Effect of Bias Gas Flow on Tracheal Cytokine Concentrations in Ventilated Extremely Preterm Infants: A Randomized Controlled Trial.

BACKGROUND: The objective of this study was to determine whether ventilator bias gas flow affects tracheal aspirate (TA) cytokine concentrations in ventilated extremely preterm infants. METHODS: This is a randomized controlled trial in a tertiary neonatal unit in New Zealand. Preterm infants (<28 weeks' gestation/<1,000 g) requiring intubation in the first 7 days after birth were randomized to bias gas flows of 4 or 10 L/min. Cytokine concentrations in TA and plasma were measured at 24, 72, and 120 h after the onset of ventilation. The primary outcome measure was concentration of interleukin (IL)-8 in TA 24 h after the onset of mechanical ventilation. RESULTS: Baseline demographics were similar in babies randomized to 4 (n = 50) and 10 (n = 45) L/min bias gas flow. TA IL-8 concentrations were not different between groups. Plasma IL-8 concentrations decreased over time (p < 0.05). Respiratory support and incidence of bronchopulmonary dysplasia at 36 weeks' corrected gestational age were similar between groups. Fewer babies ventilated at 4 L/min developed necrotizing enterocolitis (NEC) ≥ stage 2 (n = 0 vs. n = 5; p = 0.02) and fewer died (n = 1 vs. n = 5, p = 0.06). CONCLUSIONS: Lower bias gas flow in ventilated extremely preterm infants did not alter TA cytokine concentrations but the lower incidence of NEC and mortality warrants further investigation.

Changed ophthalmic workload following introduction of digital retinal photography for retinopathy of prematurity screening.

BACKGROUND: ROP screening is vital in care of premature infants but is considered burdensome, difficult and time consuming for ophthalmologists. This study assessed the reduction in workload following the introduction of nurse-led WFDRI to a large neonatal nursery. METHODS: We report a retrospective audit of 628 infants screened for ROP in the years 2010, 2013 and 2019 at the Royal Women's Hospital, Victoria. The last complete year of screening for ROP using binocular indirect ophthalmoscopy (BIO) alone (2010) was compared with two subsequent years after the introduction of nurse-led WFDRI. The main outcome measures were the time taken to report and document WFDRI and the time taken to undertake BIO examination of a premature infant and document the results. RESULTS: The ophthalmologist's time taken to conduct BIO, review images and document the results per 100 patient examinations was reduced from 16.7 hours before introduction of WFDRI to 3.7 hours. Similarly, the weekly time spent on this component of ROP screening fell from 2.3 hours per week to 0.8 and 1.0 hours per week after introduction of WFDRI. CONCLUSIONS: The introduction of nurse-led WFDRI has resulted in a dramatic and sustained reduction in ophthalmologist workload involved in ROP screening in a large Australian neonatal nursery. This may result in improved retention of the ophthalmic workforce required to undertake ROP screening.

Higher Rates of Retinopathy of Prematurity after Increasing Oxygen Saturation Targets for Very Preterm Infants: Experience in a Single Center.

Randomized trials of oxygen saturation target ranges for extremely preterm infants showed increased survival but increased retinopathy of prematurity with higher compared with lower target ranges. In our center, changing from a target range of 88%-92% to 91%-95% has been associated with increased rates and severity of retinopathy of prematurity.

Randomized controlled trial of oxygen saturation targets in very preterm infants: two year outcomes.

OBJECTIVE: To assess whether an oxygen saturation (Spo2) target of 85%-89% compared with 91%-95% reduced the incidence of the composite outcome of death or major disability at 2 years of age in infants born at <28 weeks' gestation. STUDY DESIGN: A total 340 infants were randomized to a lower or higher target from <24 hours of age until 36 weeks' gestational age. Blinding was achieved by targeting a displayed Spo2 of 88%-92% using a saturation monitor offset by ±3% within the range 85%-95%. True saturations were displayed outside this range. Follow-up at 2 years' corrected age was by pediatric examination and formal neurodevelopmental assessment. Major disability was gross motor disability, cognitive or language delay, severe hearing loss, or blindness. RESULTS: The primary outcome was known for 335 infants with 33 using surrogate language information. Targeting a lower compared with a higher Spo2 target range had no significant effect on the rate of death or major disability at 2 years' corrected age (65/167 [38.9%] vs 76/168 [45.2%]; relative risk 1.15, 95% CI 0.90-1.47) or any secondary outcomes. Death occurred in 25 (14.7%) and 27 (15.9%) of those randomized to the lower and higher target, respectively, and blindness in 0% and 0.7%. CONCLUSIONS: Although there was no benefit or harm from targeting a lower compared with a higher saturation in this trial, further information will become available from the prospectively planned meta-analysis of this and 4 other trials comprising a total of nearly 5000 infants.

Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.

BACKGROUND: Preterm infants ≤32 weeks' gestation are increasingly being managed on continuous positive airway pressure (CPAP), without prior intubation and surfactant therapy. Some infants treated in this way ultimately fail on CPAP and require intubation and ventilation. OBJECTIVES: To define the incidence, predictors and consequences of CPAP failure in preterm infants managed with CPAP from the outset. METHODS: Preterm infants 25-32 weeks' gestation were included in the study if inborn and managed with CPAP as the initial respiratory support, with division into two gestation ranges and grouping according to whether they were successfully managed on CPAP (CPAP-S) or failed on CPAP and required intubation <72 h (CPAP-F). Predictors of CPAP failure were sought, and outcomes compared between the groups. RESULTS: 297 infants received CPAP, of which 65 (22%) failed, with CPAP failure being more likely at lower gestational age. Most infants failing CPAP had moderate or severe respiratory distress syndrome radiologically. In multivariate analysis, CPAP failure was found to be predicted by the highest FiO2 in the first hours of life. CPAP-F infants had a prolonged need for respiratory support and oxygen therapy, and a higher risk of death or bronchopulmonary dysplasia at 25-28 weeks' gestation (CPAP-F 53% vs. CPAP-S 14%, relative risk 3.8, 95% CI 1.6, 9.3) and a substantially higher risk of pneumothorax at 29-32 weeks. CONCLUSION: CPAP failure in preterm infants usually occurs because of unremitting respiratory distress syndrome, is predicted by an FiO2 ≥0.3 in the first hours of life, and is associated with adverse outcomes.

Minimally-invasive surfactant therapy in preterm infants on continuous positive airway pressure.

OBJECTIVE: To evaluate the applicability and potential effectiveness of a technique of minimally-invasive surfactant therapy (MIST) in preterm infants on continuous positive airway pressure (CPAP). METHODS: An open feasibility study of MIST was conducted at two sites. Infants were eligible for MIST if needing CPAP pressure ≥7 cm H(2)O and FiO(2) ≥0.3 (25-28 weeks gestation, n=38) or ≥0.35 (29-32 weeks, n=23). Without premedication, a narrow-bore catheter was inserted through the vocal cords under direct vision. Surfactant (100 or 200 mg/kg Curosurf) was then instilled, followed by reinstitution of CPAP. Outcomes were compared between surfactant-treated infants and historical controls achieving the same CPAP and FiO(2) thresholds. RESULTS: Surfactant was successfully administered via MIST in all cases, with a rapid and sustained reduction in FiO(2) thereafter. For infants at 25-28 weeks gestation, need for intubation <72 h was diminished after MIST compared with controls (32% vs 68%; OR 0.21, 95% CI 0.083 to 0.55), with a similar trend at 29-32 weeks (22% vs 45%; OR 0.34, 95% CI 0.11 to 1.1). Duration of ventilation and incidence of bronchopulmonary dysplasia were similar, but infants receiving MIST had a shorter duration of oxygen therapy. CONCLUSION: Surfactant delivery via a narrow-bore tracheal catheter is feasible and potentially effective, and deserves further investigation in clinical trials.

Fluid recovery during lung lavage in meconium aspiration syndrome.

UNLABELLED: Lung lavage using two aliquots of 15 mL/kg of dilute surfactant was performed in 30 ventilated infants with severe meconium aspiration syndrome (MAS). Mean recovery of instilled lavage fluid was 46%, with greater fluid return associated with lower mean airway pressure at 24 h and a shorter duration of respiratory support. CONCLUSION: Recovery of instilled lavage fluid is paramount in effective lung lavage in MAS and must be afforded priority in the lavage technique.

High bias gas flows increase lung injury in the ventilated preterm lamb.

BACKGROUND: Mechanical ventilation of preterm babies increases survival but can also cause ventilator-induced lung injury (VILI), leading to the development of bronchopulmonary dysplasia (BPD). It is not known whether shear stress injury from gases flowing into the preterm lung during ventilation contributes to VILI. METHODS: Preterm lambs of 131 days' gestation (term = 147 d) were ventilated for 2 hours with a bias gas flow of 8 L/min (n = 13), 18 L/min (n = 12) or 28 L/min (n = 14). Physiological parameters were measured continuously and lung injury was assessed by measuring mRNA expression of early injury response genes and by histological analysis. Control lung tissue was collected from unventilated age-matched fetuses. Data were analysed by ANOVA with a Tukey post-hoc test when appropriate. RESULTS: High bias gas flows resulted in higher ventilator pressures, shorter inflation times and decreased ventilator efficiency. The rate of rise of inspiratory gas flow was greatest, and pulmonary mRNA levels of the injury markers, EGR1 and CTGF, were highest in lambs ventilated with bias gas flows of 18 L/min. High bias gas flows resulted in increased cellular proliferation and abnormal deposition of elastin, collagen and myofibroblasts in the lung. CONCLUSIONS: High ventilator bias gas flows resulted in increased lung injury, with up-regulation of acute early response genes and increased histological lung injury. Bias gas flows may, therefore, contribute to VILI and BPD.

Improvement in mortality of very low birthweight infants and the changing pattern of neonatal mortality: the 50-year experience of one perinatal centre.

AIM: Neonatology is a relatively new sub-specialty so we aimed to review survival data in the context of advances in neonatal care. METHOD: Review of neonatal survival for very low birthweight babies over the last 50 years. RESULTS: In the data collected from a single tertiary neonatal unit, survival for babies 501-1000 g improved from below 10% in 1959 to over 60% in 2009. Similarly, survival for babies 1001 to 1500 g has improved from approximately 50% to over 90%. During the study period, death due to extreme prematurity or cardiorespiratory problems, namely respiratory distress syndrome, fell from 90% in 1964 to only 45% of neonatal deaths in 2008. CONCLUSION: In addition to reporting the remarkable improvement in neonatal survival over this period, we have highlighted items of historical context.

Enteral feeding practices in very preterm infants: an international survey.

OBJECTIVE: To evaluate enteral feeding practices in neonatal units in different countries and on different continents. DESIGN: A web-based survey of 127 tertiary neonatal intensive care units in Australia, Canada, Denmark, Ireland, New Zealand, Norway, Sweden and the UK. RESULTS: 124 units (98%) responded. 59 units (48%) had a breast milk bank or access to donor human milk (Australia/New Zealand 2/27, Canada 6/29, Scandinavia 20/20 and UK/Ireland 31/48). The proportion of units initiating enteral feeding within the first 24 h of life was: 43/124 (35%) if gestational age (GA) <25 weeks, 53/124 (43%) if GA 25-27 weeks and 88/124 (71%) if GA 28-31 weeks. In general, Scandinavian units introduced enteral feeds the earliest, followed by UK/Ireland. Continuous feeding was routinely used for infants below 28 weeks' gestation in almost half of the Scandinavian units and in approximately one sixth of units in UK/Ireland, but rarely in Australia/New Zealand and Canada. Minimal enteral feeding for 4-5 days was common in Canada, but rare in Scandinavia. Target enteral feeding volume in a 'stable' preterm infant was 140-160 ml/kg/day in most Canadian units and 161-180 ml/kg/day or higher in units in the other regions. There were also marked regional differences in criteria for use and timing when human milk fortifier was added. CONCLUSIONS: This study highlights areas of uncertainty and demonstrates marked variability in feeding practices. It provides valuable data for planning collaborative feeding trials to optimise outcome in preterm infants.

Improved neonatal survival and outcomes at borderline viability brings increasing ethical dilemmas.

With improvements in neonatal intensive care over the past five decades, the limits of viability have reduced to around 24 weeks' gestation. While increasing survival has been the predominant driver leading to lowering the gestation at which care can be provided, these infants remain at significant risk of adverse long-term outcomes including neuro-developmental disability. Decisions about commencing and continuing intensive care are determined in partnership with parents, considering the best interests of the baby and the family. Occasionally, clinicians and parents come to an impasse regarding institution or continuation of intensive care. Inevitably, these ethical dilemmas need to consider the uncertainty of the long-term prognosis and challenges surrounding providing or withdrawing active treatment. Further reduction in the gestational age considered for institution of intensive care will need to be guided by short- and long-term outcomes, community expectations and the availability of sufficient resources to care for these infants in the neonatal intensive care unit and beyond.

Does more protein in the first week of life change outcomes for very low birthweight babies?

BACKGROUND: Following publication of revised recommended nutrient intakes (RNI) for infants <1500 g, our intravenous nutrition (IVN) solutions were reformulated to deliver RNI in a restricted volume to ensure additional non-nutritional fluids did not detract from nutritional intake. An audit was performed to determine whether these changes achieved RNI and influenced growth, clinical or neurodevelopmental outcomes. METHODS: Two cohorts of 40 infants <1500 g were identified from a prospectively maintained database: babies born before and after reformulation of the IVN solutions. Data on nutritional intakes for the first 30 days of life, growth and clinical outcomes were collected. Neurodevelopmental outcomes at 18 months corrected age (CA) were obtained from a Bayley III assessment. Results are presented as mean ± SD. RESULTS: The 'after' group received significantly less fluid (105 ± 12 vs. 132 ± 15 mL/kg/day, P < 0.001) but more protein (3.2 ± 0.6 vs. 2.4 ± 0.5 g/kg/day, P < 0.001) in the first week of life. There were no differences in clinical outcome, growth z-scores at 4 weeks of age or neurodevelopmental outcome at 18 months CA between the 'before' and 'after' infants. Enteral protein intake in the first 2 weeks of life was positively associated with neurodevelopmental outcome (cognitive score r(2) = 0.13 P= 0.03, motor score r(2) = 0.27 P= 0.001). CONCLUSION: Although the new IVN regimen achieved intakes closer to RNI, there were no major effects on growth, clinical outcome or neurodevelopmental outcome at 18 months CA. Enteral protein intake in the first two weeks was positively associated with neurodevelopmental outcome, suggesting early enteral protein intake is important for optimal brain function.

Randomized controlled trial of lung lavage with dilute surfactant for meconium aspiration syndrome.

OBJECTIVE: To evaluate whether lung lavage with surfactant changes the duration of mechanical respiratory support or other outcomes in meconium aspiration syndrome (MAS). STUDY DESIGN: We conducted a randomized controlled trial that enrolled ventilated infants with MAS. Infants randomized to lavage received two 15-mL/kg aliquots of dilute bovine surfactant instilled into, and recovered from, the lung. Control subjects received standard care, which in both groups included high frequency ventilation, nitric oxide, and, where available, extracorporeal membrane oxygenation (ECMO). RESULTS: Sixty-six infants were randomized, with one ineligible infant excluded from analysis. Median duration of respiratory support was similar in infants who underwent lavage and control subjects (5.5 versus 6.0 days, P = .77). Requirement for high frequency ventilation and nitric oxide did not differ between the groups. Fewer infants who underwent lavage died or required ECMO: 10% (3/30) compared with 31% (11/35) in the control group (odds ratio, 0.24; 95% confidence interval, 0.060-0.97). Lavage transiently reduced oxygen saturation without substantial heart rate or blood pressure alterations. Mean airway pressure was more rapidly weaned in the lavage group after randomization. CONCLUSION: Lung lavage with dilute surfactant does not alter duration of respiratory support, but may reduce mortality, especially in units not offering ECMO.

Ventilator gas flow rates affect inspiratory time and ventilator efficiency index in term lambs.

BACKGROUND: Despite increasing survival in the smallest preterm infants, the incidence of chronic lung disease has not decreased. Research into ventilatory strategies has concentrated on minimising barotrauma, volutrauma and atelectotrauma, but little attention has been paid to the role of bias gas flow rates and the potential for rheotrauma or shear stress injury. Ventilated preterm infants frequently receive relatively high gas flow rates. OBJECTIVES: We hypothesised that altering bias gas flow rates would change the efficiency of ventilation and thereby affect ventilatory parameters. METHODS: We tested this hypothesis using an artificial lung followed by ventilation of 8 term lambs. RESULTS: Between flows of 2 and 15 l/min, inflation time (Ti) in the artificial lung was inversely related to the bias gas flow rate. In the ventilated lambs, Ti was inversely related to flow rates up to 10 l/min, with no statistically significant effect at flow rates >10 l/min. There were no adverse effects on gas exchange or cardiovascular parameters until a flow rate of 3 l/min was used, when inadequate gas exchange occurred. CONCLUSIONS: Ti is inversely associated with the bias gas flow rate. Flow rates much lower than those used in many neonatal units seem to provide adequate ventilation. We suggest that the role of ventilator gas flow rates, which may potentially influence shear stress in ventilator-induced lung injury, merits further investigation.

The reliability of 2D and colour Doppler ultrasound in localising longline position.

BACKGROUND: The position of percutaneously inserted central venous catheters (longlines) in neonates is critical, as malpositioned longlines are associated with potentially fatal complications. AIM: To determine if cardiac ultrasound (two-dimensional (2D) and colour Doppler) is useful in evaluating longline position, when compared with the position identified by contrast radiography. SETTING: Single level 3 neonatal unit. PARTICIPANTS: Forty-four neonates undergoing insertion of 24-gauge silastic longlines between July 2004 and September 2005. METHODS: Infants who had a longline inserted underwent echocardiography by a novice and an experienced operator. Operators identified longline position using a 2D then colour Doppler echocardiography during a rapid bolus infusion of saline. The position was identified from contrast radiography by two independent observers. RESULTS: Using 2D echocardiography, the novice and experienced operators could identify 41 and 59% of longlines, respectively. However, only 34% of longlines were identified by both operators. In 15 infants whose longline positions were identified by both operators, there was agreement in only eight infants (53%). Colour Doppler improved the experienced operator's success but did not assist the novice operator. For radiographs, there was 68% agreement on longline position between observers. The experienced echocardiographer located three (7%) longlines within the heart that from radiographs were thought to be in a proximal central vessel. CONCLUSIONS: This technique is experience-dependent and complements rather than replaces the use of contrast radiography. However, some infants with an apparently acceptable longline position on contrast radiography have longlines located within the heart on echocardiography.

AP-ROP in an infant with minimal oxygen exposure.

Retinopathy of prematurity (ROP) is a multifactorial disease affecting the developing retinal vasculature and remains an important cause of blindness in very preterm infants. Rush disease, or aggressive posterior ROP (AP-ROP), progresses rapidly to stage 5 disease without exhibiting the classical course that includes stages 1-3. We describe an infant with minimal exposure to oxygen who developed AP-ROP that led to bilateral retinal detachments and a poor visual outcome, despite following current recommended screening guidelines.

Does retrograde diastolic flow in the descending aorta signify impaired systemic perfusion in preterm infants?

High-volume systemic-to-pulmonary ductal shunting occurs frequently in preterm infants and is indicated by diastolic flow reversal in the descending aorta (DAo). We studied the relationship between ductal diameter, diastolic DAo reversal, and left ventricular output (LVO); and superior vena caval (SVC) flow (upper body perfusion) and DAo flow (lower body perfusion) in preterm (<31 wk) infants. Echocardiographic assessments were performed at 5, 12, 24, and 48 h postnatal age (80 infants, median gestation 28 wk, 1060 g). Incidence of ductal patency fell from 100% at 5 h to 72% at 48 h; incidence of pure systemic-to-pulmonary shunting increased from 66% to 95% of infants with patent ducts. In infants with duct diameter greater than the median, 35-48% of infants had DAo flow reversal. In infants with duct diameter greater than median, DAo reversal was associated with 23-29% increases in LVO at 5-48 h, and 35% decreases in DAo flow volume at 24-48 h, but no differences in SVC flow. In conclusion, a large duct with left-to-right shunting is common in preterm infants. Retrograde DAo flow is a marker of high-volume shunt, evidenced by increased LVO. Preterm infants with high-volume ductal shunt may have preserved upper body perfusion but reduced lower body perfusion.

Survey of the management of neonatal hyperglycaemia in Australasia.

AIM: Hyperglycaemia is a common problem in very low birthweight (VLBW) preterm neonates and has been associated with an increase in intraventricular haemorrhage and mortality. There are few data to guide clinicians on the best range of blood glucose levels to aim for when treating hyperglycaemic preterm babies with insulin. The aim of this study was to survey all Australasian tertiary neonatal intensive care units for their current practice in the definition and management of neonatal hyperglycaemia to aid in the design of a randomised controlled trial of the effect of tight glycaemic control on long-term outcome in VLBW babies. METHODS: An online survey was sent to the 27 tertiary neonatal units in Australasia asking the respondents for details of their unit's definition and management of hyperglycaemia in VLBW infants. RESULTS: Twenty-three tertiary neonatal units responded to the questionnaire. There were six different definitions of hyperglycaemia, with most units defining neonatal hyperglycaemia as a blood glucose level greater than 10 mM. There were large variations in the criteria for commencing insulin (blood glucose level 8-15 mM +/- glycosuria) and target blood glucose ranges for babies on insulin (ranging from 2.5-8 mM to 8-15 mM). CONCLUSIONS: There is a wide variation in the management of neonatal hyperglycaemia between tertiary neonatal units in Australasia. This reflects the paucity of data available in this area. Further research on the management of neonatal hyperglycaemia is needed.

Early low cardiac output is associated with compromised electroencephalographic activity in very preterm infants.

Low cerebral blood flow in preterm infants has been associated with discontinuous electroencephalography (EEG) activity that in turn has been associated with poor long-term prognosis. We examined the relationships between echocardiographic measurements of blood flow, blood pressure (BP), and quantitative EEG data as surrogate markers of cerebral perfusion and function with 112 sets of paired data obtained over the first 48 h after birth in 40 preterm infants (24-30 wk of gestation, 510-1900 g at delivery). Echocardiographic measurements of right ventricular output (RVO) and superior vena caval (SVC) flow were performed serially. BP recordings were obtained from invasive monitoring or oscillometry. Modified cotside EEGs were analyzed for quantitative amplitude and continuity measurements. RVO 12 h after birth was related to both EEG amplitude at 12 and 24 h and continuity at 24 h. Mean systemic arterial pressure (MAP) at 12 and 24 h was related to continuity at 12 and 24 h after birth. Multiple regression analyses revealed that RVO at 12 h was related to median EEG amplitude at 24 h and diastolic BP at 24 h was related to simultaneous EEG continuity. In addition, at 12 h, infants in the lowest quartile for RVO measurements (<282 mL/kg/min) had lower EEG amplitude and those in the lowest quartile for MAP measurements (<31 mm Hg) had lower EEG continuity. These results suggest a relationship between indirect measurements of cerebral perfusion and cerebral function soon after birth in preterm infants.