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A pilot study of the effects of non-invasive mechanical ventilation on the prognosis of ischemic cerebrovascular events in patients with obstructive sleep apnea syndrome

A pilot study of the effects of non-invasive mechanical ventilation on the prognosis of ischemic cerebrovascular events in patients with obstructive sleep apnea syndrome
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  ORIGINAL ARTICLE A pilot study of the effects of non-invasive mechanical ventilationon the prognosis of ischemic cerebrovascular events in patientswith obstructive sleep apnea syndrome Gulcin Benbir  • Derya Karadeniz Received: 31 October 2010/Accepted: 21 October 2011/Published online: 3 November 2011   Springer-Verlag 2011 Abstract  Obstructive sleep apnea syndrome (OSAS) isan independent risk factor for ischemic cerebrovasculardiseases, and results in worse prognosis and higher mor-tality. We aimed to investigate the effects of early treat-ment of OSAS on the prognosis of ischemic stroke. Weprospectively evaluated patients with acute supratentorialischemic stroke and OSAS on admission (acute stage), atsecond week (subacute stage) and at second month(chronic stage); 11 (73.3%) out of 15 patients put on thenon-invasive mechanical ventilation treatment within 48 hof stroke constituted the treatment group, and 13 patientsconstituted the control group. Patients with OSAS treat-ment showed significantly better prognosis and betterfunctioning in activities of daily living in both subacute andchronic stages. The rate of shrinkage of the ischemic lesionwas higher in the treatment group, though not significant.The early and effective treatment of OSAS provides abetter clinical prognosis in ischemic stroke. The beneficialeffects on radiological parameters need to be furtherstudied. Keywords  Obstructive sleep apnea syndrome    Ischemiccerebrovascular diseases    Non-invasive mechanicalventilation therapy    Prognosis    Ischemic lesion size Introduction The high incidence of cerebrovascular diseases (CVD), theneed for emergent treatment, and its poor prognosis withsocial and economical consequences highlight the impor-tance of primary and secondary management of stroke,which necessitates to be knowledgeable about risk factorsand their treatments. Many risk factors defined for CVDinclude old age, male gender, hypertension (HT), ischemicheart disease (IHD), atrial fibrillation (AF), diabetes mel-litus (DM), hyperlipidemia (HL), hypercoagulable states,and cigarette smoking. Among probable risk factors of CVD are alcohol consumption, obesity, hyperuricemia, andobstructive sleep apnea syndrome (OSAS).The risk of having a stroke is demonstrated to be twoto three times more common in patients with OSAS [1].Hypoxia, sympathetic activation [2], release of active freeoxygen radicals, C-reactive protein and other cytokines[3], increased thrombocyte activation/aggregation anddecreasedfibrinolyticactivityinOSAS[4,5]areproposedto cause ischemic CVD. Moreover, OSAS was shown to be anindependent risk factor for other diseases, such as HT, IHDor cardiac arrhythmias, which in turn constitute the risk factors of CVD. OSAS was also found to be an independentrisk factor for atherosclerotic carotid artery disease [6].The prevalence of OSAS was reported to be as high as60% in patients with ischemic CVD [5, 7–9]. Furthermore, the prognosis of stroke patients was also found to be worsein case of OSAS comorbidity [8, 10]. There is limited number of studies in stroke patients with OSAS investi-gating the effects of non-invasive mechanical ventilation,which is the gold standard therapy for OSAS [11]. Theyshowed the positive effects of OSAS treatment on dailyliving activities, cognitive functions, and depressivesymptoms in stroke patients [12, 13]. On the basis of these data, we aimed to investigate the benefits of effective andearly treatment of OSAS on clinical prognosis and radio-logical measures in patients with ischemic cerebrovasculardiseases and obstructive sleep apnea syndrome. G. Benbir ( & )    D. KaradenizSleep Disorders Unit, Department of Neurology, CerrahpasaFaculty of Medicine, Istanbul University, Istanbul, Turkeye-mail:  1 3 Neurol Sci (2012) 33:811–818DOI 10.1007/s10072-011-0835-6  Methods SubjectsDuring the 18-month study period, we questioned allpatients hospitalized to our neurology department with thediagnosis of acute ischemic CVD. The inclusion criteriawere acute ischemic stroke within 12 h of onset andage  ± 45 years. Infratentorial strokes, lacunar strokes, andstrokes secondary to other disorders were excluded, as theypossess different pathophysiological mechanisms. Patientswith a Glasgow Coma Scale below 7 were also excluded.Overall, 41 patients with acute ischemic stroke wereevaluated, but only 24 patients completed the study; 11patients constituted the ‘treatment group’ and 13 patientswho did not accept the non-invasive mechanical ventilationtherapy due to intolerance constituted the ‘control group’.Among dropouts, 10 patients were excluded (5 had norespiratory problems, 5 had central apnea), 3 patients didnot continue treatment, and 4 patients did not come forfollow-up controls.Baseline evaluationsThe whole-night PSG and titration study for non-invasivemechanical ventilation therapy (continuous positive air-way pressure, CPAP, or bilevel positive airway pressure,BPAP) were performed in our sleep laboratory and scoredaccording to the AASM Manual for the Scoring of Sleepand Associated Events [14]. The diagnosis of OSAS wasestablished as 15 or more scorable respiratory events perhour of sleep [15]. All patients with treatment had theirtreatment started within the first 48 h of stroke. All werecompliant with treatment for at least 5 h or more pernight.Otherriskfactorsofischemicstrokeevaluatedinthestudyconsisted of age, gender, body mass index (BMI), smoking,alcohol intake, hypertension (systolic blood pressure [ 140mmHg and/or diastolic blood pressure [ 90 mmHg; or use of anti-hypertensivetreatment),atrialfibrillation,ischemicheartdisease, hyperlipidemia (total cholesterol [ 200 mg/dL, tri-glyceride [ 150 mg/dL, low-density lipoprotein cholesterol C 100 mg/dL; or useof cholesterol-lowering drugs), diabetesmellitus (fasting blood glucose [ 140 mg/dL or plasma glu-coselevel [ 200 mg/dL2 haftermeals;oruseofantidiabeticdrugs), and degree of carotid atherosclerosis measured byDoppler ultrasonography.On the radiological arm of the study, T1, T2, Flair anddiffusion-weighted magnetic resonance images (MRI), andmagnetic resonance angiography (MRA) were performedin all patients at acute stage. The MRA was performed toexclude any pathology other than large-vessel occlusion asthe cause of supratentorial ischemic stroke, aiming to havea uniform homogeneous study population with shared risk factors mediated by OSAS.Follow-up evaluationsAll patients were hospitalized for 2 weeks. The compliancewith CPAP/BPAP therapy in treatment group wasobserved. The blood pressure level on admission, thehighest, the lowest and the average blood pressure levelsduring hospitalization were recorded. All patients wereevaluated at three time points, on admission (acute stage),at second week (subacute stage), and at second month(chronic stage), for clinical, biochemical and radiologicalparameters. In clinical evaluation, neurological examina-tion, the National Institute of Health Stroke Scale (NIHSS),Barthel Scale (BS), and Mini-Mental Status Examination(MMSE) were applied. From a psychiatric view, HamiltonDepression Rating Scale (HDRS) was questioned. Theobjective evaluation of sleep quality was tested by PSG;the subjective evaluation of sleep quality was tested byPittsburgh Sleep Quality Test (PSQT), and daytime sleep-iness was tested by Epworth Sleepiness Scale (ESS). Allevaluations were performed at three time points, exceptthat PSQT was applied twice (on admission and at secondmonth), as it measures the sleep quality for the past3 months.Biochemical parameters evaluated in the study consistedof hematocrit, C-reactive protein (CRP), fibrinogen, fastingglucose level, total cholesterol, triglyceride, and low-den-sity lipoprotein cholesterol.Radiologically, T1, T2, Flair and diffusion-weightedmagnetic MRI were repeated in all patients at subacute andchronic stages. The size of infarctions was determined bythe largest diameter of the lesion in any of multiplanar MRimages. The measurements of lesion size were done by oneof the researchers (GB) blind to any clinical data, andguided by a senior neuroradiologist.Statistical analysisIn comparison of risk factors with nominal values, PearsonChi-square test was used. For the comparison of carotidDoppler measurements with multiple nominal values, non-parametricMann–Whitney U  testwasused.Therelationshipbetweenclinical and biochemicalmeasures was searched byPearson correlation analysis. The changes of clinical andbiochemical measures during acute-subacute or acute-chronic stages were calculated as delta-change ratio, andanalyzed by using  t  test and Mann–Whitney U  test. Pearsoncorrelation analysis for nominal values and Spearman orKendall correlation analysis for ordinal or nominal non-parametric values were applied to explore whether theeffects of CPAP/BPAP treatment were influenced by other 812 Neurol Sci (2012) 33:811–818  1 3  risk factors. The change in radiological measures was ana-lyzed by Pearson Chi-square test. For multiple comparisons,we performed multiway analysis of variance (MANOVA),Waller-Duncan post-hoc analysis (for type I/II error) andregression analysis with adjustments for age, gender,smoking, BMI, hypertension and depression. The thresholdlevel for statistical significance was established at  p \ 0.05. Results A total of 24 patients with ischemic CVD and OSAS wereincluded; 11 patients out of 15 patients put on CPAP/BPAPtherapy completed the study and constituted the treatmentgroup (73.3%); 9 of these had CPAP therapy, and 2 hadBPAP therapy. The mean positive airway pressure was7.36  ?  1.68 cmH 2 O (5.0–10.0 cmH 2 O). Of the patientswho underwent CPAP/BPAP treatment, 7 were men and 4were women; in the control group, 9 were men and 4 werewomen. The gender (  p  =  0.556) and the mean age of patients (  p  =  0.485) were not different between the twogroups (Table 1).In the treatment group, 9 patients had atherothromboticand 2 patients had cardioembolic stroke; in the controlgroup, 7 patients had atherothrombotic and 6 patients hadcardioembolic stroke (  p  =  0.252). The risk factors forischemic stroke were not different between the two groupsexcept for hypertension, which was present in all thepatients of the treatment group, and in 53.8% of the patientsof the control group (  p  =  0.013, Table 1). On the otherhand, the blood pressure levels on admission, the highest,lowest, and average blood pressure levels during 2 weeks of hospitalization showed no difference between the twogroups (Table 1).Clinical evaluationAt acute stage, NIHSS, BS, and MMSE values were notdifferent between the groups (Table 1). The presence of motor dysfunction (  p  =  0.468), facial paralysis (  p  = 0.226), or aphasia (  p  =  0.406) were not different either.HDRS values were significantly lower in the treatmentgroup than in the control group (  p  =  0.004). The poly-somnographic parameters are given in Table 2. The sleepparameters, ESS and PSQT values were not statisticallydifferent in the two groups (Table 1).In the treatment group, NIHSS values showed a signifi-cant improvement at subacute (5.6  ±  4.6 points,  p  = 0.002) and chronic (3.1  ±  2.2 points,  p \ 0.001) stages. BSvaluesshowedasignificantriseatbothsubacuteandchronicstages (13.4  ±  4.8 and 16.2  ±  2.6 points,  p \ 0.001).MMSE values showed no statistically significant change Table 1  The risk factors andclinical characteristics of patients CPAP  continuous positiveairway pressure,  BPAP  bilevelpositive airway pressure, n  number of patients,  NIH  National Institute of Health* Pearson Chi-square test # Mann–Whitney  U   test § t   testRisk factors and clinicalevaluationPatients with CPAP/BPAPtreatment ( n  =  11)Patients withouttreatment ( n  =  13)  p  valueAge (years; mean  ±  SD) 68.2  ±  8.8 70.4  ±  6.4 0.485Gender (M/F) 7/4 9/4 0.556Body mass index (kg/m 2 ) 29.6  ±  4.3 25.9  ±  3.8 0.461Smoking (%) 27.2 15.3 0.506*Alcohol intake (%) 9.1 15.3 0.565*Hypertension (%) 100 53.8  0.013* Atrial fibrillation (%) None 30.7 0.067*Ischemic heart disease (%) 27.2 30.7 0.605*Hyperlipidemia (%) 27.2 46.1 0.300*Diabetes mellitus (%) 18.1 38.4 0.264*Carotid Doppler ultrasonography 0.556 # Increased intima-media thickness 5 4Presence of plaque 2 7Stenosis ( ± 50%) 2 2Average systolic blood pressure (mmHg) 137.6  ±  16.3 132.6  ±  16.4 0.486Average diastolic blood pressure (mmHg) 79.6  ±  10.8 80.3  ±  10.2 0.877NIH stroke scale 8.0  ±  5.0 9.6  ±  4.8 0.442 § Barthel scale 10.4  ±  5.2 9.3  ±  5.6 0.611 § Mini-mental status examination 26.6  ±  3.2 24.8  ±  3.0 0.186 § Hamilton depression rating scale 7.9  ±  2.6 12.4  ±  4.0  0.004 § Epworth sleepiness scale 11.0  ±  3.4 8.6  ±  4.2 0.137 § Pittsburgh sleep quality test 8.5  ±  2.8 7.0  ±  1.6 0.145 § Neurol Sci (2012) 33:811–818 813  1 3  (  p  =  0.280). HDRS values showed a significant fall atsubacute (5.2  ±  2.4 points,  p  =  0.003) and chronic(4.1  ±  1.6 points,  p  =  0.017) stages. ESS values showed asignificant decrease at subacute (8.2  ±  2.2 points,  p \ 0.001)andchronic(7.0  ±  2.2points,  p  =  0.022)stages,andPSQT showed a significant decrease at chronic stage(5.8  ±  3.1 points,  p  =  0.030). The correlation analysis of other risk factors revealed that minimum oxygen saturationvalues had a significant correlation with NIHSS scores atsubacute stage (  p  =  0.023). The mean oxygen saturationvalues showed a significant correlation with BS scores atacute (  p  =  0.019) and subacute (  p  =  0.023) stages. All theother parameters failed to show any significant correlationwith clinical outcomes.In the control group, NIHSS values showed no signifi-cance change at any stage. BS values showed a significantrise at subacute (12.5  ±  5.8 points,  p  =  0.032) and chronic(14.1  ±  5.6 points,  p  =  0.048) stages. MMSE valuesshowed no statistically significant difference. HDRS valuesshowed a significant worsening at subacute (15.4  ±  3.5points,  p  =  0.034) and chronic (17.7  ±  5.6 points,  p  =  0.024) stages. ESS or PSQT values showed no change.NIHSS values were significantly correlated with ESS val-ues at acute, subacute, and chronic stages (  p  =  0.003,  p  =  0.002 and  p  =  0.004, correspondingly). All the otherparameters did not correlate with clinical outcomes.The delta-change ratio in NIHSS values showed a sig-nificantly greater improvement in the treatment group atboth subacute (56.2  ?  25.4 vs. 20.2  ?  14.6%,  p  =  0.012)and chronic (43.2  ?  29.4 vs. 9.4  ?  20.7%,  p  =  0.020)stages (Fig. 1a). The improvement in BS values was alsogreater in the treatment group at subacute (50.2  ?  80.4 vs.34.2  ?  23.8%,  p  =  0.345) and chronic (72.8  ?  100.0 vs.46.5  ?  30.6%,  p  =  0.672) stages, though not significant(Fig. 1b). The changes in MMSE were not differentbetween groups (Fig. 1c). HDRS values showed a signifi-cant improvement in the treatment group at subacute andchronic stages (36.2  ?  23.9 and 45.7  ?  20.0%), while asignificant worsening was observed in the control group(18.4  ?  18.8 vs. 37.2  ?  28.6%) (  p \ 0.001, Fig. 1d).ESSvaluesshoweda significantfall intreatmentgroup atsubacute (11.4  ?  29.0%) and chronic (14.4  ?  25.4%)stages, while there was an increase in control group at sub-acute (28.9  ?  8.3%) and chronic (43.5  ?  12.0%) stages(  p  =  0.002forsubacutestage,  p  =  0.003forchronicstage).PSQT values evaluated at chronic stage were also signifi-cantly different in the two groups, with a decrease in thetreatment group (40.6  ?  24.7%) versus an increase in thecontrol group (19.8  ?  30.6%,  p  =  0.006).Biochemical evaluationOn admission, except for higher CRP values in the treat-ment group (18.4  ±  17.6 versus 5.4  ±  3.6 mg/L,  p  =  0.042), all parameters showed no difference betweentreatment and control groups. At the subacute stage, noneof the biochemical parameters showed a significant dif-ference. At the chronic stage, except for higher meanfasting glucose level in the treatment group (153.8  ±  36.8versus 93.5  ±  13.8 mg/dL,  p  =  0.037), all parametersshowed no difference too.Radiological evaluationSeventeen patients had right-sided and seven patients hadleft-sided infarction. Topographic localization or the size Table 2  Polysomnographicparameters of patients CPAP  continuous positiveairway pressure,  BPAP  bilevelpositive airway pressure, n  number of patients,  REM  rapid eye movements,  N  1  N  2and  N  3 sleep stages 1, 2, and 3  RERA  respiratory effort-relatedarousal;  O 2  oxygen,  PLMS  periodic leg movements in sleep*  t   testPolysomnographicparametersPatients with CPAP/BPAPtreatment ( n  =  11)Patients withouttreatment ( n  =  13)  p  value*Total sleep duration (min) 337.6  ±  79.2 298.0  ±  62.0 0.196Sleep efficiency (%) 78.6  ±  14.6 69.7  ±  15.4 0.165Sleep continuity (%) 81.2  ±  12.8 71.9  ±  15.6 0.121Sleep latency (min) 17.4  ±  19.8 14.4  ±  16.8 0.695REM latency (min) 167.4  ±  139.2 140.9  ±  101.4 0.621Wakefulness duration (min) 18.7  ±  12.8 28.0  ±  15.6 0.121N1 duration (min) 8.6  ±  4.2 17.2  ±  10.2  0.013 N2 duration (min) 57.0  ±  12.9 56.2  ±  15.2 0.884N3 duration (min) 24.0  ±  8.8 17.8  ±  11.8 0.151REM duration (min) 10.3  ±  7.4 8.8  ±  8.4 0.646Apnea-hypopnea index 24.6  ±  22.9 23.1  ±  14.8 0.858RERA index 20.7  ±  10.2 18.4  ±  12.7 0.625Average O 2  level in wakefulness (%) 94.2  ±  1.6 94.7  ±  1.8 0.525Average O 2  level in sleep (%) 93.5  ±  1.0 93.9  ±  1.5 0.435Lowest O 2  level (%) 80.4  ±  8.6 79.5  ±  10.7 0.836PLMS index 45.3  ±  19.3 48.2  ±  48.8 0.846814 Neurol Sci (2012) 33:811–818  1 3  of infarctions showed no relationship with any variables.None of the patients had hemorrhagic transformation. Atthe subacute stage, 40% of patients in the treatment groupshowed shrinkage in infarction size, while only 20% of patients in the control group had shrinkage in lesion size.At the chronic stage, the shrinkage in infarction size waspresent in 36.4% of patients in the treatment group, and in28.5% of patients in the control group. However, this dif-ference was not statistically significant (  p  =  0.344). Discussion Most recent guidelines on stroke emphasize the importanceof the management of ‘modifiable’ risk factors. Obstructivesleep apnea syndrome is an important factor in primary orsecondary prevention of stroke, and efficiently treatable byCPAP/BPAPtherapy.Inafewnumberofstudies[12,13,16], the compliance with CPAP/BPAP therapy in patients withOSAS was reported to be rather low especially at longerfollow-up ranging between 30 and 50%. The predictors of CPAP non-compliance in OSAS patients were summarizedas female gender, current smoking, BMI \ 30 kg/m 2 , ESSscore \ 15, apnea/hypopnea index \ 30, and CPAP pressure [ 12 cmH 2 O[17].Thepresenceofaphasiaandseveremotordysfunction was also found to be related to low compliance[13, 16]. In our study, 15 patients were put on CPAP/BPAP therapy, but 11 patients (73.3%) completed the study andconstituted the treatment group. The above-mentioned clin-ical factors were not found to be related to the compliancewith CPAP/BPAP therapy; however, we found that thepresence of depressive symptoms was related to lowercompliance. A similar conclusion was made in the study of Kjelsberg et al. [18], though their study consisted of OSASpatients without stroke. Other than clinical measures, poly-somnographic parameters were also not related to compli-ance with treatment in our study, in convenience withprevious reports [12, 13]. Although the blood pressure values were shown todecrease following CPAP treatment [13, 16]; one study did not repeat the same conclusion [19]. Similarly, in our study,there was no significant difference in blood pressure levelswith CPAP/BPAP treatment in compared to control group.The blood pressure measurements were done by the moni-toring during 2 weeks of hospitalization, however, the smallpopulation of the study to detect smaller changes in bloodpressure. Another explanation could be the presence of refractory hypertension in this particular group of patients. Fig. 1  The schematic drawingof the change in NIH StrokeScale ( a ), Barthel Scale ( b ),Mini-Mental StatusExamination ( c ) and HamiltonDepression Rating Scale ( d ) atacute, subacute, and chronicstagesNeurol Sci (2012) 33:811–818 815  1 3
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