Practical Aspects of Cardiopulmonary Exercise Testing in Children.

The use of cardiopulmonary exercise testing (CPET) in pediatrics provides critical insights into potential physiological causes of unexplained exercise-related complaints or symptoms, as well as specific pathophysiological patterns based on physiological responses or abnormalities. Furthermore, CPET helps evaluate exercise performance in children with chronic (lung/heart) diseases. For instance, it can ascertain any adverse reaction to exercise and estimate the effects of specific treatment measures. It affords a global assessment of the pathophysiological patterns, responses and abnormalities to exercise that is inadequately reflected by resting lung function and/or cardiac function assessment. Clinical interpretation of the results of a CPET in pediatrics requires specific knowledge regarding pathophysiological responses and interpretative strategies that can be adapted to address concerns specific to the child's medical condition or disability.

Organized Sports Activities Are Safe for Children With Sickle Cell Disease: A Pilot Intervention Study.

Historically, children with sickle cell disease (SCD) are advised to refrain from sports activities, based on the assumption that physical exercise can trigger vaso-occlusive episodes. This pilot intervention study examined the safety (ie, no vaso-occlusive episodes) of a 10-week organized sports program for children with SCD. Eight children with SCD (5 boys/3 girls), aged 7 to 12 years old, received 10 training sessions (each 90 min) once a week. Training sessions were performed by a professional soccer club under the supervision of a medical team from the Wilhelmina Children's Hospital. During the study period, one child experienced a vaso-occlusive crisis, which could not be directly related to the organized sports program. None of the other children experienced vaso-occlusive episodes. The results of this study indicate that children with SCD can participate safely in moderate-intensity organized sports activities when personalized medical background and practical training information is shared with the trainer beforehand. All children continued their sports participation after the study period.

The RESISTANT study (Respiratory Muscle Training in Patients with Spinal Muscular Atrophy): study protocol for a randomized controlled trial.

BACKGROUND: Spinal Muscular Atrophy (SMA) is characterized by progressive and predominantly proximal and axial muscle atrophy and weakness. Respiratory muscle weakness results in impaired cough with recurrent respiratory tract infections, nocturnal hypoventilation, and may ultimately lead to fatal respiratory failure in the most severely affected patients. Treatment strategies to either slow down the decline or improve respiratory muscle function are wanting. OBJECTIVE: The aim of this study is to assess the feasibility and efficacy of respiratory muscle training (RMT) in patients with SMA and respiratory muscle weakness. METHODS: The effect of RMT in patients with SMA, aged ≥ 8 years with respiratory muscle weakness (maximum inspiratory mouth pressure [PImax] ≤ 80 Centimeters of Water Column [cmH2O]), will be investigated with a single blinded randomized sham-controlled trial consisting of a 4-month training period followed by an 8-month open label extension phase. INTERVENTION: The RMT program will consist of a home-based, individualized training program involving 30-breathing cycles through an inspiratory and expiratory muscle training device. Patients will be instructed to perform 10 training sessions over 5-7 days per week. In the active training group, the inspiratory and expiratory threshold will be adjusted to perceived exertion (measured on a Borg scale). The sham-control group will initially receive RMT at the same frequency but against a constant, non-therapeutic resistance. After four months the sham-control group will undergo the same intervention as the active training group (i.e., delayed intervention). Individual adherence to the RMT protocol will be reviewed every two weeks by telephone/video call with a physiotherapist. MAIN STUDY PARAMETERS/ENDPOINTS: We hypothesize that the RMT program will be feasible (good adherence and good acceptability) and improve inspiratory muscle strength (primary outcome measure) and expiratory muscle strength (key secondary outcome measure) as well as lung function, patient reported breathing difficulties, respiratory infections, and health related quality of life (additional secondary outcome measures, respectively) in patients with SMA. DISCUSSION: RMT is expected to have positive effects on respiratory muscle strength in patients with SMA. Integrating RMT with recently introduced genetic therapies for SMA may improve respiratory muscle strength in this patient population. TRIAL REGISTRATION: Retrospectively registered at clinicaltrial.gov: NCT05632666.

Lung function decline preceding chronic respiratory failure in spinal muscular atrophy: a national prospective cohort study.

BACKGROUND: Progressive lung function decline, resulting in respiratory failure, is an important complication of spinal muscular atrophy (SMA). The ability to predict the need for mechanical ventilation is important. We assessed longitudinal patterns of lung function prior to chronic respiratory failure in a national cohort of treatment-naïve children and adults with SMA, hypothesizing an accelerated decline prior to chronic respiratory failure. METHODS: We included treatment-naïve SMA patients participating in a prospective national cohort study if they required mechanical ventilation because of chronic respiratory failure and if lung function test results were available from the years prior to initiation of ventilation. We analyzed Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV1), Peak Expiratory Flow (PEF) and Maximum Expiratory Pressure (PEmax). We studied the longitudinal course using linear mixed-effects models. We compared patients who electively started mechanical ventilation compared to patients who could not be weaned after acute respiratory failure. RESULTS: We analyzed 385 lung function tests from 38 patients with SMA types 1c-3a. At initiation of ventilation median age was 18.8 years (IQR: 13.2-30.1) and median standardized FVC, FEV1 and PEF were 28.8% (95% CI: 23.5; 34.2), 28.8% (95% CI: 24.0; 33.7) and 30.0% (95% CI: 23.4; 36.7), with an average annual decline of 1.75% (95% CI: 0.86; 2.66), 1.72% (95% CI: 1.04; 2.40) and 1.65% (95% CI: 0.71; 2.59), respectively. Our data did not support the hypothesis of an accelerated decline prior to initiation of mechanical ventilation. Median PEmax was 35.3 cmH2O (95% CI: 29.4; 41.2) at initiation of mechanical ventilation and relatively stable in the years preceding ventilation. Median FVC, FEV1, PEF and PEmax were lower in patients who electively started mechanical ventilation (p < 0.001). CONCLUSIONS: Patterns of lung function decline cannot predict impending respiratory failure: SMA is characterized by a gradual decline of lung function. We found no evidence for an accelerated deterioration. In addition, PEmax remains low and stable in the years preceding initiation of ventilation. Patients who electively started mechanical ventilation had more restrictive lung function at initiation of ventilation, compared to patients who could not be weaned after surgery or a respiratory tract infection.

Is Measuring Physical Literacy in School-Aged Children With Cystic Fibrosis or Congenital Heart Disease Needed?

PURPOSE: To explore the association between cardiorespiratory fitness and other physical literacy domains in children with cystic fibrosis (CF) or congenital heart disease (CHD). METHODS: In 28 children with CF (n = 10) or CHD (n = 18), aged 7 to 11 years, cardiorespiratory fitness and the following physical literacy domains were measured: ( a ) physical competence, ( b ) motivation and confidence, ( c ) knowledge and understanding, and ( d ) daily behavior (ie, self-perceived moderate-to-vigorous physical activity [MVPA]). RESULTS: Cardiorespiratory fitness was significantly associated with motivation and confidence and self-perceived MVPA. There were no other significant associations. CONCLUSIONS: Cardiorespiratory fitness is associated with self-perceived MVPA, motivation, and confidence in children with CF or CHD.

Respiratory muscle fatigability in patients with spinal muscular atrophy.

BACKGROUND: Respiratory failure is a major cause of morbidity and mortality in patients with Spinal Muscular Atrophy (SMA). Lack of endurance, or "fatigability," is an important symptom of SMA. In addition to respiratory muscle weakness, respiratory function in SMA may be affected by Respiratory Muscle Fatigability (RMF). AIM: The purpose of this study was to explore RMF in patients with SMA. METHODS: We assessed a Respiratory Endurance Test (RET) in 19 children (median age [years]: 11) and 36 adults (median age [years]: 34) with SMA types 2 and 3. Participants were instructed to breath against an inspiratory threshold load at either 20%, 35%, 45%, 55%, or 70% of their individual maximal inspiratory mouth pressure (PImax). RMF was defined as the inability to complete 60 consecutive breaths. Respiratory fatigability response was determined by change in maximal inspiratory mouth pressure (ΔPImax) and perceived fatigue (∆perceived fatigue). RESULTS: The probability of RMF during the RET increased by 59%-69% over 60 breaths with every 10% increase in inspiratory threshold load (%PImax). Fatigability response was characterized by a large variability in ΔPImax (-21% to +16%) and a small increase in perceived fatigue (p = 0.041, range 0 to +3). CONCLUSION AND KEY FINDINGS: Patients with SMA demonstrate a dose-dependent increase in RMF without severe increase in exercise-induced muscle weakness or perceived fatigue. Inspiratory muscle loading in patients with SMA seems feasible and its potential to stabilize or improve respiratory function in patients with SMA needs to be determined in further research.

Motor Unit and Capillary Recruitment During Fatiguing Arm-Cycling Exercise in Spinal Muscular Atrophy Types 3 and 4.

BACKGROUND: Exercise intolerance is an important impairment in patients with SMA, but little is known about the mechanisms underlying this symptom. OBJECTIVE: To investigate if reduced motor unit and capillary recruitment capacity in patients with SMA contribute to exercise intolerance. METHODS: Adolescent and adult patients with SMA types 3 and 4 (n = 15) and age- and gender matched controls (n = 15) performed a maximal upper body exercise test. We applied respiratory gas analyses, non-invasive surface electromyography (sEMG) and continuous wave near-infrared spectroscopy (CW-NIRS) to study oxygen consumption, arm muscle motor unit- and capillary recruitment, respectively. RESULTS: Maximal exercise duration was twofold lower (p < 0.001) and work of breathing and ventilation was 1.6- and 1.8-fold higher (p < 0.05) in patients compared to controls, respectively. Regarding motor unit recruitment, we found higher normalized RMS amplitude onset values of sEMG signals from all muscles and the increase in normalized RMS amplitudes was similar in the m. triceps brachii, m. brachioradialis and m. flexor digitorum in SMA compared to controls. Median frequency, onset values were similar in patients and controls. We found a similar decrease in median frequencies of sEMG recordings from the m. biceps brachii, a diminished decrease from the m. brachioradialis and m. flexor digitorum, but a larger decrease from the m. triceps brachii. With respect to capillary recruitment, CW-NIRS recordings in m. biceps brachii revealed dynamics that were both qualitatively and quantitatively similar in patients and controls. CONCLUSION: We found no evidence for the contribution of motor unit and capillary recruitment capacity of the upper arm muscles in adolescent and adult patients with SMA types 3 and 4 as primary limiting factors to premature fatigue during execution of a maximal arm-cycling task.

Oscillometry: A substitute of spirometry in children with neuromuscular diseases?

INTRODUCTION: Spirometry plays an important role in the assessment of possible respiratory failure in children with neuromuscular diseases (NMDs). However, obtaining reliable spirometry results is a major challenge. We studied the relation between oscillometry and spirometry results. Oscillometry is an easy, noninvasive method to measure respiratory resistance R and reactance X. We hypothesized an increased R and reduced X in patients with more reduced lung function. METHODS: In this prospective single-center study, we included all children with NMDs able to perform spirometry. We consecutively measured R and X at 5, 11, and 19 Hz and (forced) vital capacity, peak expiratory flow. Spearman correlation coefficients and positive and negative predictive values were calculated. Regression curves were estimated. RESULTS: We included 148 patients, median age 13 years (interquartile range: 8-16). A negative correlation was found between R and spirometry outcomes (Spearman correlation coefficient [ρ]: -0.5 to -0.6, p < 0.001). A positive correlation was found between X (i.e., less negative outcomes) and spirometry outcomes (ρ: 0.4-0.6, p < 0.001). Highest correlation was found at lower frequencies. Regression analysis showed a nonlinear relation. Measurement of inspiratory and expiratory R and X did not provide added value. Positive predictive values of 80%-85% were found for z-scores of R measured at 5 Hz versus (F)VC ≤ 60%. CONCLUSION: We found a nonlinear relation between oscillometry and spirometry results with increased R and reduced X in patients with more restrictive lung function decline. Given the difficulties with performing spirometry, oscillometry may be a promising substitute.

Short-term effect and effect on rate of lung function decline after surgery for neuromuscular or syndromic scoliosis.

INTRODUCTION: Understanding the impact of scoliosis surgery on lung function is important for counseling patients about risks and benefits of surgery. We prospectively compared the trends in lung function test (LFT) results before and after scoliosis surgery in children with neuromuscular diseases or dysmorphic syndromes. We hypothesized a stabilization. METHODS: We prospectively included children with neuromuscular or syndromic scoliosis able to perform LFTs. We studied (forced) vital capacity ([F]VC), ratio of forced expiratory volume in 1 s (FEV1 ) and FVC, and peak expiratory flow (PEF). Preoperative LFT results were compared with results 3-4 months after surgery. The mean monthly change in LFT results up to 2 years after surgery was compared with the preoperative natural history using linear mixed-effects models. RESULTS: We included 43 patients. No significant change was observed in absolute values of (F)VC, FEV1 /FVC, and PEF before and after surgery. In 23 neuromuscular patients median standardized VC, FVC, and PEF decreased significantly after surgery from 43% to 33%, 42% to 31%, and 51% to 40%, respectively. In 20 syndromic patients, median FVC decreased from 68% to 65%. The monthly rate of change in FVC did not change significantly in both groups with a mean difference of 0.18% (95% CI: -0.27, -0.61) and -0.44% (95% CI: -1.05, 0.16). CONCLUSION: No stabilization of lung function 3-4 months after scoliosis surgery was observed in children with neuromuscular and syndromic scoliosis with restrictive lung function disease. The effect on the rate of lung function decline remains inconclusive.

Natural history of respiratory muscle strength in spinal muscular atrophy: a prospective national cohort study.

BACKGROUND: Respiratory complications are the most important cause of morbidity and mortality in spinal muscular atrophy (SMA). Respiratory muscle weakness results in impaired cough, recurrent respiratory tract infections and eventually can cause respiratory failure. We assessed longitudinal patterns of respiratory muscle strength in a national cohort of treatment-naïve children and adults with SMA, hypothesizing a continued decline throughout life. METHODS: We measured maximal expiratory and inspiratory pressure (PEmax and PImax), Sniff Nasal inspiratory pressure (SNIP), peak expiratory flow (PEF), and peak cough flow (PCF) in treatment-naïve patients with SMA. We used mixed-models to analyze natural history patterns. RESULTS: We included 2172 measurements of respiratory muscle function from 80 treatment-naïve patients with SMA types 1c-3b. All outcomes were lower in the more severe phenotypes. Significant differences in PEF were present between SMA types from early ages onwards. PEF decline was linear (1-2%/year). PEF reached values below 80% during early childhood in types 1c-2, and during adolescence in type 3a. PEmax and PImax were severely lowered in most patients throughout life, with PEmax values abnormally low (i.e. < 80 cmH2O) in virtually all patients. The PEmax/PImax ratio was < 1 throughout life in all SMA types, indicating that expiratory muscles were most affected. All but SMA type 3b patients had a lowered PCF. Patients with types 2b and 3a had PCF levels between 160 and 270 L/min, those with type 2a around 160 L/min and patients with type 1c well below 160 L/min. Finally, SNIP was low in nearly all patients, most pronounced in more severely affected patients. CONCLUSIONS: There are clear differences in respiratory muscle strength and its progressive decline between SMA types. We observed lower outcomes in more severe SMA types. Particularly PEF may be a suitable outcome measure for the follow-up of respiratory strength in patients with SMA. PEF declines in a rather linear pattern in all SMA types, with clear differences at baseline. These natural history data may serve as a reference for longer-term treatment efficacy assessments.

Recommendations for Hospital-Based Physical Therapists Managing Patients With COVID-19.

OBJECTIVE: The COVID-19 pandemic is rapidly evolving and has led to increased numbers of hospitalizations worldwide. Hospitalized patients with COVID-19 experience a variety of symptoms, including fever, muscle pain, tiredness, cough, and difficulty breathing. Elderly people and those with underlying health conditions are considered to be more at risk of developing severe symptoms and have a higher risk of physical deconditioning during their hospital stay. Physical therapists have an important role in supporting hospitalized patients with COVID-19 but also need to be aware of challenges when treating these patients. In line with international initiatives, this article aims to provide guidance and detailed recommendations for hospital-based physical therapists managing patients hospitalized with COVID-19 through a national approach in the Netherlands. METHODS: A pragmatic approach was used. A working group conducted a purposive scan of the literature and drafted initial recommendations based on the knowledge of symptoms in patients with COVID-19 and current practice for physical therapist management for patients hospitalized with lung disease and patients admitted to the intensive care unit. An expert group of hospital-based physical therapists in the Netherlands provided feedback on the recommendations, which were finalized when consensus was reached among the members of the working group. RESULTS: The recommendations include safety recommendations, treatment recommendations, discharge recommendations, and staffing recommendations. Treatment recommendations address 2 phases of hospitalization: when patients are critically ill and admitted to the intensive care unit, and when patients are severely ill and admitted to the COVID ward. Physical therapist management for patients hospitalized with COVID-19 comprises elements of respiratory support and active mobilization. Respiratory support includes breathing control, thoracic expansion exercises, airway clearance techniques, and respiratory muscle strength training. Recommendations toward active mobilization include bed mobility activities, active range-of-motion exercises, active (assisted) limb exercises, activities-of-daily-living training, transfer training, cycle ergometer, pre-gait exercises, and ambulation.

Clinical recommendations for cardiopulmonary exercise testing in children with respiratory diseases.

INTRODUCTION: Cardiopulmonary exercise testing (CPET) quantitates and qualitates the integrated physiological response of a person to incremental exercise and provides additional information compared to static lung function tests alone. AREAS COVERED: This review covers rationale for the use of CPET parameters beyond the usual parameters like peak oxygen uptake and peak minute ventilation in children with respiratory disease. EXPERT OPINION: CPET provides a wealth of data from rest, submaximal and maximal exercise and data during recovery from exercise. In this review, an interpretative approach is described for analyzing CPET data in children with respiratory disease.

Natural history of lung function in spinal muscular atrophy.

BACKGROUND: Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural history of lung function in SMA has, however, not been studied in much detail. RESULTS: We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c-4, aged 4-74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV1 and FVC tests. In early-onset SMA types (1c-3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV1 ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from - 0.1% to - 1.4% for FEV1, - 0.2% to - 1.4% for FVC, and + 0.2% to - 1.7% for VC. In contrast to SMA types 1c-3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV1 values measured in either sitting or supine position. CONCLUSIONS: Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV1 or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.

Effect of mechanical insufflation-exsufflation in children with neuromuscular weakness.

INTRODUCTION: Children with neuromuscular diseases develop cough impairment. Airway clearance techniques (ACTs) may help to prevent recurrent respiratory tract infections (RTIs). A commonly used ACT is mechanical insufflation-exsufflation (MI-E), but evidence for efficacy is limited. We hypothesize that MI-E has beneficial effect on RTI related hospital admission rate. METHODS: In this single-center retrospective study, we reviewed all children who used daily MI-E between 2005 till June 2019. Primary outcome studied was the number of RTIs requiring hospital admission. Patient satisfaction and burden experienced by MI-E use were explored by questionnaires using a Likert scale. The relative number of RTIs requiring admission and the number of admission days per eligible period before and after the introduction of MI-E were compared using the Friedman test and the Wilcoxon signed-rank test. RESULTS: Thirty-seven children were included. The median number of RTI related hospital admissions per 1000 eligible days after the introduction of MI-E was 0.9 (interquartile range [IQR] 0.0-3.1) compared to the 3 preceding years (median 3.7; IQR 1.4-5.9; P = .006). The median number of RTI related admission days per 1000 eligible days after the introduction of MI-E was significantly lower with a median of 2.7 (IQR 0.0-17.4) compared to the 3 preceding years (median 33.6; IQR 15.0-51.1; P = .001). Patient satisfaction was high with low burden, even in patients who discontinued treatment. CONCLUSION: A significantly lower number of RTIs requiring hospital admission and shorter admission duration after the introduction of MI-E was found, with high patient satisfaction and low burden.

Exercise responses in children and adults with a Fontan circulation at simulated altitude.

BACKGROUND: Traveling to high altitude has become more popular. High-altitude exposure causes hypobaric hypoxia. Exposure to acute high altitude, during air travel or mountain stays, seems to be safe for most patients with congenital heart disorders (CHD). Still, current guidelines for CHD patients express concerns regarding safety of altitude exposure for patients with a Fontan circulation. Therefore, investigating hemodynamic and pulmonary responses of acute high-altitude exposure (±2500 m) at rest and during maximal exercise in patients with Fontan circulation can provide clarity in this dispute and may contribute to improvement of clinical counseling. METHODS: Twenty-one Fontan patients with 21 age-matched healthy controls, aged 8-40 years, were enrolled in an observational study. Participants performed two cardiopulmonary exercise tests on a cycle ergometer with breath-by-breath respiratory gas analyses combined with noninvasive impedance cardiac output measurements: one at sea level (±6 m) and one at simulated high altitude (±2500 m), respectively. RESULTS: The effect of altitude exposure was different in rest for saturation (-2.3% vs -4.1%) between Fontan patients and healthy controls (P < .05). At peak exercise the effects of high altitude exposure was different on VO2 (-5.1% vs 9.6%) and AvO2 -diff (-0.3% vs -12.8%) between Fontan patients and healthy controls. CONCLUSION: Although, acute high-altitude exposure has a detrimental effect on exercise capacity, the impact on pulmonary and hemodynamic responses of high-altitude exposure is comparable between Fontan patients and healthy controls.

Assessment of fatigability in patients with spinal muscular atrophy: development and content validity of a set of endurance tests.

BACKGROUND: Fatigability has emerged as an important dimension of physical impairment in patients with Spinal Muscular Atrophy (SMA). At present reliable and valid outcome measures for both mildly and severely affected patients are lacking. Therefore the primary aim of this study is the development of clinical outcome measures for fatigability in patients with SMA across the range of severity. METHODS: We developed a set of endurance tests using five methodological steps as recommended by the 'COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). In this iterative process, data from multiple sources were triangulated including a scoping review of scientific literature, input from a scientific and clinical multidisciplinary expert panel and three pilot studies including healthy persons (N = 9), paediatric patients with chronic disorders (N = 10) and patients with SMA (N = 15). RESULTS: Fatigability in SMA was operationalised as the decline in physical performance. The following test criteria were established; one method of testing for patients with SMA type 2-4, a set of outcome measures that mimic daily life activities, a submaximal test protocol of repetitive activities over a longer period; external regulation of pace. The scoping review did not generate suitable outcome measures. We therefore adapted the Endurance Shuttle Walk Test for ambulatory patients and developed the Endurance Shuttle Box and Block Test and the - Nine Hole Peg Test for fatigability testing of proximal and distal arm function. Content validity was established through input from experts and patients. Pilot testing showed that the set of endurance tests are comprehensible, feasible and meet all predefined test criteria. CONCLUSIONS: The development of this comprehensive set of endurance tests is a pivotal step to address fatigability in patients with SMA.

A Systematic Approach to Interpreting the Cardiopulmonary Exercise Test in Pediatrics.

The use of cardiopulmonary exercise testing in pediatrics provides critical insights into potential physiological causes of unexplained exercise-related complaints or symptoms, as well as specific pathophysiological patterns based on physiological responses or abnormalities. Clinical interpretation of the results of a cardiopulmonary exercise test in pediatrics requires specific knowledge with regard to pathophysiological responses and interpretative strategies that can be adapted to address concerns specific to the child's medical condition or disability. In this review, the authors outline the 7-step interpretative approach that they apply in their outpatient clinic for diagnostic, prognostic, and evaluative purposes. This approach allows the pediatric clinician to interpret cardiopulmonary exercise testing results in a systematic order to support their physiological reasoning and clinical decision making.

Cardiopulmonary Exercise Testing Provides Additional Prognostic Information in Cystic Fibrosis.

RATIONALE: The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic factors, is unclear. OBJECTIVES: To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake ( V. o2peak) following rigorous adjustment for other predictors. METHODS: Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups. MEASUREMENTS AND MAIN RESULTS: Cox regression showed, even after adjustment for sex, FEV1% predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that V. o2peak in % predicted (hazard ratio [HR], 0.964; 95% confidence interval [CI], 0.944-0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951-0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041-1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007-1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity. CONCLUSIONS: CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling.