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.

METHODS

Subjects

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

Exercise testing

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 (P_ETCO₂, 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 P_ETCO₂ were recorded.

Data analysis

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 P_ETCO₂ from the first work rate until the peak work rate and a failure to reduce P_ETCO₂ 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,ΔP_ETCO₂ as a continuous variable, peak V˙O₂, pulse oximetry, and initial FEV₁. ΔP_ETCO₂ was [(change in P_ETCO₂ to peak exercise) + (change in P_ETCO₂ from peak to termination of exercise)]. Using the presented definition of CO₂ retention, the parameter ΔP_ETCO₂ 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).

RESULTS

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 P_ETCO₂ 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 P_ET CO₂ by 2.12 mm Hg (SD 0.80) and 3.70 mm Hg (SD 0.70) respectively. The mean P_ETCO₂ 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).

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): ΔP_ETCO₂ 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 ΔP_ETCO₂ as [(change in P_ETCO₂ to peak exercise) + (change in P_ETCO₂ from peak to termination of exercise)].

DISCUSSION

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 P_ETCO₂ values in an individual person, particularly in patients with lung disease or with disorders affecting ventilation/perfusion relationships, measurement of P_ETCO₂ 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,ΔP_ETCO₂ would be ⩾2 mm Hg for CO₂R and <2 mm Hg for CO₂NR. This study shows that for every 1 mm Hg ΔP_ETCO₂ [ΔP_ETCO₂ = (change in P_ETCO₂ to peak exercise) + (change in P_ETCO₂ 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.

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 P_ETCO₂ >41 mm Hg at peak exercise were more than twice as likely to die within seven years as patients with a P_ETCO₂ ⩽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.