Neonatal and fetal therapy of congenital diaphragmatic hernia-related pulmonary hypertension

Congenital diaphragmatic hernia (CDH) is a complex malformation characterised by a triad of pulmonary hypoplasia, pulmonary hypertension (PH) and cardiac ventricular dysfunction. Much of the mortality and morbidity in CDH is largely accounted for by PH, especially when persistent beyond the neonatal period and refractory to available treatment. Gentle ventilation, haemodynamic optimisation and pulmonary vasodilation constitute the foundations of neonatal treatment of CDH-related PH (CDH-PH). Moreover, early prenatal diagnosis, the ability to assess severity and the developmental nature of the condition generate the perfect rationale for fetal therapy. Shortcomings of currently available clinical therapies in combination with increased understanding of CDH pathophysiology have spurred experimental drug trials, exploring new therapeutic mechanisms to tackle CDH-PH. We herein discuss clinically available neonatal and fetal therapies specifically targeting CDH-PH and review the most promising experimental treatments and future research avenues.

Implementing two-stage consent pathway in neonatal trials

Perinatal trials sometimes require rapid recruitment processes to facilitate inclusion of participants when interventions are time-critical. A two-stage consent pathway has been used in some trials and is supported by national guidance. This pathway includes seeking oral assent for participation during the time-critical period followed by informed written consent later. This approach is being used in the fluids exclusively enteral from day one (FEED1) trial where participants need to be randomised within 3 hours of birth. There is some apprehension about approaching parents for participation via the oral assent pathway. The main reasons for this are consistent with previous research: lack of a written record, lack of standardised information and unfamiliarity with the process. Here, we describe how the pathway has been implemented in the FEED1 trial and the steps the trial team have taken to support sites. We provide recommendations for future trials to consider if they are considering implementing a similar pathway. Trial registration number: ISRCTN89654042.

Effect of chlorhexidine cleansing on healthcare-associated infections in neonates: a systematic review and meta-analysis

BackgroundHealthcare-associated infections (HAIs) have a significant impact on neonatal morbidity, mortality and long-term prognosis, which have a high incidence in neonates. Many studies have shown that chlorhexidine cleansing is effective in reducing HAIs in adults, but the effect of chlorhexidine cleansing on HAIs in neonates remains controversial.AimThe purpose of this study was to conduct a systematic review and meta-analysis of the effect of chlorhexidine cleansing on HAIs in neonates. The protocol of this review has been registered with the PROSPERO international prospective register of systematic reviews.MethodsA systematic literature search was performed on five medical literature databases, namely MEDLINE, Web of Science, Embase, Scopus and Cumulative Index to Nursing and Allied Health Literature (CINAHL), published up until 3 March 2021. In the end, six studies were eligible for inclusion, including four randomised controlled trials and two quasi-experimental studies. Version 2 of the Cochrane tool for assessing risk of bias in randomised trials and the Joanna Briggs Institute critical appraisal checklist for quasi-experimental studies were used for quality assessment. Pooled risk ratios (RRs) and their associated 95% CIs were calculated using the fixed effects model (I2 <50%) or the random effects model (I2 ≥50%).Findings and conclusionsThe results of the meta-analysis revealed that chlorhexidine cleansing had no significant effect on neonatal sepsis (RR: 0.49, 95% CI 0.18 to 1.38, p=0.18, I2=0%), but significantly reduced neonatal skin bacterial colonisation (RR: 0.61, 95% CI 0.42 to 0.90, p=0.01, I2=50%). In addition, this systematic review showed that chlorhexidine cleansing could significantly reduce central line-associated bloodstream infection in neonates based on large-sample studies. However, more studies are needed to determine the optimal concentration and frequency of chlorhexidine cleansing.PROSPERO registration number CRD42021243858.

Global incidence proportion of intraventricular haemorrhage of prematurity: a meta-analysis of studies published 2010–2020

ObjectiveTo investigate differences and calculate pooled incidence of any intraventricular haemorrhage (IVH), severe IVH (Grade III/IV, sIVH) and ventriculoperitoneal shunt (VPS) placement in preterm infants across geographical, health and economic regions stratified by gestational age (GA).DesignMEDLINE, Embase, CINAHL and Web of Science were searched between 2010 and 2020. Studies reporting rates of preterm infants with any IVH, sIVH and VPS by GA subgroup were included. Meta-regression was performed to determine subgroup differences between study designs and across United Nations geographical regions, WHO mortality strata and World Bank lending regions. Incidence of any IVH, sIVH and VPS by GA subgroups<25, <28, 28–31, 32–33 and 34–36 weeks were calculated using random-effects meta-analysis.ResultsOf 6273 publications, 97 met inclusion criteria. Incidence of any IVH (37 studies 87 993 patients) was: 44.7% (95% CI 40.9% to 48.5%) for GA <25 weeks, 34.3% (95% CI 31.2% to 37.6%) for GA <28 weeks, 17.4% (95% CI 13.8% to 21.6%) for GA 28–31 weeks, 11.3% (95% CI 7.3% to 17.0%) for GA32–33 weeks and 4.9% (95% CI 1.4% to 15.2%) for GA 34–36 weeks. Incidence of sIVH (49 studies 328 562 patients) was 23.7% (95% CI 20.9% to 26.7%) for GA <25 weeks, 15.0% (95% CI 13.1% to 17.2%) for GA <28 weeks, 4.6% (95% CI 3.5% to 6.1%) for GA 28–31 weeks, 3.3% (95% CI 2.1% to 5.1%) for GA 32–33 weeks and 1.8% (95% CI 1.2% to 2.8%) for GA 34–36 weeks. Europe had lower reported incidence of any IVH and sIVH relative to North America (p<0.05). Proportion of VPS across all GA groups was 8.4% (95% CI 4.7% to 14.7%) for any IVH and 17.2% (95% CI 12.2% to 26.2%) for sIVH. Heterogeneity was high (I2 >90%) but 64%–85% of the variance was explained by GA and study inclusion criteria.ConclusionsWe report the first pooled estimates of IVH of prematurity by GA subgroup. There was high heterogeneity across studies suggesting a need for standardised incidence reporting guidelines.

Outcome of non-cooled asphyxiated infants with under-recognised or delayed-onset encephalopathy

ObjectiveTo describe the clinical characteristics, MRI findings and neurodevelopmental outcome of infants with documented perinatal asphyxia and seizure onset within 24 hours after birth who were not selected for therapeutic hypothermia (TH).DesignRetrospective cohort study.Setting and patients(Near-)term infants with documented perinatal asphyxia referred to two Dutch level III neonatal units with neonatal encephalopathy (NE) and seizures <24 hours after birth not treated with TH. Infants with a diagnosis other than NE following perinatal asphyxia causing the seizures were excluded.Main outcome measuresClinical characteristics, findings on cranial MRI performed within 8 days after birth and neurodevelopmental outcome assessed using the Griffiths Mental Development Scales at 18 months or Bayley Scales of Infant and Toddler Development–Third Edition at 2 years of age.Results39 infants were included. All had abnormalities on MRI. Predominant white matter/watershed injury was the most common pattern of injury, 23 (59%). 7 (18%) infants had predominant basal ganglia/thalamus injury, 3 (8%) near total brain injury, 5 (13%) arterial ischaemic stroke, 1 (3%) an intraventricular haemorrhage. Adverse outcome was seen in 51%: 6 died, 11 developed cerebral palsy (spastic n=8, dyskinetic n=3), 2 had neurodevelopmental delay, 1 had severe hearing impairment.ConclusionsAll infants with documented perinatal asphyxia and seizure onset within 24 hours after birth who did not receive TH had abnormalities on MRI. 51% had an adverse outcome. Better methods for recognition of infants who might benefit from TH and careful neurodevelopmental follow-up are urgently needed.

Effects of tactile stimulation on spontaneous breathing during face mask ventilation

ObjectiveWe sought to determine the effect of stimulation during positive pressure ventilation (PPV) on the number of spontaneous breaths, exhaled tidal volume (VTe), mask leak and obstruction.DesignSecondary analysis of a prospective, randomised trial comparing two face masks.SettingSingle-centre delivery room study.PatientsNewborn infants ≥34 weeks’ gestation at birth.MethodsResuscitations were video recorded. Tactile stimulations during PPV were noted and the timing, duration and surface area of applied stimulus were recorded. Respiratory flow waveforms were evaluated to determine the number of spontaneous breaths, VTe, leak and obstruction. Variables were recorded throughout each tactile stimulation episode and compared with those recorded in the same time period immediately before stimulation.ResultsTwenty of 40 infants received tactile stimulation during PPV and we recorded 57 stimulations during PPV. During stimulation, the number of spontaneous breaths increased (median difference (IQR): 1 breath (0–3); padj<0.001) and VTe increased (0.5 mL/kg (−0.5 to 1.7), padj=0.028), whereas mask leak (0% (−20 to 1), padj=0.12) and percentage of obstructed inflations (0% (0–0), padj=0.14) did not change, compared with the period immediately prior to stimulation. Increased duration of stimulation (padj<0.001) and surface area of applied stimulus (padj=0.026) were associated with a larger increase in spontaneous breaths in response to tactile stimulation.ConclusionsTactile stimulation during PPV was associated with an increase in the number of spontaneous breaths compared with immediately before stimulation without a change in mask leak and obstruction. These data inform the discussion on continuing stimulation during PPV in term infants.Trial registration numberAustralian and New Zealand Clinical Trial Registry (ACTRN12616000768493).