Prophylactic Oropharyngeal Surfactant for Preterm Newborns at Birth: A Randomized Clinical Trial.

Importance: Preterm newborns at risk of respiratory distress syndrome are supported with continuous positive airway pressure (CPAP). Many newborns worsen despite CPAP and are intubated for surfactant administration, an effective therapy for treatment of respiratory distress syndrome. Endotracheal intubation is associated with adverse effects. Pharyngeal administration of surfactant to preterm animals and humans has been reported as an alternative. Objective: To assess whether giving prophylactic oropharyngeal surfactant to preterm newborns at birth would reduce the rate of intubation for respiratory failure. Design, Setting, and Participants: This unblinded, parallel-group randomized clinical trial (Prophylactic Oropharyngeal Surfactant for Preterm Infants [POPART]) was conducted from December 17, 2017, to September 11, 2020, at 9 tertiary neonatal intensive care units in 6 European countries. Newborns born before 29 weeks of gestation without severe congenital anomalies, for whom intensive care was planned, were eligible for inclusion. The data were analyzed from July 27, 2022, to June 20, 2023. Intervention: Newborns were randomly assigned to receive oropharyngeal surfactant at birth in addition to CPAP or CPAP alone. Randomization was stratified by center and gestational age (GA). Main Outcomes and Measures: The primary outcome was intubation in the delivery room for bradycardia and/or apnea or in the neonatal intensive care unit for prespecified respiratory failure criteria within 120 hours of birth. Caregivers were not masked to group assignment. Results: Among 251 participants (mean [SD] GA, 26 [1.5] weeks) who were well matched at study entry, 126 (69 [54.8%] male) with a mean (SD) birth weight of 858 (261) grams were assigned to the oropharyngeal surfactant group, and 125 (63 [50.4%] male) with a mean (SD) birth weight of 829 (253) grams were assigned to the control group. The proportion of newborns intubated within 120 hours was not different between the groups (80 [63.5%) in the oropharyngeal surfactant group and 81 [64.8%] in the control group; relative risk, 0.98 [95% CI, 0.81-1.18]). More newborns assigned to the oropharyngeal surfactant group were diagnosed with and treated for pneumothorax (21 [16.6%] vs 8 [6.4%]; P = .04). Conclusions and Relevance: This randomized clinical trial found that administration of prophylactic oropharyngeal surfactant to newborns born before 29 weeks' GA did not reduce the rate of intubation in the first 120 hours of life. These findings suggest that administration of surfactant into the oropharynx immediately after birth in addition to CPAP should not be routinely used. Trial Registration: EudraCT: 2016-004198-41.

Long-Term Effect of Switching From an Anti-CGRP Receptor to an Anti-CGRP Ligand Antibody in Treatment-Refractory Chronic Migraine: A Prospective Real-World Analysis.

In migraine patients with a poor response to a calcitonin gene-related peptide monoclonal antibody against the receptor, switching to a calcitonin gene-related peptide monoclonal antibodies against the ligand may be beneficial. This was a long-term real-world prospective analysis conducted in treatment-refractory chronic migraine patients coming from two large tertiary referral headache centres, who did not achieve a meaningful response to erenumab and were switched to fremanezumab. Responders to fremanezumab were considered those who achieved at least 30% reduction in monthly migraine days by month 3, compared to the post-erenumab baseline. Secondary efficacy and disability outcomes were analysed. Thirty-nine patients (female n = 32, 82.1%; median age: 49 years old, IQR = 29.0-56.0) were included. After three months of treatment with fremanezumab, ten out of 39 patients (25.6%) were considered responders. Four of the 11 patients who continued fremanezumab became responders at month 6, increasing the number of responders to 14 patients (35.9%). Responders received a median of 12 injections (IQR = 9.0-18.0) at the time of the analysis. After the last treatment, 13 patients (33.3%) remained responders. The number of mean monthly migraine days significantly decreased from 21.4 at baseline (IQR = 10.7-30.0) to 8.6 (IQR = 3.8-13.9) at the last follow-up. Painkillers intake and HIT-6 score were significantly reduced at the last follow-up. About 1/3 of patients with treatment refractory chronic migraine who have a disappointing response to erenumab and switch to fremanezumab, obtained a meaningful and sustained improvement of their migraine load over time, supporting the appropriateness of this therapeutic approach in clinical practice.

Cerebrovascular reactivity measurements using 3T BOLD MRI and a fixed inhaled CO2 gas challenge: Repeatability and impact of processing strategy.

Introduction: Cerebrovascular reactivity (CVR) measurements using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) are commonly used to assess the health of cerebral blood vessels, including in patients with cerebrovascular diseases; however, evidence and consensus regarding reliability and optimal processing are lacking. We aimed to assess the repeatability, accuracy and precision of voxel- and region-based CVR measurements at 3 T using a fixed inhaled (FI) CO2 stimulus in a healthy cohort. Methods: We simulated the effect of noise, delay constraints and voxel- versus region-based analysis on CVR parameters. Results were verified in 15 healthy volunteers (28.1±5.5 years, female: 53%) with a test-retest MRI experiment consisting of two CVR scans. CVR magnitude and delay in grey matter (GM) and white matter were computed for both analyses assuming a linear relationship between the BOLD signal and time-shifted end-tidal CO2 (EtCO2) profile. Results: Test-retest repeatability was high [mean (95% CI) inter-scan difference: -0.01 (-0.03, -0.00) %/mmHg for GM CVR magnitude; -0.3 (-1.2,0.6) s for GM CVR delay], but we detected a small systematic reduction in CVR magnitude at scan 2 versus scan 1, accompanied by a greater EtCO2 change [±1.0 (0.4,1.5) mmHg] and lower heart rate [-5.5 (-8.6,-2.4] bpm]. CVR magnitude estimates were higher for voxel- versus region-based analysis [difference in GM: ±0.02 (0.01,0.03) %/mmHg]. Findings were supported by simulation results, predicting a positive bias for voxel-based CVR estimates dependent on temporal contrast-to-noise ratio and delay fitting constraints and an underestimation for region-based CVR estimates. Discussion: BOLD CVR measurements using FI stimulus have good within-day repeatability in healthy volunteers. However, measurements may be influenced by physiological effects and the analysis protocol. Voxel-based analyses should be undertaken with care due to potential for systematic bias; region-based analyses are more reliable in such cases.

Two-year effectiveness of erenumab in resistant chronic migraine: a prospective real-world analysis.

BACKGROUND: Controlled and real-world evidence have demonstrated the efficacy of calcitonin gene related peptide (CGRP) monoclonal antibodies (MABs) in migraine. However, data on the over-one-year sustained effectiveness of CGRP MABs in resistant chronic migraine (CM) is sparse.  METHODS: This is a two-year real-world prospective analysis of an ongoing single centre audit conducted in patients with resistant CM. Patients received monthly erenumab for six months before assessing its effectiveness. Responders were considered those who achieved at least 30% reduction in monthly migraine days (MMD) by month 6, compared to baseline. Secondary outcomes were also analysed, including changes of the Headache Impact Test version 6 (HIT-6). RESULTS: One hundred sixty-four patients [135 (82.3%) females; mean age 46 SD 14) years] were included in the audit and 160 patients analysed. Patients had failed a mean of 8.4 preventive treatments at baseline. At month 6, 76 patients (48%) were 30% responders to erenumab, 50 patients (31%) were 50% responders and 25 (15%) were 75% responders. The mean reduction in MMD at month 6 was 7.5 days compared to baseline (P < 0.001). At month 12 and month 18, 61 patients (38%) and 52 patients (33%) remained 30% responders respectively. At month 24, 36 patients (23%) remained 30% responders, 25 patients (16%) and 13 patients (8%) were respectively 50% and 75% responders. Compared to 95% of patients at baseline, at months 6, 12 and 24, 46%, 29% and 16% of responders respectively had severe disability. At least one adverse event at month 6, 12, 18 and 24 was reported by 49%, 19%, 11% and 3% of patients. By month 6, 13% of patients discontinued the treatment because of side effects, often constipation. CONCLUSIONS: Long-term sustained effectiveness of erenumab was reported only by a minority of resistant CM patients. Although more research in resistant migraine is needed, Erenumab can provide long-term meaningful reduction in migraine load and migraine-related disability in some patients.

Research in the Delivery Room: Can You Tell Me It's Evolution?

Many of the recommendations for newborn care in the delivery room (DR) are based on retrospective observational studies, preclinical studies of mannequins or animal models, and expert opinion. Conducting DR research is challenging. Many deliveries occur in fraught circumstances with little prior warning, making it difficult to get prospective consent from parents and buy-in from clinicians. Many DR interventions are difficult to mask for the purpose of a clinical trial and it is not easy to identify appropriate outcomes for studies that are sufficiently "short-term" that they are likely to be influenced by the intervention, yet sufficiently "long-term" to be considered clinically important. However, despite these challenges, much information has been accrued from clinical studies in recent years. In this article, we outline our experience of conducting clinical research in the DR. In our initial studies almost 20 years ago, we found wide variation in the equipment used both nationally and internationally, reflecting the paucity of evidence to support practice. This started a journey that has included many observational studies and randomized controlled trials that have attempted to refine how we care for newborn infants in the DR. Each has given further information and, inevitably, raised many more questions about the approach to caring for newborns in the DR.

Effectiveness of Alberta Family-Integrated Care on Neonatal Outcomes: A Cluster Randomized Controlled Trial.

Family-Integrated Care (FICare) empowers parents to play an active role as a caregiver for their infant in the neonatal intensive care unit (NICU). This model of care is associated with improved neonatal outcomes, such as improved weight gain and higher breastfeeding rates at discharge in infants admitted to level III NICUs; however, its effectiveness in level II NICUs remains unproven. The objective of this study was to evaluate the effectiveness of the model on neonatal outcomes in a cluster randomized controlled trial conducted in 10 level II NICUs randomized to Alberta FICare or standard care. Mothers and their preterm infants born between 32+0 and 34+6 weeks' gestational age were included. The primary outcome was the proportion of infants who regained their birth weight (BW) after 14 days of life. The analysis included 353 infants/308 mothers at Alberta FICare sites and 365 infants/306 mothers at standard care sites. There was no difference in the proportion of infants who had regained their BW by 14 days between the groups. A lack of perceived improved weight gain trajectory for those in the FICare group is attributed to a shorter length of hospital stay and infants being discharged prior to regaining BW.

Tensor-structured decomposition improves systems serology analysis.

Systems serology provides a broad view of humoral immunity by profiling both the antigen-binding and Fc properties of antibodies. These studies contain structured biophysical profiling across disease-relevant antigen targets, alongside additional measurements made for single antigens or in an antigen-generic manner. Identifying patterns in these measurements helps guide vaccine and therapeutic antibody development, improve our understanding of diseases, and discover conserved regulatory mechanisms. Here, we report that coupled matrix-tensor factorization (CMTF) can reduce these data into consistent patterns by recognizing the intrinsic structure of these data. We use measurements from two previous studies of HIV- and SARS-CoV-2-infected subjects as examples. CMTF outperforms standard methods like principal components analysis in the extent of data reduction while maintaining equivalent prediction of immune functional responses and disease status. Under CMTF, model interpretation improves through effective data reduction, separation of the Fc and antigen-binding effects, and recognition of consistent patterns across individual measurements. Data reduction also helps make prediction models more replicable. Therefore, we propose that CMTF is an effective general strategy for data exploration in systems serology.

Relationship between inferior frontal sulcal hyperintensities on brain MRI, ageing and cerebral small vessel disease.

Raised signal in cerebrospinal fluid (CSF) on fluid-attenuated inversion recovery (FLAIR) may indicate raised CSF protein or debris and is seen in inferior frontal sulci on routine MRI. To explore its clinical relevance, we assessed the association of inferior frontal sulcal hyperintensities (IFSH) on FLAIR with demographics, risk factors, and small vessel disease markers in three cohorts (healthy volunteers, n=44; mild stroke patients, n=105; older community-dwelling participants from Lothian birth cohort 1936, n=101). We collected detailed clinical data, scanned all subjects on the same 3T MRI scanner and 3-dimensional FLAIR sequence and developed a scale to rate IFSH. In adjusted analyses, the IFSH score increased with age (per 10-year increase; OR 1.69; 95% CI, 1.42-2.02), and perivascular spaces score in centrum semiovale in stroke patients (OR 1.73; 95% CI, 1.13-2.69). Since glymphatic CSF clearance declines with age and drains partially via the cribriform plate to the nasal lymphatics, IFSH on 3T MRI may be a non-invasive biomarker of altered CSF clearance and justifies further research in larger, more diverse samples.

Randomised study of heart rate measurement in preterm newborns with ECG plus pulse oximetry versus oximetry alone.

AIM: To determine whether the IntelliVue monitor (ECG plus Masimo pulse oximeter (PO)) displays heart rate (HR) at birth more quickly than Nellcor PO (PO alone) among infants of 29-35 weeks' gestational age. METHODS: Unmasked parallel group randomised (1:1) study. RESULTS: We planned to enrol 100 infants; however, the study was terminated due to the COVID-19 pandemic when 39 infants had been enrolled (17 randomised to IntelliVue, 22 to Nellcor). We found no differences between the groups in the time to first HR display (median (IQR) IntelliVue ECG 49 (33, 71) vs Nellcor 47 (37, 86) s, p>0.999), in the proportion who had a face mask applied for breathing support, or in the time at which it was applied. Infants monitored with IntelliVue were handled more frequently and for longer. CONCLUSION: IntelliVue ECG did not display HR more quickly than Nellcor PO in preterm infants. We found no differences in the rate of or time to intervention between groups. Our study was terminated early so these findings should be interpreted with caution. TRIAL REGISTRATION NUMBER: ISRCTN16473881.

Initiation of respiratory support for extremely preterm infants at birth.

Neonatal resuscitation algorithms recommend assessing breathing and heart rate (HR) of newborns and giving respiratory support when one or both are unsatisfactory. Recommendations also state that preterm infants may be supported with continuous positive airway pressure rather than routinely intubated for positive pressure ventilation (PPV). We wished to describe the prevalence and time of initiation of respiratory support of extremely preterm and extremely low birthweight (ELBW) infants at our hospital. We reviewed videos of 55 infants. Although most were breathing, practically all newly born extremely preterm ELBW infants were given respiratory support soon after arrival to the resuscitation cot. For the majority, this was done without knowing the HR. The majority received PPV; again, this was often done without knowing the HR. A quarter of infants were managed without any PPV.

Study protocol for the POPART study-Prophylactic Oropharyngeal surfactant for Preterm infants: A Randomised Trial.

INTRODUCTION: Many preterm infants develop respiratory distress syndrome (RDS), a condition characterised by a relative lack of surfactant. Endotracheal surfactant therapy revolutionised the care of preterm infants in the 1990s. However, supporting newborns with RDS with continuous positive airway pressure (CPAP) and reserving endotracheal surfactant for those who develop respiratory failure despite CPAP yield better results than intubating all infants for surfactant. Half of preterm infants born before 29 weeks gestation initially managed with CPAP are intubated for surfactant. Intubation is difficult to learn and associated with adverse effects. Surfactant administration into the oropharynx has been reported in preterm animals and humans and may be effective. We wished to determine whether giving oropharyngeal surfactant at birth reduces the rate of endotracheal intubation for respiratory failure in preterm infants within 120 hours of birth. METHODS AND ANALYSIS: Prophylactic Oropharyngeal surfactant for Preterm infants: A Randomised Trial (POPART, Eudract No. 2016-004198-41) is an investigator-led, unblinded, multicentre, randomised, parallel group, controlled trial. Infants are eligible if born at a participating centre before 29 weeks gestational age (GA) and there is a plan to offer intensive care. Infants are excluded if they have major congenital anomalies. Infants are randomised at birth to treatment with oropharyngeal surfactant (120 mg vial <26 weeks GA stratum; 240 mg vial 26-28+6 weeks GA stratum) in addition to CPAP or CPAP alone. The primary outcome is intubation within 120 hours of birth, for bradycardia and/or apnoea despite respiratory support in the delivery room or respiratory failure in the intensive care unit. Secondary outcomes include incidence of mechanical ventilation, endotracheal surfactant use, chronic lung disease and death before hospital discharge. ETHICS AND DISSEMINATION: Approval for the study has been granted by the Research Ethics Committees at the National Maternity Hospital, Dublin, Ireland (EC31.2016) and at each participating site. The trial is being conducted at nine centres in six European countries. The study results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: 2016-004198-41; Pre-results.

A prospective real-world analysis of erenumab in refractory chronic migraine.

BACKGROUND: Clinical trials have shown the safety and clinical superiority of erenumab compared to placebo in chronic migraine (CM). The aim of this analysis is to evaluate the effectiveness and tolerability of erenumab in a real-world setting in patients with refractory CM. METHODS: This is a prospective single centre real-world audit conducted in patients with CM with and without medication overuse, refractory to established preventive medications, who received monthly erenumab for 6 months. RESULTS: Of 164 patients treated, 162 patients (female = 135, mean age 46 ± 14.3 years old) were included in the audit. Patients had failed a mean of 8.4 preventive treatments at baseline and 91% of patients failed Botulinum toxin type A at baseline. The mean reduction in monthly migraine days was 6.0 days at month 3 (P = 0.002) and 7.5 days at month 6 (P < 0.001) compared to baseline. The mean reduction in monthly headache days was 6.3 days (P < 0.001) at month 3 and 6.8 days (P < 0.001) at month 6. At month 3, 49%, 35% and 13% and at month 6, 60%, 38% and 22% of patients obtained at least a 30%, 50% and 75% reduction in migraine days, respectively. The percentage of patients with medication overuse was reduced from 54% at baseline to 20% at month 3 and to 25% at month 6. Compared to baseline, the mean reduction of Headache Impact Test-6 score was 7.7 points at month 3 (from 67.6 ± 0.4 to 59.9 ± 0.9) (P < 0.001) and of 7.5 points at month 6 (60.1 ± 1.3) (P = 0.01). The percentage of patients with severe headache-related disability (HIT-6: 60-78) was reduced from 96% at baseline to 68% after three monthly treatments and to 59% after six treatments. At least one side effect was reported by 48% of patients at month 1, 22% at month 3 and 15% at month 6. Constipation (20%) and cold/flu-like symptoms (15%) were the most frequent adverse events reported. CONCLUSION: Erenumab may be an effective and well tolerated therapy for medically refractory CM patients with and without medication overuse.

Sphenopalatine Ganglion Pulsed Radiofrequency for the Treatment of Refractory Chronic SUNCT and SUNA: A Prospective Case Series.

OBJECTIVES: We aimed to evaluate the safety and effectiveness of sphenopalatine ganglion pulsed radiofrequency (SPG-PRF) for the treatment of patients with refractory chronic short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and with cranial autonomic symptoms (SUNA). BACKGROUND: SPG-PRF is a minimally invasive, non-neurodestructive procedure already tested in refractory chronic cluster headache with mixed outcomes. However, no data have been produced in SUNCT/SUNA. METHODS: This was a prospective clinical audit of outcomes. Consecutive patients with chronic SUNCT/SUNA refractory to medical treatments and treated with SPG-PRF, were included in the analysis. The SPG-PRF was performed percutaneously via a lateral, infra-zygomatic approach. Responders were defined as patients with a reduction in number and/or severity of headache episodes by ≥30% for ≥3 months. Responders to the first procedure were offered to have the treatment repeated. RESULTS: Nine patients (6 female) were analyzed. After a median follow-up of 30 months (range 2-30), 7 patients were considered responders to the treatment (77.8%) for a median of 6 months (range: 4-10), 1 patient obtained 40% improvement for 2 months, and 1 patient did experience any improvement. No procedure-related immediate or delayed side effects were reported. Three patients (33.3%) experienced a worsening of the head pain for 2-4 weeks immediately after the procedure. Four responders had SPG-PRF repeated; a reproducible response was obtained in two of them. CONCLUSIONS: In our small series of patients with refractory chronic SUNCT/SUNA, SPG-PRF was a safe and effective treatment modality. The potential reproducible positive effect of subsequent treatments may prevent or delay the use of more invasive and costly interventions for at least a proportion of these patients.

Randomised trial of estimating oral endotracheal tube insertion depth in newborns using suprasternal palpation of the tip or weight.

BACKGROUND: Endotracheal tube (ETT) tip position is determined on chest X-ray (CXR) and should lie between the upper border of the first thoracic vertebra (T1) and the lower border of second thoracic vertebra (T2). Infant weight is commonly used to estimate how far the ETT should be inserted but frequently results in malpositioned ETT tips. Palpation of the ETT tip at the suprasternal notch has been recommended as an alternative. OBJECTIVE: To determine whether estimating ETT insertion depth using suprasternal palpation of the ETT tip rather than weight results in more correctly positioned ETT tips. DESIGN: Single-centre randomised controlled trial. SETTING: Level III neonatal intensive care unit (NICU) at a university maternity hospital. PATIENTS: Newborn infants without congenital anomalies intubated in the NICU. INTERVENTIONS: Participants were randomised to have ETT insertion depth estimated using palpation of the ETT tip at the suprasternal notch or weight [insertion depth (cm)=6 + wt (kg)]. MAIN OUTCOME MEASURE: Correct ETT position, that is, between the upper border of T1 and lower border of T2 on CXR, determined by one consultant paediatric radiologist masked to group assignment. RESULTS: There was no difference in the proportion of correctly placed ETT tips between the groups (suprasternal palpation 27/58 (47%) vs weight 23/60 (38%), p=0.456). Most incorrectly positioned ETTs were too low (56/68 (82%)). CONCLUSION: Estimating ETT insertion depth using suprasternal palpation did not result in more correctly positioned ETTs. TRIAL REGISTRATION NUMBER: ISRCTN13570106.

Crying and breathing by new-born preterm infants after early or delayed cord clamping.

Guidelines recommend delayed cord clamping (DCC) of at least 30 s for vigorous preterm infants who do not require resuscitation. It is not known whether DCC affects the rate of crying and breathing after birth. We reviewed videos of 80 preterm infants in the delivery room. Most infants cried and breathed after both immediate and delayed cord clamping before respiratory support was given. Infants arrived at the resuscitaire in similar physiological condition, regardless of the time after birth at which they arrived.

Randomised study comparing heart rate measurement in newly born infants using a monitor incorporating electrocardiogram and pulse oximeter versus pulse oximeter alone.

AIM: To determine whether IntelliVue (ECG plus Masimo pulse oximeter (PO)) measures heart rate (HR) in low-risk newborns more quickly than Nellcor PO (PO alone). METHODS: Unmasked parallel group randomised (1:1) study. RESULTS: We studied 100 infants, 47 randomised to IntelliVue, 53 to Nellcor. Time to first HR was shorter with IntelliVue ECG than Nellcor (median (IQR) 24 (19, 39) vs 48 (36, 69) s, p<0.001). There was no difference in time to display both HR and SpO2 (52 (47, 76) vs 48 (36, 69) s, p=0.507). IntelliVue PO displayed initial bradycardia more often than the Nellcor (55% vs 6%). Infants monitored with IntelliVue were handled more frequently and for longer. CONCLUSIONS: IntelliVue ECG displayed HR more quickly than Nellcor PO. IntelliVue PO often displayed initial bradycardia. Infants monitored with IntelliVue were handled more often. Study of ECG in high-risk infants is warranted.

Comparison of infant heart rate assessment by auscultation, ECG and oximetry in the delivery room.

Clinical assessment of an infant's heart rate (HR) in the delivery room (DR) has been reported to be inaccurate. We compared auscultation of the HR using a stethoscope with electrocardiography (ECG) and pulse oximetry (PO) for determining the HR in 92 low-risk newborn infants in the DR. Caregivers auscultated the HR while masked to the HR on the monitor. Auscultation underestimated ECG HR (mean difference (95% CI) by -9 (-15 to -2) beats per minute (bpm)) and PO HR (mean difference (95% CI) by -5 (-12 to 2) bpm). The median (IQR) time to HR by auscultation was 14 (10-18) s. As HR was determined quickly and with reasonable accuracy by auscultation in low-risk newborns, study in high-risk infants is warranted.