You are here

Obstructive Sleep Apnea as a Risk Factor for Pulmonary Embolism

Dr. Ibrahim

 

Co-Authored By: Matthew D. Epstein, MD, Leopoldo N. Segal, MD, Sherin M. Ibrahim, DO, Neil Friedman, RN, RPSGT, Rami Bustami, PhD

Abstract:
Background
Obstructive sleep apnea is associated with prothrombotic effects that could lead to venous thromboembolic disease.  We performed a prospective, cross sectional study to determine the prevalence of obstructive sleep apnea in patients with acute pulmonary embolism. 

Methods
Between October 2005 and March 2006, we evaluated 270 consecutive patients who underwent a computed tomographic angiogram for suspected pulmonary embolism.  Patients without pulmonary embolism served as a control group.  The Berlin Questionnaire was used to determine the presence of obstructive sleep apnea.  A subset of patients also underwent formal nocturnal polysomnography. 

Results
Pulmonary embolism was present in 71 (26%) of the 270 patients who underwent a computed tomographic angiogram.  The Berlin Questionnaire performed with 100% sensitivity and 80% specificity.  There was an increased prevalence of obstructive sleep apnea in pulmonary embolism vs. non-pulmonary embolism patients (65% vs. 36%, p<0.001). 

Conclusions
We found a higher prevalence of obstructive sleep apnea in patients with acute pulmonary embolism, in comparison to patients in whom pulmonary embolism was suspected but ruled out.  Obstructive sleep apnea may be a risk factor for the development of pulmonary embolism.

 

Introduction:
The annual incidence of pulmonary embolism exceeds 1 per 1000 in the United States, with an associated mortality of up to 40%.1,2   Pulmonary embolism is thought to account for 5-10% of deaths in hospitalized patients.3,4  If untreated, approximately one third of those who survive an initial pulmonary embolism die of a future embolic episode.2  Although risk factors for the development of pulmonary embolism are well established, up to 30% of cases have no identifiable cause.5   Moreover, risk factor assessment may have important implications for both prevention and treatment of pulmonary embolism.6
Obstructive sleep apnea is characterized by episodes of recurrent upper airway obstruction during sleep, leading to repetitive sleep disruption, with or without concomitant oxygen desaturation.7  Recent studies estimate that obstructive sleep apnea affects up to 25% of the adult population in the United States.8,9  Obstructive sleep apnea is increasingly recognized as a risk factor for cardiovascular disease.10-13  Some of the proposed mechanisms whereby obstructive sleep apnea contributes to cardiovascular complications include hemodynamic alterations,14  sympathetic nervous activation,15 oxidative stress,16 systemic inflammation,17 hypercoagulability11 and vascular endothelial dysfunction.18   These same pathophysiologic derangements are prothrombotic and could promote the development of venous thromboembolic disease.
Several previous case reports and uncontrolled cohort studies have reported a possible association between obstructive sleep apnea and venous thromboembolism.19-24  We performed a prospective, cross-sectional study to determine the prevalence of obstructive sleep apnea in  patients with acute pulmonary embolism. 

Methods:
Study Population
We performed a prospective assessment for the presence of obstructive sleep apnea in consecutive patients >18 years old who underwent a helical contrast enhanced computed tomographic scan of the chest (CT angiogram) for suspected pulmonary embolism.  All in-patients and out-patients were included.  The study took place between October 2005 and March 2006 at a 650 bed, tertiary care teaching hospital.  A board-certified radiologist determined results of the CT angiogram.  Patients in whom the CT angiogram was negative for PE comprised the control group.  The research protocol was approved by the hospital’s Institutional Review Board and registered with ClinicalTrials.gov # NCT00409045.  All patients provided informed consent.  The only exclusion criteria were an inability or unwillingness to participate or to provide consent. 
Patients were evaluated either in the emergency department, during their hospitalization or by telephone if already discharged from the hospital.  Demographic and clinical characteristics were collected, including current and past medical history and known risk factors for pulmonary embolism.6,25,26  Laboratory investigation for thrombophilia was performed at the discretion of the patients’ treating physicians. 

Berlin Questionnaire
A Berlin Questionnaire was completed for all study participants and was used to determine the risk of obstructive sleep apnea.  The Berlin Questionnaire consists of ten questions divided into 3 categories, including snoring, daytime somnolence, and hypertension and obesity (defined as a body mass index [BMI] > 30 kg/m2).27  A high risk of obstructive sleep apnea is defined as a positive response in two or more of the following categories: persistent symptoms (>3 to 4 times per week) in two or more questions about snoring; persistent symptoms (>3 to 4 times per week) of daytime sleepiness or falling asleep while driving; history of hypertension or obesity.
The Berlin Questionnaire has been demonstrated to have good validity (Cronbach’s alpha: 0.86 to 0.92) with a sensitivity of 86%, specificity of 77%, and a positive predictive value of 89% in a primary care setting.27  Subsequent studies have confirmed the accuracy in specific medical populations.28,29

Polysomnography
The accuracy of the Berlin Questionnaire was validated in a subgroup of our study population (n=23) who had completed both the Berlin Questionnaire and formal nocturnal polysomnography.  Polysomnography included monitoring of the electroencephalogram, electrooculogram, electromyogram, electrocardiogram, thoracic and abdominal movements, oro-nasal airflow, and pulse oximetry (Compumedics, Victoria, Australia).  Sleep scoring was performed using criteria of Rechtschaffen and Kales.30  An obstructive apnea was defined as an episode of complete airflow cessation lasting at least 10 seconds with persistent respiratory effort, while an hypopnea was defined as at least a 50% reduction in airflow lasting at least 10 seconds associated with either oxygen desaturation or an arousal.31  The sensitivity, specificity and positive and negative predictive values of the Berlin Questionnaire were determined using the polysomnographic findings as the gold standard.  Polysomnography results were analyzed without knowledge of the patients’ other clinical information.  Obstructive sleep apnea was defined by criteria set forth by the American Academy of Sleep Medicine.32

Statistical Analysis
Unadjusted analyses were performed to compare the pulmonary embolism and non- pulmonary embolism group in terms of the presence of obstructive sleep apnea or snoring using the Chi-square test. The two groups were also compared in terms of various categorical demographic and clinical variables using the Chi-square or Fisher’s exact test.  For continuous variables that are normally distributed, a t-test was used.  Comparisons based on non-normally distributed variables were made using the non-parametric Mann-Whitney U test.

Results
Study Population
During the study period, 452 consecutive patients underwent CT angiography for suspected pulmonary embolism, with 80 patients testing positive.  Two hundred seventy patients were enrolled in the study, of whom 71 tested positive.  Patients that were not included in the study could not be contacted, could not complete the questionnaire or refused to participate. 
Table 1 provides demographic and clinical characteristics of both groups. The mean age of patients in each group was similar.  The pulmonary embolism group was predominantly male (61% vs. 37%, p<0.001).  Weight was greater among patients in the pulmonary embolism group (mean 86.1 vs. 78.0 kg, p = 0.012), but BMI was not significantly different (p=0.39). 

Association of Pulmonary Embolism and Obstructive Sleep Apnea
Pulmonary embolism patients had a significantly higher prevalence of obstructive sleep apnea and snoring compared to non- pulmonary embolism patients (65% vs. 36%, p<0.001, and 75% vs. 50%, p<0.001, respectively)  (see Table 1).  Hereditary risk factors for pulmonary embolism were significantly more prevalent in the pulmonary embolism group (49% vs. 15%, p<0.001), while acquired risk factors for pulmonary embolism did not show a statistically significant difference (69 % vs. 62%, p=0.28).  There was a lower prevalence of congestive heart failure in the pulmonary embolism group (6% vs.15%, p = 0.040).  There was no significant difference between the two groups with regard to other pulmonary embolism risk factors. 

Berlin Questionnaire Validation
Twenty-three consecutive patients, 19 of whom were positive for pulmonary embolism, underwent polysomnography in addition to completing the Berlin Questionnaire.  An apnea-hypopnea index of 15 was used to define a positive study.  Polysomnography was positive in 13 patients (median AHI 16.9, range 7-106), all of whom had a positive Berlin Questionnaire.  Polysomnography was negative in 10 patients (median AHI 3.45, range 0.8-8.9), 8 of whom had a negative Berlin Questionnaire.  Comparing results of polysomnography as the gold standard, the Berlin Questionnaire performed with a sensitivity of 100% and specificity of 80%.  The positive predictive value was 87% and the negative predictive value was 100%. 

Discussion
We found the prevalence of obstructive sleep apnea to be significantly higher in patients with acute pulmonary embolism, in comparison to patients in whom pulmonary embolism was suspected but ruled out. 
Thromboemboli arise in the setting of venous stasis, endothelial injury and hypercoagulability (Virchow’s triad).  Each of these conditions may develop in the setting of obstructive sleep apnea.  Obstructive sleep apnea-related hemodynamic alterations may lead to acute reductions in venous return and chronic venous stasis.14  Obstructive sleep apnea is associated with an increase in circulating thrombogenic factors, including fibrinogen and von Willebrand Factor, platelet activation, plasminogen activator inhibitor-1 and D-dimer levels.11,16,33-35  Obstructive sleep apnea directly impairs vascular endothelial function, causing an increase in endothelin-1 levels, leading to vasoconstriction, and a reduction in nitric oxide, impairing vasodilation.18  Obstructive sleep apnea is associated with sympathetic nervous system activation15 and an increase in inflammatory mediators, catecholamines, cellular and vascular endothelial adhesion molecules and oxidative stress, all of which have prothrombotic effects.13,16,17,36  Hence, obstructive sleep apnea may be sufficient, in and of itself, to fulfill the conditions of Virchow’s triad.  Our results support the concept that obstructive sleep apnea may be causal in the development of pulmonary embolism.
An association between sleep-disordered breathing and pulmonary embolism was first described over 30 years ago in case reports of pulmonary embolism in patients with the so-called Pickwickian syndrome.19-21  Several more recent studies have examined the prevalence of obstructive sleep apnea in uncontrolled case series of patients with acute pulmonary embolism.22,23  A small, uncontrolled, prospective cohort study of newly diagnosed obstructive sleep apnea patients found an increased incidence of venous thromboembolism over 3 years following obstructive sleep apnea diagnosis.24  
This is the first cross-sectional study to prospectively evaluate the association between obstructive sleep apnea and pulmonary embolism.  Although we found a high prevalence of obstructive sleep apnea in patients with acute pulmonary embolism, our results must be interpreted in light of several limiting factors.  First, a majority of patients who tested negative for pulmonary embolism by CT scanning did not participate in the study.  Most were out-patients treated in the emergency department and either declined to participate or could not be contacted. 
Second, the presence of obstructive sleep apnea was determined for most patients by the Berlin Questionnaire, rather than by polysomnography, which is the gold standard for diagnosis.  The Berlin Questionnaire has been shown to be very accurate in predicting obstructive sleep apnea in an outpatient primary care setting as well as other patient populations.  The Berlin Questionnaire was also highly accurate in our validation study, with performance comparable to that described in previous reports.27-29  Utilizing the Berlin Questionnaire, the 2005 National Sleep Foundation poll of adults in the United States found a prevalence of obstructive sleep apnea of approximately 25%.9  The increased prevalence of obstructive sleep apnea in our study population (36% non- pulmonary embolism and 65% pulmonary embolism) likely reflects the characteristics and co-morbidities of our patient population. 
Third, laboratory testing for thrombophilia was performed at the discretion of the treating physicians and was not obtained for all pulmonary embolism patients.  Although attempts at subsequent out-patient follow-up were made, it is possible that testing for thrombophilia performed after hospital discharge was not included in our analysis.  Also, most of the laboratory testing for thrombophilia was performed during the acute phase of the thromboembolism, which could potentially reduce the accuracy of the test results.37  Of the 71 pulmonary embolism patients, 38 underwent laboratory testing for thrombophilia.  The other 33 patients had no hypercoagulable work-up, although 28 of these patients had other identifiable risk factors for pulmonary embolism. 
Finally, we enrolled only patients who underwent a CT angiogram of the chest, and the concomitant presence of deep vein thrombosis was not routinely ascertained.  Even though deep vein thrombosis is considered part of the spectrum of venous thromboembolism, our study did not address whether obstructive sleep apnea is also a risk factor for deep vein thrombosis.
We found a higher prevalence of pulmonary embolism in males, consistent with previous reports.38   The lower prevalence of pulmonary embolism in patients with congestive heart failure and hypertension may be explained by the fact that the negative pulmonary embolism patients’ presenting symptoms were more likely due to cardiovascular disease.  Obesity constitutes a well known risk factor for obstructive sleep apnea, although its association with pulmonary embolism has been debated.6,39  Weight was higher in the pulmonary embolism group, perhaps because the majority of pulmonary embolism patients were male, but BMI was similar between the two groups.  Interestingly, it has been hypothesized that sleep apnea may be one of the mechanisms whereby obesity contributes to the development of cardiovascular disease.40   It is possible that this same relationship could exist between obesity and pulmonary embolism. 
In summary, our study found a high prevalence of obstructive sleep apnea in patients diagnosed with acute pulmonary embolism.  Based on a growing body of evidence suggesting pathophysiologic plausibility, our findings support the concept that obstructive sleep apnea may represent an independent risk factor for the development of pulmonary embolism.  Given the high prevalence of obstructive sleep apnea and the high morbidity and mortality associated with pulmonary embolism, additional studies are warranted to address this relationship.   

 

 

 

References:
1. Silverstein MD, Heit JA, Nohr DN, Petterson TM, O’Fallon WM, Melton LJ III.  Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.  Arch Int Med.  1998; 158:585-593.
2. Goldhaber SZ, Morrison RB.  Pulmonary embolism and deep vein thrombosis. Circulation 2002;106:1436-1438.
3. Baglin TP, White K, Charels A. Fatal pulmonary embolism in hospitalised medical patients. J Clin Pathol 1997; 50:609-10. 
4. Francis CW.  Prophylaxis for thromboembolism in hospitalized medical patients.  New Engl J Med 2007; 356:1438-44.
5. Heit J. Venous thromboembolism epidemiology: implications for prevention and management.  Semin Thromb Hemost 2002; 28:Suppl 2:3-13. 
6. Anderson GA, Spencer FA.  Risk factors for venous thromboembolism.  Circulation 2003; 107: I-9 – I-16.
7. Caples SM, Gami AS, Somers VK.  Obstructive sleep apnea.  Ann Intern Med 2005;142:187-97.
8. 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; 328:1230-5.
9. Hiestand DM, Britz P, Goldman M, Phillips B.  Prevalence of symptoms and risk of sleep apnea in the US population.  Results from the National Sleep Foundation’s Sleep in America poll.  Chest 2006; 130:780-6.
10. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive Sleep Apnea: implications for cardiac and vascular disease. JAMA 2003; 290:1906-1914.
11. Von Kanel R, Dimsdale JE.  Hemostatic alterations in patients with obstructive sleep apnea and the implications for cardiovascular disease.  Chest 2003; 124:1956-1967.
12. Quan S, Gersh B. Cardiovascular consequences of sleep-disordered breathing: past, present, future. Circulation 2004: 109:951-957.
13. McNicholas WT,  Bonsignore MR.  Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities.  Eur Resp J 2007; 29:156-78.
14. Marrone O, Bonsignore MR.  Pulmonary haemodynamics  in obstructive sleep apnoea.  Sleep Med Rev 2002;6:175-193.
15. Somers VK, Dyken ME, Clary MP, Abboud FM.  Sympathetic neural mechanisms in obstructive sleep apnea.  J Clin Invest. 1995;96:1897-1904.
16. Von Kanel R, Loredo JS, Ancoli-Israel S, Mills PJ, Natarajan L, Dimsdale JE. Association between polysomnographic measures of disrupted sleep and prothrombotic factors. Chest 2007; 131: 733-739.
17. Ryan S, Taylor CT, McNicholas WT.   Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome.  Circulation 2005;112: 2660-2667.
18. Budhiraja R, Parthasarathy S, Quan SF.  Endothelial dysfunction in obstructive sleep apnea.  J Clin Sleep Med 2007;3(4):409-415.
19. MacGregor MI, Block AJ, Ball WC.  Serious complications and sudden death in the pickwickian syndrome. Johns Hopkins Med J 1970; 126:279-295.
20. Godfrey S, Meltzer E, Shabbath T.  Pulmonary embolism and the pickwick syndrome. Brit J Dis Chest 1972; 66: 155-161.
21. Hasan FM, Auchincloss JH, Gilbert R.  Thromboembolic disease and cardiorespiratory syndrome of obesity.  New York State Journal of Medicine, February 1976; 272-275.
22. Hasegawa R, Shiomi T, Sasanabe R, et al.  Sleep apnea syndrome in patients with pulmonary thromboembolism. Psychiatry and Clinical Neurosciences 2000; 54: 342-343.
23. Arnulf I, Merino-Andreu M. Pierre A, Birolleau S, Similowski T, Derenne J-P.  Obstructive sleep apnea and venous thromboembolism. JAMA. 2002; 287:2655-2656.
24. Ambrosetti M, Lucioni A, Ageno W, Conti S, Neri M.  Is venous thromboembolism more frequent in patients with obstructive sleep apnea syndrome?  J Thromb Haemost 2004; 2:1858-50.
25.  Heit JA, O’Fallon WM, Petterson TM, et al.  Relative impact of risk factors for deep vein thrombosis and pulmonary embolism.  Arch Intern Med 2002;162:1245-8.
26. Tapson VF.  Acute Pulmonary Embolism.  N Engl J Med 2008;358:1037-52.
27. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP.  Using the Berlin questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med 1999; 131: 485-491.
28. Gami AS, Pressman G, Caples SM, et al.  Association of atrial fibrillation and  obstructive sleep apnea.  Circulation. 2004;110:364-367.
29. Chung F, Ward B, Ho J, Yuan H, Kayumov L, Shapiro C.  Preoperative identification of sleep apnea risk in elective surgical patients using the Berlin questionnaire.  J Clin Anesth 2007; 19(2):130-4.
30. Rechtschaffen A, Kales A, eds.  A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects.  Los Angeles, CA: UCLA Brain Information Service/Brain Research Institute, 1968.
31. Hosselet JJ, Ayappa I, Norman RG, Krieger AC, Rapoport DM.  Classification of  sleep-disordered breathing.  Am J Resp Crit Care Med 2001;163:398-405.
32. American Academy of Sleep Medicine (AASM).  International Classification of Sleep Disorders. Westchester, AASM, 2005.
33. Sanner BM, Konermann M, Tepel M, Groetz J, Mummenhoff C, Zidek W.  Platelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J 2000; 16:648-652.
34. Olson LJ, Olson EJ, Somers VK. Obstructive sleep apnea and platelet activation. Chest 2004, 126:339-341.
35. Shitrit D, Peled N, Shitrit A B-G, Meidan S, Bendayan D, Sahar G.  An association between oxygen desaturation and D-dimer in patients with obstructive sleep apnea syndrome. Thromb Haemost. 2005; 94: 544-547.
36. Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y.  Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome.  J Appl Physiol 1999;87:10-14.
37. Franchini M, Veneri D, Salvagno GL, Manzato F, Lippi G.  Inherited thrombophilia.  Crit Rev Clin Lab Sci 2006; 43(3):249-290.
38. Stein PD, Beemath A, Olson RE.  Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118: 978-980
39. Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: “the study of men born in 1913” Arch Inter Med 1999; 159(16): 1886-1890.
40. Pack AI.  Advances in sleep-disordered breathing.  Am J Resp Crit Care Med 2006; 173: 7-15.

Table 1:  Demographic and Clinical Characteristics of the Study Population

Factor PE p-value*
Positive (N = 71) Negative (N = 199)
Age (years) 60.0 ± 15.7 61.3 ± 17.2 0.56
Gender (Male/Female) 61% / 39% 37% / 63% < 0.001
Weight (kg) 86.1 ± 23.6 78.0 ± 20.3 0.012
Body Mass Index (BMI) (kg/m2) 28.7 ± 7.0 27.9 ± 6.7 0.39
OSA 65% 36% <0.001
Snoring 75% 50% <0.001
Hereditary PE risk factors**   49% 15% <0.001
Acquired PE risk factors***  69% 62% 0.28
Hypertension 44% 53% 0.17
Congestive Heart Failure  6% 15% 0.04
Myocardial Infarction  6% 10% 0.31
Smoking 18% 20% 0.81
Pacemaker / Central Line 15% 8% 0.14
Inflammatory Bowel Disease 2% 3% 0.61
Nephrotic Syndrome 2% 0% 0.57
OSA = Obstructive sleep apnea, PE = Pulmonary embolism, DVT = Deep vein thrombosis
* Based on the Chi-Square / Fisher’s Exact Test or T-Test / Mann Whitney U Test
**  Family history of DVT/PE or thrombophilia.
***  Personal history of DVT/PE, oral contraceptive use, pregnancy, malignancy, immobility, trauma, fractures, spinal cord injury, surgery, travel, and varicose veins