublin with ethical approval and explicit consent. The preterm neonates (eight female, 13 male) were recruited with a mean gestation at birth (mean ± SD) of 28 ± 2 weeks and corrected gestation at the time of sampling was 30 + 2.6 weeks. The mean birth weight of preterm neonates was 1084 ± 246 g. Peripheral blood samples were used to analyze immune cell phenotypes, miRNA human panel, and RNA profiles for inflammasome and inflammatory genes. RESULTS: Dividing neutrophil results by sex showed no differences in baseline CD11b between sexes among either term or preterm neonates. Examining monocyte CD11b by sex shows, that at baseline, total and classical monocytes have higher CD11b in preterm females than preterm males. Neutrophil TLR2 did not differ between sexes at baseline or following lipopolysaccharide (LPS) exposure. CD11b expression was higher in preterm male non-classical monocytes following Pam3CSK treatment when compared to females, a finding which is unique to our study. Preterm neonates had higher TLR2 expression at baseline in total monocytes, classical monocytes and non-classical monocytes than term. A sex difference was evident between preterm females and term females in TLR2 expression only. Hormone treatment showed no sex differences and there was no detectable difference between males and females in X-linked gene expression. Two miRNAs, miR-212-3p and miR-218-2-3p had significantly higher expression in preterm female than preterm male neonates. CONCLUSIONS: This study examined immune cell phenotypes and x-linked gene expression in preterm neonates and stratified according to gender. Our findings suggest that the responses of females mature with advancing gestation, whereas male term and preterm neonates have very similar responses. Female preterm neonates have improved monocyte activation than males, which likely reflects improved innate immune function as reflected clinically by their lower risk of sepsis. Dividing results by sex showed changes in preterm and term infants at baseline and following LPS stimulation, a difference which is reflected clinically by infection susceptibility. The sex difference noted is novel and may be limited to the preterm or early neonatal population as TLR2 expression on monocytes of older children does not differ between males and females. The differences shown in female and male innate immune cells likely reflect a superior innate immune defense system in females with sex differences in immune cell maturation. Existing human studies on sex differences in miRNA expression do not include preterm patients, and most frequently use either adult blood or cord blood. Our findings suggest that miRNA profiles are similar in neonates of opposite sexes at term but require further investigation in the preterm population. Our findings, while novel, provide only very limited insights into sex differences in infection susceptibility in the preterm population leaving many areas that require further study. These represent important areas for ongoing clinical and laboratory study and our findings represent an important contribution to exiting literature.

Correlation of fetal lung area with MRI derived pulmonary volume.

BACKGROUND: Neonatal chest-Xray (CXR)s are commonly performed as a first line investigation for the evaluation of respiratory complications. Although lung area derived from CXRs correlates well with functional assessments of the neonatal lung, it is not currently utilised in clinical practice, partly due to the lack of reference ranges for CXR-derived lung area in healthy neonates. Advanced MR techniques now enable direct evaluation of both fetal pulmonary volume and area. This study therefore aims to generate reference ranges for pulmonary volume and area in uncomplicated pregnancies, evaluate the correlation between prenatal pulmonary volume and area, as well as to assess the agreement between antenatal MRI-derived and neonatal CXR-derived pulmonary area in a cohort of fetuses that delivered shortly after the antenatal MRI investigation. METHODS: Fetal MRI datasets were retrospectively analysed from uncomplicated term pregnancies and a preterm cohort that delivered within 72 h of the fetal MRI. All examinations included T2 weighted single-shot turbo spin echo images in multiple planes. In-house pipelines were applied to correct for fetal motion using deformable slice-to-volume reconstruction. An MRI-derived lung area was manually segmented from the average intensity projection (AIP) images generated. Postnatal lung area in the preterm cohort was measured from neonatal CXRs within 24 h of delivery. Pearson correlation coefficient was used to correlate MRI-derived lung volume and area. A two-way absolute agreement was performed between the MRI-derived AIP lung area and CXR-derived lung area. RESULTS: Datasets from 180 controls and 10 preterm fetuses were suitable for analysis. Mean gestational age at MRI was 28.6 ± 4.2 weeks for controls and 28.7 ± 2.7 weeks for preterm neonates. MRI-derived lung area correlated strongly with lung volumes (p < 0.001). MRI-derived lung area had good agreement with the neonatal CXR-derived lung area in the preterm cohort [both lungs = 0.982]. CONCLUSION: MRI-derived pulmonary area correlates well with absolute pulmonary volume and there is good correlation between MRI-derived pulmonary area and postnatal CXR-derived lung area when delivery occurs within a few days of the MRI examination. This may indicate that fetal MRI derived lung area may prove to be useful reference ranges for pulmonary areas derived from CXRs obtained in the perinatal period.

Counting atoms in a deep optical microtrap.

We demonstrate a method to count small numbers of atoms held in a deep, microscopic optical dipole trap by collecting fluorescence from atoms exposed to a standing wave of light that is blue detuned from resonance. While scattering photons, the atoms are cooled by a Sisyphus mechanism that results from the spatial variation in light intensity. The use of a small blue detuning limits the losses due to light-assisted collisions, thereby making the method suitable for counting several atoms in a microscopic volume.

Cardiac Output Monitoring in Preterm Infants.

Maintaining optimal circulatory status is a key component of preterm neonatal care. Low-cardiac output (CO) in the preterm neonate leads to inadequate perfusion of vital organs and has been linked to a variety of adverse outcomes with heightened acute morbidity and mortality and adverse neurodevelopmental outcomes. Having technology available to monitor CO allows us to detect low-output states and potentially intervene to mitigate the unwanted effects of reduced organ perfusion. There are many technologies available for the monitoring of CO in the preterm neonatal population and while many act as useful adjuncts to aid clinical decision-making no technique is perfect. In this review, we discuss the relative merits and limitations of various common methodologies available for monitoring CO in the preterm neonatal population. We will discuss the ongoing challenges in monitoring CO in the preterm neonate along with current gaps in our knowledge. We conclude by discussing emerging technologies and areas that warrant further study.

Are different groups of patients with stroke more likely to be excluded from the new UK general medical services contract? A cross-sectional retrospective analysis of a large primary care population.

BACKGROUND: In April 2004, an incentive based contract was introduced to UK primary care. An important element of the new contract is the ability to exclude individuals from quality indicators for a variety of reasons (known as 'exception reporting'). Exception of patients with stroke or TIA from the recording and achievement of quality indicators may have important consequences in terms of stroke recurrence and mortality. METHODS: A cross-sectional retrospective analysis of anonymised patient data was performed using 312 Scottish primary care practices. RESULTS: Patients recorded as unsuitable for inclusion in the contract were more likely to be female (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.36-1.68), older (>75 years:OR 3.15, 95%CI 2.69-3.69), and have dementia (OR 4.40, 95%CI 3.57-5.43) when compared to those patients without such a code. Patients were less likely to be older (>75 years:OR 0.70, 95%CI 0.56-0.87) and were more likely to be from the most deprived areas of Scotland (Quintile 5: OR 2.02, 95%CI 1.50-2.70) if they refused to attend for review or did not reply to letters asking for attendance at primary care clinics. Patients with multiple co-morbidities were more likely to have exclusions for achieving diagnostic clinical targets such as cholesterol control (3 or more co-morbidities: OR 3.37, 95%CI 2.50-4.50). CONCLUSION: Scottish practices have appeared to use exception reporting appropriately by excluding patients who are older or have dementia. However, younger or more socio-economically deprived patients were more likely to be recorded as having refused to attend for review or not replying to letters asking for attendance at primary care clinics. It is important for primary care practices to identify and monitor these individuals so that all patients fully benefit from the implementation of an incentive based contract and receive appropriate clinical care to prevent stroke recurrence, further disability and mortality.

Ultrasound investigation of sacral dimples and other stigmata of spinal dysraphism.

OBJECTIVE: To assess whether there was any relationship between the number of clinical markers for spinal dysraphism and its presence on ultrasound and whether there was any relationship between the presence of an isolated sacral dimple and the presence of spinal dysraphism. Outcomes and further imaging were also examined. METHODS: All patients who underwent spinal ultrasound (SUS) in University Hospital Galway (UHG) over a 5-year period (2006-2011) were identified. Patients were excluded based on age (>14 years old excluded) and indication for imaging (only patients being investigated for suspected spinal dysraphism were included). Indications for imaging, ultrasound results and information on further imaging were accessed from the computerised radiology software in UHG. Statistical analysis was performed using SPSS-18. RESULTS: Data were analysed for 216 patients. A single clinical indication was recorded for 174 ultrasound requests, ≥2 indications for 42 requests. Nineteen of 216 (8.8%) ultrasound images were abnormal, 7 having spinal dysraphism. Multiple clinical indications were 6 times more likely to have dysraphism than those imaged on the basis of a single marker (OR 6.0, 95% CI 1.289 to 27.922, p=0.022), and there was no significant correlation between the presence of a sacral dimple and the presence of dysraphism (95% CI 0.71 to 6.622, p=0.722). CONCLUSIONS: SUS performed on the basis of multiple clinical indications is six times more likely to detect spinal dysraphism than imaging performed for isolated abnormalities or risk factors. Sacral dimple is a poor marker for occult spinal pathology.