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(Chest. 2003;123:244-260.)
© 2003 American College of Chest Physicians

The Association of Hypertension and Secondary Cardiovascular Disease With Sleep-Disordered Breathing*

Richard A. Dart, MD, FCCP; James R. Gregoire, MD; David D. Gutterman, MD, FCCP and Steven H. Woolf, MD

* From the Department of Nephrology and Hypertension (Dr. Dart), Marshfield Clinic Marshfield, WI; Division of Hypertension and Internal Medicine (Dr. Gregoire), Mayo Clinic Rochester, MN; Medical College of Wisconsin (Dr. Gutterman), Milwaukee, WI; and Virginia Commonwealth University (Dr. Woolf), Fairfax, VA.

Correspondence to: Richard Dart, MD, Department of Nephrology, Marshfield Clinic, 1000 North Oak Ave, Marshfield, WI; e-mail: dartr{at}mfldclin.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Summary of Association Studies
 Pathophysiology
 Approach to the Patient...
 Final Summary of Conclusions
 References
 
We present a review of the English-language literature from 1972 through 2000 pertaining to systemic high BP in patients with sleep-disordered breathing (SDB). We reviewed studies assessing the relationship between obstructive sleep apnea, central sleep apnea or periodic breathing, and systemic high BP, and present an approach to the management of these patients. Complications of obesity and the role of the sympathetic nervous system are reviewed as well. It is the aim of these reviews to draw qualified conclusions, based on the current literature, with regard to SDB as a causative or contributory factor in systemic hypertension.

Key Words: antihypertensive drugs • central sleep apnea • obstructive sleep apnea • periodic breathing • pulmonary disease • sleep-disordered breathing • systemic high BP


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Summary of Association Studies
 Pathophysiology
 Approach to the Patient...
 Final Summary of Conclusions
 References
 
Sleep-disordered breathing (SDB) is frequently found in conjunction with systemic hypertension. Determining cause and effect in that relationship has been very difficult to demonstrate. An association between systemic hypertension and SDB was first recognized in the 1970s by Coccagna et al,1 Lugaresi et al,2 and Motta et al3 in case reports of improvement in BP following surgical intervention for a variety of SDB problems. The authors raised the possibility of cause-and-effect relationship between SDB and systemic hypertension. Since the publication of those case reports, numerous studies have been conducted to try to confirm or clarify this relationship. The American College of Chest Physicians asked this panel to conduct a systematic and critical review of the literature, and to provide relevant conclusions regarding the evidence supporting SDB as a causative or contributory factor in systemic hypertension.

Several questions are addressed: Do patients with SDB have an increased incidence of systemic hypertension, and vice versa? Are there common factors to both, such as obesity, that contribute to the relationship? What is the role of the sympathetic nervous system? Does SDB treatment affect hypertension control? We report conclusions based on an extensive literature review covering studies performed from 1970 through 2000. We begin with definitions. We identify inconsistencies in the literature. Discussions of cardiovascular pathology of SDB follow.

Questions addressed include the following: Do patients with systemic hypertension have an increased incidence of sleep apnea and altered response to hypoxia? Do the increased catecholamine levels associated with sleep apnea affect daytime systemic hypertension, or alter the risk of arrhythmias and ischemic events in patients with coronary artery disease? What role is played by the sympathetic nervous system? What is the interplay of obesity, hypertension, and sleep apnea, and can resulting hypoxia and hypercapnic acidosis be improved? Is there a relationship between sleep apnea and ischemic heart disease and/or idiopathic dilated cardiomyopathy? Will SDB treatment affect hypertension control? Finally, we tabulate and summarize those clinical studies that have directly addressed these relationships, and come to a consensus as to the conclusions that can currently be drawn from these studies.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Summary of Association Studies
 Pathophysiology
 Approach to the Patient...
 Final Summary of Conclusions
 References
 
Database Searches
For this review, the PubMed database was systematically searched for articles published between 1972 and 2000, using keywords and the medical subject heading terms to identify all human clinical studies specifically designed to assess the association between SDB and systemic hypertension,3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 and sympathetic nervous system, SDB, and systemic hypertension.62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 Studies were considered relevant if they addressed hypertension, arterial hypertension, or systemic hypertension in conjunction with obstructive or central sleep apnea, snoring, or periodic breathing disorders. Both medical subject headings and keywords were used in searches, due to concerns about potential accuracy of National Library of Medicine indexing.

Inclusion/Exclusion Criteria
Only randomized or nonrandomized control trials, observational, control cohort (longitudinal), case control, cross sectional, uncontrolled case series/cohort, time series, cross-cultural, ecologic, descriptive epidemiologic, and case reports were included. The literature search excluded pulmonary hypertension, editorials, position papers, editorial opinions, abstracts, and letters to the editor. Exceptions to this rule were editorials, position papers, editorial opinions, or letters to the editor that provided additional references thought to be of relevance and not found in the original search. All English-language articles identified in these searches and fitting these criteria were included for review.

Tabulated Study Grade Assessments
Criteria for judging the retrieved articles was internally developed and uses the following scheme: level 1, randomized (controlled trials) or nonrandomized controlled trials; level 2, observational studies, control cohort (longitudinal), case control including prospective and retrospective, cross-sectional, uncontrolled case series/cohort, time-series, cross-cultural, ecologic, descriptive epidemiologic studies; and level 3, case reports. A quality judgment was also added based on attributes of sample size, appropriate subjects, methods, outcome measures, statistical analysis, and confounding variables. This judgment was expressed in an "a, b, c" system, where a = good, b = fair, and c = poor. As an example, 1a = evidence of a well-designed, well-conducted, controlled trial with statistically significant results.

Grading the Strength of Conclusions
The strength of a recommendation is expressed in an "A, B, C" system, with degrees of relative strength within each level: level A, evidence provided by well-designed, well-conducted, controlled trials (randomized and nonrandomized) with statistically significant results to support the recommendation (A-1 = all studies meet level A criteria, A-2 = some studies meet level A criteria, A-3 = a few studies meet level A criteria); level B, evidence provided by observational studies or by controlled trials with less consistent results to support the recommendation, or by well-designed trials that are conflicting (B-1 = all studies meet level B criteria, B-2 = some studies meet level B criteria; B-3 = a few studies meet level B criteria); and level C, expert opinion that supports the recommendation because the available scientific evidence did not present consistent results, or controlled trials are lacking.


   Results and Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Summary of Association Studies
 Pathophysiology
 Approach to the Patient...
 Final Summary of Conclusions
 References
 
Review of the Physiology
Definitions of SDB and sleep cycles used here are those cited as being the accepted standards, or those most frequently and consistently used in the literature.

SDB:
For the purposes of this review only, obstructive and central sleep apneas are included. Upper airway resistance syndrome, chronic alveolar hypoventilation, and pickwickian syndrome are not included, in that they contribute to breathing dysfunction during both sleep and wake periods.

Obstructive Sleep Apnea:
Cessation of airflow at the nose and mouth during sleep due to partial or complete occlusion of the upper airway at the oropharyngeal level despite continued activation of respiratory muscles. Obesity is often associated with obstructive sleep apnea (OSA).

Central Sleep Apnea:
Cessation of breathing during sleep as a result of transient lack of central neurologic drive to the respiratory muscles.

Periodic Breathing:
Regular waxing and waning of ventilation resulting from fluctuations in respiratory drive.

Apnea:
Complete cessation of air flow for at least 10 s.

Hypopnea:
Defined as a >= 30% reduction of airflow or thoracoabdominal excursion accompanied by a >= 4% drop in oxyhemoglobin saturation. Apnea/hypopnea index is defined as the average number of apneas plus hypopneas (obstructive, central, or mixed) per hour of sleep, and graded as none (0 to 5), mild (> 5 to < 10), moderate (> 10 to < 15), and severe (> 15). This index is normally determined by polysomnography, which monitors brain waves (EEG), eye movements (electrooculography), muscle activity (electromyography), heartbeat (ECG), blood oxygen levels, and respiration.

Respiratory Disturbance Index:
The American Sleep Disorders Association and most others equate the apnea/hypopnea index (AHI) with the respiratory disturbance index (RDI). However, the RDI is less commonly identified as the total number of respiratory events per total number of hours of sleep. This index is determined by a portable Madaus electronic sleep apnea monitor (MESAM IV; Medizintechnik für Artz und Patient GmbH; Martinsried, Germany), which records overnight laryngeal sounds and heart rate, and then analyzes the time intervals of constant heart rate and intervals between snoring sounds to quantify respiratory disturbances during sleep.81 Grading is the same as AHI: none (0 to 5), mild (> 5 to < 10), moderate (> 10 to < 15), and severe (> 15).

Hypoxia:
Generally described as an oxygen desaturation of at least 4%. A cutoff point defining hypoxia cannot be defined.82 Hypoxia can only be defined as an excursion from the normal value for that person in the tissue of interest. A drop in hemoglobin saturation of > 4% can be expected to trigger a physiologic response, and thus be considered a hypoxic event. The term hypoxia usually includes several causal subtypes (anemic, hypoxic, ischemic, oxygen affinity, and stagnant hypoxias). As used in sleep studies, hypoxia refers to hypoxic hypoxia, ie, that resulting from a defective mechanism of oxygenation of the lungs, especially as caused by abnormal pulmonary function, specifically airway obstruction.

Rapid Eye Movement Sleep:
A state of sleep characterized by rapid eye movements (REMs), fast low-voltage brain waves, mild involuntary muscle jerks, irregular heart rate and respiration, and a higher threshold of arousal. Typically, it lasts from 5 to 20 min, occurs at approximately 90-min intervals, and, in adults, occupies approximately 20% of overall sleep time. Time spent in REM increases toward the last 3 to 4 h of sleep. Dreaming frequently occurs during REM sleep. The significance of REM sleep is not as well known. The body increases time spent in REM if deprivation occurs due to drugs, disease, or fragmented sleep.

Non-REM Sleep:
The time between REM sleep. Non-REM (NREM) sleep is essential for rest, rejuvenation, and the maintenance of overall health. Dreams may also occur in NREM sleep. A person with normal sleep usually has four to five cycles of REM and NREM sleep during a night. NREM sleep is further divided into four stages: stage 1, initiates sleep (15 min and 30 min, known as relaxed wakefulness); stage 2, relatively light sleep (approximately 50% of total sleep time, known as rapid-wave sleep); stages 3 and 4, the deep, restorative sleep time during which immune function is fortified and growth hormone is secreted (15 to 20% of total sleep time, known as delta sleep). Time spent in delta sleep diminishes as patients age. At 75 years of age, the stage is often nonexistent.


   Summary of Association Studies
TOP
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Summary of Association Studies
Pathophysiology
 Approach to the Patient...
 Final Summary of Conclusions
 References
 
Tables 1, 2, 2A, 2B, 2C, 2D ,3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 and 3, 3A 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 contain the results of all those studies found that met the inclusion criteria described in the "Materials and Methods" section. Overall, the findings are mixed with regards to a definitive direct cause-and-effect relationship between SDB and hypertension, most often due to significant design flaws. Some studies reported that the incidence and degree of systemic hypertension was not any higher in obese patients with SDB than in obese patients without SDB. Some studies found an association between BP and the severity of SDB, as measured by such markers as degree of hypoxia or apnea, combined AHI, or the RDI. Other studies found that BP correlated best with weight, sometimes completely independent of the severity of SDB. In some studies, the effect of weight was not addressed. Most studies did not comment on other factors that can affect the level of BP, such as alcohol consumption and family history of hypertension.


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  		Table 1. Abbreviations Used in Tables

 

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  		Table 2. Obstructive Sleep Apnea Studies

 

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  		Table 2A. Continued

 

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  		Table 2B. Continued

 

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  		Table 2C. Continued

 

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  		Table 2D. Continued

 

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  		Table 3. Sympathetic Nervous System Studies

 

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  		Table 3A. Continued

 
The few population-based studies that looked at the incidence and association of systemic hypertension and SDB found that the incidence of SDB in patients with systemic hypertension was not much higher than the incidence of SDB in the entire population. Two studies60 61 showed a more direct relationship between SDB and systemic hypertension when adjusted for covariables, but the lack of matched controls hampers the conclusions of both of these studies. The lack of a matched control was a frequently noted flaw, as was the concern about selection bias, short-term follow-up, and small study populations.

Several studies that assessed the effect of treatment of SDB on systemic hypertension were reviewed. Again the results were mixed. The short-term studies, during which the subjects received continuous positive airway pressure (CPAP) for a few weeks, often showed some decline in either daytime or nocturnal BP, or both. However, some short-term studies showed that the effect of CPAP was not independent of weight loss. Longer-term studies, during which the patients received CPAP for several months, showed little effect on BP and even less effect when weight loss was considered. Only a few studies included untreated control subjects, usually patients who declined or could not tolerate CPAP gear. In these studies, the effect of CPAP on BP was not impressive.

Table 3 contains studies that looked at the effect of SDB on the sympathetic nervous system. The studies measured markers such as plasma and urinary catecholamines in patients with SDB, usually OSA. The studies consistently showed that patients with SDB have increased sympathetic nervous system activity. Some studies looked at such covariables as body mass and circadian activity.83 84 85 86 However, few if any of the studies found a correlation between the level of sympathetic activity and BP.

We conclude that any causal association between systemic hypertension and SDB is inconsistent and weak. The association is likely to be strongest in patients with the most severe SDB. Other significant cofactors that may exist in patients with SDB can account for the presence of systemic hypertension: body mass, alcohol consumption, or family history of hypertension. Nonetheless, the morbidities of systemic hypertension and SDB are significant when they occur separately, and may be even more significant when they occur together. Therefore, it is very important to question all patients with systemic hypertension about the possible presence of SDB.

It is possible that larger studies of longer duration, in particular with matched control subjects, may clarify a causal relationship, if any, that may exist between systemic hypertension and SDB. Studies are needed to assess whether systemic hypertension causes alterations in brain function that leads to central SDB, and whether a particular class of antihypertensive drugs might be more effective than others in patients with the comorbidities of systemic hypertension and SDB.

Based on the tabulated studies, a consensus was reached as to the conclusions that could be drawn with qualified levels of confidence: (1) patients with systemic hypertension have an increased incidence of sleep apnea, although comorbidities such as obesity probably contribute to the hypertension (levels A-2, B-3); (2) increased catecholamines associated with sleep apnea may contribute to daytime systemic hypertension (levels B-2, B-3); (3) because obesity is such a frequent comorbid condition with SDB and systemic hypertension, some patients with low daytime arterial oxygen tension and high carbon dioxide tension will improve with nasal CPAP or tracheostomy (levels B-2, C); (4) the incidence of ischemic heart disease is threefold higher among patients with sleep apnea syndrome than in the general population (levels A-2, B-3); (5) investigators conducting sleep studies may be advised to exclude sleep apnea syndrome in patients with idiopathic dilated cardiomyopathy and morphologic findings compatible with OSA (levels A-2, B-3); and (6) in patients with documented coronary artery disease, the increased catecholamine response to sleep apnea may increase the risk of arrhythmias and ischemic events, including angina, myocardial infarction, and sudden death (level C).


   Pathophysiology
TOP
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Summary of Association Studies
 Pathophysiology
Approach to the Patient...
 Final Summary of Conclusions
 References
 
Circadian Pacemakers and the Physiologic System:
In humans, hierarchically coupled ultradian rhythms (biorhythms of < 24 h periodicity) generate rhythms of circadian (24 h) periodicity early in life. Two coupled ultradian oscillators make up the circadian pacemaker87 : oscillator 1 contributes to control of activities including slow-wave sleep, plasma growth hormone release, and skin temperature; oscillator 2 contributes to control of activities including REM sleep, plasma corticosteroid concentration, body core temperature, and potassium excretion. Visual pathways are important in modulation of at least one of the oscillators (a "light pulse" sets the 24-h rhythm). Fine control of this system is provided by neuropeptides encoded by genes that have been associated with nervous system control in a variety of organisms.88

Circadian systems have been found to have multiple interconnected feedback loops involved in physiologic control that can be influenced by numerous social as well as environmental factors. Each individual’s circadian rhythm occurs in relationship to patterns of daily activities. While an individual functions within a particular environment, choices are made over what to participate in according to his/her particular mood or emotional affect as determined by the phase of his/her circadian rhythm. For the most part, an individual’s circadian rhythms are synchronized. Rhythms can be desynchronized by a person’s activities, as occurs with the gastrocephalic reflex after a large meal, or with the familiar jet lag. Such influences have been called Zeitgeber effects or "time givers." The relation between disturbed circadian cycles, abnormal wake-sleep patterns, and day-night variations in physiologic functions, such as thermoregulation and systemic high BP, have not been fully elucidated and await further investigation.

Cardiovascular and Cardiorespiratory Pathology of SDB:
During normal NREM sleep, the heart rate and cardiac output decrease by 5 to 10%.89 The stroke volume remains unchanged and BP decreases due to recumbency and decreased sympathetic activity. During REM sleep, there is evidence of increased sympathetic vasomotor activity and peripheral vasoconstriction. In patients with OSA, the heart rate decreases during apnea and increases abruptly immediately after apnea. The development of bradycardia in OSA is related to the duration of apnea and the degree of arterial oxygen desaturation. Sleep apnea patients have a bradycardiac response to the Müller maneuver, suggesting that upper airway obstruction may activate parasympathetic receptors at the site of airway collapse. Thus, in OSA, heart rates may be highly variable, and respiratory sinus arrhythmia (increased heart rate during inspiration) is common.

When the peripheral chemoreceptors in the carotid bodies are stimulated by hypoxia, there is an increase in minute ventilation, sympathetic stimulation of the peripheral blood vessels, and parasympathetic stimulation of the heart. This results in hyperventilation, peripheral vasoconstriction, and cerebral and coronary vasodilation. The cardiac chronotropic response to hypoxia is bradycardia, similar to the "diving reflex." The interactions of the peripheral chemoreceptors, trigeminal receptors, and upper airway receptors mediate the apnea, peripheral vasoconstriction, and bradycardia of the diving reflex. These reflexes attempt to restore and maintain perfusion of the vital organs. Hypoxia also stimulates local vasodilatory responses of the cerebral blood vessels.90

Hypercapnia and hypoxia are potent noxious stimuli mediated principally via central chemoreceptors that increase minute ventilation and sympathetic stimulation to peripheral blood vessels. This results in hyperventilation and peripheral vasoconstriction. Hypercapnia increases the peripheral chemoreflex response to hypoxia and hypercapnia.

Thus, the chemoreflex response to sleep apnea combines the effects of acidosis, hypoxia, and hypercapnia. Simulated sleep apnea studies have shown marked increases in sympathetic activity during the apnea and increased BP and heart rate on termination of the apnea.

OSA, Obesity, Pulmonary Hypertension, and Systemic Hypertension:
Obesity, restricted ventilatory patterns and reduced chemosensitivity to hypoventilation may be responsible for daytime hypoxia and pulmonary hypertension in OSA patients. Obesity is a risk factor for both pulmonary and systemic hypertension in OSA patients.

Hypoxia and hypercapnic acidosis can lead to pulmonary vasoconstriction and pulmonary hypertension. Episodes of nocturnal hypoxia, acidosis, and hypercapnia may remodel the pulmonary vasculature through smooth muscle hypertrophy and hypoxic pulmonary vasoconstriction. Over time, these changes lead to chronic pulmonary hypertension and cor pulmonale in 12% of patients with sleep apnea syndrome.91 These patients have significantly lower daytime arterial oxygen tension and significantly higher carbon dioxide tension.

Central Sleep Apnea and Cardiac Disorders (Systolic and Diastolic Dysfunction, Ischemic Heart Disease and Dilated Cardiomyopathy):
Sleep apnea syndrome is frequently seen in obese, middle-aged men who have concomitant recurrent hypercapnic respiratory failure, pulmonary edema, ventricular arrhythmias, and refractory left ventricular systolic dysfunction. In addition, many of these patients have dilated cardiomyopathy. Reversal of the apnea with nasal CPAP may improve the left ventricular ejection fraction by reducing preload and afterload.92

Fifty-five percent of patients with diastolic heart failure have SDB, predominantly OSA.93 Transient diastolic dysfunction during the apneic phase of Cheyne-Stokes respiration has been reported in patients with systolic dysfunction.93

Fifty percent of male patients with stable left ventricular dysfunction (ejection fraction < 45%) are reported to have sleep apnea.94 Sleep disruption and arterial oxygen desaturation are more severe in men with sleep apnea. Twenty-two percent of these patients have atrial fibrillation (compared to 5% in control subjects), and 51% have nocturnal tachycardia (compared to 37% in control subjects).

Sleep Apnea, Systemic Hypertension, and Diastolic Dysfunction:
During periods of hypoxia and apnea termination after partial or total occlusion of the upper airway, there is increased catecholamine release of norepinephrine. Left ventricular afterload increases, stroke volume decreases, and the pulmonary capillary wedge pressure increases.95 96 Severe hypoxia during repeated apneic episodes impairs myocardial contractility.97 This results in decreased left ventricular compliance, diastolic dysfunction, and finally reduced cardiac output.

Elevations in systemic BP and/or the lack of diurnal, chronotherapeutic dipping of systolic and diastolic BPs may eventually result in left ventricular hypertrophy. These changes are frequently seen in obese, middle-aged patients who deny previous hypertension, but have left ventricular hypertrophy on ECG or echocardiography without evidence of valvular heart disease, aortic coarctation, or other causes of systemic hypertension.98

In patients with OSA, inspiratory efforts against a closed upper airway generate a negative intrathoracic pressure.99 Right atrial pressure decreases, venous return increases, and the right ventricle becomes overdistended. The interventricular septum shifts to the left, impairing left ventricular filling, reducing stroke volume, and decreasing cardiac output. A paradoxical pulse, with a fall in systolic BP of > 10 mm Hg during inspiration may be observed in patients with OSA. The transmural gradient for both ventricles increases, ventricular afterload and left ventricular wall tension increase, and left ventricular compliance decreases. These changes lead to left ventricular hypertrophy and an elevated pulmonary capillary wedge pressure.100

OSA and Ischemic Heart Disease:
Cases of nocturnal angina and acute pulmonary edema have been reported in patients who have OSA, but without history of left ventricular systolic dysfunction. Flash pulmonary edema can occur in patients with left ventricular hypertrophy, diastolic left ventricular dysfunction, and coronary artery disease.101 These patients have impaired left ventricular relaxation, and during periods of myocardial ischemia have reduced cardiac filling and output.102

The increased left ventricular afterload from the systemic hypertension increases myocardial oxygen demand. Increased sympathetic activity may contribute to myocardial ischemia and coronary plaque disruption. Chronically elevated catecholamine levels may injure the myocardium and cause myocardial hypertrophy. Myocardial ischemia is observed during REM sleep, and reflects the frequency and severity of oxygen desaturation. An apnea index > 5.3 episodes per hour of sleep is an independent predictor of myocardial infarction.103

Sleep Apnea and Cardiac Arrhythmias:
Hypoxia and acidosis accompanying sleep apnea can result in malignant cardiac arrhythmias and nocturnal sudden death. Hypoxia during apnea results in peripheral vasoconstriction and bradycardia. Nocturnal palpitations on awakening may be due to increased catecholamines from apneic phases of sleep apnea syndrome.

Tachyarrhythmias and bradyarrhythmias have been reported in > 75% of patients with sleep apnea syndrome. During the apneic phase, increases in vagal tone cause sinus bradycardias, sinus pauses of 2 to 13 s, and atrioventricular node conduction delays in 8% of patients.104 105 Atrial and ventricular tachycardias and premature ventricular contractions are due to the catecholamine surges and hypoxemia at termination of the apnea.

Sudden unexplained nocturnal death syndrome primarily affects men aged 25 to 44 years from Asian countries including the Philippines, Japan, Thailand, Cambodia, and Laos. Ventricular fibrillation has been documented on ECG monitoring during successful resuscitation. Witnesses have reported choking, gasping, and labored breathing just before sudden death. Excess sympathetic discharge during REM sleep is postulated, as death occurs 3 to 4 h after sleep onset. The exact cause of sudden unexplained nocturnal death syndrome, however, is unknown.106 107

Sleep Apnea and Neurologic Disorders:
Elevations in intracranial pressure and reduced cerebral blood flow to the temporal and parietal areas have been reported in patients during sleep apnea.10 83 These phenomena may contribute to the increased risk for cerebral infarction and hypoxic seizures observed in patients with OSA.


   Approach to the Patient With SDB and Systemic Hypertension
TOP
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Summary of Association Studies
 Pathophysiology
 Approach to the Patient...
Final Summary of Conclusions
 References
 
SDB and systemic hypertension are two relatively common conditions that may occur in the same patient. The following discussion gives the clinician some guidance on how to evaluate patients for both conditions. Management issues are discussed.

First, how might SDB affect a patient with systemic hypertension? Potentially, the SDB contributes to the hypertension, as discussed in previous sections. Many patients with systemic hypertension complain of insomnia, fatigue, or both; in these patients, SDB might contribute to their symptoms.108 Patients with systemic hypertension often have anxiety, which can affect sleep, and SDB may be an ongoing factor in the anxiety. Stress may contribute to systemic hypertension, although its role remains less than clear.109 110 111 112 113

There may be other factors contributing to the fatigue and impaired sleep that patients with hypertension can experience. Antihypertensive medications may account for some of the fatigue. While long-term studies tend to show little difference in side effects between the classes of antihypertensive medications; in general, central-acting drugs and ß-blockers are more often associated with fatigue and impaired sleep.114 115 116 117 118 Sometimes fatigue is the result of overtreatment of the hypertension causing effects such as out-of-office hypotension.

When should SDB be considered in a patient with systemic hypertension? One might consider an investigation for SDB especially if the patient has symptoms (such as headache or fatigue) or signs (such as body habitus) of SDB. Questionnaires have been developed to help clinicians identify patients likely to have SDB. A developing practice is to screen for SDB in patients with resistant hypertension, even when clear signs or symptoms of SDB are not present, in the hope that identification and treatment of the SDB will lead to improved BP control. Anecdotally, improved BP and overall sense of well-being have been seen in some patients with hypertension who had their SDB treated. If the patient has unexplained or worse cardiac disease than expected based on the level of BP, one might consider an evaluation for SDB. Because of the significant morbidity of SDB, perhaps one should consider the possibility of SDB in any patient with systemic hypertension.

In the patient with established SDB, are there any suggestions for management of hypertension? Clearly, these patients should be monitored closely for the development of hypertension and cardiovascular disease, and many will have hypertension and cardiovascular disease when the diagnosis of SDB is made. Lifestyle measures, especially weight loss and exercise, will be important components of the hypertension treatment plan. Patients with significant SDB tend to be volume expanded, and thus sodium restriction can help control the BP. As far as antihypertensive medication choice, this decision is best made based on the patient’s comorbidities. For example, if congestive heart failure is present, then one should consider an angiotensin-converting enzyme inhibitor, diuretic, and ß-blocker for management of hypertension. In the absence of comorbidities, the choice of drug depends on such factors as patient characteristics, drug expense, and drug side effects. Because of the evidence that suggests heightened sympathetic nervous system activity in SDB, an inhibitor of the sympathetic nervous system, such as a ß-blocker or centrally acting medication might be valuable, although there are no studies to support that hypothesis. A ß-blocker should be used with caution if the patient also has obstructive airway disease.


   Final Summary of Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Summary of Association Studies
 Pathophysiology
 Approach to the Patient...
 Final Summary of Conclusions
References
 
Many patients with systemic hypertension, particularly those with concomitant significant obesity, will have sleep apnea. Sleep apnea is associated with an increased ventilatory and sympathetic response to hypoxia. Exaggerated increases in BP after sleep apneic episodes are often associated with increased incidence of cardiac disorders in patients with sleep apnea.

Hypoxia, associated with SDB, may increase catecholamine release, contributing to the development of systemic hypertension. However, studies to date have not convincingly demonstrated a causal relationship.

Although the treatment of OSA with CPAP may improve systemic hypertension, this effect is often nullified or significantly reduced due to concomitant weight loss. Assessment for sleep apnea should be seriously considered, particularly in significantly obese patients with either systemic hypertension or idiopathic dilated cardiomyopathy and morphologic findings compatible with OSA.

Limited echocardiography may have a role in evaluation of cardiovascular pathology associated with SDB and systemic hypertension to help assess left ventricular mass and the potential for increased morbidity and mortality from cardiovascular disease. Future studies of the relationships that exist between SDB and systemic hypertension need to include matched control subjects, tighter and more consistent definitions, and stricter criteria for outcomes


   Acknowledgements
 
We owe a debt of gratitude to the American College of Chest Physicians who encouraged the initiation of this review. We would also like to acknowledge the technical writing assistance of James Breeling, Alice Stargardt, and Graig Eldred, and the assistance in literature research by Barbara Bartkowiak and Rose Sterzinger-Johnson.


   Footnotes
 
Abbreviations: AHI = apnea/hypopnea index; CPAP = continuous positive airway pressure; NREM = non-rapid eye movement; OSA = obstructive sleep apnea; RDI = respiratory disturbance index; REM = rapid eye movement; SDB = sleep-disordered breathing

Received for publication November 19, 2001. Accepted for publication July 10, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Summary of Association Studies
 Pathophysiology
 Approach to the Patient...
 Final Summary of Conclusions
 References
 

  1. Coccagna, G, Mantovani, M, Brignani, F, et al (1972) Tracheostomy in hypersomnia with periodic breathing. Bull Physiopathol Respir 8,1217-1227
  2. Lugaresi, E, Coccagna, G, Mantovani, M, et al Effects of tracheostomy in two cases of hypersomnia with periodic breathing. J Neurol Neurosurg Psychiatry 1973;36,15-26[ISI][Medline]
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