Aidan Laverty

Reduced upper airway nitric oxide in cystic fibrosis.

Nitric oxide (NO) produced within the respiratory tract is detectable in exhaled and nasal air. Its synthesis may be induced by inflammatory cytokines and reduced by glucocorticoids. Increased concentrations have been found in asthma and bronchiectasis. In this study, NO concentrations were determined in 63 children with cystic fibrosis, of whom 13 were on inhaled steroids (mean age 13.3 years) and 50 were not (mean age 12.3 years); 57 normal children (mean age 12.2 years) were also studied. NO was measured by chemiluminescence analyser, exhaled NO following a relaxed vital capacity manoeuvre, and nasal NO with the breath held following a full inspiration. Mean concentration of exhaled NO in cystic fibrosis patients (no steroids) was 4.7 parts per billion (ppb) (95% confidence interval (CI) 4.0 to 5.3); this did not differ from values in normal children (mean 4.8 ppb, 95% CI 3.8 to 5.8) or in cystic fibrosis patients on inhaled steroids (mean 3.6 ppb, 95% CI 2.5 to 4.8). Nasal concentrations were significantly lower in cystic fibrosis patients, with or without inhaled steroids, than in normal children (cystic fibrosis, no inhaled steroids: 460 ppb, 95% CI 399 to 520; cystic fibrosis, inhaled steroids: 522 ppb, 95% CI 313 to 730, v normal children: 1024 ppb, 95% CI 896 to 1152, p < 0.0001). Considering the inflammatory nature of cystic fibrosis, it is surprising exhaled NO levels were not increased, but this may have been due to alteration in NO diffusion through thick mucus. The low nasal NO concentrations, which are probably the result of impaired flow from the paranasal sinuses, may contribute to the recurrent respiratory infections typical of cystic fibrosis.

A step in the right direction: Assessing exercise tolerance in cystic fibrosis

Exercise tolerance may be reduced in patients with cystic fibrosis, but it is not always possible to predict this from standard lung function measurements. Formal exercise testing may, therefore, be necessary, and the test should be simple and readily available. We have developed a “3‐minute step test” and compared it with the standard 6‐minute walking test. Subjects stepped up and down a 15‐cm‐high single step at a rate of 30 steps per minute for 3 minutes. The effect of the step test on spirometry was tested first in 31 children with CF (mean age, 12.0 years), who had a mean (range) baseline forced expired volume in 1 second (FEV1) of 64% (18–94%) of predicted values. The step test was then compared with the standard 6‐minute walk in a further 54 patients with cystic fibrosis (mean age, 12.5 years), with mean (range) baseline FEV1 of 61% (14–103%) of predicted values. Outcome measures were minimum arterial oxygen saturation (SaO2), maximum pulse rate, and the modified Borg dyspnea score.

Distinct patterns of respiratory difficulty in young children with achondroplasia: a clinical, sleep, and lung function study

AIM Achondroplasia can result in respiratory difficulty in early infancy. The aim of this study was to document lung growth during infancy, together with the cause of any cardiorespiratory and sleep dysfunction. PATIENTS AND METHODS Seventeen prospectively ascertained infants (14 boys and three girls) with respiratory symptoms starting before 1 year of age underwent clinical, sleep, and lung function studies. RESULTS Three distinct groups were identified. Group 1 (n = 6) were the least symptomatic and only had obstructive sleep apnoea. Group 2 (n = 6) had obstructive sleep apnoea of muscular aetiology and, neurologically, hydrocephalus and a small foramen magnum were common. Group 3 (n = 5), the most severely affected group, all developed cor pulmonale, with three deaths occurring as a result of terminal cardiorespiratory failure. All five had obstructive sleep apnoea with a muscular aetiology (a small foramen magnum predominated) with severe or moderately severe gastro-oesophageal reflux. Initially, lung function studies found no evidence of restriction or reduced lung volumes standardised according to weight. However, with growth these infants had worsening function, with raised airway resistance and severe reductions in respiratory compliance. CONCLUSIONS These groups appear to be distinct phenotypes with distinct anatomical aetiologies: “relative” adenotonsillar hypertrophy, resulting from a degree of midfacial hypoplasia (group 1); muscular upper airway obstruction along with progressive hydrocephalus, resulting from jugular foramen stenosis (group 2); and muscular upper airway obstruction, but without hydrocephalus, resulting from hypoglossal canal stenosis with or without foramen magnum compression and no jugular foramen stenosis (group 3). The aetiology of these abnormalities is consistent with localised alteration of chondrocranial development: rostral, intermediary and caudal in groups 1, 2, and 3, respectively.

Sickle cell disease: ischemia and seizures

Although the prevalence of seizures in children with sickle cell disease (SCD) is 10 times that of the general population, there are few prospectively collected data on mechanism. With transcranial Doppler and magnetic resonance imaging (MRI) and angiography, we evaluated 76 patients with sickle cell disease, 29 asymptomatic and 47 with neurological complications (seizures, stroke, transient ischemic attack, learning difficulty, headaches, or abnormal transcranial Doppler), who also underwent bolus‐tracking perfusion MRI. The six patients with recent seizures also had electroencephalography. Group comparisons (seizure, nonseizure, and asymptomatic) indicated that abnormal transcranial Doppler was more common in the seizure (4/6; 67%) and nonseizure (26/41; 63%) groups than in the asymptomatic (10/29; 34%) group (χ2; p = 0.045), but abnormal structural MRI (χ2; p = 0.7) or magnetic resonance angiography (χ2; p = 0.2) were not. Relative decreased cerebral perfusion was found in all seizure patients and in 16 of 32 of the remaining patients with successful perfusion MRI (p = 0.03). In the seizure patients, the perfusion abnormalities in five were ipsilateral to electroencephalographic abnormalities; one had normal electroencephalogram results. These findings suggest that vasculopathy and focal hypoperfusion may be factors in the development of sickle cell disease–associated seizures. Ann Neurol 2005;58:290–302

The Young Everest Study: effects of hypoxia at high altitude on cardiorespiratory function and general well-being in healthy children

Objectives: To assess the effect of altitude and acclimatisation on cardiorespiratory function and well-being in healthy children. Methods: A daily symptom diary, serial measurements of spirometry, end-tidal carbon dioxide (etCO2) and daytime and overnight pulse oximetry (SpO2), were undertaken at sea level and altitudes up to 3500 m in healthy children during a trekking holiday. SpO2 at altitude was compared with that in flight and during acute hypoxic challenge (breathing 15% oxygen) at sea level. Results: Measurements were obtained in nine children aged 6–13 years (median 8). SpO2 decreased significantly during the hypoxic challenge (difference −5%, 95% CI −6 to −3%, p<0.01) but remained above 90% in all children. There was a significant fall in daytime and overnight SpO2 (95% CI −11.9 to −7.5% and −12 to −8, respectively) and etCO2 (−8.5 to −4.5 mm Hg) as the children ascended to 3500 m. There was a significant increase in SpO2 (95% CI 1.1 to 4.9%) and a further drop in etCO2 (−5.9 to −0.8 mm Hg) after a week at altitude, etCO2 being negatively correlated with SpO2. There was no correlation between SpO2 during hypoxic challenge, in flight or at altitude. Lung function remained within 7% of baseline in all but two children, in whom reductions of up to 23% in FVC and 16% FEV1 were observed at altitude. The children generally remained well, but the Lake Louise scoring system was unreliable in this age group. Conclusions: A wide range of physiological responses to altitude are evident in healthy children. This study should inform future larger studies in children to improve understanding of responses to hypoxia in health and disease.

Establishment of a web-based registry for rare (orphan) pediatric lung diseases in the United Kingdom: the BPOLD registry.

Children with orphan lung diseases (defined as a prevalence of <1 in 2000) receive suboptimal care due to a lack of understanding of pathophysiology and management.

Exhaled nitric oxide increases following admission for intravenous antibiotics in children with cystic fibrosis

BACKGROUND Lack of standardisation for the measurement of exhaled nitric oxide (NO) (FENO) has resulted in conflicting data in cystic fibrosis (CF). The aim of this study was to assess whether FENO is a useful non-invasive marker of lung disease in CF by assessing the effect of intravenous (IV) antibiotics on FENO. METHODS FENO was measured on line, according to recently published ERS/ATS guidelines, using a chemiluminescence analyser together with pulmonary function in 14 CF children prior to and following a course of IV antibiotics. RESULTS There was a significant improvement in mean (S.E.M.) % FEV1 from 60.0 (6.3) to 68.0 (5.4) (P < 0.05) and mean (S.E.M.) % FVC from 66.3 (5.5) to 75.1 (4.9) (P < 0.01). FENO increased significantly from median (range) 5.8 (2.0-14.3) to 9.2 ppb (0.8-25.1) (P < 0.05). There was no correlation between FE(NO) and lung function. Subgroup analysis on those with chronic Pseudomonas aeruginosa infection (n = 6) demonstrated no significant change in FENO. CONCLUSIONS Using a flow of 50 ml/s, FENO increases following admission for IV antibiotic treatment in children with CF but does not correlate with lung function. It is not a useful marker of lung diseases in CF, which has implications for clinical practice.

The Young Everest Study: preliminary report of changes in sleep and cerebral blood flow velocity during slow ascent to altitude in unacclimatised children

Background Cerebral blood flow velocity (CBFV) and sleep physiology in healthy children exposed to hypoxia and hypocarbia are under-researched. Aim To investigate associations between sleep variables, daytime end-tidal carbon dioxide (EtCO2) and CBFV in children during high-altitude ascent. Methods Vital signs, overnight cardiorespiratory sleep studies and transcranial Doppler were undertaken in nine children (aged 6–13 years) at low altitude (130 m), and then at moderate (1300 m) and high (3500 m) altitude during a 5-day ascent. Results Daytime (130 m: 98%; 3500 m: 90%, p=0.004) and mean (130 m: 97%, 1300 m: 94%, 3500: 87%, p=0.0005) and minimum (130 m: 92%, 1300 m: 84%, 3500 m: 79%, p=0.0005) overnight pulse oximetry oxyhaemoglobin saturation decreased, and the number of central apnoeas increased at altitude (130 m: 0.2/h, 1300 m: 1.2/h, 3500 m: 3.5/h, p=0.2), correlating inversely with EtCO2 (R2 130 m: 0.78; 3500 m: 0.45). Periodic breathing occurred for median (IQR) 0.0 (0; 0.3)% (130 m) and 0.2 (0; 1.2)% (3500 m) of total sleep time. At 3500 m compared with 130 m, there were increases in middle (MCA) (mean (SD) left 29.2 (42.3)%, p=0.053; right 9.9 (12)%, p=0.037) and anterior cerebral (ACA) (left 65.2 (69)%, p=0.024; right 109 (179)%; p=0.025) but not posterior or basilar CBFV. The right MCA CBFV increase at 3500 m was predicted by baseline CBFV and change in daytime SpO2 and EtCO2 at 3500 m (R2 0.92); these associations were not seen on the left. Conclusions This preliminary report suggests that sleep physiology is disturbed in children even with slow ascent to altitude. The regional variations in CBFV and their association with hypoxia and hypocapnia require further investigation.

Effect of Palate Re-Repairs and Hynes Pharyngoplasties on Pediatric Airways: An Analysis of Preoperative and Postoperative Cardiorespiratory Sleep Studies

Objectives To determine whether Sommerlad palate re-repairs and Hynes pharyngoplasties cause obstructive sleep apnea/hypopnea or increased upper airway resistance. Design Prospective before-and-after study. Setting Tertiary cleft unit. Patients A total of 44 patients undergoing a Sommerlad palate re-repair or a Hynes pharyngoplasty. Interventions Preoperative and postoperative multichannel cardiorespiratory sleep studies. Main Outcome Measures The main outcome measures were mean arterial oxygen saturation, desaturation index, percentage of time spent with arterial oxygen saturation <90%, mean pulse rate, number of pulse rate rises (arousals) per hour, inspiratory effort derived from pulse transit time, pulse transit time arousals, and snoring. Results No patient in either group required intervention for airway obstruction or obstructive sleep apnea/hypopnea. Re-repairs caused no significant change in any parameter. Hynes caused an increase in inspiratory effort (P = .04) and obstructive sleep apnea/hypopnea grading (P = .002). All other parameters showed no significant deterioration. No patient developed more than mild/ moderate obstructive sleep apnea/hypopnea. Snoring and arterial oxygen saturation levels were not reliable indicators of increased inspiratory effort. Conclusions A palate re-repair had no significant adverse effect on the airway. A Hynes, in patients with optimized velar function, caused a significant increase in inspiratory effort and obstructive sleep apnea/hypopnea grade. However, compared with studies on midline flaps and on sphincter pharyngoplasties, a Hynes appears to be less obstructive. Failure to study changes in inspiratory effort in patients undergoing velopharyngeal incompetence surgery may underestimate the obstructive effect of pharyngoplasties.

Hypoventilation disproportionate to OSAS severity in children with Prader-Willi syndrome

Objective To test the hypothesis that children with Prader-Willi syndrome (PWS) and obstructive sleep apnoea syndrome (OSAS) have hypercapnia for higher proportion of total sleep time (TST) than non-syndromic children with similar obstructive apnoea–hypopnoea index (OAHI). Design Cross-sectional study. Setting Two tertiary care hospitals. Patients Patients with PWS and non-syndromic children with snoring who underwent polygraphy and were of similar age, body mass index (BMI) z-score and OAHI. Main outcome measure The two groups were compared regarding %TST with transcutaneous CO2 (PtcCO2) >50 mm Hg. The interaction between PWS diagnosis and OSAS severity (OAHI <1 episode/h vs 1–5 episodes/h vs >5 episodes/h) regarding %TST with PtcCO2 >50 mm Hg was tested using multiple linear regression. Results 48 children with PWS and 92 controls were included (median age 2.3 (range 0.2–14.1) years vs 2.2 (0.3–15.1) years; BMI z-score 0.7±1.9 vs 0.8±1.7; median OAHI 0.5 (0–29.5) episodes/h vs 0.5 (0–33.9) episodes/h; p>0.05). The two groups did not differ in %TST with PtcCO2 >50 mm Hg (median 0% (0–100%) vs 0% (0–81.3%), respectively; p>0.05). However, the interaction between PWS and OSAS severity with respect to duration of hypoventilation was significant (p<0.01); the estimated mean differences of %TST with PtcCO2 >50 mm Hg between children with PWS and controls for OAHI <1 episode/h, 1–5 episodes/h and >5 episodes/h were +0.2%, +1% and +33%, respectively. Conclusion Increasing severity of upper airway obstruction during sleep in children with PWS is accompanied by disproportionately longer periods of hypoventilation when compared with non-syndromic children with similar frequency of obstructive events.