Lung (2015) 193:269–274 DOI 10.1007/s00408-015-9694-x
Continuous Positive Airways Pressure and Uvulopalatopharyngoplasty Improves Pulmonary Hypertension in Patients with Obstructive Sleep Apnoea Maurizio Marvisi • Maurizio Giuseppe Vento • Laura Balzarini • Chiara Mancini • Chiara Marvisi
Received: 17 September 2014 / Accepted: 3 February 2015 / Published online: 14 February 2015 Ó Springer Science+Business Media New York 2015
Abstract Objective Data are sparse regarding the prevalence of pulmonary hypertension (PH) in obstructive sleep apnoea (OSA) patients without COPD and clinically manifest cardiac diseases and the role of continuous positive airway pressure (CPAP) and Uvulopalatopharyngoplasty (UPPP) in normalizing this parameter. Patients/Methods We studied 75 consecutive OSA patients, 55 of them men, using transthoracic echocardiography. A mild PH [pulmonary artery pressure (PAPs) 38.2 ± 6.8] was found in 25 subjects (prevalence 33 %). These patients were divided into two groups: group 1A (n = 17), those treated with CPAP, and group 1B (n = 8), those who have the indication for a UPPP. We scheduled a follow-up at 3, 6 and 9 months. During follow-up, we performed echocardiography, measurement of anthropometric parameters (BMI, neck and waist–hip circumference), and of biochemical parameters (uric acid, fasting glucose, cholesterol, triglycerides) and blood pressure. Results Patients with PH had a higher BMI: 32 ± 6 versus 29 ± 4 (p \ 0.001) and NC: 39.8 ± 4.76 versus 37.14 ± 3.49 (p = 0.003), were predominantly men (72 %) and older: 64 ± 20 versus 55 ± 16 (p = 0.025) and had a significantly higher value of uric acid: 7.91 ± 2.35 versus 6.56 ± 1.31 (p = 0.003). We found a positive correlation between PH and BMI (r = 0.456;
M. Marvisi (&) L. Balzarini C. Mancini C. Marvisi Departments of Internal Medicine, Cardiology and Pneumology, Istituto Figlie di S. Camillo, Cremona, Italy e-mail: [email protected] M. G. Vento Department of Otolaryngology, Ospedale di Vaio, Parma, Italy
p \ 0.001) and between uric acidic and PH (r = 0.636; p \ 0.001). PAPs significantly changed, from 39.8 ± 4.1 to 27.1 ± 4, to 25.2 ± 3.1 and to 22.2 ± 3 mmHg (CI 95 %; 15.09–20.11; p \ 0.001) in group 1A and from 39.5 ± 5.1 to 23.4 ± 3.2, to 23.0 ± 3.1 and to 21.9 ± 2.9 mmHg (CI 95 %; 13.15–22.05; p \ 0.001) in group 1B (difference between the groups p = 0.12). Conclusions PH was frequent in OSA patients and normalized after 6 months with both CPAP and UPPP. A similar trend was noted in diastolic blood pressure. Keywords Pulmonary hypertension Obstructive sleep apnea CPAP Uvulophalathopharingoplasty
Introduction Cardiovascular disturbances are frequent complications in patients with obstructive sleep apnoea (OSA) producing severe morbidity and mortality [1]. An increase in pulmonary artery hypertension (PH) secondary to repeated episodes of upper airway obstruction and alveolar hypoxia during sleep has been documented in patients with OSA syndrome and it is thought to be associated with pulmonary vascular remodelling and increased risk of death. On the other hand, OSA and PH are both linked to the so-called metabolic syndrome (MS), that is, a constellation of obesity, insulin resistance, hypertension and dyslipidemia. Whether PH and pulmonary vascular remodelling in OSAS are reversible with treatment is uncertain: experiments in animals of intermittent hypoxia-related PH indicate that morphological changes are potentially reversible with the abolition of hypoxia [2]. However, there is a paucity of human study in this field.
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In the English language literature, there are very few data regarding the prevalence of PH in OSA patients without COPD and clinically manifest cardiac diseases. On the other hand, there are no data regarding the role of continuous positive airway pressure (CPAP) and Uvulopalatopharyngoplasty (UPPP) in normalizing pulmonary artery pressure (PAP) and parameters forming MS. The goals of this study were (1) to assess the prevalence of PH in OSA patients without pulmonary and cardiac diseases and (2) to evaluate the efficacy of CPAP and UPPP in normalizing PH and some parameters of MS.
Materials and Methods Patient Selection Seventy-five consecutive patients recruited from the sleep lab of our institution (from 2007 to 2012) (group 1) and 20 healthy subjects (group 2) as a control group were recruited for the study. In group 1, fifty-five were men, with a mean age of 55 ± 16; mean BMI was 29 ± 4. The two groups were matched for age, sex and ethnic group. Control subjects were recruited from a list of healthy subjects from our health catchment area that had a routine health test in the previous 3 months. OSA patients fulfilled the following inclusion criteria: (1) apnoea–hypopnoea index (AHI) [ 10/h and excessive daytime sleepiness [Epworth sleepiness scale (ESS) C 10 points] and (2) no previous treatment for OSA. Exclusion criteria were as follows: (1) obstructive or restrictive lung disease demonstrated on pulmonary function testing; (2) left ventricular ejection fraction (EF) \ 45 %, ischaemic or valvular heart disease; (3) connective tissue, thyroid diseases and chronic thromboembolic disease; (4) history of cocaine or appetite suppressant drug use and (5) morbid obesity (body mass index [ 40 Kg/m2). All patients underwent sleep study, pulmonary function testing and transthoracic echocardiogram both at baseline and 30 and 90 days after interventions. The study was approved by the Institutional ethic committee at the hospital, and all subjects gave their written informed consent. Pulmonary Function Test Detailed lung function test, including forced expiratory lung volumes, static lung volumes and single-breath carbon monoxide diffusing capacity (DL co.), was performed in accordance with the American Thoracic Society recommendations using Vmax 22 (Sensormedics, USA). The values were expressed as a percentage of predicted normal.
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Sleep Study A sleep study was performed in all subjects (study group and controls) with a 25-channel portable polysomnography recording device (Somte` PSG. Compumedics. Australia). The data were scored according to the recommendations of the American Academy of Sleep Medicine. Respiratory events were classified as either obstructive or central on the basis of the presence or absence of respiratory effort. Respiratory events were scored as apnoea when there was a cessation of oronasal airflow lasting [10 s. Hypopnoea was defined as a 50 % decrease in oronasal airflow lasting [10 s associated with a fall in arterial oxygen saturation (SaO2) [ 4 % of the preceding baseline level. Mean and maximum night time SaO2, desaturation index and sleep time with SaO2 \ 90 % on nocturnal oximetry were computed. Echocardiography Examinations were performed using high-quality echocardiography (Mod. Megas, Esaote, Biomedica; Florence, Italy). All echocardiograms were performed blindly by experienced cardiologists who were unaware of the patients’ clinical conditions. Systolic PAPs was determined in resting subjects at sea level by the transtricuspid regurgitation method using a modification of Bernoulli’ s equation (DP = 4V2, where P is the systolic transtricuspid gradient and V represents the maximum velocity recorded in the regurgitant jet), a noninvasive technique that shows a good correlation with cardiac catheterization [3]. Measurements of cardiac output (CO) were performed from apical two-dimensional echocardiograms using a modified Simpson technique and multiplying systolic stroke volume by heart rate. To test the extent of inter-observer variability, all patients were analysed after a few minutes by a second investigator who was blinded to the results obtained by the first observer. CPAP Treatment and Monitoring of Compliance The therapeutic pressure required to abolish obstructive apnoeas and hypopneas was manually titrated in the sleep laboratory in all patients. The effective compliance (time spent at the effective pressure, hours of daily use, and days used per month) with nasal CPAP was digitally recorded by a microprocessor and downloaded onto a personal computer. We defined a good compliance as being a daily use [4 h. During the follow-up time, data regarding the AHI and minimal oxygen saturation were taken during CPAP treatment.
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UPPP Treatment All patients underwent a complete otolaryngological assessment and a fibre optic examination with Muller’s manoeuvre to identify areas of airway collapse. In patients with redundant soft palate and uvula, the retropalatal airway is enlarged by excising excess palatal mucosa and by repositioning the tonsillar pillars. In selected patients, we performed a tonsillectomy and a base tongue reduction. The decision to undertake a UPPP was made on clinical grounds after an interdisciplinary meeting involving pulmonologist and otolaryngologist. All surgical procedures were performed by the same surgeon.
Anthropometric Measurements, Clinical Analyses and Blood Pressure All measurements were made by one investigator using standard techniques as follows: (1) neck circumference (NC) at mid-neck height, between mid-cervical spine and mid-anterior neck to within 1 mm; in men with laryngeal prominence (Adam’s apple), it was measured just below the prominence; (2) waist and hip circumferences using plastic tapes, waist midway between the lowest rib and the iliac crest, the patient standing at the end of gentle expiration, and hips at the greater trochanter. All circumference measurements were taken with subjects standing upright and facing the investigator, with the shoulder relaxed. After 12 h fast, blood samples were sent to the clinical biochemistry laboratory for analyses using a BM Hitachi automated clinical chemistry analyzer (Hitachi, Japan) by means of standard biochemical procedures. Blood pressure was measured with a periodically calibrated mercury sphygmomanometer in the sitting position after at least 5 min of rest. The mean of three measurements was recorded. All parameters were evaluated on the day of enrolment and, in accordance with the study follow-up, after 3, 6 and 9 months.
Data Analysis and Statistics Baseline haemodynamic, lung function and gas exchange parameters were compared with corresponding values after 1 and 3 months using analysis of variance (ANOVA) for repeated measurements. Where the F statistic indicated statistical significance, post hoc comparisons were performed using Bonferroni’s method. Student’s t test was used to compare numerical variables (e.g., age, body mass index) between patients with and without PH.
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The agreement between measurements was assessed by the method of the differences against the means according to Bland and Altman . Results are presented as mean ± SEM. A p value\0.05 was considered significant.
Results By design, all routine lung function tests were within the normal range: FEV1 (98 ± 5 % of that predicted in group 1 vs. 97 ± 4 % in group 2; p = 0.41); FEV1/FVC (99 ± 8 % in group 1 vs. 97 ± 5% in group 2; p = 0.29); DLco (101 ± 2.1 % in group 1 vs. 100 ± 3.8 in group 2; p = 0.12). BMI was 28 ± 3.4 in group 1 versus 25 ± 3 (p = 0.002) (Table 1). The EF and CO were 65 ± 8 versus 68 ± 9 (p = 0.15) and 4.96 ± 0.64 L/min versus 4.66 ± 0.76 (p = 0.077), respectively. Interestingly, the group 1 patients had a significantly higher value of PCR, 1.54 ± 1.35 versus 0.63 ± 0.43 (p = 0.004); fasting plasma glucose 113.5 ± 34.1 versus 90.8 ± 17.3 (p = 0.004) and triglyceride 163.9 ± 21.9 versus 146.2 ± 18.9 (p = 0.001) (Table 1). The study group had higher values of systemic diastolic blood pressure: 86.4 ± 9.4 versus 77 ± 9.3 (p = 0.002). A mild PH with a PAPs [ 35 mmHg was found in 25 subjects from group 1 (33 %). Mean PAP values were 38.2 ± 6.8 in group 1 and 21.1 ± 3.0 in group 2, respectively (p \ 0.001) (Fig. 1). The variability was low, with a mean discrepancy of 0.166 mmHg and a standard deviation of 1.32 mmHg. Patients with PH had a higher BMI: 32 ± 6 versus 29 ± 4 (p \ 0.001) and NC: 39.8 ± 4.76 versus 37.14 ± 3.49 (p = 0.003), were predominantly men (72 %) and older: 64 ± 20 versus 55 ± 16 (p = 0.025) and had a significantly higher value of uric acid: 7.91 ± 2.35 versus 6.56 ± 1.31 (p = 0.003). We found a positive correlation between PH and BMI (r = 0.456; Table 1 Anthropometric and metabolic parameters
NC (cm) W/H ratio
Group 1 (n = 75)
Controls (n = 20)
p value
37.14 ± 3.49 1.32 ± 0.55
34.83 ± 2.72 0.96 ± 0.29
0.012 0.006
BMI
28 ± 3.4
25 ± 3
0.002
PCR
1.54 ± 1.35
0.63 ± 0.43
0.004
UA (mg\dl)
6.56 ± 1.31
5.77 ± 1.10
0.016
FG (mg\dl)
113.5 ± 34.1
90.8 ± 17.3
0.004
Colest/HDL
5.74 ± 1.31
4.92 ± 0.94
0.010
Triglyceride
163.9 ± 21.9
146.2 ± 18.9
0.001
NC neck circumference, WH waist/hip ratio, BMI body mass index, PCR c reactive protein, UA uric Acid, FG fasting plasma glucose, Colest/HDL cholesterol/high density lipoprotein ratio
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Fig. 1 Systolic pulmonary artery pressure (PAPs) in OSA patients and in control group
Fig. 2 Correlation between systolic pulmonary artery pressure (PAPs) and body mass index (BMI) in the study Group
p \ 0.001) and between uric acidic and PH (r = 0.636; p \ 0.001) (Figs. 2, 3). Patients with PH were divided into two groups: group 1A (n = 17) including those who were treated with CPAP, and group 1B (n = 8) including those who were treated with UPPP. All CPAP patients used the device for more than 4 h per night. Interestingly, following interventions PAPs returned to baseline values. They significantly changed from 39.8 ± 4.1 to 27.1 ± 4, to 25.2 ± 3.1 and 22.2 ± 3 mmHg (CI 95 %; 15.09– 20.11; p \ 0.001) in group 1A and from 39.5 ± 5.1 to 23.4 ± 3.2, to 23.0 ± 3.1 and to 21.9 ± 2.9 mmHg (CI 95 %; 13.15–22.05; p \ 0.001)) in group 1B (difference between the groups p = 0.12). Similarly, the AHI decreased significantly in both groups, from 59.3 ± 24 to 15 ± 8.1, to 14.0 ± 7.7 and to 10 ± 7 in group 1A (CI 95 %; 36.95–61.65; p \ 0.001) and from 59.5 ± 23.6 to 14.1 ± 5.2, to 12.5 ± 6.0 and to 9.8 ± 6.6 (CI 95 %; 31.12–68.28; p \ 0.001) in group 1B, with no difference between the groups (p = 0.99). A similar trend was registered for the minimal SaO2 min and ESS.
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Fig. 3 Correlation between systolic pulmonary artery pressure (PAPs) and Uric Acid in the study group
The minimal SaO2 min increased from 77.1 ± 9.2 to 89.7 ± 3.3, to 89.1 ± 3.2 and to 89 ± 2.7 in group 1A versus 76.8 ± 9.0 to 89.1 ± 3, to 89.0 ± 3.3 and to 89.2 ± 2.9 in group 1B (p \ 0.001; difference between the groups: p = 0.87). The ESS decreased from 19 ± 5 to 14 ± 3, to 12 ± 2 and to 9 ± 6 in group 1A versus 18 ± 4 to 15 ± 3, to 10 ± 3 and to 8 ± 5 in group 1B (p \ 0.001; difference between the groups: p = 0.38) However, in UPPP patients, BMI decreased more rapidly than in CPAP patients and went from a baseline value of 31 ± 3 to 31 ± 3, to 30 ± 5 and to 30 ± 4 in group 1A versus 31 ± 4 to 25 ± 2, to 27 ± 3 and to 26 ± 4 in group 1B (p = 0.005; difference between the groups: p \ 0.002). The diastolic blood pressure tended to normalize after 3 months in both groups, from 86.5 ± 9.6 to 81.4 ± 3.7 in group 1A (CI 95 %: -0.017, -10.18; p = 0.049) and from 86.3 ± 9.5 to 79.0 ± 2.5 (CI 95 %: -0.14, -14.75; p = 0.05) in group 1B. We did not witness any significant reduction in either group, during the follow-up, in uric acid, PCR, blood pressure or other metabolic parameters.
Discussion Both OSA, with or without PH, and the MS are important cardiovascular risk factors and they may act synergistically. CPAP is the first line treatment for moderately severe OSA and may be useful for treating PH and the MS or metabolic abnormalities associated with OSA [4–6]. On the other hand, UPPP is indicated in a selected phenotype of patients [7]. The role of UPPP in treating the above-mentioned phenomena is unclear. The main findings of this study were as follows: (1) a substantial proportion (33 %) of patients with OSA and without any other primary lung and cardiac disease exhibits
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mild daytime PH at rest; (2) the emergence of PH seems to be related to male sex, older age, high BMI, high NC and serum concentration of uric acid (UA) and (3) treatment with CPAP and UPPP resulted in a normalization of PAPS after only 3 months of treatment. A secondary end point of the study is that OSA patients present a significant increase in many recognized cardiovascular risk factors such as PCR, fasting plasma glucose, triglyceride serum concentration and day time diastolic blood pressure. Of these, only diastolic blood pressure reduces significantly after both treatments (CPAP and UPPP). Previous studies dealing with the prevalence of PH in OSA subjects present values that vary widely from 17 to 52% [1, 6]. The vast majority of early clinical studies suggested that abnormalities in underlying lung function sufficient to induce day time hypoxaemia were required for the development of PH and right-side heart failure. Only four studies, however, checked for the influence of concomitant heart and lung diseases. The pathophysiological mechanism of PH associated with OSA is not fully understood, and this may be due to a combination of precapillary and postcapillary factors including pulmonary arteriolar remodelling, hyper-reactivity to hypoxia, left ventricular diastolic dysfunction and left atrial enlargement [1]. One of the largest published samples to date numbers 220 subjects with OSA, 17 % of whom met the diagnostic criteria for PH [1]. Population-based data are currently lacking. Papers dating back more than three decades have documented increases in PAPs associated with sleep-related hypoxaemia. Coccagna and colleagues continuously measured PAPs during sleep in ten patients with sleep disorder breathing and found sleep stage dependent increases in PAPs, with more marked changes occurring during rapid eye movement sleep [8]. Bady and co-workers reported only precapillary factors in 12 out of 44 patients (27 %) [9]. Sajkov studied 27 patients with OSA. A total of 11 (41 %) were found to have PH, with a mean PAP of 26 mmHg [4]. In this series, those with PH were found to be more hypoxaemic during daytime wakefulness than patients without PH. Treatment in the form of tracheostomy or supplemental oxygen was shown to reduce PH. There are limited data on the effects of CPAP treatment on PH, and to the best of our knowledge this is the only study considering the effect of UPPP. Alchanatis et al studied a group of 29 patients with OSA. A total of 20.7 %. of patients had mild PH. Greater age and increased BMI distinguished these from the patients with OSA without PH. Interestingly, 6 months of CPAP treatment was associated with a reduction in the mean PAP in patients with and without PH [10]. Sajkov and colleagues treated 20 patients with OSA with 4 months of nasal CPAP. Only five patients met the criteria for PH and PAPs; PAPs decreased in all patients to a mean 13.9 mmHg [4].
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Arias et al reported the results of a randomized crossover trial of CPAP and sham CPAP over 12 weeks in 23 patients with OSA, ten of them presenting with PH. He found a direct association between the presence of diastolic dysfunction and PH and, using multiple logistic regression analysis, selected both AHI, BMI and reduced FVC as independent factors related to the development of PH. CPAP therapy reduced PAPs in all patients with OSA (mean reduction was 8.5 vs. 2.6 mmHg in the sham CPAP group) [11]. Furthermore, Minic M et al designing a retrospective cross-sectional analysis of 52 consecutive subjects with known WHO group 1 PH referred for assessment, demonstrated with overnight polysomnography that OSA was present in 71 % of patients. In this population, 56 % had OSA and 44 % central sleep apnoea. They suggested considering a systematic screening, using polysomnography, in subjects with WHO group 1 PH [12]. Interestingly, BMI which positively correlates with PH, decreases more quickly in UPPP patients. The most likely reason for this phenomenon is the most prevalent side effect of UPPP: odynophagia, which induces decreased food intake in the first 3 weeks [13, 14]. Another parameter that shows a correlation with BMI and PH is serum UA, which is a widely available biomarker that increases in chronic respiratory diseases such as OSA, COPD and pulmonary hypertension, especially in the presence of hypoxia and systemic inflammation [15]. Moreover, recent data suggest a potential role of UA as a mediator of cardiovascular morbidity in OSA [16]. Our study has limitations. The control group BMI is lower than that of the study group. We did not perform cardiac catheterization, but it is important to consider that all patients were free of pulmonary symptoms and PH was mild in all subjects. Moreover, the follow-up time was too short and not suitable to evaluate variations in metabolic parameters such as uric acid and PCR. In conclusion, our study confirms the high prevalence of PH in OSA patients (33 %). Risk factors for the development of PH are: male sex, older age, higher BMI and NC, UA concentration in serum. Both CPAP and UPPP reduce PAPs, which in this study normalized after 3 months.
Conflict of interest
We have no conflicts of interest.
References 1. Atwood CW, Mc Crory D, Garcia JGN et al (2004) Pulmonary artery hypertension and sleep disordered breathing. ACCP evidence based clinical practice guidelines. Chest 126:72S–77S
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274 2. Minai OA, Ricaurte B, Kaw R et al (2009) Frequency and impact of pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am J Cardiol 104:1300–1306 3. Naeije R, Torbicki A (1995) More on the non invasive diagnosis of pulmonary hypertension: Doppler echocardiography revisited. Eur Respir J 8:1445–1449 4. Sajkov D, Wang T, Saunders NA et al (2002) Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med 165:152–158 5. Gordon P, Sanders MH (2005) Positive airway pressure therapy for obstructive sleep apnoea/hypopnoea syndrome. Thorax 60:68–75 6. Sun X, Luo J, Xiao J (2014) Continuous positive airway pressure is associated with a decrease in pulmonary artery hypertension in patients with OSA: a meta-analysis. Respirology 19:670–674 7. Braga A, Grechi TH, Eckeli A et al (2013) Predictors of UPPP success in the treatment of obstructive sleep apnoea syndrome. Sleep Med 14:1266–1271 8. Coccagna G, Pollini A, Provini F (2006) Cardiovascular disorders and obstructive sleep apnoea. Clin Exp Hypertens 28:217–224 9. Bady E, Achkar A, Pascal S et al (2000) Pulmonary arterial hypertension in patients with sleep apnoea syndrome. Thorax 55:934–939
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Lung (2015) 193:269–274 10. Alchanatis M, Tourkohoriti G, Kakouros S et al (2001) Daytime pulmonary hypertension in patients with obstructive sleep apnea. The effect of continuous positive airway pressure on pulmonary hemodynamics. Respiration 68:566–572 11. Arias MA, Garcia Rio F, Alfonso Fernandez A et al (2006) Pulmonary hypertension in obstructive sleep apnoea: effects of continuous positive airway pressure. A randomized control crossover study. Eur Heart J 27:1106–1113 12. Minic M, Granton JT, Ryan CM (2014) Sleep disordered breathing in group 1 pulmonary arterial hypertension. J Clin Sleep Med 10:277–283 13. Bhattacharyya N (2014) Revisits and readmissions following ambulatory uvulopalatopharyngoplasty. Laryngoscope. doi:10. 1002/lary.24706 14. Varendh M, Berg S, Andersson M (2012) Long term follow-up of patients operated with UPPP from 1985 to 1991. Respir Med 106:1788–1793 15. Prudon B, Roddy E, Stradling JR et al (2013) Serum urate levels are unchanged with CPAP therapy for OSA: a randomized controlled trial. Sleep Med 14:1419–1421 16. Kanbay A, Inou H, Solak Y et al (2014) Uric acid as a potential mediator of cardiovascular morbidity in obstructive sleep apnea syndrome. Eur J Intern Med 25:471–476
Continuous Positive Airways Pressure and Uvulopalatopharyngoplasty Improves Pulmonary Hypertension in Patients with Obstructive Sleep Apnoea Maurizio Marvisi • Maurizio Giuseppe Vento • Laura Balzarini • Chiara Mancini • Chiara Marvisi
Received: 17 September 2014 / Accepted: 3 February 2015 / Published online: 14 February 2015 Ó Springer Science+Business Media New York 2015
Abstract Objective Data are sparse regarding the prevalence of pulmonary hypertension (PH) in obstructive sleep apnoea (OSA) patients without COPD and clinically manifest cardiac diseases and the role of continuous positive airway pressure (CPAP) and Uvulopalatopharyngoplasty (UPPP) in normalizing this parameter. Patients/Methods We studied 75 consecutive OSA patients, 55 of them men, using transthoracic echocardiography. A mild PH [pulmonary artery pressure (PAPs) 38.2 ± 6.8] was found in 25 subjects (prevalence 33 %). These patients were divided into two groups: group 1A (n = 17), those treated with CPAP, and group 1B (n = 8), those who have the indication for a UPPP. We scheduled a follow-up at 3, 6 and 9 months. During follow-up, we performed echocardiography, measurement of anthropometric parameters (BMI, neck and waist–hip circumference), and of biochemical parameters (uric acid, fasting glucose, cholesterol, triglycerides) and blood pressure. Results Patients with PH had a higher BMI: 32 ± 6 versus 29 ± 4 (p \ 0.001) and NC: 39.8 ± 4.76 versus 37.14 ± 3.49 (p = 0.003), were predominantly men (72 %) and older: 64 ± 20 versus 55 ± 16 (p = 0.025) and had a significantly higher value of uric acid: 7.91 ± 2.35 versus 6.56 ± 1.31 (p = 0.003). We found a positive correlation between PH and BMI (r = 0.456;
M. Marvisi (&) L. Balzarini C. Mancini C. Marvisi Departments of Internal Medicine, Cardiology and Pneumology, Istituto Figlie di S. Camillo, Cremona, Italy e-mail: [email protected] M. G. Vento Department of Otolaryngology, Ospedale di Vaio, Parma, Italy
p \ 0.001) and between uric acidic and PH (r = 0.636; p \ 0.001). PAPs significantly changed, from 39.8 ± 4.1 to 27.1 ± 4, to 25.2 ± 3.1 and to 22.2 ± 3 mmHg (CI 95 %; 15.09–20.11; p \ 0.001) in group 1A and from 39.5 ± 5.1 to 23.4 ± 3.2, to 23.0 ± 3.1 and to 21.9 ± 2.9 mmHg (CI 95 %; 13.15–22.05; p \ 0.001) in group 1B (difference between the groups p = 0.12). Conclusions PH was frequent in OSA patients and normalized after 6 months with both CPAP and UPPP. A similar trend was noted in diastolic blood pressure. Keywords Pulmonary hypertension Obstructive sleep apnea CPAP Uvulophalathopharingoplasty
Introduction Cardiovascular disturbances are frequent complications in patients with obstructive sleep apnoea (OSA) producing severe morbidity and mortality [1]. An increase in pulmonary artery hypertension (PH) secondary to repeated episodes of upper airway obstruction and alveolar hypoxia during sleep has been documented in patients with OSA syndrome and it is thought to be associated with pulmonary vascular remodelling and increased risk of death. On the other hand, OSA and PH are both linked to the so-called metabolic syndrome (MS), that is, a constellation of obesity, insulin resistance, hypertension and dyslipidemia. Whether PH and pulmonary vascular remodelling in OSAS are reversible with treatment is uncertain: experiments in animals of intermittent hypoxia-related PH indicate that morphological changes are potentially reversible with the abolition of hypoxia [2]. However, there is a paucity of human study in this field.
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In the English language literature, there are very few data regarding the prevalence of PH in OSA patients without COPD and clinically manifest cardiac diseases. On the other hand, there are no data regarding the role of continuous positive airway pressure (CPAP) and Uvulopalatopharyngoplasty (UPPP) in normalizing pulmonary artery pressure (PAP) and parameters forming MS. The goals of this study were (1) to assess the prevalence of PH in OSA patients without pulmonary and cardiac diseases and (2) to evaluate the efficacy of CPAP and UPPP in normalizing PH and some parameters of MS.
Materials and Methods Patient Selection Seventy-five consecutive patients recruited from the sleep lab of our institution (from 2007 to 2012) (group 1) and 20 healthy subjects (group 2) as a control group were recruited for the study. In group 1, fifty-five were men, with a mean age of 55 ± 16; mean BMI was 29 ± 4. The two groups were matched for age, sex and ethnic group. Control subjects were recruited from a list of healthy subjects from our health catchment area that had a routine health test in the previous 3 months. OSA patients fulfilled the following inclusion criteria: (1) apnoea–hypopnoea index (AHI) [ 10/h and excessive daytime sleepiness [Epworth sleepiness scale (ESS) C 10 points] and (2) no previous treatment for OSA. Exclusion criteria were as follows: (1) obstructive or restrictive lung disease demonstrated on pulmonary function testing; (2) left ventricular ejection fraction (EF) \ 45 %, ischaemic or valvular heart disease; (3) connective tissue, thyroid diseases and chronic thromboembolic disease; (4) history of cocaine or appetite suppressant drug use and (5) morbid obesity (body mass index [ 40 Kg/m2). All patients underwent sleep study, pulmonary function testing and transthoracic echocardiogram both at baseline and 30 and 90 days after interventions. The study was approved by the Institutional ethic committee at the hospital, and all subjects gave their written informed consent. Pulmonary Function Test Detailed lung function test, including forced expiratory lung volumes, static lung volumes and single-breath carbon monoxide diffusing capacity (DL co.), was performed in accordance with the American Thoracic Society recommendations using Vmax 22 (Sensormedics, USA). The values were expressed as a percentage of predicted normal.
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Sleep Study A sleep study was performed in all subjects (study group and controls) with a 25-channel portable polysomnography recording device (Somte` PSG. Compumedics. Australia). The data were scored according to the recommendations of the American Academy of Sleep Medicine. Respiratory events were classified as either obstructive or central on the basis of the presence or absence of respiratory effort. Respiratory events were scored as apnoea when there was a cessation of oronasal airflow lasting [10 s. Hypopnoea was defined as a 50 % decrease in oronasal airflow lasting [10 s associated with a fall in arterial oxygen saturation (SaO2) [ 4 % of the preceding baseline level. Mean and maximum night time SaO2, desaturation index and sleep time with SaO2 \ 90 % on nocturnal oximetry were computed. Echocardiography Examinations were performed using high-quality echocardiography (Mod. Megas, Esaote, Biomedica; Florence, Italy). All echocardiograms were performed blindly by experienced cardiologists who were unaware of the patients’ clinical conditions. Systolic PAPs was determined in resting subjects at sea level by the transtricuspid regurgitation method using a modification of Bernoulli’ s equation (DP = 4V2, where P is the systolic transtricuspid gradient and V represents the maximum velocity recorded in the regurgitant jet), a noninvasive technique that shows a good correlation with cardiac catheterization [3]. Measurements of cardiac output (CO) were performed from apical two-dimensional echocardiograms using a modified Simpson technique and multiplying systolic stroke volume by heart rate. To test the extent of inter-observer variability, all patients were analysed after a few minutes by a second investigator who was blinded to the results obtained by the first observer. CPAP Treatment and Monitoring of Compliance The therapeutic pressure required to abolish obstructive apnoeas and hypopneas was manually titrated in the sleep laboratory in all patients. The effective compliance (time spent at the effective pressure, hours of daily use, and days used per month) with nasal CPAP was digitally recorded by a microprocessor and downloaded onto a personal computer. We defined a good compliance as being a daily use [4 h. During the follow-up time, data regarding the AHI and minimal oxygen saturation were taken during CPAP treatment.
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UPPP Treatment All patients underwent a complete otolaryngological assessment and a fibre optic examination with Muller’s manoeuvre to identify areas of airway collapse. In patients with redundant soft palate and uvula, the retropalatal airway is enlarged by excising excess palatal mucosa and by repositioning the tonsillar pillars. In selected patients, we performed a tonsillectomy and a base tongue reduction. The decision to undertake a UPPP was made on clinical grounds after an interdisciplinary meeting involving pulmonologist and otolaryngologist. All surgical procedures were performed by the same surgeon.
Anthropometric Measurements, Clinical Analyses and Blood Pressure All measurements were made by one investigator using standard techniques as follows: (1) neck circumference (NC) at mid-neck height, between mid-cervical spine and mid-anterior neck to within 1 mm; in men with laryngeal prominence (Adam’s apple), it was measured just below the prominence; (2) waist and hip circumferences using plastic tapes, waist midway between the lowest rib and the iliac crest, the patient standing at the end of gentle expiration, and hips at the greater trochanter. All circumference measurements were taken with subjects standing upright and facing the investigator, with the shoulder relaxed. After 12 h fast, blood samples were sent to the clinical biochemistry laboratory for analyses using a BM Hitachi automated clinical chemistry analyzer (Hitachi, Japan) by means of standard biochemical procedures. Blood pressure was measured with a periodically calibrated mercury sphygmomanometer in the sitting position after at least 5 min of rest. The mean of three measurements was recorded. All parameters were evaluated on the day of enrolment and, in accordance with the study follow-up, after 3, 6 and 9 months.
Data Analysis and Statistics Baseline haemodynamic, lung function and gas exchange parameters were compared with corresponding values after 1 and 3 months using analysis of variance (ANOVA) for repeated measurements. Where the F statistic indicated statistical significance, post hoc comparisons were performed using Bonferroni’s method. Student’s t test was used to compare numerical variables (e.g., age, body mass index) between patients with and without PH.
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The agreement between measurements was assessed by the method of the differences against the means according to Bland and Altman . Results are presented as mean ± SEM. A p value\0.05 was considered significant.
Results By design, all routine lung function tests were within the normal range: FEV1 (98 ± 5 % of that predicted in group 1 vs. 97 ± 4 % in group 2; p = 0.41); FEV1/FVC (99 ± 8 % in group 1 vs. 97 ± 5% in group 2; p = 0.29); DLco (101 ± 2.1 % in group 1 vs. 100 ± 3.8 in group 2; p = 0.12). BMI was 28 ± 3.4 in group 1 versus 25 ± 3 (p = 0.002) (Table 1). The EF and CO were 65 ± 8 versus 68 ± 9 (p = 0.15) and 4.96 ± 0.64 L/min versus 4.66 ± 0.76 (p = 0.077), respectively. Interestingly, the group 1 patients had a significantly higher value of PCR, 1.54 ± 1.35 versus 0.63 ± 0.43 (p = 0.004); fasting plasma glucose 113.5 ± 34.1 versus 90.8 ± 17.3 (p = 0.004) and triglyceride 163.9 ± 21.9 versus 146.2 ± 18.9 (p = 0.001) (Table 1). The study group had higher values of systemic diastolic blood pressure: 86.4 ± 9.4 versus 77 ± 9.3 (p = 0.002). A mild PH with a PAPs [ 35 mmHg was found in 25 subjects from group 1 (33 %). Mean PAP values were 38.2 ± 6.8 in group 1 and 21.1 ± 3.0 in group 2, respectively (p \ 0.001) (Fig. 1). The variability was low, with a mean discrepancy of 0.166 mmHg and a standard deviation of 1.32 mmHg. Patients with PH had a higher BMI: 32 ± 6 versus 29 ± 4 (p \ 0.001) and NC: 39.8 ± 4.76 versus 37.14 ± 3.49 (p = 0.003), were predominantly men (72 %) and older: 64 ± 20 versus 55 ± 16 (p = 0.025) and had a significantly higher value of uric acid: 7.91 ± 2.35 versus 6.56 ± 1.31 (p = 0.003). We found a positive correlation between PH and BMI (r = 0.456; Table 1 Anthropometric and metabolic parameters
NC (cm) W/H ratio
Group 1 (n = 75)
Controls (n = 20)
p value
37.14 ± 3.49 1.32 ± 0.55
34.83 ± 2.72 0.96 ± 0.29
0.012 0.006
BMI
28 ± 3.4
25 ± 3
0.002
PCR
1.54 ± 1.35
0.63 ± 0.43
0.004
UA (mg\dl)
6.56 ± 1.31
5.77 ± 1.10
0.016
FG (mg\dl)
113.5 ± 34.1
90.8 ± 17.3
0.004
Colest/HDL
5.74 ± 1.31
4.92 ± 0.94
0.010
Triglyceride
163.9 ± 21.9
146.2 ± 18.9
0.001
NC neck circumference, WH waist/hip ratio, BMI body mass index, PCR c reactive protein, UA uric Acid, FG fasting plasma glucose, Colest/HDL cholesterol/high density lipoprotein ratio
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Fig. 1 Systolic pulmonary artery pressure (PAPs) in OSA patients and in control group
Fig. 2 Correlation between systolic pulmonary artery pressure (PAPs) and body mass index (BMI) in the study Group
p \ 0.001) and between uric acidic and PH (r = 0.636; p \ 0.001) (Figs. 2, 3). Patients with PH were divided into two groups: group 1A (n = 17) including those who were treated with CPAP, and group 1B (n = 8) including those who were treated with UPPP. All CPAP patients used the device for more than 4 h per night. Interestingly, following interventions PAPs returned to baseline values. They significantly changed from 39.8 ± 4.1 to 27.1 ± 4, to 25.2 ± 3.1 and 22.2 ± 3 mmHg (CI 95 %; 15.09– 20.11; p \ 0.001) in group 1A and from 39.5 ± 5.1 to 23.4 ± 3.2, to 23.0 ± 3.1 and to 21.9 ± 2.9 mmHg (CI 95 %; 13.15–22.05; p \ 0.001)) in group 1B (difference between the groups p = 0.12). Similarly, the AHI decreased significantly in both groups, from 59.3 ± 24 to 15 ± 8.1, to 14.0 ± 7.7 and to 10 ± 7 in group 1A (CI 95 %; 36.95–61.65; p \ 0.001) and from 59.5 ± 23.6 to 14.1 ± 5.2, to 12.5 ± 6.0 and to 9.8 ± 6.6 (CI 95 %; 31.12–68.28; p \ 0.001) in group 1B, with no difference between the groups (p = 0.99). A similar trend was registered for the minimal SaO2 min and ESS.
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Fig. 3 Correlation between systolic pulmonary artery pressure (PAPs) and Uric Acid in the study group
The minimal SaO2 min increased from 77.1 ± 9.2 to 89.7 ± 3.3, to 89.1 ± 3.2 and to 89 ± 2.7 in group 1A versus 76.8 ± 9.0 to 89.1 ± 3, to 89.0 ± 3.3 and to 89.2 ± 2.9 in group 1B (p \ 0.001; difference between the groups: p = 0.87). The ESS decreased from 19 ± 5 to 14 ± 3, to 12 ± 2 and to 9 ± 6 in group 1A versus 18 ± 4 to 15 ± 3, to 10 ± 3 and to 8 ± 5 in group 1B (p \ 0.001; difference between the groups: p = 0.38) However, in UPPP patients, BMI decreased more rapidly than in CPAP patients and went from a baseline value of 31 ± 3 to 31 ± 3, to 30 ± 5 and to 30 ± 4 in group 1A versus 31 ± 4 to 25 ± 2, to 27 ± 3 and to 26 ± 4 in group 1B (p = 0.005; difference between the groups: p \ 0.002). The diastolic blood pressure tended to normalize after 3 months in both groups, from 86.5 ± 9.6 to 81.4 ± 3.7 in group 1A (CI 95 %: -0.017, -10.18; p = 0.049) and from 86.3 ± 9.5 to 79.0 ± 2.5 (CI 95 %: -0.14, -14.75; p = 0.05) in group 1B. We did not witness any significant reduction in either group, during the follow-up, in uric acid, PCR, blood pressure or other metabolic parameters.
Discussion Both OSA, with or without PH, and the MS are important cardiovascular risk factors and they may act synergistically. CPAP is the first line treatment for moderately severe OSA and may be useful for treating PH and the MS or metabolic abnormalities associated with OSA [4–6]. On the other hand, UPPP is indicated in a selected phenotype of patients [7]. The role of UPPP in treating the above-mentioned phenomena is unclear. The main findings of this study were as follows: (1) a substantial proportion (33 %) of patients with OSA and without any other primary lung and cardiac disease exhibits
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mild daytime PH at rest; (2) the emergence of PH seems to be related to male sex, older age, high BMI, high NC and serum concentration of uric acid (UA) and (3) treatment with CPAP and UPPP resulted in a normalization of PAPS after only 3 months of treatment. A secondary end point of the study is that OSA patients present a significant increase in many recognized cardiovascular risk factors such as PCR, fasting plasma glucose, triglyceride serum concentration and day time diastolic blood pressure. Of these, only diastolic blood pressure reduces significantly after both treatments (CPAP and UPPP). Previous studies dealing with the prevalence of PH in OSA subjects present values that vary widely from 17 to 52% [1, 6]. The vast majority of early clinical studies suggested that abnormalities in underlying lung function sufficient to induce day time hypoxaemia were required for the development of PH and right-side heart failure. Only four studies, however, checked for the influence of concomitant heart and lung diseases. The pathophysiological mechanism of PH associated with OSA is not fully understood, and this may be due to a combination of precapillary and postcapillary factors including pulmonary arteriolar remodelling, hyper-reactivity to hypoxia, left ventricular diastolic dysfunction and left atrial enlargement [1]. One of the largest published samples to date numbers 220 subjects with OSA, 17 % of whom met the diagnostic criteria for PH [1]. Population-based data are currently lacking. Papers dating back more than three decades have documented increases in PAPs associated with sleep-related hypoxaemia. Coccagna and colleagues continuously measured PAPs during sleep in ten patients with sleep disorder breathing and found sleep stage dependent increases in PAPs, with more marked changes occurring during rapid eye movement sleep [8]. Bady and co-workers reported only precapillary factors in 12 out of 44 patients (27 %) [9]. Sajkov studied 27 patients with OSA. A total of 11 (41 %) were found to have PH, with a mean PAP of 26 mmHg [4]. In this series, those with PH were found to be more hypoxaemic during daytime wakefulness than patients without PH. Treatment in the form of tracheostomy or supplemental oxygen was shown to reduce PH. There are limited data on the effects of CPAP treatment on PH, and to the best of our knowledge this is the only study considering the effect of UPPP. Alchanatis et al studied a group of 29 patients with OSA. A total of 20.7 %. of patients had mild PH. Greater age and increased BMI distinguished these from the patients with OSA without PH. Interestingly, 6 months of CPAP treatment was associated with a reduction in the mean PAP in patients with and without PH [10]. Sajkov and colleagues treated 20 patients with OSA with 4 months of nasal CPAP. Only five patients met the criteria for PH and PAPs; PAPs decreased in all patients to a mean 13.9 mmHg [4].
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Arias et al reported the results of a randomized crossover trial of CPAP and sham CPAP over 12 weeks in 23 patients with OSA, ten of them presenting with PH. He found a direct association between the presence of diastolic dysfunction and PH and, using multiple logistic regression analysis, selected both AHI, BMI and reduced FVC as independent factors related to the development of PH. CPAP therapy reduced PAPs in all patients with OSA (mean reduction was 8.5 vs. 2.6 mmHg in the sham CPAP group) [11]. Furthermore, Minic M et al designing a retrospective cross-sectional analysis of 52 consecutive subjects with known WHO group 1 PH referred for assessment, demonstrated with overnight polysomnography that OSA was present in 71 % of patients. In this population, 56 % had OSA and 44 % central sleep apnoea. They suggested considering a systematic screening, using polysomnography, in subjects with WHO group 1 PH [12]. Interestingly, BMI which positively correlates with PH, decreases more quickly in UPPP patients. The most likely reason for this phenomenon is the most prevalent side effect of UPPP: odynophagia, which induces decreased food intake in the first 3 weeks [13, 14]. Another parameter that shows a correlation with BMI and PH is serum UA, which is a widely available biomarker that increases in chronic respiratory diseases such as OSA, COPD and pulmonary hypertension, especially in the presence of hypoxia and systemic inflammation [15]. Moreover, recent data suggest a potential role of UA as a mediator of cardiovascular morbidity in OSA [16]. Our study has limitations. The control group BMI is lower than that of the study group. We did not perform cardiac catheterization, but it is important to consider that all patients were free of pulmonary symptoms and PH was mild in all subjects. Moreover, the follow-up time was too short and not suitable to evaluate variations in metabolic parameters such as uric acid and PCR. In conclusion, our study confirms the high prevalence of PH in OSA patients (33 %). Risk factors for the development of PH are: male sex, older age, higher BMI and NC, UA concentration in serum. Both CPAP and UPPP reduce PAPs, which in this study normalized after 3 months.
Conflict of interest
We have no conflicts of interest.
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