Basics of Sleep Apnea and Ischemic Stroke
Sleep apnea is frequent in patients with acute ischemic stroke
Although many early epidemiological studies found an association between sleep apnea and cardiovascular diseases, it took a long time until stroke clinicians and scientists adopted the notion that sleep apnea has potential deleterious effects on the cerebral vasculature as well. While in the general population approximately one in ten adults suffer sleep apnea of various subtypes and degrees, its frequency in acute stroke patients appears much higher, reaching almost 70%.1-3
Sleep apnea is a risk factor for acute ischemic stroke
Two prospective cohort studies revealed a 2- to 4.5- fold independent risk for a first-ever ischemic stroke in patients with sleep apnea compared to those without,4-5 suggesting that sleep apnea constitutes a pre-existing condition rather than a consequence of acute ischemic brain damage. Moreover, the cumulative risk of suffering a recurrent ischemic stroke may grow notably in stroke victims who have co-existing sleep apnea.6,7 Yet it still remains a matter of debate whether the deleterious effects of sleep apnea are independent of other comorbidities often existing in those who have suffered a stroke, such as hypertension, atherosclerotic disease or atrial fibrillation.
The pathophysiologic mechanism by which sleep apnea contributes to cerebrovascular complications is not fully understood
A variety of mechanisms such as inflammatory processes, endothelial malfunction, enhanced activity of thrombocytes and coagulation factors leading to hypercoagulable state, and progression of atherosclerosis may trigger atherothrombotic and embolic strokes.2,8 The latter mechanism is supported by a recent observation that the intima media thickness in the carotid arteries, a marker for general atherosclerotic burden, seems much more accentuated in patients with sleep apnea than in those without.9 Cardiac arrhythmias may be of particular interest, as approximately 50% of patients with atrial fibrillation presenting for cardioversion have obstructive sleep apnea as compared with 30% in the general cardiology population.8 Also, intrathoracic pressure changes in patients with obstructive sleep apnea may boost the risk for paradoxical embolism in those who have a co-existing patent foramen ovale, justifying further diagnostic evaluation for sleep apnea. In addition, a wide spectrum of further cardiovascular abnormalities affecting systemic hemodynamics (i.e., increased sympathetic activity, disturbed heart rate variability) has been reported in patients with sleep apnea.8 However, the variety of proposed underlying mechanisms might explain why no particular stroke etiology (e.g., large artery atherosclerosis, small vessel occlusion, cardioembolism, other cause, undetermined cause) has been linked to sleep apnea so far.1,2 Of note, the assumption that abnormal cardiovascular responses to nocturnal apnea episodes contribute to sleep-related ischemic strokes has not been fully supported by various studies with divergent results.(10)
Sleep apnea may alter cerebral hemodynamics
Sleep apnea may negatively influence the clinical course in the acute phase of ischemic stroke. More specifically, up to an 8-fold increased risk for early worsening of neurological symptoms within 72 hours from stroke onset has been described.11 In patients with sleep apnea, cerebral autoregulation is impaired as demonstrated by transcranial Doppler studies,12 putting further brain tissues at risk of ischemic injury. In the most severe case, this may lead to depletion of the collateral blood flow when vessels in the non-ischemic area dilate more, leading to blood flow diversion from the ischemic area to the non-ischemic areas. This process is mediated by vasomotor reactivity in response to simple stimuli, such as arterial carbon dioxide increase with hypoventilation. Apnea may further worsen hypoperfusion in the ischemic brain area. This "cerebral blood flow steal - phenomenon" was demonstrated by transcranial Doppler in real time. When it lead to early neurological worsening it was termed the reversed Robin Hood syndrome as it serves "to rob the poor to feed the rich."13 When found during the initial hospitalization for an ischemic stroke, this syndrome leads to a 4-fold increase in stroke recurrence within the same arterial territory.14
Sleep apnea needs to be considered when it comes to secondary stroke prevention
As with other vascular diseases, secondary prevention is crucial for short- and long-term outcome as well as recurrence risk in patients with acute ischemic stroke. Organized stroke unit care enables optimized acute stroke management, early detection of the underlying stroke etiology and corresponding vascular risk factors. Improved outcomes and reduced recurrent stroke risk for patients admitted to a stroke unit have been shown as opposed to patients who are admitted to a general neurological ward. However, acute management and routine screening for sleep apnea in acute ischemic stroke patients has not yet been implemented in stroke guidelines. As recently shown, the early utilization of cardiorespiratory polygraphy, an easy-to-handle unattended screening device, allows proper identification of stroke patients with sleep apnea and its routine implementation on a stroke unit could facilitate appropriate post-stroke sleep apnea management.(10) Moreover, sleep apnea and intracranial blood flow steal represent novel and linked therapeutic targets for both early correction of brain hypoperfusion and secondary stroke prevention.15
Non-invasive ventilatory correction for acute ischemic stroke patients
Some, though not all studies have shown the safety and beneficial effects of non-invasive ventilation on improved quality of life and reduced cardio- and cerebrovascular morbidity and mortality in the general sleep apnea population. However, only a few studies investigated the use of non-invasive ventilation in stroke patients and the definite benefit for a better clinical outcome. For example, continuous positive airway pressure (CPAP) started within two months from acute stroke onset lead to a reduced 5-year-mortality and a reduced 7-year- stroke recurrence rate.16,17
In the acute phase of ischemic stroke, an ischemic tissue-at-risk (i.e., penumbra) may be present for many hours and amenable to reperfusion. Consequently, any treatment that potentially augments cerebral perfusion may be justified. Administration of oxygen via nasal cannula, as is commonly performed in many stroke units, may not be sufficient to reverse cerebral hemodynamic disturbances that may occur during apnea episodes and may result in acute deterioration in stroke patients with sleep apnea. In fact, hypoxemia and hypercapnia may affect cerebral blood flow by inducing vasodilation, and diversion of blood flow during hypoventilation or apneic episodes was established.13-15 To counteract potentially harmful effects of sleep apnea, recent approaches focus on the prompt initiation of CPAP or bilevel positive airway pressure (BPAP) in the hyper-acute phase of stroke, when hemodynamically compromised tissue can potentially be salvaged. However, only a few smaller investigations aimed at tolerability and safety showed promising results.18-20 However, most of these studies had to deal with low recruitment rates and poor patients adherence to treatment, a well-known issue that may be even more pronounced in stroke patients due to post stroke-related neurological impairments. Auto-titrating non-invasive ventilation devices seem to be worth further investigation as tolerability exceeds common devices.21 Currently, a multicenter randomized trial utilizing auto-BPAP in acute ischemic stroke patients within 48 hours from symptom-onset is underway and will contribute to a better understanding of how early treatment with non-invasive ventilation helps to counterbalance, or possibly reverse, the deleterious effects of sleep apnea in acute ischemic stroke patients.
Key Learning Points
- Sleep apnea is very frequent among ischemic stroke patients and contributes to an increased risk for both first-ever and recurrent ischemic stroke. Also, it may affect the clinical course and short- and long-term outcome in acute ischemic stroke patients negatively.
- As part of secondary stroke prevention, screening for sleep apnea should be considered in organized stroke unit care as it is done for other well-known vascular risk factors.
- The benefit of non-invasive ventilation in ischemic stroke patients is not completely elucidated. In the acute phase of stroke, further studies are needed to show whether early initiation of non-invasive ventilation has a beneficial effect.
- Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med 2010;6:131-7.
- Hermann DM, Bassetti CL. Sleep-related breathing and sleep-wake disturbances in ischemic stroke. Neurology 2009;73:1313-22.
- 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; 29;328:1230-5.
- Arzt M, Young T, Finn L, Skatrud JB, Bradley TD. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 2005;172:1447-51.
- Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010;182:269-277.
- Martínez-García MA, Campos-Rodríguez F, Soler-Cataluña JJ, et al. Increased incidence of nonfatal cardiovascular events in stroke patients with sleep apnoea: effect of CPAP treatment. Eur Respir J 2012;39:906-12.
- Martinez-Garcia MA, Galiano-Blancart R, Roman-Sanchez P, Soler-Cataluna JJ, Cabero-Salt L, Salcedo-Maiques E. Continuous positive airway pressure treatment in sleep apnea prevents new vascular events after ischemic stroke. Chest 2005;128:2123–2129.
- Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/american College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118:1080-1111.
- Tan TY, Liou CW, Friedman M, Lin HC, Chang HW, Lin MC. Factors associated with increased carotid intima-media thickness in obstructive sleep apnea/hypopnea syndrome. Neurologist 2012;18:277-281.
- Kepplinger J, Barlinn K, Albright KC, et al. Early sleep apnea screening on a stroke unit is feasible in patients with acute cerebral ischemia. J Neurol 2012; [Epub ahead of print].
- Iranzo A, Santamaría J, Berenguer J, Sánchez M, Chamorro A. Prevalence and clinical importance of sleep apnea in the first night after cerebral infarction. Neurology 2002;58:911-6.
- Tsivgoulis G, Alexandrov AV. Cerebral autoregulation impairment during wakefulness in obstructive sleep apnea syndrome is a potential mechanism increasing stroke risk. Eur J Neurol 2009;16:283-284.
- Alexandrov AV, Sharma VK, Lao AY, Tsivgoulis G, Malkoff MD, Alexandrov AW. Reversed Robin Hood syndrome in acute ischemic stroke patients. Stroke 2007;38:3045-3048.
- Palazzo P, Balucani C, Barlinn K, et al. Association of reversed Robin Hood syndrome with risk of stroke recurrence. Neurologyem 2010; 75: 2003–8.
- Barlinn K, Alexandrov AV. Sleep-disordered breathing and arterial blood flow steal represent linked therapeutic targets in cerebral ischaemia. Int J Stroke 2011;6:40-41.
- Martinez-Garcia MA, Soler-Cataluna JJ, Ejarque-Martinez L, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a 5-year follow-up study. Am J Respir Crit Care Med 2009;180:36-41.
- Martínez-García MA, Campos-Rodríguez F, Soler-Cataluña JJ, Catalán-Serra P, Román-Sánchez P, Montserrat JM. Increased incidence of nonfatal cardiovascular events in stroke patients with sleep apnoea: effect of CPAP treatment. Eur Respir J 2012;39:906-12.
- Bravata DM, Concato J, Fried T, et al. Auto-titrating continuous positive airway pressure for patients with acute transient ischemic attack: a randomized feasibility trial. Stroke 2010;41:1464-1470.
- Tsivgoulis G, Zhang Y, Alexandrov AW, et al. Safety and tolerability of early noninvasive ventilatory correction using bilevel positive airway pressure in acute ischemic stroke. Stroke 2011;42:1030-4.
- Minnerup J, Ritter MA, Wersching H, et al. Continuous positive airway pressure ventilation for acute ischemic stroke: a randomized feasibility study. Stroke 2012;43:1137-9.
- Ip S, D'Ambrosio C, Patel K, et al. Auto-titrating versus fixed continuous positive airway pressure for the treatment of obstructive sleep apnea: a systematic review with meta-analyses. Syst Rev 2012;1:20.
Keywords: Cardiovascular Diseases, Epidemiologic Studies, Sleep Apnea Syndromes, Stroke
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