0
Original Research: Sleep Disorders |

High Occurrence of Hypoxemic Sleep Respiratory Disorders in Precapillary Pulmonary Hypertension and MechanismsPulmonary Hypertension and Sleep Hypoxemia FREE TO VIEW

Fadia Nicolas Jilwan, MD; Pierre Escourrou, MD, PhD; Gilles Garcia, MD, PhD; Xavier Jaïs, MD; Marc Humbert, MD, PhD; Gabriel Roisman, MD, PhD
Author and Funding Information

From the Faculté de Médecine (Drs Jilwan, Escourrou, Garcia, Jaïs, Humbert, and Roisman), Université Paris-Sud, Le Kremlin-Bicêtre; Assistance Publique-Hôpitaux de Paris, Unité de Médecine du Sommeil (Drs Jilwan, Escourrou, Garcia, and Roisman), Hôpital Antoine-Béclère, Clamart; Assistance Publique-Hôpitaux de Paris, Service de Pneumologie et Réanimation Respiratoire (Drs Jaïs and Humbert), Hôpital Antoine-Béclère, Clamart; Institut National de la Santé et de la Recherche Médicale U999 Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique (Drs Garcia, Jaïs, and Humbert), Le Plessis-Robinson; and Faculté de Pharmacie (Drs Jilwan and Escourrou), Université Paris-Sud, EA3544, Châtenay-Malabry, France.

Correspondence to: Gabriel Roisman, MD, PhD, Unité de Médecine du Sommeil, Hôpital Antoine-Béclère, 157 Rue de la Porte de Trivaux, 92140 Clamart, France; e-mail: gabriel.roisman@abc.aphp.fr


Funding/support: The sponsor was Assistance Publique-Hôpitaux de Paris (Département de la Recherche Clinique et du Développement).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(1):47-55. doi:10.1378/chest.11-3124
Text Size: A A A
Published online

Background:  The occurrence and mechanisms of nocturnal hypoxemia in precapillary pulmonary hypertension (PH) are not clearly defined.

Methods:  In an observational, prospective, and transversal design, we studied 46 clinically stable patients with PH and a BMI < 35 kg/m2, an FEV1 > 60% predicted, and idiopathic pulmonary arterial hypertension (n = 29) or chronic thromboembolic pulmonary hypertension (n = 17). They underwent nocturnal polysomnography with transcutaneous capnography.

Results:  Most patients (69.6%) had New York Heart Association functional class II disease. Mean pulmonary artery pressure was 44 ± 13 mm Hg, and the cardiac index was 3.2 ± 0.6 L/min/m2. Duration of sleep time spent with oxygen saturation as measured by pulse oximetry < 90% was 48.9% ± 35.9%, and 38 of 46 patients (82.6%) had nocturnal hypoxemia. Mean apnea-hypopnea index was 24.9 ± 22.1/h, and 41 patients (89%) had sleep apnea. The major mechanism of nocturnal hypoxemia was a ventilation/perfusion mismatch alone or associated with obstructive apneic events. Multivariate logistic regression identified both FEV25%-75% (OR, 0.9519; 95% CI, 0.9089-0.9968; P = .036) and mean pulmonary artery pressure (OR, 1.1068; 95% CI, 1.0062-1.2175; P = .037) as significant predictors of nocturnal hypoxemia. Clinical symptoms were not predictive of nocturnal hypoxemia.

Conclusions:  The occurrence of nocturnal hypoxemia is high in PH and should be screened for systematically. Further studies are needed to determine the impact of nocturnal hypoxemia on the outcome of patients with PH.

Trial registry:  ClinicalTrials.gov; No.: NCT01371669; URL: www.clinicaltrials.gov

Figures in this Article

Idiopathic pulmonary arterial hypertension (IPAH) is associated with remodeling and obliteration of small pulmonary arterioles, whereas chronic thromboembolic pulmonary hypertension (CTEPH) is the consequence of persistent pulmonary artery obstruction due to chronic thromboembolic disease.1,2 Most patients with precapillary pulmonary hypertension (PH) are not hypoxemic during the daytime, but some studies in small cohorts found an increase in the prevalence of sleep-related hypoxemia in PH, accounting for up to 77% of cases.3 Although hypoxemia was not related to respiratory events like hypopnea or apnea in one study,4 other studies mentioned Cheyne-Stokes respiration (CSR), which usually is observed in severe heart failure,5,6 and Prisco et al3 reported an increased prevalence of obstructive sleep apnea (OSA)-hypopnea, accounting for 50% of patients with PH.

Thus, all these studies revealed an increased frequency of nocturnal hypoxemia in PH but failed to agree on its mechanisms. Because chronic hypoxemia may promote pulmonary artery vasoconstriction and remodeling,79 it may contribute to the pathogenesis of pulmonary vascular remodeling in PH. The purpose of the present study, therefore, was to evaluate the occurrence and mechanisms of hypoxemic respiratory sleep disturbances in patients with IPAH or CTEPH.

This observational, prospective, and transversal study was proposed to patients being treated for IPAH or CTEPH and who were hospitalized for follow-up in the pulmonary department of Antoine-Béclère Hospital, which is the national referral center for PH in France. PH was defined by right-sided heart catheterization with a mean pulmonary artery pressure (mPAP) of > 25 mm Hg and a mean pulmonary wedge pressure of ≤ 15 mm Hg.1 In IPAH, there was no identified cause for the disease, but in CTEPH, contrast-enhanced spiral CT imaging of the chest and pulmonary angiography confirmed chronic thromboembolic disease. Other types of PH were not included in the study.

Patients were hospitalized in the pulmonary department for a standard follow-up. PH had already been diagnosed in all patients by cardiac catheterization and treated to achieve the best functional New York Heart Association (NYHA) functional class and hemodynamic parameters. To participate in the study, patients also had to be in a stable clinical condition for at least the 3 preceding months, as defined by NYHA functional class and a walking distance difference within 10% of the previous 3-month measurement during the 6-min walk test (6MWT). Moreover, no change in medical therapy could have occurred during this period. Other exclusion criteria were age > 75 years, restrictive or obstructive pulmonary diseases with a total lung capacity and an FEV1 < 60% predicted, severe obesity as defined by a BMI ≥ 35 kg/m2, or previously diagnosed sleep breathing disorder.

Patients already treated with long-term oxygen therapy were not excluded because one of the objectives of the study was to determine the mechanisms of nocturnal hypoxemia and not only its occurrence. In these patients, polysomnography (PSG) was performed while breathing room air. Significant anatomic shunting was excluded by pure oxygen breathing in the sitting position and contrast echocardiography in patients with diurnal hypoxemia. Current and former smokers were not excluded but were analyzed separately when necessary.

All recruited patients provided written informed consent for the study, which was approved by the Comité de Protection des Personnes Ile de France VII (N: 10-008). They had a physical examination that evaluated for NYHA functional class and clinical symptoms of PH. Patients also completed a specialized autoquestionnaire for sleep symptoms, including the Epworth Sleepiness Scale, which ranges from 0 to 24 points, with > 10 points considered to reflect excessive daytime sleepiness.10 Patients were selected regardless of their answers to the sleep questionnaire.

Other tests done for routine follow-up were a right-sided heart catheterization, a 6MWT, lung function tests, arterial blood gas analysis, and brain natriuretic peptide (BNP) and hematocrit levels. A 1-night PSG (CIDELEC) was also performed during the patient’s hospital stay. It recorded three EEG channels, two electrooculographic channels, submental and pretibial electromyograms, airflow with a nasal pressure channel, thoracic and abdominal inductance belts, tracheal sounds, sleeping position, pulse oximetry, and transcutaneous capnography (TOSCA 500; Radiometer Medical ApS). Scoring was done visually by a sleep specialist in accordance with French clinical practice guidelines.11 An apnea was defined as a ≥ 90% reduction of airflow lasting ≥ 10 s. Apneas were defined as obstructive when there was evidence of persistent respiratory effort and central in the absence of any respiratory effort. Hypopneas were defined as a reduction in airflow by > 50% of baseline lasting ≥ 10 s or as a lower reduction in airflow associated with an oxyhemoglobin desaturation of ≥ 3% or an arousal. The apnea-hypopnea index (AHI) was considered mildly elevated when ranging between 5 and 14/h, moderately elevated when between 15 and 29/h, and severely elevated if ≥ 30/h. Periodic respiration like CSR consisted of at least three crescendo and decrescendo pattern changes in breathing amplitude lasting > 10 consecutive min or associated with a central AHI ≥ 5/h.12 Sleep apnea-hypopnea-related hypoxemia was recognized by its typical intermittent (saw-tooth) pattern, which is characterized by periodic falls of ≥ 3% in oxygen saturation as measured by pulse oximetry (SpO2) following airflow obstruction or central apnea with a return to baseline or near baseline level (e-Fig 1).

Sustained hypoxemia periods in the absence of simultaneous apneic events or an alveolar hypoventilation pattern were considered to be the consequence of a worsening in alveolar ventilation-perfusion (V˙ A/Q˙ ) heterogeneity. Thus, V˙ A/Q˙  mismatch-related hypoxemia was defined as sustained hypoxemia periods lasting for ≥ 10 consecutive min without any concomitant increase in transcutaneous PCO2 (TcPCO2) suggestive of alveolar hypoventilation or the presence of apneas or hypopneas (e-Fig 2).

Alveolar hypoventilation-related hypoxemia was defined as an increase of at least 10 mm Hg in PaCO2 during sleep from awake supine values with a simultaneous sustained oxyhemoglobin desaturation not explained by apnea or hypopnea events.12 We used TcPCO2 as a surrogate measurement of PaCO2 because the TOSCA device has demonstrated good accuracy in adult patients compared with blood gas analysis.1315 The duration of sleep time spent with SpO2 < 90% (D90%), was derived from a cumulative frequency curve of pulse oximetry. Desaturation was considered significant if D90% was ≥ 60 min, the oxygen desaturation index was ≥ 20/h, or both, with a significant decrease in SpO2 of ≥ 3%.

Comparisons between groups (IPAH vs CTEPH, nocturnal desaturators vs nondesaturators) were made using unpaired Student t test. Nonparametric Mann-Whitney U test was used for variables as appropriate. Comparisons of proportions were made using the Fisher exact test. Nonparametric correlations among data were made using Spearman rank analysis.

Potential factors that increase the probability of nocturnal hypoxemia were assessed using a multivariate logistic regression model that was built with purposeful selection of covariates as described by Hosmer et al.16 Independent variables having a significant P < .25 on univariate testing were included in the multivariate model. In the multivariate model, covariates were iteratively removed if they were nonsignificant and not a confounder. Significance was evaluated at α = .1 and confounding as a change ≥ 15% in any remaining parameter estimate. Model performance was assessed according to both discrimination (by means of the area under the receiver operating characteristic [ROC] curve) and calibration (by using the Hosmer-Lemeshow goodness-of-fit test).16P ≤ .05 was considered significant. Results are expressed as mean ± SD. All statistical analyses were performed using MedCalc, version 12.2.1.0 (MedCalc Software bvba) software.

The charts of 218 patients admitted to the Antoine-Béclère referral center for PH between June 2010 and July 2011 were examined. The study was proposed to 81 patients fulfilling the inclusion criteria. Final analyses were done on 46 of 50 eligible patients (Fig 1).

Figure Jump LinkFigure 1. Patient flowchart. The charts of 218 patients were examined; 27 patients refused to participate, and four could not undergo the PSG for logistical reasons due to a short hospital stay. Fifty eligible patients were enrolled in the study and underwent a 1-night PSG. Four of the 50 PSGs were not conclusive for technical reasons. Analyses were done on the remaining 46 patients. CTEPH = chronic thromboembolic pulmonary hypertension; IPAH = idiopathic pulmonary arterial hypertension; PSG = polysomnography.Grahic Jump Location

Baseline characteristics of the study population are detailed in Table 1. Right-sided heart catheterization confirmed PH with an mPAP of 44 ± 13 mm Hg and cardiac index of 3.2 ± 0.6 L/min/m2. The group included 29 patients with IPAH and 17 with CTEPH. Five of the 17 patients with CTEPH had already underwent a thromboendarterectomy in the past but had persistent PH related to surgically inaccessible endovascular lesions. The remainder of the patients with CTEPH had an inoperable condition and were treated medically. Parameters reported in Table 1 (6-min walk distance, BNP levels, NYHA functional class, and hemodynamics with cardiac index within the normal range) allowed for highlighting the characteristics of a stable PH population. All patients were receiving optimal medical treatment for PH, with the majority taking a combination of drugs (Table 1).

Table Graphic Jump Location
Table 1 —Baseline Characteristics of the Study Population (N = 46)

Data are presented as mean ± SD or No. (%). 6MWT = 6-min walk test; AHI = apnea-hypopnea index; BNP = brain natriuretic peptide; CTEPH = chronic thromboembolic pulmonary hypertension; D90% = duration of sleep time spent with oxygen saturation as measured by pulse oximetry < 90%; DLCO = diffusing capacity of lung for carbon monoxide; ESS = Epworth Sleepiness Scale; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary artery pressure; mPWP = mean pulmonary wedge pressure; NYHA = New York Heart Association; ODI = oxygen desaturation index; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; RAP = right atrial pressure; REM = rapid eye movement; sleep efficiency = ratio of total sleep time over time in bed; SpO2 = oxygen saturation as measured by pulse oximetry; TLC = total lung capacity; TST = total sleep time.

a 

Not all patients could correctly execute spirometry maneuvers, especially DLCO, which requires holding breath for at least 10 s. Some patients refused blood gas analysis, considering it very painful. In two patients, mPWP could not be technically measured, and so the resulting PVR could not be calculated.

Nocturnal hypoxemia was observed in 38 of the 46 patients (82.6%). Characteristics of patients with desaturation (desaturators) and patients with normal nocturnal saturation (nondesaturators) are presented in Table 2. The two groups differed by diurnal PaO2, alveolar-arterial gradient, SpO2 prior to the 6MWT (resting SpO2), and FEV25%-75%; desaturators were more hypoxemic than nondesaturators during the day and had significant distal narrowing of small airways. When excluding smoking as a confounding factor for distal airways obstruction (13 patients), the difference in mean FEV25%-75% between the two groups remained statistically significant (P = .038) (Table 2). Other variables, such as pulmonary hemodynamics and BNP or hematocrit levels, did not show significant differences between the two groups. Given the identical distribution of nondesaturators and desaturators among patients with IPAH and CTEPH, comparisons between the two groups were performed irrespective of the type of PH (e-Appendix 1, e-Tables 1, 2).

Table Graphic Jump Location
Table 2 —Comparisons Between Patients Without Nocturnal Hypoxemia (Nondesaturators) and Patients With Significant Nocturnal Hypoxemia (Desaturators)

Data are presented as mean ± SD or No. (%). See Table 1 legend for expansion of abbreviations.

a 

P < .05 with Mann-Whitney test

b 

P < .05 with t test.

The major mechanism identified for nocturnal hypoxemia was a V˙ A/Q˙  mismatch that was observed in 29 of 38 patients (76%) (Fig 2A) because other diagnoses for nocturnal hypoxemia were excluded. Sleep apneas were also common (89% of patients), with a severe AHI (≥ 30/h) in 28% of patients, a moderate AHI (15-29/h) in 39%, and a mild AHI (5-14/h) in the remaining 22% (Fig 2B). Their mechanism was obstructive in the majority of cases because > 50% of the respiratory events were obstructive. It was the only mechanism of nocturnal hypoxemia in 21% of patients and was associated with a V˙ A/Q˙  mismatch in the others (45%).

Figure Jump LinkFigure 2. A, Identified nocturnal hypoxemia mechanisms (n = 38). VA/Q mismatch was a prevalent nocturnal abnormality, frequently associated with sleep apnea. B, AHI severity and prevalence in precapillary pulmonary hypertension (n = 46). Moderate and severe AHIs represent 67% of patients with pulmonary hypertension with a predominance of obstructive forms. AHI = apnea-hypopnea index; CSA = central sleep apnea; OSA = obstructive sleep apnea; SAS = sleep apnea; VA/Q = alveolar ventilation-perfusion.Grahic Jump Location

A single case of alveolar hypoventilation associated with a moderate OSA was identified: TcPCO2 increased by > 30 mm Hg during sleep, with a marked decrease in SpO2. The cause of the alveolar hypoventilation observed in this patient is not clear, although it seemed not to be associated to the apneic events. His AHI was 22/h, which is not usually sufficient to induce alveolar hypoventilation in patients with normal respiratory drive. Although the ventilatory response to hypercapnia was not measured, this patient had periods of clear alveolar hypoventilation in the absence of apneic events (e-Fig 3).

Central respiratory events were rare and always associated with V˙ A/Q˙  mismatch periods. CSR was found in three of the four patients with central sleep apnea. These patients were in NYHA functional class III and had a mean cardiac index of 2.7 ± 0.8 L/min/m2.

D90% was correlated with diurnal PaO2 (ρ = 0.60, P < .05) (Fig 3A), alveolar-arterial gradient (ρ = 0.49, P < .05), resting SpO2 (ρ = 0.44, P < .05), walking SpO2 (ρ = 0.32, P = .03), and FEV25%-75% (ρ = 0.53, P < .05) (Fig 3B, correlation done on nonsmoker patients). Mean SpO2 was identical in all sleep stages (Table 1).

Figure Jump LinkFigure 3. A, Correlation between D90% and diurnal PaO2 (mm Hg) obtained on arterial blood gas analysis in patients with pulmonary hypertension (N = 46, ρ = 0.60, P < .05). D90% ≥ 60 min was considered a significant nocturnal hypoxemia (dashed line). B, Correlation between D90% and FEV25/75 (% predicted) in nonsmoking patients with pulmonary hypertension (n = 35, ρ = 0.53, P < .05). D90% = duration of sleep time spent with oxygen saturation as measured by pulse oximetry < 90%.Grahic Jump Location

AHI was also correlated with diurnal PaO2 (ρ = 0.36, P = .02) and alveolar-arterial gradient (ρ = 0.40, P < .05). All other clinical, functional, and hemodynamic variables did not show significant correlations with sleep hypoxemia parameters (AHI, D90%, and oxygen desaturation index). PH-specific treatments did not interfere with nocturnal hypoxemia occurrence (data not shown). The two most relevant correlations are presented in Figure 3.

In addition to age, logistic regression analysis identified FEV25%-75% (OR, 0.9519; 95% CI, 0.9089-0.9968; P = .036) as a predictor factor of nocturnal hypoxemia. The mPAP became a significant covariate as a predictor of nocturnal hypoxemia after adjusting the model for age (OR, 1.1068; 95% CI, 1.0062-1.2175; P = .037). PaO2 at rest was not identified as an independent predictor of nocturnal hypoxemia in the final multivariate model because of multicollinearity with FEV25%-75%, mPAP, and age. Adjusting the model by sex did not change the results. Thus, in the age-adjusted model, the OR of nocturnal hypoxemia increased 4.81% with each unit (% predicted) of decrement in FEV25%-75% and increased 10.68% with each millimeter of Hg increment in mPAP. The final multivariate model had an area under the ROC curve of 0.865 (SE, 0.073; 95% CI, 0.728-0.949). For detailed results of logistic regression, see e-Table 3. We performed a post hoc ROC analysis for both FEV25%-75% and mPAP. A cutoff value of < 80% of the predicted FEV25%-75% had a 75% sensitivity and specificity as a predictor of nocturnal hypoxemia. An mPAP of > 38 mm Hg predicted nocturnal hypoxemia with a sensitivity of 74% and a specificity of 75%.

The relevant findings of this study are that nocturnal hypoxemia is common in patients with stable IPAH and CTEPH (observed in > 80% of cases) and that the most frequent mechanism responsible for this hypoxemia is V˙ A/Q˙  mismatch, which was present in 76% of desaturator patients, alone or associated with apneic events. We studied a well-defined population with two major causes of PH, namely IPAH and CTEPH, at a steady state for at least 3 months without any confounding factors inducing hypoxemia, such as severe obesity or other respiratory diseases, which was not the case in previous studies.3,4,6,17,18

The results extend data from the literature regarding the high occurrence of nocturnal hypoxemia in PH. Rafanan et al4 mentioned a prevalence of nocturnal hypoxemia of 77% in 13 patients with IPAH, and Minai et al18 observed a prevalence of 69.7% in 43 patients with IPAH and PH associated with connective tissue diseases.

Sleep apneas were frequent in the present study (89% of patients) and considerably more prevalent than in the general population aged 30 to 60 years (reported in about 24% of men and 9% of women19). The present results are in line with the findings of Prisco et al,3 who observed an increased prevalence of OSA and the absence of central events in patients with PH, but the prevalence of OSA in the current patients was higher (89% vs 50%), whereas the severity of PH was similar (mPAP, 44 ± 13 mm Hg vs 40.9 ± 15.8 mm Hg, respectively). This difference may be related not only to the phenotype of the patients with connective tissue diseases in Prisco et al3 but also to the difference in the definition of desaturation level and hypopneas compared with the present study; Prisco et al3 stated a significant desaturation level of ≥ 4% for hypopnea compared with 3% in the present study.

By multivariate logistic regression, we found a significant association of nocturnal hypoxemia with FEV25%-75% and mPAP. This result is also in line with the relationship between mPAP and nocturnal hypoxemia obtained by Prisco et al.3

Schulz et al5 and Ulrich et al6 found 30% and 45% of periodic breathing (CSR) in 20 and 38 patients with PH, respectively, studied by PSG. Periodic breathing usually is observed in the setting of severe congestive heart failure.2023 Indeed, Schulz et al5 and Ulrich et al6 reported on patients with a more severe manifestation of PH than those in the present study (NYHA functional class III/IV) and above all, with clinical stability defined over a shorter period of only 4 weeks. The mean cardiac index of their patients was 1.96 and 2.4 L/min/m2, respectively, whereas in the stable patients of the present study, the mean cardiac index was normal at rest (3.2 ± 0.6 L/min/m2) and similar to the mean cardiac index (2.9 ± 0.8 L/min/m2) observed by Prisco et al.3 Therefore, the higher prevalence of CSR observed by these authors is probably the result of heart failure rather than the consequence of PH itself. The different characteristics of these populations are illustrated in Table 3.

Table Graphic Jump Location
Table 3 —Comparison of Studies on Sleep Breathing Disorders in PAH

6MWD = 6-min walking distance; AH = apnea-hypopnea; CSR = Cheyne-Stokes respiration; ND = not determined; OSAS = obstructive sleep apnea syndrome; PAH = pulmonary arterial hypertension; pts = patients; SPAH = secondary pulmonary arterial hypertension. See Table 1 legend for expansion of other abbreviations.

a 

ProBNP.

Changes in ventilation during sleep, such as mild hypoventilation,24,25 decreased functional residual capacity,26 blunted responses to hypoxemia and hypercapnia,27 and increased upper airway resistance, are well established.28 Such ventilatory perturbations are mild and well tolerated in healthy individuals but may exhibit more profound gas exchange abnormalities in patients with PH, given the already elevated alveolar-arterial gradient present in wakefulness and at exercise, particularly in CTEPH.29

Sleep-related alveolar hypoventilation due to a possible reduction of functional residual capacity in the supine position and to predisposing respiratory muscle weakness as previously described in patients with PH was not evident in the present population.3032 In fact, TcPCO2 recorded overnight did not show any significant increase (≥ 10 mm Hg), except in one patient with normal BMI and moderate OSA (AHI = 22/h). Moreover, this patient did not have daytime hypoventilation at rest or at exercise and was successfully treated with oxygen supplementation, which corrected nocturnal hypoxemia and hypercapnia.

Another possible explanation for long desaturation periods recorded during sleep was perturbation in the V˙ A/Q˙  ratio given the absence of associated apneas-hypopneas or alveolar hypoventilation. This abnormality may be secondary to the obliteration of small pulmonary arterioles which increases pulmonary physiologic dead space, but also to narrowed distal airways as already described in patients with PH.3335 The relationship between FEV25%-75% and D90% found in the present study suggests that small airways obstruction may contribute to V˙ A/Q˙  mismatch by increasing the shunt effect.

Clinical symptoms were not reliable in the evaluation of sleep-related breathing disorders in the present population. Sleep apnea was not clinically suspected because patients did not experience typical symptoms, such as excessive daytime sleepiness, although snoring was reported in 59% of patients as in the healthy population of the same age range. This lack of clinical symptoms of sleep apnea was outlined in previous studies.3,6

The study had some limitations. The sample was restricted to 46 patients, but to our knowledge, it is the largest and most homogeneous population of patients with stable PH studied to date for sleep-related disorders. We cannot exclude an underestimation of central events because of the absence of the gold standard, which is the esophageal pressure measurements, but our choice was not to use this invasive technique because of sleep disturbance and the potential risk in anticoagulated patients.36 The evaluation of V˙ A/Q˙  mismatch was based on the occurrence of long desaturation periods without concomitant increase in TcPCO2. The validity of such measurements using these kinds of devices was questioned in the past,12 but the TOSCA device we used has demonstrated good accuracy in adult patients compared with blood gas analysis.1315

In conclusion, sleep-related hypoxemia is frequent in patients with IPAH and CTEPH. It is likely due to major V˙ A/Q˙  mismatch and OSA. Because there is no clinical predicting factor for sleep-related hypoxemia in PH, it is reasonable to screen all patients to diagnose and treat other additional possible factors compromising pulmonary hemodynamics. The guidelines recommending PSG only in patients with PH with clinical suspicion of sleep apnea certainly need to be reconsidered. Further studies are needed to evaluate whether management of hypoxemic sleep respiratory disorders may improve outcome in patients with PH.

Author contributions: Dr Roisman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Jilwan: contributed as the main investigator and as a writer.

Dr Escourrou: contributed as a senior coinvestigator and as a writer.

Dr Garcia: contributed as an assistant writer.

Dr Jaïs: contributed as an assistant writer.

Dr Humbert: contributed as an assistant writer.

Dr Roisman: contributed as a senior coinvestigator and as a writer.

Other contributions: We thank the patients who participated to this study and Kaixian Zhu, MSc; Gérald Simonneau, MD; Olivier Sitbon, MD, PhD; Florence Parent, MD; David Montani, MD, PhD; and Laurent Savale, MD, PhD, for their contribution.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Additional information: The e-Appendix, e-Figures, and e-Tables can be found in the “Supplemental Materials” area of the online article.

6MWT

6-min walk test

AHI

apnea-hypopnea index

BNP

brain natriuretic peptide

CSR

Cheyne-Stokes respiration

CTEPH

chronic thromboembolic pulmonary hypertension

D90%

duration of sleep time spent with oxygen saturation as measured by pulse oximetry < 90%

IPAH

idiopathic pulmonary arterial hypertension

mPAP

mean pulmonary artery pressure

NYHA

New York Heart Association

OSA

obstructive sleep apnea

PH

precapillary pulmonary hypertension

PSG

polysomnography

SpO2

oxygen saturation as measured by pulse oximetry

TcPCO2

transcutaneous PCO2

V˙ A/Q˙ 

alveolar ventilation/perfusion

Galiè N, Hoeper MM, Humbert M, et al; Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC) Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC) European Respiratory Society (ERS) European Respiratory Society (ERS) International Society of Heart and Lung Transplantation (ISHLT) International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219-1263. [CrossRef] [PubMed]
 
Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12):S:13S-24. [CrossRef]
 
Prisco DL, Sica AL, Talwar A, et al. Correlation of pulmonary hypertension severity with metrics of comorbid sleep-disordered breathing. Sleep Breath. 2011;15(4):633-639. [CrossRef] [PubMed]
 
Rafanan AL, Golish JA, Dinner DS, Hague LK, Arroliga AC. Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest. 2001;120(3):894-899. [CrossRef] [PubMed]
 
Schulz R, Baseler G, Ghofrani HA, Grimminger F, Olschewski H, Seeger W. Nocturnal periodic breathing in primary pulmonary hypertension. Eur Respir J. 2002;19(4):658-663. [CrossRef] [PubMed]
 
Ulrich S, Fischler M, Speich R, Bloch KE. Sleep-related breathing disorders in patients with pulmonary hypertension. Chest. 2008;133(6):1375-1380. [CrossRef] [PubMed]
 
Pak O, Aldashev A, Welsh D, Peacock A. The effects of hypoxia on the cells of the pulmonary vasculature. Eur Respir J. 2007;30(2):364-372. [CrossRef] [PubMed]
 
Pidgeon GP, Tamosiuniene R, Chen G, et al. Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2. Circulation. 2004;110(17):2701-2707. [CrossRef] [PubMed]
 
Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res. 2006;99(7):675-691. [CrossRef] [PubMed]
 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540-545. [PubMed]
 
Société de Pneumologie de Langue Française; Société Française d’Anesthésie Réanimation; Société Française de Cardiologie; Société Française de Médecine du Travail; Société Française d’ORL; Société de Physiologie; Société Française de Recherche et de Médecine du Sommeil. Recommendations for clinical practice. Obstructive sleep apnea hypopnea syndrome in adults [in French]Rev Mal Respir.2010;27(7):806-833.
 
Redline S, Budhiraja R, Kapur V, et al. The scoring of respiratory events in sleep: reliability and validity. J Clin Sleep Med. 2007;3(2):169-200. [PubMed]
 
Janssens JP, Borel JC, Pépin JL SomnoNIV Group SomnoNIV Group. Nocturnal monitoring of home non-invasive ventilation: the contribution of simple tools such as pulse oximetry, capnography, built-in ventilator software and autonomic markers of sleep fragmentation. Thorax. 2011;66(5):438-445. [CrossRef] [PubMed]
 
Nicolini A, Ferrari MB. Evaluation of a transcutaneous carbon dioxide monitor in patients with acute respiratory failure. Ann Thorac Med. 2011;6(4):217-220. [CrossRef] [PubMed]
 
Parker SM, Gibson GJ. Evaluation of a transcutaneous carbon dioxide monitor (“TOSCA”) in adult patients in routine respiratory practice. Respir Med. 2007;101(2):261-264. [CrossRef] [PubMed]
 
Hosmer DW, Lemeshow S Applied Logistic Regression.2nd ed. New York, NY: John Wiley and Sons; 2000.
 
Launay D, Humbert M, Berezne A, et al. Clinical characteristics and survival in systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease. Chest. 2011;140(4):1016-1024. [CrossRef] [PubMed]
 
Minai OA, Pandya CM, Golish JA, et al. Predictors of nocturnal oxygen desaturation in pulmonary arterial hypertension. Chest. 2007;131(1):109-117. [CrossRef] [PubMed]
 
Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-1235. [CrossRef] [PubMed]
 
Bradley TD, Floras JS. Sleep apnea and heart failure: part II: central sleep apnea. Circulation. 2003;107(13):1822-1826. [CrossRef] [PubMed]
 
Escourrou P, Pellerin D, Nedelcoux H. Heart failure and sleep respiratory disorders. Prevalence, physiopathology and treatment [in French]. Rev Mal Respir. 2000;17(suppl 3):S31-S40. [PubMed]
 
Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol. 2006;106(1):21-28. [CrossRef] [PubMed]
 
Yumino D, Bradley TD. Central sleep apnea and Cheyne-Stokes respiration. Proc Am Thorac Soc. 2008;5(2):226-236. [CrossRef] [PubMed]
 
Douglas NJ, White DP, Pickett CK, Weil JV, Zwillich CW. Respiration during sleep in normal man. Thorax. 1982;37(11):840-844. [CrossRef] [PubMed]
 
Robin ED, Whaley RD, Crump CH, Travis DM. Alveolar gas tensions, pulmonary ventilation and blood pH during physiologic sleep in normal subjects. J Clin Invest. 1958;37(7):981-989. [CrossRef] [PubMed]
 
Hudgel DW, Devadatta P. Decrease in functional residual capacity during sleep in normal humans. J Appl Physiol. 1984;57(5):1319-1322. [PubMed]
 
Douglas NJ. Control of ventilation during sleep. Clin Chest Med. 1985;6(4):563-575. [PubMed]
 
Hudgel DW, Martin RJ, Johnson B, Hill P. Mechanics of the respiratory system and breathing pattern during sleep in normal humans. J Appl Physiol. 1984;56(1):133-137. [PubMed]
 
Zhai Z, Murphy K, Tighe H, et al. Differences in ventilatory inefficiency between pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Chest. 2011;140(5):1284-1291. [CrossRef] [PubMed]
 
Bauer R, Dehnert C, Schoene P, et al. Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension. Respir Med. 2007;101(11):2366-2369. [CrossRef] [PubMed]
 
de Man FS, van Hees HW, Handoko ML, et al. Diaphragm muscle fiber weakness in pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(10):1411-1418. [CrossRef] [PubMed]
 
Meyer FJ, Lossnitzer D, Kristen AV, et al. Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension. Eur Respir J. 2005;25(1):125-130. [CrossRef] [PubMed]
 
Jing ZC, Xu XQ, Badesch DB, et al. Pulmonary function testing in patients with pulmonary arterial hypertension. Respir Med. 2009;103(8):1136-1142. [CrossRef] [PubMed]
 
Meyer FJ, Ewert R, Hoeper MM, et al; German PPH Study Group German PPH Study Group. Peripheral airway obstruction in primary pulmonary hypertension. Thorax. 2002;57(6):473-476. [CrossRef] [PubMed]
 
Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol. 2003;41(6):1028-1035. [CrossRef] [PubMed]
 
Bodler K, Trudgill N. Guidelines for oesophageal manometry and pH monitoring.. In: BSG Guidelines in Gastroenterology. London, England: British Society of Gastroenterology; 2006:1-11.
 

Figures

Figure Jump LinkFigure 1. Patient flowchart. The charts of 218 patients were examined; 27 patients refused to participate, and four could not undergo the PSG for logistical reasons due to a short hospital stay. Fifty eligible patients were enrolled in the study and underwent a 1-night PSG. Four of the 50 PSGs were not conclusive for technical reasons. Analyses were done on the remaining 46 patients. CTEPH = chronic thromboembolic pulmonary hypertension; IPAH = idiopathic pulmonary arterial hypertension; PSG = polysomnography.Grahic Jump Location
Figure Jump LinkFigure 2. A, Identified nocturnal hypoxemia mechanisms (n = 38). VA/Q mismatch was a prevalent nocturnal abnormality, frequently associated with sleep apnea. B, AHI severity and prevalence in precapillary pulmonary hypertension (n = 46). Moderate and severe AHIs represent 67% of patients with pulmonary hypertension with a predominance of obstructive forms. AHI = apnea-hypopnea index; CSA = central sleep apnea; OSA = obstructive sleep apnea; SAS = sleep apnea; VA/Q = alveolar ventilation-perfusion.Grahic Jump Location
Figure Jump LinkFigure 3. A, Correlation between D90% and diurnal PaO2 (mm Hg) obtained on arterial blood gas analysis in patients with pulmonary hypertension (N = 46, ρ = 0.60, P < .05). D90% ≥ 60 min was considered a significant nocturnal hypoxemia (dashed line). B, Correlation between D90% and FEV25/75 (% predicted) in nonsmoking patients with pulmonary hypertension (n = 35, ρ = 0.53, P < .05). D90% = duration of sleep time spent with oxygen saturation as measured by pulse oximetry < 90%.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline Characteristics of the Study Population (N = 46)

Data are presented as mean ± SD or No. (%). 6MWT = 6-min walk test; AHI = apnea-hypopnea index; BNP = brain natriuretic peptide; CTEPH = chronic thromboembolic pulmonary hypertension; D90% = duration of sleep time spent with oxygen saturation as measured by pulse oximetry < 90%; DLCO = diffusing capacity of lung for carbon monoxide; ESS = Epworth Sleepiness Scale; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary artery pressure; mPWP = mean pulmonary wedge pressure; NYHA = New York Heart Association; ODI = oxygen desaturation index; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; RAP = right atrial pressure; REM = rapid eye movement; sleep efficiency = ratio of total sleep time over time in bed; SpO2 = oxygen saturation as measured by pulse oximetry; TLC = total lung capacity; TST = total sleep time.

a 

Not all patients could correctly execute spirometry maneuvers, especially DLCO, which requires holding breath for at least 10 s. Some patients refused blood gas analysis, considering it very painful. In two patients, mPWP could not be technically measured, and so the resulting PVR could not be calculated.

Table Graphic Jump Location
Table 2 —Comparisons Between Patients Without Nocturnal Hypoxemia (Nondesaturators) and Patients With Significant Nocturnal Hypoxemia (Desaturators)

Data are presented as mean ± SD or No. (%). See Table 1 legend for expansion of abbreviations.

a 

P < .05 with Mann-Whitney test

b 

P < .05 with t test.

Table Graphic Jump Location
Table 3 —Comparison of Studies on Sleep Breathing Disorders in PAH

6MWD = 6-min walking distance; AH = apnea-hypopnea; CSR = Cheyne-Stokes respiration; ND = not determined; OSAS = obstructive sleep apnea syndrome; PAH = pulmonary arterial hypertension; pts = patients; SPAH = secondary pulmonary arterial hypertension. See Table 1 legend for expansion of other abbreviations.

a 

ProBNP.

References

Galiè N, Hoeper MM, Humbert M, et al; Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC) Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC) European Respiratory Society (ERS) European Respiratory Society (ERS) International Society of Heart and Lung Transplantation (ISHLT) International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219-1263. [CrossRef] [PubMed]
 
Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12):S:13S-24. [CrossRef]
 
Prisco DL, Sica AL, Talwar A, et al. Correlation of pulmonary hypertension severity with metrics of comorbid sleep-disordered breathing. Sleep Breath. 2011;15(4):633-639. [CrossRef] [PubMed]
 
Rafanan AL, Golish JA, Dinner DS, Hague LK, Arroliga AC. Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest. 2001;120(3):894-899. [CrossRef] [PubMed]
 
Schulz R, Baseler G, Ghofrani HA, Grimminger F, Olschewski H, Seeger W. Nocturnal periodic breathing in primary pulmonary hypertension. Eur Respir J. 2002;19(4):658-663. [CrossRef] [PubMed]
 
Ulrich S, Fischler M, Speich R, Bloch KE. Sleep-related breathing disorders in patients with pulmonary hypertension. Chest. 2008;133(6):1375-1380. [CrossRef] [PubMed]
 
Pak O, Aldashev A, Welsh D, Peacock A. The effects of hypoxia on the cells of the pulmonary vasculature. Eur Respir J. 2007;30(2):364-372. [CrossRef] [PubMed]
 
Pidgeon GP, Tamosiuniene R, Chen G, et al. Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2. Circulation. 2004;110(17):2701-2707. [CrossRef] [PubMed]
 
Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res. 2006;99(7):675-691. [CrossRef] [PubMed]
 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540-545. [PubMed]
 
Société de Pneumologie de Langue Française; Société Française d’Anesthésie Réanimation; Société Française de Cardiologie; Société Française de Médecine du Travail; Société Française d’ORL; Société de Physiologie; Société Française de Recherche et de Médecine du Sommeil. Recommendations for clinical practice. Obstructive sleep apnea hypopnea syndrome in adults [in French]Rev Mal Respir.2010;27(7):806-833.
 
Redline S, Budhiraja R, Kapur V, et al. The scoring of respiratory events in sleep: reliability and validity. J Clin Sleep Med. 2007;3(2):169-200. [PubMed]
 
Janssens JP, Borel JC, Pépin JL SomnoNIV Group SomnoNIV Group. Nocturnal monitoring of home non-invasive ventilation: the contribution of simple tools such as pulse oximetry, capnography, built-in ventilator software and autonomic markers of sleep fragmentation. Thorax. 2011;66(5):438-445. [CrossRef] [PubMed]
 
Nicolini A, Ferrari MB. Evaluation of a transcutaneous carbon dioxide monitor in patients with acute respiratory failure. Ann Thorac Med. 2011;6(4):217-220. [CrossRef] [PubMed]
 
Parker SM, Gibson GJ. Evaluation of a transcutaneous carbon dioxide monitor (“TOSCA”) in adult patients in routine respiratory practice. Respir Med. 2007;101(2):261-264. [CrossRef] [PubMed]
 
Hosmer DW, Lemeshow S Applied Logistic Regression.2nd ed. New York, NY: John Wiley and Sons; 2000.
 
Launay D, Humbert M, Berezne A, et al. Clinical characteristics and survival in systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease. Chest. 2011;140(4):1016-1024. [CrossRef] [PubMed]
 
Minai OA, Pandya CM, Golish JA, et al. Predictors of nocturnal oxygen desaturation in pulmonary arterial hypertension. Chest. 2007;131(1):109-117. [CrossRef] [PubMed]
 
Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-1235. [CrossRef] [PubMed]
 
Bradley TD, Floras JS. Sleep apnea and heart failure: part II: central sleep apnea. Circulation. 2003;107(13):1822-1826. [CrossRef] [PubMed]
 
Escourrou P, Pellerin D, Nedelcoux H. Heart failure and sleep respiratory disorders. Prevalence, physiopathology and treatment [in French]. Rev Mal Respir. 2000;17(suppl 3):S31-S40. [PubMed]
 
Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol. 2006;106(1):21-28. [CrossRef] [PubMed]
 
Yumino D, Bradley TD. Central sleep apnea and Cheyne-Stokes respiration. Proc Am Thorac Soc. 2008;5(2):226-236. [CrossRef] [PubMed]
 
Douglas NJ, White DP, Pickett CK, Weil JV, Zwillich CW. Respiration during sleep in normal man. Thorax. 1982;37(11):840-844. [CrossRef] [PubMed]
 
Robin ED, Whaley RD, Crump CH, Travis DM. Alveolar gas tensions, pulmonary ventilation and blood pH during physiologic sleep in normal subjects. J Clin Invest. 1958;37(7):981-989. [CrossRef] [PubMed]
 
Hudgel DW, Devadatta P. Decrease in functional residual capacity during sleep in normal humans. J Appl Physiol. 1984;57(5):1319-1322. [PubMed]
 
Douglas NJ. Control of ventilation during sleep. Clin Chest Med. 1985;6(4):563-575. [PubMed]
 
Hudgel DW, Martin RJ, Johnson B, Hill P. Mechanics of the respiratory system and breathing pattern during sleep in normal humans. J Appl Physiol. 1984;56(1):133-137. [PubMed]
 
Zhai Z, Murphy K, Tighe H, et al. Differences in ventilatory inefficiency between pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Chest. 2011;140(5):1284-1291. [CrossRef] [PubMed]
 
Bauer R, Dehnert C, Schoene P, et al. Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension. Respir Med. 2007;101(11):2366-2369. [CrossRef] [PubMed]
 
de Man FS, van Hees HW, Handoko ML, et al. Diaphragm muscle fiber weakness in pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(10):1411-1418. [CrossRef] [PubMed]
 
Meyer FJ, Lossnitzer D, Kristen AV, et al. Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension. Eur Respir J. 2005;25(1):125-130. [CrossRef] [PubMed]
 
Jing ZC, Xu XQ, Badesch DB, et al. Pulmonary function testing in patients with pulmonary arterial hypertension. Respir Med. 2009;103(8):1136-1142. [CrossRef] [PubMed]
 
Meyer FJ, Ewert R, Hoeper MM, et al; German PPH Study Group German PPH Study Group. Peripheral airway obstruction in primary pulmonary hypertension. Thorax. 2002;57(6):473-476. [CrossRef] [PubMed]
 
Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol. 2003;41(6):1028-1035. [CrossRef] [PubMed]
 
Bodler K, Trudgill N. Guidelines for oesophageal manometry and pH monitoring.. In: BSG Guidelines in Gastroenterology. London, England: British Society of Gastroenterology; 2006:1-11.
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Supporting Data

Online Supplement

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543