Analysis of oxygen uptake efficiency parameters in young people with cystic fibrosis.

PURPOSE: This study characterised oxygen uptake efficiency (OUE) in children with mild-to-moderate cystic fibrosis (CF). Specifically, it investigated (1) the utility of OUE parameters as potential submaximal surrogates of peak oxygen uptake ([Formula: see text]), and (2) the relationship between OUE and disease severity. METHODS: Cardiopulmonary exercise test (CPET) data were collated from 72 children [36 CF, 36 age- and sex-matched controls (CON)], with OUE assessed as its highest 90-s average (plateau; OUEP), the gas exchange threshold (OUEGET) and respiratory compensation point (OUERCP). Pearson's correlation coefficients, independent t tests and factorial ANOVAs assessed differences between groups and the use of OUE measures as surrogates for [Formula: see text]. RESULTS: A significant (p < 0.05) reduction in allometrically scaled [Formula: see text] and all OUE parameters was found in CF. Significant (p < 0.05) correlations between measurements of OUE and allometrically scaled [Formula: see text], were observed in CF (r = 0.49-0.52) and CON (r = 0.46-0.52). Furthermore, measures of OUE were significantly (p < 0.05) correlated with pulmonary function (FEV1%predicted) in CF (r = 0.38-0.46), but not CON (r = -0.20-0.14). OUEP was able to differentiate between different aerobic fitness tertiles in CON but not CF. CONCLUSIONS: OUE parameters were reduced in CF, but were not a suitable surrogate for [Formula: see text]. Clinical teams should, where possible, continue to utilise maximal CPET parameters to measure aerobic fitness in children and adolescents with CF. Future research should assess the prognostic utility of OUEP as it does appear sensitive to disease status and severity.

Airflow limitation following cardiopulmonary exercise testing and heavy-intensity intermittent exercise in children with cystic fibrosis.

UNLABELLED: The clinical importance of exercise testing and training in the healthcare management of young patients with cystic fibrosis (CF) is growing. The aim of the present study was to determine the incidence of airflow limitation following cardiopulmonary exercise testing (CPET) and heavy-intensity intermittent exercise (HIIE) in young patients with CF. Nineteen young patients with CF and respective paired-matched controls performed CPET and HIIE on separate days. Forced expiratory volume in one second (FEV1) was measured pre- and post each exercise modality. A fall in FEV1 of 10 % or greater was used to define airflow limitation. The incidence of airflow limitation was significantly greater in the CF group than in the controls following CPET (32 vs. 5 %; p = 0.03); however, no significant difference in the incidence of airflow limitation was shown following HIIE between the CF group and controls (11 vs. 16 %; p = 0.64). CONCLUSION: Our data show that the incidence of airflow limitation following CPET in young patients with CF is high. Therefore, clinicians may wish to identify whether young CF patients experience airflow limitation following strenuous exercise, such as CPET, before it is performed. However, HIIE carries a low risk for airflow limitation and may be prescribed as a safe, yet effective exercise modality for young patients with CF.

The effect of ivacaftor in adolescents with cystic fibrosis (G551D mutation): an exercise physiology perspective.

PURPOSE: The purpose of this report was to evaluate the influence of 12 weeks of ivacaftor treatment on the aerobic function of 2 teenage patients with cystic fibrosis (CF; ΔF508/G551D) using a maximal cardiopulmonary exercise test. SUMMARY OF KEY POINTS: One patient, with relatively mild disease, demonstrated no clinically meaningful changes in maximal oxygen uptake ((Equation is included in full-text article.)O2max). However, in the second case, with more established lung disease on imaging, (Equation is included in full-text article.)O2max improved by approximately 30%, an improvement out of proportion with early lung function changes. This improvement resulted from increased muscle oxygen delivery and extraction. STATEMENT OF CONCLUSIONS: Cardiopulmonary exercise testing can monitor the extent and cause(s) of change following interventions such as ivacaftor, with the potential to identify functional changes independent from spirometry indices. RECOMMENDATIONS FOR CLINICAL PRACTICE: Cardiopulmonary exercise testing represents an important and comprehensive clinical assessment tool, and its use as an outcome measure in the functional assessment of patients with CF is encouraged.

Skeletal muscle contributions to reduced fitness in cystic fibrosis youth.

Background: Increased maximal oxygen uptake (V̇O2max) is beneficial in children with cystic fibrosis (CF) but remains lower compared to healthy peers. Intrinsic metabolic deficiencies within skeletal muscle (muscle "quality") and skeletal muscle size (muscle "quantity") are both proposed as potential causes for the lower V̇O2max, although exact mechanisms remain unknown. This study utilises gold-standard methodologies to control for the residual effects of muscle size from V̇O2max to address this "quality" vs. "quantity" debate. Methods: Fourteen children (7 CF vs. 7 age- and sex-matched controls) were recruited. Parameters of muscle size - muscle cross-sectional area (mCSA) and thigh muscle volume (TMV) were derived from magnetic resonance imaging, and V̇O2max obtained via cardiopulmonary exercise testing. Allometric scaling removed residual effects of muscle size, and independent samples t-tests and effect sizes (ES) identified differences between groups in V̇O2max, once mCSA and TMV were controlled for. Results: V̇O2max was shown to be lower in the CF group, relative to controls, with large ES being identified when allometrically scaled to mCSA (ES = 1.76) and TMV (ES = 0.92). Reduced peak work rate was also identified in the CF group when allometrically controlled for mCSA (ES = 1.18) and TMV (ES = 0.45). Conclusions: A lower V̇O2max was still observed in children with CF after allometrically scaling for muscle size, suggesting reduced muscle "quality" in CF (as muscle "quantity" is fully controlled for). This observation likely reflects intrinsic metabolic defects within CF skeletal muscle.

Quantification of thigh muscle volume in children and adolescents using magnetic resonance imaging.

Abstract Estimating muscle volume (MV) using variable numbers of cross-sectional area (CSA) slices obtained from magnetic resonance imaging (MRI) introduces an error that is known in adults, but not in children and adolescents, whereby body sizes differ due to growth and maturation. Therefore, 15 children and adolescents (11 males, 14.8 ± 2.1 years) underwent MRI scans of the right thigh using a 1.5 T scanner to establish this error. A criterion MV was determined by tracing around and summing all CSAs, with MV subsequently estimated using every second, third, fourth and fifth CSA slice. Bland-Altman plots identified mean bias and limits of agreement (LoA) between methods. Error rates between 1.0 and 10.4% were seen between criterion and estimated MV. Additional analyses identified an impact of formulae selection, with a cylindrical formula preferred to a truncated cone. To counter high error between criterion and estimated MV due to the discrepancies in the number of CSA slices analysed, length-matched criterion volumes were established, with reduced error rates (0.5-2.0%) being produced as a result. CSA at 50% thigh-length also predicted MV, producing a high error (13.8-39.6%). Pearson's correlation coefficients determined relationships between error and measures of body size/composition, with all body size/composition measures being correlated (r = -0.78-0.86, p < 0.05) with the error between criterion and estimated MV. To conclude, MV can be accurately estimated using fewer CSA slices. However, the associated error must be considered when calculating MV in children and adolescents, as body size biases estimates.

The oxygen uptake efficiency slope is not a valid surrogate of aerobic fitness in cystic fibrosis.

BACKGROUND: Maximal cardiopulmonary exercise testing is recommended on an annual basis for children with cystic fibrosis (CF), due to clinically useful prognostic information provided by maximal oxygen uptake (V̇O2max ). However, not all patients are able, or willing, to reach V̇O2max , and therefore submaximal alternatives are required. This study explored the validity of the oxygen uptake efficiency slope (OUES) as a submaximal measure of V̇O2max in children and adolescents with CF. METHODS: Data were collated from 72 cardiopulmonary exercise tests (36 CF, 36 controls), with OUES determined relative to maximal and submaximal parameters of exercise intensity, time, and individual metabolic thresholds. Pearson's correlation coefficients, independent t-tests, and factorial ANOVAs were used to determine validity. RESULTS: Significant (P < 0.05) correlations with V̇O2max were observed for most expressions of OUES, but were consistently weaker in CF (r = 0.30-0.47) when compared to CON (r = 0.58-0.89). Mean differences for all OUES parameters between groups were not significant (P > 0.05). When split by V̇O2max tertiles, minimal significant differences were found between, and within, groups for OUES, indicating poor discrimination of V̇O2max . CONCLUSIONS: The OUES is not a valid (sub) maximal measure of V̇O2max in children and adolescents with mild-to-moderate CF. Clinicians should continue to use maximal markers (ie, V̇O2max ) of exercise capacity.

Scaling the Oxygen Uptake Efficiency Slope for Body Size in Cystic Fibrosis.

PURPOSE: The aim of this study was to describe the relationship between body size and oxygen uptake efficiency slope (OUES) in pediatric patients with cystic fibrosis (CF) and healthy controls (CON), to identify appropriate scaling procedures to adjust the influence of body size upon OUES. METHODS: The OUES was derived using maximal and submaximal points from cardiopulmonary exercise testing in 72 children (36 CF and 36 CON). OUES was subsequently scaled for stature, body mass (BM), and body surface area (BSA) using ratio-standard (Y/X) and allometric (Y/X) methods. Pearson's correlation coefficients were used to determine the relationship between body size and OUES. RESULTS: When scaled using the ratio-standard method, OUES had a significant positive relationship with stature (r = 0.54, P < 0.001) and BSA (r = 0.25, P = 0.031) and significant negative relationship with BM (r = -0.38, P = 0.016) in the CF group. Combined allometric exponents (b) for CF and CON were stature 3.00, BM 0.86, and BSA 1.40. A significant negative correlation was found between OUES and stature in the CF group when scaled allometrically (r = -0.37, P = 0.027). Nonsignificant (P > 0.05) correlations for the whole group were found between OUES and allometrically scaled BM (CF r = -0.25, CON, r = 0.15) and BSA (CF r = -0.27, CON r = 0.13). CONCLUSIONS: Only allometric scaling of either BM or BSA, and not ratio-standard scaling, successfully eliminates the influence of body size upon OUES. Therefore, this enables a more direct comparison of the OUES between patients with CF and healthy controls.

Coma due to cannabis toxicity in an infant.

In young children, cannabis ingestion resulting in coma is very rare. Only nine cases have been reported in the literature and most have occurred in inquisitive toddlers. We review the cases to date and report the youngest recorded case of coma due to cannabis ingestion in an 11-month-old girl. This case highlights the importance of considering toxicological causes and the parental recreational drug history in young children who present with an altered level of consciousness. Child protection considerations are also discussed.

Impaired Pulmonary V˙O2 Kinetics in Cystic Fibrosis Depend on Exercise Intensity.

PURPOSE: This study aimed to investigate the effects of mild-to-moderate cystic fibrosis (CF) on the pulmonary oxygen uptake (V˙O2) kinetics of seven pediatric patients (13.5 ± 2.8 yr) versus seven healthy matched controls (CON; 13.6 ± 2.4 yr). We hypothesized that CF would slow the V˙O2 kinetic response at the onset of moderate (MOD) and very heavy (VH) intensity cycling. METHODS: Changes in breath-by-breath V˙O2, near-infrared spectroscopy-derived muscle deoxygenation ([HHb]) at the vastus lateralis muscle and thoracic bioelectrical impedance-derived heart rate (HR), stroke volume index, and cardiac index were measured during repeat transitions to MOD (90% of the gas exchange threshold) and VH (Δ60%) intensity cycling exercise. RESULTS: During MOD, the phase II V˙O2 τ (P = 0.84, effect size [ES] = 0.11) and the overall mean response time (MRT) (P = 0.52, ES = 0.11) were not significantly slower in CF versus CON. However, during VH exercise, the phase II V˙O2 τ (P = 0.02, ES = 1.28) and MRT (P = 0.01, ES = 1.40) were significantly slower in CF. Cardiac function, central O2 delivery (stroke volume index and cardiac index), and muscle [HHb] kinetics were unaltered in CF. However, the arteriovenous O2 content difference ((Equation is included in full-text article.)) was reduced during VH at 30 s (P = 0.03, ES = 0.37), with a trend for reduced levels at 0 s (P = 0.07, ES = 0.25), 60 s (P = 0.05, ES = 0.28), and 120 s (P = 0.07, ES = 0.25) in CF. Furthermore, (Equation is included in full-text article.)significantly correlated with the VH phase II V˙O2 τ (r = -0.85, P = 0.02) and MRT (r = -0.79, P = 0.03) in CF only. CONCLUSION: Impairments in muscle oxidative metabolism during constant work rate exercise are intensity dependent in young people with mild-to-moderate CF. Specifically, V˙O2 kinetics are slowed during VH but not MOD cycling and appear to be mechanistically linked to impaired muscle O2 extraction and utilization.

Exercise capacity following a percutaneous endoscopic gastrostomy in a young female with cystic fibrosis: a case report.

Cystic fibrosis (CF) is a genetic condition affecting the respiratory and gastrointestinal systems, with patients experiencing problems maintaining weight, especially during rapid growth periods such as puberty. The aim of this case report was to monitor the effect of gastrostomy insertion and implementation of overnight supplemental feeding upon clinical outcomes, including body mass index (BMI), lung function (FEV1), and exercise-related variables (maximal oxygen uptake [VO2max] and ventilatory efficiency [VE/VO2]) in an 11-year-old female with CF Combined incremental and supramaximal exercise testing to exhaustion was performed at four time points: 3 months prior to the procedure (T1), 2 days prior to (T2), 4 months (T3), and 1 year following the procedure (T4). Improvements following gastrostomy insertion were observed at the 1 year follow-up with regards to BMI (+20%); whereas absolute VO2max remained stable and lung function fluctuated throughout the period of observation. Declines in function with regards to body weight relative VO2max (-16.3%) and oxygen uptake efficiency (+7.5%) were observed during this period. This case report is the first to consider exercise-related clinical outcomes in assessing the effect of implementing gastrostomy feeding in CF The varied direction and magnitude of the associations between variables shows that further investigations are required.

Impaired aerobic function in patients with cystic fibrosis during ramp exercise.

PURPOSE: This study aimed to document the matching of muscle O2 delivery to O2 use in young patients with cystic fibrosis (CF) from muscle deoxygenation (HHb) dynamics during ramp exercise. METHODS: Ten patients with stable, mild-to-moderate CF (12.7 ± 2.8 yr) and 10 healthy controls (CON, 12.8 ± 2.8 yr) completed a combined ramp and supramaximal cycling test to determine maximal O2 uptake (V˙O2max). Changes in gas exchange and ventilation, HR, and m. vastus lateralis HHb (near-infrared spectroscopy) were assessed. Δ[HHb]-work rate and Δ[HHb]-V˙O2 profiles were normalized and fit using a sigmoid function. RESULTS: Aerobic function was impaired in CF, indicated by very likely reduced fat-free mass-normalized V˙O2max (mean difference, ±90% confidence interval: -7.9 mL·kg·min, ±6.1), very likely lower V˙O2 gain (-1.44 mL·min·W, ±1.12), and a likely slower V˙O2 mean response time (11 s, ±13). An unclear effect was found upon the absolute and relative work rate (-14 W, ±44, and -0.7% peak power output, ±12.0, respectively) and the absolute and percentage (-0.10 L·min, ±0.43, and 3.3% V˙O2max, ±6.0) V˙O2 corresponding to 50% Δ[HHb] amplitude, respectively, between groups. However, arterial oxygen saturation (SpO2) was very likely lower in CF (-1%, ±1) and demonstrated moderate-to-very large relations with parameters of aerobic function. CONCLUSIONS: Young patients with mild-to-moderate CF present with impaired aerobic function during ramp incremental cycling exercise. Because the rate of fractional O2 extraction during ramp cycling exercise was not altered by CF, yet SpO2 was lower, the present findings support the notion of centrally mediated oxygen delivery to principally limit the aerobic function of pediatric patients with CF during ramp incremental cycling exercise.

A protocol to determine valid V˙O2max in young cystic fibrosis patients.

OBJECTIVES: Measuring aerobic fitness (V˙O2max) via a maximal cardiopulmonary exercise test is an important clinical tool in cystic fibrosis. This study sought to establish: (1) the validity of traditional criteria to verify maximal efforts during a ramp cardiopulmonary exercise test; and (2) whether V˙O2 measured during an exhaustive cardiopulmonary exercise test represents a valid V˙O2max in paediatric patients, using a subsequent exhaustive supramaximal (Smax) exercise test. DESIGN: Cross-sectional. METHODS: Fourteen patients (7-18 years; 10 males) completed an exhaustive ramp test to determine V˙O2max. Following 15-min recovery, Smax (110% ramp peak power output) was performed. RESULTS: Ramp test V˙O2peak was significantly higher than V˙O2 documented at traditional endpoint criteria, including a RER of 1.00 (0.99±0.47 L min(-1) vs. 1.83±0.78 L min(-1), p<0.001) and 1.10 (1.36±0.59 L min(-1) vs. 1.83±0.78 L min(-1), p<0.001), despite 100% of patients satisfying these two criteria. Only 23% and 75% of patients satisfied the 95% age-predicted heart rate (HR) maximum and 180 b min(-1) criteria. Whilst mean ramp and Smax V˙O2peak were not significantly different (1.83±0.78 L min(-1) vs. 1.82±0.67 L min(-1); p=0.88), at the individual level Smax elicited a 'meaningful' (>9%) increase in V˙O2peak (range 9.9-38.3%) compared with V˙O2peak from the ramp test in 3 of 14 cases (21.4%). CONCLUSIONS: Traditional criteria significantly underestimate V˙O2max in young cystic fibrosis patients. Conversely, Smax can confirm when 'true' V˙O2max is achieved. The use of Smax following cardiopulmonary exercise test represents an appropriate method to measure V˙O2max in young cystic fibrosis patients.

Reproducibility of maximal cardiopulmonary exercise testing for young cystic fibrosis patients.

BACKGROUND: The reproducibility of cardiopulmonary exercise testing (CPET) has not been established in young cystic fibrosis (CF) patients using a valid protocol. METHODS: Thirteen 7-18 year olds completed three CPETs, separated by 48 h and 4-6 weeks. CPET involved a ramp-incremental cycling test with supramaximal verification. RESULTS: Maximal oxygen uptake was repeatedly determined with no learning effect and typical errors expressed as a coefficient of variation (TE(CV%)) of 9.3% (48 h) and 13.3% (4-6 weeks). The reproducibility of additional parameters of aerobic function [gas exchange threshold (TE(CV%): 11.2%, 16.8%); VO2 mean response time (TE(CV%): 37.8%, 89.4%); VO2 gain (TE(CV%): 17.4%, 24.5%)] and clinical utility [e.g. SaO2% (TE(CV%): 2.2%, 3.1%); ventilatory drive (V(E)/VCO2-slope) (TE(CV%): 7.8%, 17.7%)] was also established over the short- and the medium-term, respectively. CONCLUSION: These results establish limits of variability to determine meaningful changes over the short- and the medium-term for CPET outcomes in young CF patients.

Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. METHODS: In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. FINDINGS: 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. INTERPRETATION: AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. FUNDING: European Union's Seventh Framework Programme; European Research Council.

Exercise metabolism during moderate-intensity exercise in children with cystic fibrosis following heavy-intensity exercise.

Muscle metabolism is increased following exercise in healthy individuals, affecting exercise metabolism during subsequent physical work. We hypothesized that following heavy-intensity exercise (HIE), disease factors in children with cystic fibrosis (CF) would further exacerbate exercise metabolism and perceived exertion during subsequent exercise. Nineteen children with CF (age, 13.4 ± 3.1 years; 10 female) and 19 healthy controls (age, 13.8 ± 3.5 years; 10 female) performed 10 bouts of HIE interspersed with 1 min of recovery between each bout. Three minutes later participants completed a 10-min moderate-intensity exercise (MIE) test (test 1). The MIE test was subsequently repeated 1 h (test 2) and 24 h (test 3) later. Each MIE test was identical and participants exercised at individualized work rates, calibrated by an initial graded maximal cardiopulmonary exercise test, while metabolic and perceived exertion measurements were taken. Following HIE, mixed-model ANOVAs showed a significant difference in oxygen uptake (VO2) and rating of perceived exertion (RPE) between the 2 groups across the MIE tests (p < 0.01). In controls, VO2 (L·min⁻¹) and RPE decreased significantly from test 1 to test 2 (p < 0.01) and test 2 to test 3 (p < 0.05). However, in children with CF, VO2 (L·min⁻¹) increased significantly from test 1 to test 2 (p < 0.01), while RPE did not differ, both VO2 and RPE decreased significantly from test 2 to test 3 (p < 0.01). In conclusion, following HIE the metabolic and perceptual responses to MIE in both groups decreased 24 h later during test 3. These data show that children with mild-to-moderate CF have the capability to perform HIE and 24 h allows sufficient time for recovery.

Obstructive sleep apnea syndrome with bilateral papilledema and vision loss in a 3-year-old child.

We describe bilateral papilledema and vision loss in a 3-year-old child with obstructive sleep apnea. Although lumbar puncture initially disclosed a normal opening pressure, cerebrospinal fluid (CSF) pressure monitoring during sleep confirmed intermittent episodes of elevated intracranial pressure corresponding to increased airway resistance. The association of obstructive sleep apnea and raised intracranial pressure is recognized in children with craniosynostosis but has not been reported in its absence.