Diagnosis, management and long term cardiovascular outcomes of phenotypic profiles in pulmonary hypertension associated with congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm resulting in herniation of viscera into the chest. This condition is characterized by pulmonary hypoplasia, pulmonary hypertension (PH) and cardiac ventricular dysfunction. PH is a key component of the pathophysiology of CDH in neonates and contributes to morbidity and mortality. Traditionally, PH associated with CDH (CDH-PH) is thought to be secondary to increased pulmonary arterial resistance and vasoreactivity resulting from pulmonary hypoplasia. Additionally, there is increasing recognition of associated left ventricular hypoplasia, dysfunction and elevated end diastolic pressure resulting in pulmonary venous hypertension in infants with CDH. Thus, hemodynamic management of these infants is complex and cautious use of pulmonary vasodilators such as inhaled nitric oxide (iNO) is warranted. We aim to provide an overview of different phenotypic profiles of CDH associated PH and potential management options based on current evidence and pathophysiology.

Minor painful procedures in extremely preterm infants admitted to a tertiary neonatal intensive care unit: Opportunities to improve pain mitigation.

AIM: This study aims to characterise current pain management practices in extremely preterm infants (gestational age less than or equal to 28 weeks) admitted to neonatal intensive care unit (NICU). METHODS: Retrospective audit pertaining to patient characteristics, as well as minor painful procedures (MPP), pain mitigation and pain scoring in 25 extremely preterm infants admitted to a tertiary NICU in 2016 over the first 14 days of NICU admission. Opportunities to bundle MPP were identified according to pre-specified criteria. Bayley Scales of Infant Development, Third Edition (BSID-III) cognitive, language and motor composite scores were available from the neurodevelopmental follow-up clinic at 12- and 24-months of corrected age. Linear mixed methods regression was used to examine for correlation between increased exposure to MPP and BSID-III scores at follow-up. RESULTS: Extremely preterm infants underwent an average of 11.24 ± 4.12 MPP per day for the first 14 days of NICU admission. Opportunities to bundle MPP were missed 75.98% (408/537) of the time; most of these were invasive blood collections. A total of 12.2% (481/3933) of MPP occurred within 4 h of pharmacological or non-pharmacological pain mitigation. BSID-III motor composite score was associated with an 11.75 (95% confidence interval 1.99, 21.27) decrease in patients experiencing more than or equal to the third quartile of MPP in the 14 days post-NICU admission (P = 0.0329, n = 42). Association was not found for BSID-III cognitive and language composite scores. CONCLUSIONS: There is readily scope for quality improvement initiatives to reduce harm in extremely preterm infants admitted to NICU.

Vaccinations in the newborn.

Neonatal immunisation includes vaccination in the first 4 weeks of life (Neonatal period) as well as in high-risk preterm infants in the first few months (until 44 weeks corrected gestational age). Neonates have an immature immune system, which renders them highly susceptible to life-threatening infections. This highlights the importance of vaccination in this vulnerable population; however, at the same time also making it challenging because of their inability to generate a protective immune response. Other challenges include interference from maternal antibodies and excessive skewing towards T Helper Cell Type 2 (Th2) immunity. Despite these challenges, several vaccines have been developed and proven safe and effective at birth. Presently, there are 3 vaccines - Hepatitis B vaccine, Bacillus Calmette-Guerine (BCG) and Oral Polio vaccine (OPV) widely used in neonates, which provides evidence that certain antigen-adjuvant combinations can elicit protective neonatal responses. This review focusses on current vaccinations in neonates, including preterm infants and highlights some novel approaches to enhance neonatal vaccination.

Impact of inhaled nitric oxide stewardship programme in a neonatal intensive care unit.

AIM: Inhaled nitric oxide (iNO) is the most common, although expensive, therapy for persistent pulmonary hypertension of the newborn and hypoxaemic respiratory failure. With significant variation in iNO delivery practices amongst clinicians, this study aimed to assess the effectiveness of a stewardship programme in increasing clinician compliance with revised, standardised protocols and to measure the impact of compliance on iNO therapy use. METHODS: Initiation and weaning protocols for iNO were introduced to the neonatal intensive care unit at The Centenary Hospital on 01 March 2016. A 2-year stewardship programme was utilised to assess protocol compliance and the resulting iNO usage impacts were measured. A combined retrospective and prospective study from 1 March 2014 to 28 February 2018 was conducted to compare the patterns of iNO utilisation between the pre- and post-stewardship cohorts. RESULTS: The pre-stewardship cohort incorporated 18 neonates, receiving 19 iNO treatment episodes, and 18 neonates, receiving 21 iNO treatment episodes, in the post-stewardship cohort. No significant difference in patient demographics was determined. Compliance with the protocols improved from 61% in year 1 to 88% in year 2 of the stewardship programme. Significant reductions were observed in median total hours of iNO therapy per patient (P = 0.0014) and in median time from therapy initiation to initial wean (P < 0.0001). The cost of iNO therapy reduced 52% during the stewardship programme with no increase in adverse patient outcomes. CONCLUSION: An iNO stewardship programme could be safely implemented in any NICU leading to increased protocol compliance with a beneficial reduction in iNO usage and cost.

Comparison of cranial ultrasound and MRI for detecting BRAIN injury in extremely preterm infants and correlation with neurological outcomes at 1 and 3 years.

This study aimed to investigate the accuracy of different grades of brain injuries on serial and term equivalent age (TEA)-cranial ultrasound imaging (cUS) as compared to TEA magnetic resonance imaging (MRI) in extremely preterm infants < 28 weeks, and determine the predictive value of imaging abnormalities on neurodevelopmental outcome at 1 and 3 years. Seventy-five infants were included in the study. Severe TEA-cUS injury had high positive predictive value-PPV (100%) for predicting severe MRI injury compared to mild to moderate TEA-cUS injury or severe injury on worst cranial ultrasound scan. Absence of moderate to severe injury on TEA cUS or worst serial cUS was a good predictor of a normal MRI (negative predictive values > 93%). Severe grade 3 injuries on TEA-US had high predictive values in predicting abnormal neurodevelopment at both 1 and 3 years of age (PPV 100%). All grades of MRI and worst serial cUS injuries poorly predicted abnormal neurodevelopment at 1 and 3 years. Absence of an injury either on a cranial ultrasound or an MRI did not predict a normal outcome. Multiple logistic regression did not show a significant correlation between imaging injury and neurodevelopmental outcomes.Conclusion: This study demonstrates that TEA cUS can reliably identify severe brain abnormalities that would be seen on MRI imaging and positively predict abnormal neurodevelopment at both 1 and 3 years. Although MRI can pick up more subtle abnormalities that may be missed on cUS, their predictive value on neurodevelopmental impairment is poor. Normal cUS and MRI scan may not exclude abnormal neurodevelopment. Routine TEA-MRI scan provides limited benefit in predicting abnormal neurodevelopment in extremely preterm infants. What is Known: • Preterm neonates are at increased risk of white matter and other brain injuries, which may be associated with adverse neurodevelopmental outcome. • MRI is the most accurate method in detecting white matter injuries. What is New: • TEA-cUS can reliably detect severe brain injuries on MRI, but not mild/moderate lesions as well as abnormal neurodevelopment at 1 and 3 years. • TEA-MRI brain injury is poor in predicting abnormal neurodevelopment at 1 and 3 years and normal cUS or MRI brain injury may not guarantee normal neurodevelopment.

Retrospective Cohort Analysis of Central Line Associated Blood Stream Infection following Introduction of a Central Line Bundle in a Neonatal Intensive Care Unit.

BACKGROUND: Central Line Associated Bloodstream Infections (CLABSI) constitute a leading cause of morbidity and mortality in neonatal populations. There has been an overwhelming increase in the use of evidence-based care practices, also known as bundles, in the reduction of these infections. In this report, rates of CLABSI and central line utilisation were examined following the introduction of a central line bundle in our Neonatal Intensive Care Unit (NICU) at the Canberra Hospital. METHODS: The research undertaken was a retrospective cohort study in which newborn infants admitted to the Canberra Hospital NICU between January 2011 and December 2016 and had a central line inserted were included in the study. Data regarding central line days, bed days, infection rates, and patient demographics were collected before and after the introduction of an intervention bundle. CLABSI rates were calculated per 1,000 central line days for before (2011-2013) and after (2014-2016) the introduction of the bundle. The postintervention period was retrospectively analysed for compliance, with data regarding the completion of maintenance forms and insertion forms collected. RESULTS: Overall, the results showed a significant decrease in CLABSI rates from 8.8 per 1,000 central line days to 4.9 per 1,000 central line days in the intervention period (p<0.001). Central line utilisation ratio (CLUR: ratio of central line days to bed days) was also reduced between pre- and postintervention periods, from 0.177 (4414/25013) to 0.13 (3633/27384; p<0.001). Compliance to insertion forms and maintenance forms was observed to increase within the intervention period. CONCLUSION: The implementation of a central line bundle was effective in reducing both CLABSI rates and dwell time (CLUR) for central venous catheters.

Morbidity and Mortality in Preterm Infants following Antacid Use: A Retrospective Audit.

Background and Objectives. Antacids are often prescribed to preterm infants due to misdiagnosis of gastro-oesophageal reflux. This suppresses gastric acidity, a major defence mechanism against infection. This study aims to determine if ranitidine and omeprazole use in very low birth weight (VLBW) neonates, <1500 grams, is associated with increased risk of late onset sepsis, necrotising enterocolitis (NEC), and mortality. Methods. Retrospective analysis was conducted on neonates, <1500 grams, born and admitted into the Neonatal Intensive Care Unit at The Canberra Hospital during the period from January 2008 to December 2012. Information regarding late onset sepsis, NEC, mortality, ranitidine/omeprazole use, and other neonatal/hospital factors was collected for each neonate. Results. 360 neonates were evaluated, 64 received ranitidine and/or omeprazole, and 296 had not. There were no statistically significant differences in incidence of late onset sepsis (OR = 0.52, CI = 0.24-1.1, and p = 0.117), NEC Stage 2 and above (OR = 0.4, CI = 0.05-3.2, and p = 0.7), or mortality (OR = 0.35, CI = 0.08-1.5, and p = 0.19) between the two groups. After adjusting significant differences in neonatal and hospital factors, risk of late onset sepsis was significantly lower in those that received ranitidine/omeprazole (OR = 0.28, CI = 0.13-0.65, and p = 0.003). Conclusions. Ranitidine and omeprazole use in VLBW preterm infants may not be associated with an increased risk of infection, NEC, and mortality.

Noradrenaline in preterm infants with cardiovascular compromise.

Noradrenaline (NA) is beneficial in the treatment of term newborns with cardiovascular compromise due to sepsis or pulmonary hypertension, but experiences with NA in preterm infants are limited. The aim of this study is to describe the efficacy and safety of NA in preterm infants. Patient records of preterm infants ≤32 weeks' gestation admitted to two hospitals between 2004 and 2015 and who received NA were reviewed for perinatal morbidities and mortality. Clinical details were collected at the time of NA use, and response on blood pressure, perfusion and oxygenation was documented as well as possible side effects. Forty-eight infants with primary diagnoses of sepsis (63 %) and pulmonary hypertension (23 %) received NA. Normotension was achieved at a median of 1 h in all but one infant at a median dose of 0.5 mcg/kg/min. Infants who died (46 %) were of younger gestational age and had worse cardiovascular function at start of NA compared to infants who survived. Tachycardia was common (31 %), but no additional effects were found on kidney or liver function. CONCLUSION: NA appears to be tolerated safely by preterm infants with no major side effects. However, effectiveness needs to be studies further in structured trials. What is Known: • Noradrenaline is beneficial in the treatment of term newborns and infants with cardiovascular compromise. • Noradrenaline is known for its potent vasoconstrictive effects and, therefore, infrequently used in preterm infants. What is New: • Noradrenaline used in relative low dose and as first or second line support increases blood pressure in preterm infants with cardiovascular compromise. • Tachycardia was common, but no additional side effects were found.

Determinants of neonatal blood pressure.

Blood pressure (BP) measurements have been increasingly used across neonatal intensive care units to determine and monitor hemodynamic status in neonates. A number of studies have attempted to derive normative blood pressure data in both preterm and term infants. However, this still remains a complex process, as several maternal and neonatal factors influence neonatal blood pressure. Maternal conditions, including hypertension and preeclampsia, seem to have some impact on neonatal BP, while maternal drugs, in particular antenatal steroids, seem to have a strong influence. Among the neonatal factors, gestational age, post-conceptual age and weight seem to have the strongest influence. The paucity of data on the short and long term effects of maternal conditions and medication on neonatal BP requires further research.

Maternal ventilation and sedation for H1N1 influenza resulting in fetal bladder rupture and urinary ascites.

Urinary ascites in a newborn infant is unusual and most commonly results from bladder perforation following umbilical arterial catheterisation or obstructive uropathy. The following report describes a case of fetal bladder rupture with urinary ascites in a mother ventilated and sedated with narcotics and benzodiazepines for H1N1 influenza. This was associated with a unique biochemical profile of hyponatraemia and elevated serum urea and creatinine characteristic of urinary autodialysis in the neonate.

Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy.

BACKGROUND: Delayed neuronal death following a perinatal hypoxic insult is due partly to xanthine oxidase-mediated production of cytotoxic free radicals. Evidence exists that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in experimental models of perinatal asphyxia and in people with organ reperfusion injury. OBJECTIVES: To determine the effect of allopurinol on mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2012, Issue 1), MEDLINE (1966 to March 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared allopurinol administration versus placebo or no drug in newborn infants with hypoxic-ischaemic encephalopathy. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: We included three trials in which a total of 114 infants participated. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately severe encephalopathy. These studies were generally of good methodological quality, but were too small to exclude clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death (typical risk ratio 0.88; 95% confidence interval (95% CI) 0.56 to 1.38; risk difference -0.04; 95% CI -0.18 to 0.10) or a composite of death or severe neurodevelopmental disability (typical risk ratio 0.78; 95% CI 0.56 to 1.08; risk difference -0.14; 95% CI -0.31 to 0.04). AUTHORS' CONCLUSIONS: The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy. Much larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude important effects on mortality and adverse long-term neurodevelopmental outcomes.

Has anti-D prophylaxis increased the rate of positive direct antiglobulin test results and can the direct antiglobulin test predict need for phototherapy in Rh/ABO incompatibility?

AIM: To determine the impact of Rhesus (Rh) D prophylaxis on positive direct antiglobulin test (DAT) results and ability of a DAT grade to predict an infant's need for phototherapy. METHODS: Laboratory and infant medical records were reviewed for DAT status, DAT grade, interventions for hyperbilirubinemia including phototherapy, blood transfusion, exchange transfusion and intravenous immunoglobulin. Two epochs of DAT results were reviewed, the first in the era prior to Rh D prophylaxis, the second after introduction of standardised Rh D prophylaxis for Rh negative women. RESULTS: A total of 165 DAT-positive infants' medical records were reviewed. The number of positive DAT results increased from 1.5% to 2.3% (P < 0.0001) following introduction of anti-Rh D prophylaxis, the increase related to an increase in anti-D DATs (7.4% to 32% -P < 0.0001). An infant with a DAT grade of 5-8 was 2.6 times more likely to need phototherapy than an infant with a DAT grade of 2-4 (odds ratio (OR), 2.571; 95% confidence interval (CI), 1.225-5.393; P = 0.08) and an infant with a DAT grade of 10-12 was 4.7 times more likely to need phototherapy than an infant with a DAT grade of 2-4 (OR, 4.724; 95% CI, 1.602-13.926, P =0.013). CONCLUSIONS: Rh D prophylaxis has increased positive DAT results, which may increase the number of unnecessary bilirubin measurements. A low or high DAT grade is strongly predictive of whether an infant does or does not require phototherapy. However, an intermediate DAT requires concomitant bilirubin measurements to determine phototherapy requirements.

Phenotypic heterogeneity and parental origin of extra chromosome 21 in Down syndrome.

We compared the frequency of phenotypic features of 40 children with Down syndrome between individuals with a maternally or paternally derived extra chromosome 21, using quantitative FISH for comparing heteromorphisms of the nucleolar organizing region. Parental origin was determined in 90% of families. Hypotonia and craniofacial abnormalities were present in 90% or more individuals, irrespective of parental origin of chromosome 21. Congenital heart defects were more frequent in cases with a maternally derived extra chromosome 21. Imprinted gene(s) may contribute to the development of congenital heart defects in Down syndrome.

Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy.

BACKGROUND: Delayed neuronal death following a perinatal hypoxic insult is due partly to xanthine oxidase-mediated production of cytotoxic free radicals. Evidence exists that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in animal models of perinatal asphyxia and in human patients with other forms of organ reperfusion injury. OBJECTIVES: To determine the effect of allopurinol on mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 - December 2007), EMBASE (1980 - December 2007), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared allopurinol administration vs. placebo or no drug in newborn infants with suspected hypoxic-ischaemic encephalopathy. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two authors. Data were synthesised using a fixed effects model and reported using typical relative risk, typical risk difference and weighted mean difference. MAIN RESULTS: Three trials in which a total of 114 infants participated were identified. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately-severe encephalopathy. These studies were generally of good methodological quality, but were underpowered to detect clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death during infancy [typical relative risk 0.92 (95% confidence interval 0.59 to 1.45); typical risk difference -0.03 (95% confidence interval -0.16 to 0.11)], nor in the incidence of neonatal seizures [typical relative risk 0.93 (95% confidence interval 0.75 to 1.16); typical risk difference -0.05 (95% confidence interval -0.21 to 0.11)]. Only one trial assessed neurodevelopment in surviving children and did not find a statistically significant effect. AUTHORS' CONCLUSIONS: The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy and, therefore, larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude clinically important effects on mortality and adverse long-term neurodevelopmental outcomes.