Electrical Cardiometry during transition and short-term outcome in very preterm infants: a prospective observational study.

The purpose of this study is to evaluate the association of Electrical Cardiometry (EC)-derived cardiac output indexed to weight (CO) and its changes during the first 48 h in relation to adverse short-term outcome in very preterm infants. In this prospective observational study of preterm infants < 32 weeks gestational age (GA), the combined adverse outcome was defined as mortality or abnormal cranial ultrasound (any grade intracranial hemorrhage (ICH) or periventricular leukomalacia) within the first 2 weeks postnatally. Logistic regression models were used to investigate the association between median CO and outcome and mixed-effects models for the time trajectory of CO. In the absence of device-specific thresholds for low or high CO, no thresholds were used in our analysis. Fifty-three infants (median (IQR) GA 29.0 (25.4-30.6) weeks, birthweight 1020 (745-1505) g) were included in the analysis. Median CO was 241 (197-275) mL/kg/min for the adverse outcome and 198 (175-227) mL/kg/min for normal outcome (odds ratio (OR) (95% confidence interval (95% CI)), 1.01 (1.00 to 1.03); p = 0.028). After adjustment for GA, the difference was not significant (adjusted OR (95% CI), 1.01 (0.99 to 1.02); p = 0.373). CO trajectory did not differ by outcome (p = 0.352). A post hoc analysis revealed an association between CO time trajectory and ICH ≥ grade 2.          Conclusions: EC-derived CO estimates within 48 h postnatally were not independently associated with brain injury (any grade) or mortality in the first 14 days of life. CO time trajectory was found to be associated with ICH ≥ grade 2. What is Known: • Bioreactance-derived cardiac output indexed to bodyweight (CO) in the transitional period has been associated with adverse short-term outcome in preterm infants. What is New: • Electrical Cardiometry (EC)-derived CO measurements in very preterm infants during the transitional period are not independently associated with adverse outcome (death or ultrasound detected brain damage) within 2 weeks postnatally. • In the first 48 h EC-derived CO increases over time and is higher in extremely preterm infants compared to very preterm and differs from previously reported bioreactance-derived CO values.

Influence of innate immune activation on endocrine and metabolic pathways in infancy.

Prematurity is the leading cause of neonatal morbidity and mortality worldwide. Premature infants often require extended hospital stays, with increased risk of developing infection compared with term infants. A picture is emerging of wide-ranging deleterious consequences resulting from innate immune system activation in the newborn infant. Those who survive infection have been exposed to a stimulus that can impose long-lasting alterations into later life. In this review, we discuss sepsis-driven alterations in integrated neuroendocrine and metabolic pathways and highlight current knowledge gaps in respect of neonatal sepsis. We review established biomarkers for sepsis and extend the discussion to examine emerging findings from human and animal models of neonatal sepsis that propose novel biomarkers for early identification of sepsis. Future research in this area is required to establish a greater understanding of the distinct neonatal signature of early and late-stage infection, to improve diagnosis, curtail inappropriate antibiotic use, and promote precision medicine through a biomarker-guided empirical and adjunctive treatment approach for neonatal sepsis. There is an unmet clinical need to decrease sepsis-induced morbidity in neonates, to limit and prevent adverse consequences in later life and decrease mortality.

Nonstationary coupling between heart rate and perfusion index in extremely preterm infants in the first day of life.

Objective.Adaptation to the extra-uterine environment presents many challenges for infants born less than 28 weeks of gestation. Quantitative analysis of readily available physiological signals at the cotside could provide valuable information during this critical time. We aim to assess the time-varying coupling between heart rate (HR) and perfusion index (PI) over the first 24 h after birth and relate this coupling to gestational age (GA), inotropic therapy, and short-term clinical outcome.Approach.We develop new nonstationary measures of coupling to summarise both frequency- and direction-dependent coupling. These measures employ a coherence measure capable of measuring time-varying Granger casuality using a short-time information partial-directed coherence function. Measures are correlated with GA, inotropic therapy (yes/no), and outcome (adverse/normal).Main results.In a cohort of 99 extremely preterm infants (<28 weeks of gestation), we find weak but significant coupling in both the HR → PI and PI → HR directions (P< 0.05). HR → PI coupling increases with maturation (correlationr = 0.26;P = 0.011). PI → HR coupling increases with inotrope administration (r = 0.27;P = 0.007). And nonstationary features of PI → HR coupling are associated with adverse outcome (r = 0.27;P = 0.009).Significance.Nonstationary features are necessary to distinguish different coupling types for complex biomedical systems. Time-varying directional coupling between PI and HR provides objective and independent biomarkers of adverse outcome in extremely preterm infants.

Antimicrobial stewardship in the neonatal unit reduces antibiotic exposure.

AIM: Antimicrobial stewardship plays an important role in ensuring that the appropriate drug, dose, route and duration are employed to provide adequate treatment while minimising the risks of unnecessary antibiotic use. Surveillance of antibiotic use with prescriber feedback is recommended as a high-impact stewardship intervention. The aim of this study was to reduce unnecessary antimicrobial use in a neonatal unit. METHODS: A prospective audit was performed to assess compliance with antimicrobial guidelines. Following this, educational interventions were applied, electronic prescribing was introduced to the neonatal unit, and re-audit was performed. The primary outcome was a reduction in days of therapy (DOT). RESULTS: There were 312 neonatal admissions. There was a significant overall reduction in the primary outcome of DOT/1000 patient days from 572 to 417 DOT. This represents a 27% reduction in total antibiotic use. Prolonged antibiotic treatment courses >36 hours in negative sepsis evaluations were reduced from 82 DOT to 7.5 DOT. Similarly, treatment courses greater than five days for culture-negative sepsis were reduced from 46.5 DOT to 7 DOT. CONCLUSION: Monitoring antibiotic prescribing data can provide useful insights into the trends of antibiotic use and also inform clinicians of potential areas where antibiotic use may be safely reduced.

Monitoring cerebral oxygenation of preterm infants using a neonatal specific sensor.

INTRODUCTION: Cerebral oxygenation (rcSO2) monitoring in preterm infants may identify periods of cerebral hypoxia or hyperoxia. We hypothesised that there was a relationship between rcSO2 values and short term outcome in infants of GA < 32weeks. METHODS: RcSO2 values were recorded for the first 48 h of life using an INVOS monitor with a neonatal sensor. The association between cranial ultrasound scan measured brain injury and rcSO2 was assessed. RESULTS: 120 infants were included. Sixty-nine percent (83) of infants had a normal outcome (no IVH, no PVL, and survival at 1 month); less than one-quarter, 22% (26), had low grade IVH 1 or 2 (moderate outcome); and 9% (11) of infants had a severe outcome (IVH ≥ 3, PVL or died before 1 month age). rcSO2 values were lower for infants GA < 28weeks when compared with those GA 28-32, p < 0.001. There was no difference in absolute rcSO2 values between the three outcome groups but a greater degree of cerebral hypoxia was associated with preterm infants who had low grade 1 or 2 IVH. CONCLUSION: Infants of GA < 28 weeks have lower cerebral oxygenation in the first 2 days of life. A greater degree of hypoxia was seen in infants with grade 1 or 2 haemorrhage. Normative ranges need to be gestation specific.

Effects of therapeutic hypothermia on the gut microbiota and metabolome of infants suffering hypoxic-ischemic encephalopathy at birth.

Neonatal hypoxic ischemic encephalopathy (HIE) in the perinatal period can lead to significant neurological deficits in later life. Total body cooling (TBC) is a neuroprotective strategy used in the treatment of HIE and has been shown to reduce seizures and improve neurodevelopmental outcomes in treated infants. Little is known, however, about the effects of HIE/TBC on the developing gut microbiota composition and subsequent metabolic profile. Ten term infants with HIE who received TBC at 33.5°C for 72h were recruited. A control group consisted of nine healthy full term infants. Faecal samples were collected from both groups at 2 years of age and stored at -20°C. 16S rRNA amplicon Illumina sequencing was carried out to determine gut microbiota composition and 1H NMR analysis was performed to determine the metabolic profile of faecal water. The gut microbiota composition of the HIE/TBC infants were found to have significantly lower proportions of Bacteroides compared to the non-cooled healthy control group. Alpha diversity measures detected significantly lower diversity in microbial richness in the HIE/TBC infant group compared to the control infants (Shannon index, <0.05). High inter-individual variation was found in gut microbiota composition and metabolic profile of both groups. Initial principal coordinate analysis and hierarchal clustering of compounds on MetaboAnalyst 3.0 indicated no clear separation in the metabolic profile of these two infant groups. These results suggest that there is no significant impact on the gut microbial development of HIE/TBC infants compared to healthy infants at 2years of life. To our knowledge this is the first study to report the gut microbiota composition and metabolic profile of infants who have experienced HIE/TBC at birth.

A conservative treatment of patent ductus arteriosus in very low birth weight infants.

BACKGROUND: Treatment of the patent ductus arteriosus (PDA) in the preterm infant remains contentious. There are numerous options of the PDA management from early targeted treatment, late (symptomatic) treatment to no treatment at all. AIMS: To evaluate a three different PDA management approaches in very low birth weight (VLBW) infants. STUDY DESIGN: A retrospective observational time series study of three cohorts of VLBW infants born between 2004 and 2011. SUBJECTS: Infants in Symptomatic Treatment Group (STG) were echocardiographically evaluated when clinical signs suggestive of a PDA were present and treated if a haemodynamically significant PDA was confirmed. Early Targeted Group (ETG) underwent echocardiography within the first 48h and infants received ibuprofen if a large PDA was present. Conservative Treatment Group (CTG) was screened by echocardiography on day seven of life; patients with PDA were managed with increased positive end expiratory pressure and fluid restriction as a first line intervention. OUTCOMES: The primary outcome was medical and surgical treatment in the three time periods. Secondary outcomes included mortality, severe periventricular and intraventricular haemorrhage, respiratory distress syndrome and chronic lung disease. RESULTS: There were 138 infants diagnosed with PDA; 52 infants in STG, 52 infants in ETG and 34 infants in CTG. Ibuprofen therapy and ligation were less frequent in CTG. There was significantly decreased incidence of chronic lung disease in CTG compared to STG (18% vs. 51%; p=0.003) and to ETG (18% vs. 46%; p=0.02). There was no difference in the other short term outcomes. CONCLUSION: Conservative treatment of persistent ductus arteriosus in VLBW infants is a feasible option and future randomized trials of conservative management are warranted.

Emergency uncross-matched blood transfusions in a tertiary neonatal unit.

AIM: To determine the neonatal incidence, indications and outcomes following transfusions with emergency uncross-matched O-negative blood. METHODS: A five-year retrospective review in a single tertiary neonatal unit was conducted. The blood transfusion laboratory's database was analysed for all infants who had received an emergency released blood transfusion (ERBT) between January 2010 and December 2014. RESULTS: We calculated a total ERBT rate of 0.91 per 1000 live births (39/42 657) and a rate of 0.43 per 1000 in infants >34 weeks' gestation (18/41 637). A rate of 0.14 per 1000 births (6/42 657) received an ERBT as part of newborn stabilisation despite almost half of our infant cohort having intrapartum haemorrhages (n = 18, 46%). One-third (13/39) of all infants who were transfused died. Outcome varied depending on underlying aetiology, gestation and birthweight. The highest mortality was in preterm infants weighing <1000 g, of whom 70% died. CONCLUSION: This study establishes an ERBT rate of <1 per 1000 births, and 0.14 per 1000 infants received an ERBT as part of newborn delivery room stabilisation. ERBTs are associated with a high mortality rate. This study highlights the need for further research and guidelines that clarify the role of ERBTs in newborn stabilisations.

Timing of Therapeutic Hypothermia for Inborn and Outborn Infants with Neonatal Encephalopathy.

Therapeutic hypothermia is now the standard of care for infants with moderate to severe hypoxic ischaemic encephalopathy. Sixty-three infants received therapeutic hypothermia at Cork University Maternity Hospital (CUMH) from 2010-2014. Median gestational age was 40 weeks. Eighteen (29%) infants were Sarnat grade 3, 41(65%) grade 2 and 4(6%) grade 1. Nineteen outborn infants arrived in CUMH at a median (IQR) age of 310 (270, 420) minutes. Four (21%) outborn infants were within the target temperature range on arrival. Median (IQR) time (minutes) from birth to achieve target temperature was 136 (90, 195) for inborn and 300 (240, 360) for outborn infants (p < .01). Overall, 35 (56%) infants had electrical seizures, 42 (74%) had a normal MRI at a median (IQR) age of 7(6,9) days and the median(IQR) length of stay was 9 (7,11) days. Although no difference in seizures or MRI findings was seen, passive cooling does not achieve consistent temperature control for outborn infants.

Auscultate, palpate and tap: time to re-evaluate.

AIM: To determine the accuracy of current methods of heart rate (HR) assessment. METHODS: All participants palpated a simulated pulsating umbilicus (UMB), listened to a tapping rate (TAP) and auscultated a simulated HR (AUSC). A simulated HR of 54, 88 and 128 beats per minute (bpm) was randomised for all methods. RESULTS: Twenty-nine healthcare staff participated in this study. Correct assessment of HR of 54 bpm as being within the 0-59 range occurred in 17.2% UMB, 17.2% TAP and 31% AUSC and was obtained in <10 seconds by 48.3%, 65.5% and 62.1%, respectively. A rate of 88 bpm was correctly assessed as within the 60-100 range in 82.8% UMB, 79.3% TAP and 79.3% AUSC and was obtained in <10 seconds by 55.2%, 58.6% and 55.2%, respectively. A rate of 128 bpm was identified as >100 bpm by 96.6% UMB, 93.1% TAP, and 93.1% AUSC and was obtained in <10 seconds by 51.7%, 55.2% and 62.1%, respectively. CONCLUSION: Current methods in assessing rates below 60 bpm are inaccurate and may overestimate HR. We recommend that these methods alone should not be relied upon in neonatal resuscitation and objective assessment of heart rate should be readily available at all newborn resuscitations.

Perfusion index in the preterm infant immediately after birth.

AIM: To evaluate PI in preterm infants during the first 10 min of life. DESIGN/METHODS: An observational study was conducted in the delivery room on preterm infants (less than 32 week gestation). PI values were obtained from a pre ductal saturation probe placed on the right wrist. Analysis was performed on the first 10 min of data to investigate the correlation of PI with gestational age, heart rate, blood pressure, and lactate values. RESULTS: 33 infants with a median gestational age of 29 wks (IQR, 26-30 wks) and median birth weight of 1205 g (IQR, 925-1520 g) were included for analysis. The overall median PI value for the first 10 min was 1.3 (IQR, 0.86-1.68). There was no significant correlation found between delivery room PI and gestational age(r=0.28, 95% CI: -0.09, 0.59), lactate levels (r=-0.25, 95% CI: -0.62, 0.18) and blood pressure values (r=-0.18, 95% CI: -0.46, 0.20). An average correlation value of r=-0.417 (95% CI: - 0.531, -0.253) was found between PI and heart rate values. There was no statistical difference between the median of the median PI value over the first 5 min of life compared to the second 5 min (p=0.22). Variability, as quantified by the IQR, was higher in the first 5 min compared to the second 5 min: median of 0.5(IQR, 0.27, 0.92) vs 0.2(IQR, 0.10, 0.30) (p<0.00). CONCLUSIONS: Delivery room PI values are easily obtained, however, have significant variability over the first 5 min of life and may add little to delivery room assessment.

Current research suggests that the future looks brighter for cerebral oxygenation monitoring in preterm infants.

UNLABELLED: Brain injuries remain a significant problem for preterm infants, despite extensive physiological monitoring. Near infrared spectroscopy (NIRS) monitoring in the neonatal intensive care unit has to date remained limited to research activities. CONCLUSION: This review highlights the increasing clinical application of NIRS in delivery suites and neonatal units. Four randomised controlled trials incorporating NIRS monitoring suggest that the future may indeed be brighter for this technology in the care of very preterm infants.

Diastolic ventricular function improves during the first 48-hours-of-life in infants weighting <1250 g.

AIM: Few studies have focused on cardiac ventricular diastolic function in preterm neonates in the immediate post-natal period. This study evaluated Doppler-derived parameters of diastolic ventricular function in infants with birth weights of <1250 g during the transitional period. METHODS: This was a prospective observational study conducted in the Coombe Women and Infants University Hospital in Dublin, Ireland. Flow patterns on the mitral and tricuspid valve, isovolumic relaxation time (IVRT), left and right ventricular output and superior vena cava flow were measured in 22 infants with a birth weight of below 1250 g at six, 12, 24 and 48 h of age. RESULTS: Early filling peak velocity of the left and right ventricle increased significantly from 30.3 to 39.5 cm/sec and 26.6 to 32.1 cm/sec, respectively. IVRT of the right ventricle decreased from 70 to 57 ms, and there was a nonsignificant decrease in IVRT of the left ventricle from 61.6 to 54 ms over the first 48 h. CONCLUSION: We have demonstrated that parameters of diastolic ventricular function change significantly over the first 48 h of life in preterm infants <1250 g and that these changes may represent early diastolic dysfunction during the transitional period.

Peak systolic to end diastolic flow velocity ratio is associated with ductal patency in infants below 32†weeks of gestation.

BACKGROUND: Early diagnosis and effective treatment of the patent ductus arteriosus (PDA) in infants less than 32 weeks gestation remains contentious. OBJECTIVE: To determine which clinical and echocardiographic parameters are associated with PDA patency in preterm infants less than 32 weeks gestation. DESIGN/METHODS: This was a prospective cohort study. An echocardiography (echo) was performed within 12-48 h of birth and a follow-up echo at 1 month of life. Parental consent was obtained. RESULTS: 55 babies were enrolled. Median (range) gestation was 28 (24-31) weeks and birth weight 1090 g (470-1800 g). ECHO 1 demonstrated that 50 babies had a PDA present within 48 h of birth, of which 19 were large (≥2 mm) (36%) and 31 were small (59%) on colour Doppler assessment of duct diameter. Three babies died before 1 month. At 1 month 30 babies still had a PDA (58%), 10 of which were large (19%) and 19 were small (36%). Parameters significantly associated with large PDAs versus no PDA at 1 month were gestational age (26 weeks vs 30 weeks, p=0.002), birth weight (860 g vs 1290 g, p=0.007) and ventilator support at 48 h (80% vs 17%, p=0.001). Echo parameters revealed that ductal size on colour Doppler (2.5 mm vs 1.5 mm, p=0.003), end diastolic flow velocity (57 m/s vs 147 m/s, p<0.001) and peak systolic to end diastolic flow velocity ratio (2.29 vs 1.23, p=0.001) at 48 h were associated with large PDAs at 1 month. CONCLUSIONS: For infants less than 32 weeks gestation a peak systolic to end diastolic flow velocity ratio>2 within 48 h of birth is associated with a persistent large PDA at 1 month of age.

Quantitative or qualitative carbon dioxide monitoring for manual ventilation: a mannequin study.

AIM: To compare the effectiveness of an in-line EtCO2 detector (DET) and a quantitative EtCO2 detector (CAP), both attached to a t-piece resuscitator, during PPV via a face mask. METHODS: Paediatric trainees were randomly assigned to determine the method of PPV they commenced with (No device (ND), DET or CAP). Participants used each method for 2 min. Participants were video-recorded to determine the amount of effective ventilations delivered with each method. RESULTS: Twenty-three paediatric trainees provided a total of 6035 ventilations, and 91.2% were deemed effective. The percentages of median effective ventilations with the ND, the DET and the CAP were 91.0%, 93.0% and 94.0%, respectively. Fourteen (61%) of the trainees indicated a preference for the DET method, 8 (35%) for the CAP method, and 1 (4%) of the trainees indicated a preference for the ND method. Capnography was the most effective method per patient. CONCLUSION: There was no adverse effect with the addition of EtCO2 detectors. Trainees favoured methods of EtCO2 monitoring during ventilation. The NeoStat device was the preferred device by the majority. The greatest efficacy was achieved with the capnography device. Capnography may enhance face mask ventilation.

A review of carbon dioxide monitoring in preterm newborns in the delivery room.

INTRODUCTION: The physiologic adaptation to extra uterine life during the immediate neonatal period is unique. Many newborns require assistance in this adaptive process. Recent evidence now supports titrating oxygen to guide resuscitation but no guidance is provided on utilizing exhaled CO2 measurements. AIM: To review the current evidence relating to the use of CO2 monitoring in preterm newborns in the delivery room. METHODS: Search was performed using the Cochrane Central Register of Controlled Trials, MEDLINE (1966-2014) and PREMEDLINE, EMBASE (1980-2014), CINAHL (1982-2014), Web of Science (1975-2014) and the Oxford Database of Perinatal Trials. RESULTS: The search revealed 21 articles relating to CO2 detection, either quantitative or qualitative, in the newborn infant. The majority of these were observational studies, eight relating to CO2 detection as a means of confirming correct endotracheal tube placement in the newborn infant. The other indication is for mask ventilation, and there is one randomized control trial and four observational studies of CO2 detection during mask ventilation. The overall recommendation for CO2 detection for both clinical uses in the delivery suite is level B. DISCUSSION: CO2 detection may be of particular benefit for preterm infants in the delivery suite. However there is a need for further research into CO2 detection, in particular capnography, as a means of confirming effective PPV in neonatal resuscitation.

Management of hypotension in preterm infants (The HIP Trial): a randomised controlled trial of hypotension management in extremely low gestational age newborns.

BACKGROUND: Extremely preterm babies (delivered at <28 completed weeks of gestation) are frequently diagnosed with hypotension and treated with inotropic and pressor drugs in the immediate postnatal period. Dopamine is the most commonly used first-line drug. Babies who are treated for hypotension more frequently sustain brain injury, have long-term disability or die compared to those who are not. Despite the widespread use of drugs to treat hypotension in such infants, evidence for efficacy is lacking, and the effect of these agents on long-term outcomes is unknown. HYPOTHESIS: In extremely preterm babies, restricting the use of dopamine when mean blood pressure (BP) values fall below a nominal threshold and using clinical criteria to determine escalation of support ('restricted' approach) will result in improved neonatal and longer-term developmental outcomes. RESEARCH PLAN: In an international multi-centre randomised trial, 830 infants born at <28 weeks of gestation, and within 72 h of birth, will be allocated to 1 of 2 alternative treatment options (dopamine vs. restricted approach) to determine the better strategy for the management of BP, using a conventional threshold to commence treatment. The first co-primary outcome of survival without brain injury will be determined at 36 weeks' postmenstrual age and the second co-primary outcome (survival without neurodevelopmental disability) will be assessed at 2 years of age, corrected for prematurity. DISCUSSION: It is essential that appropriately designed trials be performed to define the most appropriate management strategies for managing low BP in extremely preterm babies.