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.

Continuous non-invasive measurement of cardiac output in neonatal intensive care using regional impedance cardiography: a prospective observational study.

OBJECTIVES: To compare agreement between echocardiography and regional impedance cardiography (RIC)-derived cardiac output (CO), and to construct indicative normative ranges of CO for gestational age groups. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort observational study performed in a tertiary centre in London, UK, including neonates born between 25 and 42 weeks' gestational age. EXPOSURES: Neonates on the postnatal ward had 2 hours of RIC monitoring; neonates in intensive care had RIC monitoring for the first 72 hours, then weekly for 2 hours, with concomitant echocardiography measures. MAIN OUTCOMES AND MEASURES: RIC was used to measure CO continuously. Statistical analyses were performed using R (V.4.2.2; R Core Team 2022). RIC-derived CO and echocardiography-derived CO were compared using Pearson's correlations and Bland-Altman analyses. Differences in RIC-derived CO between infants born extremely, very and late preterm were assessed using analyses of variance and mixed-effects modelling. RESULTS: 127 neonates (22 extremely, 46 very, 29 late preterm and 30 term) were included. RIC and echocardiography-measured weight-adjusted CO were correlated (r=0.62, p<0.001) with a Bland-Altman bias of -31 mL/min/kg (limits of agreement -322 to 261 mL/min/kg). The RIC-derived CO fell over 12 hours, then increased until 72 hours after birth. The 72-hour weight-adjusted mean CO was higher in extremely preterm (424±158 mL/min/kg) compared with very (325±131 mL/min/kg, p<0.001) and late preterm (237±81 mL/min/kg, p<0.001) neonates; this difference disappeared by 2-3 weeks of age. CONCLUSIONS: RIC is valid for continuous, non-invasive CO measurement in neonates. Indicative normative CO ranges could help clinicians to make more informed haemodynamic management decisions, which should be explored in future studies. TRIAL REGISTRATION NUMBER: NCT04064177.

Sedaghatian spondylometaphyseal dysplasia in two siblings.

Sedaghatian type spondylometaphyseal dysplasia (SSMD) is a rare skeletal dysplasia with only 24 reported cases to date. Despite the limited literature available, evidence suggests this is a multi-system disorder, with neurological and cardiovascular abnormalities reported in addition to the skeletal features. We report a new family with two affected siblings and detailed phenotypic description of the affected proband. Diagnosis in the neonatal period led to retrospective genetic diagnosis of a previous affected pregnancy that was terminated due to severe ventriculomegaly. We suggest that a diagnosis of SSMD should be considered when shortened long bones are found in combination with significant brain abnormalities.

European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT).

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial.Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an "AVM" bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening:1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion.2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients.3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider.4) Any screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection of, or intervention on, a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly.We consider this nuanced Position Statement provides a helpful, evidence-based framework for informed discussions between healthcare providers and patients in an emotionally charged area.

Therapeutic hypothermia for mild neonatal encephalopathy: a systematic review and meta-analysis.

OBJECTIVES: To examine if therapeutic hypothermia reduces the composite outcome of death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). DATA SOURCE: MEDLINE, Cochrane database, Scopus and ISI Web of Knowledge databases, using 'hypoxic ischaemic encephalopathy', 'newborn' and 'hypothermia', and 'clinical trials' as medical subject headings and terms. Manual search of the reference lists of all eligible articles and major review articles and additional data from the corresponding authors of selected articles. STUDY SELECTION: Randomised and quasirandomised controlled trials comparing therapeutic hypothermia with usual care. DATA EXTRACTION: Safety and efficacy data extracted independently by two reviewers and analysed. RESULTS: We included the data on 117 babies with mild NE inadvertently recruited to five cooling trials (two whole-body cooling and three selective head cooling) of moderate and severe NE, in the meta-analysis. Adverse outcomes occurred in 11/56 (19.6%) of the cooled babies and 12/61 (19.7%) of the usual care babies (risk ratio 1.11 (95% CIs 0.55 to 2.25)). CONCLUSIONS: Current evidence is insufficient to recommend routine therapeutic hypothermia for babies with mild encephalopathy and significant benefits or harm cannot be excluded.

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.

Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic-ischaemic encephalopathy: a non-randomised cohort study.

OBJECTIVE: To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE). DESIGN: Non-randomised cohort study. SETTING: Eight tertiary neonatal units in the UK and the USA. PATIENTS: 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth. INTERVENTIONS: Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for <12 hours). MAIN OUTCOME MEASURES: MRI and MR spectroscopy (MRS) within 2 weeks after birth, and a neurodevelopmental outcome assessment at 2 years. RESULTS: The baseline characteristics in both groups were similar except for lower 10 min Apgar scores (p=0.02) in the cooled babies. Despite this, the mean (SD) thalamic NAA/Cr (1.4 (0.1) vs 1.6 (0.2); p<0.001) and NAA/Cho (0.67 (0.08) vs 0.89 (0.11); p<0.001) ratios from MRS were significantly higher in the cooled group. Cooled babies had lower white matter injury scores than non-cooled babies (p=0.02). Four (27%) non-cooled babies with mild HIE developed seizures after 6 hours of age, while none of the cooled babies developed seizures (p=0.008). Neurodevelopmental outcomes at 2 years were available in 40 (85%) of the babies. Adverse outcomes were seen in 2 (14.3%) non-cooled babies, and none of the cooled babies (p=0.09). CONCLUSIONS: Therapeutic hypothermia may have a neuroprotective effect in babies with mild HIE, as demonstrated by improved MRS biomarkers and reduced white matter injury on MRI. This may warrant further evaluation in adequately powered randomised controlled trials.

Perinatal network consensus guidelines on the resuscitation of extremely preterm infants born at <27 weeks' gestation.

In spite of recent advances in perinatal care and an increase in survival of extremely preterm infants over the last few years, there remains a lack of consensus about practical aspects of resuscitation of extremely preterm infants born before 27 weeks' gestation. With this in the background, the working group of one of the Perinatal Networks in London, UK, set out to conduct a survey to explore the opinions of the doctors and nurses on resuscitation practices of infants born before 27 weeks' gestation, with the aim of developing consensus guidelines. The working group emailed a questionnaire to all neonatal units within the Perinatal Network to seek the views of paediatric medical and nursing staff on resuscitation of infants born at <27 weeks' gestation. The questionnaire was returned anonymously by post. The responses highlighted the difference of opinion that currently exists amongst the clinicians and nurses across the world around the resuscitation practices of extremely preterm infants; yet at the same time, there seemed to be some consensus on certain issues. Based on the survey (questionnaire) results and already existing literature, the working group of the North West London Perinatal Network (NWLPN) produced and implemented specific consensus guidelines on practical aspects of resuscitation for infants born before 27 weeks' gestation for the network. The network plans to audit these guidelines in future and also produce a parent information leaflet explaining the relevance of these guidelines.