Accepted Manuscript Title: Treatment of obstructive sleep apnea syndrome associated with stroke Author: Luciane Mello-Fujita, Lenise Jihe Kim, Luciana de Oliveira Palombini, Camila Rizzi, Sergio Tufik, Monica Levy Andersen, Fernando Morgadinho Coelho PII: DOI: Reference:
S1389-9457(15)00624-3 http://dx.doi.org/doi:10.1016/j.sleep.2014.12.017 SLEEP 2687
To appear in:
Sleep Medicine
Received date: Revised date: Accepted date:
19-6-2014 20-11-2014 4-12-2014
Please cite this article as: Luciane Mello-Fujita, Lenise Jihe Kim, Luciana de Oliveira Palombini, Camila Rizzi, Sergio Tufik, Monica Levy Andersen, Fernando Morgadinho Coelho, Treatment of obstructive sleep apnea syndrome associated with stroke, Sleep Medicine (2015), http://dx.doi.org/doi:10.1016/j.sleep.2014.12.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Review Article Treatment of obstructive sleep apnea syndrome associated with stroke Luciane Mello-Fujitaa, Lenise Jihe Kima, Luciana de Oliveira Palombinia, Camila Rizzia, Sergio Tufika, Monica Levy Andersena, Fernando Morgadinho Coelhoa,b,* a
Departamento de Psicobiologia and b Departamento de Neurologia e
Neurocirurgia, Universidade Federal de São Paulo, São Paulo, Brazil
*Corresponding
author.
Departamento
de
Neurologia
e
Neurocirurgia,
Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 925, Vila Clementino, São Paulo, 04024-002, Brazil. E-mail address: [email protected] (F.M. Coelho) Highlights
We reviewed the main studies about the association between stroke and SDB treatment.
We described the general indications of CPAP in stroke patients.
We examined the main factors associated with CPAP adherence in stroke patients.
ABSTRACT The association between sleep-disordered breathing and stroke has been a subject of increased interest and research. Obstructive sleep apnea (OSA) is an important risk factor for stroke incidence and mortality. Moreover, OSA is a common clinical outcome after stroke, directly influencing the patient’s recovery. The treatment of choice for OSA is positive airway pressure (PAP) support and the PAP appliance is considered the most recommended clinical management for the treatment of patients with cardiovascular complications. However, the implementation of PAP in stroke patients remains a challenge,
Page 1 of 30
2 considering the increased frequency of motor and language impairments associated with the cerebrovascular event. In the present study, we reviewed the main findings describing the association between stroke and OSA treatment with continuous positive airway pressure. We also discussed the types of OSA treatment, the different options and indications of PAP treatment, PAP adherence and the clinical outcomes after treatment. Keywords: Obstructive sleep apnea syndrome Stroke CPAP CPAP adherence Bilevel PAP APAP
1. Introduction Cerebrovascular disease is one of the most important causes of morbity and increased mortality [1]. It has been demonstrated that stroke patients present a high prevalence of sleep-disordered breathing (SDB) and other sleep disturbances [2]. Obstructive sleep apnea syndrome (OSAS) increases the risk of stroke by two-fold even after controlling for potential confounding factors [3]. Marin et al. [4] concluded in an observational study that in men, OSAS may increase the risk of fatal and non-fatal cardiovascular events. Considering the high prevalence of SDB in the stroke population, it seems reasonable that OSA diagnosis and treatment may be crucial for primary and secondary stroke prevention [5]. Some possible mechanisms have been suggested. Dysphagia
Page 2 of 30
3 and paralysis of the accessory respiratory muscles may contribute to the pathophysiological mechanism of OSAS after stroke [6,7]. The eventual central respiratory depression observed during the acute phase of stroke can also be linked to SDB prevalence in this period; however, there is a low prevalence of central sleep apnea post stroke [6]. Positive airway pressure (PAP) is the treatment of choice for OSAS depending on its severity and patient’s comorbidities [8]. When OSAS is associated with cardiovascular complications, PAP is also the preferred treatment [9]. Excessive daytime sleepiness is an important indicator for OSAS [10–12]. However, patients who suffer stroke can have a weak perception about their daytime sleepiness or social isolation, and consequently, the Epworth scores are usually low [13]. The different clinical presentation of OSA in this patient group may lead to under-recognition and lack of treatment of SDB in these patients. Thus, considering the high prevalence of OSA, SDB must be investigated when there is a clinical history of obesity, snoring, systemic arterial hypertension, diabetes or stroke, particularly in male patients [14]. The
standard
method
to
diagnose
SDB
is
full
attended
polysomnography (PSG) or portable monitoring [15]. However, the higher complexity of cognitive and motor impairments in stroke patients and higher costs limit the use of PSG on a routine basis. A good alternative may be to conduct portable PSG studies for stroke patients admitted to hospital facilities. Currently, the ideal moment to perform a sleep study in these patients is not well established. In the present review, we discuss the association between stroke and SDB treatment with nocturnal non-invasive ventilation. We focused on the types and general indications of OSA treatment, PAP ventilation onset,
Page 3 of 30
4 choice of suitable equipment, PAP adherence and the clinical outcomes after treatment.
2. Types of PAP and indications 2.1. Continuous positive airway pressure Continuous positive airway pressure (CPAP) is considered the gold standard treatment for OSAS [8], and it normalizes sleep architecture, increases productivity, improves mood, and reduces excessive daytime sleepiness, traffic accidents and the risk of cardiovascular events [16]. Adherence to CPAP by the patient is also a crucial factor for treatment success. Some important and prevalent aspects should be considered during the ventilatory support of OSA after stroke [17,18]. Changes in the level of consciousness, ineffective cough, deglutition inability and a higher incidence of nausea and vomiting must be monitored. Recently, reduction in pressure during expiration was implemented in CPAP, minimizing the difficulty in exhaling air (CPAP with expiratory relief). However, the effectiveness was found to be similar to conventional CPAP in OSAS treatment [19]. 2.2. Bilevel PAP Bilevel positive airway pressure support, or Bilevel PAP, adjusts to different inspiratory and expiratory levels. Bilevel PAP is used to treat OSAS with pressure higher than 15 cmH2O in conditions with hypoventilation syndrome and obesity or in central hypoventilation associated with OSAS [20]. However, there is no evidence of better adherence or effectiveness of Bilevel PAP compared with CPAP [21]. 2.3. Automatic positive airway pressure
Page 4 of 30
5 Automatic positive airway pressure (APAP) consists of an automatic ventilatory support that adjusts the pressure levels in upper airway according to patient’s needs via airflow and pressure sensors. APAP was first used to optimize the CPAP adherence to automatic pressure titrations. As defined by the American Academy of Sleep Medicine (AASM), APAP is not recommended for patients with congestive heart failure, chronic obstructive pulmonary disease, hypoventilation syndrome, non-snoring patients or patients with associated central apneas [22]. There are few studies demonstrating the effectiveness and safety of APAP use for SDB treatment during the first weeks after a stroke event. Mulgrew et al. [23] demonstrated that APAP with expiratory relief was as effective as conventional CPAP for reducing the AHI. In addition, a trend toward improving patient satisfaction and preference was observed. In cases where there is no improvement in symptoms, a revaluation with titration PSG in the laboratory is necessary [22]. 2.4. Adaptive servo-ventilation Adaptive servo-ventilation (ASV) is a new therapy that provides positive expiratory airway pressure and inspiratory pressure support. ASV is automatically adjusted, according to a breath-by-breath analysis of the patient, with the goal of maintaining ventilation at 90% during a 3-min reference period. ASV has been increasingly used for treatment of central apneas and CheyneStokes respiration in patients with heart failure [24]. There is a lack of data regarding the safety and benefits of ASV treatment in stroke patients. A recent systematic review found only a 7% frequency of primarily central apnea in patients with ischemic or hemorrhagic stroke and transient ischemic attack. Considering that stroke patients present predominantly obstructive respiratory
Page 5 of 30
6 events, ASV does not seem suitable [25]. Furthermore, ASV is a high-cost therapeutic approach for the treatment of SDB compared with CPAP, which could discourage its use in stroke patients.
3. CPAP adherence For SAOS treatment, CPAP must be used for at least 4 h per night for
Comment [AU1]: Please define SAOS.
more than 70% of the time. There is a dose–response relationship between the amount of CPAP use and reduction of daytime sleepiness as well as improvement in the quality of life [26]. However, 39–83% of all OSA patients fail to adhere to the PAP treatment [27]. The main causes of non-adherence to PAP are claustrophobia, facial or thoracic discomfort, mask leakage or irritation, upper-airway obstruction, or other sleep disorders such as insomnia and aerophagia [28-30]. Factors associated with favorable adherence include education addressing PAP treatment, family support, knowledge of OSAS risks, adequate mask fit and use of a heated air humidifier [31–34]. The AASM recommends continuous PAP monitoring and effective follow up of the patient to ensure rapid and effective correction of any problems [20]. The majority of PAP machines provide an objective measure of device use. Continuous monitoring of the patient allows identification and management of early difficulties and complaints, such as sleep fragmentation and daytime sleepiness. Education programs providing information to patients and their families about their sleep disorder and the importance of PAP treatment promote better adherence to CPAP [34]. Cognitive behavioral therapy may also be administered to increase the amount of PAP use and improve motivation and
Page 6 of 30
7 the perception of the long-term benefits of PAP treatment [35]. Patients must been evaluated at least once per year during PAP therapy. It is important to examine the mask and the PAP machine as well as to double check clinical complaints (Table 1) [36]. An important aspect associated with PAP adherence is the presence of several motor limitations in stroke patients. Brown et al. [37] tested two different headgear systems, one with a head frame and another with traditional strap headgear. The length of time the patient wears and removes each mask and the difficulties in putting on and removing the mask were recorded. All participants reported that the frame headgear was easier to apply and remove than the straps. These results reinforce the importance of the selection of headgear that is easier to apply in a CPAP interface in great part of stroke patients. Also, aphasia is very common after stroke affecting language aspects associated with dominant frontal or temporal lobes resulting in difficulties producing and/or understanding speech. The success of CPAP treatment depends largely on education on how to use the machine and apply the facial interface. Aphasia may impair the communication about CPAP importance. Determining the most appropriate mode of communication is very important. In some situations it may be necessary to use written communication. A speech pathologist may also be helpful [38].
4. PAP in stroke patients It has been suggested that early treatment of SDB after stroke can be more cost-effective [39,40]. Long-term studies evaluating the effectiveness will be necessary to establish these benefits. CPAP is the main treatment for OSAS
Page 7 of 30
8 and has been proposed as the treatment for patients with concomitant stroke and SDB [18]. Despite the increasing body of evidence, the implementation of CPAP treatment is still a challenge. In different studies CPAP treatment has a limited adherence, ranging from a rate of 12% up to 50% of expected treatment interruption, considering studies which followed stroke patients in a period no shorter than 2 months and no longer than 5 years [41–43]. In addition, the effectiveness of CPAP treatment in stroke patients is also influenced by the timing of CPAP use (acute or chronic phase of stroke) and the required length of patient follow-up. A randomized placebo-controlled study with 32 acute stroke patients with SDB diagnosed by complete PSG or portable respiratory monitoring was performed [44]. After randomization, 15 patients underwent a titration with APAP and began CPAP treatment. The other group of patients were allocated to a sham-CPAP group (pressure 15 events/h admitted to a rehabilitation center and observed for CPAP use for 10 days [46]. Aphasia and increased severity of stroke were the main factors associated with poor adherence. It should be emphasized that this study had methodological limitations due to the small number of subjects enrolled, however this is most relevant to the outcome results rather than the adherence results. In another study, the authors reported an adherence of 29% after 5 years of follow-up in a sample of 51 patients who were included in the study 2 months after stroke onset [41]. The main causes related to poor adherence to treatment were aging and illness. The adherence to CPAP in stroke patients after 12 months was evaluated in a group of 275 patients. The only independent predictors of adherence were the side effects observed during the first month of CPAP use. The authors suggest that early interventions improve CPAP compliance in these patients [45]. The available literature has not yet determined the role of automatic non-invasive ventilatory support for the treatment of SDB in stroke patients. According to the AASM, APAP is contraindicated for titration in patients with central events [22]. Johnson et al. [25] recently reported a metaanalysis with 2343 hemorrhagic or ischemic stroke and transient ischemic attack patients. The authors found that only 7% of these patients had primary central apnea. Bravata et al. [9] submitted 16 subjects to APAP intervention for 30 days. Significant tolerance and neurological improvement after treatment were observed in these patients. The authors also demonstrated that APAP was beneficial in the treatment of OSAS. They found an acceptable adherence to CPAP (≥4 h/night). The treated-CPAP group showed a significant
Comment [AU2]: Please check this symbol.
Page 9 of 30
10 improvement in the neurological impairment scale (NIHSS) compared with the control group. This improvement was greater in patients with more APAP use hours. The authors concluded that APAP may be applied to the treatment of OSAS in these patients. Further studies must be performed to evaluate the safety and effectiveness of different PAP modalities in stroke patients. In conclusion, the adherence to CPAP in stroke patients is very low (12–25%), and is lower than in OSAS patients without stroke. Also, the mean duration of CPAP (h/night) use is reduced in this group of patients. Several conditions may promote CPAP intolerance in different groups of patients, including claustrophobia, rhinorrhea, thoracic discomfort, exhaling difficulties, contact dermatitis due to the mask material, aerophagia, and insomnia. In addition to these factors, we highlight the potential causes for poor adherence to CPAP in the stroke population in Table 2 [36]. It is very important to provide
Comment [AU3]: OK as edited?
education and information regarding SDB and the importance of CPAP treatment. It is also important to develop specific methods to overcome the motor and communication impairments that may be present in this clinical situation in order to increase the chances of successful treatment.
5. Clinical effects after CPAP treatment There are currently few studies demonstrating significant clinical benefits of SDB treatment with CPAP in stroke patients (Table 3). In a prospective observational study with 105 stroke patients with SDB, CPAP treatment improved subjective well-being of participants and decreased mean arterial blood pressure after 10 days of regular use [46]. In this study, intolerance to CPAP was higher in patients with aphasia and limitations evaluated by the ADL
Page 10 of 30
11 scale. Sixty-three of 105 stroke patients with SDB were randomized into CPAPtreated or control groups. An improvement in depression symptoms was observed after 28 days of CPAP use with a mean duration of 4.1 h per night; however, no significant changes were observed in the Barthel Index, MiniMental assessment or the prevalence of deliriums. Stroke patients had a higher risk of suffering a new vascular event, especially another episode of stroke. This aspect is responsible for increasing mortality and morbidity of these patients. Considering the difficulties for adherence to CPAP treatment in stroke patients, several studies have evaluated the long-term outcomes of CPAP. In an observational study, Martinez-Garcia et al. [41] followed the treatment of a group of patients over 5 years. One hundred and sixty-six patients with ischemic stroke were included in this study after the acute phase of stroke (2 months after stroke). They found a poor adherence among these patients. The percentage of mortality from cardiovascular diseases (stroke or coronary heart disease) was significantly higher in patients with moderate to severe SDB who did not tolerate CPAP treatment compared with CPAP-treated participants and those with mild SDB. The authors suggested that other mechanisms could be involved in the positive effect of CPAP on cardiovascular mortality. These effects may be associated with other cardiovascular risk factors such as decreased fibrinogen and inflammatory biomarker levels. In another observational study, no significant benefits were observed; however, stroke patients exhibited poor adherence to CPAP therapy [47]. From a total of 32 stroke patients selected for CPAP treatment, only 21 agreed to undergo a PSG. Twelve patients agreed to use CPAP, but only seven
Page 11 of 30
12 participants (22% from the total sample) continued using CPAP treatment for 8 weeks, and the other five patients did not adhere to the treatment. Clinical improvement was observed in five of the patients who remained on CPAP treatment (decrease in nocturia and excessive daytime sleepiness and improvement in the quality of life). However, these results were not statistically significant. Bassetti et al. [48] in a prospective observational study evaluated 70 ischemic stroke patients with an AHI >15 events/h or an AHI >10 events/h who also had excessive daytime sleepiness. CPAP was administered to 69% of the participants; however, only eight of the 36 patients (22%) continued using the treatment, showing that poor adherence to CPAP treatment may be a great concern in this population. Considering the lack of adherence, no reports regarding the beneficial effects of CPAP treatment were generated by this study. Nevertheless, the authors emphasized that patients can be treated with CPAP. In a clinical trial, Ryan et al. [49] evaluated CPAP effects on rehabilitation of stroke patients with SDB during the first 3 weeks after stroke. No changes were observed in the primary outcomes (cognitive tests). However, the authors found an improvement in functional and motor rehabilitation after 1 month of CPAP treatment. The adherence was high (88%), and the mean duration per night of CPAP use was 4.6 h. The higher CPAP adherence observed could be due to the continuous assistance of trained nurses. Minnerupt et al. [50], investigated the feasibility of CPAP treatment in patients with acute stroke, in a clinical trial with 50 stroke patients. They were randomly assigned to CPAP and control groups. The intervention group
Page 12 of 30
13 received CPAP for three nights, beginning in the first night after stroke, and for an additional fout nights after a polysomnography exhibiting apnea hypopnea index (AIH) > 10/hour. CPAP therapy reduced AIH significantly, the nursing workload did not differ between groups, and a significantly improvement in NIH Stroke Scale was observed in patients with CPAP compliance of more than 4 h/night. Thus, the earlier CPAP treatment seems to be possible in acute stroke. The treatment of OSA with CPAP following stroke was assessed by Parra et al. [51] in a randomized controlled multicentre trial. Stroke patients with AIH >20 events/h were randomly allocated to early CPAP (N=71), 3–6 days after stroke, or conventional treatment for stroke (N=69). They observed significant neurological improvement in the CPAP group after 1 month (Rankin scale 90.9% vs 56.3%, p15/h or Bassetti et al.(2006) [48]
Short-term adherence: 69%
AHI >10/h with somnolence; 1
56 13
26 4
week after
of the patients; mediumterm adherence: 51%; longterm adherence: 15%
stroke; up to 5 years of followup
12 patients accepted the
14 patients with
CPAP use; seven
stroke; AHI Palombini &
≥10/h;
Guilleminault
hospitalized
(2006) [47]
patients; up to 8 weeks of followup
participants completed the 62 13
23 3
protocol; reasons for nonacceptance: cognitive alteration, inability to place the mask and to adjust the device
Page 27 of 30
28 96 patients with ischemic stroke Martinez-Garcia et al. (2009) [41]
and AHI ≥20/h; 2 months after the stroke; up to 5 years of
Control
Control
76
28
CPAP
CPAP
71
27
Age
BMI
Prolonged CPAP-treated patients showed lower mortality (50%) compared with non-treated participants (68%)
follow-up Clinical trials Studies
Sample
Results Randomized, CPAP in 27/30 patients over 4
63 patients with
Sandberg et al.(2001) [18]
ischemic stroke;
Control
Control
RDI ≥15; 2–4
77 8
25 5
stroke; up to 28
CPAP
CPAP
days of follow-
78 6
24 4
weeks after
up
weeks; less depressive symptoms in CPAP-treated group compared to control (p=0.004); No improvement in deliriums; cognitive function impairment explained the poor CPAP adherence Mean adherence: 1.4 h/night; low recruitment
30 patients with
rate; No improvement in
stroke and
Hsu et al. (2006) [43]
quality of life, anxiety, and
AHI≥30;
Control
Randomized for
74 (73–
Control
8 weeks CPAP
81)
26.8
treated; 21–25
CPAP
CPAP
days after
73 (65–
25.1
stroke; up to 6
77)
treatment or not
months of follow-up
depression; No changes in diurnal and nocturnal arterial blood pressure; eight patients abandoned the CPAP due to mask problems, airway symptoms, or mental confusion; positive correlation between CPAP and the Barthel index
Page 28 of 30
29 48 patients with stroke; IAH Ryan et al. (2011) [49]
≥15/h ; 3 weeks after stroke; up to 4 weeks of follow-up
Control
Control
22 CPAP-treated patients
60.7
27.3
showed motor (P10/h , an additional 4 nights of APAP therapy 32 randomized
Brown et al.(2013) [44]
Sham-CPAP patients with
patients with
Sham-
Sham-
3.5 h/night in 3 months of
stroke; IAH ≥5/h;
CPAP
CPAP
treatment; CPAP patients
first 7 days after
61
28
with 4.5 h/night; first study
stroke; 3 months
CPAP
CPAP
that evaluated stroke
of follow-up
74
29
patients with Sham-CPAP
BMI, body mass index; AHI, apnea–hypopnea index; CPAP, continuous positive airway pressure; SaO2, arterial oxygen saturation; RDI, respiratory disturbance index; APAP, automatic positive airway pressure; NIHSS, neurological impairment scale. Data are represented as mean standard deviation.
Page 30 of 30
S1389-9457(15)00624-3 http://dx.doi.org/doi:10.1016/j.sleep.2014.12.017 SLEEP 2687
To appear in:
Sleep Medicine
Received date: Revised date: Accepted date:
19-6-2014 20-11-2014 4-12-2014
Please cite this article as: Luciane Mello-Fujita, Lenise Jihe Kim, Luciana de Oliveira Palombini, Camila Rizzi, Sergio Tufik, Monica Levy Andersen, Fernando Morgadinho Coelho, Treatment of obstructive sleep apnea syndrome associated with stroke, Sleep Medicine (2015), http://dx.doi.org/doi:10.1016/j.sleep.2014.12.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Review Article Treatment of obstructive sleep apnea syndrome associated with stroke Luciane Mello-Fujitaa, Lenise Jihe Kima, Luciana de Oliveira Palombinia, Camila Rizzia, Sergio Tufika, Monica Levy Andersena, Fernando Morgadinho Coelhoa,b,* a
Departamento de Psicobiologia and b Departamento de Neurologia e
Neurocirurgia, Universidade Federal de São Paulo, São Paulo, Brazil
*Corresponding
author.
Departamento
de
Neurologia
e
Neurocirurgia,
Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 925, Vila Clementino, São Paulo, 04024-002, Brazil. E-mail address: [email protected] (F.M. Coelho) Highlights
We reviewed the main studies about the association between stroke and SDB treatment.
We described the general indications of CPAP in stroke patients.
We examined the main factors associated with CPAP adherence in stroke patients.
ABSTRACT The association between sleep-disordered breathing and stroke has been a subject of increased interest and research. Obstructive sleep apnea (OSA) is an important risk factor for stroke incidence and mortality. Moreover, OSA is a common clinical outcome after stroke, directly influencing the patient’s recovery. The treatment of choice for OSA is positive airway pressure (PAP) support and the PAP appliance is considered the most recommended clinical management for the treatment of patients with cardiovascular complications. However, the implementation of PAP in stroke patients remains a challenge,
Page 1 of 30
2 considering the increased frequency of motor and language impairments associated with the cerebrovascular event. In the present study, we reviewed the main findings describing the association between stroke and OSA treatment with continuous positive airway pressure. We also discussed the types of OSA treatment, the different options and indications of PAP treatment, PAP adherence and the clinical outcomes after treatment. Keywords: Obstructive sleep apnea syndrome Stroke CPAP CPAP adherence Bilevel PAP APAP
1. Introduction Cerebrovascular disease is one of the most important causes of morbity and increased mortality [1]. It has been demonstrated that stroke patients present a high prevalence of sleep-disordered breathing (SDB) and other sleep disturbances [2]. Obstructive sleep apnea syndrome (OSAS) increases the risk of stroke by two-fold even after controlling for potential confounding factors [3]. Marin et al. [4] concluded in an observational study that in men, OSAS may increase the risk of fatal and non-fatal cardiovascular events. Considering the high prevalence of SDB in the stroke population, it seems reasonable that OSA diagnosis and treatment may be crucial for primary and secondary stroke prevention [5]. Some possible mechanisms have been suggested. Dysphagia
Page 2 of 30
3 and paralysis of the accessory respiratory muscles may contribute to the pathophysiological mechanism of OSAS after stroke [6,7]. The eventual central respiratory depression observed during the acute phase of stroke can also be linked to SDB prevalence in this period; however, there is a low prevalence of central sleep apnea post stroke [6]. Positive airway pressure (PAP) is the treatment of choice for OSAS depending on its severity and patient’s comorbidities [8]. When OSAS is associated with cardiovascular complications, PAP is also the preferred treatment [9]. Excessive daytime sleepiness is an important indicator for OSAS [10–12]. However, patients who suffer stroke can have a weak perception about their daytime sleepiness or social isolation, and consequently, the Epworth scores are usually low [13]. The different clinical presentation of OSA in this patient group may lead to under-recognition and lack of treatment of SDB in these patients. Thus, considering the high prevalence of OSA, SDB must be investigated when there is a clinical history of obesity, snoring, systemic arterial hypertension, diabetes or stroke, particularly in male patients [14]. The
standard
method
to
diagnose
SDB
is
full
attended
polysomnography (PSG) or portable monitoring [15]. However, the higher complexity of cognitive and motor impairments in stroke patients and higher costs limit the use of PSG on a routine basis. A good alternative may be to conduct portable PSG studies for stroke patients admitted to hospital facilities. Currently, the ideal moment to perform a sleep study in these patients is not well established. In the present review, we discuss the association between stroke and SDB treatment with nocturnal non-invasive ventilation. We focused on the types and general indications of OSA treatment, PAP ventilation onset,
Page 3 of 30
4 choice of suitable equipment, PAP adherence and the clinical outcomes after treatment.
2. Types of PAP and indications 2.1. Continuous positive airway pressure Continuous positive airway pressure (CPAP) is considered the gold standard treatment for OSAS [8], and it normalizes sleep architecture, increases productivity, improves mood, and reduces excessive daytime sleepiness, traffic accidents and the risk of cardiovascular events [16]. Adherence to CPAP by the patient is also a crucial factor for treatment success. Some important and prevalent aspects should be considered during the ventilatory support of OSA after stroke [17,18]. Changes in the level of consciousness, ineffective cough, deglutition inability and a higher incidence of nausea and vomiting must be monitored. Recently, reduction in pressure during expiration was implemented in CPAP, minimizing the difficulty in exhaling air (CPAP with expiratory relief). However, the effectiveness was found to be similar to conventional CPAP in OSAS treatment [19]. 2.2. Bilevel PAP Bilevel positive airway pressure support, or Bilevel PAP, adjusts to different inspiratory and expiratory levels. Bilevel PAP is used to treat OSAS with pressure higher than 15 cmH2O in conditions with hypoventilation syndrome and obesity or in central hypoventilation associated with OSAS [20]. However, there is no evidence of better adherence or effectiveness of Bilevel PAP compared with CPAP [21]. 2.3. Automatic positive airway pressure
Page 4 of 30
5 Automatic positive airway pressure (APAP) consists of an automatic ventilatory support that adjusts the pressure levels in upper airway according to patient’s needs via airflow and pressure sensors. APAP was first used to optimize the CPAP adherence to automatic pressure titrations. As defined by the American Academy of Sleep Medicine (AASM), APAP is not recommended for patients with congestive heart failure, chronic obstructive pulmonary disease, hypoventilation syndrome, non-snoring patients or patients with associated central apneas [22]. There are few studies demonstrating the effectiveness and safety of APAP use for SDB treatment during the first weeks after a stroke event. Mulgrew et al. [23] demonstrated that APAP with expiratory relief was as effective as conventional CPAP for reducing the AHI. In addition, a trend toward improving patient satisfaction and preference was observed. In cases where there is no improvement in symptoms, a revaluation with titration PSG in the laboratory is necessary [22]. 2.4. Adaptive servo-ventilation Adaptive servo-ventilation (ASV) is a new therapy that provides positive expiratory airway pressure and inspiratory pressure support. ASV is automatically adjusted, according to a breath-by-breath analysis of the patient, with the goal of maintaining ventilation at 90% during a 3-min reference period. ASV has been increasingly used for treatment of central apneas and CheyneStokes respiration in patients with heart failure [24]. There is a lack of data regarding the safety and benefits of ASV treatment in stroke patients. A recent systematic review found only a 7% frequency of primarily central apnea in patients with ischemic or hemorrhagic stroke and transient ischemic attack. Considering that stroke patients present predominantly obstructive respiratory
Page 5 of 30
6 events, ASV does not seem suitable [25]. Furthermore, ASV is a high-cost therapeutic approach for the treatment of SDB compared with CPAP, which could discourage its use in stroke patients.
3. CPAP adherence For SAOS treatment, CPAP must be used for at least 4 h per night for
Comment [AU1]: Please define SAOS.
more than 70% of the time. There is a dose–response relationship between the amount of CPAP use and reduction of daytime sleepiness as well as improvement in the quality of life [26]. However, 39–83% of all OSA patients fail to adhere to the PAP treatment [27]. The main causes of non-adherence to PAP are claustrophobia, facial or thoracic discomfort, mask leakage or irritation, upper-airway obstruction, or other sleep disorders such as insomnia and aerophagia [28-30]. Factors associated with favorable adherence include education addressing PAP treatment, family support, knowledge of OSAS risks, adequate mask fit and use of a heated air humidifier [31–34]. The AASM recommends continuous PAP monitoring and effective follow up of the patient to ensure rapid and effective correction of any problems [20]. The majority of PAP machines provide an objective measure of device use. Continuous monitoring of the patient allows identification and management of early difficulties and complaints, such as sleep fragmentation and daytime sleepiness. Education programs providing information to patients and their families about their sleep disorder and the importance of PAP treatment promote better adherence to CPAP [34]. Cognitive behavioral therapy may also be administered to increase the amount of PAP use and improve motivation and
Page 6 of 30
7 the perception of the long-term benefits of PAP treatment [35]. Patients must been evaluated at least once per year during PAP therapy. It is important to examine the mask and the PAP machine as well as to double check clinical complaints (Table 1) [36]. An important aspect associated with PAP adherence is the presence of several motor limitations in stroke patients. Brown et al. [37] tested two different headgear systems, one with a head frame and another with traditional strap headgear. The length of time the patient wears and removes each mask and the difficulties in putting on and removing the mask were recorded. All participants reported that the frame headgear was easier to apply and remove than the straps. These results reinforce the importance of the selection of headgear that is easier to apply in a CPAP interface in great part of stroke patients. Also, aphasia is very common after stroke affecting language aspects associated with dominant frontal or temporal lobes resulting in difficulties producing and/or understanding speech. The success of CPAP treatment depends largely on education on how to use the machine and apply the facial interface. Aphasia may impair the communication about CPAP importance. Determining the most appropriate mode of communication is very important. In some situations it may be necessary to use written communication. A speech pathologist may also be helpful [38].
4. PAP in stroke patients It has been suggested that early treatment of SDB after stroke can be more cost-effective [39,40]. Long-term studies evaluating the effectiveness will be necessary to establish these benefits. CPAP is the main treatment for OSAS
Page 7 of 30
8 and has been proposed as the treatment for patients with concomitant stroke and SDB [18]. Despite the increasing body of evidence, the implementation of CPAP treatment is still a challenge. In different studies CPAP treatment has a limited adherence, ranging from a rate of 12% up to 50% of expected treatment interruption, considering studies which followed stroke patients in a period no shorter than 2 months and no longer than 5 years [41–43]. In addition, the effectiveness of CPAP treatment in stroke patients is also influenced by the timing of CPAP use (acute or chronic phase of stroke) and the required length of patient follow-up. A randomized placebo-controlled study with 32 acute stroke patients with SDB diagnosed by complete PSG or portable respiratory monitoring was performed [44]. After randomization, 15 patients underwent a titration with APAP and began CPAP treatment. The other group of patients were allocated to a sham-CPAP group (pressure 15 events/h admitted to a rehabilitation center and observed for CPAP use for 10 days [46]. Aphasia and increased severity of stroke were the main factors associated with poor adherence. It should be emphasized that this study had methodological limitations due to the small number of subjects enrolled, however this is most relevant to the outcome results rather than the adherence results. In another study, the authors reported an adherence of 29% after 5 years of follow-up in a sample of 51 patients who were included in the study 2 months after stroke onset [41]. The main causes related to poor adherence to treatment were aging and illness. The adherence to CPAP in stroke patients after 12 months was evaluated in a group of 275 patients. The only independent predictors of adherence were the side effects observed during the first month of CPAP use. The authors suggest that early interventions improve CPAP compliance in these patients [45]. The available literature has not yet determined the role of automatic non-invasive ventilatory support for the treatment of SDB in stroke patients. According to the AASM, APAP is contraindicated for titration in patients with central events [22]. Johnson et al. [25] recently reported a metaanalysis with 2343 hemorrhagic or ischemic stroke and transient ischemic attack patients. The authors found that only 7% of these patients had primary central apnea. Bravata et al. [9] submitted 16 subjects to APAP intervention for 30 days. Significant tolerance and neurological improvement after treatment were observed in these patients. The authors also demonstrated that APAP was beneficial in the treatment of OSAS. They found an acceptable adherence to CPAP (≥4 h/night). The treated-CPAP group showed a significant
Comment [AU2]: Please check this symbol.
Page 9 of 30
10 improvement in the neurological impairment scale (NIHSS) compared with the control group. This improvement was greater in patients with more APAP use hours. The authors concluded that APAP may be applied to the treatment of OSAS in these patients. Further studies must be performed to evaluate the safety and effectiveness of different PAP modalities in stroke patients. In conclusion, the adherence to CPAP in stroke patients is very low (12–25%), and is lower than in OSAS patients without stroke. Also, the mean duration of CPAP (h/night) use is reduced in this group of patients. Several conditions may promote CPAP intolerance in different groups of patients, including claustrophobia, rhinorrhea, thoracic discomfort, exhaling difficulties, contact dermatitis due to the mask material, aerophagia, and insomnia. In addition to these factors, we highlight the potential causes for poor adherence to CPAP in the stroke population in Table 2 [36]. It is very important to provide
Comment [AU3]: OK as edited?
education and information regarding SDB and the importance of CPAP treatment. It is also important to develop specific methods to overcome the motor and communication impairments that may be present in this clinical situation in order to increase the chances of successful treatment.
5. Clinical effects after CPAP treatment There are currently few studies demonstrating significant clinical benefits of SDB treatment with CPAP in stroke patients (Table 3). In a prospective observational study with 105 stroke patients with SDB, CPAP treatment improved subjective well-being of participants and decreased mean arterial blood pressure after 10 days of regular use [46]. In this study, intolerance to CPAP was higher in patients with aphasia and limitations evaluated by the ADL
Page 10 of 30
11 scale. Sixty-three of 105 stroke patients with SDB were randomized into CPAPtreated or control groups. An improvement in depression symptoms was observed after 28 days of CPAP use with a mean duration of 4.1 h per night; however, no significant changes were observed in the Barthel Index, MiniMental assessment or the prevalence of deliriums. Stroke patients had a higher risk of suffering a new vascular event, especially another episode of stroke. This aspect is responsible for increasing mortality and morbidity of these patients. Considering the difficulties for adherence to CPAP treatment in stroke patients, several studies have evaluated the long-term outcomes of CPAP. In an observational study, Martinez-Garcia et al. [41] followed the treatment of a group of patients over 5 years. One hundred and sixty-six patients with ischemic stroke were included in this study after the acute phase of stroke (2 months after stroke). They found a poor adherence among these patients. The percentage of mortality from cardiovascular diseases (stroke or coronary heart disease) was significantly higher in patients with moderate to severe SDB who did not tolerate CPAP treatment compared with CPAP-treated participants and those with mild SDB. The authors suggested that other mechanisms could be involved in the positive effect of CPAP on cardiovascular mortality. These effects may be associated with other cardiovascular risk factors such as decreased fibrinogen and inflammatory biomarker levels. In another observational study, no significant benefits were observed; however, stroke patients exhibited poor adherence to CPAP therapy [47]. From a total of 32 stroke patients selected for CPAP treatment, only 21 agreed to undergo a PSG. Twelve patients agreed to use CPAP, but only seven
Page 11 of 30
12 participants (22% from the total sample) continued using CPAP treatment for 8 weeks, and the other five patients did not adhere to the treatment. Clinical improvement was observed in five of the patients who remained on CPAP treatment (decrease in nocturia and excessive daytime sleepiness and improvement in the quality of life). However, these results were not statistically significant. Bassetti et al. [48] in a prospective observational study evaluated 70 ischemic stroke patients with an AHI >15 events/h or an AHI >10 events/h who also had excessive daytime sleepiness. CPAP was administered to 69% of the participants; however, only eight of the 36 patients (22%) continued using the treatment, showing that poor adherence to CPAP treatment may be a great concern in this population. Considering the lack of adherence, no reports regarding the beneficial effects of CPAP treatment were generated by this study. Nevertheless, the authors emphasized that patients can be treated with CPAP. In a clinical trial, Ryan et al. [49] evaluated CPAP effects on rehabilitation of stroke patients with SDB during the first 3 weeks after stroke. No changes were observed in the primary outcomes (cognitive tests). However, the authors found an improvement in functional and motor rehabilitation after 1 month of CPAP treatment. The adherence was high (88%), and the mean duration per night of CPAP use was 4.6 h. The higher CPAP adherence observed could be due to the continuous assistance of trained nurses. Minnerupt et al. [50], investigated the feasibility of CPAP treatment in patients with acute stroke, in a clinical trial with 50 stroke patients. They were randomly assigned to CPAP and control groups. The intervention group
Page 12 of 30
13 received CPAP for three nights, beginning in the first night after stroke, and for an additional fout nights after a polysomnography exhibiting apnea hypopnea index (AIH) > 10/hour. CPAP therapy reduced AIH significantly, the nursing workload did not differ between groups, and a significantly improvement in NIH Stroke Scale was observed in patients with CPAP compliance of more than 4 h/night. Thus, the earlier CPAP treatment seems to be possible in acute stroke. The treatment of OSA with CPAP following stroke was assessed by Parra et al. [51] in a randomized controlled multicentre trial. Stroke patients with AIH >20 events/h were randomly allocated to early CPAP (N=71), 3–6 days after stroke, or conventional treatment for stroke (N=69). They observed significant neurological improvement in the CPAP group after 1 month (Rankin scale 90.9% vs 56.3%, p15/h or Bassetti et al.(2006) [48]
Short-term adherence: 69%
AHI >10/h with somnolence; 1
56 13
26 4
week after
of the patients; mediumterm adherence: 51%; longterm adherence: 15%
stroke; up to 5 years of followup
12 patients accepted the
14 patients with
CPAP use; seven
stroke; AHI Palombini &
≥10/h;
Guilleminault
hospitalized
(2006) [47]
patients; up to 8 weeks of followup
participants completed the 62 13
23 3
protocol; reasons for nonacceptance: cognitive alteration, inability to place the mask and to adjust the device
Page 27 of 30
28 96 patients with ischemic stroke Martinez-Garcia et al. (2009) [41]
and AHI ≥20/h; 2 months after the stroke; up to 5 years of
Control
Control
76
28
CPAP
CPAP
71
27
Age
BMI
Prolonged CPAP-treated patients showed lower mortality (50%) compared with non-treated participants (68%)
follow-up Clinical trials Studies
Sample
Results Randomized, CPAP in 27/30 patients over 4
63 patients with
Sandberg et al.(2001) [18]
ischemic stroke;
Control
Control
RDI ≥15; 2–4
77 8
25 5
stroke; up to 28
CPAP
CPAP
days of follow-
78 6
24 4
weeks after
up
weeks; less depressive symptoms in CPAP-treated group compared to control (p=0.004); No improvement in deliriums; cognitive function impairment explained the poor CPAP adherence Mean adherence: 1.4 h/night; low recruitment
30 patients with
rate; No improvement in
stroke and
Hsu et al. (2006) [43]
quality of life, anxiety, and
AHI≥30;
Control
Randomized for
74 (73–
Control
8 weeks CPAP
81)
26.8
treated; 21–25
CPAP
CPAP
days after
73 (65–
25.1
stroke; up to 6
77)
treatment or not
months of follow-up
depression; No changes in diurnal and nocturnal arterial blood pressure; eight patients abandoned the CPAP due to mask problems, airway symptoms, or mental confusion; positive correlation between CPAP and the Barthel index
Page 28 of 30
29 48 patients with stroke; IAH Ryan et al. (2011) [49]
≥15/h ; 3 weeks after stroke; up to 4 weeks of follow-up
Control
Control
22 CPAP-treated patients
60.7
27.3
showed motor (P10/h , an additional 4 nights of APAP therapy 32 randomized
Brown et al.(2013) [44]
Sham-CPAP patients with
patients with
Sham-
Sham-
3.5 h/night in 3 months of
stroke; IAH ≥5/h;
CPAP
CPAP
treatment; CPAP patients
first 7 days after
61
28
with 4.5 h/night; first study
stroke; 3 months
CPAP
CPAP
that evaluated stroke
of follow-up
74
29
patients with Sham-CPAP
BMI, body mass index; AHI, apnea–hypopnea index; CPAP, continuous positive airway pressure; SaO2, arterial oxygen saturation; RDI, respiratory disturbance index; APAP, automatic positive airway pressure; NIHSS, neurological impairment scale. Data are represented as mean standard deviation.
Page 30 of 30
