Relationship Between Episodic Nocturnal Hypercapnia and History of Exacerbations in Patients with Advanced Chronic Obstructive Pulmonary Disease

Introduction

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide.¹ Exacerbations are common events that have a significant impact on COPD patients and healthcare services,² affecting lung function, health status, and mortality.^3,4 In addition, a history of exacerbations has been reported to be the best predictor of future exacerbations,⁵ and repeated severe exacerbations were associated with high future mortality.⁴

Certain studies have shown that daytime hypercapnia is associated with frequent exacerbation and poor prognosis in COPD patients.^6–8 In particular, daytime hypoventilation is considered to be associated with repeated COPD exacerbation and a poor prognosis. In patients with advanced COPD, hypercapnic respiratory failure manifests earlier during sleep than during the awake state as a consequence of pathophysiological changes in ventilation.⁹ Therefore, sleep-related hypoventilation disorders may be related to COPD exacerbations before daytime hypercapnia becomes apparent. However, there are few reports showing the importance of sleep-related ventilation disorders on exacerbations in patients with COPD without remarkable daytime hypercapnia.

The American Academy of Sleep Medicine (AASM) defines hypoventilation during sleep as sleep-associated hypoventilation (SH),¹⁰ which needs to meet the following criteria: (1) an increase in the PaCO₂ or transcutaneous carbon dioxide pressure (PtcCO₂) to a value >55 mmHg for ≥10 min and (2) ≥10 mmHg increase in PaCO₂ or transcutaneous carbon dioxide pressure (PtcCO₂) during sleep (compared to the awake supine value) to a value exceeding 50 mmHg for ≥10 min. Unfortunately, no research has shown the relationship between SH and COPD exacerbation.

Aside from SH, we defined episodic nocturnal hypercapnia (eNH) as an episodic increase of ≥5 mmHg from baseline PtcCO₂ for ≥5 min at least once during the night as reported in a previous study.¹¹ eNH is more focused on rapid eye movement (REM) sleep-related hypoventilation than SH. Nocturnal hypercapnia often worsens during REM sleep⁹ because of the decreased activity of the respiratory muscles and diminished hypercapnic and hypoxic ventilatory response.^12–14 REM sleep-related hypoventilation can be observed as episodic nocturnal increases in PtcCO₂ during overnight PtcCO₂ monitoring.¹² We have shown that eNH seems to be related to exacerbation frequency in COPD patients with daytime PaCO₂ <55 mmHg.¹¹ eNH-targeted non-invasive positive pressure ventilation (NPPV) also reduced COPD exacerbation.

Next, we analyzed whether COPD exacerbations were associated with overall sleep-related hypoventilation or only eNH, ie, REM sleep-related hypoventilation. Thereafter, we added more cases to our analyses and retrospectively analyzed overnight PtcCO₂ monitoring data and the frequency of COPD exacerbations during the previous year. We also evaluated the relationship between the history of exacerbations and eNH or SH in patients with stable, severe, or very severe COPD with daytime PaCO₂ <55 mmHg.

Materials and Methods

Patients

We enrolled consecutive patients diagnosed with stable, severe, or very severe COPD who were admitted to Kitano Hospital, Tazuke Kofukai Medical Research Institute, from April 2013 to January 2017 for the evaluation of respiratory failure with overnight PtcCO₂ monitoring. All patients who met the following criteria were retrospectively reviewed: age ≥40 years; baseline daytime PaCO₂ <55.0 mmHg; no abnormalities of the thorax or lung other than COPD; no medical history of obstructive sleep apnea (OSA) body mass index (BMI) <25 kg/m²; no malignant comorbidities within the past 5 years; and no severe heart failure (New York Heart Association stage 3–4). Patients were judged to be clinically stable if they had no exacerbation (lasting ≥2 days and requiring any change in pharmacological treatment) during the past 3 weeks.

Measurements and Data Collection

Sociodemographic, clinical, and laboratory data were extracted from medical records. The BMI was calculated as kg/m². Pulmonary function tests were performed by trained operators in accordance with the guidelines of the American Thoracic Society and European Respiratory Society.¹⁵

Arterial blood gas was measured during the daytime in the supine position using a RAPIDLAB 1200 System (Siemens Healthcare Diagnostic Incorporated, USA). At sampling, all patients were breathing room air, with the exception of those on long-term oxygen therapy who used their prescribed dose of supplementary oxygen. Polysomnography (PSG) was performed using PSG-1100 (Nihon Kohden, Tokyo, Japan), and evaluated by sleep laboratory technicians.

Peak Nocturnal PtcCO₂ and eNH

PtcCO₂ monitoring was performed using a SenTec Digital Monitor (SenTec, Therwil, Switzerland) or a TOSCA TCM4 (Radiometer, Copenhagen, Denmark), which are reported to show small difference in PtcCO₂.^16,17 Data on PtcCO₂ monitoring were evaluated by two board-certified members of the Japanese Respiratory Society with over 10 years of clinical practice. In the present study, eNH was defined as a continuous episodic increase of ≥5 mmHg from baseline PtcCO₂ for ≥5 min, at least once during the night, according to the criteria of a previous study¹¹ (Figure 1A). The PtcCO₂ increase range was measured as the difference between the baseline PtcCO₂ and peak PtcCO₂ for each hypoventilation event (Figure 1B). Furthermore, all patients with eNH were evaluated using PSG to rule out complications of OSA and episodic PtcCO₂ increases corresponding to REM sleep. The nocturnal mean PtcCO₂ and maximum PtcCO₂ were also collected from the overnight PtcCO₂ monitoring data.

Figure 1 Episodic nocturnal transcutaneous carbon dioxide pressure increase observed during overnight transcutaneous carbon dioxide pressure monitoring. Abbreviation: PtcCO2, transcutaneous carbon dioxide pressure. Notes: (A) Episodic nocturnal hypercapnia, (B) peak PtcCO2 increase value, and PtcCO2 increase range.

Evaluation of Sleep-Associated Hypoventilation

According to the American Society of Sleep Medicine (ASSM) scoring manual for the scoring of sleep and associated events, SH was defined as an event that met the following criteria during sleep: SH criterion (1), which was an increase in the PaCO₂ (or PtcCO₂) to a value >55 mmHg for ≥10 min; or SH criterion (2), which was a ≥ 10 mmHg increase in PaCO₂ (or PtcCO₂) during sleep (compared to the awake supine value) to a value exceeding 50 mmHg for ≥10 min.¹⁰ SH and eNH were judged by two board-certified members of the Japanese Respiratory Society with over 10 years of clinical experience.

Definition of COPD Exacerbation

COPD exacerbations were defined as acute worsening of respiratory symptoms that resulted in additional therapy.¹⁸ In this study, we retrospectively counted the frequency of moderate and severe exacerbations in the previous year. Moderate exacerbations were defined as events requiring short-acting bronchodilators plus antibiotics and/or oral corticosteroids.¹⁸ Severe exacerbations were defined as those requiring hospitalizations or visits to the emergency room.¹⁸

Ethics and Statistics

The study was carried out in accordance with the ethical guidelines of the Japanese Ministry of Health, Labor, and Welfare and was approved by the Institutional Review Board of the Kitano Hospital Medical Research Institute Ethics Committee (ethics board approval number: P210101300). In addition, we focused on the protection of personal information based on ethical guidelines. Prior comprehensive written informed consent for the use of patients’ data for research purposes was obtained from the patients at their first visit to our hospital. Moreover, our hospital’s website stated that the study patients were free to opt out of the study. The study conforms to the Declaration of Helsinki. We examined the normality of our data using the Shapiro–Wilk test. Parametric data were presented as mean ± standard deviation and nonparametric data as median (interquartile range [IQR]). Data were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). For all analyses, a p-value <0.05 was considered statistically significant. Data analyses were conducted using SPSS version 25 (IBM Corp., Armonk, NY, USA).

Results

Figure 2 shows the patient selection flowchart for this study. Finally, 24 patients with COPD (19 men and five women) met the inclusion criteria. Table 1 shows patient characteristics. Patients had a mean age of 73.5 (64.5–78.8) years and a very severe airflow limitation, with a mean FEV₁ of 28.8 ± 10.4%. Supplemental oxygen was used in four patients. Daytime PaO₂, PaCO₂, and bicarbonate levels were 72.0 ± 9.5 mmHg, 43.3 ± 6.8 mmHg, and 29.3 ± 4.2 mmol/L, respectively. The modified Medical Research Council (mMRC) and COPD assessment test scores were 2.9 ± 0.6 and 22.4 ± 9.6 points, respectively.

Table 1 Patient Characteristics

Figure 2 Flow diagram representing the patient selection process. Abbreviations: COPD, chronic obstructive pulmonary disease; PtcCO2, transcutaneous carbon dioxide pressure; NPPV, non-invasive positive-pressure ventilation; CPAP, continuous positive airway pressure; PaCO2, arterial carbon dioxide pressure.

COPD Exacerbation

Figure 3 shows the frequency distribution chart of COPD exacerbations in the analyzed population. The median frequency of COPD exacerbations was 1 (0–2.0) times/year. Although eight out of 24 (33.3%) patients were not diagnosed with COPD exacerbation during the previous year, eight (33.3%) patients developed COPD exacerbation ≥2 times during the previous year.

Figure 3 Frequency distribution chart of exacerbations in the analyzed population. Abbreviation: COPD, chronic obstructive pulmonary disease.

Overnight PtcCO₂ and PaCO₂ Analysis

Twenty-three patients were evaluated by Sentec and only one was evaluated by TOSCA. The nocturnal maximum PtcCO₂, mean PtcCO₂, and PtcCO₂ increase was 48.6 ± 9.5 mmHg, 42.9 ± 9.2 mmHg, and 5.1 ± 3.3 mmHg, respectively (Table 1).

Of the 24 analyzed patients, six (25.0%) patients met the SH criteria, four patients met only SH criterion (1), one patient met only SH criterion (2), and one patient met SH criteria (1) and (2). Daytime PaCO₂, bicarbonate level, nocturnal maximum PtcCO₂, mean PtcCO₂, and PtcCO₂ increases were significantly higher range in patients with SH than in patients without SH (Table 2). On the other hand, there was no significant difference in daytime PaO₂ between patients with SH and patients without SH (Table 2).

Table 2 Characteristics of Patients with and without Sleep-Associated Hypoventilation

Of the 24 analyzed patients, 11 (45.9%) patients met the eNH criteria. Daytime PaCO₂, bicarbonate levels, and PtcCO₂ increases were significantly higher in patients with eNH than those without eNH (Table 3). There was no significant difference in daytime PaO₂, nocturnal maximum PtcCO₂, or mean PtcCO₂ in patients with and without eNH (Table 3). In the PSG analysis of the patients with eNH, the mean total sleep time and sleep efficiency were 308 ± 80.7 min and 61.6 ± 15.5 min, respectively. REM sleep time accounted for 17.1 ± 6.0% of the sleep period. The apnea hypopnea index, central apnea index, and OSA index were 16.8 ± 8.0 episodes/h, 0.2 ± 0.3 episodes/h, and 1.6 ± 2.4 episodes/h, respectively. Most hypopneas were associated with alveolar hypoventilation during REM sleep.

Table 3 Characteristics of Patients with and without Episodic Nocturnal Hypercapnia

SH and COPD Exacerbation Relationship

The median frequency of COPD exacerbation was 1.0 (1.0–1.3) times/year in patients with SH. Table 4 represents the sensitivity, specificity, and OR of SH for a history of exacerbation. The OR of SH did not reach statistical significance.

Table 4 Sensitivity, Specificity, and Odds Ratio Values of Sleep-Associated Hypoventilation and Episodic Nocturnal Hypercapnia for the Prediction of Chronic Obstructive Pulmonary Disease Exacerbations

The median frequency of COPD exacerbation was 1.0 (0–1.5) times/year in patients with SH criterion (1) and 1.0 (1.0–1.0) times/year in patients with SH criterion (2). Table 5 represents the sensitivity, specificity, and OR of SH criterion (1) or criterion (2) for a history of exacerbation. The OR of SH criterion (1) or criterion (2) did not reach statistical significance.

Table 5 Sensitivity, Specificity, and Odds Ratio Values of Sleep-Associated Hypoventilation Criterion (1) and (2) for the Prediction of Chronic Obstructive Pulmonary Disease Exacerbations

eNH and COPD Exacerbation History

The median frequency of COPD exacerbation was 2.0 (1.0–4.0) times/year in patients with eNH. Table 4 represents the sensitivity, specificity, and OR of eNH for a history of exacerbation. The OR of eNH reached statistical significance, with an OR of 11.1 [95% CI: 1.39–87.7] for at least one annual exacerbation and an OR of 6.6 [95% CI: 1.06–39.4] for two or more exacerbations per year.

Discussion

We have shown that eNH measured by overnight PtcCO₂ is associated with a history of COPD exacerbations in the last year in patients with advanced COPD with baseline daytime PaCO₂ <55.0 mmHg. Furthermore, eNH was more sensitive than SH in relation to the history of COPD exacerbation, while the specificity of eNH was similar to that of SH. There were no significant differences in daytime physiological parameters, excluding pH, daytime PaCO₂, and bicarbonate levels, with or without eNH or SH (Tables 2 and 3).

The results of this study suggest that eNH, but not SH, is related to COPD exacerbation. The most important difference between SH and eNH is that eNH is exclusively focused on nocturnal episodic PtcCO₂ increases, which corresponds to REM-related hypoventilation, as confirmed by PSG.¹¹ This indicates that COPD exacerbations are closely associated with REM-related hypoventilation detected as eNH.

On the other hand, SH does not always correspond to episodic PtcCO₂ increases, but also sustained hypercapnia during the night. The SH criterion (1) was defined as an increase in the arterial PaCO₂ (or PtcCO₂) to a value >55 mmHg for ≥10 min during sleep. Therefore, the SH criterion (1) theoretically includes not only REM-related hypoventilation but also hypoventilation during non-REM sleep. Therefore, for detection of REM-related hypoventilation, the sensitivity of eNH is better than that of SH.

In addition, the absolute value of PaCO₂ is included in the SH criterion (1), although it is not easy to continuously measure PaCO₂ in clinical practice.¹⁹ We used PtcCO₂ as a surrogate marker for PaCO₂ to evaluate sleep-related disorders in patients with chronic respiratory failure.^19,20 However, the average difference between PaCO₂ and PtCO₂ is reported to be 4.6–6.1 mmHg,^19,20 and changes in PtcCO₂ are reportedly more reliable than the absolute values of PtcCO₂.^19,20 In the present study, in patients with SH, five out of six patients (83.3%) met the SH criterion (1), which depends on the uncertain absolute values of PtcCO₂. Therefore, eNH could be a more reliable marker than SH because it focuses only on the change in PtcCO₂ and not the absolute values of PtcCO₂.

The SH criterion (2) was defined as a ≥ 10 mmHg increase in PtcCO₂ during sleep (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 min. Therefore, SH criterion (2) focuses on the change in PtcCO₂ and may be useful for specifically detecting REM-related hypoventilation, similar to eNH. In patients with a history of at least one exacerbation, the specificities of the SH criterion (2) and eNH were 94.1% and 87.5%, respectively. However, the sensitivity of the SH criterion (2) (12.5%) was lower than that of eNH (62.5%). In the SH criterion (2), the PtcCO₂ increase of ≥10 mmHg during sleep seemed to be too high as a cut-off value for detecting REM-related hypoventilation. Eleven patients met the eNH criteria, but only two patients met the SH criterion (2) in the present study. In patients with COPD (average ratio of FEV₁ to forced vital capacity was 42%), PaCO₂ during the awake state, stage 2, stage 3–4, and REM sleep were reported 49.7 ± 1.59 mmHg, 53.4 ± 1.52 mmHg, 54.5 ± 1.94 mmHg, and 57.4 ± 1.71 mmHg, respectively.²¹ Namely, it is uncommon for PtcCO₂ to increase to ≥10 mmHg during REM sleep.²¹ In contrast, the sensitivity was improved by the eNH criteria (PtcCO₂ increase ≥ 5 mmHg) in the present study. Changing the criteria for PtcCO₂ increase from ≥10 mmHg to ≥5 mmHg seemed to improve the sensitivity associated with a history of COPD exacerbation.

The reason why REM sleep-related hypoventilation is associated with exacerbation of COPD can be explained as follows. During REM sleep, respiratory activity relies almost exclusively on the diaphragm, whereas the activity of the intercostal and accessory muscles ceases.²² In patients with advanced COPD, the diaphragm flattens as pulmonary hyperinflation,²³ causing inefficient contraction of the diaphragm, resulting in marked alveolar hypoventilation and episodic nocturnal hypercapnia during REM sleep. Surges in PaCO₂ accompanied by episodic hypoventilation may have an important impact on pulmonary artery pressure, since even short-duration hypercapnia may cause pulmonary vasoconstriction,²⁴ and respiratory acidosis also causes pulmonary artery hypertension, regardless of hypoxic pulmonary vasoconstriction.²⁴ Repetition of episodic nocturnal hypoventilation and hypercapnia may result in permanent pulmonary hypertension (PH). In our previous study, COPD patients with eNH had significantly higher estimated pulmonary artery systolic pressure (47.0 ± 4.8 mmHg vs 33.6 ± 2.6 mmHg, p = 0.037) and pulmonary artery: aorta ratio (0.96 ± 0.05 vs 0.79 ± 0.03, p = 0.019) than those without eNH.¹¹ REM-related hypoventilation with eNH may lead to PH. Namely, the patient group with eNH may be a subgroup with a high likelihood of pulmonary hypertension, including the patients with baseline daytime PaCO₂ <55.0 mmHg. Pulmonary artery hypertension is known to be associated with COPD exacerbation and mortality.²⁵ This hypothesis should be further verified by prospective large-scale studies with overnight PtcCO₂ monitoring.

Fletcher et al proposed episodic nocturnal desaturation criteria (the patient’s SaO₂ falls below a baseline of 90% for 5 ≥ min) to focus on episodic hypoventilation mainly during REM sleep and showed that patients with COPD based on Fletcher’s desaturation criteria had poor survival prognosis.^26,27 However, we believe that evaluation by overnight PtcCO₂ monitoring is more important than that by SpO₂ monitoring. This is because hypoventilation may be overlooked as SpO₂ is affected by oxygen therapy. In addition, episodic nocturnal desaturation may be misidentified as desaturation due to REM-related hypoventilation owing to its similarity to desaturation due to exertion, such as night urination, which is not always reported by the patient.

There is not enough evidence for the usefulness of long-term NPPV in COPD patients without marked elevation in daytime PaCO₂. However, we previously demonstrated that eNH-targeted NPPV resulted in a significant decrease in daytime PaCO₂ and COPD exacerbation frequency in COPD patients with daytime PaCO₂ <55 mmHg.¹¹ In the near future, nocturnal PtcCO₂ monitoring could be a useful measure to detect frequent exacerbations among advanced COPD patients without marked daytime alveolar hypoventilation. Furthermore, we could select a more appropriate patient with daytime PaCO₂ <55 mmHg for long-term NPPV therapy, resulting in a decreased frequency of COPD exacerbation.

The present study had some limitations. First, this study enrolled a relatively small number of patients with stable advanced COPD and daytime PaCO₂ <55 mmHg in a single general hospital. However, to the best of our knowledge, this is the first report to compare the significance of eNH with SH in terms of the history of COPD exacerbations. Our findings may lead to new approaches for the detection of subgroups with frequent COPD exacerbations. Second, although we showed that eNH was associated with a history of COPD exacerbations, it remains unclear whether the presence of eNH can predict future exacerbations. A prospective study is needed to validate the relationship between eNH and COPD exacerbation. However, it is not easy to adjust the influence of treatment such as NPPV. Patients with COPD with eNH met the indication criteria of NPPV for stable COPD in Japanese Respiratory Society’s NPPV guidelines.²⁸ Therefore, we treated the patients with eNH with NPPV in clinical practice, and eNH targeted NPPV reduced the frequency of exacerbations.¹¹ Third, we could not correctly evaluate the history of mild COPD exacerbation. This is because we retrospectively counted the frequency of exacerbations from the medical records. Although we demonstrated the importance of eNH in moderate or severe COPD exacerbations, additional prospective studies are required to confirm our findings. Fourth, six of 24 patients could not be evaluated using polysomnography. We might not have completely excluded patients with OSA from the present study. However, we excluded patients with a history of OSA or BMI ≥ 25 kg/m², and the mean BMI was 19.5 ± 3.7 kg/m² in the present study. Moreover, the nocturnal continuous monitoring of SpO₂ showed that the 3% and 4% oxygen desaturation indexes were 7.3 ± 3.8 episodes/h and 4.4 ± 3.3 episodes/h, respectively, in patients without polysomnography evaluation. All patients with eNH were evaluated using PSG, as described above. Our study showed that patients with COPD with low BMI are common in Japan.²⁹ On the other hand, we should pay attention to apply the results of our study to patients of COPD in the west with high BMI.

Conclusion

In conclusion, we focused on the association between a history of COPD exacerbations and eNH in patients with advanced COPD and daytime PaCO₂ <55 mmHg. eNH may be a better biomarker than SH defined by ASSM for detecting subgroups with frequent COPD exacerbations. Our research was a small observational study, and further studies are required to evaluate our findings.