Construct Validity and Minimal Important Difference of 6-Minute Walk Distance in Survivors of Acute Respiratory Failure

Transcription

1 [ Originl Reserh Critil Cre ] Construt Vlidity nd Miniml Importnt Differene of 6-Minute Wlk Distne in Survivors of Aute Respirtory Filure Kitty S. Chn, PhD ; Elizeth R. Pfoh, PhD ; Lind Denehy, PhD ; Doug Elliott, PhD ; Anne E. Hollnd, PhD ; Vitor D. Dingls, MPH ; nd Dle M. Needhm, MD, PhD OBJECTIVE: The 6-min wlk distne (6MWD), widely used test of funtionl pity, hs limited evidene of onstrut vlidity mong ptients surviving ute respirtory filure (ARF) nd ARDS. The ojetive of this study ws to exmine onstrut vlidity nd responsiveness nd estimte miniml importnt differene (MID) for the 6MWD in ptients surviving ARF/ARDS. METHODS: For this seondry dt nlysis of four interntionl studies of dult ptients surviving ARF/ARDS (N 5 641), onvergent nd disriminnt vlidity, known group vlidity, preditive vlidity, nd responsiveness were ssessed. MID ws exmined using nhor- nd distriution-sed pprohes. Anlyses were performed within studies nd t vrious time points fter hospitl dishrge to exmine generlizility of findings. RESULTS: The 6MWD demonstrted good onvergent nd disriminnt vlidity, with moderte to strong orreltions with physil helth mesures ( r ) nd weker orreltions with mentl helth mesures ( r ). Known-groups vlidity ws demonstrted y differenes in 6MWD etween groups with differing musle strength nd pulmonry funtion (ll P,.01). Ptients reporting improved funtion wlked frther, supporting responsiveness. 6MWD lso predited multiple outomes, inluding future mortlity, hospitliztion, nd helth-relted qulity of life. The 6MWD MID, smll ut onsistent ptient-pereivle effet, ws 20 to 30 m. Findings were similr for 6MWD % predited, with n MID of 3% to 5%. CONCLUSIONS: In ptients surviving ARF/ARDS, the 6MWD is vlid nd responsive mesure of funtionl pity. The MID will filitte plnning nd interprettion of future group omprison studies in this popultion. CHEST 2015; 147(5): Mnusript reeived July 22, 2014; revision epted Jnury 3, 2015; originlly pulished Online First Mrh 5, ABBREVIATIONS: 6MWD 5 6-min wlk distne; ALTOS 5 ARDSNet Long Term Outomes Study; ARF 5 ute respirtory filure; ED-5D 5 Euro-QOL; HRQL 5 helth-relted qulity of life; ICAP 5 Improving Cre of Aute Lung Injury Ptients; MID 5 miniml importnt differene; PF 5 physil funtioning; SF-36 5 Medil Outomes Survey 36-Item Short Form AFFILIATIONS: From the Deprtment of Helth Poliy nd Mngement (Drs Chn nd Pfoh), Johns Hopkins Bloomerg Shool of Puli Helth, Bltimore, MD; Deprtment of Physiotherpy (Dr Denehy), The University of Melourne, Melourne, VIC, Austrli; Fulty of Helth (Dr Elliott), University of Tehnology, Sydney, NSW, Austrli; Deprtment of Physiotherpy (Dr Hollnd), L Troe University, Melourne, VIC, Austrli; Deprtment of Physiotherpy (Dr Hollnd), Alfred Helth, Melourne, VIC, Austrli; Institute for Brething nd Sleep (Dr Hollnd), Melourne, VIC, Austrli; nd Outomes After Critil Illness nd Surgery (OACIS) Group (Mr Dingls nd Dr Needhm), Division of Pulmonry nd Critil Cre Mediine (Mr Dingls nd Dr Needhm), nd Deprtment of Physil Mediine nd Rehilittion (Dr Needhm), Johns Hopkins University Shool of Mediine, Bltimore, MD. FUNDING/SUPPORT: This reserh ws supported y the Ntionl Hert, Lung, nd Blood Institute [R24HL111895, R01HL091760, R01HL S1, R01HL096504, nd P050HL7399], the Johns Hopkins Institute for Clinil nd Trnsltionl Reserh [UL1TR ], the Aluterol to Tret Aute Lung Injury (ALTA), the Erly vs Delyed Enterl Feeding to Tret People With Aute Lung Injury or Aute Respirtory Distress Syndrome (EDEN), nd the Omeg-3 Ftty Aid/Antioxidnt Supplementtion for Treting People With Aute Lung Injury or Aute Respirtory Distress Syndrome (OMEGA) trils [ontrts for sites prtiipting in this study: HSN C, HHSN C, HHSN C, HHSN C, HSN C, nd HHSN C]. The Elliott tril ws supported y the Austrlin Ntionl Helth nd Medil Reserh Counil (NHMRC) 1316 Originl Reserh [ 147 # 5 CHEST MAY 2015 ] Downloded From: y CAPES User on 01/28/2016

2 Ptients who survive ute respirtory filure (ARF) nd ARDS frequently experiene importnt nd longlsting physil impirments. 1,2 The 6-min wlk distne (6MWD) is widely used mesure of funtionl pity in studies of ptients surviving ARF/ARDS. 1 Roust literture on the vlidity of the 6MWD exists for geritri, rdi, neurologi, nd COPD popultions, 3-9 ut omprehensive vlidtion of the 6MWD hs not een done mong ptients surviving ARF/ARDS. These ptients differ from hronilly ill popultions due to ute onset of physil impirments nd younger ge; therefore, determining the vlidity, responsiveness, nd miniml importnt differene (MID), defined s the smllest differene pereivle y ptients, for the 6MWD is importnt for plnning nd interprettion of future reserh studies. 10 Th e present study used dt from four interntionl longitudinl studies to exmine the onstrut vlidity of the 6MWD in ptients surviving ARF/ARDS. Mterils nd Methods Study Design Seondry nlyses were performed using dt from two US-sed studies (ARDSNet Long Term Outomes Study [ALTOS] nd Improving Cre of Aute Lung Injury Ptients [ICAP]) 11,12 nd two Austrlinsed studies. 13,14 Ptients from these studies with t lest one 6MWD ssessment in the 12 months fter ritil illness were inluded. The ALTOS inluded ptients surviving ARDS from 12 hospitls ross five study sites, with 6- nd 12-month follow-up ourring etween 2008 nd ALTOS sujets were reruited sed on prtiiption in t lest one of three o-enrolling Ntionl Hert, Lung, nd Blood Institute ARDS Network rndomized trils evluting erosolized luterol vs pleo (Aluterol to Tret Aute Lung Injury [ALTA] tril), 15 e rly vs delyed enterl feeding (Erly vs Delyed Enterl Feeding to Tret People With Aute Lung Injury or Aute Respirtory Distress Syndrome [EDEN] tril), 16 nd omeg-3 ftty id nd ntioxidnt supplement vs pleo (Omeg-3 Ftty Aid/Antioxidnt Supplementtion for Treting People With Aute Lung Injury or Aute Respirtory Distress Syndrome [OMEGA] tril). 17 The ICAP study ws prospetive ohort study in ptients surviving ARDS reruited from four demi tehing hospitls in Bltimore, Mrylnd, with 3-, 6-, nd 12-month follow-up ourring etween 2005 nd The Denehy et l 13 study ws linded rndomized tril of intensive rehilittion ross ICU, hospitl, nd ommunity settings vs usul physiotherpy re in ptients with ARF in single hospitl in Melourne, Vitori, Austrli. Ptient ssessments t hospitl dishrge nd 3-, 6-, nd 12-month follow-up etween 2008 nd 2010 were inluded in this nlysis. The Elliott et l 14 study ws linded rndomized tril of n 8-week home-sed rehilittion progrm onduted in ptients with ARF reruited from 12 hospitls ross three study sites in Austrli. Ptient evlutions onduted t 1, 8, nd 26 weeks fter hospitl dishrge (oded s hospitl dishrge, 3 nd 6 month, for this nlysis) etween 2005 nd 2009 were inluded in this nlysis. In ll studies, the rndomized interventions did not hve n effet on physil outomes, so ptients in oth rms of eh tril were pooled for this nlysis. 11,13,14,18,19 All studies otined informed onsent from prtiipnts nd were pproved y relevnt institutionl review ords (Johns Hopkins Shool of Mediine IRB-X #_ [ICAP] nd IRB-5 #_ [ALTOS]; Austin Helth Humn Reserh Ethis Committee #H2006/ [Grnt ]. The Denehy tril ws ompleted with funds from the NHMRC [Grnt ], the Physiotherpy Reserh Foundtion, the Austin Hospitl Medil Reserh Foundtion, nd the Austrlin nd New Zelnd Intensive Cre Soiety. CORRESPONDENCE TO: Kitty S. Chn, PhD, Deprtment of Helth Poliy nd Mngement, Johns Hopkins Bloomerg Shool of Puli Helth, 624 N Brodwy, Hmpton House #633, Bltimore, MD ; e-mil: khn10@jhu.edu 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reprodution of this rtile is prohiited without written permission from the Amerin College of Chest Physiins. See online for more detils. DOI: /hest [Denehy]; nd University of Tehnology t Sydney Humn Reserh Ethis Committee # [Elliott]). Consistent with the 2012 Berlin onsensus meeting, 20 we use the term ARDS rther thn ute lung injury throughout this rtile. Study Mesures The primry study mesure 6MWD ws sed on Amerin Thori Soiety guidelines 21 in ll studies with modest vritions, inluding using single 6MWD t eh follow-up in the studies (s done in prior ARF/ARDS reserh 2 ) nd using the longest ville distne (sed on Amerin Thori Soiety guidelines 21 ) during home visits. The 6MWD ws presented in meters nd s % predited (lulted using US 22 nd Austrlin 23 normtive vlues) for ll studies exept Elliott et l 14 in whih % predited vlues were not ville. Well-estlished performne-sed nd ptient-reported mesures refleting importnt spets of physil funtioning (PF) were used to ssess onvergent nd known-groups vlidity of the 6MWD. These inlude the 4-m timed wlk speed (in meters per seond), mnul musle testing using the Medil Reserh Counil sum sore 27,28 (rnge, 0-60, with, 48 inditing ICU-quired wekness 29 ), nd spirometry 30 (reported s FEV 1 % predited sed on normtive vlues 31 ). Ptient-reported mesures inluded the Medil Outomes Survey 36-Item Short Form (SF-36) 32 PF domin, the Funtionl Performne Inventory 33 overll sore, nd the Euro-QOL (EQ-5D) 34 moility susle. These mesures often re used in studies of physil outomes in ptients surviving ARF/ARDS Well-estlished ptient-reported mentl helth mesures were used to ssess disriminnt vlidity, inluding the SF-36 mentl helth domin, nxiety susles of the Hospitl Anxiety nd Depression Sle 40 nd EQ-5D, nd the overll posttrumti stress disorder symptom sore of the Impt of Event Sle Revised. 41 Prior reports of the orreltion etween physil nd mentl helth mesures hve een wek (typilly, r, 0.3) Hospitliztion, mortlity, live-t-home sttus (whether ptients were living t home), return to norml tivity (return to work, shool, homemking, or volunteering s ws ourring prior to hospitliztion), nd helthrelted qulity of life (HRQL) up to 12 months postdishrge were used to test preditive vlidity. Dt were otined through ptient or proxy report, lthough medil reords were lso used in Denehy et l. 13 Hospitliztions ourring within 3 nd 6 months n e self-reported with 98% nd 96% ury, respetively. 45 Mortlity dt were not ville in Elliott et l. 14 The normed version of the SF-36 PF domin sore, ville in ll studies, ws used to ssess responsiveness. Ptient rting of glol hnge in PF, dministered t 6 nd 12 months in the Denehy et l 13 tril, ws lso used in responsiveness nlyses. This mesure sked ptients to rte improvement in their ility to perform dily PF tivities using visul nlog sle with 0 inditing no improvement nd 10 inditing mximum improvement. Sttistil Anlysis Construt Vlidity: Person orreltions were used to exmine onvergent nd disriminnt vlidity. To estlish onvergent vlidity, we journl.pulitions.hestnet.org 1317 Downloded From: y CAPES User on 01/28/2016

3 hypothesized tht physil helth outomes would e t lest modertely orrelted ( r. 0.40) with 6MWD. To estlish disriminnt vlidity, we hypothesized negligile to wek reltionships ( r, 0.30) etween mentl helth outomes nd 6MWD. Furthermore, we expeted the orreltion of 6MWD with physil helth outomes to e onsistently stronger thn with mentl helth outomes. For known-groups vlidity tests, the twosmple independent t test ws used to determine whether men 6MWD signifintly differed in groups sed on physil helth. We hypothesized tht ptients with ICU-quired wekness (mnul musle testing strength sore, 48) nd impired pulmonry funtion (FEV 1, 70% predited) would perform signifintly worse s determined y 6MWD thn ptients with greter musle strength nd pulmonry funtion. Preditive Vlidity: We used logisti nd liner regression to exmine the ssoition of 30-m differene in the 6MWD, refleting meningful differene for 6MWD in other popultions. 46,47 6MWD t dishrge, 3 months, nd 6 months were hypothesized to predit future mortlity, rehospitliztion, live-t-home sttus, return to norml tivity, nd HRQL (SF-36 PF domin nd EQ-5D utility) t or y 12 months. Responsiveness: Liner regression ws used to test whether hnge in 6MWD prllels sustntil hnge oserved in relted physil outomes in the sme period. We exmined responsiveness for three postdishrge periods: dishrge to 3 months, 3 to 6 months, nd 6 to 12 months. We tegorized hnge in the normed SF-36 PF domin etween two time points s negtive if sores deresed y 10 points, no hnge if sores deresed or inresed y, 10 points, nd positive if sores inresed y 10 points. The 10-point inrement represented 1 SD for the normed SF-36 PF domin nd hs een identified s n importnt hnge y linil experts. 48 A ptient PF improvement rting of. 5 in Denehy et l 13 re fl eted sustntil improvement. Survivors with positive hnge or sustntil improvement in PF were expeted to wlk sustntilly frther thn survivors reporting no hnge, negtive hnge, or nonsustntil improvement. We further exmined whether hnge in 6MWD ould disriminte etween ptients reporting sustntil improvement from those reporting less improvement y evluting the re under the reeiver operting hrteristi urve. Estimting MID: We used multiple nhor- nd distriution-sed methods to estimte the 6MWD MID. 49 Anhor-sed methods used the SF-36 PF domin (sle, 0-100) nd EQ-5D utility (originl multiplied y 100 for omprison with SF-36). These outomes were hosen s nhors given their distint, ut importnt onepts of HRQL (EQ-5D utility inludes physil nd mentl spets), strong onvergent vlidity with the 6MWD (SF-36 PF, r ; EQ-5D, r ; P,.01), nd the vilility of previously reported MIDs. To estimte n nhor-sed MID, we used liner regression model with 6MWD s the outome nd the nhor mesure SF-36 PF or EQ-5D utility s the preditor. The -oeffiient from this model represents the numer of meters from the 6MWD equivlent to one point in the nhor mesure ssessed t the sme time point. The -oeffiient multiplied y the nhor s MID (five points for SF-36 PF nd 7.4 for EQ-5D [whih is the pulished MID for the utility sore ]) 50,51 determines the 6MWD MID estimte. For the distriution-sed methods, SE of mesurement, miniml detetle hnge t the 90% CI, nd 0.50 SD, were lulted s in prior studies. 49,52,53 We lso evluted 0.20 SD of 6MWD to reflet smll effet size sed on Cohen s 54 riteri. We onduted nlyses seprtely for eh study nd for vrious time points to exmine whether findings were onsistent despite differenes in study design, ptient hrteristis, nd time sine dishrge. The preeding nlyses were lso replited using 6MWD % predited (rther thn 6MWD in meters), whih ounts for differenes in wlk distnes ross ptient ge, sex, nd physil differenes. TABLE 1 ] Prtiipnt Chrteristis y Study Vrile ICAP 12 (n 5162 ) ALTOS 11 (n 5183) Elliott et l 14 (n 5180) Denehy et l 13 (n 5126) Age, y Mle sex 93 (57) 90 (48) 109 (61) 76 (60) BMI, kg/m Re White 96 (59) 163 (89) Blk 63 (39) 15 (8) Other 3 (2) 5 (3) Edution, y Employed 68 (42) 96 (53) Chrlson Comoridity Index Funtionl Comoridity Index APACHE sore Ventiltion durtion, d ICU length of sty, d Hospitl length of sty, d MWD t 6 mo, m MWD, % predited Dt re presented s men SD or No. (%). 6MWD 5 6-min wlk distne; ALTOS 5 ARDSNet Long Term Outomes Study; APACHE 5 Aute Physiology nd Chroni Helth Evlution; ICAP 5 Improving Cre of Aute Lung Injury Ptients. APACHE II. APACHE III. 6MWD % predited dt were not ville for the Elliott et l 14 tril Originl Reserh [ 147 # 5 CHEST MAY 2015 ] Downloded From: y CAPES User on 01/28/2016

4 TABLE 2 ] Construt Vlidity: Cross-setionl Reltionship of 6MWD (in Meters) With Moility nd PF (Convergent Vlidity) nd MH Mesures (Disriminnt Vlidity) Aross Studies nd Dt Colletion Time Points Convergent Vlidity Correltion With Mesures of PF Disriminnt Vlidity Correltion With Mesures of MH Time Point Study n 4-m Wlk FPI SF-36 PF Domin EQ-5D Moility SF-36 MH Domin EQ-5D Anxiety HADS Anxiety Symptoms IES-R PTSD Symptoms Dishrge Elliott et l Dishrge Denehy et l mo Elliott et l mo Denehy et l mo ICAP mo Elliott et l mo Denehy et l mo ALTOS mo ICAP mo Denehy et l mo ALTOS mo ICAP Dt re presented s Person r unless otherwise indited. ED-5D 5 Euro-QOL; FPI 5 Funtionl Performne Inventory; HADS 5 Hospitl Anxiety nd Depression Sle; IES-R 5 Impt of Event Sle Revised; MH 5 mentl helth; PF 5 physil funtioning; PTSD 5 posttrumti stress disorder; SF-36 5 Medil Outomes Survey 36-Item Short Form. See Tle 1 legend for expnsion of other revitions. For these sles, higher sore indites worse PF nd poorer MH, resulting in negtive orreltion with the 6MWD for whih greter distne wlked indites etter funtionl pity. Sore rnges for ptientreported outomes re s follows: SF-36 PF nd MH (0-100); EQ-5D moility nd nxiety susles (0-2); FPI totl (0-3); HADS nxiety susle (0-21); nd IES-R (0-4). P,.01. P,.05. journl.pulitions.hestnet.org 1319 Downloded From: y CAPES User on 01/28/2016

5 Results Ptient ge, sex, nd BMI were similr, with rnge of mehnil ventiltion durtions nd ICU lengths of sty represented ross studies ( Tle 1 ). 6MWDs t 6 months were modestly higher in the two Austrlin trils vs the two US studies. Findings for 6MWD % predited, whih ounts for ptient ge, sex, nd physil differenes, were omprle to those for 6MWD in meters nd re reported in e-tles 1 to 5. Construt Vlidity Consistently ross studies, ountries, nd follow-up time points, orreltions of the 6MWD with other PF mesures were modertely strong nd were mostly wek to negligile with mentl helth mesures, supporting onstrut vlidity ( Tle 2, e-tle 1). Knowngroups vlidity tests further supported onstrut vlidity, with signifintly shorter distne wlked for survivors with ICU-quired wekness nd impired pulmonry funtion ompred with their higher-funtioning ounterprts ( Tle 3, e-tle 2). Preditive Vlidity Bsed on pooled nlyses, 6MWD n signifintly predit future mortlity, rehospitliztion, live-t-home sttus, return to norml tivity, nd HRQL ( Tle 4, e-tle 3). Predition of 12-month HRQL ws prtiulrly onsistent ross the studies nd time points 6MWD ws ssessed. 6MWD ws less onsistently ssoited with the remining outomes in the individul studies possily euse of the rrity of these events in some studies. Responsiveness Survivors with positive SF-36 PF domin hnges wlked frther thn those reporting no hnge or negtive hnge ( Tle 5, e-tle 4). This finding ws most pprent in the pooled nlysis. Positive SF-36 PF domin hnges etween 3 nd 6 months were ssoited with 6MWD inreses of 65 (95% CI, 46-83) m ompred with 26 (95% CI, 9-42) m for the no-hnge group nd 2 29 (95% CI, 2 53 to 2 5) m for the negtivehnge group ( Tle 5 ). Similr results were oserved etween 6 nd 12 months ut not for the period from dishrge to 3-month follow-up when ll three hnge groups wlked sustntilly longer distnes. However, the ltter finding ppers to e lrgely due to one of the two trils exmining this erlier period. For the ptient rting of glol hnge, the group reporting sustntil vs modest or no improvement hd lrger men inrese in 6MWD etween dishrge nd 6 months (239 [95% CI, ] vs 113 [95% CI, ] m, respetively; P,.001) nd etween 6 nd 12 months (21 [95% CI, 10-38] vs 2 44 [95% CI, 2 59 to 230] m, respetively; P 5.003). Similr to the SF-36 PF domin results for this study, men 6MWD inresed sustntilly in the immedite postdishrge period, even if survivors rted their funtionl improvement s modest or no improvement. Chnge in 6MWD disriminted etween the sustntil vs modest or no improvement groups t oth 6 nd 12 months, with res under the reeiver operting hrteristi urve of 0.79 (95% CI, ) nd 0.79 (95% CI, ), respetively. TABLE 3 ] Known-Group Vlidity, t Tests of Group Differenes in 6MWD (in Meters) y Mesures of Musle Wekness nd Pulmonry Funtion Time Point Pooled nlysis Study MMT, 48 (n ) MMT 48 (n ) P Vlue FEV 1, 70% (n ) FEV 1 70% (n ) P Vlue 6 mo ALTOS 11 nd ICAP , , mo ALTOS 11 nd ICAP , ,.001 Individul study nlysis 3 mo ICAP mo ALTOS , mo ICAP , mo ALTOS , mo ICAP , MMT 5 mnul musle testing. See Tle 1 legend for expnsion of other revitions. n for ells: ICAP t 3 mo: MMT, ; MMT ; FEV 1, 70% 5 49; FEV 1. 70% ALTOS t 6 mo: MMT, ; MMT ; FEV 1, 70% 5 48; FEV 1. 70% ICAP t 6 mo: MMT, ; MMT ; FEV 1, 70% 5 31; FEV 1. 70% ALTOS t 12 mo: MMT, ; MMT ; FEV 1, 70% 5 46; FEV 1. 70% ICAP t 12 mo: MMT, ; MMT ; FEV 1, 70% 5 39; FEV 1. 70% Pooled nlysis t 6 mo: MMT, ; MMT ; FEV 1, 70% 5 79; FEV 1. 70% Pooled nlysis t 12 mo: MMT, ; MMT ; FEV 1, 70% 5 85; FEV 1. 70% Originl Reserh [ 147 # 5 CHEST MAY 2015 ] Downloded From: y CAPES User on 01/28/2016

6 TABLE 4 ] Preditive Vlidity of 6MWD (per 30 Meters) for Postdishrge Outomes: All-Cuse Mortlity, Any Hospitliztion, Alive-t-Home Sttus, Return to Norml Ativity, nd Helth-Relted Qulity of Life Mortlity Hospitliztion Alive-t-Home Sttus Return to Norml Ativity 6MWD Time Point Study By 12 mo Undjusted OR (95% CI) Between 6 nd 12 mo Undjusted OR (95% CI) At 12 mo Undjusted OR (95% CI) At 12 mo Undjusted OR (95% CI) SF-36 PF t 12 mo (95% CI) EQ-5D Utility t 12 mo (95% CI) Pooled nlysis 3 mo ICAP 12 nd Denehy et l 13 N Died, n ( ) N n ( ) N 5 93 Norml, n ( ) 3.3 ( ) N mo ICAP 12 nd ALTOS 11 N Died, n ( ) N n ( ) N Home, n ( ) N Norml, n ( ) 4.1 ( ) N ( ) N ICAP, 12 ALTOS, 11 nd Denehy et l 13 N Died, n ( ) N n ( ) N Norml, n ( ) 3.9 ( ) N Individul study nlysis Dishrge Elliott et l 14 N Died, n 5 4 (y 6 mo) d 0.92 ( ) N n 5 35 (y 6 mo) d 1.02 ( ) N Home, n (t 6 mo) d 1.10 ( ) 2.7 ( ) N (t 6 mo) Denehy et l 13 N Died, n ( ) N n ( ) 1.8 ( ) N mo ICAP 12 N Died, n ( ) N 5 87 n ( ) N Home, n ( ) N 5 74 Norml, n ( ) 3.6 ( ) N ( ) N 5 89 (Continued) journl.pulitions.hestnet.org 1321 Downloded From: y CAPES User on 01/28/2016

7 TABLE 4 ] (ontinued) Mortlity Hospitliztion Alive-t-Home Sttus Return to Norml Ativity 6MWD Time Point Study By 12 mo Undjusted OR (95% CI) Between 6 nd 12 mo Undjusted OR (95% CI) At 12 mo Undjusted OR (95% CI) At 12 mo Undjusted OR (95% CI) SF-36 PF t 12 mo (95% CI) EQ-5D Utility t 12 mo (95% CI) Denehy et l 13 N Died, n ( ) N n ( ) N 5 28 Norml, n ( ) 2.7 ( ) N mo ICAP 12 N Died, n ( ) N 5 93 n ( ) N Home, n ( ) N 5 66 Norml, n ( ) 4.1 ( ) N ( ) N Denehy et l 13 N 5 89 Died, n ( ) N 5 89 n ( ) N 5 23 Norml, n ( ) 2.9 ( ) N 5 71 ALTOS 11 N Died, n ( ) N n ( ) N Home, n ( ) N 5 94 Norml, n ( ) 4.2 ( ) N ( ) N Eh nlysis ws sed on prtiipnts with n oservtion for oth outome nd 6MWD t the speified time point. OR for 30-m inrese in 6MWD. hosp. 5 hospitl; 5 not ville. See Tle 1 nd 2 legends for expnsion of other revitions. Outomes oding: died 5 1; live 5 0; ny hospitliztion during period 5 1; no hospitliztion 5 0; live-t-home sttus 5 1; not t home/died 5 0; return to norml tivity 5 1; did not return to norml tivity 5 0; SF-36 PF (sore rnge, 0-100), EQ-5D utility (sore rnge, 0-100). P.01. P.05. d Elliott dt only hve outomes mesured up to 6 mo postdishrge. All other studies hve outome dt up to 12 mo postdishrge Originl Reserh [ 147 # 5 CHEST MAY 2015 ] Downloded From: y CAPES User on 01/28/2016

8 TABLE 5 ] Responsiveness to Chnge in Reovery Trjetory: Men Chnge in 6MWD (in Meters) Reltive to Ptient-Reported Chnge of. 10 points on Normlized SF-36 PF Domin Sore Chnge Period Study Pooled nlysis Dishrge to 3 mo Denehy et l, 13 Elliott et l mo ICAP, 12 Denehy et l, 13 Elliott et l 14 Negtive Chnge. 10 Points SF-36 PF Domin Normlized Sore (n ) No Chnge (n ) Positive Chnge. 10 Points SF-36 PF Domin Normlized Sore (n ) , 26 65, 6-12 mo ICAP, 12 ALTOS , Individul study nlysis Dishrge to 2 mo Elliott et l , Dishrge to 3 mo Denehy et l , mo Elliott et l mo Denehy et l , mo ICAP mo ICAP , mo ALTOS ALTOS nd ICAP sores normlized to US generl popultion with men SD of Denehy nd Elliott sores normlized to Austrlin generl popultion. Smple size y study nd time point: Elliott dishrge to 2 mo: positive hnge (n 5 89), no hnge (n 5 56), negtive hnge (n 5 1). Denehy dishrge to 3 mo: positive hnge (n 5 31), no hnge (n 5 55), negtive hnge (n 5 11). Elliott 2-6 mo: positive hnge (n 5 20), no hnge (n 5 104), negtive hnge (n 5 10). Denehy 3-6 mo: positive hnge (n 5 11), no hnge (n 5 64), negtive hnge (n 5 8). ICAP 3-6 mo: positive hnge (n 5 15), no hnge (n 5 65), negtive hnge (n 5 2). ICAP 6-12 mo: positive hnge (n 5 14), no hnge (n 5 71), negtive hnge (n 5 8). ALTOS 6-12 mo: positive hnge (n 5 16), no hnge (n 5 106), negtive hnge (n 5 2). Pooled dishrge to 3 mo: positive hnge (n 5 120), no hnge (n 5 111), negtive hnge (n 5 12). Pooled 3-6 mo: positive hnge (n 5 46), no hnge (n 5 233), negtive hnge (n 5 20). Pooled 6-12 mo: positive hnge (n 5 30), no hnge (n 5 177), negtive hnge (n 5 10). See Tle 1 nd 2 legends for expnsion of revitions. P.05 for omprison etween the positive hnge group vs the negtive hnge group. P.01 for omprison etween eh hnge group vs the no-hnge group. P.05 for omprison etween eh hnge groups vs the no-hnge group. Estimting MID Using known MIDs for the SF-36 nd the EQ-5D utility sore, nhor-sed MID estimtes for the 6MWD rnged etween 14 nd 30 m ( Tle 6 ), whih ws onsistent ross time points, study, nd ountry. Estimtes using the EQ-5D MID were modestly lrger thn those using the SF-36 MID ( Tle 6, e-tle 5). Distriution-sed MID estimtes were generlly lrger thn nhor-sed estimtes ut were lso onsistent ross time points, study, nd ountry. Speifilly, the rnge of estimtes for eh mesure ws s follows: SE of mesurement, 31 to 38 m; miniml detetle hnge t the 90% CI, 67 to 88 m; 0.5 SD, 53 to 84 m; nd 0.2 SD, 21 to 34 m ( Tle 6, e-tle 5). Disussion Overll, the 6MWD is vlid mesure of funtionl pity for ptients surviving ARF/ARDS. Consistent evidene of onurrent onstrut vlidity ws found t vrious time points postdishrge nd ross interntionl studies with different ptient smples nd study designs. The 6MWD ws lso found to hve preditive vlidity nd ws responsive to hnges in PF. Using reommended methods for estimting MID, 49 we determined tht 20 to 30 m reflets the 6MWD MID. Anhor-sed estimtes, whih were given greter weight, 49 were pproximtely 20 m nd omprle with or only modestly smller thn prior reports for nhor-sed MIDs in geritri ptients nd ptients with COPD. 46,55 The present distriution-sed MID estimtes were modestly lrger thn the nhor-sed ones ut were lso onsistent with prior studies with geritri, COPD, nd hroni pulmonry disese popultions. 47,55-57 Identifying single MID is diffiult given the hllenges in defining minimum. However, the onvergene of the present nhor-sed estimtes with the distriution-sed SE of mesurement nd 0.2 SD 49,53,58 suggests tht nrrow rnge of 20 to 30 m would e resonle MID for the 6MWD. Overll, nhor- nd distriution-sed MID estimtes were surprisingly onsistent ross the studied ptient popultions, settings, nd points long the reovery trjetory. Although nhor-sed MID my e determined ross-setionlly or longitudinlly, 59 the present nhor-sed estimtes re from ross-setionl, etween-group nlyses nd journl.pulitions.hestnet.org 1323 Downloded From: y CAPES User on 01/28/2016

9 TABLE 6 ] Miniml Importnt Differene for 6MWD (in Meters) Approh ALTOS, 11 m ICAP, 12 m Denehy et l, 13 m Elliott et l, 14 m Anhor sed SF-36 PF domin 3 mo mo mo EQ-5D utility sore 3 mo 30 6 mo mo Distriution sed SE of mesurement 3 mo mo MDC-90 3 mo mo SD ICU dishrge 53 Hospitl dishrge mo mo mo SD d ICU dishrge 21 Hospitl dishrge mo mo mo MCD-90 5 miniml detetle hnge t the 90% CI. See Tle 1 nd 2 legends for expnsion of other revitions. MID lulted y multiplying liner regression -estimte with SF-36 MID of 5 points, 40 using the SF nonnormlized sle. MID lulted y multiplying liner regression -estimte with MID of 7.4 for the EQ-5D utility sore. 41 EQ-5D utility sore nd MID multiplied y 100 to filitte omprison with SF-36 estimtes. Cross-setionl orreltion for 6MWD with the SF-36 PF sore ( , P,.01) nd with the EQ-5D utility sore ( , P,.01). Equivlent to moderte Cohen effet size. d Equivlent to smll Cohen effet size. re most pproprite for group omprisons thn for within-sujet hnge. The findings on 6MWD % predited lrgely prlleled those from the 6MWD in meters, with evidene of onurrent onstrut vlidity, preditive vlidity, nd responsiveness ross studies nd time points. Similrly, lthough distriution-sed MID estimtes were lrger thn nhorsed MIDs, nrrow rnge of 3% to 5% predited 6MWD ws oserved tht likely represents smll ut ptientpereivle differene. The similrity of findings for oth 6MWD in meters nd % predited suggests tht ge, sex, nd physil ttriutes (height, weight) do not sustntilly influene the vlidity of the 6MWD. This study provides omprehensive vlidtion of 6MWD mong ptients surviving ARF/ARDS. However, potentil limittions to this reserh exist. First, the seleted vriles (eg, ptient rting of improvement in funtioning) were not ville in ll studies, limiting our ility to replite or pool dt ross studies for smll numer of the nlyses. Seond, we relied on the SF-36 PF domin nd EQ-5D s nhor mesures. These mesures ssess funtioning more rodly nd do not 1324 Originl Reserh [ 147 # 5 CHEST MAY 2015 ] Downloded From: y CAPES User on 01/28/2016

10 preisely mth the onstrut ssessed y the 6MWD tht fouses more speifilly on wlking spets of funtionl pity. Third, nlyses tht require tegoriztion n led to smll smple sizes within speifi ells. The lk of sttistil signifine for some omprisons in the responsiveness nd preditive vlidity nlyses my e due to this issue; however, pooling dt ross studies generlly ddresses this prolem. Finlly, our MID nlyses were foused on group-level omprisons, nd the findings nnot e extended to intrptient MIDs. Despite these limittions, n extensive set of similr vriles ross these four interntionl studies hs provided rigorous evlution of the vlidity of the 6MWD. Furthermore, the onsisteny of the findings ross diverse study popultions, study designs, nd time points nd for 6MWD evluted in oth meters nd s % predited support generlizility. Conlusions The 6MWD is ommonly used evlution of PF in oth linil nd reserh settings. This test requires miniml equipment nd n e undertken y ptients with vrious funtionl ilities. The study demonstrtes tht 6MWD is vlid mesure for liniins nd reserhers to ssess funtionl pity mong ptients surviving ARF/ARDS. The 6MWD MID, whih is 20 to 30 m or 3% to 5% predited, n help liniins using the 6MWD to ssess nd interpret the effiy of reserh interventions mong ptients with ARF/ARDS postdishrge. Aknowledgments Author ontriutions: K. S. C. hd full ess to ll of the dt in the study nd tkes responsiility for the integrity of the dt nd the ury of the dt nlysis. K. S. C. ontriuted to the study onept nd design nd drfting of the mnusript; E. R. P. ontriuted to the dt nlyses; L. D., D. E., nd V. D. D. ontriuted to the dt quisition; D. M. N. ontriuted to the study onept nd design nd dt quisition; nd K. S. C., E. R. P., L. D., D. E., A. E. H., V. D. D., nd D. M. N. ontriuted to the nlysis pln, interprettion of study results, ritil revision of the mnusript for importnt intelletul ontent, nd finl pprovl of the mnusript. Finnil/nonfinnil dislosures: The uthors hve reported to CHEST tht no potentil onflits of interest exist with ny ompnies/orgniztions whose produts or servies my e disussed in this rtile. Role of sponsors: The sponsors were not involved in ny spet of the design, nlysis, or interprettion of this study. Other ontriutions: The uthors thnk ll the ptients nd their proxies who prtiipted in the studies. They lso knowledge the importnt ontriutions provided y the investigtors nd reserh stff from the Ntionl Institutes of Helth Ntionl Hert, Lung, nd Blood Institute ARDS Network, ALTOS, ICAP, nd the trils y Denehy et l 13 nd Elliott et l. 14 Additionl informtion: The e-tles n e found in the Supplementl Mterils setion of the online rtile. Referenes 1. Desi SV, Lw TJ, Needhm DM. Longterm omplitions of ritil re. Crit Cre Med ;39(2): Herridge MS, Tnsey CM, Mtté A, et l ; Cndin Critil Cre Trils Group. Funtionl disility 5 yers fter ute respirtory distress syndrome. N Engl J Med ;364(14): Bellet RN, Adms L, Morris NR. The 6-minute wlk test in outptient rdi rehilittion: vlidity, reliility nd responsiveness systemti review. Physiotherpy ;98(4): Tyson S, Connell L. The psyhometri properties nd linil utility of mesures of wlking nd moility in neurologil onditions: systemti review. Clin Rehil ;23(11): Hmilton DM, Hennel RG. Vlidity nd reliility of the 6-minute wlk test in rdi rehilittion popultion. J Crdiopulm Rehil ;20(3): Hrd ND, Chiu V, Stewrt AL. Moilityrelted funtion in older dults: ssessment with 6-minute wlk test. Arh Phys Med Rehil ;80(7): Poole-Wilson PA. The 6-minute wlk. A simple test with linil pplition. Eur Hert J ;21(7): O Keeffe ST, Lye M, Donnelln C, Crmihel DN. Reproduiility nd responsiveness of qulity of life ssessment nd six minute wlk test in elderly hert filure ptients. Hert ;80(4): Rsek T, Lee AL, Nughton MT, Willims TJ, Hollnd AE. The sixminute wlk test: useful metri for the rdiopulmonry ptient. Intern Med J ;39(8): Jones PW, Beeh KM, Chpmn KR, Dermer M, Mhler DA, Wedzih JA. Miniml linilly importnt differenes in phrmologil trils. Am J Respir Crit Cre Med ;189(3): Needhm DM, Woznik AW, Hough CL, et l ; Ntionl Institutes of Helth NHLBI ARDS Network. Risk ftors for physil impirment fter ute lung injury in ntionl, multi-enter study. Am J Respir Crit Cre Med ; 189 (10): Fn E, Dowdy DW, Colntuoni E, et l. Physil omplitions in ute lung injury survivors: two-yer longitudinl prospetive study. Crit Cre Med ;42(4): Denehy L, Skinner EH, Edrooke L, et l. Exerise rehilittion for ptients with ritil illness: rndomized ontrolled tril with 12 months of follow-up. Crit Cre ;17(4):R Elliott D, MKinley S, Alison J, et l. Helth-relted qulity of life nd physil reovery fter ritil illness: multientre rndomised ontrolled tril of home-sed physil rehilittion progrm. Crit Cre ;15(3):R Mtthy MA, Brower RG, Crson S, et l ; Ntionl Hert, Lung, nd Blood Institute Aute Respirtory Distress Syndrome (ARDS) Clinil Trils Network. Rndomized, pleo-ontrolled linil tril of n erosolized 2 -gonist for tretment of ute lung injury. Am J Respir Crit Cre Med ;184(5): Rie TW, Wheeler AP, Thompson BT, et l ; Ntionl Hert, Lung, nd Blood Institute Aute Respirtory Distress Syndrome (ARDS) Clinil Trils Network. Initil trophi vs full enterl feeding in ptients with ute lung injury: the EDEN rndomized tril. JAMA ; 307 (8): Rie TW, Wheeler AP, Thompson BT, deboisln BP, Steingru J, Rok P ; NIH NHLBI Aute Respirtory Distress Syndrome Network of Investigtors. Enterl omeg-3 ftty id, gmmlinoleni id, nd ntioxidnt supplementtion in ute lung injury. JAMA ;306(14): Needhm DM, Dingls VD, Morris PE, et l ; NIH NHLBI ARDS Network. Physil nd ognitive performne of ptients with ute lung injury 1 yer fter initil trophi versus full enterl feeding. EDEN tril follow-up. Am J Respir Crit Cre Med ;188(5): Needhm DM, Dingls VD, Bienvenu OJ, et l ; NIH NHLBI ARDS Network. One yer outomes in ptients with ute lung injury rndomised to initil trophi or full enterl feeding: prospetive follow-up of EDEN rndomised tril. BMJ ;346:f1532. journl.pulitions.hestnet.org 1325 Downloded From: y CAPES User on 01/28/2016

11 20. Rnieri VM, Ruenfeld GD, Thompson BT, et l ; ARDS Definition Tsk Fore. Aute respirtory distress syndrome: the Berlin Definition. JAMA ;307(23): ATS Committee on Profiieny Stndrds for Clinil Pulmonry Funtion Lortories. ATS sttement: guidelines for the six-minute wlk test. Am J Respir Crit Cre Med ;166(1): Enright PL, Sherrill DL. Referene equtions for the six-minute wlk in helthy dults. Am J Respir Crit Cre Med ;158(5): Jenkins S, Ceins N, Cmrri B, Willims C, Thompson P, Estwood P. Regression equtions to predit 6-minute wlk distne in middle-ged nd elderly dults. Physiother Theory Prt ;25(7): Gurlnik JM, Simonsik EM, Ferrui L, et l. A short physil performne ttery ssessing lower extremity funtion: ssoition with self-reported disility nd predition of mortlity nd nursing home dmission. J Gerontol ;49(2):M85-M Gurlnik JM, Ferrui L, Pieper CF, et l. Lower extremity funtion nd susequent disility: onsisteny ross studies, preditive models, nd vlue of git speed lone ompred with the short physil performne ttery. J Gerontol A Biol Si Med Si ;55(4):M221-M Gurlnik JM, Ferrui L, Simonsik EM, Slive ME, Wlle RB. Lower-extremity funtion in persons over the ge of 70 yers s preditor of susequent disility. N Engl J Med ;332(9): Fn E, Ciesl ND, Truong AD, Bhoopthi V, Zeger SL, Needhm DM. Inter-rter reliility of mnul musle strength testing in ICU survivors nd simulted ptients. Intensive Cre Med ;36(6): Medil Reserh Counil. Aids to the Investigtion of the Peripherl Nervous System. London, Englnd : Her Mjesty s Sttionry Offie ; De Jonghe B, Shrshr T, Lefuheur JP, et l ; Groupe de Réflexion et d Etude des Neuromyopthies en Rénimtion. Presis quired in the intensive re unit: prospetive multienter study. JAMA ;288(22): Miller MR, Hnkinson J, Brusso V, et l ; ATS/ERS Tsk Fore. Stndrdistion of spirometry. Eur Respir J ;26(2): Hnkinson JL, Odenrntz JR, Fedn KB. Spirometri referene vlues from smple of the generl US popultion. Am J Respir Crit Cre Med. 1999;159(1): Wre JE, Snow KK, Kosinski M, Gndek B. SF-36 Helth Survey: Mnul nd Interprettion Guide. Boston, MA: The Helth Institute, New Englnd Medil Center; Leidy NK. Psyhometri properties of the funtionl performne inventory in ptients with hroni ostrutive pulmonry disese. Nurs Res ;48(1): Willims A ; EuroQol Group. EuroQol new fility for the mesurement of helth-relted qulity of life. Helth Poliy ;16(3): Hermns G, Vn Mehelen H, Clerkx B, et l. Aute outomes nd 1-yer mortlity of intensive re unit-quired wekness. A ohort study nd propensity-mthed nlysis. Am J Respir Crit Cre Med ;190(4): Burtin C, Clerkx B, Roeets C, et l. Erly exerise in ritilly ill ptients enhnes short-term funtionl reovery. Crit Cre Med ;37(9): Heylnd DK, Groll D, Ceser M. Survivors of ute respirtory distress syndrome: reltionship etween pulmonry dysfuntion nd long-term helthrelted qulity of life. Crit Cre Med ;33(7): Neff TA, Stoker R, Frey HR, Stein S, Russi EW. Long-term ssessment of lung funtion in survivors of severe ARDS. Chest ;123(3): Herridge MS, Cheung AM, Tnsey CM, et l ; Cndin Critil Cre Trils Group. One-yer outomes in survivors of the ute respirtory distress syndrome. N Engl J Med ;348(8): Zigmond AS, Snith RP. The hospitl nxiety nd depression sle. At Psyhitr Snd ;67(6): Weiss D, Mmr CR. The impt of event sle - revised. In: Wilson JP, Kene TM, eds. Assessing Psyhologil Trum nd PTSD. New York, NY: Guilford; 1997 : Reuen DB, Siu AL. An ojetive mesure of physil funtion of elderly outptients. The Physil Performne Test. J Am Geritr So ;38(10): MHorney CA, Wre JE Jr, Rzek AE ; Psyhometri nd Clinil Tests of Vlidity in Mesuring Physil nd Mentl Helth Construts. The MOS 36-Item Short-Form Helth Survey (SF-36): II. Psyhometri nd linil tests of vlidity in mesuring physil nd mentl helth onstruts. Med Cre ;31(3): Simon GE, Reviki DA, Grothus L, Vonkorff M. SF-36 summry sores: re physil nd mentl helth truly distint? Med Cre ;36(4): Kjellsson G, Clrke P, Gerdthm UG. Forgetting to rememer or rememering to forget: study of the rell period length in helth re survey questions. J Helth Eon ;35: Polkey MI, Spruit MA, Edwrds LD, et l ; Evlution of COPD Longitudinlly to Identify Preditive Surrogte Endpoints (ECLIPSE) Study Investigtors. Six-minute-wlk test in hroni ostrutive pulmonry disese: miniml linilly importnt differene for deth or hospitliztion. Am J Respir Crit Cre Med ;187(4): Puhn MA, Mdor MJ, Held U, Goldstein R, Guytt GH, Shünemnn HJ. Interprettion of tretment hnges in 6-minute wlk distne in ptients with COPD. Eur Respir J ;32(3): Wyrwih KW, Tierney WM, Bu AN, Kroenke K, Wolinsky FD. A omprison of linilly importnt differenes in helth-relted qulity of life for ptients with hroni lung disese, sthm, or hert disese. Helth Serv Res ;40(2): Reviki D, Hys RD, Cell D, Slon J. Reommended methods for determining responsiveness nd minimlly importnt differenes for ptientreported outomes. J Clin Epidemiol ;61(2): Hys RD, Morles LS. The RAND-36 mesure of helth-relted qulity of life. Ann Med ;33(5): Wlters SJ, Brzier JE. Comprison of the minimlly importnt differene for two helth stte utility mesures: EQ-5D nd SF-6D. Qul Life Res ;14(6): Lthm NK, Meht V, Nguyen AM, et l. Performne-sed or self-report mesures of physil funtion: whih should e used in linil trils of hip frture ptients? Arh Phys Med Rehil ;89(11): Turner D, Shünemnn HJ, Griffith LE, et l. The miniml detetle hnge nnot relily reple the miniml importnt differene. J Clin Epidemiol ;63(1): Cohen J. Sttistil Power Anlysis for the Behviorl Sienes, 2nd ed. Hillsdle, NJ: Lwrene Erlum; Perer S, Mody SH, Woodmn RC, Studenski SA. Meningful hnge nd responsiveness in ommon physil performne mesures in older dults. J Am Geritr So ;54(5): Redelmeier DA, Byoumi AM, Goldstein RS, Guytt GH. Interpreting smll differenes in funtionl sttus: the six minute wlk test in hroni lung disese ptients. Am J Respir Crit Cre Med ;155(4): Wise RA, Brown CD. Miniml linilly importnt differenes in the six-minute wlk test nd the inrementl shuttle wlking test. COPD ;2(1): Wyrwih KW, Tierney WM, Wolinsky FD. Further evidene supporting n SEM-sed riterion for identifying meningful intr-individul hnges in helth-relted qulity of life. J Clin Epidemiol ;52(9): Cell D, Eton DT, Li JS, Petermn AH, Merkel DE. Comining nhor nd distriution-sed methods to derive miniml linilly importnt differenes on the Funtionl Assessment of Cner Therpy (FACT) nemi nd ftigue sles. J Pin Symptom Mnge ;24(6): Originl Reserh [ 147 # 5 CHEST MAY 2015 ] Downloded From: y CAPES User on 01/28/2016