Self-Reported Symptoms of Depression and Memory Dysfunction in Survivors of ARDS*

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1 Originl Reserch CRITICAL CARE MEDICINE Self-Reported Symptoms of Depression nd Memory Dysfunction in Survivors of ARDS* Neill K J. Adhikri, MDCM, MSc; Mry Pt McAndrews, PhD; Ctherine M. Tnsey, MSc; Andre Mtte, BSc; Ruxndr Pinto, PhD; Angel M. Cheung, MD, PhD; Ntli Diz-Grndos, MSc; Ail Brr, PhD; nd Mrgret S. Herridge, MD, MPH Bckground: Survivors of ARDS hve well documented physicl limittions. but psychologicl effects re less cler. We determined the prevlence of self-reported depression nd memory dysfunction in ARDS -survivors. Method: Six to 48 (medin 22) months fter ICU dischrge. we dministered instruments ssessing depression symptoms (Beck DepressionInventory-II [BDI-II]) nd memorydysfunction (Memory Assessment Clinics Self-Rting Scle [MAC-S]) to 82 ARDS ptients who were enrolled in prospective cohort study in four university-f6iited lcus. liernd,.: Sixty-one (74%). 64 (78%). nd 61 (74%) ptients fully completed the BDI-II. MAC S (Ability subsele), nd MAC-S (Frequency of Occurrence subscle) instruments. Responders (siinilr to nonresponders)wereyoung (medin 42 yers.interqurtilernge [IQR] 35 to 56). with highdmissionillness severityndorgndysfunction. The medin BDI-IIscorews 12 (IQR 5 to 25). Twenty-Bve (41%) ptients reported moderte-severe depression symptoms nd were less likely to return to work thn those with miniml mild symptoms (8/25 [32%] vs [69%]; p =0.(05). Medin MAC-S (Ability) nd MAC-S (FrequencyofOccurrence) scores were 76 (IQR 61 to 93) nd 91 (IQR 77 to 102). respectively; 8%. 16%. nd 20% scored > 2. > 1.5. nd > 1 SD(s). respectively. below ge-djusted popultion norms for ech subscle. BDI-II nd MAC-S scores were negtively correlted (Spermn coefficient nd for Ability nd Frequency of Occurrence subscles, respectively; p < ). Univrible nlyses showed no demogrphic orillness-severity predictors ofbdi-ii (including the Cognitive subscle) or MAC-S (both subscles); results were similr when restricted to ptients whose primry lnguge ws English. COncluWR8: ARDS survivors report high prevlence of depression symptoms nd lower prevlence of memory dysfunction 6 to 48 months fter ICU dischrge. Depression symptoms my hinder the return to work, or ptients my report these symptoms becuse of inbility to re-enter the workforce. (CHEST 2009; 135: ) Key words: cross-sectionl; depression; memory disorders; outcomes survey; respirtory distress syndrome, dult Abbrevitions: APACHE = cute physiology nd chronic helth evlution; BDI-II = Beck Depression Inventory-II; CI = confidence intervl; IQR = interqurtiie rnge; LIS = lung injury score; MAC-S = Memory Assessment Clinics Self-Rting Scle; MODS = multiple orgn dysfunction score; OR = Odds rtio ptients with cute lung injury hve cute hypoxemic respirtory filure with bilterl pulmonry infiltrtes not due to left tril hypertension. 1 This disorder, including the more hypoxemic subgroup of ARDS, is ssocited with pulmonry nd nonpulmonry risk fctors nd hs n estimted incidence of nerly 200,000 cses/yer in the United Sttes.s with cse-ftlity rte of 25% to 50%.3--8 Given the lrge number of ptients with cute lung injury surviving their ICU nd hospitl sty. interest in long-term outcomes is growing. Current evidence suggests tht survivors hve persistent generlized wekness? nd reduced qulity of life 9-13 compred to ge-mtched popultion controls, but reltively preserved pulmo- 878 Originl R.-rch

2 nry function. 9,ll,14,15 Long-tenn outcomes include significnt cognitive impirment nd emotionl distress, u, 16 but the prevlence of these findings, their pthophysiology, nd their functionl consequences remin uncler. We followed ARDS survivors enrolled in 5-yer prospective cohort study fter hospitl dischrge? nd observed'tht some ptients reported symptoms of depression nd memory loss; others were unble to return to work. In light of these ccruing observtions, we decided to more formlly evlute the prevlence of depression symptoms nd selfreported memory deficits in ARDS survivors nd to determine the reltionship between depression symptoms nd return to work. We hve previously reported some results in bstrct form.'? Ptients MATERIALS AND METHODS The ptients in this study hd prticipted in previously reported prospective cohort study of ARDS survivors enrolled from ICUs t four University of Toronto teching hospitl, between My 1998 nd My ,11,18 Eligible ptients were t lest 16 yers old nd hd Polinspired frction of oxygen rtio of 200 or less while receiving mechnicl ventiltion with positive end-expirtory pressure of t lests em H 2 0, irspce chnges in ll four qudrnts on chest rdiogrphy, nd n identifible risk fctor for ARDS. Ptients were excluded ifthey were immobile prior to ICU dmission, hd history of lung resection, or hd neurologic disese or psychitric disorder documented in their chrt. We obtined informed consent for questionnire completion. The University Helth Network Reserch Ethics Bord pproved this study. "From the Interdeprtmentl Division of Criticl Cre nd Deprtment of Medicine (Drs. Adhikri nd Herridge), University of Toronto; Deprtment of Criticl Cre Medicine (Dr. Pinto), Sunnybrook Helth Sciences Centre; Krembil Neuroscience Progrm (Dr. McAndrews), University Helth Network; Medicl-Surgicl Intensive Cre Unit (Ms. Tnsey nd Ms. Mtte), University Helth Network; Deprtment of Medicine (Dr. Cheung), University of Toronto; Women's Helth Progrm (Ms. Diz-Crndos), University Helth Network; nd Deprtment of Public Helth Sciences (Dr. Brr), University of Toronto, Toronto, ON, Cnd. This study ws supported by Physicins' Services Incorported, Ontrio Thorcic Society,nd Cndin Intensive Cre Fonndtion. All uthors declre tht no finncil or other potentil conflicts of interest exist. Dr. Adhikri hd full ccess to ll the dt in the study nd tkes responsibility for the integrity of the dt nd the ccurcy ofthe dt nlrsis, Mnuscript received Apri 11, 2008; revision ccepted September 27,2008. Reproduction of thisrticle is prohibitedwithout written permission from the Americn College of Chest Physicins ( orgtmisclreprints.shtml). Correspondence to: Neill K t. Adhikri, MDCM, MSc, Deprtment ofcriticl Cre Medicine, Room D1.0B, Sunnybrook Helth Sciences Centre, 2075 Byview Ave, Toronto, ON, Cnd M4N3M5; e-mil: netl1.dhtkri@utoronto.c DOl: lo.13781chest Suroey Administrtton nd Outcomes We miled ptients questionnire contining two selfdministered instruments: the Beck Depression Inventory II (BDI-II)19 nd Memory Assessment Clinics Self-Rting Scle (MAC-S) We followed up nonresponders with two telephone clls. Study personnel or fmily members helped dminister the instruments for those who needed ssistnce (eg. trnsltion for non-english reders), ccording to ptient preference. Ptients returned the questionnires in person t follow-up visit or by mil. Becuse we designed this study while follow-up of ptients enrolled in the prospective cohort ws underwy, questionnires were dministered over brod rnge of times fter ICU dischrge. The BDI-II instrument consists of 21 questions nd screens for depression using criteri consistent with the Dignostic nd Sttisticl Mnul of Mentl Disorders-Fourth Edition. Higher scores (rnge, 0 to 63) indicte more depression symptoms. This scle consists of two subscles mesuring cognitive (9 items) nd somtic-ffective (12 items) symptoms.p fctor structure which hs been vlidted in medicl ptients Bsed on testing in psychitric outptients, depression symptom severity is clssified s miniml (score 0 to 13), mild (14 to 19), moderte (20 to 28), nd severe (29 to 63),19 Psychometric properties of the BDI-II instrument include high internl consistency, high content vlidity, vlidity in differentiting between depressed nd nondepressed persons, nd sensitivity to chnge ARDS survivors recruited 6 months post hospitl dischrge 8 questionnires sent, 8 returned 1yer post hospitl dischrge 18 questionnires sent, 15 returned 2 yers post hospitl dischrge 33 questionnires sent, 29 returned 3 yers post hospitl dischrge 21 questionnires sent, 17 returned 4 yers post hospitl dischrge 2 questionnires sent, 2 returned TOTAL: 82 questionnires sent, 71 (MAC-S) nd 68 (8DI-II) returned FIGURE 1. Flow through the study. 9 died 2 died II withdrew I died 3 withdrew I died CHEST/135/3/ MARCH m

3 The MAC-S instrument mesures self-reported performnce in dily memory tsks, divided into two subscles. Ability (21 items) probes the bility to remember specific types of informtion, nd Frequency of Occurrence (24 items) sks bout the frequency ofprticulr memory problems. Higher scores (rnge for Ability, 21 to 105; rnge for Frequency of Occurrence, 24 to 120) indicte better performnce. Investigtors hve confirmed the high test-retest relibility of this scle. 26 Sttistill Anlysis We summrized non-normlly distributed continuous dt using medins (interqurtile rnge [IQR]) nd compred groups using Wilcoxon rnk-sum tests. Ctegoricl dt were summrized s proportions nd compred using x 2 tests or Fisher exct tests. Correltion between instruments ws mesured using Spermn correltion. We excluded questionnires with ny missing items, which constituted 10% of questionnires for BDI-I1 nd MAC-S (Ability subscle) nd 14% for MAC-S (Frequency of Occurrence subscle), from ll primry nlyses. However, we included ll responses when describing bseline demogrphic chrcteristics. We exmined the influence of time of questionnire return on instrument scores using liner regression, nd plnned to nlyze ll surveys together in subsequent nlyses in the bsence ofny ssocition. We were interested in hypothesis-generting nlyses of predictors of BDI-II nd MAC-S scores, including priori selected bseline vribles (ge, sex, cute physiology nd chronic helth evlution [APACHE] II SCOr&7) nd ICU vribles (multiple orgn dysfunction score [MODS, slope nd mximum]28; lung injury score [US, slope nd mximumj2.9; use of steroids, muscle relxnts, or high frequency ventiltion; dys of mechnicl ventiltion nd ICU sty). We tested ssocitions in univrible liner regression nlyses. For the BDI-II regression, we log-trnsformed the outcome vrible nd two predictor vribles, dys of mechnicl ventiltion nd ICU sty, to ensure normlly distributed residuls. Residuls for the MAC-S regressionswere normlly distributed using the untrnsformed outcome vribles, but we log-trnsformed the sme two predictorvribles becuse theirdistributions were skewed. We conducted four secondry nlyses to explore effects of missing dt, English fluency, nd exclusion of somtic items from the BDI-II instrument, nd the ssocition between depression symptoms nd return to work. First, we included questionnires with < 50% missing items by clcultingn djusted score bsed on items nswered s (totl possible score for ll items) X (score foritems nswered)/(mximum possible score for items nswered). Second, we restrictedthe regression nlyses to ptients whose primry lnguge ws English. Third, we seprtelytested ssocitions between BDI-II Cognitive nd Somticffective subscles nd the sme predictor vribles. Becuse these outcome vribles were not normlly distributed regrdless of trnsformtions, we used Spermn correltions to test continuous predictors nd Wilcoxon rnk-sum tests for discrete predictors. Finlly, for ptients with complete BDI-I1 dt, we exmined the ssocition between depression symptoms (using totl BDI-II score nd the Cognitive subscle seprtely) nd return to work t the time of questionnire completion. nd seprtely djusted for time since ICU dischrge to questionnire completion. We used ptients' definitions of work, which included both pid nd unpid work inside or outside the home. All sttisticl tests were two-sided; we interpreted p < 0.05 s sttisticlly significnt. Anlyses were conducted using sttisticl softwre (SAS, version 8; SAS Institute; Cry, NC). Study Prticipnts RESULTS We enrolled 109 ARDS survivors in the cohort, of whom 13 hd died nd 14 hd withdrwn from the study t the time of questionnire miling. We sent questionnires to ll remining 82 ptients in the cohort; they were returned t medin of 22 (IQR Vribles Age, yr Femle gender Primry lnguge English Eduction! High school or less Some college University degree APACHE II score Mximum LIS during ICU dmission] Mximum MODS during ICU dmission ICU length of sty, d Time since ICU dischrge, mo 6-min wlk distnce t the clinic visit closestin time to return of questionnire, m; % predicted (n = 67) Tble l-chrcteriticl ofabds Sumvon* Responders (n = 71) 42(35-56) 33 (46) 46(65) 30 (43) 21 (30) 19(27) 23 (15-27) 3.7 (3--4) 11 (10-13) 27 (16--51) 22 (12-29) 425 ( ); 67 (54--82) Nonresponders (n = 11) 48 (44-65) 4 (36) 6(55) 6(55) 2 (18) 3 (27) 26 (21-31) 3.3 ( ) 10 (7-12) 17(10-25) Not pplicble Not vilble p Vlue *Dt re presented s medin (interqurtile rnge) or No. (%). The 71 responders returned the MAC-S. Three of these respondents did not return the BOI-II questionnire. tinformtion is missing for one ptient in the responders group. [The LIS included the sum of the chest rdiogrphy, hypoxemi,nd positive end-expirtory pressure scores, while excluding mesures of sttic complince. Four ptients did not complete the 6-min wlk test or the visit ws missed. Nonresponders missed follow-up clinic visits nd thus did not complete 6-min wlk test Originl R8lI88rCh

4 12 to 29; rnge 6 to 48) months post-icu dischrge (Fig 1). Sixty-eight (83%) ptients returned the BDI-II nd 71 (87%) ptients returned the MAC-S questionnires. Responders were similr to nonresponders (Tble 1); they were young (42 [IQR 35 to 56] yers), nd the mjority ws mle (54%), spoke English s first lnguge (65%), nd hd some post-secondry eduction (57%). Responders hd high illness severity t presenttion (s mesured by APACHE II score-") nd substntil orgn dysfunction during the ICU course (s mesured by mximum MODS28 nd mximum LIS29). Responders hd longer ICU stys thn nonresponders (medin, 27 vs 17 dys) of borderline sttisticl significnce (p = 0.06), nd they hd modertely limited 6-min wlk distnce (67% [IQR 54% to 82%] of predicted) t the clinic visit closest in time to when the questionnires were returned. Instrument Scores Complete questionnires (zero missing items) for BDI-II, MAC-S (Ability), nd MAC-S (Frequency of Occurrence) were vilble from 61/68 (90%), 64/71 (90%), nd (86%) respondents, respectively; the number of items missing per questionnire ws generlly < 10% (Tble 2 nd Fig 2). Liner regression nlyses of instrument scores by time fter ICU dischrge to questionnire completion showed no significnt ssocitions (Fig 3). The medin BDI-II score ws 12 (IQR 5 to 25). Using BDI-II-defined depression symptom severity ctegories, 36 (59%) respondents reported miniml or mild depression symptoms nd 25 (41%) reported moderte or severe symptoms. Cognitivend Somticffective subscle scores were highly correlted (Spermn correltion coefficient 0.78, p < 0.001). Scores on the MAC-S instrument were 76 (IQR 61 to 93) for Ability nd 91 (IQR 77 to 102) for Frequency of Occurrence. Reltive to US communitybsed smple, % of respondents in ech subscle scored> 2 SDs below ge-djusted norms; the proportion incresed to 16% nd 20% with cutoff points of 1.5 nd 1 SD respectively (Tble 2). BDI-II scores were modertely negtively correlted with MAC-S scores (Spermn correltion coefficient nd for Ability nd Frequency of Occurrence subscles, respectively; p < ), implying n ssocition between symptoms of depression nd memory loss. Univrible nlyses (Tbles 3, 4) did not demonstrte ny consistent demogrphic or illness severity ssocitions with BDI-II or MAC-S scores. Secondry nlyses of subgroups gin showed no sttisticlly Significnt ssocitions; these subgroups were (1) ptients with questionnires with < 50% missing Tble 2--DepreIBion Symptom nd Memory Function in AlWS Suroioors'" Vribles (n = 61)f Depression symptom severity ctegory (BDI-II score). n=6h Miniml (0-13) Mild (14-19) Moderte (20-28) Severe (29--63) MAC-S Ability (n = 64) Frequency of Occurrence (n = 61)11 MAC-S, comprison to normtive smple' Ability (n = 64) <2 SDs < 1.5 SDs < 1 SD Frequency of occurrence (n = 61) <2 SDs < 1.5SDs < 1 SD Dt 12 (5-25) 33(54) 3(5) 14 (23) 11(18) 76 (61-93) 91 (77-102) 5 (8) 10 (16) 13(20) 5(8) 11(18) 11(18) "'Dt re presented s medin (interqurtile rnge) or No. (%). Percentges my not sum to 100% becuse of rounding. [Of 68 BOI-II questionnires (21 items), 61 hd no missing items. 4 hd 1 missing item. 2 hd 3 missing items, nd 1 hd 11 missing items. [Depression ctegories re from the BDI-II scle. Of the 71 questionnires with MAC-S bility responses (21 items). 64 hd no missing items, 5 hd 1 missing item, nd 2 hd 2 missing items. 110fthe 71 questionnires with MAC-S Frequency of Occurrence responses (24 items). 61 hd no missing items, 6 hd 1 missing item, nd 1 ech hd 2, 3, 4. nd 6 missing items. 'Proportion of smple below , or 1 SD below ge-djusted US smple men (66, SD 13 for bility; 81, SD 15 for Frequency of Occurrence). items (BDI-II, n = 67; MAC-S, n = 71 for both subscles) nd (2) ptients with English s primry lnguge nd questionnires with no missing items (BDI-II, n = 40; MAC-S Ability, n = 41; MAC-S Frequency of Occurrence, n = 40). When BDI-II Cognitive nd Somtic-ffective subscles were nlyzed seprtely, the only sttisticlly significnt finding ws positive ssocition between the slope of the LIS nd BDI-II Cognitive subscle (p = 0.041). Eight of 25 ptients (32%) with moderte-tosevere depression symptoms hd returned to work, compred to 25/36 (69%) ptients with miniml-mild depression symptoms (odd rtio [OR], 0.21; 95% confidence intervl [CI], 0.07 to 0.62; P = 0.005). The ssocition remined Significnt when djusted for time from ICU dischrge to questionnire completion (OR, 0.20; 95% CI, 0.06 to 0.62; P = 0.006); ptients returning to work completed questionnires lter thn those not returning to work (26 [IQR 17 to 31] vs 17 [11 to 25] months; p = 0.02). These ssocitions were lso Significnt when only cognitive CHEST / 135/ 3 / MARCH,

5 q q CI:l o CI:l o III.. "l tiii 0 I0 0!! 0 '5 '0,.--- J t i "" "" "" ~ i <'i o <'i o q o II I I I q :Jl IlO 40 IlO 80 loll IlO T«lII BDI-I. renge~ MAC S (lillliy), renge MAC.S(frequency of occuronce),renge FIGURE 2. Histogrms of BDI-II (n = 61), MAC-S Ability subscle (n = 64), nd MAC-S Frequency of Occurrence subscle (n = 61). Ctegories represent lo-point bins nd only include questionnires with no missing items. symptoms of depression were considered (OR per I-U increse in BDI-II Cognitive subscle, 0.87; 95% CI, 0.79 to 0.97; P = 0.009; djusted OR, 0.88; 95% CI, 0.79 to 0.97;P = 0.01). Allssocitionswere similr when nlyses included questionnires with < 50% missing items (n = 67). DISCUSSION In this study, criticlly ill ptients who survived n episode of ARDS completed vlidted instruments ssessing self-reported symptoms of depression nd memory dysfunction between 6 nd 48 months fter ICU dischrge. These ptients hd high initil illness severity nd no documented psychitric comorbidity. Our min findings were high prevlence (41%) of moderte-severe depression symptoms nd lower prevlence (8 to 20%, depending on the definition used) of self-reported memory deficits. We did not identify ny demogrphic or clinicl predictors of these bnormlities, possibly becuse the study lcked sttisticl power or becuse unmesured vribles were more importnt determinnts of outcome. A novel finding ws tht survivors with modertesevere depression symptoms were less likely to hve returned to work thn those with less severe symptoms. However, our dt re insufficient to drw conclusions regrding the direction of the cusl reltionship, if ny, between depression symptoms nd work sttus. Although we did not ssess these ptients for clinicl dignosis of depression. our findings re consistent with other studies highlighting the potentil importnce of depression symptoms in survivors of criticl illness Otherinvestigtors hve evluted neurocognitive function (using vlidted forml tests) nd psychitric symptoms in ptients with ARDS, prolonged mechnicl ventiltion,40 41 nd generl criticl illness Hopkins nd [ckson!" reviewed these studies nd reported prevlence of neurocognitive impirment of 28% to 75% in ptients evluted 2 months to > 6 yers following hospitl dischrge. Studies noted some improvements in the first yer fter dischrge but residul persistent deficits. Affected neurocognitive domins included mentl processing speed, memory, ttention, problem-solving (executive function), intellectul function, nd visulsptil bility. Using vlidted self-reported symp- 682 Originl RetI8lII'Ch

6 ... "'.90 ep.: 00 ooq) 0 cl..,-----r--,---,------r---,-j l(j c & 8 00 o 0 00 'l. o 0000 ODD 000 '-r r--,---,-----r' c ", e '" o OClll) OCD 0 OCI:OCIDO 0 0 CZl o o f} 8 o f 0 0 'b o o FIGURE 3. Instrument scores vs time of completion in months fter lcu dischrge, for the BDI-II, BDI-II Somtic-ffective subscle, BDI-II Cognitive subscle, MAC-S Ability subscle, nd MAC-S Frequency of Occurrence subscle. p Vlues for the l3-eoefficient of the stright regression lines (not plotted) re 0.26, 0.33, 0.53, 0.70, nd 0.35, respectively. tom scle, we found tht the prevlence of memo!)' dysfunction depended on the definition: for ech subscle, 8% of ptients hd scores of > 2SD below ge-djusted norms (potentilly reflecting modertely severe memo!)' impirment), wheres 20% of ptients hd scores > lsd below ge-djusted norms (potentilly including ptients with mild memory impirment). Other investigtors hve performed forml memo!)' testing rther thn mesuring self-reported symptoms nd found higher prevlence of dysfunction, o-42 rising the possibility tht our ptients my hve hd more severe objective memory impirment thn they perceived nd/or reported. Alterntively, self-reported symptoms of memo!)' dysfunction my be poorly correlted with objective testing in ARDS survivors, finding described in other ptient popultions Interprettion of literture regrding memo!)' dysfunction is chllenging becuse of the vribility in instruments dministered nd specific dignostic criteri. These criteri hve included certin number of test scores > 1, 1.5, or 2 SD below popultion men or hve used other definitions Using objective testing, Suchyt et l 38 reported low prevlence (2.9%) of severe memo!)' impirment, defined s t lest two test scores > 2 SD below popultion-bsed norms, in 30 ARDS survivors t men of 6 yers fter leu dischrge. Although their finding is similr to ours, the low prevlence my be underestimted by the prolonged time from leu dischrge, retrospective dt collection, nd limittions of memory tests dministered by telephone (R. Hopkins; personl communiction; Jnury 1, 2007). Similr to our study, others hve found no consistent ssocitions between bseline clinicl vribles, illness severity, nd subsequent neurocognitive dysfunction.!" There re fewer dt on depression fter criticl illness. 54 A recent systemtic reviews 1 of psychitric morbidityin ARDS survivors included three cohorts (169 ptients)13,34,36 of ARDS ptients with self-rted questionnire-scertined depression tht reported the prevlence of "cliniclly significnt" depression symptoms. One cohort ws exmined 1 yer36 nd 2 yers 32 fter hospitl dischrge. The medin prevlence of cliniclly significnt depression symptoms (using questionnire-detennined cutoff scores) in the four studies 13.32,34.36 ws 28% (rnge, 17% to 43%)3112 to 28 months fter hospitl dischrge. Our finding tht 41% of ARDS survivors hd modertesevere depression symptoms is similr, but it is higher thn reported in studies tht used the originl CHEST/135/3/ MARCH,

7 Tble 3-Univrible Anlyses ofpredictors ofthe Logrithm oftotl BDI-U Score* Vribles APACHE II t ICU dmission Femle gender Age Mximum MODS during ICU dmission Slope of MODSt Mximum LIS during ICU dmission p -Coefficient(SE) (0.020) 0.30 (0.31) (0.01) (0.051) (0.23) (0.33) p Vlue Slope of LISt 0.21 (0.19) 0.26 Steroid use in ICU (0.33) 0.97 ICU dys 0.11 (0.19) 0.56 Mechnicl ventiltion dys 0.12 (0.18) 0.53 Any muscle relxnts (0.32) 0.94 High-frequency ventiltion (0.33) 0.89 *Anlyses included 61 ptients whose questionnires hd no missing items. For three ptients with score of zero, we dded 0.5 to their score before tking the logrithm. Positive(negtive) Ii-coefficients imply tht the predictor is ssocited with higher (lower) logtrnsfonned BDI-II scores. [The chnge in MODS over time during ICU dmissionis expressed s the slope of the score. [The chnge in LIS over time during ICU dmissionis expressed s the slope of the score. The logrithm of thisvrible wsused becuse the untrnsfonned vrible hd skewed distribution. BDI instrument (-20%) Potentil explntions my include differences in illness severity (medin APACHE II score of23 in the current study vs men APACHE II score of 18 in the previous studies)32,36 or the processes of cre during nd fter ICU dmission. One smll study (n = 24)55 found tht dys oficu cre, dys ofmechnicl ventiltion, nd dys tht ny sedtives were given were ll positively correlted with depression symptoms s mesured by the Center for Epidemiologic Studies-Depression scle.56 Our dt re lso consistent with outcomes in other ICU survivors. For exmple, in ptients pproximtely 1 yer fter cute respirtory filure'" or mechnicl ventiltion for > 48 h,58 the prevlence of moderte-severe depression syrnptoms''? or questionnire-scertined depression's ws 32% to 34%. In contrst, depression prevlence vries more in noncriticlly ill ptients: 1.6% to 50% in 27 studies of post-myocrdil-infrction depression (medin 31% in 7 studies using the originl BDI instrument)59 nd 5% to 63% in 49 studies of post-stroke depression.w In the criticlly ill, there re few studies ofobjectively scertined depression. Kpfhmmer et l reported tht 2 of 46 ptients (4%) exmined t medin of 8 yers (rnge, 3 to 13 yers) fter ICU dischrge hd mjor depression s determined by stndrdized psychitric interviews." In nother study ssessing 164 ptients 2 months fter cute respirtory filure, Weinert nd MelletID conducted stndrdized psychitric interviews nd found high combined prevlence of mjor depressive episode (16%) nd depressive disorder not otherwise specified (16%); the estimted combined incidence ws 25% to 28% in ptients without bseline depression. Of the 109 ptients not tking n ntidepressnt before ICU dmission, 28% were tking them during the post-icu period. 30 Symptoms of depression nd memory loss were modertely correlted in this study, but we did not use stndrdized interviews to dignose mjor de- Tble 4-Unwrible Anlyse ofpredictrs ofmemory ABsement Clinics Self-Bting Scle Scores* Vribles Ability I 1 p-coefficient(se) P Vlue I Frequency of Occurrence P-Coefficient (SE) APACHE II t ICU dmission (0.35) (0.35) 0.99 Femle gender (5.19) (5.26) 0.13 Age (0.18) (0.18) 0.17 Mximum MODS during ICU dmission 0.91 (0.85) (0.93) 0.11 Slope of MODSt (3.51) (3.92) 0.49 Mximum LIS during ICU dmission 3.48 (5.40) (5.63) 0.84 Slope of LISt (2.89) (3.24) 0.34 Steroid use in ICU 2.63 (5.47) (5.51) 0.89 ICU dys] 0.32 (3.14) (3.29) 0.91 Mechnicl ventiltion dys 0.52 (2.95) (3.11) 0.97 Any muscle relxnts 0.39 (5.30) (5.47) 0.98 High-frequency ventiltion 2.03 (5.59) (5.56) 0.72 I p Vlue *Ability nd Frequency of Occurrence refer to subscles of the MAC-S. Anlyses included 64 ptients (bility) nd 61 ptients (Frequency of Occurrence) whose questionnires hd no missing items. Positive(negtive) p-coefficients imply tht the predictor is ssocited with higher (lower)scores. fthe chnge in MODS over time during lcu dmission is expressed s the slope of the score. [The chnge in LIS over time during ICU dmissionis expressed s the slope of the score. The logrithm of this vrible ws used becuse the untrnsfonned vrible hd skewed distribution. 884 Originl RlI8lIIIICh

8 citions between leu vribles nd outcomes. Similrly, we did not collect dt on ny potentilly confounding events occurring between the index hospitliztion nd dministrtion of the instruments, We did not dminister the instruments t leudischrge, preventing insights into the evolution of these symptoms prior to our study. Although we did not detect temporl vrition in instrument scores, the time from ICU dischrge to questionnire completion ws highly vrible in our study, nd it is possible tht such temporl vrition will be found in n ongoing lrger study."? We excluded ptients with documented psychitric disorders in their medicl chrt, but it is possible tht some post-cute-illness symptoms were preexisting rther thn new; we did not perform ny post hoc tests of premorbid cognitive function or ffect. We did not dminister brod rnge of mentl helth instruments to screen for other dignoses such s generlized nxiety disorder, post-trumtic stress disorder, delirium, or dementi, nor did we conduct stndrdized psychitric interviews. Finlly, lthough we used instruments vlidted in other popultions, their reltionship to forml neurocognitive testing nd clinicl outcomes in the criticlly ill is uncler. In prticulr, we cnnot determine the prevlence of mjor depressive disorder in our cohort. The mesurement properties of psychitric screening instruments should be investigted to determine if they re relible surrogtes for clinicl disorders in ICU survivors. In summry, we found high prevlence of moderte-severe depression symptoms nd substntilly lower prevlence of extreme self-reported memory deficits in cohort of ARDS survivors 6 to 48 months fter ICU dischrge. An importnt functionl ssocition ws tht survivors with modertesevere depression symptoms were less likely to hve returned to work thn those with less severe symptoms. Further investigtions into the clinicl nd economic burden of these symptoms nd methods of mitigting them, including ptient screening nd referrl to pproprite mentl helth services, re wrrnted. ACKNOWLEDGMENT: We thnk Ftm l-sidi for mjor contributions to dt collection nd erly nlyses. REFERENCES 1 Bernrd GR, Artigs A. Brighm KL. et l. The Americn- Europen Consensus Conference on ARDS; definitions, mechnisms, relevnt outcomes, nd clinicl tril coordintion. Am JRespir Crit Cre Med 1994; 149: Rubenfeld GD, Cldwell E, Pebody E. et l. Incidence nd outcomes of cute lung injury. N Engl JMed 2005; 353: pression. Complex reltionships between subjective cognitive nd memory complints, objective evidence of such dysfunction, nd depression nd personlity hve been documented cross vrious popultions Mny studies hve reported poor correltion between self-rted nd observed cognitive dysfunction, including memory loss, nd much stronger positive reltionship between subjective complints nd depression However, some studies using rigorous methods, including community smpling, longitudinl design, nd sttisticl djustment for depression nd level of eduction, indicte tht subjective complints hve moderte construct vlidity with respect to correltions with objective tests 62 nd prediction of lter dementi in older dults.53 Furthermore, studies demonstrte direct reltionship between mjor depression (not merely depression symptoms) nd objective memory deficits,54 nd emerging dt suggests reduced hippocmpl neurogenesis s the common biologicl bsis for these findings The precise reltionship between mood nd cognitive function, including memory, remins to be estblished in AROS, nd inconsistencies in reserch findings re likely to continue s the prticulr modultory fctors re further explored. Strengths of this study include the lrge size nd detiled description of the cohort, with little loss to follow-up nd high response rte. To our knowledge, we re the second group fter Hopkins et l to exmine depression symptoms in ARDS ptients using prospective cohort design, nd our 61 ptients dd 36% to the smple size (n = 169) of three cohorts in whom the prevlence of questionnirescertined clinicllysignificnt depression hs been reported. As fr s we re wre, this study is the first to report n inverse ssocition between more severe depression symptoms nd return to work. Another unique feture is our ssessment of self-reported memory dysfunction in AROS survivors,which complements the existing literture tht hs focused on objective neurocognitive testing. The prospective design permitted nlyses of potentil predictors of symptoms of depression nd memory loss bsed on detiled nd relibly scertined bseline nd ICU cre vribles. Nevertheless, our study hs severl importnt limittions. It is possible tht nonresponders or those who withdrew from the initil cohort hd lredy returned to work. Similr to previous investigtors, we did not collect dt on other possible determinnts of subjective cognitive nd ffective outcomes, such s medictions (eg, sedtion, nlgesi, ntipsychotics), hypoxemi,32,35,36 nd environmentl issues (eg, sleep, noise, sensory deprivtion) in the ICU. Our dt set is likely underpowered to detect ssowww.chestfouml.org CHEST/ 135/3/ MARCH, 2009 _

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