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(Chest. 2005;127:1904-1910.)
© 2005 American College of Chest Physicians

Survival of Chronic Hypercapnic COPD Patients Is Predicted by Smoking Habits, Comorbidity, and Hypoxemia*

Tessa A. C. Nizet, MD; Frank J. J. van den Elshout, MD, PhD; Yvonne F. Heijdra, MD, PhD; Marjo J. T. van de Ven, MD, PhD; Paul G. H. Mulder, PhD and Hans Th. M. Folgering, MD, PhD

* From the Department of Pulmonary Diseases (Drs. Nizet, van den Elshout, and van de Ven), Rijnstate Hospital Arnhem, Arnhem; Department of Pulmonary Diseases (Dr. Heijdra), University Medical Center St. Radboud Nijmegen, Nijmegen; Department of Epidemiology & Biostatistics (Dr. Mulder), Erasmus University Medical Center Rotterdam, Rotterdam; and Department of Pulmonary Diseases Dekkerswald (Dr. Folgering), University of Nijmegen, Nijmegen, the Netherlands.

Correspondence to: Tessa A. C. Nizet, MD, Department of Pulmonary Diseases, Rijnstate Hospital Arnhem, PO Box 9555, 6800 TA Arnhem, the Netherlands; e-mail: tnizet{at}mmc.nl


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Chronic hypercapnia in patients with COPD has been associated with a poor prognosis. We hypothesized that, within this group of chronic hypercapnic COPD patients, factors that could mediate this hypercapnia, such as decreased maximum inspiratory mouth pressure (PImax), decreased maximum expiratory mouth pressure (PEmax), and low hypercapnic ventilatory response (HCVR), could be related to survival. Other parameters, such as arterial blood gas values, airway obstruction (FEV1), body mass index (BMI), current smoking status, and the presence of comorbidity were studied as well.

Methods: A cohort of 47 chronic hypercapnic COPD patients recruited for short-term trials (1 to 3 weeks) in our institute was followed up for 3.8 years on average. Survival was analyzed using a Cox proportional hazards model. The risk factors considered were analyzed, optimally adjusted for age and gender.

Results: At the time of analysis 18 patients (10 male) were deceased. After adjusting for age and gender, PImax, PEmax, and HCVR were not correlated with survival within this hypercapnic group. Current smoking (hazard ratio [HR], 7.0; 95% confidence interval [CI], 1.4 to 35.3) and the presence of comorbidity (HR, 5.5; 95% CI, 1.7 to 18.7) were associated with increased mortality. A higher PaO2 affected survival positively (HR, 0.6 per 5 mm Hg; 95% CI, 0.4 to 1.0). PaCO2 tended to be lower in survivors, but this did not reach statistical significance (HR, 2.0 per 5 mm Hg; 95% CI, 0.9 to 4.3). FEV1 and BMI were not significantly related with survival in hypercapnic COPD patients.

Conclusion: In patients with chronic hypercapnia, only smoking status, the presence of comorbidity, and PaO2 level are significantly associated with survival. Airway obstruction, age, and BMI are known to be predictors of survival in COPD patients in general. However, these parameters do not seem to significantly affect survival once chronic hypercapnia has developed.

Key Words: control of breathing • pulmonary diseases, chronic obstructive • hypercapnia • respiratory muscle function • survival


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
COPD is an important cause of death and leads to a substantial disability.12 By the year 2020, COPD might become the fifth-leading cause of combined mortality and disability worldwide.3 Therefore, determining factors that might influence the course and prognosis of this disease is essential for making treatment decisions.

Several studies145678910 have been performed to establish parameters associated with an increased risk of death in COPD patients. A low FEV16111213 and cigarette smoking are the most important factors related to mortality.111121415161718 A number of other variables, such as hypercapnia, hypoxemia,1920 body mass index (BMI),5679111213 environmental exposures, bronchial responsiveness, {alpha}1-antitrypsin deficiency, lower social economic status,14 and the presence of comorbidities621 are also considered to be related to poor prognosis. Regarding treatment options, long-term oxygen therapy (LTOT) improves outcome in severely hypoxemic COPD patients.222324 Nevertheless, the course and prognosis of COPD are still partially unclear, and some factors associated with death remain controversial.

Previous studies determining predictors of survival in COPD patients have mostly been conducted in normocapnic patients14579 or in severe hypoxemic patients requiring LTOT.6810 Survival studies192526 among hypercapnic COPD patients have focused on hypercapnia acquired during an acute exacerbation of the disease. Costello et al,19 as well as Saryal et al,25 included COPD patients during an acute exacerbation, and classified them into three patient groups: normocapnic, reversible hypercapnic, and chronic hypercapnic COPD. Costello et al19 found a higher mortality rate in patients with chronic hypercapnia after 5 years of follow-up. Saryal et al25 were not able to demonstrate a difference in survival between groups after 10 years of follow-up.

Hypercapnia is an expression of alveolar hypoventilation resulting from an imbalance between load on the ventilatory pump vs its capacity. The load on the ventilatory pump is determined by airway resistance or the degree of hyperinflation. The capacity of the pump depends on chemoreceptor drive, the strength and endurance of its respiratory muscles, and on the acid-base status of the muscles. A rise in PaCO2 causes a disturbance in the acid-base equilibrium, manifested in plasma pH changes in the acute phase before renal compensation has occurred. These pH changes are sensed by central as well as peripheral chemoreceptors and initiate a respiratory response. A stimulation of ventilation follows, resulting in a higher PaO2 and an increased CO2 washout. In COPD patients with a chronic CO2 retention, this ventilatory response is often diminished.2728

We hypothesized that respiratory muscle failure and a diminished ventilatory response to CO2 might be predictors of survival of chronic hypercapnic COPD patients because these factors may sustain or augment hypercapnia. Beside these parameters, already known factors related to a poor prognosis in normocapnic COPD patients, such as the severity of hypoxemia, the severity of airway obstruction, BMI, smoking status, and comorbidity, were analyzed as well.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
A cohort of 47 chronic hypercapnic COPD patients (28 male; mean age, 66.3 ± 6.7 years [± SD]) recruited for other trials, of 1 to 3 weeks in duration, in our institute between January 1996 and February 2000 was prospectively followed up, yielding 178.8 person-years in total.293031 Follow-up time ranged from 3.1 to 7.1 years among survivors.

COPD was defined according to the standards of the American Thoracic Society.17 Chronic hypercapnia was defined as PaCO2 > 45.0 mm Hg recorded twice with an interval of at least 6 weeks. At time of entry, all patients were in clinically stable condition (ie, no changes in medication dosage or frequency, and no exacerbations of disease or hospital admissions in the preceding 6 weeks). Patients with sleep-related breathing disorders or chronic renal or liver failure were excluded. During follow-up, patients received their usual medical care, and adjustments were made if necessary, according to Global Initiative for Chronic Obstructive Lung Disease standards.32 Subjects were included after giving written informed consent. The study was evaluated and approved by the local Medical Ethics Committee.

Data Collection
The following data were collected: anthropometric parameters (including age, gender, and BMI), smoking status (described as smoking one or more cigarettes per day at study entry), the presence of significant comorbidity (defined as the existence of malignancies, cardiovascular disease, diabetes mellitus, rheumatologic diseases, or immunosuppression), use of medication (maintenance of oral steroids > 5 mg/d, inhaled steroids, theophylline, diuretics, and LTOT), pulmonary function parameters, arterial blood gas values, respiratory muscle strength (maximum inspiratory mouth pressure [PImax], maximum expiratory mouth pressure [PEmax]), and ventilatory response data.333435

Statistical Analysis
Analyses were performed using statistical software (SPSS for Windows, Version 10.0; SPSS; Chicago, IL; and Egret, Version 2.0.3; CYTEL Software; Cambridge, MA). Descriptive data are presented as mean ± SD or as number (percentage). Survival was analyzed using the Cox proportional hazards model. Due to a small number of deaths, risk factors were analyzed one by one. Comorbidity and use of diuretics were the only parameters analyzed simultaneously because we reasoned that the presence of cardiovascular disease would be related with the use of diuretics. All survival analyses were optimally adjusted for age and gender simultaneously, by taking age as staggered entry-time variable while stratifying by gender. Estimated hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated; p < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
At the time of analysis, 18 deaths had occurred (10 male patients) in 47 chronic hypercapnic subjects, contributing in total 178.8 person-years of follow-up. Thus, the overall survival rate after 3.8 years was 61.7%. Ten subjects (55.6%) died of acute-on-chronic respiratory failure triggered by an acute exacerbation of COPD (n = 9) or pneumonia (n = 1). Two subjects (11.1%) died of the consequences of late-stage lung cancer. The others died of unknown causes.

Our group of subjects consisted of 14 current smokers (30.6 ± 18.3 pack-years), 30 ex-smokers (35.1 ± 22.6 pack-years), and 3 never-smokers. The number of pack-years smoked was not significantly different between current smokers and ex-smokers (p = 0.5).

Comorbidity was present at study entry in 38.3% of our study population. The most common comorbidities found in our group of hypercapnic COPD patients were cardiovascular diseases (17%), followed by diabetes mellitus (14.9%) and hypertension (8.5%). Patient characteristics are further presented in Table 1 .


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  		Table 1. General Characteristics of All Subjects*

 
HRs for death were calculated for each of the collected variables. Results are shown in Table 2 . After optimal adjustment for age and gender, analysis demonstrated an increased mortality risk in current smokers (HR, 7.0; 95% CI, 1.4 to 35.3) and in patients with comorbidity (HR, 5.5; 95% CI, 1.7 to 18.7). Use of diuretics seemed to be predictive as well (HR, 4.4; 95% CI, 1.3 to 14.7). However, after correction for comorbidity, no independent risk of death was found for use of diuretics (HR, 2.0; 95% CI, 0.5 to 8.5) [Table 2]).


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  		Table 2. HRs for Death After Optimal Simultaneous Correction for Age and Gender, and Effects of Comorbidity and Diuretics Simultaneously

 
A higher PaO2 positively affected the survival rate (HR, 0.6 per 5 mm Hg; 95% CI, 0.4 to 1.0). A higher PaCO2 showed a tendency toward increasing the death rate (HR, 2.0 per 5 mm Hg), but this did not reach statistical significance (95% CI, 0.9 to 4.3).

Analysis revealed that BMI, FEV1, FEV1/vital capacity (VC), functional residual capacity (FRC), total lung capacity (TLC), residual volume (RV), oral steroid use, inhaled steroid use, theophylline use, and LTOT were not significantly predictive in these chronic hypercapnic COPD patients. The same holds true for PImax, PEmax, and hypercapnic ventilatory response (HCVR).

To ensure that our results would not be biased by a possible difference in the blood gas profile of patients receiving LTOT, we also analyzed our data with the exception of these patients. LTOT patients did not significantly differ (p > 0.05) from patients without LTOT in terms of age (66.2 ± 6.4 years vs 63.5 ± 6.7 years), FEV1 (32.9 ± 13.0% predicted vs 24.0 ± 10.6% predicted), PaCO2 (48.8 ± 3.8 mm Hg vs 49.5 ± 4.5 mm Hg), or PaO2 (61.5 ± 9.0 mm Hg vs 58.5 ± 6.8 mm Hg). HRs for death of the patients without LTOT were comparable to HRs for death of the total cohort, and did not alter our conclusions.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Respiratory muscle strength and HCVR were not related to the prognosis of chronic hypercapnic COPD patients. Current smoking, the presence of comorbidity, and the level of hypoxemia, however, did predict survival in these patients.

Respiratory muscle weakness in COPD patients causes hypoventilation with subsequent hypercapnia and hypoxemia. Hypercapnia is regarded a poor prognostic indicator in COPD patients in general.1926 We hypothesized that within the subgroup of hypercapnic COPD patients, the severity of CO2 retention would further influence survival. Moreover, knowing that respiratory muscle weakness and hypercapnic ventilatory response are mediators of hypercapnia, we reasoned that it would be possible to predict survival by the level of respiratory muscle function and HCVR. We were not able to confirm this hypothesis. Survival analysis in our group of patients demonstrated no difference in respiratory muscle strength, nor in HCVR in survivors compared to nonsurvivors. We did find a tendency toward a lower PaCO2 level in survivors. The narrow range in PaCO2 (48.8 ± 4.5 mm Hg) in our group of hypercapnic COPD patients makes it difficult to detect differences between survivors and nonsurvivors. In our opinion, however, a tendency of lower PaCO2 in survivors probably underlines the prognostic value of hypercapnia in hypercapnic COPD patients. The absence of effect of chronic ventilatory support on survival by noninvasive ventilation, as described by Clini et al36 and Cuvelier and Muir,37 support the notion that the degree of hypercapnia does not further affect survival once the COPD patient has become hypercapnic. Some authors3839 have suggested that "permissive hypercapnia" may be a physiologic adaptation that may lead to better survival rates. By allowing PaCO2 to rise, work of breathing can be decreased. However, Zimmerman et al20 studied 50 patients with chronic airflow obstruction for 4 years and found that hypercapnia was related to survival. As one would expect, also a relationship between HCVR and hypercapnia was found. However, these authors did not observe a relationship between chemoreceptor sensitivity to hypercapnia and ventilatory response, nor to survival. Their suggestion was that other, not-yet-identified factors might affect the relationship between HCVR and survival.

Many studies demonstrated111121415161718 that smoking is the most dominant etiologic factor causing COPD. Smoking cessation in older adults was shown to slow the rate of decline in pulmonary function.18 In our study, we demonstrated a significant higher mortality among current smokers, although the number of pack-years smoked did not significantly differ from ex-smokers. In previous studies,18 this high mortality was found as well and has been associated with the development and progression of several major chronic conditions, loss of mobility, and poorer physical function in patients who continue smoking.

The presence of comorbidities lowered the survival rates in our group of hypercapnic COPD patients. Crockett et al6 studied 505 patients with chronic airflow limitation (249 males) to whom LTOT was prescribed. Multivariate analysis of their data showed that the number of comorbidities was a prognostic indicator for death in female patients. Antonelli Incalzi et al21 demonstrated that survival was predicted by the presence of chronic renal failure, myocardial infarction, or ischemia in 270 COPD patients (mean age, 67 ± 9 years) consecutively discharged after hospital admission for an acute exacerbation. The most common comorbid diseases in their study population were hypertension (28%), diabetes mellitus (14%), and ischemic heart disease (10%).21 In our own group of chronic hypercapnic COPD patients, cardiovascular diseases were the most common comorbidity, followed by diabetes mellitus and hypertension (Table 1). We also found that use of diuretics could predict survival in chronic hypercapnic COPD patients (Table 2). Ischemic heart diseases and hypertension are comorbidities that are often treated with diuretics. Therefore, we were interested whether the use of diuretics was directly related to survival or indirectly via the presence of comorbidities. By analyzing the two parameters simultaneously, we corrected the use of diuretics for the presence of comorbidities. We did not find an independent risk for diuretics.

Severe COPD is often accompanied by failure in gas exchange, expressed as hypoxemia and hypercapnia. Chronic hypoxemia eventually leads to hypertension and right heart failure (cor pulmonale). Costello et al19 observed a cohort of COPD patients (mean age, 68.3 ± 7.1 years; FEV1, 32.1 ± 13.4% predicted) admitted to an emergency hospital because of an acute exacerbation. The authors conducted a survival analysis after dividing the group into 19 chronic hypercapnic patients (mean age, 68.4 ± 3.9 years; FEV1, 26.6 ± 7.0% predicted), 22 reversible hypercapnic patients (mean age, 69.1 ± 8.4 years; FEV1, 32.7 ± 13.3% predicted) and 27 normocapnic COPD patients (mean age, 69.1 ± 8.0 years; FEV1, 36.4 ± 16.2% predicted). Hypercapnia was defined as PaCO2 > 50 mm Hg. Five-year survival in chronic hypercapnic COPD patients was significantly lower (11%); in patients with reversible hypercapnia and normocapnia, 5-year survival rates were 28% and 33%, respectively.

LTOT improves survival in selected patients with severe hypoxic COPD, especially in patients with few comorbidities. In patients with mild or moderate hypoxemia, this effect is less obvious.222324 A study by the Medical Research Working Party demonstrated that in hypoxemic COPD patients (PaO2, 40 to 60 mm Hg; FEV1 < 1.2 L), survival was improved after 3 years of oxygen administration, 2 L/min for 15 h/d.23 Statistical analysis of our hypercapnic patients did not show better survival rates among those receiving LTOT. However, only 7 of 47 patients received LTOT. Therefore, this number was too small to draw any definite conclusion.

Results of previous studies6111213 among COPD patients demonstrate that the degree of airway obstruction predicts long-term outcome. Hypercapnia was not a selection criterion in these studies. Surprisingly, in our study we did not find evidence for an association between severity of airway obstruction and mortality risk. This was also described in a study by Oswald-Mammosser et al40 among 84 COPD patients receiving LTOT. Survival analysis of their study revealed that not FEV1, but the level of pulmonary artery pressure predicted survival. These authors40 suggested that this might have been due to a small cohort, as may also be the case in our study. Nevertheless, Cooper et al,41 who included 72 patients, were able to detect an association between a low FEV1 and lower survival rates. Oswald- Mammosser et al40 concluded that their relatively homogeneous study population explained their lack of effect of FEV1 on survival (FEV1, 0.85 ± 0.34 L). The narrower the range of the included parameters, the smaller the prognostic value will be. Our own study also shows this relative homogeneity (FEV1, 0.83 ± 0.33 L).

Several studies5679111213 have demonstrated a relationship between low BMI and survival in COPD patients. Landbo et al9 studied 2,132 COPD patients (FEV1, 64.7 ± 18% predicted for men, and 66.1 ± 16.6% for women). The relative risk ratios (RRs) for all-cause mortality in these COPD patients were 1.6 (1.2 to 2.2) for men and 1.4 (1.1 to 1.9) for women with a BMI < 20. However, in patients with a BMI of 25 to 29.9, no increased risk for death was found: RR, 1.0 (0.9 to 1.2) for men; RR, 0.9 (0.6 to 1.1) for women. Our group of hypercapnic COPD patients had a mean BMI of 25.6 ± 5.5. Similar to Landbo et al,9 we were not able to demonstrate a relationship with survival.

The survival rate in this study of 61.7% is higher than the rates found in other studies.1022 Foucher et al10 analyzed survival in 252 hypoxemic COPD patients (mean age, 69.7 ± 9.9 years; FEV1, 0.77 ± 0.28 L) with a mean PaO2 level of 49.7 ± 7.0 mm Hg and a mean PaCO2 level of 45.6 ± 7.1 mm Hg. After correction for follow-up time, the survival rate in that study was 41.4% after 3.8 years of follow-up.10 Connors et al26 studied a prospective cohort of 1,016 hypercapnic COPD patients (523 males; mean age, 70 ± 7 years; mean FEV1, 0.80 L) hospitalized for an acute exacerbation of their disease. Their mean PaCO2 was 56.3 mm Hg. A 2-year survival of 51% was found. Survival rates after 3.8 years in the study by Costello et al19 were 43% for COPD patients with normocapnia and reversible hypercapnia, and 22% for patients with chronic hypercapnia. In comparison to the studies by Foucher et al,10 Costello et al,19 and Connors et al,26 our group of hypercapnic COPD patients was clinically stable at the time of measurement. The COPD patients included in the studies by Foucher et al10 were severely hypoxemic, and those included in the studies by Costello et al19 and Connors et al26 were analyzed during an acute exacerbation. This could explain the differences in survival rates.

Studying a small cohort of hypercapnic COPD patients, in which even a smaller number of deaths has occurred, causes two difficulties in the analysis of the results. The first difficulty is that the asymptotically normal behavior of the estimates is not yet reached. Therefore, we analyzed only one variable at a time. Secondly, a small cohort of severe COPD patients with hypercapnia decreases the possibility to detect relationships between explanatory variables and mortality, ie, the so-called type-2 error problem. This was probably the case in our analysis of FEV1, PaCO2, and HCVR.

The purpose of our study was to define predictors of a decreased survival of clinically stable hypercapnic COPD patients. Identification of these factors is crucial for a better understanding of not only the course and prognosis of the disease, but also of its possibilities for treatment and rehabilitation. We hypothesized that a low survival in hypercapnic COPD patients could be associated with a low respiratory muscle strength, a decreased HCVR and a lower FEV1. However, we were not able to confirm this hypothesis. However, we did find a low survival rate in hypercapnic COPD patients who were currently smoking. Also the presence of comorbidity was associated with a poorer outcome. This stresses the need for interventions reducing mortality in this subgroup of COPD patients, such as smoking cessation programs and the treatment of comorbidities. Moreover, future studies should focus on therapeutic interventions that will improve arterial blood gas values, eg, the use of respiratory stimulants, or respiratory muscle training. Unlike other trials studying survival parameters in COPD patients in general, we did not find airway obstruction, age, or BMI to be predictors of survival in hypercapnic COPD patients, suggesting that once COPD patients have become hypercapnic, these factors no longer affect survival.


   Acknowledgements
 
The authors thank Drs. F. Brijker and M. Wagenaar for assistance in conducting this study.


   Footnotes
 
Abbreviations: BMI = body mass index; CI = confidence interval; FRC = functional residual capacity; HCVR = hypercapnic ventilatory response; HR = hazard ratio; LTOT = long-term oxygen therapy; PImax = maximum inspiratory mouth pressure; PEmax = maximum expiratory mouth pressure; RR = relative risk ratio; RV = residual volume; TLC = total lung capacity; VC = vital capacity

Received for publication May 19, 2004. Accepted for publication December 1, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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