Amnioinfusion in very early preterm prelabor rupture of membranes (AMIPROM): pregnancy, neonatal and maternal outcomes in a randomized controlled pilot study.

OBJECTIVE: To assess short- and long-term outcomes of pregnant women with very early rupture of membranes randomized to serial amnioinfusion or expectant management, and to collect data to inform a larger, more definitive clinical trial. METHODS: This was a prospective non-blinded randomized controlled trial with randomization stratified for pregnancies in which the membranes ruptured between 16 + 0 and 19 + 6 weeks' gestation and 20 + 0 and 23 + 6 weeks' gestation to minimize the risk of random imbalance in gestational age distribution between randomized groups. Intention-to-treat analysis was used. The study was conducted in four UK hospital-based fetal medicine units (Liverpool Women's NHS Trust, St Mary's Hospital Manchester, Birmingham Women's NHS Foundation Trust and Wirral University Hospitals Trust). The participants were women with confirmed preterm prelabor rupture of membranes at 16 + 0 to 24 + 0 weeks' gestation. Women with multiple pregnancy, fetal abnormality or obstetric indication for immediate delivery were excluded. Participants were randomly allocated to either serial weekly transabdominal amnioinfusions if the deepest pool of amniotic fluid was < 2 cm or expectant management until 37 weeks' gestation. Short-term maternal, pregnancy and neonatal and long-term outcomes for the child were studied. Long-term respiratory morbidity was assessed using validated respiratory questionnaires at 6, 12 and 18 months of age and infant lung function test at around 12 months of age. Neurodevelopment was assessed using the Bayley Scales of Infant Development, second edition (BSID-II) at corrected age of 2 years. RESULTS: Fifty-eight women were randomized to the study. Two babies were excluded from the analysis because of termination of pregnancy for lethal anomaly, leaving 56 participants (28 assigned to serial amnioinfusion and 28 to expectant management) recruited between 2002 and 2009. There was no significant difference in perinatal mortality (19/28 vs 19/28; relative risk (RR) 1.0 (95% CI, 0.70-1.43)) and maternal or neonatal morbidity. The overall chance of surviving without long-term respiratory or neurodevelopmental disability was 4/56 (7.1%); 4/28 (14.3%) in the amnioinfusion group and 0/28 in the expectant group (RR 9.0 (95% CI, 0.51-159.70)). CONCLUSIONS: This pilot study found no major differences in maternal, perinatal or pregnancy outcomes. The study was not designed to show a difference between the groups and the number of survivors was too small to draw any conclusions about long-term outcomes. It does, however, signal that a larger definitive study to evaluate amnioinfusion for improvement in healthy survival is needed. The pilot suggests that, with appropriate funding, such a study is feasible.

Reference equations for specific airway resistance in children: the Asthma UK initiative.

Plethysmographic specific airway resistance (sR(aw)) is a useful research method for discriminating lung disease in young children. Its use in clinical management has, however, been limited by lack of consensus regarding equipment, methodology and reference data. The aim of our study was to collate reference data from healthy children (3-10 yrs), document methodological differences, explore the impact of these differences and construct reference equations from the collated dataset. Centres were approached to contribute sR(aw) data as part of the Asthma UK initiative. A random selection of pressure-flow plots were assessed for quality and site visits elucidated data collection and analysis protocols. Five centres contributed 2,872 measurements. Marked variation in methodology and analysis excluded two centres. sR(aw) over-read sheets were developed for quality control. Reference equations and recommendations for recording and reporting both specific effective and total airway resistance (sR(eff) and sR(tot), respectively) were developed for White European children from 1,908 measurements made under similar conditions. Reference sR(aw) data collected from a single centre may be misleading, as methodological differences exist between centres. These preliminary reference equations can only be applied under similar measurement conditions. Given the potential clinical usefulness of sR(aw), particularly with respect to sR(eff), methodological guidelines need to be established and used in prospective data collection.

Standardizing lung function laboratories for multicenter trials.

Multi-center studies provide advantages in clinical research but differences between centers can introduce bias. Three specialist pediatric respiratory laboratories standardized their methodology and examined differences between centers. The specific aims were to (i) assess the variability of measurements on adults within and between centers and (ii) to exchange and cross-analyze data from children to assess the extent of agreement between centers. Each laboratory used identical equipment and software. Inter-laboratory visits were used to (i) standardize protocols for data collection and analysis and (ii) make spirometric and plethysmographic measurements on participating staff at each location. Staff also had repeat measurements in their home laboratories. Measurements from children in each laboratory were exchanged on disk, cross-analyzed, and data compared by ANOVA. There were no significant within-subject, between-center differences in FVC, FEV1, FEF50, FRCpleth, or VC. There was a slight trend for TLC and RV (P=0.07) to be higher at one center. The 95% limits of agreement within and between centers were similar for all parameters. There were no differences between centers in cross-analyzed data from 10 children. By standardizing hardware, software, and protocol, potential inter-laboratory differences can be minimized. We recommend that this approach be adopted prior to multi-center studies.

The shifting sands of research ethics and governance: effect on research in paediatrics.

Basic principles governing the ethical conduct of research have not changed but recent years have seen the burgeoning of bureaucracy to support and monitor research ethics and governance. More changes are planned, and the effect of the proposed changes on paediatric research are examined and broadly welcomed.

Are ethnic differences in lung function explained by chest size?

BACKGROUND: Ethnic differences in lung function (LF) are recognised in adults and children. Most prediction equations for LF are derived from whites, so non-whites are at risk of erroneous assessment. It was hypothesised that differences in chest dimensions would explain differences in LF between Asian (Indian) and white schoolchildren. AIMS: To quantify the impact of chest dimensions on LF, which would inform our understanding of ethnic differences that have implications for health care. METHODS: Children aged 6-11 were studied in school. A questionnaire provided information on ethnicity and respiratory health. Spirometry was used to record FVC, FEV1, FEF25-75, and PEF. Weight, height, sitting height, and chest dimensions (chest height, circumference, antero-posterior and transverse diameters) were measured. RESULTS: Data were obtained from 294 healthy children. Standing height was the most important predictor of LF. Ethnicity was an independent predictor for all LF measures except PEF, where the effect was marginal. FVC in whites was 13.4% bigger than in Asians of the same height, and the FEV1 was 10.6% greater in whites. The influence of chest dimensions on lung function was trivial. Body mass index was smaller in Asians but did not explain differences in LF. CONCLUSIONS: Differences in chest dimensions did not explain the substantial effect of ethnicity on LF. Mechanisms whereby ethnicity exerts its influence may include differences in inspiratory muscle strength or lung compliance but remain speculative. Nevertheless it remains imperative that ethnic differences are recognised when interpreting LF tests.

Breath-hold MRI in evaluating patients with pectus excavatum.

Pectus excavatum (PE) is a congenital condition in which the sternum is displaced posteriorly with associated changes in the adjacent costal cartilages. The aetiology of PE is uncertain although various underlying abnormalities of the diaphragm have been implicated. There is sparse information regarding the use of fast MRI in evaluating the deformity. Our aims were to use fast MRI to evaluate static and respiratory-related dynamic chest wall characteristics, the extent of cardiac displacement and diaphragmatic excursion in patients. FLASH and TurboFLASH MR sequences in axial and coronal planes were performed on the thoraces of six young patients with PE and six individually matched healthy controls during full inspiratory and full expiratory breath-holds. The Pectus Index was derived from chest wall measurements using axial images. The distances of the left and right cardiac borders from the midline were measured using axial images, and excursion of the dome of each hemidiaphragm was measured using coronal images. The degree of sternal depression worsened substantially in expiration. Anterior chest wall movement was similar in the two groups. Patients had significantly flatter chests than the controls. There was a trend towards leftward cardiac displacement in the patients (maximum distance between left heart border and midline during full expiration 99.5 mm in patients and 91.8 mm in controls). The right diaphragmatic dome excursion was greater than the left in the controls (53.6 mm and 47.4 mm, respectively), but this was not seen in the patients (50.2 mm and 50.4 mm, respectively). It is concluded that fast MRI is very informative in evaluating skeletal abnormalities, chest wall motion, and cardiac and diaphragmatic changes seen in PE.

Plethysmographic measurements of lung volume and airway resistance. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. European Respiratory Society/ American Thoracic Society.

Functional residual capacity (FRC) is the only static lung volume that can be measured routinely in infants. It is important for interpreting volume-dependent pulmonary mechanics such as airway resistance or forced expiratory flows, and for defining normal lung growth. Despite requiring complex equipment, the plethysmographic method for measuring FRC is very simple to apply and, unlike the gas dilution techniques, enables repeat measures of lung volume to be obtained within a few minutes. This method has the further advantage that with suitable adaptations to the equipment, simultaneous measurements of airway resistance can also be obtained. The aim of this paper is to provide recommendations pertaining to equipment requirements, study procedures and reporting of data for plethysmographic measurements in infants. Implementation of these recommendations should help to ensure that such measurements are as accurate as possible and that meaningful comparisons can be made between data collected in different centres or with different equipment. These guidelines cover numerous aspects including terminology and definitions, equipment, data acquisition and analysis and reporting of results and also highlight areas where further research is needed before consensus can be reached.

Effect of maternal smoking on ventilatory responses to changes in inspired oxygen levels in infants.

Maternal smoking is a major independent risk factor for sudden infant death syndrome (SIDS). Respiratory control deficits have been implicated in SIDS. The aim of this study was to test the hypothesis that infants born to smoking mothers have reduced ventilatory responses to changes in inspired oxygen. Smoking and nonsmoking women were recruited in midpregnancy and smoking status confirmed by measurement of urinary cotinine. To control for confounding factors of smoking each mother-infant pair in the smoking group was matched to a pair in the nonsmoking group for social class, maternal age and parity, feeding, birthweight, gestational age, and infant sex. Infants were seen overnight at approximately 10 wk of age for tests of respiratory control, using the alternating breath test. Ventilation was measured by respiratory inductance plethysmography and inspired and end-tidal oxygen levels were determined by mass spectrometry. Data were obtained from 40 infants (17 in the smoking group). Responses were similar in both groups for 10 respiratory parameters including respiratory drive and timing, and there were no significant differences. The mean end-tidal oxygen level when 40% O(2) was delivered was an average of 1.13% higher in the smoking group (p = 0.0067), although the inspired oxygen levels were not different. In conclusion, we did not find an independent effect of maternal smoking on respiratory control. The differences in end-tidal oxygen levels during the alternating breath test may represent differences in alveolar ventilation.

Alterations in airway wall properties in infants with a history of wheezing disorders.

Airway diameter and airway wall mechanics (compliance) are important determinants of flow limitation and wheezing. We have previously used the high-speed interrupter technique (HIT) to measure input impedance (Zin) in infants at frequencies up to 900 Hz, including antiresonance phenomena, which are known to be related to wave propagation velocity, and have shown that the frequency at which the first antiresonance occurs (f(ar,1)) is a function of airway wall compliance. We aimed to determine whether f(ar,1) (and thus airway wall compliance) was different in infants with a history of wheezing disorders. We compared 23 asymptomatic infants (aged 36 to 81 wk) with a history of wheezing with an age-matched group of 19 healthy control infants. We found that f(ar,1) was significantly lower in infants with wheezing disorders than in the control group (p < 0. 005), implying differences in airway wall compliance, even when they were clinically asymptomatic. Developmental differences in airway wall mechanics may be important in the pathogenesis of wheezing disorders or, alternatively, alterations in airway wall mechanics might be a consequence of postinflammatory remodeling.

Respiratory function in survivors of the United Kingdom Extracorporeal Membrane Oxygenation Trial.

Extracorporeal membrane oxygenation (ECMO) improves survival in mature neonates with reversible lung disease. However, ECMO could result in survival of infants with severe respiratory dysfunction who would otherwise have died. Alternatively, infants receiving ECMO might be spared prolonged ventilation and consequent barotrauma, resulting in improved respiratory function. Our aim was to compare respiratory function at 1 yr of age in infants assigned to receive either ECMO or conventional management (CM). Seventy-eight surviving infants of the United Kingdom (UK) ECMO trial (51 in the ECMO group) were studied at 1 yr of age. Questionnaires provided details of respiratory symptoms, and laboratory measurements of respiratory function were made for respiratory rate, tidal volume, lung volume, airway conductance, specific airway conductance, and maximal expiratory flow at FRC (Vmax (FRC)). Data were exchanged on floppy disk for cross-analysis and to ensure that investigators were blinded to the status of the infants. There was a wide spectrum of respiratory function, from normal to markedly abnormal. There were few differences between the groups, but in the CM group lung volume was increased (95% confidence intervals [CIs] of the difference in ECMO versus CM subjects: -67; -4 ml), and inspiratory specific conductance was lower (95% CI: 0.03; 0.98 s(-)(1). kPa(-)(1)). There was a trend toward a lower V max(FRC) (95% CI: -2; 67 ml/s(-)(1) in the CM group. In addition to providing a survival advantage, ECMO did not worsen lung function in infants assigned to receive it. Indeed, their lung function appeared slightly better than that of infants treated conventionally.

No objective benefit from steroids inhaled via a spacer in infants recovering from bronchiolitis.

A double-blind randomized placebo-controlled trial was conducted to investigate the efficacy of 3 months' inhaled steroids delivered via a spacer device with face mask attachment to infants recovering from bronchiolitis. Forty-eight previously healthy infants recovering from their first documented episode of acute bronchiolitis were randomized to receive 150 microg fluticasone propionate (FP) b.i.d. or placebo delivered via the Babyhaler spacer. Longitudinal assessments were performed on seven occasions over 1 yr based on symptom diaries and health records, clinical examinations, overnight cough recordings and oxygen saturation readings. Lung function was measured 6 months after hospital discharge. Forty-three infants completed the trial (FP 21, placebo 22). There were no significant differences in the three objective end-points measured, recorded night cough, oxygen saturation and lung function test results. Symptom scores were low in both the FP and placebo groups with the absence of (0) or mild (1) symptoms > or =90% of the trial days. No statistical differences in symptom frequency, use of rescue respiratory medications or hospital admissions between treatment groups were found throughout the trial or follow-up periods. In conclusion, the use of inhaled fluticasone propionate in infants recovering from acute bronchiolitis cannot be recommended.

Respiratory inductance plethysmography in healthy infants: a comparison of three calibration methods.

Respiratory inductance plethysmography (RIP) measures respiration from body surface movements. Various techniques have been proposed for calibration in order that RIP may be used quantitatively. These include calculation of the proportionality constant of ribcage to abdominal volume change (K). The aims of this study were to 1) establish whether a fixed value of K could be used for calibration, and 2) compare this technique with multiple linear regression (MLR) and qualitative diagnostic calibration (QDC) in normal healthy infants. Recordings of pneumotachograph (PNT) flow and RIP were made during quiet (QS) and active sleep (AS) in 12 infants. The first 5 min in a sleep state were used to calculate calibration factors, which were applied to subsequent validation data. The absolute percentage error between RIP and PNT tidal volumes was calculated. The percentage error was similar over a wide range of K during QS. However, K became more critical when breathing was out of phase. A standard for K of 0.5 was chosen. There was good agreement between calibration methods during QS and AS. In the first minute following calibration during QS, the mean absolute errors were 3.5, 4.1 and 5.3% for MLR, QDC and fixed K respectively. The equivalent errors in AS were 11.5, 13.1 and 13.7% respectively. The simple fixed ratio method can be used to measure tidal volume with similar accuracy to multiple linear regression and qualitative diagnostic calibration in healthy unsedated sleeping infants, although it remains to be validated in other groups of infants, such as those with respiratory disease.

Ethical issues in lung function testing in children.

Most lung function tests are non-invasive and they are widely performed in children and adults for clinical reasons. The prevalence of respiratory disorders is such that there is a considerable amount of research in the area. For both clinical and research applications, professionals involved in lung function testing in children need to be aware of ethical issues pertaining to such testing. In general, these are not specific to lung function testing but are common to other non-invasive procedures. These include the need to recognize the autonomy of the child (appropriate for age and maturity) and the importance of providing information in ways that a child can understand. The issues surrounding consent, confidentiality, and risk-benefit assessment are particularly important in vulnerable groups such as children. Parents, too, have a clear influence on healthcare issues surrounding children and hitherto have not always been appropriately involved. Healthcare professionals have a duty to children and their families to safeguard their psychological, social and emotional well-being, as well as their physical health.

Respiratory function in childhood following repair of oesophageal atresia and tracheoesophageal fistula.

AIM: To determine the relation between respiratory function in infancy and at school age in children who have undergone oesophageal atresia and tracheoesophageal fistula repair, and assess the value of infant respiratory function testing; and to examine the effect of bronchodilators. METHOD: Fourteen children (6 girls, and 8 boys) who had undergone respiratory function testing in infancy were retested at school age (7-12 years). Measurements included lung volume, airways resistance, peak flow, and spirometry. Clinical problems were investigated by questionnaire. Twelve children had repeat measurements after taking salbutamol. RESULTS: Predominant complaints were non-productive cough and dysphagia, but even those children with major problems in infancy reported few restrictions at school or in sport or social activities. Respiratory function and clinical findings at school age appeared unrelated to status in infancy, such that even the patients with severe tracheomalacia requiring aortopexy did not have lung function testing suggestive of malacia at school age. Most patients showed a restrictive pattern of lung volume which would appear to result from reduced lung growth after surgery rather than being a concomitant feature of the primary congenital abnormality. Although six children reported wheeze and four had a diagnosis of asthma, only one responded to salbutamol. This suggests that a tendency to attribute all lower respiratory symptoms to asthma may have led to an overdiagnosis of this condition in this patient group. CONCLUSION: Respiratory function testing in infancy is of limited value in medium term prognosis, but may aid management of contemporary clinical signs. In children respiratory function testing is valuable in assessing suspected asthma and effects of bronchodilators.

Nasal flow limitation in children.

Nasal congestion due to the common cold may be exacerbated in small children because of their small nasal passages. Our aims were 1) to test the hypothesis that smaller children have relatively larger nasal airways compared to the intrathoracic airways, and 2) to examine the effect of stenting and a decongestant on nasal patency and nasal flow. During oral forced vital capacity (FVC) maneuvers, expiratory flow is limited by intrathoracic airways. During nasal FVC, flow at high volumes is limited by the nose. The point where the nasal flow-volume curve becomes superimposable on the oral curve (%Sup) depends on the relative resistance of nasal and intrathoracic airways. Fifty-four healthy children (28 male), median age 9.5 years (range 5.9-16.0), performed full forced respiratory maneuvers through: 1) the mouth, 2) the nose, 3) the nose after application of an external stent (Breathe Right (BR) strip), and 4) the nose following instillation of xylometazoline. Peak inspiratory and expiratory flow (PIF and PEF), and mid-inspiratory and expiratory flow (MIF50 and MEF50) all showed a significant decrease from the oral to the nasal baseline maneuver. Mean (SD) %Sup of the nasal baseline was 35.6 (13.7)% and was unrelated to height. PIF and MIF50 increased with the BR strip (P < 0.05). Xylometazoline also caused a significant increase in all measured flows (P < 0.05). Mean (SD) %Sup of the nasal maneuver after application of xylometazoline increased to 53.3 (14.0)%. We conclude that there is no evidence that relative resistance of nasal and intrathoracic airways change with height. The %Sup is easy to obtain and may prove a useful index of nasal patency.

A collaborative study of infant respiratory function testing.

The aims of this study were to compare inter-observer variability within and between two specialized infant lung function testing centres and to develop a strategy for performing and analysing infant respiratory function tests to facilitate future collaborative trials. A protocol for data collection and analysis was developed using similar equipment and identical software. All raw data were exchanged on disk and analysed, blind to infant status. All data were cross-analysed by both centres to assess inter-observer variability. Outcome measures were functional residual capacity (FRCpleth), airway resistance (Raw) and maximal expiratory flow at FRC (V'max,FRC). Subjects were recruited from the multicentre UK extracorporeal membrane oxygenation (ECMO) Trial and measured at around 1 yr of age. Forty-two infants attended the Institute of Child Health, London and 36 attended the Leicester Royal Infirmary. The proportion of infants treated with ECMO or conventional management at each centre was similar. There were no significant differences between any of the outcome measures for infants tested at either centre. During a cross-analysis, the agreement between the two centres, within infant, was closer for V'max,FRC and FRCpleth (within 10%) than for the more variable measurements of Raw (within 20%). A collaborative approach to trials with infant respiratory function as an outcome measure appears feasible, providing that close attention is paid to study design, and participants in such trials maintain a standard approach to data collection and analysis.

Respiratory responses to rapid-onset, repetitive vs. continuous hypoxia in piglets.

Repeated, frequent hypoxic exposures may precede Sudden Infant Death. This study assessed whether such hypoxic modality, vs. continuous hypoxia, compromised compensatory cardiorespiratory responses. Following aseptic, chronic instrumentation, 10 to 20 day-old, unsedated piglets underwent measurements of arterial O2 saturation, pH and gas tensions, respiration, heart rate, physical activity, O2 consumption and rectal temperature on several experimental days. The piglets were exposed to 21 min of either 10% or 6% O2 in N2, each comprising either seven, 3-min exposures alternating with 3-min intervals in 21% O2 balance N2, or 7 consecutive hypoxic exposures. Responses to 6% hypoxia were greater than those to 10% hypoxia. In 10% hypoxia, responses to repetitive vs. continuous exposure differed only in PaCO2. In 6% hypoxia, repetitive vs. continuous exposure resulted in lower respiratory frequency (p < 0.05) and in lower ventilation equivalent (p = 0.07) despite higher activity levels. Thus, the mode of hypoxic exposure determines the extent of the respiratory response: Severe, repetitive hypoxia mitigates protective respiratory responses when compared to equivalent, but sustained hypoxia.