Daytime Pulmonary Hypertension in Patients with Obstructive Sleep Apnea
The Effect of Continuous Positive Airway Pressure on Pulmonary HemodynamicsAlchanatis M.a · Tourkohoriti G.a · Kakouros S.b · Kosmas E.a · Podaras S.a · Jordanoglou J.B.a
aPulmonary Department, Athens University Medical School and bCardiology Department, ‘Sotiria’ Hospital for Chest Diseases, Athens, Greece Corresponding Author
Background: Limited information exists regarding the development of pulmonary hypertension in patients with obstructive sleep apnea (OSA) in the absence of lung and heart comorbidity. Objectives: The aims of this study were to investigate whether OSA patients without any other cardiac or lung disease develop pulmonary hypertension, and to assess the effect of continuous positive airway pressure (CPAP) treatment on pulmonary artery pressure (PPA). Methods: Twenty-nine patients aged 51 ± 10 years with OSA and 12 control subjects were studied with pulsed-wave Doppler echocardiography for estimation of PPA before and after 6-month effective treatment with CPAP. Results: A significantly higher mean PPA was found in OSA patients as compared to control subjects (17.2 ± 5.2 vs. 12.1 ± 1.9 mm Hg, p < 0.001). Six out of the 29 OSA patients had mild pulmonary hypertension (PPA ≥ 20 mm Hg). Significant differences were observed between pulmonary hypertensive and normotensive OSA patients with respect to age (62 ± 4 vs. 48 ± 15 years, respectively, p < 0.05), body mass index (41 ± 7 vs. 32 ± 4 kg/m2, p < 0.02) and daytime PaO2 (81 ± 9 vs. 92 ± 9 mm Hg, p < 0.05). CPAP treatment was effective in reducing mean PPA in both groups of pulmonary hypertensive and normotensive OSA patients (decreases in PPA from 25.6 ± 4.0 to 19.5 ± 1.5 mm Hg, p < 0.001; from 14.9 ± 2.2 to 11.5 ± 2.0 mm Hg, respectively, p < 0.001). Conclusions: A proportion (20.7%) of OSA patients without any other lung or heart disease and characterized by older age, greater obesity and lower daytime oxygenation develop mild pulmonary hypertension which has been partially or completely reversed after 6-month CPAP treatment. In conclusion, OSA alone constitutes an independent risk factor for the development of pulmonary hypertension.
Copyright © 2001 S. Karger AG, Basel
Acute increases in pulmonary artery pressure (PPA) secondary to repeated episodes of upper airway obstruction and alveolar hypoxia during sleep have been documented in patients with obstructive sleep apnea (OSA) syndrome [1, 2]. Furthermore, several investigators have reported sustained daytime pulmonary hypertension among OSA patients; however, the majority of these studies have included patients with coexisting lung disease and daytime hypoxemia [3, 4]. There is limited information regarding the development of pulmonary hypertension in the absence of lung comorbidity, and, most importantly, the response of PPA to the treatment with nasal continuous positive airway pressure (nCPAP).
It is possible that the occurrence of apneic episodes during sleep in patients with coexisting cardiac or pulmonary disease promotes the appearance of cardiac or respiratory failure . However, it is of great importance, to demonstrate whether OSA alone constitutes an independent risk factor for the development of pulmonary hypertension and, thus, for increased cardiovascular morbidity and mortality . Furthermore, and if this is the case, a clinically important question that should be addressed is whether the effective treatment of OSA with nCPAP results in a normalization of pulmonary hemodynamics.
Hence, the aim of our study was 2-fold: firstly, to investigate the possibility that OSA patients without any other active cardiac or lung disease exhibit pulmonary hypertension, and secondly, to assess the effect of nCPAP treatment on PPA.
patients and methods
Patients enrolled in the study fulfilled the following inclusion criteria: (1) polysomnographic diagnosis of OSA with an apnea-hypopnea index (AHI) >15 events·h–1, (2) no clinical or laboratory (chest X-ray, lung function testing) evidence of chronic lung disease, (3) absence of cor pulmonale, myocardial, pericardial or valvular disease and arrhythmias based on clinical and laboratory (chest X-ray, electrocardiogram, echocardiography) grounds, (4) daytime normoxemia and normocapnia, and (5) compliance with nCPAP treatment. The study was approved by the Institutional Ethics Committee and written informed consent was given by all patients.
The population of the study (fig. 1) consisted of patients referred to the Sleep Laboratory of the Pulmonary Department, Athens University Medical School, for a suspected diagnosis of OSA on clinical grounds. Between January 1998 and March 1999, 35 patients met the inclusion criteria. During the follow-up period 1 patient died of acute pancreatitis and ARDS, 1 patient did not comply with nCPAP treatment after the 2nd month and 2 patients refused to come to the last follow-up visit. In addition, Doppler estimation of PPA was not possible in 2 patients because of obesity-related echogenicity problems.
Fig. 1. Patient population of the study and study design. OREP = Patients excluded due to obesity-related echogenicity problems.
Finally, a total of 29 patients (19 males; 10 females) aged 51 ± 10 years (mean ± SD) who satisfied the above-mentioned inclusion criteria and agreed to participate were included in the study. Furthermore, 12 normal subjects (7 males; 5 females) referred to our laboratory for snoring but without proven OSA and matched for age, body mass index (BMI) and smoking history were included in the study as the control group.
Patients gave a detailed medical history and were clinically examined. They underwent arterial blood gas analysis and spirometry before and after bronchodilation. Spirometric values of FEV1 and FVC < 75% of predicted, an FEV1/FVC ratio < 75% and a postbronchodilation increase in FEV1 >10% of baseline value were all taken as exclusion criteria. Furthermore, all subjects underwent a routine cardiological evaluation (electrocardiogram, echocardiography) in order to rule out patients with heart comorbidity, such as left-sided heart diseases causing secondary pulmonary hypertension (congenital heart disease, mitral and aortic valvular disease, coronary artery disease, cardiomyopathy). Arterial hypertension was not necessarily a cause of exclusion, unless it was uncontrollable or had caused left heart failure. Full-night diagnostic polysomnography  with recordings of electroencephalogram (C4/A1, C3/A2), electrooculogram, chin electromyogram, electrocardiogram, nasal and mouth flow, rib cage and abdominal wall displacement, oxygen saturation, snoring and leg movements was performed in all patients and control subjects (Medilog SAC, Oxford, UK).
During the next day, all patients and control subjects underwent a two-dimensional, pulse-waved, color-flow Doppler echocardiography (ATL 9) of the right-sided heart (right atrium, tricuspid valve, right ventricle, pulmonary valve and artery) in parasternal long-axis, short-axis, short-axis cross section of the base of the heart and apical four-chamber view, in order to evaluate the right heart performance and to calculate the mean PPA. When tricuspid regurgitation was recorded with color-flow Doppler, the maximum velocity (V) of tricuspid incompetence was calculated with a continuous Doppler study of at least four consecutive beats . Right ventricle pressure (RVP) was derived using the equation RVP = 4 V2 + RAP (RAP = right atrial pressure). The estimated RVP is considered to represent the PPA if there is no evidence of pulmonary valvular dysfunction .
The accuracy of Doppler echocardiography in assessing mean PPA was validated by right heart catheterization. The procedure was carried out immediately after Doppler echocardiography and only in the 29 patients with a diagnosis of OSA. The measurements were obtained with the patient at rest in the supine position. After a right subclavicular approach, the fluid-filled catheter (Gould P23 strain gauge) was advanced into the right atrium, right ventricle and main pulmonary artery measuring systolic and diastolic pressures and finally into the pulmonary capillaries measuring wedge pressure. Mean PPA was calculated from the equation: mean PPA = (syst. PPA + 2 × diast. PPA)/3. A mean PPA ≥20 mm Hg was considered as evidence of pulmonary hypertension [6, 10].
All OSA patients underwent a second full-night polysomnography with CPAP for titration of the optimal pressure needed to eliminate apneas and hypopneas as well as oxygen desaturation episodes. During the next day, patients were discharged from the hospital and an nCPAP device equipped with an internal time counter was given for treatment at home. During the treatment period, all patients were followed up on a monthly basis at the outpatient Sleep Clinic while the daily use of CPAP was assessed according to the internal time counter. The difference in the time counterreadings in hours divided by the duration of the treatment in days was used for the estimation of the mean daily use of CPAP at every visit. At the end of the study the mean daily CPAP use was 5.4 h/night (range 4.2–7.5 h/night).
After CPAP treatment for at least 6 months (mean duration of CPAP use 7.6 months, range 6.0–10.7 months), all OSA patients were reevaluated with polysomnography (with nCPAP), arterial blood gas analysis, pulmonary function testing and pulsed Doppler echocardiography for reestimation of mean PPA.
Measurements are expressed as mean values ± SD. Results were analyzed using the unpaired t test for comparisons between groups of subjects and the paired t test or Wilcoxon signed rank test for comparisons between measurements (PPA) before and after CPAP treatment. Linear regression analysis was used to assess the strength of correlations between mean PPA and different variables. Statistics were carried out with a commercially available statistical software (StatView for Macintosh). Statistical significance was set at the level of p < 0.05.
Anthropometric and lung function data as well as AHI and mean PPA estimate by Doppler echocardiography and by Swan-Ganz right heart catheterization (only in OSA patients) in OSA patients and control subjects are shown in table 1. In OSA patients the mean PPA measured by Swan-Ganz right heart catheterization was 16.9 ± 5.4 mm Hg and the mean PPA estimated by echocardiography was 17.2 ± 5.2 mm Hg. A very tight correlation with characteristics of an identity line (fig. 2) was evident between those two PPA values (r2 = 0.957, p < 0.001, y intercept = 1.546, slope of regression line = 0.927). Since Doppler echocardiography-derived PPA proved to be a valid and accurate means of directly measured PPA, right heart catheterization was not performed in the control group and in the reevaluation study of the 29 OSA patients after 6-month CPAP treatment.
Fig. 2. A strong correlation is evident between Swan-Ganz-measured PPA and Doppler-derived PPA. The correlation has the characteristics of an identity line (y intercept = 1.546, slope of regression line = 0.927). Every square symbol represents a pair of PPA values for each OSA patient.
Table 1. Anthropometric characteristics, lung function data, AHI and mean PPA estimate by Doppler echocardiography in OSA patients and control subjects
A significantly higher mean PPA was found in OSA patients (17.2 ± 5.2 mm Hg) as compared to control subjects (12.1 ± 1.9 mm Hg, p < 0.001, table 1). Strong correlations were evident between mean PPA and age (r2 = 0.390, p < 0.001), BMI (r2 = 0.539, p < 0.001) and daytime PaO2 (r2 = 0.293, p < 0.01) in the whole group of the 29 OSA patients.
Based on the Doppler PPA values and by using a cutoff limit of 20 mm Hg [3, 4, 15, 16], OSA patients were classified into those with pulmonary hypertension (PH group, n = 6 patients, mean Doppler PPA = 25.6 ± 4.0 mm Hg, range 22–30 mm Hg) and those without pulmonary hypertension (non-PH group, n = 23 patients, mean Doppler PPA = 14.9 ± 2.2 mm Hg, range 11–19 mm Hg). However, even in the non-PH group of pulmonary normotensive OSA patients, mean PPA was significantly higher as compared to the mean PPA of the control subjects (14.9 ± 2.2 vs. 12.1 ± 1.9 mm Hg, respectively, p < 0.05). Comparisons between the two groups (PH and non-PH) in anthropometric characteristics, gas exchange, lung function and polysomnographic parameters are depicted in table 2. Significant differences were observed between PH and non-PH groups of OSA patients regarding age (62 ± 4 vs. 48 ± 15 years; p < 0.05), BMI (41 ± 7 vs. 32 ± 4 kg/m2; p < 0.02), daytime PaO2 (81 ± 9 vs. 92 ± 9 mm Hg; p < 0.05). Interestingly, no significant differences have been found between the two groups in respect to AHI, lowest oxygen saturation (SpO2) during sleep and the number of desaturation events throughout the night (table 2).
Table 2. Anthropometric, lung function, polysomnographic and hemodynamic data in OSA patients with (PH group) and without pulmonary hypertension (non-PH group)
The impact of the 6-month CPAP treatment on pulmonary hemodynamics is shown in table 3. The mean PPA decreased from 17.2 ± 5.2 to 13.2 ± 3.8 mm Hg (p < 0.001) in the whole OSA patient population without any significant influence on BMI (34 ± 6 kg/m2 before and 33 ± 6 kg/m2 after nCPAP treatment). The CPAP treatment was equally effective in reducing mean PPA in both groups of OSA patients with PH (from 25.6 ± 4.0 to 19.5 ± 1.6 mm Hg, p < 0.001) and without PH (from 14.9 ± 2.2 to 11.5 ± 2.0 mm Hg, p < 0.001). Only 2 out of the 6 pulmonary hypertensive patients remained with a PPA ≥20 mm Hg, while the mean PPA in the non-PH group was completely normalized. The individual changes in mean PPA before and after nCPAP treatment are depicted in figure 3. It is apparent that the CPAP-related decrease in PPA was observed consistently in every single OSA patient regardless of whether there were any abnormalities of the baseline (pretreatment) pulmonary hemodynamics.
Table 3. Mean PPA in OSA patients with and without pulmonary hypertension before and after 6-month CPAP treatment
Fig. 3. Individual changes in PPA before and after 6-month CPAP treatment. It is obvious that CPAP treatment results in a consistent reduction in PPA in all OSA patients regardless of the existence of baseline pulmonary hypertension. Every line between the two square symbols represents the PPA change before and after CPAP in an OSA patient.
The main findings of this study were (1) a substantial proportion (20.7%) of patients with OSA and without any other primary lung or cardiac disease exhibits mild daytime pulmonary hypertension at rest, (2) the emergence of pulmonary hypertension seems to be related to older age, greater BMI and daytime blood oxygenation, (3) PPA in OSA patients without pulmonary hypertension, although within normal limits, was higher as compared to control subjects without OSA, (4) treatment with nCPAP for at least 6 months resulted in a consistent and relatively equal decrease of PPA in all OSA patients regardless of the existence or not of a pretreatment pulmonary hypertension.
A collateral endpoint of our study is that pulsed-wave Doppler echocardiography is a valid method of assessing mean PPA with a great degree of accuracy and reliability as compared to Swan-Ganz right heart catheterization. Right heart catheterization has been recognized as the ‘gold standard’ method in assessing pulmonary hemodynamics. However, this method is costly, invasive and it is not easily performed in everyday clinical practice. Furthermore, it is reasonable to assume that a substantial number of patients would refuse to undergo right heart catheterization because of the invasiveness of the procedure. There are previous reports that Doppler echocardiography offers a reliable noninvasive alternative in estimating PPA [11, 12, 13]. The results of our study have shown that PPA measurements with either Swan-Ganz catheterization or Doppler echocardiography are in close agreement and, hence, Doppler echocardiography is a reliable method of PPA estimation.
The prevalence of pulmonary hypertension in OSA patients has been investigated thoroughly in the past [3, 4, 14, 15]. However, all the above studies included patients with concomitant chronic lung disease, and, subsequently, the independent impact of OSA on pulmonary hemodynamics has not been clearly shown. Our study was done in OSA patients without any clinical or laboratory evidence of chronic lung or cardiac disease and a proportion of patients (6 out of 29, 20.7%) was identified with a resting mild elevation of mean PPA. The findings of our study are in agreement with those from other studies conducted in OSA patients in the absence of chronic pulmonary disease. Sanner et al.  documented that 18 out of 92 OSA patients (20%) presented pulmonary hypertension while Sajkov et al. [17, 18] reported a higher prevalence of pulmonary hypertension (34–41%) in OSA patients with normal lung function.
We demonstrated significant correlations between PPA and age, BMI and daytime PaO2. The OSA patients with pulmonary hypertension were older, more overweight and had lower, although within normal range, daytime PaO2 as compared to the OSA patients without pulmonary hypertension. We may postulate that daytime hypoxemia, even of a mild degree, may have pathogenic significance in causing pulmonary hypertension through the mechanism of hypoxic vasoconstriction. Left ventricular dysfunction has been excluded as a possible mechanism causing pulmonary hypertension since wedge pressure was within normal limits in all of our patients. Furthermore, the observed link between pulmonary hypertension and BMI implies that obesity-related hypoventilation may play a contributing role in the emergence of mild daytime hypoxemia and subsequently of mild pulmonary hypertension. Similarly, Laaban et al.  have demonstrated a correlation between BMI, mild daytime hypoxemia and mild pulmonary hypertension in patients with OSA. In contrast, Sajkov et al.  have reported no difference in BMI between OSA patients with and without pulmonary hypertension; however, the patients in this study were significantly less obese.
Several studies in OSA patients, but with chronic lung disease, have documented correlations between OSA severity (expressed as AHI) and the occurrence of pulmonary hypertension [3, 15]. However, our study in non-COPD patients with OSA failed to demonstrate any correlation between the elevation in PPA and the OSA severity (AHI) or the degree and the duration of nocturnal hypoxemia. Our results are in accordance with other studies [17, 18], which have shown that there was no difference in nocturnal oxygenation indices and OSA severity between patients with and without pulmonary hypertension.
The role of OSA in developing pulmonary hypertension is strengthened by our findings after 6 months of CPAP treatment. A significant drop in mean PPA has been documented in every single OSA patient regardless of the existence of pretreatment pulmonary hypertension. The reduction in mean PPA was observed without any change in BMI of the patients. In contrast, there are other studies with negative results in terms of the effect of CPAP treament on pulmonary hemodynamics [20, 21]; however, these studies have included OSA patients with COPD as well and it is possible that these patients have fixed pulmonary hypertension due to structural changes and remodeling of pulmonary vasculature. One might speculate that CPAP treatment may prevent further increases in PPA in such a cohort of patients with COPD and OSA.
In summary, the present study has shown that a significant proportion of OSA patients without any other lung or cardiac disease develop mild pulmonary hypertension which has been partially or completely reversed after effective 6-month CPAP treatment. We conclude that OSA is an independent risk factor for the development of pulmonary hypertension. Since pulmonary hypertension has been observed in older and more overweight patients with lower daytime PaO2, it is possible that mild hypoxemia due to the obesity-hypoventilation syndrome may play a role. Effective treatment with CPAP remarkably lowers PPA and, hence, it has a beneficial effect on reducing the risk of developing pulmonary hypertension and right ventricular failure in OSA patients.
Manos Alchanatis, MD
10 Mpakopoulou Str.
GR–15451 Athens (Greece)
Tel. +30 1 7774163, Fax +30 1 7770423
Received: Received: February 5, 2001
Accepted after revision: May 29, 2001
Number of Print Pages : 7
Number of Figures : 3, Number of Tables : 3, Number of References : 21
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