influence of continuous positive airway pressure on...

Influence of Continuous Positive Airway Pressure onOutcomes of Rehabilitation in Stroke Patients With

Obstructive Sleep ApneaClodagh M. Ryan, MD; Mark Bayley, MD; Robin Green, PhD;

Brian J. Murray, MD; T. Douglas Bradley, MD

Background and Purpose—In stroke patients, obstructive sleep apnea (OSA) is associated with poorer functionaloutcomes than in those without OSA. We hypothesized that treatment of OSA by continuous positive airway pressure(CPAP) in stroke patients would enhance motor, functional, and neurocognitive recovery.

Methods—This was a randomized, open label, parallel group trial with blind assessment of outcomes performed in strokepatients with OSA in a stroke rehabilitation unit. Patients were assigned to standard rehabilitation alone (control group)or to CPAP (CPAP group). The primary outcomes were the Canadian Neurological scale, the 6-minute walk testdistance, sustained attention response test, and the digit or spatial span-backward. Secondary outcomes includedEpworth Sleepiness scale, Stanford Sleepiness scale, Functional Independence measure, Chedoke McMaster Strokeassessment, neurocognitive function, and Beck depression inventory. Tests were performed at baseline and 1 month later.

Results—Patients assigned to CPAP (n�22) experienced no adverse events. Regarding primary outcomes, compared to thecontrol group (n�22), the CPAP group experienced improvement in stroke-related impairment (Canadian Neurologicalscale score, P�0.001) but not in 6-minute walk test distance, sustained attention response test, or digit or spatialspan-backward. Regarding secondary outcomes, the CPAP group experienced improvements in the Epworth Sleepinessscale (P�0.001), motor component of the Functional Independence measure (P�0.05), Chedoke-McMaster Strokeassessment of upper and lower limb motor recovery test of the leg (P�0.001), and the affective component of depression(P�0.006), but not neurocognitive function.

Conclusions—Treatment of OSA by CPAP in stroke patients undergoing rehabilitation improved functional and motor, butnot neurocognitive outcomes.

Clinical Trial Registration Information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00221065.(Stroke. 2011;42:1062-1067.)

Key Words: continuous positive airway pressure � functional outcomes � neurocognitive outcomes� obstructive sleep apnea � stroke

The incidence of stroke and its consequent burden of mor-bidity and mortality remain unacceptably high. If outcomes

from stroke are to improve, then the underlying mechanisms offunctional impairment will need to be addressed. One contrib-uting factor may be obstructive sleep apnea (OSA).

Cross-sectional and prospective epidemiological data indi-cate that OSA is associated with increased risk of having astroke independently of other risk factors.1–3 Compared to thegeneral population,4 stroke patients have a 4- to 6-fold higherprevalence of OSA.5,6 In the poststroke period, patients withOSA have greater functional impairment and higher mortalitythan patients without OSA.6,7 These data suggest that OSAboth increases the risk of stroke and, in the poststroke period,exacerbates the degree of disability as well as the risk of

death. It is therefore possible that treatment of coexistingOSA might improve recovery from stroke. Accordingly, weperformed a randomized controlled trial in stroke patientswith OSA during their inpatient stroke rehabilitation todetermine if treatment with continuous positive airway pres-sure (CPAP) would improve functional, motor, and neuro-psychological outcomes over a 4-week period.

Subjects and Methods

Study DesignThis was a randomized, open label, parallel group trial with blindassessment of outcomes performed at the stroke rehabilitation unit ofthe Toronto Rehabilitation Institute.

Received August 12, 2010; accepted November 23, 2010.From the Toronto Rehabilitation Institute (C.M.R., M.B., R.G., B.J.M., T.D.B.) and the Centre for Sleep Medicine and Circadian Biology (C.M.R.,

B.J.M., T.D.B.), University of Toronto, Ontario, Canada; the Department of Medicine (C.M.R., T.D.B.), Toronto General Hospital of the UniversityHealth Network and Sunnybrook Health Sciences Centre (B.J.M.), Toronto, Ontario, Canada.

The online-only Data Supplement is available at http://stroke.ahajournals.org/cgi/content/full/STROKEAHA.110.597468/DC1.Correspondence to Clodagh M. Ryan, MD, 9N-967, Toronto General Hospital, 585 University Avenue, Toronto, Ontario, M5G 2N2. E-mail

[email protected]© 2011 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.597468

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SubjectsEligible patients were those admitted from acute care facilities to thestroke rehabilitation unit within 3 weeks of stroke onset with thefollowing inclusion criteria: (1) 18 to 89 years of age; (2) completedischemic or hemorrhagic stroke confirmed by a neurologist based onhistory of sudden onset of a neurological deficit lasting �24 hours,neurological deficit on physical examination, and brain lesioncompatible with the neurological deficit on computerized tomogra-phy or MRI; (3) ability to follow simple commands in English; (4)competency to provide informed consent; and (5) OSA on anovernight attended polysomnogram (PSG) as described. Exclusioncriteria were: (1) brain stem strokes that could increase aspirationrisk while using CPAP; (2) previously diagnosed OSA on therapy;(3) concomitant central nervous system diseases such as dementia;(4) history of psychosis; (5) traumatic brain injury; and (6) anosag-nosia, global, or Wernicke aphasia.

The study was approved by the Research Ethics Board of theToronto Rehabilitation Institute and all subjects provided writtenconsent before participation.

Baseline AssessmentsClinical classification of strokes was performed according to theOxfordshire Community Stroke Project criteria.8 Eligible patientsunderwent a clinical assessment followed by an overnight PSG. PSGwere performed using standard techniques and scoring criteria forsleep stages and arousals from sleep.9,10

The frequency of apneas and hypopneas per hour of sleep wasexpressed as the apnea–hypopnea index. Patients with an apnea–hypopnea index of �15 were classified as having sleep apnea for thepurpose of this study. OSA was diagnosed when at least 80% of therespiratory events were obstructive.

Subjects with OSA then completed the functional, motor, andneuropsychological assessments between 2:00 and 5:00 PM admin-istered by individuals blinded to subject randomization. To take theheterogeneity of stroke-related impairment into account, we evalu-ated several domains as our primary outcomes, including strokeseverity by the Canadian Neurological scale, motor function by the6-minute walk test, neurocognitive function by sustained attention toresponse test (a measure of vigilance), and the digit or spatialspan-backward (a measure of executive function). Secondary out-comes included the Functional Independence measure (FIM),Chedoke-McMaster Stroke assessment of upper and lower limbmotor recovery test, hand-grip strength, Berg Balance scale, EpworthSleepiness scale (ESS), Stanford Sleepiness scale (SSS), the PurduePegboard test and the Beck depression inventory-1 (BDI). Please seehttp://stroke.ahajournals.org for additional information.

RandomizationEligible patients were randomly assigned by a computer-generatedrandomization schedule in random blocks of 2 and 4, with allocationconcealment by opaque, sequentially numbered, sealed envelopes toeither a control group that received standard stroke occupational andphysiotherapy for the duration of the trial or a treatment group that,in addition, received CPAP for OSA.

CPAP was titrated during PSG to reduce the apnea–hypopneaindex to �5 or to the highest pressure tolerated. Patients were thenprovided with a CPAP machine (Goodknight 420G; Tyco Health-care) and were instructed to use it for at least 6 hours per night untilthe end of the trial. CPAP compliance was assessed by recordingmask-on time.

Throughout the 4-week trial, time spent, and level of participationin physiotherapy were recorded 5 days per week by a physiotherapistblind to treatment allocation. Four weeks after randomization,baseline measurements were repeated, including a PSG performedeither with or without CPAP as per treatment allocation (Figure 1).

Statistical AnalysesWe estimated that with a sample size of 22 in each group, the studywould have a 90% power to detect 1 SD difference between thegroups for the primary outcomes at a 2-tailed � of 0.05. Baseline data

of the 2 groups were compared with t tests for continuous variablesand Fisher exact test for categorical data. Outcomes were analyzedby the original assigned groups. Differences in the outcome vari-ables, from baseline to follow-up, were compared within andbetween groups by analysis of covariance with post hoc analyses asappropriate. Test scores on psychometric data were transformed to acommon metric (z scores) and aggregate scores were created.11

P�0.05 was considered statistically significant. Continuous data areexpressed as means�SD unless otherwise indicated.

Results

Characteristics of the SubjectsProgress of subjects through the trial is illustrated in Figure 1.Between June 2005 and March 2008, 466 patients withstrokes admitted to the stroke rehabilitation unit werescreened. Exclusions were mainly attributable to languagebarriers. One-hundred ninety-four met initial inclusion crite-ria, and 103 agreed to PSG. Of these, 48 (47%) had OSA withan apnea–hypopnea index �15. One patient in the controlgroup and 3 in the CPAP group left the study before trialcompletion; thus, outcome data were available for 22 patientsin each group for analysis by originally assigned group.Stroke location and type (Table 1) and time from occurrenceof the stroke to entry into the study were similar in the controland CPAP groups (19.7�16.8 days versus 21.5�8.7 days;P�0.41).

Baseline data were similar in the control and CPAP groups,except more subjects in the control group had a history ofsmoking (Table 1). The Canadian Neurological scale andFIM scores were also similar in the 2 groups, indicatingcomparable functional impairment (Table 3). The ESS andSSS were similar in the 2 groups and were within normallimits, indicating a lack of subjective sleepiness (Table 2).

Figure. Progress of patients through the trial.

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Sleep variables were similar in both groups. No adverseevents were recorded during the study.

Effects of CPAP on Sleep VariablesAmong those randomized to CPAP who completed the trial,CPAP usage averaged 4.96�2.25 hours per day at a meanpressure of 8.1�0.5 cm H20. There were no adverse effects ofCPAP. Compared to the control group, the CPAP-treatedgroup experienced a significant reduction in the apnea–

hypopnea index, as well as an increase in minimum sleepoxyhemoglobin saturation. Mean oxyhemoglobin saturationalso improved within the CPAP group (Table 2). However,there were no improvements in sleep structure in either group.

PhysiotherapyTime per day spent in physiotherapy and participation scores didnot differ between the control and CPAP groups (control:45�13 versus 45�9 minutes per day and P�0.97; CPAP:5.2�0.8 versus 5.4�0.7 and P�0.30).

Primary OutcomesThe CPAP group experienced significant improvements inthe total Canadian Neurological scale score and its cognitiveand motor components that were greater than in the controlgroup (Table 3). There was a significant increase in the6-minute walk distance (113 meters) in the CPAP group, butnot in the control group (46 meters). However, the between-group difference was not significant. The CPAP group did notexperience a significant improvement in sustained attention/vigilance on the sustained attention to response test but didshow a significant improvement in digit span and visualspatial span-backward, not seen in the control group, al-though the between-group difference was not significant(Table 4).

Secondary OutcomesThere were significant reductions in the ESS and SSS in theCPAP compared to the control group (Table 2). There werealso significant improvements in the FIM and Berg Balancescale within both groups; however, these did not differsignificantly between them. Separate analysis of the motorand cognitive components of the FIM revealed a significantlygreater improvement in the motor, but not the cognitive,component in the CPAP than in the control group. TheChedoke-McMaster Stroke Assessment scale demonstratedsignificant improvements in the arm, hand, leg, and foot

Table 1. Baseline Characteristics of the Subjects

Control (n�22) CPAP (n�22)

Age, years 60.7�10.3 62.8�12.8

Sex (M/F) 19/3 16/6

Body mass index, kg/m2 27.3�5.8 28.8�5.3

History of smoking, n (%) 11 (50) 7 (32)

Hypertension, n (%) 15 (68.2) 18 (81.8)

Hyperlipidemia, n (%) 17 (77.3) 16 (72.7)

Diabetes mellitus, n ( %) 7 (31.8) 10 (45.5)

Ischemic heart disease, n (%) 2 (9.1) 6 (27.3)

Heart failure, n (%) 1 (4.6) 1 (4.6)

Atrial fibrillation, n (%) 4 (18.2) 3 (13.6)

Total hemorrhagic strokes, n 4 1

Total ischemic strokes, n 18 21

PACI 9 11

LACI 3 6

TACI 5 4

POCI 1 0

Right/left brain, n 6/16 9/13

Right/ left handedness, n 18/4 22/0

Values are mean�SD or % as indicated.CPAP indicates continuous positive airway pressure; LACI, lacunar infarction;

PACI, partial anterior circulation infarct; POCI, posterior circulation infarct; TACI,total anterior circulation infarct.

Table 2. Sleep Outcomes

Control (N�22) CPAP (N�22)

P*Baseline Follow-Up P Baseline Follow-Up P

ESS 4.5�2.1 4.5�2.2 0.94 4.4�1.8 1.8�1.0 0.0001 �0.0001

SSS 2.5�1.3 2.0�1.0 0.06 2.2�1.1 1.3�0.6 0.005 0.05

AHI, n/hr 33.3�16.4 30.3�17.5 0.60 38.5�18.1 7.6�8.5 0.0001 �0.0001

TST, hr 6.30�0.90 5.82�1.77 0.27 5.66�1.15 5.83�1.01 0.63 0.89

S1, % 9.5�5.4 9.3�4.8 0.92 8.6�5.6 8.2�6.5 0.84 0.70

S2, % 61.3�9.1 54.4�12.4 0.06 60.3�8.7 59.7�9.9 0.84 0.17

SWS, % 12.2�6.6 17.1�13.0 0.13 14.1�9.5 14.8�7.6 0.80 0.36

REM, % 16.9�8.9 19.2�7.2 0.40 17.4�6.3 17.3�7.4 0.97 0.53

ArI, n/hr 25.5�12.8 26.2�14.4 0.87 28.6�22.0 18.8�13.4 0.09 0.10

Mean sleep SaO2, % 95.5�1.8 95.5�1.4 0.94 94.4�1.6 96.0�1.6 0.003 0.26

Minimum sleep SaO2, % 79.6�11.3 79.4�15.7 0.97 80.7�5.7 90.9�3.4 0.0001 0.005

Values are mean�SD.AHI indicates apnea–hypopnea index; ArI, arousal index; CPAP, continuous positive airway pressure; ESS, Epworth Sleepiness

scale; REM, rapid eye movement sleep; S1, stage 1 sleep; S2, stage 2 sleep; SaO2, oxyhemoglobin saturation; SSS, StanfordSleepiness scale; SWS, slow wave sleep; TST, total sleep time.

*Between-group differences by analysis of covariance adjusted for age and sex.

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scores within both groups, and a significantly greater im-provement in the leg score in the CPAP than in the controlgroup. There was no within-group or between-group differ-ence in the ratio of hand-grip strength between the affectedand nonaffected hand in either group (Table 3). CPAP had nosignificant effect on visuo-motor speed and hand dexterity asassessed by the Purdue Pegboard score or in mental effi-ciency on the digit and visual spatial span-forward (Table 4).There was no significant reduction in the total BDI in eitherthe control group (13.3�9.8 to 10.4�8.7; P�0.35) or theCPAP group (12.6�11.8 to 8.8�9.0; P�0.76). The same wastrue for the somatic component of the BDI. However, therewas a significant reduction in the affective component of theBDI in the CPAP compared to the control group (7.0�7.4 to4.3�5.7 versus 7.6�7.2 to 6.2�7.0; P�0.006).

DiscussionThis randomized trial involving stroke patients with OSAundergoing inpatient rehabilitation has demonstrated that,

compared to the control group, CPAP usage was associatedwith improvement in the overall severity of stroke-relatedimpairment manifest by a greater improvement in one of theprimary outcomes, the Canadian Neurological Scale score.Although there were improvements in some of the otherprimary outcomes within the CPAP group, including mobilityassessed by 6-minute walk test distance and neurocognitivecapacity assessed by the digit/spatial span-backward, thesewere not statistically significant compared to the controlgroup. There was no within-group or between-group im-provement in vigilance assessed by the sustained attention toresponse test score. CPAP usage was also associated withimprovements in 5 of the secondary outcomes compared tothe control group, including the motor component of the FIM,Chedoke-McMaster Stroke Assessment leg score, ESS, SSS,and the affective component of the BDI. Taken together,these results indicate a significant, although modest, benefi-cial effect of CPAP on stroke-related outcomes.

Table 3. Functional and Motor Outcomes

Control (N�22) CPAP (N�22)

P*Baseline 1 Month P Baseline 1 Month P

Canadian Neurological scale, total 7.7�1.9 8.4�1.5 0.16 7.3�1.9 9.6�1.7 �0.001 �0.001

Canadian Neurological scale, cognitive 4.6�0.2 4.6�0.2 0.72 4.4�0.5 4.8�0.3 0.01 �0.001

Canadian Neurological scale, motor 3.1�1.9 3.8�1.5 0.15 2.7�1.6 4.8�1.6 �0.001 �0.001

Functional Independence measure, total 85.8�17.7 105.8�13.9 �0.001 78.3�20.8 105.6�16.8 �0.001 0.07

Functional Independence measure, cognitive 23.4�7.1 26.6�7.4 0.14 23.5�6.0 27.4�5.4 0.03 0.76

Functional Independence measure, motor 62.5�15.1 79.2�13.8 �0.001 54.8�18.7 78.2�14.6 �0.001 0.05

Chedoke-McMaster Stroke Assessment scale

Arm 4.3�1.9 4.8�1.9 0.02 3.8�1.7 4.9�1.6 �0.001 0.08

Hand 4.0�1.7 4.7�1.6 �0.001 4.0�1.7 4.7�1.7 �0.001 0.92

Leg 4.1�1.0 4.5�1.1 0.027 4.2�1.1 5.0�1.2 �0.001 0.001

Foot 3.8�1.3 4.3�1.3 0.007 3.6�0.9 4.3�1.2 �0.001 0.19

Berg Balance scale 28.2�17.5 44.3�11.3 0.001 29.5�19.2 43.7�14.6 0.01 0.64

6-minute walk distance, m† 270�236 316�178 0.29 190�176 303�157 0.02 0.75

Hand-grip affected/nonaffected ratio 0.48�0.46 0.61�0.58 0.09 0.39�0.41 0.45�0.5 0.29 0.36

Scale ranges: Canadian Neurological scale total, 1.5–11.5; Functional Independence measure total, 18–126; Chedoke-McMaster StrokeAssessment scale, 1–7; Berg Balance scale, 0–56.

CPAP indicates continuous positive airway pressure.*Between-group differences by analysis of covariance.†n�16 control and n�16 CPAP.

Table 4. Neuropsychological Outcomes

Control (n�20) CPAP (n�17)

P*Baseline Follow-Up P Baseline Follow-Up P

SART, total n of false-positive errors 12�7 11�7 0.21 13�5 15�6 0.32 0.26

SART, mean RT in the 4 trials just beforea false press

484�121 433�141 0.24 491�120 503�148 0.53 0.26

Purdue Pegboard, dominant hand score 30�12 36�15 0.29 32�8 35�9 0.39 0.88

Purdue Pegboard, nondominant hand score 35�15 40�15 0.36 29�12 33�12 0.34 0.37

Purdue Pegboard, affected hand score 30�12 37�16 0.35 28�12 32�13 0.80 0.62

Digit�visual spatial span-forward 44�33 41�30 0.54 32�26 35�29 0.08 0.27

Digit�visual spatial span-backward 40�36 45�36 0.08 24�32 34�30 0.03 0.32

CPAP indicates continuous positive airway pressure; RT, reaction time; SART, sustained attention response time.*Analysis of covariance adjusted for age and sex.




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The most prominent beneficial effects of CPAP therapyinvolved motor and functional outcomes. These includedimprovements in the motor components of the CanadianNeurological scale, FIM, and the leg motor component of theChedoke-McMaster Impairment scale. These improvementswere greater than those observed in the control group andwere accompanied by a significant increase in 6-minutewalking distance within the CPAP group. Since impairedmotor function of the leg is a major limitation to strokerecovery because it limits functional independence,12 thesefindings suggest that treatment of coexisting OSA by CPAPin stroke patients could improve functional independence andhasten return to community living.

ESS and SSS scores were within normal limits at baseline,indicating that patients were not hypersomnolent, consistentwith the study by Arzt et al.13 Nevertheless, treatment of OSAby CPAP caused reductions in ESS and SSS scores, eventhough it did not improve sleep structure, vigilance asassessed by the sustained attention to response test, orparticipation in physiotherapy. Thus, CPAP-related improve-ments in functional and motor outcomes could not be attrib-uted to a reduction in hypersomnolence, because subjectswere not hypersomnolent at onset of rehabilitation, or toincreased physiotherapy participation.

CPAP had marginal, if any, effects on the cognitiveoutcomes that were assessed. For example, although therewas a significant improvement in digit and visual span-backward within the CPAP group, suggesting improvementin executive functioning,14,15there were no improvements insustained vigilance, attention span, and visuo-motor speedand dexterity, as tested by the sustained attention to responsetest, digit and visual span-forward, and Purdue Pegboard,respectively.

With respect to depression, compared to the control group,the CPAP group experienced a significant improvement inthe affective, but not the somatic, component of the BDI. Theformer is a better index of mood after stroke, because thesomatic component of the BDI is confounded by items thatare also sensitive to the direct physiological effects of stroke(eg, loss of appetite). After a stroke, 25% to 40% of patientsexperience depression,16 which is associated with worseneurological recovery17 and increased mortality.18 Therefore,reductions in poststroke depression may contribute to neuro-logical recovery.

An important aspect of our trial was that only 3 (12%)patients randomized to CPAP left the study. For the remain-ing 22 people who completed the trial, CPAP compliance wasexcellent, with average daily use of 4.96 hours (consideringtotal sleep times were �5.60 hours). This excellent compli-ance is most likely because our subjects were inpatientsduring the entire trial period, and because nurses were trainedto administer CPAP to study subjects.

The mechanisms by which CPAP achieved beneficialeffects on motor and functional, but not neurocognitive,outcomes are not clear. CPAP-induced abolition of intermit-tent hypoxia and negative intrathoracic pressure swingsshould increase cerebral blood flow and oxygen delivery.19

Accordingly, functional and motor improvements in theCPAP-treated group may have been attributable to alleviation

of the adverse cerebrovascular effects of OSA, possiblythrough enhanced neuroplasticity.

Two other randomized trials evaluated the response ofstroke patients with OSA to CPAP. Sandberg et al20 studiedinpatients over a 1-month period. Subjects had good fixed-pressure CPAP compliance of 4.1 hours per night. However,the only improvement in the CPAP-treated group was areduction in severity of depression.20 Several differencesbetween that study and ours could account for apparentdifferences in outcomes. For instance, their patients were 18years older, 50% had heart failure, sleep apnea was predom-inantly central, and there were no evaluations of sleepstructure, alertness, or motor and neuropsychologicalfunctions.

The study by Hsu et al21was similar to ours in that subjectspredominantly had OSA and underwent assessments of sub-jective sleepiness, functional, and stroke severity outcomes.Their study differed from ours in that subjects were 14 yearsolder, had more severe OSA, and did not undergo assessmentof sleep structure by PSG or assessment of alertness, motor,or neuropsychological function. Subjects were studied over alonger period (6 months) and auto-titrating CPAP was used,with very poor compliance (1.4 hours per night). The nega-tive results of that study therefore were likely attributable topoor CPAP compliance.

The heterogenous nature of neurological damage andstroke etiology makes evaluation of clinical interventionsdifficult.22 We took this into account by assessing the effectsof treating OSA on various aspects of stroke outcome indifferent domains. Nevertheless, the present trial was subjectto some limitations. Forty-two percent of patients were noteligible for the study, primarily because of lack of fluency inEnglish. This, coupled with the small sample size, andinability to evaluate the effect of stroke subtype, affectedvessel size, and lateralization make it difficult to knowwhether the results apply to the general stroke population.Recovery from stroke may evolve over several months andthe 1-month follow-up may not have been sufficient toevaluate the extent and duration of stroke recovery whileusing CPAP or to assess its effects once subjects left thehospital.22

ConclusionsIn conclusion, this randomized trial demonstrated that treat-ment of OSA by CPAP in stroke patients undergoing reha-bilitation was associated with significant improvements infunctional and motor outcomes as well as mood. Functionaland motor impairments are often the most disabling featuresof stroke because they limit mobility and activities of dailyliving. Although our findings suggest that treating OSA instroke patients improves these outcomes, larger longer-termtrials are needed to determine whether such improvementscan persist or evolve further over longer periods.

AcknowledgmentsThe authors thank Dr William McIlroy for his expert opinion andaccess to facilities for the performance of motor tests.

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Sources of FundingSupported by an operating grant from the Physicians ServiceIncorporated Foundation, Ontario, Canada.

DisclosuresTyco Health Care provided CPAP devices for the trial. Provision ofASV devices for investigator-initiated trial with Canadian Institutesof Health Research (to D.B. and C.R.).

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Clodagh M. Ryan, Mark Bayley, Robin Green, Brian J. Murray and T. Douglas BradleyPatients With Obstructive Sleep Apnea

Influence of Continuous Positive Airway Pressure on Outcomes of Rehabilitation in Stroke

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2011 American Heart Association, Inc. All rights reserved.

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Online Supplement – Sleep Apnea Therapy and OSA, C. Ryan et al.

Influence of Continuous Positive Airway Pressure on Outcomes of Rehabilitation in Stroke

Patients with Obstructive Sleep Apnea.

SUPPLEMENTAL MATERIAL

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Supplemental Methods:

Baseline Assessments

Upon enrollment, demographic characteristics, stroke risk factors (history of hypertension, coronary artery disease, heart failure, atrial fibrillation, diabetes mellitus, hypercholesterolemia, and cigarette smoking) handedness, height, weight and body mass index were determined for each patient. All medications used were recorded. The treating physicians prescribed appropriate secondary stroke prevention medications such as anticoagulants, antiplatelet agents, and antihypertensive agents, as per the accepted standard of care, to provide optimum therapy. Otherwise, medications were not altered during the study except as medically indicated. Eligible patients were those admitted from acute care facilities to the SRU within 3 weeks of stroke onset with the following inclusion criteria: 1) 18 to 89 years of age; 2) completed ischemic or hemorrhagic stroke confirmed by a neurologist based on: a) history of sudden onset of a neurological deficit lasting more than 24 hours, b) neurological deficit on physical examination, and c) brain lesion compatible with the neurological deficit on computerized tomography or magnetic resonance imaging of the brain; 3) able to follow simple commands in English based upon the speech therapist’s assessment, 4) competent to provide informed consent to participate in the study; and 5) OSA on an overnight attended PSG as described below. Exclusion criteria were: 1) brainstem strokes that could increase aspiration risk while on CPAP, 2) patients with previously diagnosed OSA on therapy, 3) concomitant central nervous system diseases such as dementia, Parkinson’s disease, multiple sclerosis or Huntington’s disease, 4) history of psychosis, 5) traumatic brain injury; and 6) anosagnosia, global aphasia or Wernicke’s aphasia. Protocol Subjects with OSA completed the functional, motor and neuropsychometric and outcome assessments. All these tests were performed in a quiet environment using standard protocols between 2 and 5 pm. All assessments were performed by individuals blinded to randomization of the subjects. Assessment of functional and motor outcomes was performed by occupational and physio-therapists, respectively. Neuropsychometric testing and subjective assessment of mood and sleepiness were administered by trained neuropsychometrists and a research assistant, respectively. Sample Size Estimation The study was based on 4 primary outcome measures which were SART, digit span/spatial span-backwards, 6-minute walk test and the Canadian Neurological Scale (CNS). For all of these tests we want to detect a difference between the control and CPAP treated groups equivalent to 1 SD around the mean of normative data, because in clinical terms, this represents the difference between normal function and mild impairment, or mild to moderate impairment, or moderate to severe impairment. We also assumed that because we are examining several primary outcomes, that the power of the test should be 90%, rather than the usual 80% to avoid the potential for type II errors. For SART and digit span/spatial span backwards, at a 2-tailed alpha of 0.05 and power of 90%, a sample size of 22 subjects per group with complete data was estimated. For the 6-minute walk

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test, the sample size required to detect a clinically meaningful change of 52 meters with a two-tailed alpha of 0.05 and power of 90% was 16 per group. For the Canadian Neurological Scale, to detect a clinically important change at a 2-tailed alpha of 0.05 and power of 90%, a sample size of 13 subjects per group was estimated. Therefore, we required 22 subjects in each group to complete the trial. The trial was stopped upon reaching the prespecified group numbers. Randomization A computer-generated equal randomization schedule with a randomly varying block size of 2 to 4 was created to ensure equal numbers of subjects in each group. The statistician then enclosed the randomization codes in opaque sealed and stapled envelopes in sequence. These numbered envelopes were opened in sequence by a research assistant, once the subjects had completed all baseline assessments. The control group received standard stroke occupational and physiotherapy for the duration of the trial. The treatment group received standard stroke occupational and physiotherapy and in addition, received CPAP for their OSA. Personnel blind to the patients’ treatment allocation performed assessments and also analyzed and interpreted the data. CPAP CPAP was titrated during an overnight PSG to a pressure that reduced the AHI to < 5 or to the highest pressure tolerated. Patients were then provided with a CPAP machine (Tyco Healthcare, Goodknight 420G) and instructed to use it for at least 6 hours per night until the end of the trial. Night nursing staff were instructed how to apply CPAP to patients unable to apply it on their own, and assisted patients in reapplying it at night if they removed it for any reason. Compliance with CPAP was recorded automatically with a meter that records mask-on time. Details of Tests PSG Routine PSGs were performed using standard techniques and scoring criteria for sleep stages and arousals from sleep {Iber C, 2007 #86; Rechtschaffen, 1968 #18}. Thoracoabdominal movements and their electronic sum were monitored by respiratory inductance plethysmograph (RIP) (Respitrace; Ambulatory Monitoring Inc., White Plains, NY) 1. Arterial oxygen saturation (SaO2) was continuously monitored by a pulse oximeter (Nellcor, Puritan Bennett, LLC). Apneas were defined as an absence of excursion of the RIP sum channel for at least 10 seconds and were classified as obstructive or central in the presence or absence of thoracoabdominal motion, respectively. Hypopneas were defined as a 50% or greater reduction in the RIP sum channel for at least 10 seconds and were classified as obstructive if there was out-of-phase thoracoabdominal motion on RIP, and as central if thoracoabdominal motion was in-phase. The frequency of apneas and hypopneas per hour of sleep was expressed as the apnea-hypopnea index (AHI). Patients with an AHI of 15 were classified as having sleep apnea for the purpose of this study. OSA was diagnosed when at least 80% of the respiratory events were obstructive. Stanford Sleepiness Scale (SSS) This is a Likert-type 7-point scale in which each point has a descriptive label, ranging from 1 – ‘feeling active and vital; alert; wide awake’, to 7 – ‘almost in reverie; sleep onset soon; lost struggle to remain awake.’ Subjects are asked to select the number that they feel most accurately

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describes their level of alertness/sleepiness at that moment 2. The SSS has been found to be sensitive to changes in alertness due to both circadian variations and sleep loss. SSS scores were obtained after completion of the neuropyschological tests described below, as the SSS has been found to be more sensitive at the end of a performance test than before 3. Epworth Sleepiness Scale (ESS) The subjective Epworth Sleepiness Scale score is used to assess the general level of sleepiness under certain conditions. While imperfect, as it is not objective, it is widely validated and used in a number of populations for comparison4. The ESS alone may not be sufficient for assessment of sleepiness over the course of a day due to sleep apnea5, and therefore the SSS was also included. Scores greater than 10 on the ESS are indicative of excessive daytime sleepiness. Sustained Attention to Response Task (SART) The SART is a well-validated test of alertness and sustained attention in brain-damaged patients. Subjects were seated in a quiet environment in front of a computer screen. In this test numbers (each of the digits 0-9) are displayed briefly in random order, one at a time, on the screen. The subjects are instructed to press a key in response to each digit, unless the displayed digit is the number 3, in which case they are not to press the key. The number of errors (i.e. key presses in response to the number 3) is recorded. A complete test consists of 225 digits presented serially over a 4.3 minute period. Participation Assessment This included a daily documentation by the physiotherapists of actual time spent by the subjects performing physiotherapy. Furthermore, they also documented their perceived participation of each subject on a 7 point scale following each session. For participation 7 – ‘maximum’ 1- ‘no participation’ (Figure S1). Canadian Neurological Scale (CNS) This scale assesses the severity of the stroke according to the degree of neurologic impairment from brain damage6. This test includes 8 items that measure level of consciousness, orientation, speech, motor function, and facial weakness. Functional Independence Measure (FIM) This tool measures functional capacity7. It includes 18 items that measure self-care, sphincter control, mobility, locomotion, communication, and social cognition. It is used as an important determinant of fitness to be discharged from hospital. Berg Balance Scale This is an objective measure of balance abilities. The scale consists of 14 tasks common in everyday life. The items test the subject’s ability to maintain positions or movements of increasing difficulty by diminishing the base of support from sitting, standing, to single leg stance 8,9. Chedoke-McMaster Scale This scale measures the specific change in limb function among individuals who sustained cortical damage resulting in hemiplegia 10,11. This assessment tool stages the recovery from stroke based on Brunnstroms stages of recovery. A score ranging from 1 (flaccid paralysis) to 7

4


(normal movement patterns) provides an indication of the level of physical impairment resulting from the stroke. Walking Ability Walking ability was assessed with the 6-minute walk test 12. The 6-minute walk test assesses walking endurance 13. Subjects were instructed to walk from one end of the corridor to the other, covering as much distance as possible in a 6-minute period. At baseline, non-ambulant subjects were given a 6-minute walk test distance of 0. Upper Limb Strength Grip strength was assessed with a Baseline Hydraulic Hand dynamometer in both paretic and non-paretic hands 14. Subjects performed three repetitions and the highest value was taken as the measure of maximum grip strength. Grip strength has been used to provide a proxy measure of overall strength in healthy individuals, correlating well with lower limb strength. In stroke subjects, the ratio of strength between the paretic and non-paretic side was used to assess change over time. Neuropsychometric Assessment Beck Depression Inventory I (BDI I) This is one of the most widely used instruments for measuring the severity of self-reported depression in adults, and its reliability and validity have been established across a broad spectrum of clinical populations including geriatric patients 15,16. Neuropsychological Test Battery The battery comprises tests of mental efficiency (attention, concentration, vigilance, speed of processing), executive function and memory (verbal and visuospatial). In addition, a test of pre-morbid verbal intellectual function is included in order to rule out an explanation of intellectual function for any group differences that are observed between the CPAP and no-CPAP group. Please see Table S1 for the test list, the area of cognitive function measured by each test, and the test references. Tests with high test-retest reliability were selected because of the repeated measures design. The battery was brief in order to minimize patient burden and maximize reliability. Patients were offered breaks as needed. The test order was approximately counterbalanced in order to avert order effects. The Purdue Pegboard test is a well-validated test of both fine motor (fingertip) and gross motor (arm and hand) dexterity17. It has been used extensively as a test of the speed and accuracy of upper limb motor skills. In subjects with impaired motor function in the dominant hand/arm, whose performance on this test would be compromised, the non-dominant hand was used.

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Supplementa1 Figure S1:

Participation Assessment Form Please fill in all details on this form Date: Allotted Duration of Physiotherapy Session: minutes Time spent by patient performing physiotherapy: minutes This is to assess an individual’s level of participation in physiotherapy as perceived by the physiotherapist. It is designed to assess the level of co-operation, willingness and enthusiasm of the individual for the physiotherapy. It is not designed to measure an individual’s functional outcome or exercise capacity. It is to be completed by the physiotherapist following the individual’s completion of the daily physiotherapy. Please mark the relevant box APPENDIX 2 Supplemental Table Table S1

SCALE RATING

LEVEL OF PARTICIPATION

Maximum - individual participates fully & is engaged throughout the activities

7

6 Very Good – individual participates extremely well

5 Good – individual participates well

Adequate – individual participates, but not to maximum of present capabilities

4

3 Poor – individual does not actively participate

2 Very Poor – little participation by the individual

1 None – individual refuses to participate

6


Supplemental Table S1: Neuropyschological Tests

DOMAIN TEST FUNCTION MEASURED

Digit Span, forwards 18 Auditory verbal attention span (Spatial Span, forwards, for patients with language production deficits; 18

Visuospatial attention span Mental Efficiency

Sustained attention to response test 19 Sustained attention / Vigilance Digit Span, backwards 18 Auditory working memory Executive

functioning Spatial Span, backwards; for patients with language production deficits; 18

Visuospatial working memory

Manual Dexterity Purdue Pegboard Test 17

Motor speed & dexterity Subjects complete two 30sec trials with each hand

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8

Supplemental References: 1. Chadha TS, Watson H, Birch S, et al. Validation of respiratory inductive plethysmography

using different calibration procedures. Am Rev Respir Dis 1982;125(6):644-9. 2. Hoddes E, Zarcone V, Smythe H, Phillips R, Dement WC. Quantification of sleepiness: a new

approach. Psychophysiology 1973;10(4):431-6. 3. Babkoff H, Caspy T, Mikulincer M, Sing HC. Monotonic and rhythmic influences: a

challenge for sleep deprivation research. Psychol Bull 1991;109(3):411-28. 4. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale.

Sleep 1991;14(6):540-5. 5. Sangal RB, Sangal JM, Belisle C. Subjective and objective indices of sleepiness (ESS and

MWT) are not equally useful in patients with sleep apnea. Clin Electroencephalogr 1999;30(2):73-5.

6. Cote R, Battista RN, Wolfson C, Boucher J, Adam J, Hachinski V. The Canadian Neurological Scale: validation and reliability assessment. Neurology 1989;39(5):638-43.

7. Keith RA, Granger CV, Hamilton BB, Sherwin FS. The Functional Independence Measure: a new tool for rehabilitation. In: Eisenberg MG, Grzesiak, R.C., ed. Advances in Clinical Rehabilitation. New York: Springer, 1987: 6-18.

8. Berg KO, Maki BE, Williams JI, Holliday PJ, Wood-Dauphinee SL. Clinical and laboratory measures of postural balance in an elderly population. Arch Phys Med Rehabil 1992;73(11):1073-80.

9. Berg KO, Wood-Dauphinee SL, Williams JI, Maki B. Measuring balance in the elderly: validation of an instrument. Can J Public Health 1992;83 Suppl 2:S7-11.

10. Gowland C, Stratford P, Ward M, et al. Measuring physical impairment and disability with the Chedoke-McMaster Stroke Assessment. Stroke 1993;24(1):58-63.

11. Gowland C VH, S., Torresin, W., et al. Chedoke-McMaster Stroke Assessment: development, validation, and administration manual. In: Science SoR, ed. Hamilton, Ontario, Canada: McMaster University., 1995.

12. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166(1):111-7.

13. Guyatt GH, Thompson PJ, Berman LB, et al. How should we measure function in patients with chronic heart and lung disease? J Chronic Dis 1985;38(6):517-24.

14. Bohannon RW, Smith MB. Assessment of strength deficits in eight paretic upper extremity muscle groups of stroke patients with hemiplegia. Phys Ther 1987;67(4):522-5.

15. Beck AT, Steer RA, Brown GK. Manual for Beck Depression Inventory-II. San Antonio, TX.: Psychological Corporation, 1996b.

16. Steer RA, Rissmiller DJ, Beck AT. Use of the Beck Depression Inventory-II with depressed geriatric inpatients. Behav Res Ther 2000;38(3):311-8.

17. Spreen O, Strauss E. A Compendium of Neuropsychological Tests. New York: Oxford Press, 1991.

18. Wechsler D. Wechsler Adult Intelligence Scale (WAIS-III). 3rd ed. San Antonio: The Psychological Corporation, 1997.

19. Robertson IH, Manly T, Andrade J, Baddeley BT, Yiend J. 'Oops!' performance correlates of everyday attentional failures in traumatic brain injured and normal subjects. Neuropsychologia 1997;35(6):747-58.

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