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(Chest. 2007;131:109-117.)
© 2007 American College of Chest Physicians

Predictors of Nocturnal Oxygen Desaturation in Pulmonary Arterial Hypertension*

Omar A. Minai, MD, FCCP; Chirag M. Pandya, MD; Joseph A. Golish, MD, FCCP; Jaime F. Avecillas, MD; Kevin McCarthy, R-CPT; Scott Marlow, RRT and Alejandro C. Arroliga, MD, FCCP

* The Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic, Cleveland, OH.

Correspondence to: Omar A. Minai, MD, FCCP, Staff Physician, Department of Pulmonary, Allergy, and Critical Care, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: minaio{at}ccf.org

Abstract

Background: Sleep may be associated with significant respiratory compromise in patients with lung disease and can result in hypoxia. In patients with pulmonary arterial hypertension (PAH), nocturnal desaturation may not be reflected in daytime evaluations of oxygenation and can lead to worsening pulmonary hemodynamics. The study was conducted to determine the prevalence and significance of nocturnal oxygen desaturation in patients with PAH.

Methods: A cross-sectional study conducted at the Cleveland Clinic. Patients were followed up at our institution except for the overnight oximetry study done at home. Data regarding degree of nocturnal desaturation, demographics, hemodynamics, pulmonary function, and functional capacity were collected.

Results: Forty-three patients (mean age, 47.9 ± 13.5 years [± SD]; 36 women and 7 men) underwent nocturnal oximetry. The etiology of PAH included idiopathic PAH (88%) and PAH associated with connective tissue diseases (12%). The majority of patients were New York Heart Association functional class II (42%) or III (53%). Thirty patients (69.7%) spent > 10% of sleep time with oxygen saturation by pulse oximetry < 90%. Desaturators were older (p = 0.024) and had higher hemoglobin (p = 0.002). Sixteen of 27 patients (59%) without desaturation < 90% during a 6-min walk test were nocturnal desaturators. Nocturnal desaturators had higher brain natriuretic protein (p = 0.004), lower cardiac index (p = 0.03), and higher mean right atrial pressure (p = 0.09), mean pulmonary artery pressure, and pulmonary vascular resistance. On echocardiography, desaturators were more likely to have moderate or severe right ventricular dilation (p = 0.04) and pericardial effusion. Only one patient had significant sleep apnea.

Conclusions: Nocturnal hypoxemia is common in PAH patients and correlates with advanced pulmonary hypertension and right ventricular dysfunction. Approximately 60% patients without exertional hypoxia had nocturnal desaturation. Overnight oximetry should be considered in the routine workup of PAH patients who do not demonstrate exertional desaturation.

Key Words: hypoxia • oxygen • pulmonary hypertension • pulmonary vascular disease • sleep

Pulmonary arterial hypertension (PAH) may be associated with various diseases or may occur without obvious etiology (idiopathic PAH [IPAH])1 and remains a progressive disease with limited survival.2 The sleep state may be associated with significant respiratory compromise,345 which may be magnified in patients with lung disease and result in hypoxia.46 Hypoxia induces pulmonary arterial constriction due to its effects on the pulmonary vascular endothelial cells and pulmonary artery smooth-muscle cells.789 Transient hypoxia can lead to elevated pulmonary arterial pressures,10 and prolonged hypoxia can result in "fixed" elevations in pulmonary arterial pressure.111213 Improved functional capacity and survival have been demonstrated with the treatment of hypoxemia in patients with COPD.1415

Since daytime arterial blood gases may not reflect nighttime gas exchange, nocturnal oxygen desaturations may be underestimated in patients with IPAH,16 and unsuspected nocturnal hypoxia may lead to worsening pulmonary hemodynamics. The aims of this cross-sectional study were to determine the prevalence of nocturnal oxygen desaturation in a cohort of patients with PAH, and to evaluate the associated factors that could correlate with a low nocturnal oxygen saturation by pulse oximetry (SpO2) in these patients.

Materials and Methods

The study was approved by our institutional review board, and all patients with PAH followed up in the pulmonary hypertension (PH) clinic at our institution were eligible for enrollment. Patients underwent extensive evaluation including a detailed history and physical examination, pulmonary function testing,17 chest radiographs and CT scans, ventilation-perfusion scans, transthoracic echocardiography with bubble studies, and right-sided heart catheterization. Patients performed a 6-min walk test (6MW) according to a standardized protocol.18 Total 6MW distance (6MWD) and SpO2 measured at rest and during ambulation were recorded. If needed, oxygen supplementation was provided to keep SpO2 ≥ 90%. Patients were assigned a New York Heart Association (NYHA) functional class based on symptomatology prior to nocturnal oximetry.

Patients were included if they gave consent to have a nocturnal oximetry test performed. Patients were excluded if they had the following: (1) evidence of significant parenchymal lung disease (FEV1 < 70%, FVC or total lung capacity < 70%, moderate or severe emphysema or fibrosis on chest CT); (2) underlying congenital heart disease; or (3) documented obstructive sleep apnea. Percentage of total sleep time (TST) spent with SpO2 < 90% was calculated. Patients who spent > 10% of the TST with SpO2 < 90% were considered nocturnal desaturators, and the others were considered nondesaturators. Patients who had desaturation were advised to undergo overnight polysomnography.19

Echocardiograms were graded by blinded reviewers for velocity of tricuspid regurgitation (in centimeters per second), right ventricular systolic pressure, pericardial effusion (normal, mild, moderate, severe, or tamponade), right ventricular dilation (normal, mild, moderate, or severe), right ventricular dysfunction (normal, mild, moderate, or severe), right atrial dilation (normal, mild, moderate, or severe), right atrial cavity size (in centimeters), and left ventricular diastolic dysfunction (none, mild, moderate, or severe). The polysomnograms were analyzed for apnea-hypopnea index (events per hour).

The sample was described by mean and SD on continuous measures and by number and percentage in each level of categorical variables (Table 1 ). The desaturation group was described over two categorical measures of desaturation severity (Table 2 ). Desaturators and nondesaturators were compared on continuous measures using a two-sample t test, and on categorical measures using the {chi}2 or Fisher exact test (Tables 345 ).


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  		Table 1. Baseline Characteristics of the Overall Study Group (n = 43)*

 

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  		Table 2. Severity of Nocturnal Desaturation Among 30 Patients With Desaturation

 

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  		Table 3. Comparison of Baseline Characteristics Between Desaturators and Nondesaturators*

 

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  		Table 4. Comparison of Echocardiographic and Hemodynamic Characteristics Between Desaturators and Nondesaturators*

 

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  		Table 5. Comparison of Parameters of Pulmonary Function and Oxygenation Between Desaturators and Nondesaturators*

 
The "best" cut points for select continuous measures were chosen by using receiver operator characteristic (ROC) curves that optimized the sensitivity and specificity of each measure in predicting desaturation. The ROC curve is a graph in which the Y-axis represents sensitivity (the proportion of true-positive results) and the X-axis represents 1 minus specificity (the proportion of false-positive results). The most accurate curve is one that arches up to the upper-left-hand corner of the graph before moving to the upper-right corner. Desaturators and nondesaturators were then compared on these cut points using {chi}2 or Fisher exact test (Table 6 ). A difference in proportion of desaturation within each level of several categorical variables and within categories created by the cut points was also assessed (Table 7 , Fig 1 ). The p value in these tables represents a test of whether the proportion of desaturators for that variable is different from the proportion of nondesaturators. Clinical cut points explored in previous literature were also tested using one-sample test for single proportion (Fig 2 ). Although multiple tests were performed, this was done as a planned evaluation and not post hoc; therefore, corrections for multiple tests were not performed. Individual results displaying statistical significance may require further study.


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  		Table 6. Evaluation of Nocturnal Desaturators by the Best Determined Cut Point*

 

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  		Table 7. Difference in Proportion of Desaturators and Nondesaturators for Various Categorical Variables

 

Figure 1
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  		Figure 1. Difference in proportion of desaturators and nondesaturators within each level of several ROC cut points. HB = hemoglobin; MVO2 = myocardial oxygen consumption; O2 need 6MW = oxygen required during the 6MW; p values calculated using one-sample test for single proportion; RSVP = right ventricular systolic pressure.

 

Figure 2
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  		Figure 2. Difference in proportion of desaturators and nondesaturators by cut points believed to denote a worse prognosis; p values calculated using one-sample test for single proportion. See Figure 1 for expansion of abbreviations.

 
Results

Baseline Characteristics and Severity of Nocturnal Desaturation Among Desaturators
Forty-three consecutive patients who met inclusion criteria and gave consent underwent nocturnal oximetry between 2002 and June 2005. Table 1 describes the characteristics of the study population. The etiology of PAH included IPAH (n = 38, 88%) and PAH associated with connective tissue diseases (n = 5, 12%). Thirty patients (69.7%) had significant nocturnal hypoxia (> 10% TST with SpO2 < 90%). Eighty-seven percent of nocturnal desaturators (26 of 30 patients) spent > 20% of TST with SpO2 < 90% (Table 2). TST < 85% was not available for one patient.

Baseline and Hemodynamic Characteristics of Desaturators and Nondesaturators
Table 3 compares the desaturators and nondesaturators based on their baseline demographic and treatment characteristics. Desaturators were older (p = 0.024) and had higher hemoglobin levels (p = 0.002). Two patients died, and both were nocturnal desaturators. Patients who desaturated had higher levels of brain natriuretic peptide (BNP) [p = 0.004] and lower cardiac index (CI) [p = 0.03; Table 4]. On echocardiography, desaturators were more likely to have moderate or severe right ventricular dilation (p = 0.04) and pericardial effusion.

Comparison of Desaturators and Nondesaturators: Pulmonary Function, Oxygenation, and 6MW Characteristics
Desaturators had lower FVC and FEV1, but there was no difference in diffusion capacity of the lung for carbon monoxide (DLCO) [Table 5]. The desaturators had a lower resting SpO2 on room air, a lower SpO2 nadir during the 6MW (p = 0.009), and a lower 6MWD. Eleven patients who desaturated during the 6MW were nocturnal desaturators, as compared to two nocturnal nondesaturators.

Comparison of Desaturators and Nondesaturators: Difference in Proportion
Table 7 presents the difference in proportion of desaturation within each level of several categorical variables, and the p value represents a test of whether the proportion of desaturators for that variable is different from the proportion of nondesaturators. Among the 40 patients not receiving nocturnal oxygen at baseline, 27 patients (67.5%) were desaturators. Of the 40 patients who underwent a 6MW, 27 patients did not desaturate < 90% during the 6MW; however, 16 of these 27 patients (59%) were nocturnal desaturators. Of the 13 patients who desaturated < 90% during the 6MW, 11 patients (85%) were nocturnal desaturators. Patients with pericardial effusions, moderate or severe right ventricular dilation or dysfunction, and patients receiving epoprostenol therapy were significantly more likely to be nocturnal desaturators than nondesaturators.

Evaluation of Nocturnal Desaturators by the Best Determined Cut Point by ROC Curves
Table 6 presents a comparison of the two groups by the best available cut point on several continuous measures. Nocturnal desaturators tended to be > 46 years of age (p = 0.03), have a CI < 2.6 L/min/m2 (p = 0.04), BNP > 40 pg/mL (p = 0.006), and hemoglobin > 13.6 g/dL (0.001). A body mass index (BMI) > 28 showed a trend toward an increased risk of nocturnal desaturation (p = 0.085). Evaluation of difference in proportion of desaturators and nondesaturators within each level of several ROC cut points (Fig 1) showed that older, overweight patients with poor functional capacity and worse hemodynamics were statistically more likely to be desaturators than nondesaturators.

Figure 2 represents some factors identified in the literature as either indicators of worse prognosis in PH (presence of pericardial effusion, CI < 2 L/min/m2, 6MWD < 330 m),2 potential reason for hypoxia (mixed venous oxygen saturation [SvO2] < 55%),20 or indicator of nocturnal hypoxia (low DLCO).21 All patients with CI < 2 L/min/m2, SvO2 < 55%, DLCO < 50% predicted, and eight of nine patients (89%) with 6MWD < 332 m were nocturnal desaturators (Fig 2).

Overnight Polysomnography
Of the 30 patients with desaturation, 20 patients underwent overnight polysomnography. Only one patient had an apnea index > 20, indicating significant sleep apnea, and two patients had an apnea index > 5. The sleep apnea was not believed by the treating physician to be a significant contributor to the pathogenesis of PH.

Discussion

The most significant findings of our study are that nocturnal hypoxemia is common in patients with PAH, that nocturnal hypoxia is more common in older patients with more advanced PH and right ventricular dysfunction, and that the lack of exertional hypoxia cannot rule out nocturnal hypoxia since approximately 60% of such patients were nocturnal desaturators. This is the first study looking at the prevalence, risk factors, and significance of nocturnal hypoxia in a well-characterized group of patients with PAH with no evidence of significant lung disease. As the first study to show that nocturnal hypoxia in patients with PAH is related to PH severity and right ventricular dysfunction, our study also strengthens the recommendations22 of the American College of Chest Physicians regarding oxygen supplementation in these patients. Demographics showed a young and predominantly female, white population similar to studies2324 of patients with IPAH.

It is well known that people with normal lungs can desaturate during sleep,2526 possibly as a consequence of intercostal muscle hypotonia.27 Multiple mechanisms may contribute to nocturnal hypoxia, including alterations in ventilation perfusion,3 reduced functional residual capacity, reduced respiratory drive,4 and alveolar hypoventilation.5 These mechanisms take on added importance in patients with preexisting pulmonary disease.46 Chronic hypoxia can cause increased cardiac output, erythrocytosis, and pulmonary vasoconstriction resulting in sustained elevations in pulmonary arterial pressure and pulmonary vascular resistance (PVR), right ventricular failure, and death.14152829 A higher hemoglobin level among nocturnal desaturators in our study indicates that the hypoxia was chronic.

Previous reports1213 in COPD patients have suggested that even COPD patients with daytime PaO2 > 60 mm Hg may have nocturnal hypoxia if they have associated PH. It is recommended that nocturnal supplemental oxygen be provided to patients who are hypoxemic while awake and those who are well saturated during the day but desaturate at night and have complications attributable to sleep hypoxia such as PH or cardiac arrhythmias.25 We also feel that the severity of desaturation was moderate to severe in that approximately 20% of desaturators spent > 10% of TST < 85%, and 87% of them spent > 20% of TST with SpO2 < 90%. We speculate that since 23 patients (80%) spent > 10% of TST with SpO2 between 85% and 90%, oxygen supplementation will be able to restore adequate oxygenation during sleep (SpO2 ≥ 90%).

It has been suggested that ventilation-perfusion matching is only minimally altered and shunt is uncommon in PAH not associated with congenital heart disease; therefore, arterial hypoxemia is mild and explained by a low SvO2.20 In our group of patients, there was no significant difference in SvO2 between the desaturators and nondesaturators. However, patients with SvO2 ≤ 68% were more likely to be nocturnal desaturators (p = 0.02), and the three patients with SvO2 < 55% were all nocturnal desaturators. This indicates that although patients with low SvO2 are more likely to be nocturnal desaturators, even those patients with higher SvO2 may desaturate during sleep.

Even though pulmonary function was normal in both groups, desaturators had significantly lower FEV1 and FVC than nondesaturators. A study21 in COPD patients found that a DLCO > 55% was 100% specific in excluding exercise desaturators. Among our group of patients, there was no significant difference in DLCO between desaturators and nondesaturators. Of the nocturnal desaturators, 21 of 30 patients (70%) had DLCO > 55% and 17 of 30 patients (57%) had DLCO > 70%. However, none of the nondesaturators had DLCO < 60%, so that all patients with DLCO < 60% were nocturnal desaturators. From this we can conclude that patients with DLCO < 60% are at a higher risk of desaturating during sleep, but even patients with "normal" DLCO are at risk of nocturnal desaturation. Although this study sheds some light on potential mechanisms, the exact mechanism for nocturnal hypoxia in PAH patients remains elusive. Other mechanisms such as reduced functional residual capacity in the supine position, and central hypoventilation that can occur in patients with left ventricular dysfunction may also play a role in these patients. At least one study30 has pointed to the increased prevalence of respiratory muscle weakness in patients with PAH. These are important potential mechanisms for nocturnal hypoxia, and their etiologic or exacerbating role in patients with PAH awaits further study.

There was no significant difference in terms of 6MWD between the two groups, and 16 of 27 nocturnal desaturators (60%) did not desaturate during the 6MW. Of the 13 patients who desaturated during the 6MW, 11 patients (85%) were nocturnal desaturators. As such, in patients with PAH, desaturation during the 6MW is a good indicator of high risk for nocturnal desaturation, but lack of desaturation during the 6MW cannot be taken as an indicator of lack of oxygen need during sleep.

Previous studies31 have identified demographic covariates such as age as important predictors of survival. In our study, older patients were more likely to be nocturnal desaturators. A comparison of hemodynamic variables indicated that nocturnal desaturators had more advanced PH as indicated by higher BNP, more severe right ventricular dilation, and lower CI. A lower CI, higher mean right atrial pressure (mRAP), mean pulmonary artery pressure (mPAP), and PVR, and the presence of pericardial effusion have all been shown to denote a worse prognosis in patients with PAH.24323334 Our study indicates that the presence of nocturnal desaturation in the absence of parenchymal lung disease or sleep apnea correlates with measures that indicate a worse prognosis and may serve as an indirect measure of prognosis. Further, long-term studies are needed to clarify this issue. The two patients who died over the course of our study period were nocturnal desaturators.

Nocturnal oximetry testing may be considered as part of the initial evaluation of patients with PAH who do not desaturate with their 6MW. This is because approximately two thirds of the patients without significant airways or parenchymal lung disease showed significant nocturnal desaturation, and more than half of them did not desaturate during the 6MW. This would help identify those who could benefit from nocturnal oxygen supplementation with the potential for long-term hemodynamic benefit. The utility of long-term oxygen supplementation in improving pulmonary hemodynamics in patients with chronic hypoxia has been fairly well characterized in patients with COPD.2829 The implications of nocturnal hypoxemia in terms of long-term prognosis await further study.

Conclusions

Our study shows that nocturnal hypoxemia is common in patients with PAH and that a lack of exertional hypoxia cannot rule out nocturnal hypoxia and should not be used as a surrogate marker of lack of nocturnal desaturation in these patients. Among our group of patients, nocturnal hypoxia correlated with more advanced PH and right ventricular dysfunction. The inclusion of overnight oximetry, and oxygen supplementation if needed, may be warranted in the routine workup of patients with PAH. Larger studies are required to document the implications of chronic hypoxia in PAH, and to clarify the potential benefits of treating nocturnal hypoxia with long-term oxygen supplementation.

Footnotes

Abbreviations: 6MW = 6-min walk test; 6MWD = 6-min walk test distance; BMI = body mass index; BNP = brain natriuretic peptide; CI = cardiac index; DLCO = diffusion capacity for of the lung for carbon monoxide; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; mRAP = mean right atrial pressure; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; ROC = receiver operator characteristic; SpO2 = oxygen saturation by pulse oximetry; SvO2 = mixed venous oxygen saturation; TST = total sleep time

The authors have no personal or financial conflicts of interest to disclose.

Received for publication May 31, 2006. Accepted for publication August 4, 2006.

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S. Ulrich, M. Fischler, R. Speich, and K. E. Bloch
Sleep-Related Breathing Disorders in Patients With Pulmonary Hypertension
Chest, June 1, 2008; 133(6): 1375 - 1380.
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