An international comparison of retinopathy of prematurity grading performance within the Benefits of Oxygen Saturation Targeting II trials.

PurposeTo investigate whether the observed international differences in retinopathy of prematurity (ROP) treatment rates within the Benefits of Oxygen Saturation Targeting (BOOST) II trials might have been caused by international variation in ROP disease grading.MethodsGroups of BOOST II trial ophthalmologists in UK, Australia, and New Zealand (ANZ), and an international reference group (INT) used a web based system to grade a selection of RetCam images of ROP acquired during the BOOST II UK trial. Rates of decisions to treat, plus disease grading, ROP stage grading, ROP zone grading, inter-observer variation within groups and intra-observer variation within groups were measured.ResultsForty-two eye examinations were graded. UK ophthalmologists diagnosed treat-requiring ROP more frequently than ANZ ophthalmologists, 13.9 (3.49) compared to 9.4 (4.46) eye examinations, P=0.038. UK ophthalmologists diagnosed plus disease more frequently than ANZ ophthalmologists, 14.1 (6.23) compared to 8.5 (3.24) eye examinations, P=0.021. ANZ ophthalmologists diagnosed stage 2 ROP more frequently than UK ophthalmologists, 20.2 (5.8) compared to 12.7 (7.1) eye examinations, P=0.026. There were no other significant differences in the grading of ROP stage or zone. Inter-observer variation was higher within the UK group than within the ANZ group. Intra-observer variation was low in both groups.ConclusionsWe have found evidence of international variation in the diagnosis of treatment-requiring ROP. Improved standardisation of the diagnosis of treatment-requiring ROP is required. Measures might include improved training in the grading of ROP, using an international approach, and further development of ROP image analysis software.

The effect of implementing an automated oxygen control on oxygen saturation in preterm infants.

OBJECTIVE: To evaluate the effect of implementing automated oxygen control as routine care in maintaining oxygen saturation (SpO2) within target range in preterm infants. METHODS: Infants <30 weeks gestation in Leiden University Medical Centre before and after the implementation of automated oxygen control were compared. The percentage of time spent with SpO2 within and outside the target range (90-95%) was calculated. SpO2 values were collected every minute and included for analysis when infants received extra oxygen. RESULTS: In a period of 9 months, 42 preterm infants (21 manual, 21 automated) were studied. In the automated period, the median (IQR) time spent with SpO2 within target range increased (manual vs automated: 48.4 (41.5-56.4)% vs 61.9 (48.5-72.3)%; p<0.01) and time SpO2 >95% decreased (41.9 (30.6-49.4)% vs 19.3 (11.5-24.5)%; p<0.001). The time SpO2<90% increased (8.6 (7.2-11.7)% vs 15.1 (14.0-21.1)%; p<0.0001), while SpO2<80% was similar (1.1 (0.4-1.7)% vs 0.9 (0.5-2.1)%; ns). CONCLUSIONS: During oxygen therapy, preterm infants spent more time within the SpO2 target range after implementation of automated oxygen control, with a significant reduction in hyperoxaemia, but not hypoxaemia.

Influence of pulmonary factors on pulse oximeter saturation in preterm infants.

AIM: To describe how the stability of oxygen saturation measured by pulse oximetry (SpO2%) varies within and between infants with bronchopulmonary dysplasia (BPD). METHODS: Clinically stable infants with BPD had SpO2 measured at different inspired oxygen concentrations (FIO2 expressed as %). A computer model of gas exchange, that is, ventilation/perfusion ratio (VA/Q) and shunt, plotted the curve of SpO2 versus FIO2 best fitting these data. The slope of this curve is the change in SpO2 per % change in FIO2, hence SpO2 stability, calculated at each SpO2 from 85% to 95%. RESULTS: Data from 16 infants with BPD previously described were analysed. The dominant gas exchange impairment was low VA/Q (median 0.35, IQR, 0.16-0.4, normal 0.86). Median shunt was 1% (IQR, 0-10.5; normal <2%). Slope varied markedly between infants, but above 95% SpO2 was always <1.5. In infants with least severe BPD (VA/Q ≈0.4, shunt ≤2%) median slope at 85% SpO2 was 5.1 (IQR, 3.7-5.5). With more severe BPD (VA/Q ≤0.3) slope was flatter throughout the SpO2 range. The highest FIO2 for 90% SpO2 was in infants with the lowest VA/Q values. CONCLUSIONS: In infants with BPD, there was large variation in the slope of the curve relating SpO2% to inspired oxygen fraction in the SpO2 range 85%-95%. Slopes were considerably steeper at lower than higher SpO2, especially in infants with least severe BPD, meaning that higher SpO2 target values are intrinsically much more stable. Steep slopes below 90% SpO2 may explain why some infants appear dependent on remarkably low oxygen flows.

A simplified method for deriving shunt and reduced VA/Q in infants.

BACKGROUND: Right to left shunt and regional hypoventilation (reduced ventilation/perfusion ratio (V(A)/Q)) have different effects on the curve relating inspired oxygen (P(I)O(2)) to oxygen saturation measured by pulse oximetry (SpO(2)) and can be derived non-invasively from measurements of SpO(2) and inspired oxygen pressure (P(I)O(2)) using complex models of gas exchange. We developed a simpler computerised "slide-rule" method of making these derivations. AIMS: To describe the slide-rule method and determine agreement between measurements derived with this and a more complex algorithm. METHODS: Series of P(I)O(2) versus SpO(2) data points obtained during 43 studies in 16 preterm infants with bronchopulmonary dysplasia were analysed. Percentage shunt and the degree of right shift (kPa) of the P(I)O(2) versus SpO(2) curve compared with the oxyhaemoglobin dissociation curve (a measure of V(A)/Q) were determined for each dataset with both methods, and the results were compared using the method of Bland and Altman. RESULTS: The computer slide-rule method produced results for all 43 datasets. The more complex model could derive results for 40/43 datasets. The mean differences (95% limits of agreement) between the two methods for measurements of shunt were -1.7% (-6.5 to +3.5%) and for measurements of right shift were 0.3 kPa (-2.9 to +3.6 kPa). CONCLUSION: The slide-rule method was reliable for deriving shunt and right shift (reduced V(A)/Q) of the P(I)O(2) versus SpO(2) curve when compared with the more complex algorithm. The new method should enable wider clinical application of these measurements of oxygen exchange.

Arterial oxygen tension (Pao2) values in infants <29 weeks of gestation at currently targeted saturations.

BACKGROUND: Oxygen saturation (Spo(2)) monitors are commonly used to determine the need for supplemental oxygen. We aimed to describe the range of arterial oxygen tensions (Pao(2)) observed in preterm infants at saturation levels targeted in current trials. METHODS: In a cohort of 98 consecutive infants born at <29 weeks' gestation, the Pao(2) from each arterial blood gas result during the first week of life (n = 2076) was matched to the Spo(2) at time of sampling. The mean (95% CI) Pao(2) was calculated for each saturation. RESULTS: The 95% CI of Pao(2) for the Spo(2) range 85-95% was 3.8 to 8.9 kPa. The mean (95% CI) Pao(2) at a saturation of 85% was 5.3 (3.8 to 6.8) kPa and at a saturation of 95% it was 7.2 (5.5 to 8.9) kPa. CONCLUSION: Saturations within the range 85-95% largely exclude hyperoxia in preterm infants <29 weeks' gestation but permit Pao(2) values far lower than those recommended in traditional guidelines.

Does the monitoring method influence stability of oxygenation in preterm infants? A randomised crossover study of saturation versus transcutaneous monitoring.

INTRODUCTION: Hyperoxia and variable oxygenation are associated with morbidity in preterm infants. The optimal range of oxygen tensions is not known. This study aimed to determine whether care based on transcutaneous oxygen tension (TcPO2) or saturation (SpO2) monitoring is associated with less time spent with high oxygen tension and less variability of oxygenation. METHODS: SpO2 and TcPO2 were measured simultaneously during two 3-h study periods allocated in random order. During one period supplemental oxygen was adjusted according to TcPO2 (target range 6.0-9.0 kPa) and during the other according to SpO2 (target range 86-94%). During each period, readings from the second monitor were not displayed. Both TcPO2 and SpO2 were downloaded every second. For each period the mean level and the variability (standard deviation) of SpO2 and TcPO2 and the percentage of time spent above and below target range were calculated and compared. RESULTS: 19 infants, 13 ventilated and 6 on continuous positive airway pressure, were studied at mean corrected gestational age of 27.2 weeks and mean postnatal age of 6.8 days. Their mean fraction of inspired oxygen at the start of the study was 0.34. Care based on SpO2 monitoring was associated with more time spent with high oxygen tension (median increase 2.62%, p = 0.01), more time with low oxygen tension (median increase 17.41%, p = 0.01), more variability in oxygen tension (median increase 0.28 kPa, p = 0.02) and more variability in oxygen saturation (median increase 0.82%, p = 0.01) than care based on TcPO2 monitoring. CONCLUSION: Within the target ranges studied SpO2 monitoring was associated with significantly more variable oxygenation than TcPO2 monitoring.

Is intrapartum asphyxia preventable?

The contribution of intrapartum events to asphyxia-related mortality and morbidity and the degree to which it may be prevented are controversial. We examined trends in asphyxia-related mortality and morbidity in a single large regional perinatal centre. Between 1994 and 2005, the rate of asphyxia fell from 2.86/1000 births in 1994 to 0.91/1000 births in 2005 (P < 0.001). Hypoxic-ischaemic encephalopathy of all grades fell from 2.41 to 0.77/1000 live births (P < 0.001). This substantial and steady fall in the rate of asphyxia-related mortality and morbidity over a 12-year period suggests that a significant proportion of cases of intrapartum asphyxia may be preventable.

Non-invasive measurement of reduced ventilation:perfusion ratio and shunt in infants with bronchopulmonary dysplasia: a physiological definition of the disease.

BACKGROUND: An objective definition of bronchopulmonary dysplasia (BPD) is required to interpret trial outcomes and provide a baseline for prognostic studies. Current definitions do not quantify disease severity. The cardinal measures of impaired gas exchange are a reduced ventilation:perfusion ratio (V(A):Q) and increased right to left shunt. These can be determined non-invasively by plotting arterial oxygen saturation (Spo(2)) against inspired oxygen pressure (PIo(2)). AIMS: To describe the reduced V(A):Q and shunt in infants with BPD and evaluate these as graded measures of pulmonary dysfunction. METHODS: 21 preterm infants with BPD were studied. PIo(2) was changed stepwise to vary Spo(2) between 86% and 94%. Pairs of PIo(2) and Spo(2) data points for each infant were plotted and analysed to derive reduced V(A):Q ratio and shunt. RESULTS: In every infant, the Spo(2) versus PIo(2) curve was shifted to the right of the normal because of a reduced V(A):Q. The mean (SD) shift was 16.5 (4.7) kPa (normal 6 kPa). Varying degrees of shunt were also present, but these were less important in determining Spo(2) within the studied range. The degree of shift was strongly predictive of the PIo(2) required to achieve any Spo(2) within the range 86-94% (R(2)>0.9), permitting shift and V(A):Q to be determined from a single pair of PIo(2) and SpO(2) values in this range. CONCLUSIONS: The predominant gas exchange impairment in BPD is a reduced V(A):Q, described by the right shift of the Spo(2) versus PIo(2) relationship. This provides a simpler method for defining BPD, which can grade disease severity.

Effect of partial liquid ventilation and nebulized perfluorocarbon on CT lung density distribution: randomized controlled study of experimental lung injury.

BACKGROUND: Perfluorocarbon (PFC) liquid can improve gas exchange in acute lung injury. How PFC aerosol is distributed in the lung is unknown. METHODS: We induced lung injury in rabbits with saline lavage, followed by mechanical ventilation in the supine position. The animals were divided into three groups: a control group, a group treated with partial liquid ventilation and a group given nebulized perfluorocarbon (PF 5080). We made CT image slices of the excised lungs. In the apical, middle and caudal slices we defined three regions of interest, from anterior to posterior, and noted the mean attenuation of each area. We also studied two rabbits which had not received lung injury or mechanical ventilation. RESULTS: Group means were different between the normal rabbits and all three study groups. There was a difference between the control and partial liquid ventilation groups, and between the partial liquid ventilation and nebulized groups, but no difference between the nebulized and control groups. Within each treatment group, there was no regional difference in the distribution of density. CONCLUSIONS: PF 5080 is not deposited in large amounts by aerosol. Less PFC was found in the lungs after partial liquid ventilation than expected. Within treatment groups, lung densities indicate less gravitational and regional differences than found in other studies.

Neonatal research: the parental perspective.

OBJECTIVES: To investigate the recollections of parents consenting for their infants to be research subjects and determine their views about the need for consent. SUBJECTS: Parents of 154 sick newborn infants enrolled in a randomised trial in the early neonatal period. All parents had given written consent and received printed information. METHODS: A questionnaire and accompanying letter was sent to the parental home 18 months later. Non-responders were sent a further questionnaire and letter. RESULTS: Response rate was 64% (99/154). Some respondents (12%) did not remember being asked to consent to their baby joining a study, and a further 6% were unsure. Most of the respondents (79%) were happy, 13% neutral, and 8% unhappy with their decision to give consent. None felt heavy pressure to agree. Entering the trial caused 24% of respondents to feel more anxious, 56% neutral, and 20% less anxious about their baby. Most of the respondents (83%) would be unhappy to forgo the consent process for trials passed by the institutional ethics committee. CONCLUSIONS: A significant proportion of parents who give written consent for a trial in the early neonatal period do not later remember having done so. Parents who have had experience of neonatal research would be unhappy for their baby to be enrolled in a study that had ethics committee approval without their consent being obtained.

Preterm meconium staining of the amniotic fluid: associated findings and risk of adverse clinical outcome.

BACKGROUND: The incidence of preterm meconium staining of the amniotic fluid (MSAF) is uncertain. It may be an indicator of possible listeriosis. It is unclear how great this risk is or whether preterm MSAF is a risk factor for adverse neonatal outcome. OBJECTIVE: To investigate the incidence of preterm MSAF, the incidence of associated maternal and neonatal infection, and the outcomes of the infants at discharge. DESIGN: Retrospective case-control study. METHODS: Infants < 33 weeks gestation with preterm MSAF born in the Simpson Memorial Maternity Pavilion, Edinburgh between 1 January 1994 and 2 January 2001 were matched with the next infant of the same sex and gestation with clear liquor. Maternal and infant characteristics, culture results, placental histology, and clinical outcomes were compared. RESULTS: Preterm MSAF was observed in 45/1054 (4.3%) infants below 33 weeks gestation. No maternal or infant listeriosis was identified in cases or controls. There was no significant difference in birth weight, Apgar score, or first pH between cases and controls. Preterm MSAF was associated with prolonged rupture of the membranes (odds ratio (OR) 3.34, 95% confidence interval (CI) 1.07 to 10.49), but not maternal hypertension, sepsis, or chorioamnionitis. Severe (grade 3/4) intraventricular haemorrhage was significantly more common in infants with preterm MSAF (OR 2.03, 95% CI 1.62 to 2.53). There was no significant difference in mortality. Early onset sepsis was observed in two cases and three controls. CONCLUSIONS: Preterm meconium staining of the amniotic fluid may be associated with increased risk of intraventricular haemorrhage. It does not appear to be a useful indicator of listeriosis.

As time goes by.

The timing of birth-related events may influence neonatal outcome and is often pivotal in medicolegal cases. This prospective observational study determined the variation in displayed time on timepieces in a regional maternity unit which could result in inaccuracies of time documentation. The mean (95% CI) difference between time displayed and true time was sec (+/- 2 min 4 sec) for delivery room clocks and +1 m 8 s (+/- 7 m 12 s) for resuscitation room clocks. The maximum discrepancy between delivery room and resuscitation room clocks was 7 m 52 s. The abilities of staff to estimate the duration of time passed was also assessed. The mean (95% CI) five-minute estimate was 4 m 52 s (+/- 3 m 12 s). These disparities could have considerable medicolegal significance, and should be taken into consideration in risk management studies. Maternity units should move towards synchronising all timepieces. Meanwhile, statements about the precise timing of events should be regarded with suspicion.

Randomised comparison of partial liquid ventilation, nebulised perfluorocarbon, porcine surfactant, artificial surfactant, and combined treatments on oxygenation, lung mechanics, and survival in rabbits after saline lung lavage.

OBJECTIVE: To compare gas exchange, lung mechanics, and survival to 12 h in surfactant-depleted lung-injured rabbits, treated with partial liquid ventilation (PLV) with perfluorocarbon, nebulised perfluorocarbon, and porcine or artificial surfactant. DESIGN: Prospective randomised controlled study. SETTING: Animal laboratory, University of Edinburgh, UK. SUBJECTS: Eighty-two adult female New Zealand white rabbits with surfactant deficiency and acute lung injury induced by repeated saline lavage. INTERVENTIONS: Animals were randomised to one of seven treatments: (a) control (n = 20); (b) PLV with perfluorocarbon PF 5080 (n = 12); (c) nebulised PF 5080 (n = 10); (d) artificial surfactant (n = 10); (e) porcine surfactant (n = 10); (f) artificial surfactant+PLV (n = 10); (g) porcine surfactant+PLV (n = 10). MEASUREMENTS AND MAIN RESULTS: Arterial blood gases and dynamic compliance (Cdyn) were measured hourly until 12 h. Oxygenation was improved by PLV, porcine surfactant, porcine surfactant+PLV and artificial surfactant+PLV. Cdyn improved after treatment with PLV, porcine surfactant and PLV+porcine surfactant. Survival was greater with PLV and artificial surfactant+PLV. Neither nebulised PF 5080 nor artificial surfactant had a detectable effect. CONCLUSIONS: PLV, porcine surfactant and combinations of surfactant with PLV improved oxygenation, Cdyn and survival, but none was clearly superior to the others.

Measurement of interleukin 10 in bronchoalveolar lavage from preterm ventilated infants.

BACKGROUND: Interleukin 10 (IL-10) is a cytokine that downregulates inflammation, in part by reducing the production of the proinflammatory cytokines IL-1beta and IL-8. It has been suggested that an inability to produce IL-10 might predispose preterm infants to develop chronic lung disease. AIM: To measure IL-10, IL-1beta, and IL-8 in bronchoalveolar lavage fluid from ventilated preterm infants in a prospective cohort study. PATIENTS: 17 consecutive newborn infants < or = 29 weeks' gestational age (median, 25; 9 boys) who were ventilated from birth underwent daily bronchoalveolar lavage sampling. RESULTS: 102 samples were collected, of which 57 contained IL-10 in amounts that were comparable with those found previously in ventilated term infants with respiratory failure. Chronic lung disease developed in 9 of the 11 survivors and all 9 infants had produced IL-10. IL-1beta and IL-8 were detected in nearly all samples and were raised throughout the course of sample collection. CONCLUSION: IL-10 is readily detectable in early bronchoalveolar lavage samples from ventilated preterm infants, although it remains unclear whether this cytokine has any influence on the development of chronic lung disease.

Randomised controlled trial of respiratory system compliance measurements in mechanically ventilated neonates.

AIM: To determine whether outcomes of neonatal mechanical ventilation could be improved by regular pulmonary function testing. METHODS: Two hundred and forty five neonates, without immediately life threatening congenital malformations, were mechanically ventilated in the newborn period. Infants were randomly allocated to conventional clinical management (control group) or conventional management supplemented by regular measurements of static respiratory system compliance, using the single breath technique, with standardised management advice based on the results. RESULTS: Fifty five (45%) infants in each group experienced one or more adverse outcomes. The median (quartile) durations of ventilation and oxygen supplementation were 5 (2-12) and 6 (2-34) days for the control group, and 4 (2-9) and 6 (3-36) days for the experimental group (not significant). On post-hoc secondary analysis, control group survivors were ventilated for 1269 days with a median (quartile) of 5 (2-13) days, and experimental group survivors were ventilated for 775 days with a median (quartile) duration of 3 (2-8) days (p = 0.03). CONCLUSIONS: Although primary analysis did not show any substantial benefit associated with regular measurement of static respiratory system compliance, this may reflect a type II error, and a moderate benefit has not been excluded. Larger studies are required to establish the value of on-line monitoring techniques now available with neonatal ventilators.

Influence of erythromycin on establishment of feeding in preterm infants: observations from a randomised controlled trial.

AIM: To determine the effect of erythromycin on the establishment of enteral feeding in ventilated infants < 31 weeks gestation. METHODS: Erythromycin was randomly allocated as an antimicrobial treatment for the first 7 days of life in 76 infants: 35 received erythromycin and 41 acted as controls. Feed toleration, time taken to establish full enteral feeding, vomiting, prescription of glycerine suppositories and occurrence of necrotising enterocolitis were recorded. RESULTS: There were no significant differences between the groups for any of the outcomes. The infants treated with erythromycin reached full feeding at a median (quartile) age of 8 (5-12) days compared with 9 (6-14) days for controls. CONCLUSIONS: Intravenous erythromycin in antimicrobial doses is unlikely to benefit the introduction of feeding in preterm infants.

Life-threatening inadvertent positive end-expiratory pressure.

Inadvertent positive end-expiratory pressure (PEEP) is a potential cause of lung overdistension and impaired gas exchange in ventilated infants. It can be extremely difficult to diagnose clinically and if unrecognized can be life-threatening. Measurement of lung function can lead to the recognition of inadvertent PEEP, allowing appropriate ventilator adjustment with immediate substantial improvement in clinical state. Lung function measurements can help to optimize ventilation and may improve clinical outcome.

Reliability of clinical assessments of respiratory system compliance (Crs) made by junior doctors.

OBJECTIVE: To assess the reliability of estimates of static respiratory system compliance (Crs) made by junior hospital doctors caring for ventilated newborn infants. DESIGN: A prospective comparison of junior doctors' estimates of Crs to the Crs measured immediately afterwards. SETTING: A regional neonatal intensive care nursery in Edinburgh, Scotland. PATIENTS: 46 ventilated newborn infants. MEASUREMENTS AND RESULTS: Crs was estimated by three grades of junior doctor (Senior House Officer, Registrar and Research Fellow) using two different methods, (i) based on visual assessment of tidal volume in relation to inflation pressure (optical Crs) and (ii) directly using a visual analogue scale (analogue Crs). The Crs was then measured immediately afterwards using the single breath passive expiratory flow technique. The differences between the estimates and the measurements were calculated for each grade of observer and plotted against the corresponding measurements. The relationship between estimates and measurements was also expressed in terms of the coefficients of determination r2 calculated by least squares regression. With both methods of estimation observers tended to overestimate the Crs of infants with lower measured Crs and underestimate that of infants with higher measured Crs with many estimates differing from the measurements by more than 50%. Values of r2 ranged from 0.086 to 0.481 indicating a weak relationship between the estimates and the measurements. CONCLUSIONS: Junior doctors' estimates of Crs were unreliable and did not represent a useful method of assessing respiratory function. The clinical use of compliance measurements merits wider evaluation.