Stuart B. Hooper

Description:The approach to respiratory support in preterm infants at birth has shifted from invasive to non-invasive techniques. The effectiveness of non-invasive respiratory support relies on a good mask seal and maintaining a patent airway, but this appears to be more challenging than initially thought. The force applied to the mask must be sufficient for a good mask seal to reduce leak, but too much pressure on the face mask can inhibit breathing. Also, airway obstruction due to a closed glottis can prevent the lungs from being effectively ventilated. It is now evident that spontaneous breathing is essential for a patent airway, with oxygenation playing a key role in stimulating breathing. This can be improved by increasing the surface area available for gas exchange with appropriate continuous positive airway pressures (CPAP) and/or increasing the inspired oxygen concentration. Tactile stimulation can help promote spontaneous breathing, which promotes lung aeration and gas exchange potential, thereby improving oxygenation, which further improves the overall effectiveness of non-invasive respiratory support.

Description:X-ray imaging is a fast, precise and non-invasive method of imaging which, when combined with computed tomography, provides detailed 3D rendering of samples. Incorporating propagation-based phase contrast can vastly improve data quality for weakly attenuating samples via phase retrieval, allowing radiation exposure to be reduced. However, applying phase retrieval to multi-material samples commonly requires the choice of which material boundary to tune the reconstruction. Selecting the boundary with strongest phase contrast increases noise suppression, but at the detriment of over-blurring other interfaces and potentially removing quantitative sample information. Additionally, conventional phase retrieval algorithms cannot be used for regions bounded by more than one material, requiring alternative methods. Here we present a computationally efficient, non-iterative nor AI-mediated method for applying strong phase retrieval, whilst preserving sharp boundaries for all materials within the sample. 3D phase retrieval is combined with morphological operations to prevent over-blurring artefacts from being introduced, while avoiding the potentially long convergence times required by iterative approaches. This technique, entitled 3DMPR, was tested on phase contrast images of a rabbit kitten brain encased by the surrounding dense skull. Using 24 keV synchrotron radiation with a 5 m propagation distance, 3DMPR provided a 6.8-fold improvement in the signal-to-noise ratio (SNR) of brain tissue over the standard phase retrieval procedure, without over-smoothing the images. Simultaneous quantification of edge resolution and SNR gain was performed with an aluminium-water phantom imaged using a microfocus X-ray tube at 35 kVp and 0.576 m effective propagation distance. There, 3DMPR provided a four-fold SNR boost whilst preserving the boundary spatial resolution at 54 ± 1 µm, compared with 108 ± 2 µm using conventional phase retrieval. These results illustrate the ability of 3DMPR to create new avenues of dose reduction in clinical settings.

Description:Rationale: Infants with a congenital diaphragmatic hernia often require high peak inflation pressures to aerate and ventilate their stiff, hypoplastic lungs at birth. However, while high peak inflation pressures are associated with ventilator-induced lung injury, lower peak inflation pressures (considered to be gentle) may not sufficiently aerate the lungs. Objectives: To investigate whether a small constant external negative pressure can improve lung aeration at birth in rabbit kittens with a diaphragmatic hernia. Methods: A diaphragmatic hernia was surgically induced in 2-3 rabbit fetuses per doe (n=20) at 24d gestation. At 30d, diaphragmatic hernia kittens (n=21) and control littermates (n=19) were delivered by caesarean section, intubated and placed in a water-filled plethysmograph. Kittens were ventilated (volume targeted: 8mL/kg for control, 4mL/kg for diaphragmatic hernia kittens) with either an external negative pressure (-6cmH2O) without a positive end-expiratory pressure (PEEP; Negative/0PEEP) or at atmospheric pressure (0cmH2O) with or without PEEP (Atmos/5PEEP and Atmos/0PEEP). Meaurements: Lung aeration was measured using phase contrast X-ray imaging and plethysmography. Data (means±SD) were analysed using a repeated measures linear mixed model (p<0.05). Main Results: Diaphragmatic hernia kittens ventilated in Negative/0PEEP required lower peak inflation pressures to achieve the target tidal volume than Atmos/5PEEP (10.9±2.6 vs 15.4±2.6 cmH2O; p=0.004) and Atmos/0PEEP kittens (14.2±2.6 cmH2O; p=0.052). They also had greater functional residual capacities compared to Atmos/5PEEP (19.9±3.9 vs 13.8±3.9 mL/kg; p=0.015) and Atmos/0PEEP kittens (6.4±3.9 mL/kg; p<0.001). Conclusions: A small constant external negative pressure increased lung aeration with lower peak inflation pressures in mechanically ventilated diaphragmatic hernia rabbit kittens.

Description:Background: Cesarean section (CS) birth is a risk factor for respiratory distress (RD) in term and near-term infants, which has been steadily increasing globally. The absence of labor has been linked to RD resulting from planned CS births. Uterine contractions contribute to the dorsiflexed position of the fetus which increases abdominal and trans-pulmonary pressure resulting in lung liquid loss via nose and mouth. We recently demonstrated the feasibility and safety of applying Knee-to-Chest Flexion (KCF), where the newborn was placed in a flexed "fetal" position, leading to lung liquid expulsion. In this trial, the effectiveness of the KCF maneuver in reducing RD in infants delivered by planned CS will be examined. Methods: This will be a randomized controlled two-arm trial in which 521 infants born by elective CS at 37-42 weeks gestational age will be randomized, in 1:1 ratio, to receive either a KCF maneuver or standard care, before being followed up for at least 24 h. The study will be conducted at Kilimanjaro Christian Medical Centre hospital and Mawenzi Regional Referral hospital in Tanzania. Consent will be sought from mothers scheduled for elective CS prior to randomization. The primary outcome is the occurrence of respiratory distress. Secondary outcome is admission to Neonatal Care Unit. Conclusions: This trial investigates KCF maneuver as an intervention to facilitate lung liquid clearance in newborns born by planned CS. It is anticipated to produce evidence of KCF as a highly cost effective innovation that will improve neonatal outcomes in clinical settings. Background: ClinicalTrials.gov: NCT06270823.

Description:Antenatal inflammation/infection is a major cause of neonatal apnoea and hypoventilation. Prostaglandin E2 (PGE2) is a key inflammatory mediator associated with depression of fetal and neonatal breathing. We aimed to determine whether antenatal ibuprofen, a cyclooxygenase inhibitor that reduces synthesis of PGE2, restores fetal breathing movements (FBM) in late-gestation fetal sheep exposed to systemic lipopolysaccharide (LPS). Fetal sheep (125 days gestation, d; term ~148 d) were instrumentally monitored for continuous measurement of FBM and physiological parameters. At 130 d fetuses were randomly allocated between groups receiving i.v. saline (CTLSAL, n = 9), escalating doses of LPS (i.v.) over 3 days (LPSSAL, n = 8), or ibuprofen one hour after each LPS dose (LPSIBU, n = 8). Regular plasma samples were collected for PGE2 assessment. At 135 d, cerebrospinal fluid and brainstem tissue were collected at autopsy for assessments of PGE2 expression, and immunohistochemical quantification of astrocytes and microglia within key brainstem respiratory centres was performed to assess inflammation. LPS exposure increased PGE2 levels in plasma, cerebrospinal fluid and the RTN/pFRG (p < 0.05) and decreased the incidence, amplitude and amount of the accentuated (>5 mmHg) FBMs. Ibuprofen reduced plasma and RTN/pFRG PGE2 expression (p < 0.01 and p = 0.031, respectively) but did not restore FBMs. Astrocyte and microglial density increased in the RTN/pFRG, NTS and raphe nucleus in LPSIBU fetuses, compared to LPSSAL (p < 0.05). Antenatal ibuprofen treatment did not restore depressed FBM, despite reducing the circulating and brainstem PGE2 levels in LPS-exposed fetal sheep. Other inflammatory pathways or more specific targeting of PGE2 may be more effective in preventing apnoea caused by exposure to intrauterine infection/inflammation.