Pulmonary Thromboembolism Superimposed on Obstructive Sleep Apnea

Correspondence and requests for reprints : Dr. Yang-Ching Ko

Address : Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, St. Martin De Porres Hospital, no. 565, Sec 2, Da Ya Road, Chiayi, 600, Taiwan.

Pulmonary Thromboembolism Superimposed on Obstructive Sleep

Apnea A Case Report

Yang-Ching Ko, Kuan-Hua Lee

, Ya-Meng Chao

, and Der-Ear Huang

Abstract

Non-invasive ventilation with continuous positive airway pressure is gaining popularity as a tech- nique for achieving effective treatment in obstructive sleep apnea. However, we observed a patient at our institution complaining of dyspnea on exertion who was diagnosed with pulmonary embolism even after implementation of continuous positive airway pressure for 5 years. This is a worrying problem be- cause obstructive sleep apnea is known to be a risk for cardiovascular complications, and treatment by the mainstay therapy with continuous positive airway pressure didn't seem to eliminate the fatal com- plication of pulmonary embolism. The association of pathophysiology between obstructive sleep ap- nea and pulmonary embolism is uncertain; nevertheless, close monitoring is vital to exclude a patho- logical and fatal event such as pulmonary embolism even after implementation of continuous positive airway pressure. ( J Intern Med Taiwan 2007; 18: 350- 355 )

Key Words Pulmonary thromboembolism, Obstructive sleep apnea, Continuous positive air- way pressure

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine;

1

Division of Cardiology, Department of Internal Medicine;

and

Department of Radiology, St. Martin De Porres Hospital, Chiayi, Taiwan

Introduction

Obstructive sleep apnea ( OSA ) is a common disorder

, characterized by intermittent episodes of partial or complete obstruction of the upper airway during sleep that disrupts normal ventilation and sleep

architecture and is typically associated with snoring

and daytime sleepiness

. This leads to sleep frag-

mentation, and possibly cardiovascular sequelae ( in-

cluding pulmonary and systemic hypertension, cere-

brovascular events, and myocardial infarction)

. Of

course, pulmonary embolism ( PE ) is a potentially

fatal sequelae. Non-invasive mechanical ventilation with positive airway pressure is considered a safe pro- cedure and a mainstay therapy for OSA, aimed at maintaining a patent airway during sleep and elimi- nating apneas, improving symptoms and possibly re- ducing cardiovascular sequela

. The association of PE with OSA has been reported extensively, but to our knowledge, there has been no documentation of occurrence of PE after implementation of continuous positive airway pressure ( CPAP ) for OSA. We report this case to facilitate recognition and treatment of this possible sequela of OSA, even after imple- mentation of the mainstay therapy by CPAP.

Case Report

A 60-year-old man with a body mass index ( B- MI ) of 24.2 kg.m

, presented with progressive dys- pnea on exertion. He had been diagnosed with ob- structive sleep apnea and implemented nocturnal C- PAP therapy for 5 years. He remained free of symp- tom until 1 month ago, when he developed increas- ing dyspnea on exertion. He even searched for help in a regional hospital, where echocardiography demonstrated mild pulmonary hypertension with a maximum pressure gradient of 25 mmHg across the tricuspid valve about 1 week ago. He presented to our hospital when he could only walk 10 meters on le- vel ground.

At the time of admission, he was acutely ill-look- ing. He was afebrile with a body temperature of 36.2 . His pulse rate was 127/min, respiration rate 31/min and blood pressure of 162/94 mmHg. Physical ex- amination revealed a jugular venous pressure of 10 cm of water. There was a right ventricular heave and an accentuated P

. Laboratory studies showed an oxy- gen saturation of 92 % on room air. Echocardiography demonstrated severe pulmonary hypertension, con- centric left ventricular hypertrophy with preserved left ventricular systolic function and a pressure gra- dient of 55 mmHg across the tricuspid valve without structural abnormality ( Fig. 1).

The combination of a stable OSA after imple- mentation of CPAP therapy and marked pulmonary hypertension prompted us to investigate for alterna- tive etiologies of his symptoms. The patient denied use of tobacco, anorexigens, intravenous drugs, im- mobilization or history of traveling and EKG, sero- logic evaluation for vasculitis, collagen vascular di- sease, and HIV were unremarkable. Disorders of hemostasis were also excluded with prothrombin time 11.7 s, activated partial thromboplastin time 30.7 s, international normalized ratio 1.02 and platelet count 341000/mm

.

On hospital day 2, the patient developed pro- gressive hypoxia. Despite an increase of his F

O

to nearly 0.5, his oxygen saturation remained 90%.

A D-dimer of 3883.40 ng/dl was the only unusual laboratory data. Our suspicion of acute pulmonary em- bolism ( PE ) was confirmed by chest CT scan, which demonstrated filling defects in bilateral lower lung pulmonary arteries ( Fig. 2 ) and lung perfusion scan, which demonstrated high probability of pulmonary embolism. A source of clot was not identified in the lower extremities by computed tomography.

The patient was started on a continuous intra-

venous heparin infusion, regularly adjusted to

achieve a therapeutic activated partial thromboplas-

tin time ( aPTT ) of 45-70. Rescue therapy with an-

Fig.1.Echocardiography demonstrated a pressure gra-

dient of 55 mmHg between the right atrium and

ventricle and it indicated severe pulmonary hy-

pertension of at least 60 mmHg.

ticoagulants resulted in a rapid increase in P

O

from 67 to 149 mmHg in F

O

50% during 24 hours. The addition of warfarin acutely facilitated reduction of the F

O

and eventual discontinuation of intravascu- lar anticoagulants. The prothrombin time interna- tional normalized ratio on discharge was 2.45. The patient continued taking 5 mg warfarin orally every day as an out patient. Four weeks later, he was able to walk 500 meters on level ground.

Discussion

There is an increasing perception that OSA, via various mechanisms, increases cardiovascular mor- bidity and mortality. There is also increasing infor- mation to indicate that OSA is linked to metabolic, vascular, hematologic, and genetic markers associat- ed with increased cardiovascular disease risk.

However, many risk factors for OSA, such as obesi- ty and male gender, are the same as for cardiovascu- lar disease

and ascertaining the association of PE with OSA is difficult, particularly as cases of PE are often unidentified because of minimal or absent symptoms

. Although we also knew the strong asso- ciation between OSA and PE, the 2 events could po- tentially occur coincidentally. Patients with OSA may be at increased risk for weight gain, and obesity is a major risk factor for cardiovascular disease.

Resistance to the appetite suppressant effects of lep-

tin may be involved because OSA patients have high- er leptin levels than similarly obese controls

. Similarly, obesity is associated with increased reac- tive oxygen species ( ROS ) levels and an increase in ROS can up-regulate vascular adhesion molecules, cause platelet aggregation, and scavenge the potent vasodilator nitrogen oxide. OSA represents a likely mechanism linking obesity and elevated ROS, but it is unclear whether these increased levels are related to vascular disease and hypercoagulability. Even pa- tients with pulmonary embolism or deep vein throm- bosis have a higher incidence of OSA

. Moreover, several potential mechanisms, e.g. superoxide release from neutrophils

or increased levels of cate- cholamines

, could explain the association between OSA and a hypercoagulable state. But available studies are limited by small sample size, lack of uni- form definition, and failure to consistently control for potential confounders. Thus, a number of mecha- nisms could potentially explain the relationship be- tween hypercoagulability/thrombosis and OSA, but relevant ones have not been defined and definitive data from large well-controlled studies is lacking.

In 1981, Sullivan et al.

first described the use of nasal CPAP as a treatment of OSA. Prior studies persuasively demonstrated improvements in cogni- tive performance, sleepiness, and quality of life among OSA individuals treated with CPAP

. We also knew that platelet aggregation as well levels of plasminogen activator inhibitor-1 and fibrinogen are increased in OSA patients, and decrease after CPAP treatment

. Furthermore, increased leptin levels asso- ciated with OSA decline after treatment with CPAP

and treatment with nasal CPAP decreases ROS levels

. However, evidence that the restoration of the dipping pattern with CPAP would affect cardiovas- cular morbidity and mortality is lacking. For instance, results of studies on the effect of CPAP on nocturnal and daytime hypertension are conflicting; some studies demonstrate a reduction in blood pressure with therapy whereas others do not

. Thus, report- Fig.2.A chest CT scan showing filling defects in bilater-

al lower lung pulmonary arteries (arrow).

ing cases of identified PE after CPAP is therefore im- portant to study the benefits of CPAP in OSA. In our patient, the close relationship of PE to OSA, with a normal BMI and no other identified risk factors of trauma, prolonged inactivity, diabetes, inducible drug history or major surgery suggests OSA as the pro- voking factor. Of course, male gender was an anoth- er possible factor. To our knowledge, procoagulant and anticoagulant mechanisms are balanced under physiological conditions. The associations between defects in the homeostatic system and hypercoagula- bility is well established. Patients with activated pro- tein C resistance ( APCR ) accompanied by another genetic defects, protein S deficiency, demonstrate the increased risk of severe thromboembolic episodes.

APCR is by far the most frequent coagulation disor- der predisposing to venous thromboembolism

. Others, antithrombin ( ATIII ) is a potent inhibitor of the coagulation cascade. Congenital deficiency leads to increased risk of venous and arterial thrombosis, acquired type is most commonly seen in situations in which activation of the coagulation system is inap- propriate

. It is a pity that serum ATIII, protein C and protein S were not checked in this case.

Therefore, these rare disorders could not be exclud- ed completely by history and underlying diseases.

Nevertheless, our patient with OSA was stabilized by CPAP but still complicated by the potentially fatal PE. The role and responsible mechanisms of OSA as a risk factor "independent" of associated co-mor- bidities, and whether treatment of OSA will mitigate the risk are unknown and remain to be determined.

In the case reported, the diagnosis of PE is strongly suggested by the onset of dyspnea, oxygen desaturation, pulmonary hypertension and the pres- ence of filling defects in bilateral pulmonary vessels on computed tomography. However, acute aspiration of gastric contents, chronic obstructive pulmonary disease, acute myocardial infarction, and circulatory collapse are other possible causes of respiratory dis- tress in OSA treated by CPAP. Distinguishing pul-

monary embolism from other causes of mortality is often difficult as symptoms are similar. Chest CT has virtually replaced lung scanning for diagnosing PE at most hospitals

, resulting in more rapid and accurate diagnosis. Rapid diagnosis of PE is crucial to initiate potentially life-saving therapy. Chest CT is not only useful to diagnose PE and assess clot burden but helps to identify patients with right ventricular enlargement who are at risk of early death

.

The patient described in this report may have been at risk for venous stasis because of OSA.

However, dyspnea on exertion is also a prominent symptom in fatal cases of pulmonary embolism as- sociated with well-controlled OSA in CPAP treat- ment. Institution of physiotherapy or low-dose he- parin therapy may prevent clot formation. Evaluation of patients for observation of pulmonary hyperten- sion on echocardiography may aid in diagnosis and indicate advisability of further testing. Identification of a thrombus should result in initial anticoagulation with intravenous or subcutaneous heparin, and oral warfarin after a therapeutic aPTT value is achieved.

As the presentation of pulmonary embolism can be variable, we recommend consideration of helical computed tomography angiography or ventilation/

perfusion scanning of the lungs in patients with suspicious symptoms, particularly in high risk pa- tients with OSA, even after implementation of CPAP.

These measures would allow for earlier treatment if pulmonary thromboembolism is present, and hope- fully decrease mortality from this condition.

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