Patients with chronic thromboembolic pulmonary hypertension (CTEPH) often have substantial right ventricular dysfunction. The resulting low cardiac index might predispose to sleep disordered breathing (SDB) by increasing ventilatory instability. The prevalence of SDB and potential association with impaired cardiac index was examined in patients with CTEPH. Patients referred for evaluation for pulmonary thromboendarterectomy surgery were recruited. Subjects underwent a sleep study, unless already using positive airway pressure therapy. Hemodynamic data were obtained from contemporaneous right-sided cardiac catheterization. A total of 49 subjects were included. SDB—defined as ongoing positive airway pressure use or apnea-hypopnea index (AHI) ≥5/h—was found in 57% of subjects. SDB was generally mild in severity, with respiratory events mainly consisting of hypopneas. Cardiac index was found to be significantly lower in subjects with SDB than those without (2.19 vs 2.55 L/min/m 2 ; p = 0.024), whereas no differences were observed in other characteristics. Additionally, cardiac index was independently predictive of AHI. In a subgroup of subjects with an elevated percentage of central events, both cardiac index and lung to finger circulation time correlated with AHI. In conclusion, SDB is prevalent in patients with CTEPH and might decrease with treatments that improve cardiac index.
Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have variable degrees of right ventricular dysfunction because of chronic blood clots and remodeling of the pulmonary vasculature leading to pulmonary hypertension. Patients with CTEPH may, therefore, have impaired cardiac index but typically lack elevated left-sided cardiac pressures. Sleep disordered breathing (SDB) is prevalent in patients with left-sided heart failure, with previous research suggesting this is because of elevated left heart filling pressures leading to increased chemosensitivity. However, the independent effect of low cardiac output might additionally predispose to SDB, and therefore, patients with CTEPH may also be at risk. To our knowledge, there is no dedicated study to examining SDB in CTEPH. The aims of this study are
- 1.
Characterize SDB in patients with CTEPH.
- 2.
Examine the hypothesis that low cardiac index is predictive of SDB in this cohort of patients without left ventricular dysfunction.
Methods
Patients referred for evaluation for pulmonary thromboendarterectomy surgery were sequentially recruited for participation. Exclusion criterion was an expert clinician assessment that the etiology of pulmonary hypertension was not CTEPH. The institutional review board at the University of California San Diego approved the protocol. Written, informed consent was obtained from all subjects.
Enrolled participants underwent sleep testing with an ApneaLink Plus (ResMed, San Diego, California), consisting of nasal pressure sensor, respiratory effort band, and pulse oximeter worn on the finger. For safety of participants and consistency in baseline oxygenation, subjects on nocturnal supplemental oxygen were maintained on their prescribed setting, with the sensor placed above the oxygen cannula. Similarly, for safety of participants, subjects with a previous diagnosis of SDB actively using positive airway pressure (PAP) therapy were regarded as having SDB; no sleep study was performed.
Studies were scored by a blinded, registered polysomnographic technologist using modified American Academy of Sleep Medicine Chicago Criteria. Specifically, apnea was defined as a >90% reduction in airflow and hypopnea defined as a >30% reduction in airflow, lasting >10 seconds, and associated with a ≥3% oxyhemoglobin desaturation. Obstructive apneas were associated with thoracic effort and/or associated flow limitation. Hypopneas were scored as undifferentiated events.
Subjects underwent right-sided cardiac catheterization as part of a standard clinical evaluation. Briefly, patients were brought into the catheterization laboratory and were measured while supine at rest. A Swan-Ganz catheter was advanced to the pulmonary artery under fluoroscopic guidance. With appropriate respiratory timing, right-sided pressures were transduced hydrostatically. Cardiac output was measured by thermodilution of room temperature saline.
Lung to finger circulation time (LFCT) has been previously described as a measure of circulatory delay in patients with SDB. Flow and saturation waveforms from sleep study data were analyzed in Spike2 software (CED, Cambridge, UK). In a blinded fashion, all recordings were screened for scorable events, defined as having a distinct end of hypopnea/apnea with an associated desaturation of ≥3%. LFCT was measured from the end of a respiratory event to the onset of resaturation; 10 events from the start and 10 events from the end of the recording were selected. If <20 events were available, all events were used; however, subjects with <4 events were excluded from analysis. The mean LFCT for each subject was reported.
Analysis was performed using SigmaPlot (Systat Software Inc, San Jose, California) and SAS Studio (SAS Institute, Cary, North Carolina). Means were compared using a t test or rank-sum test, and proportions compared using a chi-square test. Pearson’s product-moment or Spearman rank-order correlation was used as appropriate. Linear regression and logistic regression were performed with variables of interest. A p value <0.05 was considered statistically significant.
Results
Of 75 patients screened for inclusion, 19 declined, 3 did not have CTEPH, 2 had missing sleep study data, and 2 did not undergo cardiac catheterization. Thus, complete data were obtained in 49 subjects, all of whom had a diagnosis of CTEPH following clinical and radiographic evaluation by expert clinician consensus; 45 subjects subsequently elected to undergo pulmonary thromboendarterectomy surgery, allowing for pathologic confirmation of CTEPH.
The prevalence of SDB among 49 total subjects is reported in Table 1 . Using a definition of SDB as either PAP use at enrollment or an apnea-hypopnea index (AHI) ≥5/h, the prevalence of SDB was 57%. Characterization of SDB found on sleep studies is reported in Table 2 , revealing primarily mild SDB with events consisting primarily of hypopneas. There were no differences with respect to age, gender, body mass index (BMI), or sedative use between those with and without SDB ( Table 1 ).
| Variable | Sleep disordered breathing | P-value | ||
|---|---|---|---|---|
| No 21 (43%) | Yes 28 (57%) | |||
| PAP use 10 (20%) | AHI ≥ 5/h 18 (37%) | |||
| Men | 43% | 57% | 0.483 | |
| Age (years) | 49.2 ± 3.9 | 54.9 ± 2.6 | 0.403 | |
| Body mass index (kg/m 2 ) | 28 (23-34) | 30 (26-34) | 0.225 | |
| Sedative/narcotic use | 29% | 21% | 0.811 | |
| Epworth sleepiness score (out of 24) | 7 ± 0.95 | 9 ± 1.18 | 0.216 | |
| Mean pulmonary artery pressure (mmHg) | 40 ± 2.4 | 46 ± 2.3 | 0.100 | |
| Pulmonary vascular resistance (dyne-s/cm 5 ) | 513 ± 65 | 668 ± 66 | 0.108 | |
| Right atrial pressure (mmHg) | 8 (5-12) | 9 (5-16) | 0.484 | |
| Pulmonary artery wedge pressure (mmHg) | 10 (8-14) | 11 (8-16) | 0.879 | |
| Cardiac index (L/min/m 2 ) | 2.55 ± 0.12 | 2.19 ± 0.10 | 0.024 | |
| Cardiac output (L/min) | 5.14 ± 0.30 | 4.55 ± 0.25 | 0.140 | |
| Variable | Apnea-hypopnea index | |
|---|---|---|
| < 5/h | ≥ 5/h | |
| Subjects (%) | 21 (54%) | 18 (46%) |
| Events/hour, Number of subjects | ||
| 5-15/h | 10 (26%) | |
| 15-30/h | 6 (15%) | |
| >30/h | 2 (5%) | |
| Apnea-hypopnea index (events/h) | 2.6 | 19.0 ∗ |
| Obstructive apnea index (events/h) | 0.3 | 4.6 ∗ |
| Central apnea index (events/h) | 0.2 | 0.9 † |
| Hypopnea index (events/h) | 2.1 | 13.4 ∗ |
| % Events obstructive apneas | 14% | 13% † |
| % Events central apneas | 7% | 4% † |
| % Events hypopneas | 80% | 82% † |
| Baseline SaO 2 (%) | 92% | 93% † |
| Time <90% SaO 2 (%) | 42% | 50% † |
| Nadir SaO 2 | 81% | 80% † |
| Supplemental O 2 use (%) | 54% | 46% † |
∗ P <0.001 compared to the AHI <5/h group.
Of the 39 subjects not using PAP, 44% were using supplemental oxygen on enrollment. The percentage of subjects using oxygen did not differ between those with and without SDB on sleep studies ( Table 2 ). There was no significant difference in the AHI between those using oxygen and those who were not (6 vs 13 events/h; p = 0.229). Similarly, no significant difference was found between the 2 groups with respect to baseline saturation (94% vs 92%; p = 0.141), nadir saturation (83% vs 79%; p = 0.402), or percentage time spent with saturation <90% (38% vs 52%; p = 0.308), although numeric differences are noted.
Compared with 18 subjects with an AHI ≥5/h on sleep testing, the 10 subjects using PAP at enrollment were found to be older (50 vs 63 years; p = 0.016); otherwise, there were no significant differences with respect to gender, BMI, Epworth sleepiness score, or hemodynamic data (data not shown).
All 49 subjects underwent right-sided cardiac catheterization. Cardiac index (i.e. cardiac output divided by estimated body surface area) was significantly lower in those with SDB compared with those without ( Table 1 ). No differences were observed in cardiac output, right atrial (RA) pressure, pulmonary vascular resistance, or pulmonary artery wedge pressure.
Thirty-nine subjects underwent sleep testing, which was performed within 2 days of catheterization in 85% of subjects. Linear regression was performed to examine the effect of cardiac index on AHI, with natural log transformation applied to AHI to satisfy the normality assumption, which revealed a significant association ( Figure 1 ). BMI and age were not found to correlate with log AHI (p = 0.133 and p = 0.648, respectively), nor was baseline saturation (p = 0.610). In 24 subjects in whom LFCT was scorable, there was a significant association between cardiac index and LFCT ( Figure 2 ), using an inverse first-order model (i.e. y = y0 + a/x), determined a priori based on an expected hyperbolic relation. Despite association between LFCT and cardiac index and between cardiac index and log AHI, no significant correlation was found between LFCT and log AHI (p = 0.129). In addition, there was no significant difference in LFCT between those with AHI <5/h and those with AHI ≥5/h ( Figure 2 ).
In subjects with a highly collapsible upper airway, SDB might be expected regardless of respiratory control stability; therefore, an a priori subgroup analysis was performed on subjects with a percentage of events that were central apneas ≥1% (i.e. ≥ the cohort median), which we believed were likely to have only a mildly collapsible airway. A linear relation between cardiac index and log AHI in this subgroup (n = 20) was found ( Figure 3 ), and the mean cardiac index was lower in those with AHI ≥5/h compared with those with AHI <5/h (2.18 vs 2.55 L/min/m 2 ; p = 0.036). Additionally, there was a significant association between LFCT (n = 14) and log AHI (β = 0.117, R 2 = 0.310; p = 0.039). Within the subgroup, LFCT was significantly shorter in subjects with AHI <5/h compared with those with AHI ≥5/h ( Figure 3 ).
