Whole-Body Hypothermia vs Targeted Normothermia for Neonates With Mild Encephalopathy: A Multicenter Pilot Randomized Clinical Trial.

Importance: Although whole-body hypothermia is widely used after mild neonatal hypoxic-ischemic encephalopathy (HIE), safety and efficacy have not been evaluated in randomized clinical trials (RCTs), to our knowledge. Objective: To examine the effect of 48 and 72 hours of whole-body hypothermia after mild HIE on cerebral magnetic resonance (MR) biomarkers. Design, Setting, and Participants: This open-label, 3-arm RCT was conducted between October 31, 2019, and April 28, 2023, with masked outcome analysis. Participants were neonates at 6 tertiary neonatal intensive care units in the UK and Italy born at or after 36 weeks' gestation with severe birth acidosis, requiring continued resuscitation, or with an Apgar score less than 6 at 10 minutes after birth and with evidence of mild HIE on modified Sarnat staging. Statistical analysis was per intention to treat. Interventions: Random allocation to 1 of 3 groups (1:1:1) based on age: neonates younger than 6 hours were randomized to normothermia or 72-hour hypothermia (33.5 °C), and those 6 hours or older and already receiving whole-body hypothermia were randomized to rewarming after 48 or 72 hours of hypothermia. Main Outcomes and Measures: Thalamic N-acetyl aspartate (NAA) concentration (mmol/kg wet weight), assessed by cerebral MR imaging and thalamic spectroscopy between 4 and 7 days after birth using harmonized sequences. Results: Of 225 eligible neonates, 101 were recruited (54 males [53.5%]); 48 (47.5%) were younger than 6 hours and 53 (52.5%) were 6 hours or older at randomization. Mean (SD) gestational age and birth weight were 39.5 (1.1) weeks and 3378 (380) grams in the normothermia group (n = 34), 38.7 (0.5) weeks and 3017 (338) grams in the 48-hour hypothermia group (n = 31), and 39.0 (1.1) weeks and 3293 (252) grams in the 72-hour hypothermia group (n = 36). More neonates in the 48-hour (14 of 31 [45.2%]) and 72-hour (13 of 36 [36.1%]) groups required intubation at birth than in the normothermic group (3 of 34 [8.8%]). Ninety-nine neonates (98.0%) had MR imaging data and 87 (86.1%), NAA data. Injury scores on conventional MR biomarkers were similar across groups. The mean (SD) NAA level in the normothermia group was 10.98 (0.92) mmol/kg wet weight vs 8.36 (1.23) mmol/kg wet weight (mean difference [MD], -2.62 [95% CI, -3.34 to -1.89] mmol/kg wet weight) in the 48-hour and 9.02 (1.79) mmol/kg wet weight (MD, -1.96 [95% CI, -2.66 to -1.26] mmol/kg wet weight) in the 72-hour hypothermia group. Seizures occurred beyond 6 hours after birth in 4 neonates: 1 (2.9%) in the normothermia group, 1 (3.2%) in the 48-hour hypothermia group, and 2 (5.6%) in the 72-hour hypothermia group. Conclusions and Relevance: In this pilot RCT, whole-body hypothermia did not improve cerebral MR biomarkers after mild HIE, although neonates in the hypothermia groups were sicker at baseline. Safety and efficacy of whole-body hypothermia should be evaluated in RCTs. Trial Registration: ClinicalTrials.gov Identifier: NCT03409770.

Congenital diaphragmatic hernia survival in an English regional ECMO center.

Introduction: Congenital diaphragmatic hernia (CDH) remains a cause of neonatal death. Our aims are to describe contemporary rates of survival and the variables associated with this outcome, contrasting these with our study of two decades earlier and recent reports. Materials and methods: A retrospective review of all infants diagnosed in a regional center between January 2000 and December 2020 was performed. The outcome of interest was survival. Possible explanatory variables included side of defect, use of complex ventilatory or hemodynamic strategies (inhaled nitric oxide (iNO), high-frequency oscillatory ventilation (HFOV), extracorporeal membrane oxygenation (ECMO), and Prostin), presence of antenatal diagnosis, associated anomalies, birth weight, and gestation. Temporal changes were studied by measuring outcomes in each of four consecutive 63-month periods. Results: A total of 225 cases were diagnosed. Survival was 60% (134 of 225). Postnatal survival was 68% (134 of 198 liveborn), and postrepair survival was 84% (134 of 159 who survived to repair). Diagnosis was made antenatally in 66% of cases. Variables associated with mortality were the need for complex ventilatory strategies (iNO, HFOV, Prostin, and ECMO), antenatal diagnosis, right-sided defects, use of patch repair, associated anomalies, birth weight, and gestation. Survival has improved from our report of a prior decade and did not vary during the study period. Postnatal survival has improved despite fewer terminations. On multivariate analysis, the need for complex ventilation was the strongest predictor of death (OR=50, 95% CI 13 to 224, p<0.0001), and associated anomalies ceased to be predictive. Conclusions: Survival has improved from our earlier report, despite reduced numbers of terminations. This may be related to increased use of complex ventilatory strategies.

Diaphragm electrical activity during weaning of nasal high-flow therapy in preterm infants.

OBJECTIVE: To determine whether electrical activity of the diaphragm (Edi) changes with weaning nasal high-flow (HF) therapy in preterm infants according to a standardised protocol. DESIGN: Prospective observational cohort study. SETTING: Neonatal intensive care unit. PATIENTS: Preterm infants born at <32 weeks gestation, receiving nasal HF as part of routine clinical care. INTERVENTIONS: Infants recruited to the study had their HF weaned according to set clinical criteria. Edi was measured using a modified gastric feeding tube serially from baseline (pre-wean) to 24-hours post-wean. MAIN OUTCOME MEASURES: Change in Edi from baseline was measured at four time points up to 24 hours after weaning. Minimum Edi during expiration, maximum Edi during inspiration and amplitude of the Edi signal (Edidelta) were measured. Clinical parameters (heart rate, respiratory rate and fraction of inspired oxygen) were also recorded. RESULTS: Forty preterm infants were recruited at a mean corrected gestational age of 31.6 (±2.7) weeks. Data from 156 weaning steps were analysed, 91% of which were successful. Edi did not change significantly from baseline during flow reduction steps, but a significant increase in diaphragm activity was observed when discontinuing HF (median increase in Edidelta immediately post-discontinuation 1.7 µV (95% CI: 0.6 to 3.0)) and at 24 hours 1.9 µV (95% CI: 0.7 to 3.8)). No significant difference in diaphragm activity was observed between successful and unsuccessful weaning steps. CONCLUSIONS: A protocolised approach to weaning has a high probability of success. Edi does not change with reducing HF rate, but significantly increases with discontinuation of HF from 2 L/min.

Life-threatening bronchopulmonary dysplasia: a British Paediatric Surveillance Unit Study.

OBJECTIVES: To assess the minimum incidence of life-threatening bronchopulmonary dysplasia (BPD), defined as need for positive pressure respiratory support or pulmonary vasodilators at 38 weeks corrected gestational age (CGA), in infants born <32 weeks gestation in the UK and Ireland; and to describe patient characteristics, management and outcomes to 1 year. METHODS: Prospective national surveillance study performed via the British Paediatric Surveillance Unit from June 2017 to July 2018. Data were collected in a series of three questionnaires from notification to 1 year of age. RESULTS: 153 notifications met the case definition, giving a minimum incidence of 13.9 (95% CI: 11.8 to 16.3) per 1000 live births <32 weeks' gestation. Median gestation was 26.1 (IQR 24.6-28) weeks, and birth weight 730 g (IQR 620-910 g). More affected infants were male (95 of 153, 62%; p<0.05). Detailed management and outcome data were provided for 94 infants. Fifteen died at median age 159 days (IQR 105-182) or 49.6 weeks CGA (IQR 43-53). Median age last receiving invasive ventilation was 50 days (IQR 22-98) and total duration of pressure support for surviving infants 103 (IQR 87-134) days. Fifty-seven (60.6%) received postnatal steroids and 22 (23.4%) pulmonary vasodilators. Death (16%) and/or major neurodevelopmental impairment (37.3%) or long-term ventilation (23.4%) were significantly associated with need for invasive ventilation near term and pulmonary hypertension. CONCLUSIONS: This definition of life-threatening BPD identified an extremely high-risk subgroup, associated with serious morbidity and mortality. Wide variability in management was demonstrated, and future prospective study, particularly in key areas of postnatal steroid use and pulmonary hypertension management, is required.

Physiological effects of high-flow nasal cannula therapy in preterm infants.

OBJECTIVE: High-flow nasal cannula (HFNC) therapy is increasingly used in preterm infants despite a paucity of physiological studies. We aimed to investigate the effects of HFNC on respiratory physiology. STUDY DESIGN: A prospective randomised crossover study was performed enrolling clinically stable preterm infants receiving either HFNC or nasal continuous positive airway pressure (nCPAP). Infants in three current weight groups were studied: <1000 g, 1000-1500 g and >1500 g. Infants were randomised to either first receive HFNC flows 8-2 L/min and then nCPAP 6 cm H2O or nCPAP first and then HFNC flows 8-2 L/min. Nasopharyngeal end-expiratory airway pressure (pEEP), tidal volume, dead space washout by nasopharyngeal end-expiratory CO2 (pEECO2), oxygen saturation and vital signs were measured. RESULTS: A total of 44 preterm infants, birth weights 500-1900 g, were studied. Increasing flows from 2 to 8 L/min significantly increased pEEP (mean 2.3-6.1 cm H2O) and reduced pEECO2 (mean 2.3%-0.9%). Tidal volume and transcutaneous CO2 were unchanged. Significant differences were seen between pEEP generated in open and closed mouth states across all HFNC flows (difference 0.6-2.3 cm H2O). Infants weighing <1000 g received higher pEEP at the same HFNC flow than infants weighing >1000 g. Variability of pEEP generated at HFNC flows of 6-8 L/min was greater than nCPAP (2.4-13.5 vs 3.5-9.9 cm H2O). CONCLUSIONS: HFNC therapy produces clinically significant pEEP with large variability at higher flow rates. Highest pressures were observed in infants weighing <1000 g. Flow, weight and mouth position are all important determinants of pressures generated. Reductions in pEECO2 support HFNC's role in dead space washout.

Pulse oximetry screening for critical congenital heart disease: a comparative study of cohorts over 11 years.

Background: Pulse oximetry (POS) has been proposed as a screening tool for CCHD in newborn. The aim was to identify the effect of POS on the rate of diagnosis after discharge and survival to one year in cases with CCHD.Material and Methods: All cases of CCHD from three tertiary level hospitals in the Northern region of UK between 1st January 2001 and 31st December 2011 were identified from the Northern Congenital Abnormality Survey (NorCAS). A retrospective cohort study comparing screened and unscreened population for CCHD was undertaken. The main outcome was post discharge diagnosis rate and mortality at one year between the cohorts.Results: Total number of births during the 11 years was 138,176. A total of 147 cases had CCHD, 59 diagnosed postnatally. Five and eight cases were diagnosed after discharge in the screened and the unscreened cohort respectively. The rate of post-discharge diagnosis in the screened population was 7/100,000 and 13/100,000 in the unscreened population with a relative risk of 0.52 (CI 0.2 to 1.42). Mortality at one year in postnatally diagnosed cases was five and one in the screened and unscreened cohorts respectively.Conclusion: With good antenatal detection rates, POS did not have a statistically significant impact in identifying cases of CCHD, when added to the present screening process of antenatal ultrasound and postnatal examination. The same conclusion cannot be made for regions with lower antenatal detection rates; perhaps it may be more appropriate to consider pulse oximetry as a screening tool for hypoxemia of any cause.Brief rationaleThis is the first study evaluating the contemporaneous post-discharge diagnosis rate between screened and unscreened populations. The rate of post-discharge diagnosis was 7/100,000 in the screened and 13/100,000 in the unscreened populations. However, this did not achieve statistical significance and in a setting with high antenatal diagnosis a very large study would be required to demonstrate efficacy of POS.

Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study.

BACKGROUND: In neonatal encephalopathy, the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy. METHODS: We did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy. We excluded infants with life-threatening congenital malformations, syndromic disorders, neurometabolic diseases, or any alternative diagnoses for encephalopathy that were apparent within 6 h of birth. We obtained T1-weighted, T2-weighted, and diffusion-weighted MRI and thalamic proton MRS 4-14 days after birth. Clinical neurodevelopmental tests were done 18-24 months later. The primary outcome was the association between MR biomarkers and an adverse neurodevelopmental outcome, defined as death or moderate or severe disability, measured using a multivariable prognostic model. We used receiver operating characteristic (ROC) curves to examine the prognostic accuracy of the individual biomarkers. This trial is registered with ClinicalTrials.gov, number NCT01309711. FINDINGS: Between Jan 29, 2013, and June 25, 2016, we recruited 223 infants who all underwent MRI and MRS at a median age of 7 days (IQR 5-10), with 190 (85%) followed up for neurological examination at a median age of 23 months (20-25). Of those followed up, 31 (16%) had moderate or severe disability, including one death. Multiple logistic regression analysis could not be done because thalamic N-acetylaspartate (NAA) concentration alone accurately predicted an adverse neurodevelopmental outcome (area under the curve [AUC] of 0·99 [95% CI 0·94-1·00]; sensitivity 100% [74-100]; specificity 97% [90-100]; n=82); the models would not converge when any additional variable was examined. The AUC (95% CI) of clinical examination at 6 h (n=190) and at discharge (n=167) were 0·72 (0·65-0·78) and 0·60 (0·53-0·68), respectively, and the AUC of abnormal amplitude integrated EEG at 6 h (n=169) was 0·73 (0·65-0·79). On conventional MRI (n=190), cortical injury had an AUC of 0·67 (0·60-0·73), basal ganglia or thalamic injury had an AUC of 0·81 (0·75-0·87), and abnormal signal in the posterior limb of internal capsule (PLIC) had an AUC of 0·82 (0·76-0·87). Fractional anisotropy of PLIC (n=65) had an AUC of 0·82 (0·76-0·87). MRS metabolite peak-area ratios (n=160) of NAA-creatine (<1·29) had an AUC of 0·79 (0·72-0·85), of NAA-choline had an AUC of 0·74 (0·66-0·80), and of lactate-NAA (>0·22) had an AUC of 0·94 (0·89-0·97). INTERPRETATION: Thalamic proton MRS measures acquired soon after birth in neonatal encephalopathy had the highest accuracy to predict neurdevelopment 2 years later. These methods could be applied to increase the power of neuroprotection trials while reducing their duration. FUNDING: National Institute for Health Research UK.

Outcomes of infants with a birthweight less than or equal to 500 g in Northern England: 15 years experience.

AIM: We aimed to evaluate mortality and short-term neonatal morbidity of babies born ≤500 g cared for in the Northern Neonatal Network over a 15-year period. METHOD: Using regional databases, we identified all live-born babies ≥22 weeks gestation and ≤500 g, in North East England and North Cumbria from 1998 to 2012. We quantified major neonatal morbidities and survival to one year. RESULTS: We identified 104 live-born babies ≥22 weeks gestation and ≤500 g (birth prevalence 0.22/1000), of which 49 were admitted for intensive care. Overall one-year survival was 11%, but survival for those receiving intensive care was 22%. There was significant short-term neonatal morbidity in survivors, in particular retinopathy of prematurity and chronic lung disease. CONCLUSION: Survival of babies born weighing ≤500 g in this cohort remains poor despite advances in neonatal care, with considerable short-term neonatal morbidity in survivors. This could be due to a combination of attitudes and a rather conservative approach towards resuscitation and intensive care, and the intrinsic nature of these tiny babies.

Outcome of babies with no detectable heart rate before 10†minutes of age, and the effect of gestation.

OBJECTIVE: Current resuscitation guidelines suggest that it is reasonable to consider stopping resuscitation where no heart rate (cardiac activity) has been detected for 10 min in a newborn baby from birth. We aimed to determine the mortality rate and 2-year neurodevelopmental outcome of all babies born with no heart rate before 10 min of age where resuscitation was attempted in a tertiary referral centre over a 5-year period. DESIGN: To identify all babies with no heart rate before age 10 min we examined two groups:▸ All babies classified as live born who received cardiac massage at birth between January 2009 and December 2013.▸ All babies classified as stillborn between January 2009 and December 2013 where attempts were made at resuscitation beyond 10 min. RESULTS: 87 babies received cardiac massage. 81 babies were live born and 6 were classified as stillborn. Twenty-two babies had no heart rate before 10 min of age. Eight babies survived to 2-year follow-up. 6/11 term babies survived, 2/4 babies born between 32 weeks and 37 weeks survived, and no infants born less than 32 weeks survived (n=7). Of the survivors, 5/8 had a normal neurodevelopmental outcome at 2 years' age. One patient was lost to follow-up, while the other two patients had hemiplegia. CONCLUSIONS: Our results add to the body of evidence suggesting that having no heart rate before 10 min of age, in term babies, may not be an appropriate prompt to discontinue resuscitation.

Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study.

INTRODUCTION: Despite cooling, adverse outcomes are seen in up to half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Rigorous evaluation of these therapies in phase II trials using surrogate MR biomarkers may speed up their bench to bedside translation. A recent systematic review of single-centre studies has suggested that MR spectroscopy biomarkers offer the best promise; however, the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makers is not known. METHODS AND ANALYSIS: The MR scanners (3 T; Philips, Siemens, GE) in all the participating sites will be harmonised using phantom experiments and healthy adult volunteers before the start of the study. We will then recruit 180 encephalopathic infants treated with whole body cooling from the participating centres. MRI and spectroscopy will be performed within 2 weeks of birth. Neurodevelopmental outcomes will be assessed at 18-24 months of age. Agreement between MR cerebral biomarkers and neurodevelopmental outcome will be reported. The sample size is calculated using the 'rule of 10', generally used to calculate the sample size requirements for developing prognostic models. Considering 9 parameters, we require 9×10 adverse events, which suggest that a total sample size of 180 is required. ETHICS AND DISSEMINATION: Human Research Ethics Committee approvals have been received from Brent Research Ethics Committee (London), and from Imperial College London (Sponsor). We will submit the results of the study to relevant journals and offer national and international presentations. TRIAL REGISTRATION NUMBER: Clinical Trials.gov Number: NCT01309711.

Persistent pulmonary interstitial emphysema presenting as solitary lung cyst in a preterm infant.

Solitary unilateral lung cyst is an unusual finding in preterm infants. It may be difficult to distinguish acquired from congenital lung cysts clinically. The definitive diagnosis is histological; however, CT scan of the chest is a useful diagnostic tool. We present an extremely preterm infant with solitary lung cyst and background chronic lung disease. The initial chest x-rays showed solitary right lung cyst. At 6 weeks he required an escalation of ventilator support coupled with x-ray evidence of increased size of the cyst. CT scan confirmed large solitary cyst of the right lower lobe with evidence of compression and mediastinal shift, suspicious of congenital cystic adenomatoid malformation. The cyst was surgically removed in view of clinical deterioration. However, histology showed persistent pulmonary interstitial emphysema (PPIE). This case illustrates that in the context of prematurity PPIE can present as a solitary lung cyst and may require surgery.

Permanent and transient congenital hypothyroidism in preterm infants.

AIM: Transient fluctuations in thyroid function are well recognized in preterm infants. We wanted to assess TSH variation in babies with transient and permanent congenital hypothyroidism (CHT). METHODS: Whole bloodspot TSH data in preterm infants (<35 weeks; 2005-2010) were assessed, and infants with bloodspot TSH values >6 mU/L identified. Permanent CHT was defined as a requirement for thyroxine beyond 3 years of age. RESULTS: A first TSH sample was obtained from 5518 infants (median gestational age, 32 w; range, 22-35), with a second sample obtained from 5134 infants (median gestational age, 32 w; range, 22-35). Five infants had raised TSH concentrations on both occasions. Three of the five infants had a serum TSH >80 mU/L on second screen but two came off thyroxine beyond 3 years of age. All preterm babies with permanent or transient hypothyroidism were detected by the first TSH cut-off of 6 mU/L. Only one infant with a birth weight <1500 g remains on thyroxine treatment beyond 2 years of age. CONCLUSIONS: The incidence of permanent CHT in preterm infants is similar to term infants. Profound abnormalities of thyroid function can occur in preterm babies with transient hypothyroidism but both categories of hypothyroidism can be detected by a 'once-only' TSH screening strategy with a relatively low cut-off.