Case–control and cross-sectional studies have proven a strong association between cerebrovascular disease, especially when evidenced as stroke, and sleep-disordered breathing (SDB), most frequently in the form of obstructive sleep apnea (OSA).1–3 In the United States stroke accounts for half of all acute neurological hospital admissions, while worldwide it is the second major cause of death and the leading cause of long-term disability.4,5 OSA is also a very frequent and serious problem, with a prevalence up to 9% in women and 24% in men in the general adult population.6 Cohort studies have shown that OSA is a risk factor for both hypertension and stroke.3,7–10 Although speculation exists regarding direct cause-and-effect relationships between OSA and stroke, there is evidence of negative synergism in regard to morbidity and mortality when these two common multifactorial health problems present together. Nevertheless, the effectiveness of treating OSA immediately after stroke has occurred is controversial, but should future studies prove a clear benefit in treating OSA in this scenario, the routine screening for OSA in patients with stroke may become the standard of care.
Overview of relationship between OSA and stroke
Case–control studies from as early as 1992 have confirmed a strong association between stroke and OSA.1 One polysomnographic investigation of 24 consecutively encountered inpatients with acute stroke and 27 gender- and age-matched control subjects without stroke found OSA in 10 of 13 men with stroke (77%) and in only 3 of 13 men without stroke (23%) (p = 0.0169).2 Seven of the 11 women with stroke were found to have OSA (64%), while only 2 of the 14 women without stroke (14%) had OSA (p = 0.0168).
In a cross-sectional analysis of 1,475 adults ages 30 to 60 years, a baseline apnea/hypopnea index (AHI) of 20 or more independently increased the odds for stroke (3.83; 95% CI 1.17–12.56; p = 0.03) when compared to an AHI of less than 5, even after adjusting for known confounding factors.3
Sleep-disordered breathing as a risk factor for stroke
A longitudinal analysis of 1,189 subjects at 4-year intervals over a 12-year period, in a model controlled for age and gender, showed that a baseline AHI of 20 or more was associated with a significantly higher odds ratio (OR) for incident stroke when compared to an AHI of less than 5 (4.48; 95% CI 1.31–15.33; p = 0.02).3
In a study of elderly subjects (median age 77.28 years) drawn from a random one-stage cluster sampling stratified by census area, age, and gender, it was determined after a 6-year period without receiving treatment for apnea, individuals with an AHI of 30 or more were at relative risk for “incident transient ischemic attack or ischemic stroke” with a hazard ratio (HR) of 2.52 (95% CI 1.04–6.01, p = 0.04).9
An analysis of 392 randomly selected subjects with symptomatic angina pectoris and coronary artery disease was performed over a 10-year period. Independent of confounders, subjects with an AHI of more than 5 but less than 15, and those with an AHI of 15 or more, respectively had a 2.44 (95% CI 1.08–5.52, p = 0.011) and a 3.56 (95% CI 1.56–8.16, p = 0.011) times increased risk of stroke compared to those without apnea.10
An observational cohort study of 1,022 subjects referred for suspected SDB compared the combined risk of developing composite stroke, transient ischemic attack (TIA), or death from any cause in a group of 697 individuals with OSA (AHI ≥ 5) to subjects without OSA (AHI ≤ 5).8 Follow-up data from 842 subjects, after a mean of 3.4 years for the SDB group and after a mean of 3.3 years for the comparison group, and after adjusting for confounding factors, showed that OSA was associated with a significant risk for composite stroke, TIA, or death (HR 1.97; 95% CI 1.12–3.48; p = 0.01).
Potential mechanisms for stroke in sleep-disordered breathing
As early as 1985, experts hypothesized that the hypoxia, blood pressure instability, and cardiac dysrhythmia associated with OSA might contribute to stroke (Fig. 19–1).11,12 Polysomnographic studies using microneurography, a tool that uses a tungsten needle electrode inserted into the peroneal nerve to directly measure efferent sympathetic nerve activity from postganglionic, unmyelinated C-fibers, have documented a simultaneous elevation in sympathetic and parasympathetic activity in OSA, evidenced as respective increases in blood pressures to 215/130 mm Hg (immediately following apneas) and up to 20 seconds of asystole during obstructions. Figures 19–2 and 19–3 respectively show concurrent polysomnographic/microneurographic studies that reveal a marked elevation in blood pressure following an apneic event, in association with a sinus arrhythmia.13
If there is an equal probability that stroke can occur at any time over a given 24-hour period, 33% of all strokes should then occur during the idealized 8-hour period allotted for sleep. Nevertheless, sleep is associated with a relatively high frequency of stroke, and one study on acute stroke has shown that significantly more than expected subjects with OSA suffer stroke during sleep (54%; p = 0.0304).2,14
The most prolonged period of rapid eye movement (REM) sleep, and the greatest circadian risk for stroke, occurs during the early morning hours. The general paresis associated with normal REM sleep tends to worsen OSA. REM sleep is also normally associated with relatively high sympathetic nerve activity (SNA), which is further elevated in OSA.15,16
In addition, the normal increase in cerebral blood flow that occurs during REM sleep can potentially lead to central nervous system (CNS) compromise from a negative synergism with the increase in intracranial pressure and reduced cerebral perfusion pressure that has been associated with OSA.17,18
The normal early morning hematological milieu is associated with low fibrinolytic activity and elevated catecholamine levels and blood viscosity.19 OSA appears to increase platelet aggregability, which may further potentiate the risk for plaque, thrombus, and embolus formation during the later stages of sleep. The increased levels of proteins associated with platelet activation (soluble CD40 ligand and soluble P-selection) found in apneics have also been linked with silent brain infarction.20
Stroke as a risk factor for sleep-disordered breathing
Although there is a relative paucity of information regarding human respiratory centers, detailed animal studies and human case reports suggest stroke can cause sleep apnea. Automatic respiration, although presumed to originate in the limbic cortex (and subject to modulation by diencephalic, pontine, and cerebellar structures), is dependent on the medullary respiratory center (MRC; Figs. 19–4 and 19–5).21
The MRC is identified with two medullary regions, the dorsal respiratory group (DRG) and the ventral respiratory group (VRG). The DRG, located in the dorsomedial region of the medulla, is physiologically coexistent with inspiratory neurons in the caudal and medial zone (cardiorespiratory zone) of the nucleus solitarius (NS) and the adjacent reticular formation. The DRG is activated by vagal impulses and changes in the chemical environment (CO2 accumulation). It initiates inspiration directly via activation of spinal motor neurons to intercostal, accessory respiratory, and diaphragmatic muscles; or through efferent connections to the VRG. The VRG, located in the ventrolateral medulla, is physiologically coexistent with the nucleus ambiguuus (NA), a caudal extension of the NA (the nucleus retroambiguus), and the adjacent reticular formation. It contains both inspiratory and expiratory neurons. The VRG initiates respiration through projections from the NA to branchiomeric muscles of the pharynx and larynx via the vagus nerve, and connections from the nucleus retroambiguus to spinal motor neurons that supply intercostal, accessory respiratory, and diaphragmatic muscles.
Injury to centers for automatic respiration can induce dependence on cortically driven, voluntary waking breathing processes (Ondine’s curse).22 Central sleep apnea has been documented after stroke involving the NS of the DRG, presumably due to impaired inspiratory mechanisms.23 On the other hand, OSA has been associated with stroke of the VRG, possibly due to NA damage, as the NA, through the vagus nerve (CN X and the accessory nerve [CN XI]), provides motor innervations to the larynx and pharynx.24,25
Review of acute events with cerebrovascular insufficiency in sleep
Despite the relative paucity of information concerning the human pathophysiological response following injury to central respiratory events, animal experiments and case reports support the hypotheses that stroke can either cause or result from SDB. A recognized temporal association exists between abnormal respiration and neurological emergencies resulting from encephalopathy, seizure, tumor, trauma, and stroke.
In critically ill patients a baseline predisposition to respiratory abnormalities can be exacerbated during sleep, and resolution of a sleep apneic event is largely dependent on the arousal phenomena. OSA has been demonstrated to increase the arousal threshold.26 The finding that the arousal threshold to hypoxia and hypercarbia is further increased after sleep deprivation, a common finding in acutely ill patients, led the authors of one study to “speculate as to the clinical significance of these findings as they apply to the patient with a precarious respiratory status.”27 Impaired arousal in such situations has led to more prolonged apneas and electroencephalographic flattening with generalized tonic spasms described as “cerebral anoxic attacks.”28
A previously healthy 32-year-old man had a 2-week flu-like illness, followed by a delirium that necessitated a medical intensive care unit (MICU) admission for the workup and treatment of possible herpes encephalitis.29 Continuous cardiac and oximetry monitoring showed that during periods of sleep, the patient had episodes of oxygen desaturations to 85% with bradycardia and asystole followed by arousals and subsequent prolonged periods of unresponsiveness.
To address possible seizure, a portable continuous video-electroencephalographic bedside analysis was performed in the MICU. During sleep, 15 events were captured that revealed paradoxical respiratory efforts associated with bradycardia and 8-second asystolic periods, without epileptiform activity. Subsequently, a portable full polysomnographic study performed in the MICU was used to formally diagnose OSA (AHI = 25.4), with obstructions occurring in association with an SaO2 low of 88% and asystolic periods lasting up to 11 seconds (Figs. 19–6 and 19–7). Emergent continuous positive airway pressure therapy (CPAP) was initiated, and 8.0 cm H2O (CWP) resulted in a resolution of all major obstructions and cardiac dysrhythmias, with an SaO2 that remained at or above 94%, including during prolonged supine sleep.
Within 10 days after clinical improvements were noted, no obvious apneas were observed during daytime naps without CPAP. As such, a subsequent polysomnogram was performed, showing an AHI of only 5.4, with an SaO2 low of 93%, and obstructions associated with bradycardia and premature ventricular complexes, but without asystolic periods (all apneas and electrocardiographic abnormalities resolved with 8 CWP of CPAP).
Within 18 days of the first polysomnogram, the patient’s cognition had markedly improved. He was alert and responsible for his own activities of daily life. Prior to discharge, a third polysomnogram, without CPAP, revealed a resolution of all major obstructions, including during prolonged REM sleep while lying in the supine position (Fig. 19–8).
Hypoxemic encephalopathy requiring emergency rescue breathing
A 52-year-old man with multiple medical problems, including previously diagnosed OSA, pulmonary hypertension, diabetes, and myocardial infarction was admitted for a coronary artery bypass graft.30 Postoperatively, despite CPAP, he had persistent apneic events in sleep, and a polysomnography study for bi-level PAP titration was requested.
During the first REM sleep period an obstructive apnea persisted for 90 seconds in association with an SaO2 low of 31% and tachy-bradycardia, followed by diffuse electroencephalographic slowing suggesting cerebral hypoxemia (Fig. 19–9). The obstruction persisted despite increasing bi-level PAP to 15/10 CWP, at which time the patient remained unresponsive, despite vigorous physical stimulation, with a flattening of all electroencephalographic activity. He then became cyanotic and emergency rescue breathing was initiated.
The patient subsequently opened his eyes, resumed a normal breathing pattern, and responded to commands in a slow encephalopathic manner. After a progressive buildup of diffuse theta slow wave activity, followed by a mixture of minimal theta with interspersed occipital alpha rhythm, the patient’s cognition returned to baseline. Later the study was continued and further increases in bi-level PAP to 29/25 CWP led to a resolution of all major obstructive events, after which the patient reported sleeping better than usual.
Hypoxemic encephalopathy and death
An 80-year-old man with Alzheimer’s disease, hypertension, and hypothyroidism was admitted for palliative care from a nursing home with an exacerbation of severe chronic obstructive pulmonary disease and congestive heart failure with atrial fibrillation/flutter, under a do-not-resuscitate/do-not-intubate status.30 The patient’s wife gave written consent for a portable polysomnogram to be performed in the MICU as part of an institutional review board-approved study, with the instructions that no heroic measures (including the use of bi-level PAP or CPAP) to sustain life were to be instituted.
While lying supine with the head of the bed elevated 15 degrees and while receiving 9 liters of supplemental oxygen, the patient was found to have OSA with a respiratory disturbance index of 37 events per hour, and an SaO2 low of 80%, prior to his final series of apneas. Following a 30-second obstructive apnea, the SaO2 dropped to 12% and the electroencephalogram assumed an irregular, disorganized, delta slow wave pattern, followed by electrocerebral silence while using a recording sensitivity of 1.0 µv/mm, with no appreciable changes despite noxious stimuli (Fig. 19–10). This was followed by a mixture of obstructive and new-onset central apneas, and finally by complete respiratory arrest.
Simultaneous to the 30-second obstruction, the heart rate decreased from 148 beats per minute (bpm) to 40 bpm. Bradycardia persisted for 29 minutes and was followed by cardiac arrest, at which time the patient was declared dead (Fig. 19–11).
Transient ischemic attack
A TIA is a focal neurological deficit that resolves within 24 hours. As one third of these events would be diagnosed as stroke based on diffusion weighted magnetic resonance imaging, the TIA is deserving of the descriptor “mini-stroke.”31,32 As such, polysomnographic investigations in TIA have been used as indirect evidence to support a cause-and-effect relationship between OSA and stroke.
In one report, an individual with a history of vertebrobasilar stroke began waking with TIAs described as hemiplegia with ophthalmoplegia.33 The polysomnogram showed that each TIA was immediately preceded by an obstructive apnea. It was hypothesized these TIAs were the result of OSA-induced transient hemodynamic impairments to a previously injured brain stem.
Evaluation and management for acute and emergent cerebrovascular events in sleep
The systemic effects of a wide variety of critical illnesses can adversely affect voluntary and automatic respiratory function at multiple levels from cortex to the MRC, and as such the evaluation and management must be tailored to the specific patient and illness.
This case (described in the previous section) used serial polysomnographic studies to document a progressive resolution of OSA that paralleled the successful treatment of a suspected viral infection of the CNS.29 The evaluation included a white blood cell count of 9.3 K/mm3 (79% polymorphonuclear cells and 11% lymphocytes), and a cerebrospinal fluid (CSF) analysis that revealed 74 mononuclear cells, 149 red blood cells, a protein level of 62 mg/dL, and a glucose level of 64 mg/dL (with a serum glucose level of 163 mg/dL). The serum and CSF were assessed for virus, bacteria, spirochetes, fungus, rickettsia, and tularemia. Studies were negative for Listeria, Mycoplasma pneumoniae, brucellosis, herpes simplex virus (HSV), lymphocytic choriomeningitis virus, adenovirus, influenza, picornavirus, syphilis, Lyme borreliosis, Leptospira, Cryptococcus, Rickettsia rickettsii, and typhus. Other unremarkable studies included a urinalysis, general blood chemistries, Westergren sedimentation rate, C-reactive protein (CRP), rapid plasma reagin (RPR), antinuclear antibody (ANA), screens for illicit drugs and heavy metals, chest x-ray, echocardiography, cerebral angiography, brain MRIs (with and without gadolinium), and a right frontal brain and dural biopsy.
Given the severity of illness, the patient was treated in the MICU for herpes encephalitis with intravenous acyclovir and broad-spectrum antibiotics. As there was concern for both seizure and poor cerebral perfusion secondary to a primary cardiac problem, the treatment regimen included both diphenylhydantoin and atropine (1 mg IV as needed for bradycardia/asystole). As the patient clinically vacillated between states of delirium, stupor, and sleep, his treatment also included haloperidol 10 mg every 12 hours per nasogastric tube. Although transient dysfunction of central respiratory centers from an inflammatory viral response might reasonably explain OSA, in this case multiple other factors, including the use of sedating medications, had to be considered in the management of such an ill patient.
Life-threatening hypoxemic encephalopathy
Research has shown that one of the immediate effects associated with the initial use of CPAP therapy is a further increase in the arousal threshold. In one study, subjects with OSA had consecutive nightly assessments, without and then with CPAP.34 Treatment resulted in an up to 370% mean increase in percent time spent in stage 3 NREM sleep, and in longer periods of REM sleep. It has been speculated that this “rebound” sleep may lead to “marked depression of the patient’s arousability,” leaving him or her “vulnerable to potential life-threatening hypoxemia.”35 In regard to rebound sleep, it has been stated that “This phenomenon can occur in patients usually with severe sleep apnea and carbon dioxide retention when a subcritical level of CPAP is selected, resulting in partial upper airway obstruction during these abnormally long episodes of REM sleep.”35
The second and third cases described in the previous section support the hypothesis that an increase in the arousal threshold in critically ill patients with OSA may predispose to cerebral dysfunction and potentially death from prolonged apnea. In critically ill patients, titration with CPAP and bi-level PAP should be undertaken with extreme caution, and on occasion more aggressive therapies such as emergency rescue breathing and mechanical ventilation may be necessary.
The third case provides strong support for routinely monitoring SaO2, arterial blood gases, and end-tidal CO2 (PETCO2) in critically ill patients with chronic obstructive pulmonary disease and neuromuscular disorders when apnea is suspected, as supplemental oxygen can lead to hypoventilation and hypercapnia and potential respiratory arrest after a brief period of time.30 When the placement of an arterial line is not practical or possible, a single arterial blood gas study can provide a baseline from which PETCO2 trends can be followed with relative confidence.36
The third patient was admitted on 5 liters of supplemental oxygen, with a PaO2 of 60 mm Hg. A subsequent increase to 9 liters of supplemental oxygen resulted in a sustained SaO2 of at least 90%, without respiratory compromise for over 6 hours. During the polysomnogram, the PETCO2 and SaO2 were simultaneously monitored, with respective waking baseline values of 23 mm Hg and 92%, and a sleeping PETCO2 that ranged from 32 mm Hg (in association with an SaO2 of 95%) to a low of 19 mm Hg with an SaO2 of 94% (noted just prior to the terminal obstructive apneic event).
Before the terminal event, this patient had only obstructive respiratory abnormalities, and the polysomnographic tracing documented the temporal, cause-and-effect association between a prolonged obstructive apnea and electroencephalographic evidence of hypoxemic encephalopathy without arousal, followed by a suspected myocardial infarction, after which all subsequent respiratory abnormalities appeared agonal in nature.37
Transient ischemic attack
The benefits of aggressive therapeutic intervention have been shown in some cases of TIA. One report concerned an obese woman with a history of loud snoring and excessive sleepiness who awoke with a TIA with transient episodes of aphasia.38 The polysomnogram in this case revealed an AHI of 83.4, with oxygen desaturations less than 50%. The implementation of CPAP paralleled the immediate resolution of any further TIAs.
Post-stroke treatment of obstructive sleep apnea: morbidity and mortality
One study determined the functional abilities of 19 stroke patients (18 with OSA) using a variety of outcome measures.39 Subjects with abnormal oximetry readings, histories of snoring, and hemispheric stroke had worse functional outcomes. In another study of 61 stroke patients, apneics had lower Functional Independence Measure (FIM) scores at admission and discharge, and apnea was independently correlated with functional impairment and length of hospitalization.40
Inconsistent treatment adherence in the stroke population with OSA has significantly limited attempts to address the overall effect of CPAP on mortality and morbidity. Although one study of 152 patients with acute ischemic stroke showed that SDB was associated with an increased post-stroke mortality, CPAP adherence was only 15%.41
In a study of 51 patients with relatively recent stroke and an AHI of at least 20, only 15 individuals (29.4%) were able to tolerate CPAP after 1 month of attempted therapy. The incidence of new vascular events was greater in subjects who could not tolerate CPAP (p = 0.03), with intolerance to CPAP increasing the probability of a new vascular event fivefold (OR 5.09).42
A study of 32 subjects with recent stroke showed that only 7 (22%) of the patients were able to tolerate nasal CPAP for 8 weeks.43 The high dropout rate was related to difficulties with CPAP use as perceived by the patient and family members, facial weakness, motor impairment, and increased difficulties and discomfort with the use of a full-face mask. Another report compared CPAP headgear systems for sleep apnea treatment of stroke patients. Patients took longer to put on (p < 0.01) and remove (p < 0.01) the traditional headgear when compared to a one-piece head frame headgear system.44 These authors concluded that headgear systems should be carefully considered when fitting a stroke patient with a CPAP mask.
One group who studied CPAP compliance in patients with recent stroke stated “Better education and support of patients and families, and special training session in rehabilitation services, will be needed to improve compliance.”43 Indeed, one small study suggested that in a supportive environment patients with stroke and OSA are able to tolerate CPAP with normalization of oxygen saturations despite moderately severe motor and cognitive FIM scores.45
In addition, positional sleep apnea (apnea that worsens in the supine position, due in part to compromising gravitational effects on the oropharynx) has been shown to be a prominent feature in acute stroke. A study of 43 individuals with either acute stroke or TIA showed that the mean supine AHI of 17.7 ± 20 was significantly higher than the mean AHI of 8.4 ± 14.6 for “other than supine” positions (p < 0.001).46 In another study of 55 patients evaluated within 72 hours of stroke, OSA was diagnosed in 78% (of whom 65% had positional apnea). After 6 months, repeat studies showed OSA in only 49%, of whom 33% had positional apnea.47 The authors said “positional sleep apnea is a predominant feature in acute stroke and its incidence decreases significantly during the following months. These findings may have implications for sleep apnea treatment in patients with acute stroke.”
The strongest relationship between SDB and cerebrovascular disease has been demonstrated in the association between OSA and stroke. These two common, serious multifactorial health problems share many risk factors and frequently occur together, often portending a relatively grim prognosis. Nevertheless, recent reports suggest in the setting of acute stroke that treatment of OSA with aggressive and closely monitored ventilatory support and positional therapy may allow for serial polysomnographic studies, which over time may permit eventual reduction in OSA treatment.
The evaluation and treatment must be tailored to each patient and the unique elements of his or her overall illness. In some cases a baseline arterial blood gas analysis, with continuous electrocardiographic, SaO2, and PETCO2 monitoring, bedside video-electroencephalography, and portable polysomnographic studies in the MICU, may prove of great benefit. Caution should be exercised when considering the use of supplemental oxygen therapy, especially when hypoventilation and CO2 retention is suspected in patients with underlying chronic obstructive pulmonary disease or neuromuscular compromise.
When OSA is diagnosed, positional therapy, including simple elevation of the head of the bed, should always be a consideration. CPAP titrations should be performed in an efficient, cautious manner using comfortable apparatus that is presented in a supportive educational manner with close follow-up for adherence. In severe cases, more aggressive and extreme forms of therapy, including intubation and tracheostomy, may be considered.
Brown et al have emphasized a need for more clinical trials to address the potential value of diagnosing and treating OSA immediately after stroke.48 If scientific methods can be used to prove that a focused and aggressive treatment plan for OSA in patients with acute stroke can improve overall morbidity and mortality, then routine screening and treatment of OSA in the stroke population might become the standard of care.
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