The effect of imposed resistance in neonatal resuscitators on pressure stability and peak flows: a bench test.

BACKGROUND: The importance of neonatal resuscitator resistance is currently unknown. In this study we investigated peak flows and pressure stability resulting from differences in imposed resistance during positive pressure ventilation(PPV) and simulated spontaneous breathing (SSB) between the r-PAP, low-resistance resuscitator, and Neopuff™, high-resistance resuscitator. METHODS: In a bench test, 20 inflations during PPV and 20 breaths during SSB were analysed on breath-by-breath basis to determine peak flow and pressure stability using the Neopuff™ with bias gas flow of 8, 12 or 15 L/min and the r-PAP with total gas flow of 15 L/min. RESULTS: Imposed resistance of the Neopuff™ was significantly reduced when the bias gas flow was increased from 8 to 15 L/min, which resulted in higher peak flows during PPV and SSB. Peak flows in the r-PAP were, however, significantly higher and fluctuations in CPAP during SSB were significantly smaller in the r-PAP compared to the Neopuff™ for all bias gas flow levels. During PPV, a pressure overshoot of 3.2 cmH2O was observed in the r-PAP. CONCLUSIONS: The r-PAP seemed to have a lower resistance than the Neopuff™ even when bias gas flows were increased. This resulted in more stable CPAP pressures with higher peak flows when using the r-PAP. IMPACT: The traditional T-piece system (Neopuff™) has a higher imposed resistance compared to a new neonatal resuscitator (r-PAP). This study shows that reducing imposed resistance leads to smaller CPAP fluctuations and higher inspiratory and expiratory peak flows. High peak flows might negatively affect lung function and/or cause lung injury in preterm infants at birth. This study will form the rationale for further studies investigating these effects. A possible compromise might be to use the traditional T-piece system with a higher bias gas flow (12 L/min), thereby reducing the imposed resistance and generating more stable PEEP/CPAP pressures, while limiting potentially harmful peak flows.

The effects of partial amniotic carbon dioxide insufflation in an ovine model.

OBJECTIVE: We aim to assess the effect of partial amniotic carbon dioxide insufflation (PACI) at increasing pressures on fetal acid-base, fetal-placental perfusion, and fetal membrane morphology in an ovine model. METHOD: Pregnant ewes and fetuses were instrumented under isoflurane anesthesia at 105 days gestation (term 145 days) to monitor utero-placental blood flow, fetal and maternal blood pressure, heart rate, and blood gas status. One group (n = 6) was exposed to PACI (unheated dry CO2 ), involving 10 mm Hg stepwise increases in insufflation pressure (5 to 25 mm Hg), for 80 minutes followed by 20 minutes of desufflation. Un-insufflated controls (n = 5) were monitored for 100 minutes. At postmortem, fetal membranes were collected for histological analysis. RESULTS: PACI at 25 mm Hg caused severe fetal hypercapnia (PaCO2  = 143 ± 5 vs 54 ± 5 mm Hg, P < 0.001), acidosis (pH = 6.85 ± 0.02 vs 7.25 ± 0.02, P < 0.001), hypoxia (SaO2  = 31 ± 4% vs 57 ± 4%, P = 0.01), and reduced uterine artery flow (50 ± 15 vs 196 ± 13 mL/min/kg, P = 0.005) compared with controls. These effects were greater at higher PACI pressures. PACI resulted in leukocyte infiltration in the amnion (1.77 × 10-5  ± 0.61 × 10-5 vs 0.38 × 10-5  ± 0.19 × 10-5  cells/µm2 , P = 0.04) and chorionic membranes (2.94 × 10-5  ± 0.67 × 10-5 vs 0.84 × 10-5  ± 0.42 × 10-5  cells/µm2 , P = 0.01). CONCLUSION: Higher PACI pressures results in larger disturbances in fetal acid-base, uterine blood flow, and fetal membrane inflammation in sheep. Differences between human and sheep utero-placental structure should be considered.

Antenatal Medical Therapies to Improve Lung Development in Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the diaphragm, allowing abdominal viscera to herniate into the thoracic cavity and subsequently impair pulmonary and vascular development. Despite improving standardized postnatal management, there remains a population of severe CDH for whom postnatal care falls short. In these severe cases, antenatal surgical intervention (fetoscopic endoluminal tracheal occlusion [FETO]) may improve survival; however, FETO increases the risk of preterm delivery, is not widely offered, and still fails in half of cases. Antenatal medical therapies that stimulate antenatal pulmonary development are therefore interesting alternatives. By presenting the animal research underpinning novel antenatal medical therapies for CDH, and considering the applications of these therapies to clinical practice, this review will explore the future of antenatal CDH management with a focus on the phosphodiesterase-5 inhibitor sildenafil.

Effect of prenatal diaphragmatic hernia on pulmonary arterial morphology.

Congenital diaphragmatic hernia (CDH) is a major cause of severe lung hypoplasia and pulmonary hypertension in the newborn. While the pulmonary hypertension is thought to result from abnormal vascular development and arterial vasoreactivity, the anatomical changes in vascular development are unclear. We have examined the 3D structure of the pulmonary arterial tree in rabbits with a surgically induced diaphragmatic hernia (DH). Fetal rabbits (n = 6) had a left-sided DH created at gestational day 23 (GD23), delivered at GD30, and briefly ventilated; sham-operated litter mates (n = 5) acted as controls. At postmortem the pulmonary arteries were filled with a radio-opaque resin before the lungs were scanned using computed tomography (CT). The 3D reconstructed images were analyzed based on vascular branching hierarchy using the software Avizo 2020.2. DH significantly reduced median number of arteries (2,579 (8440) versus 576 (442), p = .017), artery numbers per arterial generation, mean total arterial volume (43.5 ± 8.4 vs. 19.9 ± 3.1 µl, p = .020) and mean total arterial cross-sectional area (82.5 ± 2.3 vs. 28.2 ± 6.2 mm2 , p =.036). Mean arterial radius was increased in DH kittens between the eighth and sixth branching generation and mean arterial length between the sixth and 28th branching generation. A DH in kittens resulted in threefold reduction in pulmonary arterial cross-sectional area, primarily due to reduced arterial branching. Thus, the reduction in arterial cross-sectional area could be a major contributor to pulmonary hypertension infants with CDH.

The Effect of a Higher Bias Gas Flow on Imposed T-Piece Resistance and Breathing in Preterm Infants at Birth.

Objective: The resistance created by the PEEP-valve of a T-piece resuscitator is bias gas flow dependent and might affect breathing in preterm infants. In this study we investigated the effect of a higher bias gas flow on the imposed inspiratory and expiratory T-piece resistance and expiratory breaking manoeuvres (EBM) in preterm infants during spontaneous breathing on CPAP at birth. Methods: In a retrospective pre-post implementation study of preterm infants <32 weeks gestation, who were stabilised with a T-piece resuscitator, a bias gas flow of 12 L/min was compared to 8 L/min. All spontaneous breaths on CPAP within the first 10 min of starting respiratory support were analysed on a breath-by-breath basis to determine the breathing pattern of each breath and to calculate the imposed inspiratory and expiratory T-piece resistance (Ri, Re), flow rates and tidal volume. Results: In total, 54 infants were included (bias gas flow 12 L/min: n = 27, 8 L/min: n = 27) with a median GA of 29+6 (28+4-30+3) and 28+5 (25+6-30+3), respectively (p = 0.182). Ri and Re were significantly lower in the 12 L/min compared to 8 L/min bias flow group [Ri: 29.6 (26.1-33.6) vs. 46.4 (43.0-54.1) cm H2O/L/s, p < 0.001; Re: 32.0 (30.0-35.1) vs. 48.0 (46.3-53.9) cm H2O/L/s, p < 0.001], while the incidence of EBM [77% (53-88) vs. 77% (58-90), p = 0.586] was similar. Conclusion: During stabilisation of preterm infants at birth with a T-piece resuscitator, the use of a higher bias gas flow reduced both the imposed inspiratory and expiratory T-piece resistance for the infant, but this did not influence the incidence of EBMs.

The effects of cold, dry and heated, humidified amniotic insufflation on sheep fetal membranes.

INTRODUCTION: Uterine distension with pressurised carbon dioxide (CO2) (amniotic insufflation) is used clinically to improve visibility during keyhole fetal surgery. However, there are concerns that amniotic insufflation with unconditioned (cold, dry) CO2 damages the fetal membranes which leads to post-operative preterm prelabour rupture of membranes (iatrogenic PPROM). We assessed whether heating and humidifying the insufflated CO2 could reduce fetal membrane damage in sheep. METHODS: Thirteen pregnant ewes at 103-106 days gestation underwent amniotic insufflation with cold, dry (22 °C, 0-5% humidity, n = 6) or heated, humidified (40 °C, 95-100% humidity, n = 7) CO2 at 15 mmHg for 180 min. Twelve non-insufflated amniotic sacs acted as controls. Fetal membrane sections were collected after insufflation and analysed for molecular and histological markers of cell damage (caspase 3 and high mobility group box 1 [HMGB1]), inflammation (interleukin 1-alpha [IL1-alpha], IL8 and vascular cell adhesion molecule [VCAM]) and collagen weakening (matrix metalloprotease 9 [MMP9]). RESULTS: Exposure to cold, dry CO2 increased mRNA levels of caspase 3, HMGB1, IL1-alpha, IL8, VCAM and MMP9 and increased amniotic epithelial caspase 3 and HMGB1 cell counts relative to controls. Exposure to heated, humidified CO2 also increased IL8 levels relative to controls however, HMGB1, IL1-alpha and VCAM mRNA levels and amniotic epithelial HMGB1 cell counts were significantly lower than the cold, dry group. DISCUSSION: Amniotic insufflation with cold, dry CO2 damaged the amniotic epithelium and induced fetal membrane inflammation. Heated, humidified insufflation partially mitigated this damage and inflammation in sheep and may prove an important step in reducing the risk of iatrogenic PPROM following keyhole fetal surgery.

Physiologically based cord clamping improves cardiopulmonary haemodynamics in lambs with a diaphragmatic hernia.

OBJECTIVE: Lung hypoplasia associated with congenital diaphragmatic hernia (CDH) results in respiratory insufficiency and pulmonary hypertension after birth. We have investigated whether aerating the lung before removing placental support (physiologically based cord clamping (PBCC)), improves the cardiopulmonary transition in lambs with a CDH. METHODS: At ≈138 days of gestational age, 17 lambs with surgically induced left-sided diaphragmatic hernia (≈d80) were delivered via caesarean section. The umbilical cord was clamped either immediately prior to ventilation onset (immediate cord clamping (ICC); n=6) or after achieving a target tidal volume of 4 mL/kg, with a maximum delay of 10 min (PBCC; n=11). Lambs were ventilated for 120 min and physiological changes recorded. RESULTS: Pulmonary blood flow (PBF) increased following ventilation onset in both groups, but was 19-fold greater in PBCC compared with ICC lambs at cord clamping (19±6.3 vs 1.0±0.5 mL/min/kg, p<0.001). Cerebral tissue oxygenation was higher in PBCC than ICC lambs during the first 10 min after cord clamping (59%±4% vs 30%±5%, p<0.001). PBF was threefold higher (23±4 vs 8±2 mL/min/kg, p=0.01) and pulmonary vascular resistance (PVR) was threefold lower (0.6±0.1 vs 2.2±0.6 mm Hg/(mL/min), p<0.001) in PBCC lambs compared with ICC lambs at 120 min after ventilation onset. CONCLUSIONS: Compared with ICC, PBCC prevented the severe asphyxia immediately after birth and resulted in a higher PBF due to a lower PVR, which persisted for at least 120 min after birth in CDH lambs.

Physiologic-Based Cord Clamping Maintains Core Temperature vs. Immediate Cord Clamping in Near-Term Lambs.

Background: Physiologic-based cord clamping (PBCC) involves deferring umbilical cord clamping until after lung aeration. It is unclear if infant is at risk of becoming hypothermic during PBCC. Objectives: To test if PBCC would maintain core temperature more effectively than immediate cord clamping (ICC). Design: At 0.93 gestation, fetal lambs were surgically exteriorized and instrumented from pregnant ewes under general anesthesia. Prior to the start of the experiment, lambs were thoroughly dried, placed on hot water bottles, and core temperature was continuously monitored using a rectal thermometer. PBCC lambs (n = 21), received intermittent positive pressure ventilation (iPPV) for ≥5 min prior to umbilical cord clamping. In ICC lambs (n = 23), iPPV commenced within 60 s after umbilical cord clamping. iPPV was provided with heated/humidified gas. Lambs were moved under a radiant warmer after umbilical cord clamping. Additional warmth was provided using a plastic overlay, hairdryer, and extra water bottles, as needed. Two-way mixed and repeated measures one-way ANOVAs were used to compare temperature changes between and within a single group, respectively, over time. Results: Basal fetal parameters including core temperature were similar between groups. ICC lambs had a significant reduction in temperature compared to PBCC lambs (p < 0.001), evident by 1 min (p = 0.002). ICC lambs decreased temperature by 0.51°C (± 0.42) and 0.79°C (± 0.55) at 5 and 10 min respectively (p < 0.001). In PBCC lambs, temperature did not significantly change before or after umbilical cord clamping (p = 0.4 and p = 0.3, respectively). Conclusions: PBCC stabilized core temperature at delivery better than ICC in term lambs. Hypothermia may not be a significant risk during PBCC.

Effects of tracheal occlusion on the neonatal cardiopulmonary transition in an ovine model of diaphragmatic hernia.

OBJECTIVE: Fetoscopic endoluminal tracheal occlusion (FETO) aims to reverse pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) and mitigate the associated respiratory insufficiency and pulmonary hypertension after birth. We aimed to determine whether FETO improves the cardiopulmonary transition at birth in an ovine model of CDH. METHODS: In 12 ovine fetuses with surgically induced diaphragmatic hernia (DH; 80 dGA), an endotracheal balloon was placed tracheoscopically at ≈110 dGA and removed at ≈131 dGA (DH+FETO), while 10 were left untreated (DH). At ≈138 dGA, all lambs (survival at delivery: 67% [DH+FETO], 70% [DH]) were delivered via caesarean section and ventilated for 2 hours. Physiological and ventilation parameters were continuously recorded, and arterial blood-gas values were measured. RESULTS: Compared with DH, DH+FETO lambs had increased wet lung-to-body-weight ratio (0.031±0.004 vs 0.016±0.002) and dynamic lung compliance (0.7±0.1 vs 0.4±0.1 mL/cmH2O). Pulmonary vascular resistance was lower in DH+FETO lambs (0.44±0.11 vs 1.06±0.17 mm Hg/[mL/min]). However, after correction for lung weight, pulmonary blood flow was not significantly different between the groups (4.19±0.57 vs 4.05±0.60 mL/min/g). Alveolar-arterial difference in oxygen tension was not significantly different between DH+FETO and DH (402±41mm Hg vs 401±45 mm Hg). CONCLUSIONS: FETO accelerated lung growth in fetuses with CDH and improved neonatal respiratory function during the cardiopulmonary transition at birth. However, despite improved lung compliance and reduced pulmonary vascular resistance, there were less pronounced benefits for gas exchange during the first 2 hours of life.

Neonatal cardiopulmonary transition in an ovine model of congenital diaphragmatic hernia.

OBJECTIVE: Infants with a congenital diaphragmatic hernia (CDH) are at high risk of developing pulmonary hypertension after birth, but little is known of their physiological transition at birth. We aimed to characterise the changes in cardiopulmonary physiology during the neonatal transition in an ovine model of CDH. METHODS: A diaphragmatic hernia (DH) was surgically created at 80 days of gestational age (dGA) in 10 fetuses, whereas controls underwent sham surgery (n=6). At 138 dGA, lambs were delivered via caesarean section and ventilated for 2 hours. Physiological and ventilation parameters were continuously recorded, and arterial blood gas values were measured. RESULTS: DH lambs had lower wet lung-to-body-weight ratio (0.016±0.002vs0.033±0.004), reduced dynamic lung compliance (0.4±0.1mL/cmH2O vs1.2±0.1 mL/cmH2O) and reduced arterial pH (7.11±0.05vs7.26±0.05), compared with controls. While measured pulmonary blood flow (PBF) was lower in DH lambs, after correction for lung weight, PBF was not different between groups (4.05±0.60mL/min/gvs4.29±0.57 mL/min/g). Cerebral tissue oxygen saturation was lower in DH compared with control lambs (55.7±3.5vs67.7%±3.9%). CONCLUSIONS: Immediately after birth, DH lambs have small, non-compliant lungs, respiratory acidosis and poor cerebral oxygenation that reflects the clinical phenotype of human CDH. PBF (indexed to lung weight) was similar in DH and control lambs, suggesting that the reduction in PBF associated with CDH is proportional to the degree of lung hypoplasia during the neonatal cardiopulmonary transition.

Effect of lung hypoplasia on the cardiorespiratory transition in newborn lambs.

Newborns with lung hypoplasia (LH) commonly have limited respiratory function and often require ventilatory assistance after birth. We aimed to characterize the cardiorespiratory transition and respiratory function in newborn lambs with LH. LH was induced by draining fetal lung liquid in utero [110-133 days (d), term = 147d, n = 6]. At ~133d gestation, LH and Control lambs (n = 6) were instrumented and ventilated for 3 h to monitor blood-gas status, oxygenation, ventilator requirements, and hemodynamics during the transition from fetal to newborn life. Lambs with LH had significantly reduced relative wet and dry lung weights indicating hypoplastic lungs compared with Control lambs. LH lambs experienced persistent hypercapnia and acidosis during the ventilation period, had lower lung compliance, and had higher alveolar-arterial differences in oxygen and oxygenation index compared with Control lambs. As a result, LH lambs required greater respiratory support and more supplemental oxygen. Following delivery, LH lambs experienced periods of significantly lower pulmonary artery blood flow and higher carotid artery blood flow in association with the lower oxygenation levels. The detrimental effects of LH can be attributed to a reduction in lung size and poorer gas exchange capabilities. This study has provided greater understanding of the effect of LH itself on the physiology underpinning the transition from fetal to newborn life. Advances in this area is the key to identifying improved or novel management strategies for babies with LH starting in the delivery room, to favorably alter the fetal-to-newborn transition toward improved outcomes and reduced lifelong morbidity.NEW & NOTEWORTHY Current clinical management of newborns with lung hypoplasia (LH) is largely based on expert opinion rather than scientific evidence. We have generated physiological evidence for detrimental effects of LH on hemodynamics and respiratory function in newborn lambs, which mimics the morbidity observed in LH newborns clinically. The unfavorable consequences of LH can be attributed to a reduction in lung size and poorer gas exchange capabilities.