Thermoregulation and golden hour practices in extremely preterm infants: an international survey.

BACKGROUND: Are thermoregulation and golden hour practices in extremely preterm (EP) infants comparable across the world? This study aims to describe these practices for EP infants based on the neonatal intensive care unit's (NICUs) geographic region, country's income status and the lowest gestational age (GA) of infants resuscitated. METHODS: The Director of each NICU was requested to complete the e-questionnaire between February 2019 and August 2021. RESULTS: We received 848 responses, from all geographic regions and resource settings. Variations in most thermoregulation and golden hour practices were observed. Using a polyethylene plastic wrap, commencing humidity within 60 min of admission, and having local protocols were the most consistent practices (>75%). The odds for the following practices differed in NICUs resuscitating infants from 22 to 23 weeks GA compared to those resuscitating from 24 to 25 weeks: respiratory support during resuscitation and transport, use of polyethylene plastic wrap and servo-control mode, commencing ambient humidity >80% and presence of local protocols. CONCLUSION: Evidence-based practices on thermoregulation and golden hour stabilisation differed based on the unit's region, country's income status and the lowest GA of infants resuscitated. Future efforts should address reducing variation in practice and aligning practices with international guidelines. IMPACT: A wide variation in thermoregulation and golden hour practices exists depending on the income status, geographic region and lowest gestation age of infants resuscitated. Using a polyethylene plastic wrap, commencing humidity within 60 min of admission and having local protocols were the most consistent practices. This study provides a comprehensive description of thermoregulation and golden hour practices to allow a global comparison in the delivery of best evidence-based practice. The findings of this survey highlight a need for reducing variation in practice and aligning practices with international guidelines for a comparable health care delivery.

Skincare practices in extremely premature infants: A survey of tertiary neonatal intensive care units from Australia and New Zealand.

AIM: To investigate skincare practices in the first 2 weeks of life in extremely premature infants across tertiary neonatal intensive care units (NICUs). METHODS: A web-based secure survey invite was emailed to the medical directors of tertiary NICUs. The survey included questions on various aspects of skincare practices in the first 2 weeks of life in extremely premature infants (born before 28 weeks gestation). The person most familiar with local skincare practices was asked to complete the survey and only one response per unit was requested. We performed a descriptive analysis. RESULTS: We received responses from 30 out of 32 NICUs (response rate 93%). Twenty-five NICUs (89%) reported offering resuscitation and intensive care to infants born at ≥23 weeks gestation. All NICUs reported occurrences of skin breakdown, including medical adhesive-related skin injury (30%), abrasion/friction-associated skin injury (46%), perineal skin breakdown (55%), pressure site injury (47%) and diaper dermatitis (60%). A high level of consensus (≥75%) was observed for certain practices, such as the use of polyethylene occlusive plastic wraps at birth and aqueous chlorhexidine solution for sterile procedures, but a low level of consensus (<25%) was observed for many other practices, including the skin risk assessment tool used. CONCLUSIONS: Skin injuries in extremely premature infants are common and skincare practices vary considerably amongst NICUs. Clinical practice improvement projects and further clinical research will help improve consistency amongst NICUs. Further research is needed to assist the development of evidence-based guidelines and benchmarking for skincare practices in these vulnerable infants.

Neopuff T-piece resuscitator mask ventilation: Does mask leak vary with different peak inspiratory pressures in a manikin model?

AIM: The aim of this study was to compare mask leak with three different peak inspiratory pressure (PIP) settings during T-piece resuscitator (TPR; Neopuff) mask ventilation on a neonatal manikin model. METHODS: Participants were neonatal unit staff members. They were instructed to provide mask ventilation with a TPR with three PIP settings (20, 30, 40 cm H2 O) chosen in a random order. Each episode was for 2 min with 2-min rest period. Flow rate and positive end-expiratory pressure (PEEP) were kept constant. Airway pressure, inspiratory and expiratory tidal volumes, mask leak, respiratory rate and inspiratory time were recorded. Repeated measures analysis of variance was used for statistical analysis. RESULTS: A total of 12 749 inflations delivered by 40 participants were analysed. There were no statistically significant differences (P > 0.05) in the mask leak with the three PIP settings. No statistically significant differences were seen in respiratory rate and inspiratory time with the three PIP settings. There was a significant rise in PEEP as the PIP increased. Failure to achieve the desired PIP was observed especially at the higher settings. CONCLUSIONS: In a neonatal manikin model, the mask leak does not vary as a function of the PIP when the flow rate is constant. With a fixed rate and inspiratory time, there seems to be a rise in PEEP with increasing PIP.

CeasIng Cpap At standarD criteriA (CICADA): predicting a successful outcome.

This is a retrospective analysis of a multicentre randomised controlled trial (RCT) where we concluded that CeasIng Cpap At standerD criteriA (CICADA) in premature babies (PBs) <30 weeks gestational age (GA) was the significantly better method of ceasing CPAP. To identify factors that may influence the number of attempts to cease CPAP, we reviewed the records of 50 PBs from the RCT who used the CICADA method. PBs were grouped according to number of attempts to cease CPAP (fast group ≤2 attempts and slow group >2 attempts to cease CPAP). There were 26 (fast group) and 24 (slow group) PBs included in the analysis. Results showed significant differences in mean GA (27.8 ± 0.3 vs 26.9 ± 0.3 [weeks ± SE], p = 0.03) and birth weight ([Bwt]; 1080 ± 48.8 vs 899 ± 45.8 [grams ± SE], p = 0.01) between groups. Significantly fewer PBs in the fast group had a patent ductus arteriosus (PDA) compared to the slow group (5/26 (19.2%) vs 13/24 (54.2 %), p = 0.02). Bwt was a significant negative predictor of CPAP duration (r = -0.497, p = 0.03) and CPAP ceasing attempts (r = -0.290, p = 0.04). CONCLUSION: PBs with a higher GA and Bwt without a PDA ceased CPAP earlier using the CICADA method. Bwt was better than GA for predicting CPAP duration and attempts to cease CPAP. WHAT IS KNOWN: Our previous studies showed that CeasIng Cpap At standarD criteriA (CICADA) significantly reduces CPAP time, oxygen requirements and caffeine use. Some PBs however using the CICADA method required >2 attempts to cease CPAP ('slow CICADA' group). WHAT IS NEW: PBs in the 'fast CICADA' group (<3 attempts to cease CPAP) (a) have longer gestational age and higher birth weight, (b) shorter mechanical ventilation and (c) lower incidence of patent ductus arteriosus. Attempts to cease CPAP decreased by 0.5 times per 1 week increase in GA and 0.3 times per 100-g increase in birth weight for PBs <30 weeks gestation.

Sex-dependent influence of endogenous estrogen in pulmonary hypertension.

RATIONALE: The incidence of pulmonary arterial hypertension is greater in women, suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males, exogenously administered estrogen can protect against pulmonary hypertension (PH). However, in models that display female susceptibility, estrogens may play a causative role. OBJECTIVES: To clarify the influence of endogenous estrogen and sex in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. METHODS: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH: the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of sex on pulmonary expression of aromatase in these models and in lungs from patients with pulmonary arterial hypertension. MEASUREMENTS AND MAIN RESULTS: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was caused by reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor α also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased bone morphogenetic protein receptor 2 and Id1 expression compared with male. Anastrozole treatment reversed the impaired bone morphogenetic protein receptor 2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared with male. CONCLUSIONS: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential.

Mask leak increases and minute ventilation decreases when chest compressions are added to bag ventilation in a neonatal manikin model.

AIM: To determine changes in respiratory mechanics when chest compressions are added to mask ventilation, as recommended by the International Liaison Committee on Resuscitation (ILCOR) guidelines for newborn infants. METHODS: Using a Laerdal Advanced Life Support leak-free baby manikin and a 240-mL self-inflating bag, 58 neonatal staff members were randomly paired to provide mask ventilation, followed by mask ventilation with chest compressions with a 1:3 ratio, for two minutes each. A Florian respiratory function monitor was used to measure respiratory mechanics, including mask leak. RESULTS: The addition of chest compressions to mask ventilation led to a significant reduction in inflation rate, from 63.9 to 32.9 breaths per minute (p < 0.0001), mean airway pressure reduced from 7.6 to 4.9 cm H2 O (p < 0.001), minute ventilation reduced from 770 to 451 mL/kg/min (p < 0.0001), and there was a significant increase in paired mask leak of 6.8% (p < 0.0001). CONCLUSION: Adding chest compressions to mask ventilation, in accordance with the ILCOR guidelines, in a manikin model is associated with a significant reduction in delivered ventilation and increase in mask leak. If similar findings occur in human infants needing an escalation in resuscitation, there is a potential risk of either delay in recovery or inadequate response to resuscitation.

Global variation in skin injures and skincare practices in extremely preterm infants.

BACKGROUND: Globally, are skincare practices and skin injuries in extremely preterm infants comparable? This study describes skin injuries, variation in skincare practices and investigates any association between them. METHODS: A web-based survey was conducted between February 2019 and August 2021. Quantifying skin injuries and describing skincare practices in extremely preterm infants were the main outcomes. The association between skin injuries and skincare practices was established using binary multivariable logistic regression adjusted for regions. RESULTS: Responses from 848 neonatal intensive care units, representing all geographic regions and income status groups were received. Diaper dermatitis (331/840, 39%) and medical adhesive-related skin injuries (319/838, 38%) were the most common injuries. Following a local skincare guideline reduced skin injuries [medical adhesive-related injuries: adjusted odds ratios (aOR) = 0.63, 95% confidence interval (CI) = 0.45-0.88; perineal injuries: aOR = 0.66, 95% CI = 0.45-0.96; local skin infections: OR = 0.41, 95% CI = 0.26-0.65; chemical burns: OR = 0.46, 95% CI = 0.26-0.83; thermal burns: OR = 0.51, 95% CI = 0.27-0.96]. Performing skin assessments at least every four hours reduced skin injuries (abrasion: aOR = 0.48, 95% CI = 0.33-0.67; pressure: aOR = 0.51, 95% CI = 0.34-0.78; diaper dermatitis: aOR = 0.71, 95% CI = 0.51-0.99; perineal: aOR = 0.52, 95% CI = 0.36-0.75). Regional and resource settings-based variations in skin injuries and skincare practices were observed. CONCLUSIONS: Skin injuries were common in extremely preterm infants. Consistency in practice and improved surveillance appears to reduce the occurrence of these injuries. Better evidence regarding optimal practices is needed to reduce skin injuries and minimize practice variations.

Machine Learning Outperforms Logistic Regression Analysis to Predict Next-Season NHL Player Injury: An Analysis of 2322 Players From 2007 to 2017.

BACKGROUND: The opportunity to quantitatively predict next-season injury risk in the National Hockey League (NHL) has become a reality with the advent of advanced computational processors and machine learning (ML) architecture. Unlike static regression analyses that provide a momentary prediction, ML algorithms are dynamic in that they are readily capable of imbibing historical data to build a framework that improves with additive data. PURPOSE: To (1) characterize the epidemiology of publicly reported NHL injuries from 2007 to 2017, (2) determine the validity of a machine learning model in predicting next-season injury risk for both goalies and position players, and (3) compare the performance of modern ML algorithms versus logistic regression (LR) analyses. STUDY DESIGN: Descriptive epidemiology study. METHODS: Professional NHL player data were compiled for the years 2007 to 2017 from 2 publicly reported databases in the absence of an official NHL-approved database. Attributes acquired from each NHL player from each professional year included age, 85 performance metrics, and injury history. A total of 5 ML algorithms were created for both position player and goalie data: random forest, K Nearest Neighbors, Naïve Bayes, XGBoost, and Top 3 Ensemble. LR was also performed for both position player and goalie data. Area under the receiver operating characteristic curve (AUC) primarily determined validation. RESULTS: Player data were generated from 2109 position players and 213 goalies. For models predicting next-season injury risk for position players, XGBoost performed the best with an AUC of 0.948, compared with an AUC of 0.937 for LR (P < .0001). For models predicting next-season injury risk for goalies, XGBoost had the highest AUC with 0.956, compared with an AUC of 0.947 for LR (P < .0001). CONCLUSION: Advanced ML models such as XGBoost outperformed LR and demonstrated good to excellent capability of predicting whether a publicly reportable injury is likely to occur the next season.

Oestrogen receptor alpha in pulmonary hypertension.

AIMS: Pulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH. We have previously shown that serotonin can uncover a pulmonary hypertensive phenotype in BMPR2(+/-) mice and that oestrogen can increase serotinergic signalling in human pulmonary arterial smooth muscle cells (hPASMCs). Hence, here we wished to characterize the expression of oestrogen receptors (ERs) in male and female human pulmonary arteries and have examined the influence of oestrogen and serotonin on BMPR2 and ERα expression. METHODS AND RESULTS: By immunohistochemistry, we showed that ERα, ERß, and G-protein-coupled receptors are expressed in human pulmonary arteries localizing mainly to the smooth muscle layer which also expresses the serotonin transporter (SERT). Protein expression of ERα protein was higher in female PAH patient hPASMCs compared with male and serotonin also increased the expression of ERα. 17ß-estradiol induced proliferation of hPASMCs via ERα activation and this engaged mitogen-activated protein kinase and Akt signalling. Female mice over-expressing SERT (SERT(+) mice) develop PH and the ERα antagonist MPP attenuated the development of PH in normoxic and hypoxic female SERT(+) mice. The therapeutic effects of MPP were accompanied by increased expression of BMPR2 in mouse lung. CONCLUSION: ERα is highly expressed in female hPASMCs from PAH patients and mediates oestrogen-induced proliferation of hPASMCs via mitogen-activated protein kinase and Akt signalling. Serotonin can increase ERα expression in hPASMCs and antagonism of ERα reverses serotonin-dependent PH in the mouse and increases BMPR2 expression.

CeasIng Cpap At standarD criteriA (CICADA): impact on weight gain, time to full feeds and caffeine use.

INTRODUCTION: In our previous randomised controlled trial (RCT), we have shown in preterm babies (PBs) <30 weeks gestation that CeasIng Cpap At standarD criteriA (CICADA (method 1)) compared with cycling off continuous positive airway pressure (CPAP) gradually (method 2) or cycling off CPAP gradually with low flow air/oxygen during periods off CPAP (method 3) reduces CPAP cessation time in PBs <30 weeks gestation. METHOD: This retrospective study reviewed weight gain, time to reach full feeds and time to cease caffeine in PBs previously enrolled in the RCT. RESULTS: Data were collected from 162 of the 177 PBs, and there was no significant difference in the projected weight gain between the three methods. Based on intention to treat, the time taken to reach full feeds for all three methods showed no significant difference. However, post hoc analysis showed the CICADA method compared with cycling off gradually just failed significance (30.3±1.6 vs 31.1±2.4 (weeks corrected gestational age (Wks CGA±SD)), p=0.077). Analysis of time to cease caffeine showed there was a significant difference between the methods with PBs randomised to the CICADA method compared with the cycling off method ceasing caffeine almost a week earlier (33.6±2.4 vs 34.5±2.8 (Wks CGA±SD), p=0.02). CONCLUSIONS: This retrospective study provides evidence to substantiate the optimum method of ceasing CPAP; the CICADA method, does not adversely affect weight gain, time to reach full feeds and may reduce time to cease caffeine in PBs <30 weeks gestation.

Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension.

AIMS: Pulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH. METHODS AND RESULTS: Dfen (5 mg kg(-1) day(-1) PO for 28 days) increased right ventricular pressure and pulmonary vascular remodelling in female mice only. Mice dosed with Dfen showed increased whole lung expression of CYP1B1 and Dfen-induced PAH was ablated in CYP1B1(-/-) mice. In line with this, Dfen up-regulated expression of CYP1B1 in PASMCs from PAH patients (PAH-PASMCs) and Dfen-mediated proliferation of PAH-PASMCs was ablated by pharmacological inhibition of CYP1B1. Dfen increased expression of tryptophan hydroxylase 1 (Tph1; the rate-limiting enzyme in the synthesis of serotonin) in PAH-PASMCs and both Dfen-induced proliferation and Dfen-induced up-regulation of CYP1B1 were ablated by inhibition of Tph1. 17ß-Oestradiol increased expression of both Tph1 and CYP1B1 in PAH-PASMCs, and Dfen and 17ß-oestradiol had synergistic effects on proliferation of PAH-PASMCs. Finally, ovariectomy protected against Dfen-induced PAH in female mice. CONCLUSION: CYP1B1 is critical in the development of Dfen-induced PAH in mice in vivo and proliferation of PAH-PASMCs in vitro. CYP1B1 may provide a novel therapeutic target for PAH.

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile.

BACKGROUND: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression. METHODS: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3). RESULTS: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies. CONCLUSIONS: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.

The serotonin transporter, gender, and 17ß oestradiol in the development of pulmonary arterial hypertension.

AIMS: Idiopathic and familial forms of pulmonary arterial hypertension (PAH) predominantly affect females through an unknown mechanism. Activity of the serotonin transporter (SERT) may modulate the development of PAH, and mice overexpressing SERT (SERT+ mice) develop PAH and severe hypoxia-induced PAH. In the central nervous system, oestrogens influence activity of the serotonin system. Therefore, we examined the influence of gender on the development of PAH in SERT+ mice and how this is modulated by female hormones. METHODS AND RESULTS: PAH was assessed via measurement of right ventricular systolic pressure (RVSP), pulmonary vascular remodelling (PVR), and right ventricular hypertrophy. Male SERT+ mice did not develop PAH. Female SERT+ mice demonstrated increased RVSP and PVR and this was abolished by ovariectomy. Following exposure to hypoxia, SERT+ mice exhibited severe PAH and this was also attenuated by ovariectomy. Chronic administration of 17ß oestradiol re-established the PAH phenotype in ovariectomized, normoxic, and hypoxic SERT+ mice. 17ß oestradiol also up-regulated tryptophan hydroxylase-1 (TPH1), 5-hydroytryptamine(1B) (5-HT(1B)) receptor, and SERT expression in human pulmonary arterial smooth muscle cells (hPASMCs). 17ß oestradiol stimulated hPASMC proliferation and this was inhibited by both the TPH inhibitor para-chlorophenylalanine and the 5-HT(1B) receptor antagonist SB224289. CONCLUSION: 17ß oestradiol is critical to the development of PAH and severe hypoxia-induced PAH in female SERT+ mice. In hPASMCs, 17ß oestradiol-induced proliferation is dependant on de novo serotonin synthesis and stimulation of the 5-HT(1B) receptor. These interactions between the serotonin system and 17ß oestradiol may contribute to the increased risk of PAH associated with female gender.