Long-term Auto-Servoventilation or Constant Positive Pressure in Heart Failure and Coexisting Central With Obstructive Sleep Apnea

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1 CHEST Long-term Auto-Servoventiltion or Constnt Positive Pressure in Hert Filure n Coexisting Centrl With Obstrutive Sleep Apne Originl Reserh Winfrie J. Rnerth, MD, FCCP ; Gregor Nothofer ; Christin Priegnitz, MD ; Norbert Anuleit ; Mrel Treml, PhD ; Vitori Kehl, PhD ; n Wolfgng Gletke, MD SLEEP DISORDERS Bkgroun: The oexistene of obstrutive sleep pne (OSA) n entrl sleep pne (CSA) n Cheyne-Stokes respirtion (CSR) is ommon in ptients with hert filure (HF). While CPAP improves CSA/CSR by bout 50%, mximl suppression is ruil in improving linil outomes. Auto-servoventiltion (ASV) effetively suppresses CSA/CSR in HF, but few trils hve been performe in ptients with oexisting OSA n CSA/CSR. Our objetive ws to evlute rnomize, ontrolle tril to ompre the effiy of ASV n CPAP in reuing brething isturbnes n improving ri prmeters in ptients with HF n oexisting sleep-isorere brething. Methos: Both moes were elivere using the BiPAP utosv (Philips Respironis) over 12-month perio. Seventy ptients (63 men, y, BMI kg/m 2 ) h oexisting OSA n CSA/CSR, rteril hypertension, oronry hert isese, or riomyopthy n linil signs of hert filure New York Hert Assoition lsses II-III. Polysomnogrphy, brin ntriureti peptie (BNP), spiroergometry, n ehoriogrphy were performe t bseline n fter 3 n 12 months of tretment. Results: Both moes of therpy signifintly improve respirtory isturbnes, oxygen esturtions, n rousls over the stuy perio. ASV reue the entrl pne hypopne inex (bseline CPAP, ; ASV, ; 12 months CPAP, ; ASV, , P,.05) n BNP levels (bseline CPAP, ng/ml; ASV, ; 12 months CPAP, ; ASV, ; P,.05) signifintly more effetively s ompre with CPAP. There were no relevnt ifferenes in exerise performne n ehoriogrphi prmeters between the groups. Conlusions: ASV improve CSA/CSR n BNP over 12-month perio more effetively thn CPAP. Tril registry: ISRCTN Registry; No: ISRCTN ; URL: CHEST 2012; 142(2): Abbrevitions: AHI 5 pne hypopne inex; ASV 5 uto-servoventiltion; BNP 5 brin ntriureti peptie; CSA 5 entrl sleep pne; CSR 5 Cheyne-Stokes respirtion; EPAP 5 expirtory positive irwy pressure; HF 5 hert filure; IPAP 5 inspirtory positive irwy pressure; ITT 5 intention to tret; NIV 5 noninvsive positive pressure ventiltion; NYHA 5 New York Hert Assoition; OSA 5 obstrutive sleep pne; PP 5 per protool; SRBD 5 sleep-relte brething isorer In reent yers, the omplexity of sleep-relte brething isorers (SRBDs) hs been knowlege, espeilly in ptients with riovsulr isese. 1,2 Asie from the istint entities of obstrutive sleep pne (OSA), entrl sleep pne (CSA), n Cheyne- Stokes respirtion (CSR), ombintions of these brething isorers my lso mnifest in some ptients. 3 The efinition of CSA hs lso been expne to 440 inlue ptients with CPAP-resistnt CSA, CPAPemergent CSA, n opioi-inue sleep pne. 1 The ignosis n tretment of SRBD in ptients with hert filure (HF) is of ruil importne. First, SRBD often remins unobserve in this popultion beuse the typil symptoms of sleep pne n be mske by the symptoms of their unerlying hert isese. Seon, ptients with HF n SRBD re Originl Reserh Downloe From: on 08/11/2012

2 hrterize by reue left ventriulr funtion, inrese mlignnt rrhythmis, n poor prognosis. 4,5 Lst, ptients with OSA hve been shown to hve reue survivl rte ue to riovsulr events. 6,7 If SRBDs remin unresolve fter optimizing meil n interventionl ri tretment, 8 oxygen therpy, CPAP, n bilevel therpy re often evlute in trils. While there is only limite eviene to reommen oxygen or bilevel therpy, CPAP hs proven to reue brething isorers by pproximtely 50% n improve left ventriulr funtion. 9,10 However, CPAP oes not normlize SRBD in ll of these ptients or improve survivl. 9 The optiml suppression of respirtory isturbnes in HF my be of mjor importne for the prognosis. 11 The results of the Cnin Positive Airwy Pressure Tril for Hert Filure Ptients with Centrl Sleep Apne post ho nlysis suggeste tht n improve survivl my only mnifest in ptients whose pne hypopne inex (AHI) is reue to, 15/h. Aoringly, tretments whih suppress the AHI in those ptients who re not optimlly ontrolle by CPAP my be of linil importne. Auto-servoventiltion (ASV) effetively reues OSA n CSA/CSR. ASV evies provie fixe or utomti expirtory positive irwy pressure (EPAP) to eliminte upper irwy obstrution n moulte the inspirtory positive irwy pressure (IPAP) to overome CSR. 8 Thus, the lgorithms prevent hypoxi n hypopni, eliminte ventiltory overshoot, n stbilize respirtion. Short-term stuies hve emonstrte tht ASV is superior to subtherpeuti ASV, CPAP, or bilevel in improving sleep qulity, ytime performne, respirtory isturbnes, n riovsulr n symptheti mrkers More reent stuies hve fouse on ptients with omorbi OSA n CSA. 3,15,16 However, they were of short follow-up n limite smple size. Mnusript reeive August 19, 2011; revision epte Jnury 3, Affilitions: From the Institute of Pneumology t the University Witten/Hereke, Clini for Pneumology n Allergology, Center of Sleep Meiine n Respirtory Cre, Bethnien Hospitl (Drs Rnerth, Priegnitz, n Treml n Messrs Nothofer n Anuleit), Solingen; Institute of Meil Sttistis n Epiemiology (Dr Kehl), Stuy Centre Munih, Hospitl Klinikum rehts er Isr, Tehnil University of Munih, Munih; n Krnkenhus er Augustinerinnen (Dr Gletke), Cologne, Germny. Funing/Support : This stuy ws supporte in prt by Philips Respironis (Murrysville, PA). Corresponene to: Winfrie J. Rnerth, MD, FCCP, Institute of Pneumology t the University Witten/Hereke, Clini for Pneu mology n Allergology, Center of Sleep Meiine n Respirtory Cre, Bethnien Hospitl, Auferhöherstrße , Solingen, Germny; e-mil: rnerth@klinik-bethnien.e 2012 Amerin College of Chest Physiins. Reproution of this rtile is prohibite without written permission from the Amerin College of Chest Physiins. See online for more etils. DOI: /hest Bse on previous finings, we hypothesize tht ASV woul improve CSA/CSR more effetively thn CPAP in ptients with mil to moerte HF n oexisting OSA n CSA over the long term. Ptients Mterils n Methos Seventy onseutive ptients 18 yers with linilly ignose HF (left ventriulr ejetion frtion 20%, New York Hert Assoition [NYHA] lss II-III) uner optiml meil tretment n oexisting OSA n CSA (AHI 15/h, entrl proportion 80% n obstrutive proportion between 20% n 50%) were inlue. Unerlying ri isorers inlue rteril hypertension, oronry rtery isese, n ilte riomyopthy. Cri meition i not iffer between the groups n ws not signifintly hnge uring the ourse of the stuy. Exlusion riteri inlue myoril infrtion, unstble ngin petoris, or ri surgery within the lst 3 months, n pregnny. All ptients gve their written informe onsent. The stuy ws pprove by the ethil ommittee of the University of Witten/Hereke (Institutionl Review Bor No. 53/2006). Tretment Devie Both tretment moes (CPAP n ASV) were elivere using the sme evie (BiPAP utosv; Philips Respironis). When use in CPAP moe, the IPAP n EPAP were set t the sme level. When elivering ASV therpy, the EPAP pressure ws fixe oring to the CPAP titrtion n the IPAP vrie between the EPAP pressure n mximum IPAP, whih ws set by the physiin oring to the requirements of the ptient within the rnge of 4-30 m H 2 O. The evie utomtilly pplie mntory breths uring perios of entrl pne. Design This ws rnomize, prllel-group esign, opertor- n ptient-bline, single-enter linil stuy. After full-night, inptient polysomnogrphy, eligible ptients were rnomize (lots were rwn by person not involve in the stuy) to reeive CPAP or ASV therpy for 1-yer perio ( Tble 1 ). Ptients n t nlysts were bline to therpy llotion. All ptients unerwent three itionl onseutive nights in the sleep lbortory; two for titrtion purposes n one uner optiml settings (tretment night 1, Fig 1, e-appenix 1). At bseline n t 3 n 12 months, ptients unerwent ehoriogrphy, riopulmonry exerise testing, mesurement of brin ntriureti protein (BNP), n self-ministere series of questionnires, inluing the Minnesot Living with Hert Filure self-ministere questionnire (e-appenix 1). 17 Ptients were ontte by telephone fter 6 n 9 months to ollet t on qulity of life. Polysomnogrphy Polysomnogrphy ws performe using n Alie 4 Sleep Dignosti System (Philips Respironis). The nlysis of sleep stges n rousls ws rrie out oring to Rehtshffen n Kles.18 We lssifie hypopnes s entrl if there ws reution in respirtory flow n effort without flttening of the flow urve or proxil brething. Events with entrl n obstrutive proportion were lssifie s mixe. Centrl pnes were sore if journl.publitions.hestnet.org CHEST / 142 / 2 / AUGUST Downloe From: on 08/11/2012

3 Tble 1 Anthropometri n Polysomnogrphi Prmeters of the Complete Stuy Group Bseline 3 mo 12 mo CPAP ASV CPAP ASV CPAP ASV Age, y Sex, mle (femle) 32 (2) 31 (5) BMI, kg/m AHI totl, /h ,b AHI entrl, /h ,b ,b AHI perioi, /h , ,e AHI obstrutive, /h AHI mixe, /h , AI entrl, /h ,e ,e AI obstrutive, /h S o 2 min, % Time, 90% So 2, min Arousl totl, /h f f f Arousl resp, /h f WASO, min TST, min f f REM, % TST S1/S2, % TST S3/S4, % TST AHI perioi is subgroup of AHI entrl. AHI 5 pne hypopne inex; AHI entrl, /h 5 number of entrl pnes n hypopnes per hour of totl sleep time; AHI mixe, /h 5 number of mixe pnes n hypopnes per hour of totl sleep time; AHI obstrutive, /h 5 number of obstrutive pnes n hypopnes per hour of totl sleep time; AHI perioi, /h 5 number of perioi pnes n hypopnes per hour of totl sleep time (the perioi brething isturbnes re subgroup of the entrl AHI); AHI totl, /h 5 totl number of pnes n hypopnes per hour of totl sleep time; AI entrl 5 number of entrl pnes per hour of totl sleep time; AI obstrutive 5 number of obstrutive pnes per hour of totl sleep time; Arousl resp, /h 5 number of respirtion-ssoite EEG rousls per hour of totl sleep time; Arousl totl, /h 5 totl number of EEG rousls per hour of totl sleep time; ASV 5 uto-servoventiltion; % TST 5 proportion of rpi eye movement sleep per hour of totl sleep time; REM 5 rpi eye movement; REM, S1/S2, % TST 5 proportion of sleep stges 1 n 2 per hour of totl sleep time; S3/S4, % TST 5 proportion of sleep stges 3 n 4 n per hour of totl sleep time; Time, 90% So 2, min 5 time with oxygen sturtion below 90%; TST 5 totl sleep time; WASO 5 wke fter sleep onset. Bseline vs tretment (Wiloxon test): P,.001. b ASV vs CPAP (Mnn-Whitney U test): P,.05. ASV vs CPAP (Mnn-Whitney U test): P,.001. Bseline vs tretment (Wiloxon test): P,.01. e ASV vs CPAP (Mnn-Whitney U test): P,.01. f Bseline vs tretment (Wiloxon test): P,.05. respirtory effort ws bsent. Perioi brething ws sore if the pttern of wxing n wning of flow n effort ws present 19 (e-appenix 1). Sttistis The primry en point of the stuy ws the entrl AHI on tretment t 12 months. The smple size ws lulte s 35 ptients per tretment group. All nlyses were performe on the intentionto-tret (ITT) t set (e-appenix 1). The per-protool (PP) t set, whih ontine ll ptients with 12-month t, ws lso nlyze. Between-group omprisons were performe using n juste liner regression with the 12-month vlue s the epenent vrible n the bseline vlue n tretment group s the inepenent vribles. In ition, hnges in eh prmeter between bseline n 12 months were ompre between the tretment groups using n inepenent smple t test. In se of non-normlity, the Mnn-Whitney U test ws use. All sttistil tests were performe two-sie with signifine level of 5%. Results from the primry enpoint re onfirmtory. All other nlyses re explntory, n the P vlues re not juste for multipliity. All sttistil nlyses were performe with the softwre pkge PASW 18.0 (SPSS, In). Dt re presente s men n SD (e-appenix 1). Results Seventy ptients (63 men; men ge, yers; n men BMI, kg/m2 ) were enrolle into the stuy ( Tble 1 ). One ptient withrew onsent before initition, n nine ptients isontinue the stuy erly in eh group, leving 51 ptients who omplete the stuy ( Fig 1 ). The totl AHI in the whole stuy popultion ws /h with 54.7% CSA/CSR (CPAP 56.0%, ASV 53.4%, not signifint). There were no sig nifint ifferenes between the CPAP n ASV groups in nthropometri, ehoriogrphi, n polysomnogrphi prmeters t bseline ( Tbles 1, 2 ). Both methos signifintly improve the totl AHI. CPAP reue the entrl brething isturbnes by bout 50%. However, ASV improve the entrl AHI signifintly better thn CPAP, rehing men level below 10/h ( Fig 2, e-fig 1). Thus, the primry outome prmeter ws rehe ( P 5.023). ASV lso signifintly reue perioi n mixe brething 442 Originl Reserh DownloeFrom:

4 Figure 1. Digrm of the stuy esign. ASV 5 uto-servoventiltion; BR 5 brething rte; EPAP 5 expirtory positive irwy pressure; IPAP 5 inspirtory positive irwy pressure; ITT 5 intention to tret; PP 5 per protool; PSG 5 polysomnogrphy. isturbnes s ompre with CPAP t 12 months ( Tble 1, e-tble 1). In ition, the BNP level signifintly improve in the ASV group in the PP nlysis (Tble 2 ). Both moes of therpy signifintly normlize OSA. Men n miniml oxygen sturtion, totl n respirtory ssoite rousls, n snoring similrly improve with both moes. There ws no signifint ifferene between the moes in terms of sleep stges n other sleep prmeters ( Tble 1, e-tble 1). The mximum oxygen onsumption ws signifintly higher in the ASV group t ll times. However, there ws no signifint hnge over time between the groups. The ehoriogrphi prmeters i not iffer substntilly between the two groups ( Tble 2 ). The overll ompline ws. 4 h/ over the stuy perio in both groups with no signifint ifferenes between them (CPAP, h/; ASV, h/). The self-ssesse questionnire showe signifint improvements of ytime sleepiness, witnesse snoring journl.publitions.hestnet.org CHEST / 142 / 2 / AUGUST Downloe From: on 08/11/2012

5 Tble 2 Cri Prmeters (PP Anlysis) Bseline 3 mo 12 mo CPAP ASV CPAP ASV CPAP ASV NT-proBNP, ng/l LVEF, % LVEDD, mm b LVESD, mm IVST, mm IVSTs, mm LVEDWT, mm LVESWT, mm LVEDV, ml LVESV, ml LVTX o 2 mx/kg, ml/kg/min o 2 mx/hr, ml IVST 5 interventriulr septl thikness, istoli; IVSTs 5 interventriulr septl thikness, systoli; LVEDD 5 left ventriulr en-istoli imeter; LVEDV 5 left ventriulr en-istoli volume; LVEDWT 5 left ventriulr en-istoli wll thikness; LVEF 5 left ventriulr ejetion frtion; LVESD 5 left ventriulr en-systoli imeter; LVESV 5 left ventriulr en-systoli volume; LVESWT 5 left ventriulr en-systoli wll thikness; LVTX 5 left ventriulr Tei inex; NT-proBNP 5 N-terminl brin ntriureti peptie; PP 5 per protool; o 2 mx/hr 5 mximl oxygen onsumption per hert bet; o 2 mx/kg 5 mximl oxygen onsumption per kilogrm of boy weight. See Tble 1 legen for expnsion of other bbrevitions. ASV vs CPAP (Mnn-Whitney U test): P,.05. b Bseline vs tretment (Wiloxon test): P,.01. Bseline vs tretment (Wiloxon test): P,.05. ASV vs CPAP (Mnn-Whitney U test): P,.01. n pnes with both moes, n itionl improvement of ttention uner ASV. Furthermore, ASV signifintly improve the level of yspne n ftigue, but there were no signifint ifferenes between the groups (e-appenix 2, e-tbles 2, 3). Disussion These t emonstrte tht ASV is vntgeous s ompre with CPAP in ptients with linilly ignose mil to moerte HF n oexisting OSA n CSA. While both methos normlize obstrutive pnes n hypopnes similrly, ASV ws signifi ntly more effetive in suppressing entrl n mixe breth ing isturbnes, inluing perioi brething, over the long term. This fining ws ompnie by n improvement of the level of BNP s mrker of HF prognosis uner ASV s ompre with CPAP. We fouse on group of ptients with both oexisting OSA n CSA beuse it ws linilly relevnt to our prtie. Although OSA n be suffiiently trete with CPAP, the entrl portion is reue only by pproximtely 50%. 9 Furthermore, CSA my even emerge or be unmske by CPAP therpy. 1,2 Optiml suppression of respirtory isturbnes my be of ruil importne for the long-term outome of ptients with n without HF. 6,7,11 For these resons, optiml tretment of both OSA n CSA/CSR ppers to be essentilly relevnt. The proportion of obstrutive n mixe brething isturbnes n CSA/CSR ws 50% eh. Not surprisingly, CPAP n ASV both normlize OSA; however, the stuy onfirme erlier results tht CPAP reues CSA/CSR by pproximtely 50%. Thus, the room of further improvement of entrl brething isturbnes tht oul be hieve by ASV ws 50% n of the totl AHI, 25%. Nevertheless, ASV reue entrl brething isturbnes signifintly more effetively thn CPAP both in the ITT n PP nlysis t 3 n 12 months. Furthermore, the improvement in CSA/CSR on ASV le to signifint improvement in the totl AHI t 3 months n ler tren towr n improvement t 12 months s ompre with CPAP. While there were no ifferenes in the exerise performne tests between the moes, the reution of the BNP level inites n improvement of hert funtion when using ASV. This fining ws supporte by the self-ssesse reutions of yspne n ftigue uner this moe of therpy. The t presente in this stuy re in greement with previous stuies looking t the respirtory n riologi effets of ASV therpy, lthough these hve only investigte the effets of this tretment over the short to mi term. Teshler n ollegues 20 ompre one night of oxygen, CPAP, bi-level therpy, n ASV in group of 14 ptients with stble ri filure n preominnt CSA/CSR. Similr to our t, CPAP reue the entrl pne inex by 444 Originl Reserh DownloeFrom:

6 Figure 2. A-C, Tukey plots of the respirtory isturbnes. The Tukey plots of the (A) totl, (B) entrl, n (C) obstrutive AHI uner CPAP (open brs) n ASV (hthe brs). The boxes present the interqurtile istnes, the horizontl lines the mein, the whiskers the mximum n minimum vlues within 1.5 times the interqurtile rnge. Both tretment options signifintly improve ll types of respirtory isturbnes s ompre with bseline. However, ASV signifintly improve the entrl AHI t 3 n 12 months n in terms of the totl AHI t 3 months s ompre with CPAP. AHI 5 pne hypopne inex. See Figure 1 legen for expnsion of other bbrevitions. only 50%. While bi-level le to better improvement of the men entrl pne inex, there ws huge vrition in iniviul results in Teshler et l s 20 stuy. In ontrst, ASV normlize the entrl pne inex in lmost ll the ptients. 20 Arzt et l 14 showe tht ASV reue the AHI, 15 in group of ptients insuffiiently trete with bilevel n CPAP. However, this rtile inlue ptients with lmost pure CSA/CSR. Pepperell et l 12 stuie ASV n subtherpeuti ASV for 1 month. Effetive ASV improve respirtory isturbnes, ytime funtioning, n riovsulr n symptheti mrkers signifintly better thn subtherpeuti ASV. This stuy iffere from our esign ue to the more severe HF n shorter urtion. Philippe et l 13 ssigne 25 ptients with CSA n CSR, n stble HF (NYHA stges II-IV), to ASV or CPAP for 6 months. The uthors foun signifintly better improvement in respirtory isturbnes, hert funtion, qulity of life, n ompline in the ptients using ASV. In ontrst, our t o not show ifferenes in ptient ompline or selfssessment of qulity of life. However, one might journl.publitions.hestnet.org CHEST / 142 / 2 / AUGUST Downloe From: on 08/11/2012

7 ssume tht the smller mrgin of improvement in the entrl n totl AHI n the lower severity of HF in our tril were the most importnt resons for the ifferenes. Morgenthler et l 21 ompre ASV n noninvsive positive pressure ventiltion (NIV) in entrl, mixe, n omplex sleep pne over the short term. Both tretment options improve respirtion but ASV ws superior over NIV. More reently, Koym n ollegues 16 trete 10 ptients with HF NYHA II-III with ASV n seven ptients without ASV. They foun signifint improvement in the trete ptients in NYHA lss, BNP, ejetion frtion, n CRP fter 6 weeks. While our results on BNP gree with Koym s finings, the ifferene in the itionl prmeters my result from the ifferenes in the stuy popultions n the ifferent tretment in the ontrol group (CPAP vs no positive pressure tretment). Reently, some stuies fouse on ptients with oexisting OSA n CSA. Our group performe pro spetive pilot stuy on the effiy of ASV in 10 mle onseutive ptients with oexisting OSAS n CSA/CSR with n without HF over 8 weeks. ASV prove to effetively suppress ll types of respirtory isturbnes n to improve sleep qulity. 3 These results were further onfirme by Ksi et l 22 in 31 ptients with HF who were trete for 3 months with CPAP or ASV. Similrly to Philippe et l, 13 our t show improvement of some spets of qulity of life uner ASV while they i not hnge uner CPAP. The urrent stuy showe similr ily ompline rtes with both CPAP n ASV tretment n similr number of ptients isontinue tretment in eh tretment rm. These ompline levels re in line with previous stuies investigting ompline with CPAP in ptients with OSA 23 n CPAP n ASV ompline in ptients with HF. 22 These ompline levels re lso linilly relevnt given the limite mount of sleep pne symptoms observe in ptients with HF n the long-term esign use in this stuy. Some limittions shoul be isusse. The effets on ri prmeters might hve been more istint in ptients with more severely limite hert funtion. However, we fouse on ptients with mil to moerte HF for severl resons: Although bout 50% of ptients with stble HF in NYHA stges II suffer from SRBD, most stuies on ASV fouse on more severely ill ptients with overwhelming CSR rther thn oexisting OSA n CSA/CSR. However, ASV hs espeilly been esigne for those with oexisting brething isturbnes whih require linil verifition. Moreover, ue to the high prevlene of less severe HF in ily prtie, it seeme resonble to serh for suffiient tretment options for this popultion. In ition, it ws importnt to present long-term t from less severely ffete ptients prior to performing rnomize ontrolle stuy over 1 yer in ptients with left-ventriulr ejetion frtion, 20%. Finlly, hnges in tretment n other onfouning ftors might limit the interprettion of t from severely ffete ptients. As onsequene, the results nnot be generlize to other ptient popultions, for exmple, ptients with HF NYHA IV, ptients suffering from CPAPemerging CSA, or opioi-inue sleep pne. However, the results enourge one to perform long-term trils in these n other groups. This stuy ws performe using the ASV version with fixe EPAP n vrying IPAP. The first short-term t on lgorithms with itionl utomti pttion of the EPAP hve been presente, 24 showing slightly better suppression of respirtory isturbnes s ompre with the lgorithm teste here. However, long-term stuies on this tehnique re lking. In onlusion, ASV hs proven to suppress entrl, perioi, n mixe respirtory isturbnes more effetively, n obstrutive events eqully effetively s ompre with CPAP over perio of 12 months in ptients with mil to moerte HF. This ws ompnie by n improvement of the level of BNP s mrker of HF. Aknowlegments Author ontributions: Dr Rnerth h full ess to ll of the t in the stuy n tkes responsibility for the integrity of the t n the ury of the t nlysis. Dr Rnerth: ontribute to the oneption n esign of this stuy; quisition, nlysis, n interprettion of t; n mnusript preprtion. Mr Nothofer: ontribute to the quisition n interprettion of t n revision of the mnusript. Dr Priegnitz: ontribute to the quisition n interprettion of t n mnusript preprtion. Mr Anuleit: ontribute to the nlysis n interprettion of t n mnusript preprtion. Dr Treml: ontribute to the nlysis n interprettion of t n mnusript preprtion. Dr Kehl: ontribute to the nlysis n interprettion of t n preprtion of the mnusript. Dr Gletke: ontribute to the oneption n esign of this stuy n mnusript preprtion. Finnil/nonfinnil islosures: The uthors hve reporte to CHEST the following onflits of interest: Dr Rnerth hs reeive trvel grnts n speking fees from Philips Respironis. Dr Kehl hs reeive fees s ontrt sttistiin for Philips Respironis. The remining uthors hve reporte tht no potentil onflits of interest exist with ny ompnies/orgniztions whose prouts or servies my be isusse in this rtile. Role of sponsors: The sponsor h no role in the esign of the stuy, the olletion n nlysis of the t, or in the preprtion of the mnusript. Other ontributions: We thnk Crl Miltz for her effort n support in ompleting this mnusript. Furthermore, we thnk Ilon Kietzmnn n Kerstin Rihter for their support in nlyzing n evluting the t ollete in this stuy. Aitionl informtion: The e-appenixes, e-tbles, n e-figure n be foun in the Supplementl Mterils re of the online rtile. 446 Originl Reserh Downloe From: on 08/11/2012

8 Referenes 1. Jvheri S, Smith J, Chung E. The prevlene n nturl history of omplex sleep pne. J Clin Sleep Me ;5(3): Morgenthler TI, Kgrmnov V, Hnk V, Deker PA. Complex sleep pne synrome: is it unique linil synrome? Sleep ;29(9): Rnerth WJ, Gletke W, Stieglitz S, Lumnns C, Shäfer T. Aptive servo-ventiltion in ptients with oexisting obstrutive sleep pnoe/hypopnoe n Cheyne-Stokes respirtion. Sleep Me ;9(8): Bitter T, Westerheie N, Prinz C, et l. Cheyne-Stokes respirtion n obstrutive sleep pnoe re inepenent risk ftors for mlignnt ventriulr rrhythmis requiring pproprite rioverter-efibrilltor therpies in ptients with ongestive hert filure. Eur Hert J ;32(1): Sin DD, Logn AG, Fitzgerl FS, Liu PP, Brley TD. Effets of ontinuous positive irwy pressure on riovsulr outomes in hert filure ptients with n without Cheyne- Stokes respirtion. Cirultion ;102(1): Mrin JM, Crrizo SJ, Viente E, Agusti AG. Long-term riovsulr outomes in men with obstrutive sleep pnoehypopnoe with or without tretment with ontinuous positive irwy pressure: n observtionl stuy. Lnet ; 365 (9464): Buhner NJ, Snner BM, Borgel J, Rump LC. Continuous positive irwy pressure tretment of mil to moerte obstrutive sleep pne reues riovsulr risk. Am J Respir Crit Cre Me ;176(12): Rnerth WJ. Tretment options in Cheyne-Stokes respirtion. Ther Av Respir Dis ;4(6): Brley TD, Logn AG, Kimoff RJ, et l ; CANPAP Investigtors. Continuous positive irwy pressure for entrl sleep pne n hert filure. N Engl J Me ; 353 ( 19 ): Brk T, Rnerth W, Bloh KE. Cheyne-Stokes respirtion in ptients with hert filure: prevlene, uses, onsequenes n tretments [publishe online he of print Otober 18, 2011]. Respirtion. oi: / Arzt M, Flors JS, Logn AG, et l ; CANPAP Investigtors. Suppression of entrl sleep pne by ontinuous positive irwy pressure n trnsplnt-free survivl in hert filure: post ho nlysis of the Cnin Continuous Positive Airwy Pressure for Ptients with Centrl Sleep Apne n Hert Filure Tril (CANPAP). Cirultion ; 115 ( 25 ): Pepperell JC, Mskell NA, Jones DR, et l. A rnomize ontrolle tril of ptive ventiltion for Cheyne-Stokes brething in hert filure. Am J Respir Crit Cre Me ; 168 (9): Philippe C, Stoï-Hermn M, Drouot X, et l. Compline with n effetiveness of ptive servoventiltion versus ontinuous positive irwy pressure in the tretment of Cheyne- Stokes respirtion in hert filure over six month perio. Hert ;92 (3 ): Arzt M, Wensel R, Montlvn S, et l. Effets of ynmi bilevel positive irwy pressure support on entrl sleep pne in men with hert filure. Chest ;134 (1 ): Rnerth WJ, Gletke W, Kenter M, Rihter K, Shäfer T. Combine ptive servo-ventiltion n utomti positive irwy pressure (ntiyli moulte ventiltion) in o-existing obstrutive n entrl sleep pne synrome n perioi brething. Sleep Me ;10 (8 ): Koym T, Wtnbe H, Kobuki Y, et l. Benefiil effets of ptive servo ventiltion in ptients with hroni hert filure. Cir J ;74 (10 ): Retor T, Kubo S, Cohn J. Ptients self-ssessment of their ongestive hert filure: ontent, relibility n vliity of new mesure--the Minnesot Living with Hert Filure questionnire. Hert Fil ;3 : Rehtshffen A, Kles A. A Mnul of Stnrize Terminology, Tehniques n Soring System For Sleep Stges of Humn Subjets. US Dept of Helth, Eution, n Welfre. Wshington, DC: Ntionl Institutes of Helth ; Morgenthler TI, Kpen S, Lee-Chiong T, et l ; Stnrs of Prtie Committee ; Amerin Aemy of Sleep Meiine. Prtie prmeters for the meil therpy of obstrutive sleep pne. Sleep ;29 (8 ): Teshler H, Döhring J, Wng YM, Berthon-Jones M. Aptive pressure support servo-ventiltion: novel tretment for Cheyne-Stokes respirtion in hert filure. Am J Respir Crit Cre Me ;164 (4 ): Morgenthler TI, Gy PC, Goron N, Brown LK. Aptive servoventiltion versus noninvsive positive pressure ventiltion for entrl, mixe, n omplex sleep pne synromes. Sleep ;30 (4 ): Ksi T, Usui Y, Yoshiok T, et l ; JASV Investigtors. Effet of flow-triggere ptive servo-ventiltion ompre with on tinuous positive irwy pressure in ptients with hroni hert filure with oexisting obstrutive sleep pne n Cheyne-Stokes respirtion. Cir Hert Fil ;3 (1 ): MArle N, Devereux G, Heirnej H, Englemn HM, Mky TW, Dougls NJ. Long-term use of CPAP therpy for sleep pne/hypopne synrome. Am J Respir Crit Cre Me ;159 (4 Pt 1 ): Jvheri S, Goetting MG, Khyt R, Wylie PE, Goowin JL, Prthsrthy S. The performne of two utomti servoventiltion evies in the tretment of entrl sleep pne. Sleep ;34 (12 ): journl.publitions.hestnet.org CHEST / 142 / 2 / AUGUST Downloe From: on 08/11/2012