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.

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.

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.

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.

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.

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.

Peripheral chemoresponses of infants measured by a minimally invasive method utilizing two-breath alternations in Fl,02.

The aim of this study was to develop a minimally invasive and reliable method for measuring peripheral chemoresponsiveness to oxygen in infants, and to establish baseline data from normal infants at 12 weeks of age. Two-breath alternations in fractional inspired oxygen (FI,O2), switching between 0.42 to 0.00 were given for 2 min periods via a face mask (held close to the face but without contact) to 18 healthy infants during quiet sleep. End-tidal oxygen concentrations alternated between 21 and 11%. Instantaneous minute ventilation (V'E) and its components tidal volume (VT), respiratory frequency (fR) inspiratory and expiratory times (tI and tE), inspiratory flow (VT/tT), and inspiratory duty cycle (tI/ttot) were measured by respiratory inductance plethysmography. Two-breath alternations in each of the ventilatory components were matched with the corresponding alternating end-tidal oxygen record and compared with contiguous pre- and post-test data obtained in control periods of air breathing. Alternations in all ventilatory components except fR changed significantly during FI,O2 alternations; VT 26%, tE-8%, VT/tI 18%, tI/ttot 11% and V'E 28% of baseline values. Within and between infant variances are reported for the individual components of ventilation. Differences among infants were best detected by alternations in V'E; within infant variance 76, between infant variance 171. We conclude that the test described is a safe, reliable and relatively easily applied method of measuring peripheral chemoresponsiveness, which is suitable for clinical application in infancy.

The effect of sleep deprivation on sleep states, breathing events, peripheral chemoresponsiveness and arousal propensity in healthy 3 month old infants.

We wished to investigate the effects of sleep deprivation on sleep, arousal propensity, respiratory events and peripheral chemoresponses in healthy infants, since these effects might be relevant to mechanisms concerned with some cases of sudden infant death syndrome. Paired observations were made overnight during natural sleep and following sleep deprivation, in a randomized fashion, in 15 healthy infants aged 78 (7) days (mean (SD)). Polysomnograms were recorded and sleep was scored using Anders' criteria. Respiratory events were categorized into central, mixed and obstructive apnoeas. Peripheral chemoresponses were measured during quiet sleep from the respiratory response to two-breath alternations in fractional inspiratory oxygen (F1, O2) (0.42 and 0.00). Arousal propensity was determined from awakening and arousal thresholds to graded photic and auditory stimuli during quiet sleep, and from spontaneous awakenings and limb movements. Compared with natural sleep, following sleep deprivation infants maintained a greater proportion of quiet sleep (39 vs 44%). There was no measurable change in arousal propensity. During quiet sleep, obstructed breathing events tended to be more common after sleep deprivation (0.1 vs 0 events.h-1) and the expiratory time during baseline breathing increased significantly (1.27 vs 1.58 s) although the decrease in respiratory rate was not significant (32 vs 30 breaths.min-1). Peripheral chemoresponses altered significantly, alternations in tidal volume/inspiratory time (VT/tI) as a measure of inspiratory drive increased after sleep deprivation (9 vs 21%). In conclusion, following short-term sleep deprivation in infancy, respiratory control alters, peripheral chemoresponsiveness increases in magnitude and the timing of baseline breathing alters, without any detectable alteration in arousal propensity. This state may be associated with an increased vulnerability to obstructive respiratory events.

Electrocorticographic activity during repeated vs continuous hypoxia in piglets.

To assess the effects on brain activity of repeated vs continuous hypoxia, 16, 10- to 22-day-old piglets were instrumented chronically for electrocortical and arterial pH and gas tension measurements. They inhaled 10% or 6% O2 in N2 for 21 min, either continuously, or during seven, 3 min exposures interrupted by 3 min recovery periods in air, all while behaving naturally within a sealed, temperature controlled, plexiglass box. An isoelectric electrocorticogram (ECoG) and/or seizures, related to the onset of hypoxia, occurred repeatedly in 6 of the 10 exposures to 6% repetitive hypoxia, only twice in 8 exposures to 6% continuous hypoxia, and never in 10% hypoxia. A frequency analysis of the ECoG, excluding all sections exhibiting isoelectric and seizure activity, revealed no changes with 10% hypoxia, but a shift towards the lower bands during both repetitive and continuous 6% hypoxia. The extent of these shifts was greater in records that also displayed isoelectric ECoG and/or seizures. The ECoG spectrum recovered at the end of the hypoxic exposure, but not when isoelectric ECoG and/or seizures coexisted. We conclude that repeated, frequent episodes of hypoxia are more detrimental than a prolonged single event, and may contribute to the occurrence of Sudden Infant Death.

Lung function from infancy to school age in cystic fibrosis.

The aim was to investigate pulmonary mechanics in patients with cystic fibrosis during infancy and again in early childhood to see whether infant tests predicted status at school age. Plethysmographic measurements of thoracic gas volume and airways resistance were made in 29 patients at 6 months and again at 5 years 10 months. Maximum flow at functional residual capacity was measured during infancy for comparison with maximum expiratory flow rates during childhood. While many patients had normal measurements during infancy, pulmonary function had deteriorated by school age. Thoracic gas volume at school age was significantly related to the values in infancy, but other measurements made during childhood were independent of infant values. The relations between measurements in infancy and early childhood described here provide a background against which the role of external factors on pulmonary function in young children with cystic fibrosis can be investigated.

Chronic night cough and asthma severity in children with stable asthma.

The relationship between night cough and other indices of asthma severity was studied in 21 children with clinically stable asthma and persistent night cough. Overnight cough was quantified and related to symptom scores, oxygen saturation (SaO2) during sleep, evening and morning peak flow recordings and daytime tests of lung function. In the index group the median number of coughing episodes was 23 (range 1-158). Only 4 children had counts of < 10 overnight, similar to the comparison group of 12 children all of whom had counts of < 10. There was a trend towards the association of overnight cough with reduced evening peak flow (r = -0.407, P = 0.07) and reduced SaO2 (r = -0.36, P = 0.10). Abnormalities in daytime tests of lung function were observed in 13 children. There was no relationship between night cough and daytime indices of lung function abnormality although children with more severe daytime abnormalities also had significant night cough. Conversely, five children with chronic night cough had normal daytime function. Conclusion. Night-time cough in children with asthma is not simply a reflection of daytime lung function status, whereas, overnight SaO2 correlates well. Other factors need to be explored to explain the variability of night-time cough in these children.

Pulmonary function in infants with cystic fibrosis: the effect of antibiotic treatment.

Since 1982 all infants born within the East Anglian Regional Health Authority have been screened for cystic fibrosis. Between April 1985 and April 1992 infants identified in this way have been entered into a randomised prospective controlled trial of antibiotic prophylaxis. Approximately half the infants received continuous oral flucloxacillin and the remainder received antibiotics when clinically indicated. Infants underwent tests of respiratory function at 3-4 months and at 1 year of age. Measurements of thoracic gas volume and airway conductance were made with an infant whole body plethysmograph, and maximum expiratory flow by the 'squeeze' technique. A total of 73 tests was performed of 42 infants. To facilitate comparisons, measurements were expressed as scores. The mean values of the scores for the two groups of infants fell within normal limits. There was no difference between the treatment groups at either age. A reduction in airways conductance was observed between the two tests.

Clinical findings and respiratory function in infants following repair of oesophageal atresia and tracheo-oesophageal fistula.

Survival rates for infants undergoing surgical repair of oesophageal atresia with tracheo-oesophageal fistula (OA-TOF) have improved dramatically, but this condition remains associated with substantial morbidity. Most studies of patients following OA-TOF repair have concentrated on school-age and older people; whereas, the most hazardous period is infancy. We aimed to assess respiratory function in a group of infants following primary operative repair, and to relate the results to clinical findings during the first year of life. We studied 16 infants within 3 months of primary repair of OA-TOF. Measurements were made of maximum expiratory flow at functional residual capacity (VmaxFRC), thoracic gas volume (TGV) and airways resistance (Raw). Ten infants had tests repeated, usually to assess progress alongside continuing symptoms, or to ascertain improvement following additional surgery. Seven infants had essentially normal initial respiratory function tests, and six remained either symptom-free or developed only minor clinical problems. One infant subsequently developed stridor, with spontaneous improvement towards the end of the first year. The remaining nine infants had abnormal initial respiratory function tests: one was symptom-free at that time. The remainder developed respiratory and/or gastro-oesophageal symptoms. The functional abnormalities appeared to reflect the severity of the clinical problems encountered. We conclude that respiratory function testing in infants following OA-TOF repair may augment the value of clinical appraisal, help define postoperative respiratory status, and provide a general guide to likely clinical progress.