Background: Carbon dioxide (CO2) retention during exercise is uncommon in mild to moderate lung disease in cystic fibrosis (CF). The ability to deal with increased CO2 is dependent on the degree of airflow limitation and inherent CO2 sensitivity. CO2 retention (CO2R) can be defined as a rise in PETCO2 tension of ⩾5 mm Hg with exercise together with a failure to reduce PETCO2 tension after peak work by at least 3 mm Hg by the termination of exercise.
Aim: To ascertain if carbon dioxide retention during exercise is associated with more rapid decline in lung function.
Methods: Annual spirometric and exercise data from 58 children aged 11–15 years, with moderate CF lung disease between 1996 and 2002 were analysed.
Results: The mean FEV1 at baseline for the two groups was similar; the CO2R group (n = 15) was 62% and the non-CO2 retention group (CO2NR) was 64% (n = 43). The decline in FEV1 after 12 months was −3.2% (SD 1.1) in the CO2R group and −2.3% (SD 0.9) in the CO2NR group. The decline after 24 months was −6.3% (SD 1.3) and −1.8% (SD 1.1) respectively. After 36 months, the decline in FEV1 was −5.3% (SD 1.2) and −2.6% (SD 1.1) respectively. The overall decline in lung function was 14.8% (SD 2.1) in the CO2R group and 6.7% (SD 1.8) in the CO2NR group. Using the primary outcome measure as a decline in FEV1 of >9%, final multivariate analysis showed that the relative risks for this model were (95% CIs in parentheses): ΔPETCO2 11.61 (3.41 to 24.12), peak V˙O2 1.23 (1.10 to 1.43), and initial FEV1 1.14 (1.02 to 1.28).
Conclusion: Results show that the inability to defend carbon dioxide during exercise is associated with a more rapid decline in lung function.
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- CO2, carbon dioxide
- CO2R, CO2 retention
- CO2NR, CO2 non-retention
- FVC, forced vital capacity
- FEV1, forced expiratory volume in one second
- MVV, maximal voluntary ventilation
- PaCO2, arterial partial pressure CO2
- PETCO2, end-tidal CO2 partial pressure
- SD, standard deviation
- V˙E, minute ventilation, V˙CO2, CO2 production
- V˙O2, oxygen consumption
Cystic fibrosis (CF) is a multisystem condition with the greatest morbidity and mortality arising from the pulmonary component of the disease. Though the overall survival of the condition has improved markedly over the past two decades, the natural history of the disease continues to be characterised by a steady decline in lung function. Pulmonary function testing provides a more objective assessment of the progress of pulmonary disease in CF than do clinical scoring systems.1–3 Forced expiratory volume in one second (FEV1) has been shown to be closely linked to mortality.4 Other factors that play a major role in the decline of lung function are infections due to Pseudomonas aeruginosa and Burkholderia cepacia,5 nutritional status,6 and gender.1 In view of this, markers to identify children who may be at a higher risk of a more rapid decline than others are continually being sought. Identification of such markers may allow earlier intervention with more aggressive therapy and alert clinicians to their more at risk population. Previous studies have evaluated the prognostic value of exercise testing in patients with cystic fibrosis,7,8 and patients with high levels of aerobic fitness showed a three times greater likelihood of survival than patients with lower levels of fitness.7
Carbon dioxide retention during exercise is uncommon in mild to moderate CF lung disease. The ability to deal with increased carbon dioxide is dependent on the degree of airflow obstruction and the inherent sensitivity to carbon dioxide. Patients with an FEV1 less than 60% are more likely to retain CO2.9 We sought to ascertain if carbon dioxide retention during exercise is associated with a greater rate of decline in FEV1. We hypothesised that CO2 retention during exercise could be a measure that predicts children who are at higher risk of decline in FEV1. This is because CO2 retention is a marker of mechanical impairment, increased dead space, ventilation perfusion abnormalities, and the patient’s response to CO2 stimulus may not be detectable on routine pulmonary function testing.
As part of the annual evaluation of children with CF, an aerobic exercise test and pulmonary function tests are performed. This was a retrospective analysis of exercise and pulmonary function data in children with CF. The inclusion criteria for this study were children with CF who had a minimum of three consecutive years of exercise test data. The recruitment period for this study was 1996 to 2000. This ensured that there was a minimum of three consecutive years of follow up. The exercise test data were excluded from analysis if the children had an acute pulmonary exacerbation as defined by an acute >10% decrease in FEV1, increased productive cough, and/or pyrexia at the time of the exercise test. Children who had Burkholderia cepacia or proven cystic fibrosis related diabetes were excluded from the study.
Pulmonary function tests
FVC, FEV1, and MVV (Gould Sentry System 50, Gould Inc. Dayton, Ohio) were measured annually according to standard spirometric techniques.10 Pulmonary function values were expressed as a percent of predicted value based on standards previously developed in this laboratory.11 MVV was assessed by the sprint method.12
Patients performed an annual maximal incremental cycling test on an electrically braked cycle ergometer (Rodby Electronik AB, Enhorna, Sweden). One minute work increments were chosen according to sex, height, and physical activity level.13 Heart rate (lead II, ECG), inspired V˙E (Parkinson–Cowan dry gas meter, Manchester, UK), mixed expired oxygen (Applied Electrochemistry oxygen analyser, Sunnyvale CA), carbon dioxide (P.K.Morgan 901–MK2, Chatham, UK), and respiratory rate (thermister) were monitored continuously on an eight channel recorder. V˙O2, and V˙CO2 were calculated using the nitrogen balance technique.14 The test was considered complete when the patient reached exhaustion, based on an inability to maintain a continuous pedalling speed of 60 revolutions per minute. At the 15 second mark of each work rate, the end-tidal PCO2 (PETCO2, mm Hg) was calculated by measuring the expired carbon dioxide at the mouthpiece at the end of tidal breathing. The peak and end of exercise PETCO2 were recorded.
The children were divided into those who retained CO2 during progressive exercise test (CO2R group) and those who did not (CO2NR group). CO2 retention was arbitrarily defined as a rise of ⩾5 mm Hg PETCO2 from the first work rate until the peak work rate and a failure to reduce PETCO2 after the peak work rate by 3 mm Hg by the termination of the exercise.
The Shapiro Wilk statistic was used to assess if the data followed a normal distribution. One way ANOVA with repeated measures was used to detect the changes in FEV1 as the primary continuous variable over time. Statistical significance was assigned when p < 0.05. Univariate logistic regression analysis was performed on the following variables: gender, age, minute ventilation at peak exercise, BMI,ΔPETCO2 as a continuous variable, peak V˙O2, pulse oximetry, and initial FEV1. ΔPETCO2 was [(change in PETCO2 to peak exercise) + (change in PETCO2 from peak to termination of exercise)]. Using the presented definition of CO2 retention, the parameter ΔPETCO2 would be expected to be ⩾2 mm Hg in this study in the CO2R group.
Univariate predictors of moderate statistical significance (p < 0.25) were included in the multivariate logistic regression model. Decline in FEV1 over 36 months was the primary outcome, with a decline of greater than 9% over the three years deemed to be clinically significant. A value of 9% over three years was chosen as this is the approximate rate of decline in typical subjects with CF.11 Computations were made with the SAS statistical program (version 6.12, SAS Institute, Cary, NC). Results were expressed as relative risks with their 95% confidence intervals (CI).
The demographic details at baseline are presented in table 1. The mean age at entry of the subjects in the CO2R group was 13.9 years (SD 1.7) and in the CO2NR group was 13.6 years (SD 1.8). This difference was not statistically significant. The body mass index was similar in both groups. The mean FEV1 values at baseline for the two groups were similar (CO2R 62% (range 41–68%) and CO2NR 65% (range 44–69%)).
At entry in to the study, the mean change in PETCO2 from rest to peak was 6.62 mm Hg (SD 1.13) in the CO2R group and 2.27 mm Hg (SD 1.17) in the CO2NR group. With exercise, the CO2R and CO2NR group reduced their PET CO2 by 2.12 mm Hg (SD 0.80) and 3.70 mm Hg (SD 0.70) respectively. The mean PETCO2 at rest in the CO2R and CO2NR groups were 38.7 mm Hg (1.6) and 37.6 mm Hg (2.1) respectively (p > 0.05). In addition, the CO2R and CO2NR groups increased their tidal volume by 45.7% (SD 2.2) and 95.4% (SD 2.8) (p < 0.05) respectively. There was no evidence of desaturation using pulse oximetry in any of the children tested. V˙E at peak exercise was significantly less in the CO2R group: 61 l/min (SD 7) versus 78 l/min (SD 9) in the CO2NR group (p < 0.05).
What is already known on this topic
Carbon dioxide retention during exercise is uncommon in mild to moderate CF lung disease
Previous researchers have shown that the ability to deal with increased carbon dioxide is related to factors such as the degree of airflow obstruction and the inherent sensitivity to carbon dioxide
However, using the current definitions of carbon dioxide retention, the prognostic value of carbon dioxide retention in children with CF has not been evaluated
The decline in FEV1 after 1 year was −3.2% (SD 1.1) in the CO2R group and −2.3% (SD 0.9) (p > 0.05) in the CO2NR group. The decline in FEV1 in year 2 was −6.3% (SD 1.3) in the CO2R group and −1.8% (SD 1.1) in the CO2NR group (p < 0.05). In year 3, the decline was −5.3% (SD 1.2) and −2.5% (SD 1.1) in FEV1 in the CO2R and CO2NR groups respectively (p < 0.05). Overall, the FEV1% predicted declined by −14.8% (SD 2.1) in the CO2R group and −6.7% (SD 1.8) in the CO2NR group over three years (p < 0.01). The decline in FEV1 is presented graphically in fig 1.
Univariate analyses are presented in table 2. Parameters of moderate statistical significance (p < 0.25) were included in the multivariate analysis. The primary outcome measure was the relative risk of a decline in FEV1 of >9%. The final multivariate analysis results are presented in table 3. The relative risks for the final model were (95% CIs in parentheses): ΔPETCO2 11.61 (3.41 to 24.12), peak V˙O2 1.23 (1.10 to 1.43), initial FEV1 1.14 (1.02 to 1.28). We computed ΔPETCO2 as [(change in PETCO2 to peak exercise) + (change in PETCO2 from peak to termination of exercise)].
This study suggests that children with CF with a similar degree of pulmonary disease as measured by FEV1, if found to have CO2 retention on exercise testing will have a greater decline in FEV1 over a three year period compared to their counterparts who do not retain CO2. In addition to FEV1 and peak aerobic capacity, we have now shown that the presence of CO2 retention during exercise can be an additional prognostic marker of disease progress in cystic fibrosis.
Although PaCO2 values cannot be predicted accurately from PETCO2 values in an individual person, particularly in patients with lung disease or with disorders affecting ventilation/perfusion relationships, measurement of PETCO2 is often valuable for following trends in PaCO2.15 In healthy children carbon dioxide levels rarely increase during exercise and actually fall slightly in vigorous exercise.16 Using the definitions for carbon dioxide retention presented earlier,ΔPETCO2 would be ⩾2 mm Hg for CO2R and <2 mm Hg for CO2NR. This study shows that for every 1 mm Hg ΔPETCO2 [ΔPETCO2 = (change in PETCO2 to peak exercise) + (change in PETCO2 from peak to termination of exercise)], there was an almost 12-fold increase in the risk of the child dropping their FEV1 by 9% or more over the next three years.
The association of CO2 retention during exercise and poor pulmonary function has been previously reported by Cropp and colleagues.9 They also noted a significant correlation between desaturation and CO2 retention at peak work capacity and postulated that V˙E was not sufficient to maintain alveolar ventilation. This in combination with excessive dead space ventilation resulted in alveolar hypoventilation. Excessive dead space ventilation in patients with CF was also noted by Godfrey and Mearns,17 who suggested that this may be one of the more sensitive indicators of pulmonary dysfunction in cystic fibrosis. Coates and colleagues18 showed that the failure to increase tidal volume appropriately, rather than a large physiologic dead space, led to alveolar hypoventilation with consequent exertional hypercapnia.
What this study adds
Carbon dioxide (CO2) retention was defined as a rise of ⩾5 mm Hg end tidal CO2 from the first work rate until the peak work rate and a failure to reduce end tidal CO2 after the peak work rate by 3 mm Hg by the termination of the exercise
This study shows that children with CF who were found to have CO2 retention on exercise testing showed a faster rate of decline in FEV1 when compared to those who did not retain CO2
This additional information may be used to identify those children who may require more intensive therapy to prevent this increased rate in pulmonary decline
The V˙E at peak exercise was significantly less in our CO2R group. This is secondary to the significantly smaller change in tidal volume in this group compared to the CO2NR group throughout the exercise test. Compared to healthy subjects, children with severe lung disease have been shown to have an increased V˙E per unit work rate.19 The reason that some of our cohort who had similar pulmonary function profiles retained CO2 may be due to their poorer V˙E response, and/or a higher degree of ventilation/perfusion mismatch in these children.
Nixon et al reported that patients with a PETCO2 >41 mm Hg at peak exercise were more than twice as likely to die within seven years as patients with a PETCO2 ⩽36 mm Hg.7 Coates et al have shown that the ventilatory response to a CO2 stimulus in children with CF is the combined result of the degree of chronic airflow obstruction and an inherent sensitivity to the CO2 drive to breathe.20 Therefore, the different handling techniques of a CO2 stimulus may be one cause of exertional hypercapnia.
The CO2R group showed an increasingly significant decline in FEV1 over three years. Though the CO2R group had a slightly lower FEV1 profile (62.3%, range 41–68%) compared to the CO2NR group (64.7%, range 44–69%) at the commencement of the study, the difference was not great enough to explain the more rapid decline in the CO2R group. By the third year there was a decline of −5.3% (SD 1.2) and −2.5% (SD 1.1) in the CO2R and CO2NR groups respectively. The average decline in FEV1 per annum was −4.9% in the CO2R group compared with −2.3% in the CO2NR group. This estimate for the CO2NR group is similar to that reported from Toronto for a combined sample of children and adults with CF.11,21
In summary, children with CF who were found to have CO2 retention on exercise testing showed a faster rate of decline in FEV1 when compared to those who did not retain CO2. This additional information may be used to identify those children who may require more intensive therapy to prevent this increased rate in pulmonary decline.
Competing interests: none declared
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