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THE ARDS COGNITIVE OUTCOMES STUDY (ACOS): LONG-

TERM NEUROPSYCHOLOGICAL FUNCTION IN ACUTE LUNG

INJURY

SURVIVORS

Journal: American Journal of Respiratory and Critical Care Medicine

Manuscript ID: Blue-201111-2025OC.R4

Manuscript Type: OC - Original Contribution

Date Submitted by the Author: 22-Mar-2012

Complete List of Authors: Mikkelsen, Mark; Hospital of the University of Pennsylvania, Pulmonary, Allergy, and Critical Care Division Christie, Jason; University of Pennsylvania, Pulmonary, Allergy, and Critical Care Division; University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics Lanken, Paul; University of Pennsylvania, Pulmonary, Allergy, and Critical Care Division Biester, Rosette; University of Pennsylvania School of Medicine, Center for

Brain Injury and Repair Thompson, B; Massachusetts General Hospital, Department of Medicine, Pulmonary and Critical Care Unit Bellamy, Scarlett; University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics Localio, A.; University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics Demissie, Ejigayehu; University of Pennsylvania, Pulmonary, Allergy, and Critical Care Division; University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics Hopkins, Ramona; Brigham Young University, Psychology Department and Neuroscience Center

Angus, Derek; University of Pittsburgh, Department of Critical Care Medicine

Keywords: acute respiratory distress syndrome, ARDS, cognitive function, critical illness

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ARDS COGNITIVE OUTCOMES STUDY (ACOS) 1

TITLE: THE ARDS COGNITIVE OUTCOMES STUDY (ACOS): LONG-TERM

NEUROPSYCHOLOGICAL FUNCTION IN ACUTE LUNG INJURY

SURVIVORS

Authors:

Mark E. Mikkelsen, M.D., M.S.1,2 *

Jason D. Christie, M.D., M.S.1,2 * Paul N. Lanken, M.D.1

Rosette C. Biester, Ph.D3

B. Taylor Thompson, M.D.4

Scarlett L. Bellamy, Sc.D.2

A. Russell Localio, Ph.D.2

Ejigayehu Demissie, M.S.N.1,2

Ramona O. Hopkins, Ph.D. 5, 6 Derek C. Angus, M.D., M.P.H. 7

* These authors contributed equally to this work

Institution: 1Pulmonary, Allergy, and Critical Care Division

Department of Medicine University of Pennsylvania School of Medicine

2Center for Clinical Epidemiology and Biostatistics University of Pennsylvania School of Medicine

3Department of Physical Medicine and Rehabilitation University of Pennsylvania School of Medicine Philadelphia Veterans Affairs Medical Center

4Pulmonary and Critical Care Unit, Department of Medicine Massachusetts General Hospital 5Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center 6 Psychology Department and Neuroscience Center, Brigham Young University 7CRISMA Center, Department of Critical Care Medicine and Department of Health Policy and Management University of Pittsburgh

Contributions Conception and Design: Angus, Biester, Christie, Hopkins, Lanken, Thompson Data Collection: Angus, Christie, Demissie, Hopkins, Lanken, Mikkelsen, Thompson

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Analysis and Interpretation of the Data: Angus, Bellamy, Biester, Christie, Hopkins, Localio, Mikkelsen, Thompson Drafting of the manuscript: Angus, Bellamy, Biester, Christie, Demissie, Hopkins, Lanken, Localio, Mikkelsen, Thompson Critical revision of the article for important intellectual content: Angus, Christie, Hopkins, Mikkelsen, Thompson Corresponding author: Mark E. Mikkelsen, M.D., M.S.C.E. Pulmonary, Allergy, and Critical Care Division Perelman School of Medicine, University of Pennsylvania 836 W. Gates Pavilion 3400 Spruce Street Philadelphia, PA 19104 e-mail: [email protected] Phone: (215) 615-5416 Abstract Word Count: 248 Body Text Word Count: 3500 This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org Funding: The study was supported in part by N01-HR-46058, N01-HR-46046-64, N01-HR-16146-54, and T32 HL07891 training grant, National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, MD. Disclosures: For each of the above authors, no financial or other potential conflicts of interest exist. Presented in part at the American Thoracic Society International Conference, May 2008, Toronto, Canada. Running Head: ARDS COGNITIVE OUTCOMES STUDY (ACOS) Descriptor: 4.2 ALI/ARDS: Diagnosis & Clinical Issues At a Glance Commentary: Scientific Knowledge on the Subject

Cognitive and psychiatric morbidities are prevalent, long-lasting, and potentially modifiable in survivors of critical illness. Whether neuropsychological function can be assessed in a multi-center trial is unknown. Furthermore, the frequency and risk factors for long-term neuropsychological impairment in ALI survivors have not been studied in a multi-center trial.

What This Study Adds to the Field

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We found that neuropsychological function in survivors from a multi-center

trial could be assessed using a validated telephone battery. Our findings demonstrated that a majority of ALI survivors experienced long-term cognitive and psychiatric morbidity, and we detected that hypoxemia is a risk factor for the development of long-term cognitive and psychiatric impairment.

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ABSTRACT

Rationale: Cognitive and psychiatric morbidity is common and potentially

modifiable following acute lung injury (ALI). However, practical measures of

neuropsychological function for use in multi-center trials are lacking.

Objectives: To determine whether a validated telephone-based

neuropsychological test battery is feasible in a multi-center trial. To determine the

frequency and risk factors for long-term neuropsychological impairment.

Methods: As an adjunct study to the ARDSNet Fluid and Catheter Treatment

Trial, we assessed neuropsychological function at 2 and 12 months post-hospital

discharge.

Measurements and Main Results: Of 406 eligible survivors, we approached

261 to participate and 213 consented. We tested 122 subjects at least once,

including 102 subjects at 12 months. Memory, verbal fluency and executive

function were impaired in 13% (12/92), 16% (15/96), and 49% (37/76) of long-

term survivors. Long-term cognitive impairment was present in 41 of the 75

(55%) survivors who completed cognitive testing. Depression, post-traumatic

stress disorder, or anxiety was present in 36% (37/102), 39% (40/102), and 62%

(63/102) of long-term survivors. Enrollment in a conservative fluid-management

strategy (p=0.005) was associated with cognitive impairment and lower partial

pressure of arterial oxygen during the trial was associated with cognitive (p=0.02)

and psychiatric impairment (p=0.02).

Conclusions: Neuropsychological function can be assessed by telephone in a

multi-center trial. Long-term neuropsychological impairment is common in ALI

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survivors. Hypoxemia is a risk factor for long-term neuropsychological

impairment. Fluid management strategy is a potential risk factor for long-term

cognitive impairment; however, given the select population studied and an

unclear mechanism, this finding requires confirmation.

Key words: acute respiratory distress syndrome; ARDS; cognitive function;

critical illness

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In the United States, 200,000 patients will develop acute lung injury (ALI)

each year (1). Advances in ALI management have decreased mortality to 25-

40% (1-4), resulting in an expanding population of survivors who have been

ravaged by their acute illness. Survivorship, it has been put forth, will be the

defining challenge of modern day critical care (5). Beyond the physical ailments

that survivors endure, neuropsychological impairment is increasingly recognized

as a prevalent, important, and potentially modifiable outcome among ALI

survivors (6-21) and critical illness in general (22-29).

Traditionally, neuropsychological (cognitive and psychiatric) function is

assessed in-person by an expert - a constraint that has limited the ability to study

the frequency and determinants of neuropsychological impairment in critically ill

populations and to measure the effects of an intervention on long-term

neuropsychological function. Neuropsychological function has not been studied

in survivors from a multi-center trial. Consequently, the generalizability of

observations from single center cohort studies is unknown. Furthermore,

evidence regarding the etiology of neuropsychological impairment in ALI

survivors is extremely limited.

As a practical approach to assess the neuropsychological function of

survivors from a multi-center trial, we developed a telephone battery of

standardized neuropsychological tests which could be administered by a non-

expert (10). We then validated the telephone battery against standard in-person

assessments (10, 30) and in ALI survivors specifically (10-11). Here, we

administered the battery to a subset of survivors from the Acute Respiratory

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Distress Syndrome Clinical Trials Network (ARDSNet) Fluid and Catheter

Treatment Trial (FACTT) (4, 31). FACTT tested the hypothesis that a

conservative fluid-management strategy targeted to lower intravascular

pressures as measured by either a pulmonary artery catheter (PAC) or central

venous catheter improves outcomes in ALI. Our goals were to determine whether

a telephone-based neuropsychological test battery was feasible in a multi-center

trial, to determine the frequency of long-term neuropsychological morbidity in

survivors from a multi-center trial, and to identify potential risk factors for the

development of long-term cognitive and psychiatric impairment. Results of this

study were previously reported in abstract form (32).

Materials and Methods

An expanded methods section is available in an online supplement. The

study was approved by the institutional review board of participating hospitals

and as a substudy of FACTT by the ARDSNet.

Study Design

The ARDS Cognitive Outcomes Study (ACOS) is a prospective, multi-

center cohort study of a subset of survivors from FACTT. FACTT enrolled

patients between June 2000 and October 2005. Between July 2002 and July

2003, FACTT was halted and new regulatory approval related to the study was

prohibited. The regulatory process for ACOS began prior to the halt and testing

was conducted between March 2003 and September 2006 in concert with the

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Economic Analysis of the Pulmonary-Artery Catheter (EA-PAC) study, a long-

term follow-up study of FACTT (33).

To be eligible for ACOS, subjects had to be enrolled in FACTT and EA-

PAC (33) and ACOS-specific regulatory approval had to be in place. FACTT

enrolled mechanically ventilated adult ALI patients (34). Subjects not consented

prior to discharge for ACOS were recruited via the telephone and through written

communication when telephone contact failed.

Neuropsychological Function and Quality of Life

We used a validated telephone battery of standardized

neuropsychological tests (10-11, 30). The telephone battery was administered

from the University of Pittsburgh to consenting, English-speaking subjects at 2

and 12 months post-hospital discharge. Subjects were not required to undergo 2

month testing to be tested at 12 months.

The instruments used to assess cognition, anxiety, depression, and post-

traumatic stress disorder (PTSD) symptoms are presented in Table E1 (35-42).

Quality of life (43) was assessed at 12 months as part of EA-PAC (33). We

focused our study on survivors tested at 12 months to assess long-term

neuropsychological function.

Data Analysis

The cognitive battery yielded scaled scores for each domain which were

normalized to allow for comparisons across tests and subjects (44-45). We report

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the median and interquartile range of results as percentiles. We defined

impairment in a single domain as a score > 2 standard deviations below the

population normative data (6-7, 9, 44-46). Cognitive impairment at the subject

level was defined as impairment in memory, verbal fluency, and/or executive

function in subjects who completed tests in each of these domains (6, 9, 10-11,

27).

We a priori hypothesized that long-term cognitive impairment would be

associated with duration of mechanical ventilation, either conservative or liberal

fluid-management strategy (4), hypotension (9), hypoxemia (6), PAC use (19, 47-

48), sepsis as the cause of ALI (49-50), and severity of illness (26). The pre-

specified potential confounding variables (6-12, 51-53) are detailed in the

supplement.

Psychiatric impairment was defined as impairment in any of the three

psychiatric measures (anxiety, depression, and PTSD) in subjects completing

each measure. We tested the following candidate risk factors for the

development of long-term psychiatric morbidity: age (18, 27-28), gender (18, 27-

29), race/ethnicity, level of education (19, 27), APACHE III scores, trial

interventions (fluid-management strategy, PAC), hypotension, hypoxemia (18,

27), any episode of hypoglycemia (glucose < 60 mg/dL) during the hospitalization

(20, 27), corticosteroid administration (54), ICU length of stay (17, 21, 27), and

duration of mechanical ventilation (17-18, 27).

Statistical Analysis

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Multivariable logistic regression was used to investigate the relationship

between candidate risk factors and long-term neuropsychological (cognitive or

psychiatric) impairment. We adjusted for each candidate risk factor and potential

covariates with an alpha level of significance <0.20 in univariate analyses (55).

To avoid over-fitting, adjustment was performed one covariate at-a-time (56). A

p-value of ≤ 0.05 was used to signify statistical significance.

The cognitive impairment risk factor analysis was limited to 75 survivors

who completed memory, verbal fluency, and executive function testing at 12

months. The Hayling Sentence Completion Test (HSCT) assesses executive

function with an error score and response latency component to produce an

overall score (35-36). The HSCT response times were not measured before

February, 2005 due to an error in the administration of the timing of the test. The

timing error resulted in 21 survivors tested at 12 months having incomplete

testing. In secondary analyses, 90 survivors who completed assessments in

memory, verbal fluency, and the error score of the HSCT at 12 months were

carried out.

We tested for associations between identified risk factors and memory,

verbal fluency, and executive function scores as continuous variables using

Spearman rank-correlation coefficients. Finally, we performed sensitivity

analyses to determine the effects of missing data on the observed associations.

Statistical analyses were performed using Stata 10.0 software (Stata Datacorp,

College Station, TX).

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Results

Enrollment

Of 1001 patients randomized in FACTT, 406 survivors were eligible for

ACOS (Figure 1, Figure E1 for enrollment by fluid-management strategy). Of 406

eligible survivors, we approached 261 to participate and 213 consented. Consent

rates did not differ by age, gender, race/ethnicity, or geographic region after

adjusting for mortality and excluding ineligible subjects in whom the time window

to be tested had elapsed (Table E2). Of 213 consenting subjects, 14 died prior to

initial testing, and we were able to contact and test 122 of 199 alive and

consenting subjects (61%) at least once. The 122 subjects were drawn from 28

hospitals and constitute the ACOS cohort.

Compared to non-ACOS FACTT participants who survived 60-days

(N=609), the ACOS group was more likely to be female, more likely to be non-

Hispanic whites, less likely to have HIV/AIDS, and less likely to have pneumonia

as the cause of ALI (Table 1). The number of ACOS subjects enrolled from each

hospital ranged from 1 to 17 (median=3, interquartile range (IQR) 1-5).

By 12 months, 22 consenting subjects were deceased, 2 were

incarcerated, and 9 were deemed physically or mentally incapable of telephone-

based neuropsychological testing. Of the remaining 180 subjects who were alive

and able to be tested, 102 (57%) were tested at 12 months. These 102 long-term

survivors completed individual cognitive domain testing to various degrees (Table

E1), and 74% (75/102) completed testing in all cognitive domains. Long-term

survivors were tested on average 12 months post-hospital discharge (IQR 11 –

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13 months). None of these long-term survivors had a history of pre-existing

dementia.

Neuropsychological Test Battery Administration

The test battery required 45-60 minutes to complete. During the first

several tests, subject fatigue was noted to be significant when the battery was

administered during the same telephone call as the EAPAC questionnaire, which

required 15-20 minutes (33). Subsequently, the battery was administered during

a separate call. None of the initial tests were included in the primary analyses of

long-term cognitive impairment.

Using the separate testing session, survivors occasionally expressed

frustration and requested to end testing. Despite encouragement, explanation of

the reasons for the tests, and reassurance that the tests were meant to be

challenging, 8 long-term survivors declined to complete cognitive testing.

Baseline Characteristics and Effects of Fluid-Management Strategy

APACHE III score was higher (p=0.04) in the liberal-fluid strategy group

(Table E3). No other baseline characteristic differed between fluid-management

strategies. The ACOS patients in the conservative-strategy group received more

furosemide (p<0.001), resulting in a more negative seven-day cumulative fluid

balance (p=0.02), lower central venous pressures (p<0.001) and a trend towards

lower cardiac index (p=0.06) (Table E4). As in the larger FACTT study, in ACOS

the conservative fluid-management strategy resulted in shorter duration of

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mechanical ventilation (median difference of 2.5 days, p=0.04) and a trend to

shorter ICU stays (median difference of 3 ICU days, p=0.07).

Long-Term Cognitive Impairment and Psychiatric Morbidity

Cognitive function was below normal population mean scores in each

domain tested (Table E1). Cognitive impairment was observed in 41 of 75

survivors (55%) at 12 months. Using the error score of the HSCT to assess

executive function rather than the overall score, cognitive impairment was

observed in 54 of 90 survivors (60%).

Vocabulary and reasoning, domains hypothesized to be resilient to

acquired brain injury, were impaired in 3 of 98 survivors (3%). Among the

domains hypothesized to be susceptible to impairment following ALI, memory

was impaired in 12 of 92 (13%), verbal fluency in 15 of 96 (16%), and executive

function in 37 of 76 (49%) survivors at 12 months. Executive function was

impaired in 57 of 100 (57%) survivors when assessed using the error score of the

HSCT.

Symptoms of moderate or severe depression occurred in 37 of 102 (36%)

long-term survivors. PTSD screening was positive in 40 of 102 (39%) survivors.

Symptoms of moderate or severe anxiety occurred in 63 of 102 (62%) survivors.

Psychiatric symptoms were present in depression, anxiety, or PTSD in 67 of 102

(66%) survivors. Symptoms in two or more psychiatric domains occurred in 43 of

102 (42%) survivors. Cognitive impairment was significantly associated with the

presence of psychiatric symptoms (p=0.04) at 12 months. Specifically, cognitive

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impairment was associated with anxiety (p=0.04), but not depression (p=0.20) or

PTSD (p=0.33).

Long-Term Cognitive Impairment, Psychiatric Morbidity, and Quality of Life

Quality of life was low in ACOS survivors (median utility=0.67, IQR: 0.37,

0.90) at 12 months. There were no significant differences in quality of life

between cognitively impaired and non-impaired survivors (median utility in

impaired=0.66, IQR: 0.45, 0.9; non-impaired=0.69, IQR: 0.42, 0.82, p=0.85). In

survivors with psychiatric symptoms, quality of life was significantly worse

(median utility in 59 survivors with psychiatric symptoms=0.57, IQR: 0.26, 0.76;

utility in 35 survivors without symptoms=0.90, IQR: 0.53, 0.95, p<0.001).

Risk Factors for Long-Term Cognitive Impairment

Lower partial pressure of arterial oxygen (PaO2) during FACTT was

associated with cognitive impairment at 12 months (p=0.02), as were enrollment

in the conservative fluid-management strategy (p=0.004) and lower central

venous pressure (p=0.04) (Table 2, E5, Figure 2). As detailed in the supplement,

lower PaO2 values (p=0.05), lower central venous pressures (p=0.02), and

enrollment in the conservative fluid-strategy group (p<0.001) correlated with

worse executive function. After adjustment for potential covariates, lower PaO2

and enrollment in the conservative fluid-management strategy were associated

independently with cognitive impairment at 12 months (Table 2 and Table E6).

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In secondary analyses, using the untimed error score of the HSCT for the

executive function assessment, the conservative fluid-management strategy

remained associated with cognitive impairment at 12 months (71% (34/48) vs.

48% (20/42) in liberal group, p=0.02). The association between PaO2 values and

cognitive impairment was no longer significant in these analyses (p=0.32). As

detailed in the supplement, we performed multiple sensitivity analyses to

determine the effects of missing data and incomplete cognitive testing. These

analyses may suggest that a relationship exists between hypoxemia and fluid-

management strategy and long-term cognitive impairment.

Risk Factors for Long-Term Psychiatric Morbidity

Survivors with psychiatric morbidity at 12 months had lower PaO2 values

(p=0.02), lower systolic blood pressures (p=0.05), and were more likely to have

had an episode of hypoglycemia (p=0.03) (Table 3). As detailed in the

supplement, lower PaO2 values (p=0.05), lower systolic blood pressures

(p=0.04), and an episode of hypoglycemia (p=0.01), were associated with

anxiety. After adjustment for potential covariates, lower PaO2 was associated

independently with long-term psychiatric morbidity.

Discussion

We found that neuropsychological function in survivors from a multi-center

trial can be assessed using a validated telephone battery. Similar to previous

investigations, we found a majority of ALI survivors experience long-term

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cognitive and psychiatric morbidity. Furthermore, our findings demonstrate a

relationship between cognitive impairment, psychiatric symptoms, and adverse

quality of life in long-term survivors. Finally, we confirmed prior associations that

hypoxemia is a potential risk factor for the development of long-term cognitive

and psychiatric impairment.

We found that neuropsychological function can be assessed over the

telephone in a multi-center trial. This has the potential to be an important

development for future critical care trials, as neuropsychological impairment is

increasingly recognized as a common, long-lasting, and potentially modifiable

outcome. However, our experience highlights potential limitations of measuring

neuropsychological function in multi-center trials.

First, attrition was significant. Attrition is a recognized barrier to conducting

long-term outcomes studies in critical care trials (24-25, 57-59), due in part to the

mortality experienced by critically ill patients. After accounting for mortal losses,

the requirement that subjects be enrolled in EA-PAC, and the delay in study

initiation, only 406 of the 1001 subjects randomized in FACTT were alive and

eligible for ACOS.

However, as 12% of eligible survivors declined and 36% were unable to

be contacted to obtain consent for ACOS after discharge, the opportunity to

increase subject participation in future studies exists. Potential solutions to

increase consent rate in future studies include: enrolling subjects prospectively

and prioritizing in-person consent prior to discharge, and employing multiple

strategies and repeated attempts to contact potential subjects (60-61).

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Furthermore, as 12% of subjects who consented to long-term neuropsychological

assessment subsequently declined and 25% were lost to follow-up, the

opportunity to improve retention also exists. Although it is unclear why subjects

declined to be tested, potential explanations include that subjects were asked to

complete multiple follow-up interviews as part of EA-PAC and ACOS and

neuropsychological assessments were lengthy. Finally, subjects completed

cognitive testing via the telephone to varying degrees. Fatigue and/or frustration

appeared to play a role, as did an error in test administration. Future studies will

need to balance the merits of administering a more comprehensive battery with

the potential burden imposed upon study participants.

Potential solutions to improve retention and test completion in future

studies include: increasing the flexibility of scheduling by centralizing test

administration in different time-zones to minimize potential conflicts with work

and/or healthcare visits, increasing the number of trained staff to administer the

neuropsychological battery and identifying and employing the most effective

strategies to ensure test completion, selecting an intermediate testing timepoint

(e.g., 3 months) which minimizes mortal losses yet ensures adequate time for

survivors to transition through the healthcare system to home (24-25, 62-63),

using a shorter test battery (64) or limiting the domains to be assessed (62), and

using multiple strategies in a systematic fashion to retain participants (60-61).

Through the effective use of many of these strategies, more recent studies are

demonstrating the ability to recruit and retain ALI survivors successfully (61, 65-

66). Finally, compared to non-participants, ACOS subjects were more likely to

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be female and white; as such, our findings may not generalize to other

populations.

In conclusion, we found that we were able to assess long-term

neuropsychological function in survivors from a multi-center trial using a

telephone battery. However, we encountered significant challenges in regards to

recruitment, retention, and test completion. We acknowledge that these

challenges pose a potential threat to the internal and external validity of such an

approach. To improve the performance of this practical approach in future

studies, we have highlighted potential solutions to improve recruitment, retain

study participants, and ensure complete neuropsychological assessments.

The ALI subjects in our study had long-term cognitive and psychiatric

morbidity consistent with prior studies where data was obtained in-person (6-9,

24-25). Coupled with our prior work (10-11, 30), our findings validate that many

ALI survivors experience clinically important long-term cognitive impairment.

Approximately half of our ALI survivors had executive dysfunction. While

cognitive impairment was not associated with decreased quality of life in ALI

survivors enrolled in ACOS, the evidence supports that cognitive impairment has

a considerable adverse impact on individuals and society (6-21, 67-68).

ALI survivors enrolled in ACOS experienced anxiety, depression, and

PTSD symptoms. The presence of long-term psychiatric symptoms, and

symptoms of anxiety in particular, was found to be associated with lower PaO2

values and hypoglycemia during the hospitalization. Our findings validate the

recent work of Hopkins et al, wherein hypoxemia was associated with anxiety at

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1 year in ARDS survivors (18), augment the recent work of Dowdy et al which

found that hypoglycemia was associated with depression at 3 months (20), and

support the notion that psychiatric symptoms may result from brain injury

sustained during the hospitalization. We found that psychiatric morbidity was

associated with cognitive impairment and significantly worse quality of life.

Because cognitive impairment may lead to development of psychiatric symptoms

(18), and psychiatric symptoms may lead to impaired physical function (66), our

findings support the idea that cognitive impairment, psychiatric symptoms, and

quality of life are inter-related and impact upon each other in survivors of critical

illness.

We found that hypoxemia is a potential risk factor for the development of

long-term cognitive impairment. Consistent with the work of Hopkins and

colleagues (6), we found lower PaO2 values were associated with cognitive

impairment in general and executive dysfunction specifically. Enrollment in the

conservative fluid-management strategy was identified as a potential risk factor

for the development of long-term cognitive impairment and executive dysfunction.

To potentially explain this finding, we demonstrated that within the ACOS

population lower central venous pressures, the explicit target of the conservative

fluid-management strategy, were associated with cognitive impairment and

executive dysfunction. However, there was no indirect evidence for reduced

cerebral perfusion (e.g., cardiac index, systolic blood pressure) as the mediator

for the observed association, thus it is unclear how conservative fluid

management may have caused cognitive impairment. Given the highly selected

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population that enrolled in and completed ACOS testing, it is unclear if this

finding generalizes to the entire FACTT cohort. This finding will need to be

validated.

Our study sample size limits the generalizability of our findings and is a

major limitation. We also acknowledge the potential for uncontrolled confounding

as our sample size limited our ability to adjust for potential covariates

simultaneously, we were unable to adjust for sedation or delirium (25, 69), and

we did not screen for pre-existing dementia formally (70) or pre-existing

psychiatric disease. There exists the potential for informative censoring, and

although some subjects were determined to be incapable of telephone-based

neuropsychological testing, we did not assess formally for hearing loss before

testing. Although furosemide has been associated with hearing loss, there was

no association between furosemide dose administered and cognitive impairment

(Table E5). We used conservative criteria to define cognitive impairment and

limited the probability of a Type I error (46); however, our multiple comparisons

could result in falsely-rejecting the null hypothesis. If we used a Bonferroni

correction factor, only the conservative fluid-management strategy would remain

associated with cognitive impairment. Regardless, our risk factor assessment

requires confirmation. Finally, depression, anxiety, and PTSD were identified

using self-report measures, which may overdiagnose these disorders. These

psychiatric instruments, while reliable and valid, are not the gold standard for

clinical diagnosis.

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In conclusion, we found that neuropsychological function can be assessed

in a multi-center trial, but it was challenging and opportunities to improve the

performance of this strategy exist. Our findings validate that cognitive and

psychiatric morbidity are common in ALI survivors, findings that have significant

implications for these patients long-term functioning. Executive dysfunction,

specifically, was a common morbidity. We found evidence that hypoxemia is a

risk factor for long-term cognitive and psychiatric impairment and a signal that

fluid management strategy is a potential risk factor for long-term cognitive

impairment. Further studies are necessary to confirm this latter observation given

the select population studied and an unclear mechanism. Future clinical trials in

critically ill populations should include assessment of long-term outcomes,

including neuropsychological outcomes. We will need to be cautious in our

interpretation of such studies and acknowledge that confirmatory studies may be

required. Nevertheless, to improve the lives of critically ill survivors, we should

assess both the short- and long-term effects of an intervention.

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Acknowledgments

We thank the subjects for their participation in follow-up interviews and their

family members for their support to better understand long-term

neuropsychological effects of critical illness. We acknowledge the contributions of

Gilles Clermont, Lan Kong, and Kim Fusko of the University of Pittsburgh for

project and data management and for recruiting, coordinating and conducting

interviews and to investigators and study coordinators at participating ARDS

Clinical Trials Network sites for recruitment, data collection, and support.

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References

1.) Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern

EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med

2005; 353:1685-93

2.) The Acute Respiratory Distress Syndrome Network. Ventilation with lower

tidal volumes as compared with traditional tidal volumes for acute lung injury and

the acute respiratory distress syndrome. N Engl J Med 2000; 342: 1301-1308

3.) The Acute Respiratory Distress Syndrome Network. High versus lower

positive end-expiratory pressures in patients with the acute respiratory distress

syndrome. N Engl J Med 2004; 351: 327-336

4.) The National Heart, Lung, and Blood Institute Acute Respiratory Distress

Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid management

strategies in acute lung injury. N Engl J Med 2006; 354(24): 2564-75

5.) Iwashyna TJ. Survivorship will be the defining challenge of critical care in the

21st century. Ann Intern Med 2010; 153(3): 204-205

6.) Hopkins R, Weaver L, Pope D, Orme J, Bigler E, Larson-Lohr V.

Neuropsychological sequelae and impaired health status in survivors of severe

acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160:50-6

7.) Hopkins RO, Weaver LK, Chan KJ, Orme JF. Quality of life, emotional, and

cognitive function following acute respiratory distress syndrome. J Int

Neuropsychol Soc 2004; 10:1005-1017

8.) Rothenhausler HB, Ehrentraut S, Stoll C, Schelling G, Kapfhammer HP. The

relationship between cognitive performance and employment and health status in

Page 23 of 79

For Review O

nly


long-term survivors of the acute respiratory distress syndrome: results of an

exploratory study. Gen Hosp Psychiatry 2001; 23:90-96

9.) Hopkins RO, Weaver LK, Collingridge D, Parkinson RB, Chan KJ, Orme JF.

Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory

distress syndrome. Am J Respir Crit Care Med 2005; 171:340-347

10.) Christie JD, Biester R, Taichman DB, Shull WH, Hansen-Flaschen J, Shea

JA, Hopkins RO. Formation and validation of a telephone battery to assess

cognitive function in acute respiratory distress syndrome survivors. J Crit Care

2006; 21:125-132

11.) Mikkelsen ME, Shull WH, Biester RC, Taichman DB, Lynch S, Demissie

E, Hansen-Flaschen J, Christie JD. Cognitive, mood and quality of life

impairments in a select population of ARDS survivors. Respirology 2009; 14: 76-

82

12.) Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados

N, Al-Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, Stewart TE, Barr A,

Cook D, Slutsky AS, for the Canadian Critical Care Trials Group. One-year

outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med

2003; 348:683-93

13.) Herridge MS, Tansey CM, Matté A, Tomlinson G, Diaz-Granados N,

Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D,

Slutsky AS, Cheung AM, for the Canadian Critical Care Trials Group. Functional

disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;

364: 1293-1304

Page 24 of 79

For Review O

nly


14.) Adhikari NK, McAndrews MP, Tansey CM, Matté A, Pinto R, Cheung AM,

Diaz-Granados N, Barr A, Herridge MS. Self-reported symptoms of depression

and memory dysfunction in survivors of ARDS. Chest 2009; 135(3): 678-87

15.) Adhikari NK, Tansey CM, McAndrews MP, Matté A, Pinto R, Cheung AM,

Diaz-Granados N, Herridge MS. Self-reported depressive symptoms and

memory complaints in survivors five years after ARDS. Chest 2011; 140(6):

1484-93

16.) Davydow DS, Desai SV, Needham DM, Bienvenu OJ. Psychiatric

morbidity in survivors of the acute respiratory distress syndrome: a systematic

review. Psychosom Med 2008; 70: 512-519

17.) Nelson BJ, Weinert CR, Burly CL, Marinelli WA, Gross CR. Intensive care

unit drug use and subsequent quality of life in acute lung injury patients. Crit Care

Med 2000; 28(11): 3626-30

18.) Hopkins RO, Key CW, Suchyta DO, Weaver LK, Orme JF. Risk factors for

depression and anxiety in survivors of acute respiratory distress syndrome. Gen

Hosp Psych 2010; 32: 147-155

19.) Dowdy DW, Bienvenu OJ, Dinglas V, Mendez-Tellez PA, Sevransky J,

Shanholtz C, Needham DM. Are intensive care factors associated with

depressive symptoms six months after acute lung injury? Crit Care Med 2009;

37: 1702-1707

20.) Dowdy DW, Dinglas V, Mendez-Tellez PA, Bienvenu OJ, Sevransky J,

Dennison CR, Shanholtz C, Needham DM. Intensive care unit hypoglycemia

Page 25 of 79

For Review O

nly


predicts depression during early recovery from acute lung injury. Crit Care Med

2008; 36: 2726-2733

21.) Kapfhammer HP, Rothenhausler HB, Krauseneck T, Stoll C, Schelling G.

Posttraumatic stress disorder and health-related quality of life in long-term

survivors of acute respiratory distress syndrome. Am J Psych 2004; 161(1): 45-

52

22.) Ehlenbach WJ, Hough CL, Crane PK, et al. Association between acute

care and critical illness hospitalization and cognitive function in older adults.

JAMA 2010; 303(8): 763-770

23.) Iwashyna TJ, Ely EW, Smith DM, et al. Long-term cognitive impairment

and functional disability among survivors of severe sepsis. JAMA

2010;304(16):1787-1794

24.) Jackson JC, Girard TD, Gordon SM, Thompson JL, Shintani AK,

Thomason JWW, Pun BT, Canonico AE, Dunn JG, Bernard GR, Dittus RS, Ely

EW. Long-term cognitive and psychological outcomes in the awakening and

breathing controlled trial. Am J Respir Crit Care Med 2010; 182: 183-191

25.) Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL,

Shintani AK, Gordon SM, Canonico AE, Dittus RS, Bernard GR, Ely EW.

Delirium as a predictor of long-term cognitive impairment in survivors of critical

illness. Crit Care Med 2010; 38(7): 1513-20

26.) Jones C, Griffiths RD, Slater T, Benjamin KS, Wilson S. Significant

cognitive dysfunction in non-delirious patients identified during and persisting

following critical illness. Intensive Care Med 2006; 32: 923-926

Page 26 of 79

For Review O

nly


27.) Desai S, Lawa TJ, Needham DM. Long-term complications of critical care.

Crit Care Med 2011; 39(2): 371-379

28.) Davydow DS, Gifford JM, Desai SV, Needham DM, Bienvenu OJ.

Posttraumatic stress disorder in general intensive care unit survivors: a

systematic review. Gen Hosp Psych 2008; 30: 421-434

29.) Davydow DS, Gifford JM, Desai SV, Bienvenu OJ, Needham DM.

Depression in general intensive care unit survivors: a systematic review. Int Care

Med 2009; 35: 796-809

30.) Taichman DB, Christie J, Biester R, Mortensen J, White J, Kaplan S,

Hansen-Flaschen J, Palevsky HI, Elliott CG, Hopkins RO. Validation of a brief

telephone battery for cognitive assessment of patients with pulmonary arterial

hypertension. Respir Res 2005; 6: 39

31.) The National Heart, Lung, and Blood Institute Acute Respiratory Distress

Syndrome (ARDS) Clinical Trials Network. Pulmonary-artery versus central

venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354:

2213-24

32.) Mikkelsen ME, Lanken PN, Biester R, Gallop R, Bellamy S, Localio AR,

Hopkins RO, Angus DC, Christie JD for the ARDSNet. Conservative fluid

strategy is associated with neurocognitive deficits in survivors of acute lung injury

[abstract]. Am J Respir Crit Care Med 2008; 177: A819

33.) Clermont G, Kong L, Weissfeld LA, Lave JR, Rubenfeld GD, Roberts MS,

Connors AF, Bernard GR, Thompson BT, Wheeler AP, Angus DC. The effect of

Page 27 of 79

For Review O

nly


pulmonary artery catheter use on costs and long-term outcomes of acute lung

injury. PLoS ONE 2011; 6(7): e22512

34.) Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M,

Legall JR, Morris A, Spragg R. The American-European consensus conference

on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial

coordination. Am J Respir Crit Care Med 1994; 149: 818–824

35.) Burgess PW, Shallice T. The Hayling and Brixton Tests. London, England:

Thames Valley Test Company Limited, 2007

36.) Sukantarat KT, Burgess PW, Williamson RC, Brett SJ. Prolonged

cognitive dysfunction in survivors of critical illness. Anaesthesia 2005; 60, 847-

853

37.) Biggs JT, Wylie LT, Ziegler VE. Validity of the Zung self-rating depression

scale. British J Psych 1978; 132: 381-385

38.) Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring

clinical anxiety: psychometric properties. J Cons Clin Psychol 1998; 56:893-7

39.) Weisaeth L. Torture of a Norwegian ship’s crew: the torture, stress

reactions and psychiatric aftereffects. Acta Psychiatr Scand Suppl 1989; 355: 63-

72

40.) Wechsler D, ed. Wechsler Adult Intelligence Scale, Third edition. San

Antonio: The Psychological Corporation; 1997

41.) Wechsler D. Wechsler Memory Scale. San Antonio: The Psychology

Corporation, 1997

Page 28 of 79

For Review O

nly


42.) Lezak MD. Neuropsychological Assessment. New York: Oxford University

Press, 1995

43.) Torrance GW, Feeny DH, Furlong WJ, Barr RD, Zhang Y, Wang Q. Multi-

attribute preference functions for a comprehensive health status classification

system: Health utilities index Mark 2. Medical Care 1996; 34(7): 702-722

44.) Heaton RK, Grant I, Matthews CG. Comprehensive norms for an

expanded Halstead-Reitan Battery: demographic corrections, research findings

and clinical applications. Psychological Assessment Resources, Inc., Odessa,

1991

45.) Heaton RK. Comprehensive norms for an expanded Halstead-Reitan

Battery: A supplement for the WAIS-R. Psychological Assessment Resources,

Inc., Odessa, 1994

46.) Ingraham LJ, Aiken CB. An empirical approach to determining criteria for

abnormality in test batteries with multiple measures. Neuropsychology 1996;

10:120-124

47.) Doblar DD, Hinckle JC, Fay ML, Condon BF. Air embolism associated with

pulmonary artery catheter introducer kit. Anesthesiology 1982; 56: 307-309

48.) Boyd KD, Thomas SJ, Boyd AD. A prospective study of complications of

pulmonary artery catheterizations in 500 consecutive patients. Chest 1983; 84:

245-249

49.) Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A,

Pollmächer T. Cytokine-associated emotional and cognitive disturbances in

humans. Arch Gen Psychiatry 2001; 58: 445-452

Page 29 of 79

For Review O

nly


50.) Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG. Cytokine and

other immunologic markers in chronic fatigue syndrome and their relation to

neuropsychological factors. Appl Neuropsychol 2001; 8: 51-64

51.) Ngandu T, von Strauss E, Helkala EL, Winblad B, Nissinen A, Tuomilehto

J, Soininen H, Kivipelto M. Education and dementia: what lies behind the

association? Neurology 2007; 69: 1442-1450

52.) Richards PM, Ruff RM. Motivational effects on neuropsychological

functioning: comparison of depressed versus nondepressed individuals. J

Consult Clin Psychol 1989; 57: 396-402

53.) Buckelew SP, Hannay HJ. Relationships among anxiety, defensiveness,

sex, task difficulty and performance on various neuropsychological tasks.

Percept Mot Skills 1986; 63: 711-718

54.) Schelling G, Stoll C, Kapfhammer HP, Rothenhausler HB, Krauseneck T,

Durst K, Haller M, Briegel J. The effect of stress doses of hydrocortisone during

septic shock on posttraumatic stress disorder and health-related quality of life in

survivors. Crit Care Med 1999; 27: 2678-2683

55.) Maldonado G, Greenland S. Simulation study of confounder-selection

strategies. Amer J of Epid 1993; 138: 923-936

56.) Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation

study of the number of events per variable in logistic regression analysis. J Clin

Epidemiol 1996; 49: 1373-1379

57.) Rubenfeld GD. Improving clinical trials of long-term outcomes. Crit Care

Med 2009; 37: S112-S116

Page 30 of 79

For Review O

nly


58.) Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB. The long-

term psychological effects of daily sedative interruption on critically ill patients.

Am J Respir Crit Care Med 2003; 168: 1457-1461

59.) Strom T, Stylsvig M, Toft P. Long-term psychological effects of a no-

sedation protocol in critically ill patients. Critical Care 2011; 15:R293

60.) Robinson KA, Dennison CR, Wayman DM, Pronovost PJ, Needham DM.

Systematic review identified number of strategies important to retaining study

participants. J Clin Epidemiol 2007; 60(8): 757-765

61.) Chen KF, Colantuoni E, Siddiqi F, Dinglas VD, Sepulveda KA, Fan E,

Pronovost PJ, Needham DM. Repeated attempts using different strategies are

important for timely contact with study participants. J Clin Epidemiol 2011; 64:

1144-1151

62.) Jackson J, Ely EW, Morey MC, Anderson VM, Siebert CS, Denne LB,

Clune J, Archer KR, Torres R, Janz D, Schiro E, Jones J, Shintani A, Levine B,

Pun BT, Thompson J, Brummel NE, Hoenig H. Cognitive and physical

rehabilitation of intensive care unit survivors: results of the RETURN randomized

controlled pilot investigation. Crit Care Med 2012; 40: 000-000

63.) Unroe M, Kahn JM, Carson SS, Govert JA, Martinu T, Sathy SJ, Clay AS,

Chia J, Gray A, Tulsky JA, Cox CE. One-year trajectories of care and resource

utilization for recipients of prolonged mechanical ventilation: a cohort study. Ann

Intern Med 2010; 153: 167-175

64.) Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V,

Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA:

Page 31 of 79

For Review O

nly


a brief screening tool for mild cognitive impairment. J Amer Ger Soc 2005; 53:

695-699

65.) National Heart, Lung, and Blood Institute; Johns Hopkins University.

Evaluating health outcomes and quality of life after acute lung injury among

participants of the ALTA, OMEGA, and EDEN (ARDS Network) studies (The

ALTOS Study). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library

of Medicine (US). 2000-2012. Available from: http://clinicaltrials.gov/show/

NCT00719446 NLM Identifier: NCT00719446

66.) Bienvenu OJ, Colantuoni E, Mendez-Tellez PA, Dinglas VD, Shanholtz C,

Husain N, Dennison CR, Herridge MS, Pronovost PJ, Needham DM. Depressive

symptoms and impaired physical function after acute lung injury: a 2-year

longitudinal study. Am J Respir Crit Care Med 2012; 185: 517-524

67.) Rozzini L, Chilovi BV, Trabucchi M, Padovani A, Marson D, Griffith R.

Impaired financial abilities in mild cognitive impairment: A direct assessment

approach. Neurology 2003; 60: 2021

68.) Jonsson L, Lindgren P, Wimo A, Jonsson B, Winblad B. Costs of mini

mental state examination-related cognitive impairment. Pharmacoeconomics

1999; 16: 409-416

69.) Van den Boogard M, Schoonhoven L, Evers AW, van der Hoeven JG, van

Achterberg TV, Pickkers P. Delirium in critically ill patients: impact on long-term

health-related quality of life and cognitive functioning. Crit Care Med 2012; 40(1):

112-118

Page 32 of 79

For Review O

nly


70.) Pisani MA, Inouye SK, McNicoll L, Redlich CA. Screening for preexisting

cognitive impairment in older intensive care unit patients: use of proxy

assessment. J Am Geriatr Soc 2003; 51: 689-693

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Figure 1. Enrollment and outcomes. Abbreviations: ACOS=ARDS Cognitive Outcomes Study. Figure 2. Long-term cognitive impairment according to fluid management strategy. Impairment in a domain was defined as a score > 2 SD below the population norm. Cognitive impairment was defined as impairment in memory, verbal fluency, and/or executive function in the 75 survivors completing testing in each of these cognitive domains. Memory, verbal fluency, or executive function was assessed in 92, 96, and 76 subjects, respectively. Proportions of impaired subjects are specified by domain, according to fluid-management strategy. Error bars reflect upper bound of 95% confidence interval. Lib=liberal fluid strategy, Cons=conservative fluid strategy.

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Table 1. Comparison of baseline characteristics between FACTT 60-day survivors not enrolled in ACOS and ACOS participants.

FACTT Survivors

Not Enrolled in ACOS (N=609)

ACOS Cohort

(N=122)

p-value

Variable

Age (yr) 47 (37 – 57) 49 (40 – 58) 0.23

Male sex (%) 54 43 0.04

Race or ethnic group (%) White non-Hispanic Black non-Hispanic Hispanic Other

64 21 7 8

86 11 3 0

<0.001

Primary Lung Injury (%) Pneumonia Sepsis Aspiration Trauma Multiple transfusions Other

49 20 16 9 1 5

36 25 16 8 2

13

0.005

Co-existing conditions (%) None Diabetes HIV infection or AIDS Cirrhosis Solid tumors Leukemia Lymphoma Immunosuppression

71 16 7 3 1 2 0 6

75 18 0 2 1 1 2 7

0.39 0.65 0.001 0.78 1.00 1.00 0.13 0.84

APACHE III score, mean (SD) 85 (66 – 105) 85 (63 – 102) 0.32

Medical ICU

65 56 0.06

Glasgow Coma Scale 8 (6 – 12) 8 (4 – 11) 0.38

Mean arterial pressure, mm Hg 76 (68 – 87) 77 (67 – 85) 0.49

Vasopressor use, (%) 34 33 0.81

PaO2:FiO2 122 (83 – 168) 122 (86 – 165) 0.73

Conservative strategy (%) 51 55 0.38

Pulmonary artery catheter (%) 51 52 0.70

Definition of abbreviation: ACOS=ARDSNet Cognitive Outcomes Study; AIDS=acquired immunodeficiency virus; APACHE III= Acute Physiologic and Chronic Health Evaluation III scores; HIV=human immunodeficiency virus; PaO2:FiO2=ratio of partial pressure of arterial oxygen to fraction of inspired oxygen. Values expressed as a percentage or median (interquartile range).

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Table 2. Associations with long-term cognitive impairment in ALI survivors. Cognitive impairment at the subject level was defined as impairment in memory, verbal fluency, and/or executive function in the 75 subjects who completed tests in each of these domains at the 12-month follow-up.

Long-Term Cognitive Impairment

Not Impaired

(n=34) Impaired (n=41)

p-value Unadjusted Odds

Ratio (95% CI) Adjusted Odds Ratio

(95% CI) ‡

Candidate Risk Factors

Duration of mechanical ventilation 8 (4 – 11) 6 (4 – 9) 0.43

Conservative fluid-management strategy (%)

32 66 0.004 4.03 (1.53 – 10.59) 3.35 (1.16 – 9.70) –

5.46 (1.92 – 15.53)

Hypotension (hemodynamic data on-study) *

Systolic Blood Pressure (mm Hg) 108 (102 – 113) 104 (96 – 112) 0.32

Cardiac index (liters/min/m2)

† 4.5 (3.8 – 5.3) 4.5 (3.7 – 5.0) 0.49

Shock * (%) 32 29 0.77

Vasopressor use 26 24 0.84

Hypoxemia (respiratory variables on-study)

PaO2 86 (70 – 98) 71 (67 – 80) 0.02 1.56 (1.09 – 2.24) §

1.51 (1.01 – 2.26) –

1.68 (1.14 – 2.49) §

PaO2:FiO2 152 (132 – 192) 157 (133 – 190) 0.63

Oxygenation index 7.38 (4.55 –

10.42) 7.67 (5.97 –

10.02) 0.57

Oxygen saturation (%) 95.1 (93.3 – 96.8) 94.2 (92.6 – 95.8) 0.10


Primary lung injury (%) Pneumonia

24

46

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Sepsis Aspiration Trauma Multiple transfusions Other

29 9

12 6

21

20 17 10 2 5

0.10

Severity of Illness

APACHE III 87 (60 – 106) 72 (60 – 94) 0.42

ICU length of stay 11 (8 – 18) 10 (7 – 16) 0.65

Potential Covariates

Age, years 50 (43 – 58) 51 (45 – 60) 0.51

Male sex (%) 32 51 0.10

Race or ethnic group (%) White Black Hispanic

91 6 3

90 10 0

0.53

Level of education, years

13 (12 – 16) 12 (12 – 15) 0.36

Coexisting conditions (%) Heavy alcohol use Cerebrovascular disease

3 0

13 2

0.21 1.00

Psychiatric impairment, 1 year (%) 59 80 0.04

Hospital length of stay prior to enrollment, days

2 (1 – 3) 3 (1 – 4) 0.22

Time from discharge to testing, months

12 (11 – 13) 12 (11 – 13) 0.51

Definition of abbreviation: CI=confidence interval; HIV=human immunodeficiency virus; AIDS=acquired immunodeficiency syndrome; APACHE III= Acute Physiologic and Chronic Health Evaluation III scores; PaO2:FiO2=ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; CVP=central venous pressure; PaO2=partial pressure of arterial oxygen. Values expressed as a frequency (percent) or median (interquartile range).

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On-study variables were summarized at the subject level as means to account for influential observations. With the exception of systolic blood pressure, in which the worst values over the preceding 24 hours were recorded to derive the cardiovascular component of the Brussels organ failure score, values were measured and recorded daily (measure closest to 8 am) during the study. * Shock defined as mean arterial pressure < 60 or vasoactive agent use (assignment to FACTT protocol cells 1 or 2) at any time during FACTT (4). †

Cardiac index was measured in 39 survivors (20 in the liberal-strategy group and 19 in the conservative-strategy group). ‡ Potential covariates were included in the multivariable logistic regression models one covariate at-a-time. The adjusted odds ratios presented represent the range of odds ratios observed in multivariable logistic regression models. For additional details, please see Table E6 in the on-line supplement. § For each 10-unit decrease in PaO2, odds ratio for the development of cognitive impairment increased by 1.56.

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Table 3. Associations with long-term psychiatric morbidity in ALI survivors. Psychiatric morbidity was defined as present if symptoms of anxiety, depression, or post-traumatic stress disorder were identified at the 12-month follow-up.

Psychiatric Morbidity

Not Present

(n=35) Present (n=67)

p-value

Baseline characteristics

Age, years 51 (38 – 64) 50 (44 – 57) 0.58

Male sex (%) 40 45 0.64


94 6 0

81 15 4

0.19

Level of education, years 14 (12 – 16) 12 (12 – 15) 0.15

Medical ICU (%) 49 58 0.44

APACHE III

88 (63 – 108) 77 (60 – 99) 0.31



On-study variables *

Hemodynamic variables†

Systolic Blood Pressure (mm Hg) 111 (102 – 116) 104 (98 – 111) 0.05

Shock (%) 37 30 0.46

Respiratory variables

PaO2 ‡ 86 (72 – 98) 72 (68 – 90) 0.02

Metabolic variables

Glucose (mg/dL) 123 (107 – 140) 119 (109 – 136) 0.99

Hypoglycemia‡, < 60 mg/dL (%) 0 13 0.03

Hyperglycemia‡, > 180 mg/dL (%) 34 30 0.65

Corticosteroid therapy §

Corticosteroids (mg of

Methylprednisolone, cumulative) 0 (0 – 60) 0 (0 – 140) 0.58

Corticosteroids received (%) 29 33 0.66

ICU length of stay (days) 11 (7 – 20) 12 (8 – 16) 0.92

Duration of mechanical ventilation (days)

7 (4 – 15) 7 (4 – 10) 0.94

Definition of abbreviation: ICU=intensive care unit; APACHE III= Acute Physiologic and Chronic Health Evaluation III scores; PaO2=partial pressure of arterial oxygen.

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Values expressed as a frequency (percent) or median (interquartile range).

* On-study variables were summarized at the subject level as means to account for influential

observations. With the exception of systolic blood pressure, in which the worst values over the preceding 24 hours were recorded to derive the cardiovascular component of the Brussels organ failure score, values were measured and recorded daily (measure closest to 8 am) during the study. †

Shock defined as mean arterial pressure < 60 or vasoactive agent use (assignment to FACTT protocol cells 1 or 2) at any time during FACTT (4). The association between systolic blood pressure and psychiatric impairment was non-significant after adjustment for potential covariates (p=0.14). ‡

For each 10-unit decrease in PaO2, odds ratio for the development of psychiatric morbidity

increased by 1.35 (95% confidence interval 1.02, 1.78) and the association remained after adjustment for potential covariates. Hypo- and hyperglycemia were defined as any episode of serum glucose < 60 mg/dL or > 180 mg/dL, respectively, during the hospitalization. We were unable to adjust for potential covariates in the association between hypoglycemia and psychiatric morbidity as psychiatric symptoms were present in each subject who had a hypoglycemia episode. §

Corticosteroid therapy was neither associated with PTSD (11 of 32 subjects (34%) who received corticosteroids experienced symptoms of PTSD compared with 29 of 70 subjects (41%) who did not receive corticosteroids, p=0.50), nor was corticosteroid therapy associated with psychiatric morbidity in the subgroup of 27 sepsis-associated ALI subjects (6 of 12 subjects (50%) who received corticosteroids experienced long-term psychiatric morbidity compared to 11 of 15 subjects (73%) who did not receive corticosteroids, p=0.26).

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Figure 1.

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Consented to long-term follow-up for EA-PAC

N=655

Tested at 12 months ‡

N=102

Subjects randomized in FACTT N=1001

Consented to ACOS N=213

Causes outside of investigator control: Deceased: N=22 Incarcerated: N=2 Incapable

†: N=9

Causes which may be potentially remediable by future investigators: Declined: N=25 Lost to follow-up

†: N=53

Total: N=111

Ineligible: N=227 * Declined: N=119 Total: N=346

Completed Testing in All Domains

N=75

Causes outside of investigator control: Deceased: N=194 Ineligible

†: N=55

Total: N=249

Causes which may be potentially remediable by future investigators: Declined: N=48 Unable to be contacted: N=145 Total: N=193

Survivors eligible for ACOS N=406

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* Of 1001 FACTT subjects who underwent randomization, 227 were ineligible for long-term

follow-up as part of EA-PAC as no regulatory approval was in place and 119 declined consent (33). †

Subjects were categorized as ineligible if the time window to be tested had elapsed due to the regulatory halt, as incapable if self-determined or determined by a surrogate to be physically or mentally incapable of telephone-based neuropsychological testing, and as lost to follow-up if consent was obtained but the subject was not tested. Of 53 subjects categorized as lost to follow-up, no contact information was available for 1 subject, no telephone service was available for 1 subject, no explanation was provided for 1 subject, and the remaining 50 subjects were recorded as “lost to follow-up.” ‡

Of 52 subjects tested at 2 months, 32 were re-tested at 12 months. The reasons for 20 subjects being tested at 2 months but not at 12 months were that 11 patients were lost to follow-up, 5 declined, 3 died, and 1 was incarcerated. Subjects were not required to undergo testing at 2 months to be tested at 12 months.

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Figure 2.

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ARDS COGNITIVE OUTCOMES STUDY (ACOS)

1

TITLE: THE ARDS COGNITIVE OUTCOMES STUDY (ACOS): LONG-

TERM NEUROPSYCHOLOGICAL FUNCTION IN ACUTE LUNG INJURY

SURVIVORS

Authors:

Mark E. Mikkelsen, M.D., M.S.1,2 *

Jason D. Christie, M.D., M.S.1,2 * Paul N. Lanken, M.D.1

Rosette C. Biester, Ph.D3

B. Taylor Thompson, M.D.4

Scarlett L. Bellamy, Sc.D.2

A. Russell Localio, Ph.D.2

Ejigayehu Demissie, M.S.N.1,2

Ramona O. Hopkins, Ph.D. 5, 6 Derek C. Angus, M.D., M.P.H. 7

* These authors contributed equally to this work

Institution: 1Pulmonary, Allergy, and Critical Care Division

Department of Medicine University of Pennsylvania School of Medicine

2Center for Clinical Epidemiology and Biostatistics University of Pennsylvania School of Medicine

3Department of Physical Medicine and Rehabilitation University of Pennsylvania School of Medicine Philadelphia Veterans Affairs Medical Center

4Pulmonary and Critical Care Unit, Department of Medicine Massachusetts General Hospital 5Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center 6 Psychology Department and Neuroscience Center, Brigham Young University 7CRISMA Center, Department of Critical Care Medicine and Department of Health Policy and Management University of Pittsburgh

Running Head: ARDS COGNITIVE OUTCOMES STUDY (ACOS) Descriptor: 4.2 ALI/ARDS: Diagnosis & Clinical Issues

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2

Online Data Supplement

Methods

The study was reviewed and approved by the Institutional Review Boards

of each participating hospital. It was also approved by the Natural History and

Steering Committees of the NIH National Heart, Lung, and Blood Institute

(NHLBI) Acute Respiratory Distress Syndrome Clinical Trials Network

(ARDSNet) in 2002.

Study Design

The ARDS Cognitive Outcomes Study (ACOS) is a prospective, multi-

center cohort study of survivors from the ARDSNet Fluid and Catheter Treatment

Trial (FACTT). FACTT enrolled patients from 38 North American hospitals

between June 2000 and October 2005. Between July 2002 and July 2003,

FACTT was halted and new regulatory approval related to the study was

prohibited. ACOS was coordinated and executed by investigators at the

University of Pennsylvania and University of Pittsburgh. The regulatory process

for ACOS began prior to the halt and testing was conducted between March

2003 and September 2006 in concert with the Economic Analysis of the

Pulmonary-Artery Catheter (EA-PAC) study as a planned long-term assessment

of neuropsychological function in FACTT survivors (E1). As a consequence of

the regulatory halt of FACTT, ACOS ran partially concurrent with FACTT.

Subjects gave informed consent for the telephone administration of

neuropsychological tests.

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Study Patients

To be eligible for ACOS, subjects had to be enrolled in FACTT and EA-

PAC (E1) and ACOS-specific regulatory approval had to be in place. FACTT

enrolled mechanically ventilated adults who met the American-European

Consensus Conference criteria for ALI (E2). In FACTT, subjects were assigned

at random to a conservative or liberal fluid management strategy (E3), and either

a central venous catheter or PAC (E4) in a two-by-two factorial design. Baseline

characteristics, including the presence of pre-existing dementia and site of

enrollment, and medical data were collected prospectively as part of FACTT. We

categorized the geographic region within the continental United States into one of

five categories (Northeast, South, Southwest, Midwest, and West) based on the

site of enrollment, consistent with prior studies (E5). On-study data, including

hemodynamic, respiratory, renal and metabolic variables, were collected and

recorded daily by the ARDS Network data coordinating center, as were

cumulative fluid balance, organ-failure-free day assessments, ICU length of stay,

and duration of mechanical ventilation (E3).

Cognitive and Psychiatric Function

A validated telephone battery of standardized neuropsychological tests

was administered to consenting, English-speaking subjects at 2 and 12 months

post-hospital discharge. Subjects were not required to undergo 2 month testing

to be tested at 12 months. The test administration call center was centralized at

the University of Pittsburgh. The telephone battery was administered using a

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detailed standardized script by two non-neuropsychologists at the University of

Pittsburgh who were blinded to group randomization. These two investigators

received formal training from neuropsychologists and were evaluated for

competence during the pilot interview stage prior to administering tests to

subjects. The details of formation and validation of the battery used in this study

have been presented previously (E6-8).

The following cognitive domains were assessed: vocabulary, reasoning,

memory, verbal fluency and executive function. Executive function is a set of

cognitive abilities that enable individuals to engage in purposeful, goal-directed

behaviors, cognitive flexibility, abstract thinking, initiate behavior and are

necessary for effective daily functioning. Memory, verbal fluency, and executive

function were hypothesized to be domains susceptible to impairment in ALI

survivors based on previous investigations in this population (E6, E8-E10).

Anxiety, depression, and post-traumatic stress disorder (PTSD) symptoms were

assessed using standardized measures (E11-14). Neuropsychological tests were

reviewed, scored, and standardized by neuropsychologists at the University of

Pennsylvania. Instruments used to assess each neuropsychological domain are

presented in Table E1 (E11-18). To minimize the effect of order presentation, the

tests were administered in random sequence (E6-E8).

Data Analysis

The cognitive battery yielded scaled scores for each domain which were

normalized to allow for comparisons across tests and subjects (E19-20). We

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report the median and interquartile range of results as percentiles. We defined

impairment in a single domain as a score > 2 SD below the population normative

data (E9-10, 21-22), a conservative definition of cognitive impairment that

represents significant deficits outside the normal range of cognitive function.

Cognitive impairment at the subject level was defined as impairment in memory,

verbal fluency, and/or executive function in subjects who completed tests in each

of these domains. We used the most conservative criteria to define impairment in

a single domain and limited our cognitive assessment a priori to three domains

shown to be affected in ALI survivors in previous studies (E6, E8-10) to minimize

the probability of a Type I error to an acceptable alpha level of < 0.05 (E22).

The Beck Anxiety Inventory and the Zung Self-Rating Depression Scale

are scored as none, mild, moderate and severe (E11-13). Patients with moderate

or severe anxiety or depression were classified as impaired similar to previous

studies (E6, E8, E21). The modified Post-traumatic Stress Syndrome 10-

Questions Inventory (PTSS-10) is scored as normal or impaired (E14).

Psychiatric impairment was defined as impairment in any, or multiple, of the three

psychiatric measures (anxiety, depression, and PTSD) in subjects completing

tests in each of these domains. We focused our study on survivors tested at

approximately 12 months post-discharge to assess long-term neuropsychological

function.

Based on prior studies, we a priori hypothesized that cognitive impairment

would be associated with duration of mechanical ventilation, either conservative

or liberal fluid-management strategy (E3), hypotension (E10), hypoxemia (E9),

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PAC use (E4, E23), sepsis as the primary cause of lung injury (E24-25), and

severity of illness (E26). PAC use was considered as a candidate risk factor

given its association with arrhythmias and the potential risk of paradoxical air

and/or microthrombotic embolism given the prevalence of moderate-to-large

patient foramen ovale shunting in patients with ARDS (E23, E27-E28). There

was no standardized delirium assessment in FACTT (E3-4) to permit adjusting

for duration of delirium, which was recently shown to be associated with long-

term cognitive impairment (E29-30). The pre-specified potential confounding

variables included: age, gender, race, history of heavy alcohol use or

cerebrovascular disease, level of education, the presence of concomitant

psychiatric impairment, hospital length of stay prior to enrollment, and the time to

testing (E6, E8-10, E21, E31-33).

We used baseline measures and daily measurements during the study

(“on-study” data) to explore our hypotheses. On-study data from FACTT were

summarized at the subject level as means to account for influential observations.

We used hemodynamic values (systolic blood pressure (SBP), vasopressor use,

cardiac index) and protocol assignment to shock cells from FACTT (E3-E4) to

explore the potential causative role of hypotension (E10) and central venous

pressure (CVP) to explore the potential role of fluid-management strategy.

Respiratory values (partial pressure of arterial oxygen, PaO2, partial pressure of

arterial oxygen to fraction of inspired oxygen, PaO2:FiO2, oxygenation index, and

oxygen saturation) were assessed to explore the potential causative role of

hypoxemia (E9). We used Acute Physiologic and Chronic Health Evaluation

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(APACHE) III scores and intensive care unit (ICU) length of stay for severity of

illness measures.

With the exception of the shock assessment, which was measured as

often as every 4 hours, and SBP and PaO2:FiO2, in which the worst values over

the preceding 24 hours were recorded to derive the Brussels organ failure score,

values were measured and recorded daily (measure closest to 8 am) during the

study.

In addition, serum sodium, bicarbonate, blood urea nitrogen, creatinine,

glucose (E34), organ-failure-free (cardiovascular, central nervous system, and

renal) days (E35), and cumulative furosemide and corticosteroid dose given their

potential anticholinergic activity (E36-37), were assessed in exploratory analyses

(see Table E5).

Based on prior studies and/or plausibility, we tested the following

candidate risk factors for the development of psychiatric morbidity: age (E38-

E40), gender (E38-41), race/ethnicity, level of education (E39, E42), APACHE III,

the trial interventions (fluid-management strategy, PAC), hypotension, hypoxemia

(E38-39), any episode of hypoglycemia during the hospitalization (E43),

corticosteroid administration (E43), ICU length of stay (E45-E46), and duration of

mechanical ventilation (E38, E45).

Comparisons between groups were made using Student’s t-test or

Wilcoxon’s rank-sum test for continuous variables and the chi-squared statistic or

Fisher’s exact test for categorical variables. In the presence of a significant

association, continuous measurements were categorized based on the

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distribution into quartiles to assess for dose-response effects. Quality of life was

assessed at 12 months post-discharge as part of the EA-PAC study (E1). Quality

of life was measured using the Health Utilities Index Mark 2 (E47).

Statistical Analysis:

Multivariable logistic regression was used to investigate the relationship

between candidate risk factors and long-term neuropsychological impairment

(cognitive impairment and psychiatric morbidity). We adjusted for each candidate

risk factor and potential covariates with an alpha level of significance < 0.20 in

univariate analyses (E48). Age and level of education were forced into the final

cognitive models to account for potential differences in pre-morbid cognitive

impairment. Time to testing and race were forced into the final cognitive models

to account for potential time and survival biases. To avoid over-fitting the model,

adjustment for potential confounding was performed one covariate at-a-time

(E49). Multivariable logistic regression was also used to investigate the

relationship between sociodemographic factors and consent to participate in a

study of long-term neuropsychological function. For all analyses, associations

were reported as an OR with 95% confidence intervals (CI). A standard two-

tailed p-value of ≤ 0.05 was used to signify statistical significance. Statistical

analyses were performed using Stata 10.0 software (Stata Datacorp, College

Station, TX).

The primary analysis was limited to 75 survivors who completed testing in

all three cognitive domains of interest at 12 months: memory, verbal fluency, and

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executive function. The Hayling Sentence Completion Test (HSCT) assesses

executive function with an error score and response latency component to

produce an overall score. The response times for the HSCT were not measured

before February, 2005 due to an error in the administration of the timing of the

test. This error effected 21 of 102 survivors (8 randomized to the liberal-strategy

group and 13 to the conservative-strategy group) at 12 months. In secondary

analyses, 90 survivors who completed assessments in memory, verbal fluency,

and the error score of the HSCT at 12 months were carried out.

Sensitivity Analyses:

We performed multiple sensitivity analyses to determine the effects of

missing data on the observed association between fluid-management strategy

and long-term cognitive impairment. To assess the potential effects of morbidity

and mortality post-consent, we assumed that all 31 subjects who died post-

consent or were classified as incapable to have the tests administered were

impaired. To assess the potential effects of loss to follow-up post-consent, we

first assumed that all 50 survivors reported as lost to follow-up were impaired,

then we assumed that all 50 survivors reported as lost to follow-up were not

impaired, and finally we assumed that impairment in those lost to follow-up was

similar to the 55% incidence observed for the full cohort. To assess the potential

effects of the 25 survivors who refused testing, we performed separate analyses

using these same three assumptions. Finally, to gauge the potential effects of

incomplete cognitive assessments on the associations identified in the primary

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analysis, we assumed that all 27 survivors without a complete cognitive

assessment were impaired, and then assumed that survivors without a complete

cognitive assessment were not impaired. To minimize the assumptions of the

latter scenario, survivors were categorized as impaired if the subject was

impaired in a tested domain.

Results

Association between Risk Factors and Cognitive Domain Performance:

Lower PaO2 values correlated with worse executive function (rho=0.24,

p=0.05), but not verbal fluency (rho=0.16, p=0.14) or memory (rho=0.14, p=0.20).

Similarly, lower central venous pressures correlated with worse executive

function (rho=0.28, p=0.02), but not verbal fluency (rho= -0.07, p=0.47) or

memory (rho=0.14, p=0.20). Enrollment in the conservative fluid-strategy group

correlated with worse executive function (rho= -0.39, p<0.001), but not verbal

fluency (rho= -0.01, p=0.89) or memory (rho= -0.12, p=0.25).

Association between Risk Factors and Anxiety, Depression, and PTSD:

Lower PaO2 values were associated with anxiety (p=0.05), as were lower systolic

blood pressures (p=0.04). Neither lower PaO2 values, nor lower systolic blood

pressures, were found to be associated with depression or PTSD. An episode of

hypoglycemia was associated with anxiety at 12 months (p=0.01), but not

depression (p=0.28), or PTSD (p=0.31).

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Sensitivity Analyses:

Given the potential bias due to the effects of dropouts, we performed

several sensitivity analyses. Under the assumption that all 31 subjects who

consented for ACOS but died before testing (N=22) or were classified as

incapable of test performance (N=9) were impaired (Figure 1), the association

between conservative fluid-management strategy and long-term cognitive

impairment remained significant (N=106, OR=3.48, 95% CI: 1.48, 8.16, p=0.004).

The association also persisted if we assumed that the 50 survivors lost to follow-

up post-consent were all impaired (N=125, OR=2.92, 95% CI: 1.28, 6.61,

p=0.01), were all not impaired (N=125, OR=2.45, 95% CI: 1.14, 5.28, p=0.02), or

were impaired to a similar degree (55% incidence) as the overall cohort of long-

term survivors (N=125, OR=2.24, 95%CI: 1.10, 4.59, p=0.03). The association

also persisted if we assumed that the 25 patients who refused after initially

consenting were all impaired (N=100, OR=2.51, 95% CI: 1.05, 5.97, p=0.04),

were all not impaired (N=100, OR=3.76, 95% CI: 1.62, 8.72, p=0.002), or were

impaired to a similar degree (55% incidence) as the overall cohort of long-term

survivors (N=100, OR=2.78, 95% CI: 1.23, 6.31, p=0.01).

Assuming that survivors with an incomplete cognitive assessment were

not impaired, we found the association between the conservative fluid

management strategy and long-term cognitive impairment remained (N=102,

OR=2.76, 95% CI: 1.22, 6.21, p=0.014); as did the association between lower

PaO2 values and long-term cognitive impairment (N=93, OR=1.36, 95% CI: 1.03,

1.81, p=0.033). Under the assumption that survivors with an incomplete cognitive

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assessment were impaired, we observed an association similar to the unadjusted

association between the conservative-strategy group and long-term cognitive

impairment (N=102, OR=4.09, 95% CI: 1.70, 9.83, p=0.002). The association

between lower PaO2 values and long-term cognitive impairment was no longer

significant (N=93, OR=1.26, 95% CI: 0.95, 1.66, p=0.10).

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References

E1) Clermont G, Kong L, Weissfeld LA, Lave JR, Rubenfeld GD, Robertss MS,

Connors AF, Bernard GR, Thompson BT, Wheeler AP, Angus DC. The effect of

pulmonary artery catheter use on costs and long-term outcomes of acute lung

injury. PLoS ONE 2011; 6(7): e22512.

E2) Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M,

Legall JR, Morris A, Spragg R. The American-European consensus conference

on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial

coordination. Am J Respir Crit Care Med 1994; 149: 818–824

E3) The National Heart, Lung, and Blood Institute Acute Respiratory Distress

Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid management

strategies in acute lung injury. N Engl J Med 2006; 354(24): 2564-75

E4) The National Heart, Lung, and Blood Institute Acute Respiratory Distress

Syndrome (ARDS) Clinical Trials Network. Pulmonary-artery versus central

venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354:

2213-24

E5) Chan PS, Nichol G, Krumholz HM, Spertus JA, Jones PG, Peterson ED,

Rathore SS, Nallamothu BK, for the American Heart Association National

Registry of Cardiopulmonary Resuscitation (NRCPR) Investigators. Racial

differences in survivors after in-hospital cardiac arrest. JAMA 2009; 302(11):

1195-1201

E6) Christie JD, Biester R, Taichman DB, Shull WH, Hansen-Flaschen J, Shea

JA, Hopkins RO. Formation and validation of a telephone battery to assess

Page 57 of 79

For Review O

nly


14

cognitive function in acute respiratory distress syndrome survivors. J Crit Care

2006; 21:125-132

E7) Taichman DB, Christie J, Biester R, Mortensen J, White J, Kaplan S,

Hansen-Flaschen J, Palevsky HI, Elliott CG, Hopkins RO. Validation of a brief

telephone battery for cognitive assessment of patients with pulmonary arterial

hypertension. Respir Res 2005; 6: 39

E8) Mikkelsen ME, Shull WH, Biester RC, Taichman DB, Lynch S, Demissie E,

Hansen-Flaschen J, Christie JD. Cognitive, mood and quality of life impairments

in a select population of ARDS survivors. Respirology 2009; 14: 76-82

E9) Hopkins R, Weaver L, Pope D, Orme J, Bigler E, Larson-Lohr V.

Neuropsychological sequelae and impaired health status in survivors of severe

acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160:50-6

E10) Hopkins RO, Weaver LK, Collingridge D, Parkinson RB, Chan KJ, Orme

JF. Two-year cognitive, emotional, and quality-of-life outcomes in acute

respiratory distress syndrome. Am J Respir Crit Care Med 2005; 171:340-347

E11) Zung WK. A self-rating depression scale. Arch Gen Psych 1965; 12:63-70

E12) Biggs JT, Wylie LT, Ziegler VE. Validity of the Zung self-rating depression

scale. British J Psych 1978; 132: 381-385

E13) Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical

anxiety: psychometric properties. J Cons Clin Psychol 1998; 56:893-7

E14) Weisaeth L. Torture of a Norwegian ship’s crew: the torture, stress

reactions and psychiatric aftereffects. Acta Psychiatr Scand Suppl 1989; 355: 63-

72

Page 58 of 79

For Review O

nly


15

E15) Wechsler D, ed. Wechsler Adult Intelligence Scale, Third edition. San

Antonio: The Psychological Corporation; 1997

E16) Wechsler D. Wechsler Memory Scale. San Antonio: The Psychology

Corporation, 1997

E17) Lezak MD. Neuropsychological Assessment. New York: Oxford University

Press, 1995

E18) Burgess PW, Shallice T. The Hayling and Brixton Tests. London, England:

Thames Valley Test Company Limited, 2007

E19) Heaton RK, Grant I, Matthews CG. Comprehensive norms for an

expanded Halstead-Reitan Battery: demographic corrections, research findings

and clinical applications. Psychological Assessment Resources, Inc., Odessa,

1991

E20) Heaton RK. Comprehensive norms for an expanded Halstead-Reitan

Battery: A supplement for the WAIS-R. Psychological Assessment Resources,

Inc., Odessa, 1994

E21) Hopkins RO, Weaver LK, Chan KJ, Orme JF. Quality of life, emotional, and

cognitive function following acute respiratory distress syndrome. J Int

Neuropsychol Soc 2004; 10:1005-1017

E22) Ingraham LJ, Aiken CB. An empirical approach to determining criteria for

abnormality in test batteries with multiple measures. Neuropsychology 1996;

10:120-124

Page 59 of 79

For Review O

nly


16

E23) Boyd KD, Thomas SJ, Boyd AD. A prospective study of complications of

pulmonary artery catheterizations in 500 consecutive patients. Chest 1983; 84:

245-249

E24) Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A,

Pollmächer T. Cytokine-associated emotional and cognitive disturbances in

humans. Arch Gen Psychiatry 2001; 58: 445-452

E25) Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG. Cytokine and other

immunologic markers in chronic fatigue syndrome and their relation to

neuropsychological factors. Appl Neuropsychol 2001; 8: 51-64

E26) Jones C, Griffiths RD, Slater T, Benjamin KS, Wilson S. Significant

cognitive dysfunction in non-delirious patients identified during and persisting

following critical illness. Intensive Care Med 2006; 32: 923-926

E27) Doblar DD, Hinckle JC, Fay ML, Condon BF. Air embolism associated with

pulmonary artery catheter introducer kit. Anesthesiology 1982; 56: 307-309

E28) Mekontso Dessap A, Boissier F, Leon R, Carreira S, Campo FR, Lemaire

F, Brochard L. Prevalence and prognosis of shunting across patient foramen

ovale during acute respiratory distress syndrome. Crit Care Med 2010; 38(9):

1786-92

E29) Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL,

Shintani AK, Gordon SM, Canonico AE, Dittus RS, Bernard GR, Ely EW.

Delirium as a predictor of long-term cognitive impairment in survivors of critical

illness. Crit Care Med 2010; 38(7): 1513-20

Page 60 of 79

For Review O

nly


17

E30) Van den Boogard M, Schoonhoven L, Evers AW, van der Hoeven JG, van

Achterberg TV, Pickkers P. Delirium in critically ill patients: impact on long-term

health-related quality of life and cognitive functioning. Crit Care Med 2012; 40(1):

112-118

E31) Ngandu T, von Strauss E, Helkala EL, Winblad B, Nissinen A, Tuomilehto

J, Soininen H, Kivipelto M. Education and dementia: what lies behind the

association ? Neurology 2007; 69: 1442-1450

E32) Richards PM, Ruff RM. Motivational effects on neuropsychological

functioning: comparison of depressed versus nondepressed individuals. J

Consult Clin Psychol 1989; 57: 396-402

E33) Buckelew SP, Hannay HJ. Relationships among anxiety, defensiveness,

sex, task difficulty and performance on various neuropsychological tasks.

Percept Mot Skills 1986; 63: 711-718

E34) Hopkins RO, Suchyta MR, Snow GL, Jephson A, Weaver LK, Orme JF.

Blood glucose dysregulation and cognitive outcomes in ARDS survivors. Brain Inj

2010; 24(12): 1478-84

E35) Schoenfeld DA, Bernard GR. Statistical evaluation of ventilator-free days as

an efficacy measure in clinical trials of treatments for acute respiratory distress

syndrome. Crit Care Med 2002; 30: 1772-1777

E36) Milbrandt EB, Angus DC. Bench-to-bedside review: Critical-illness

associated cognitive dysfunction – mechanisms, markers, and emerging

therapeutics. Critical Care 2006; 10: 238

Page 61 of 79

For Review O

nly


18

E37) Mulsant BH, Pollock BG, Kirshner M, Shen C, Dodge H, Ganguli M. Serum

anticholinergic activity in a community-based sample of older adults: relationship

with cognitive performance. Arch Gen Psychiatry 2003; 60: 198 – 203

E38) Hopkins RO, Key CW, Suchyta DO, Weaver LK, Orme JF. Risk factors for

depression and anxiety in survivors of acute respiratory distress syndrome. Gen

Hosp Psych 2010; 32: 147-155

E39) Desai S, Lawa TJ, Needham DM. Long-term complications of critical care.

Crit Care Med 2011; 39(2): 371-379

E40) Davydow DS, Gifford JM, Desai SV, Needham DM, Bienvenu OJ.

Posttraumatic stress disorder in general intensive care unit survivors: a

systematic review. Gen Hosp Psych 2008; 30: 421-434

E41) Davydow DS, Gifford JM, Desai SV, Bienvenu OJ, Needham DM.

Depression in general intensive care unit survivors: a systematic review. Int Care

Med 2009; 35: 796-809

E42) Dowdy DW, Bienvenu OJ, Dinglas V, Mendez-Tellez PA, Sevransky J,

Shanholtz C, Needham DM. Are intensive care factors associated with

depressive symptoms six months after acute lung injury? Crit Care Med 2009;

37: 1702-1707

E43) Dowdy DW, Dinglas V, Mendez-Tellez PA, Bienvenu OJ, Sevransky J,

Dennison CR, Shanholtz C, Needham DM. Intensive care unit hypoglycemia

predicts depression during early recovery from acute lung injury. Crit Care Med

2008; 36: 2726-2733

Page 62 of 79

For Review O

nly


19

E44) Schelling G, Stoll C, Kapfhammer HP, Rothenhausler HB, Krauseneck T,

Durst K, Haller M, Briegel J. The effect of stress doses of hydrocortisone during

septic shock on posttraumatic stress disorder and health-related quality of life in

survivors. Crit Care Med 1999; 27: 2678-2683

E45) Nelson BJ, Weinert CR, Burly CL, Marinelli WA, Gross CR. Intensive care

unit drug use and subsequent quality of life in acute lung injury patients. Crit Care

Med 2000; 28(11): 3626-30

E46) Kapfhammer HP, Rothenhausler HB, Krauseneck T, Stoll C, Schelling G.

Posttraumatic stress disorder and health-related quality of life in long-term

survivors of acute respiratory distress syndrome. Am J Psych 2004; 161(1): 45-

52

E47) Torrance GW, Feeny DH, Furlong WJ, Barr RD, Zhang Y, Wang Q. Multi-

attribute preference functions for a comprehensive health status classification

system: Health utilities index Mark 2. Medical Care 1996; 34(7): 702-722

E48) Maldonado G, Greenland S. Simulation study of confounder-selection

strategies. Amer J of Epid 1993; 138:923-936

E49) Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation

study of the number of events per variable in logistic regression analysis. J Clin

Epidemiol 1996; 49: 1373-1379

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Figure E1. Enrollment and outcomes by fluid-management strategy.

Abbreviations: ACOS=ARDS Cognitive Outcomes Study

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Table E1. Outcomes measured in the neuropsychological test battery and cognitive domain performance at 12 months. Cognitive domains are listed by increasing prevalence of impairment in the 102 long-term ALI survivors.

Cognitive Domain

Instrument

No.

Percentile

Vocabulary *

WAIS-III: Vocabulary E14 98 25 (9 – 50)

Reasoning *

WAIS – III: Similarities E14 98 37 (16 – 63)

Memory † WMS – III: Logical Memory I E15

92 37 (5 – 63)

Verbal Fluency †

Controlled Oral Word Association Test E16

96 19 (4 – 34)

Executive Functioning †

Hayling Sentence Completion Test

(HSCT) E17 76 5 (<1 – 25)

Psychiatric Domain

Instrument

Anxiety

Beck Anxiety Inventory E12 102

Depression

Zung Self-Rating Depression Scale E10-E11 102

Post-traumatic stress disorder

Post-traumatic Stress Syndrome 10-Questions Inventory E13

102

Definition of abbreviation: HSCT=Hayling Sentence Completion Test; WAIS-III=Wechsler Adult Intelligence Scale-III; WMS-III: Wechsler Memory Scale-III. * Domain a priori hypothesized to be resilient to effects of acute lung injury. †

Domain a priori hypothesized to be susceptible to effects of acute lung injury. ‡

The error score of the HSCT was completed in 100 long-term survivors.

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Individual cognitive domain performance expressed as percentiles based on normative data.

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Table E2. Patient characteristics and consent to participate in a study to assess long-term neuropsychological outcomes.

Variable* Consent Rate † p-value Adjusted Odds Ratio

(95% CI) ‡

p-value

Age, years (%) Age < 39 Age 40 – 48 Age 49 – 59 Age ≥ 60

47/156 (30) 65/162 (40) 58/166 (35) 43/171 (25)

0.02

Reference

1.59 (0.93 – 2.69) 1.28 (0.75 – 2.18) 1.23 (0.70 – 2.19)

Reference

0.09 0.37 0.47

Gender (%) Female sex Male sex

114/308 (37) 99/347 (28)

0.02

Reference 0.75 (0.52 – 1.11)

Reference

0.15

Race or ethnic group (%) White non-Hispanic Black non-Hispanic Hispanic § Other §

166/446 (37) 34/136 (25) 12/60 (20)

1/13 (8)

0.001

Reference

0.73 (0.44 – 1.22) 0.55 (0.26 – 1.13)

Reference 0.23 0.10

United States geographic region (%) Northeast Southeast Southwest Midwest West

49/128 (38) 70/192 (36) 22/124 (18) 32/83 (38)

40/128 (31)

0.001

Reference 1.78 (0.90 – 3.55) 0.64 (0.32 – 1.25) 1.28 (0.74 – 2.21) 1.62 (0.90 – 2.93)

Reference

0.10 0.19 0.37 0.11

* Sociodemographic and hospital-level information in those 655 subjects who consented to long-term follow-up as part of EA-PAC (E1). Age was categorized into quartiles based on the observed distribution. † Of 442 subjects who consented to EA-PAC, but not ACOS, 194 died between EA-PAC consent and completion of long-term follow-up, 55 were

ineligible as the time window to be tested had elapsed due to the regulatory halt, 48 declined, and the remaining 145 were categorized as “not consented.”

‡ Adjusted for each variable and whether patient died during long-term follow-up after excluding the 55 ineligible subjects.

§ Hispanic and other race/ethnicity were collapsed into one group in the multivariable logistic regression model.

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Table E3. Characteristics of long-term survivors with complete cognitive testing, by fluid-management strategy.

Liberal (N=37)

Conservative (N=38)

p-value

Age, years 53 (43 – 60) 50 (47 – 56) 0.75

Male sex (%) 43 42 0.92

Race or ethnic group (%) White non-Hispanic Black non-Hispanic Hispanic

92 8 0

89 8 3

1.00


12 (12 – 16) 12 (12 – 16) 0.43

Time from enrollment to testing, months

13 (12 – 13) 12 (12 – 14) 0.64


12 (11 – 13) 12 (11 – 13) 0.97

Previously Tested 24 37 0.24

Primary lung injury (%) Pneumonia Sepsis Aspiration Trauma Multiple transfusions Other

30 30 11 5 5

19

42 18 16 16 3 5

0.20

Coexisting conditions (%)*

Diabetes HIV infection or AIDS Cirrhosis Solid tumors Leukemia Lymphoma Immunosuppression

16 0 5 0 0 5 8

19 0 3 3 3 0 11

0.76

– 1.00 1.00 1.00 0.49 1.00

Medical ICU (%) 59 53 0.87

APACHE III †

90 (64 – 107) 65 (58 – 89) 0.04


Mean arterial pressure, mm Hg

* 74 (66 – 84) 77 (65 – 86) 0.68

Met shock criteria at baseline (%) 46 39 0.57

Vasopressor use at baseline (%) 43 32 0.30

Pre-randomization fluid balance, mL

†

1869 (522 – 5564)

1261 (450 – 3744)

0.29

PaO2:FiO2 ‡ 120 (87 – 162) 124 (80 – 180) 0.61

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PaO2

¶ 80 (67 – 105) 82 (67 – 97) 0.81


Definition of abbreviation: HIV=human immunodeficiency virus; AIDS=acquired immunodeficiency syndrome; ICU=intensive care unit; APACHE III= Acute Physiologic and Chronic Health Evaluation III scores; PaO2:FiO2=ratio of partial pressure of arterial oxygen to fraction of inspired oxygen. Values expressed as a percentage or median (interquartile range). * Measured in 74 survivors;

† measured in 73 survivors;

‡ measured in 71 survivors;

¶ measured in

72 survivors. Shock at baseline present if mean arterial pressure < 60 at baseline or vasoactive agent administered.

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Table E4. On-study physiologic variables and outcomes of long-term survivors with complete cognitive testing, by fluid-management strategy.

Fluid-Management Strategy

Liberal

(N=37)

Conservative

(N=38) p-value

Hemodynamic variables

Systolic Blood Pressure (mm Hg) * 108 (102 – 114) 102 (96 – 112) 0.11


† 4.8 (4.2 – 5.5) 4.2 (3.3 – 4.7) 0.06

CVP (mm Hg) 12.0 (10.4 – 13.8) 9.4 (6.6 – 11) <0.001

CVP < 8 mm Hg (1st quartile) (%)

CVP 8 – 12 mm Hg

CVP > 12 mm Hg (4th quartile)

16

43

40

37

50

13

0.015

Shock ‡

(%)

Vasopressor use (%)

Ineffective circulation (%)

27

19

16

34

32

8

0.50

0.21

0.31

Fluid balance (cumulative over 7 days,

mL) 1659

(-4236 – 6244) -2706

(-7970 – -336) 0.02


PaO2:FiO2 158 (128 – 191) 156 (133 – 191) 0.60

Oxygenation index 7.50 (5.11 – 10.3) 7.30 (5.16 – 10.05) 0.94

PaO2 79 (70 – 97) 72 (68 – 84) 0.14

PaCO2 43 (35 – 46) 42 (36 – 48) 0.59

PEEP 7 (6.2 – 8.4) 6.9 (5 – 8) 0.39

Oxygen saturation (%) 95 (92.8 – 96.6) 94.5 (92.7 – 96) 0.54

pH 7.41 (7.37 – 7.44) 7.44 (7.40 – 7.45) 0.01


Duration of mechanical ventilation

(days) 8.5 (4.5 – 12) 6 (4 – 9) 0.04

Glasgow coma scale ‡ 11 (11 – 12) 12 (10 – 14) 0.59

Renal and metabolic variables

Sodium 140 (139 – 143) 142 (139 – 144) 0.32

Blood urea nitrogen (mg/dL) 17.8 (15.7 – 31.6) 22.4 (17.0 – 32.8) 0.32

Creatinine (mg/dl) 0.98 (0.77 – 1.16) 0.92 (0.68 – 1.24) 0.63

Bicarbonate (mmol/L) 25.8 (24.0 – 28.9) 27.4 (23.0 – 32.2) 0.15

Glucose (mg/dL) 118 (110 – 144) 121 (108 – 134) 0.44

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Dialysis to day 60 (%) 0 5 0.49

Therapy (cumulative dose)

Furosemide (mg) 120 (60 – 260) 340 (160 – 620) <0.001

Corticosteroids (mg of

Methylprednisolone) 0 (0 – 96) 0 (0 – 144) 0.38

Organ-Failure-Free Days

Days 1 to 7

Cardiovascular failure 6 (5 – 7) 6 (4 – 7) 0.24

CNS failure 7 (0 – 7) 7 (0 – 7) 0.30

Renal failure 7 (7 – 7) 7 (7 – 7) 0.81

Days 1 to 28


CNS failure 28 (21 – 28) 28 (21 – 28) 0.29

Renal failure 28 (28 – 28) 28 (28 – 28) 0.71

Psychiatric impairment, 12 months post-

hospital discharge (%) 65 76 0.28

Definition of abbreviation: CVP=central venous pressure; ICU=intensive care unit; PaO2:FiO2=ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; PaO2=partial pressure of arterial oxygen; PaCO2=partial pressure of arterial carbon dioxide; PEEP=positive end-expiratory pressure; ICU=intensive care unit; CNS=central nervous system. Values expressed as a frequency (percent) or median (interquartile range). On-study variables were summarized at the subject level as means to account for influential observations. With the exception of systolic blood pressure measurements, values were measured and recorded daily (measure closest to 8 am) during the study. * Lowest systolic blood pressure was recorded daily to determine the cardiovascular component of the Brussels organ failure score. †

Cardiac index was measured in 39 survivors (20 in the liberal-strategy group and 19 in the conservative-strategy group). ‡

Shock defined as mean arterial pressure < 60 or vasoactive agent use (assignment to FACTT

protocol cells 1 or 2) at any time during FACTT (E3). Ineffective circulation was defined as a cardiac index of less than 2.5 liters per minute per square meter in the PAC group and as cold, mottled skin with a capillary re-filling time of greater than 2 seconds in the non-PAC group (E3).

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Table E5. Associations with long-term cognitive impairment in ALI survivors. Cognitive impairment at the subject level was defined as impairment in memory, verbal fluency, and/or executive function in the 75 subjects who completed tests in each of these domains.

Cognitive Impairment

Not Impaired

(n=34) Impaired (n=41)

p-value

Baseline characteristics

Age, years 50 (43 – 58) 51 (45 – 60) 0.51

Male sex (%) 32 51 0.10


91 6 3

90 10 0

0.53


13 (12 – 16) 12 (12 – 15) 0.36

Hospital length of stay prior to enrollment, days

2 (1 – 3) 3 (1 – 4) 0.22

ARDS at enrollment 88 90 1.00

Primary lung injury (%) Pneumonia Sepsis Aspiration Trauma Multiple transfusions Other

24 29 9 12 6 21

46 20 17 10 2 5

0.10

Coexisting conditions (%) Diabetes HIV infection or AIDS Cirrhosis Solid tumors Leukemia Lymphoma Immunosuppression Heavy alcohol use Cerebrovascular disease

18 0 0 0 3 6 9 3 0

17 0 7 2 0 0

10 13 2

1.00

– 0.25 1.00 0.45 0.20 1.00 0.21 1.00

Medical ICU (%) 59 54 0.56

APACHE III

87 (60 – 106) 72 (60 – 94) 0.42


Mean arterial pressure, mm Hg

80 (72 – 87) 72 (62 – 84) 0.12

Met shock criteria * (%) 44 41 0.82

Vasopressor use (%) 44 32 0.27

Pre-randomization fluid balance, mL

2109 (450 – 5189)

1437 (679 – 3744)

0.44

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PaO2:FiO2 122 (76 – 170) 126 (87 – 166) 0.75

PaO2 81 (66 – 104) 81 (67 – 99) 0.97



On-study variables

Hemodynamic variables

Systolic Blood Pressure (mm Hg) † 108 (102 – 113) 104 (96 – 112) 0.32


‡ 4.5 (3.8 – 5.3) 4.5 (3.7 – 5.0) 0.49

CVP (mm Hg) 11.0 (8.7 – 12.7) 9.7 (6.6 – 12.0) 0.038

CVP < 8 mm Hg (1st quartile) (%)

CVP 8 – 12 mm Hg CVP > 12 mm Hg (4

th quartile)

12 53 35

39 41.5 19.5

0.02

Shock * (%) Vasopressor use Ineffective circulation *

32 26 9

29 24 15

0.77 0.84 0.50

Fluid balance (cumulative over 7 days, mL)

-2352 (-5236 – 3598)

-503 (-4236 – 5698)

0.24


PaO2:FiO2§ 152 (132 – 192) 157 (133 – 190) 0.63

Oxygenation index 7.38 (4.55 – 10.42) 7.67 (5.97 – 10.02) 0.57

PaO2 86 (70 – 98) 71 (67 – 80) 0.02

PaO2 < 68 (1st quartile) (%)

PaO2 68 – 93 PaO2 > 93 (4

th quartile)

13 50 37

27 65 8

0.014

PaCO2 43 (36 – 47) 42 (35 – 48) 0.96

PEEP 7 (5 – 9) 7 (6 – 7.8) 0.84

Oxygen saturation (%) 95.1 (93.3 – 96.8) 94.2 (92.6 – 95.8) 0.10

pH 7.42 (7.38 – 7.44) 7.43 (7.40 – 7.45) 0.27


Duration of mechanical ventilation (days)

8 (4 – 11) 6 (4 – 9) 0.43

Glasgow coma scale 11 (11 – 13) 12 (11 – 14) 0.66

Renal and metabolic variables

Sodium 141 (139 – 144) 142 (139 – 144) 0.49

Blood urea nitrogen (mg/dL) 20.6 (15.7 – 32.8) 19.8 (15.7 – 31.6) 0.94

Creatinine (mg/dl) 0.98 (0.69 – 1.24) 0.86 (0.70 – 1.14) 0.36

Bicarbonate (mmol/L) 26.6 (24.1 – 29.6) 25.9 (23.0 – 30.4) 0.95

Glucose (mg/dL) 124 (110 – 138) 118 (108 – 135) 0.74

Hypoglycemia, < 60 mg/dL (%) 6 12 0.45

Hyperglycemia, > 180 mg/dL (%) 26 37 0.35

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Dialysis to day 60 (%) 0 5 0.50

Therapy (cumulative dose)

Furosemide (mg) 200 (120 – 420) 200 (80 – 440) 0.62

Corticosteroids (mg of Methylprednisolone)

0 (0 – 144) 0 (0 – 136) 0.80

Organ-Failure-Free Days

Days 1 to 7


CNS failure 7 (0 – 7) 7 (0 – 7) 0.82

Renal failure 7 (7 – 7) 7 (7 – 7) 0.25

Days 1 to 28


CNS failure 28 (21 – 28) 28 (21 – 28) 0.59

Renal failure 28 (28 – 28) 28 (28 – 28) 0.79

Time from enrollment to testing, months

13 (12 – 13) 12 (12 – 14) 0.53


12 (11 – 13) 12 (11 – 13) 0.51

Previously Tested (%) 38 24 0.20 Neuropsychiatric impairment, 1 year (%)

59 80 0.04

Definition of abbreviation: HIV=human immunodeficiency virus; AIDS=acquired immunodeficiency syndrome;ARDS=acute respiratory distress syndrome (PaO2:FiO2 ≤ 200); ICU=intensive care unit; APACHE III= Acute Physiologic and Chronic Health Evaluation III scores; PaO2:FiO2=ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; CVP=central venous pressure; ICU=intensive care unit; PaO2=partial pressure of arterial oxygen; PaCO2=partial pressure of arterial carbon dioxide; PEEP=positive end-expiratory pressure; ICU=intensive care unit; CNS=central nervous system. Values expressed as a frequency (percent) or median (interquartile range). On-study variables were summarized at the subject level as means to account for influential observations. With the exception of systolic blood pressure measurements, values were measured and recorded daily (measure closest to 8 am) during the study. Hypo- and hyperglycemia were defined as any episode of serum glucose < 60 mg/dL or > 180 mg/dL, respectively, during the hospitalization. * Shock defined as mean arterial pressure < 60 or vasoactive agent use (assignment to FACTT protocol cells 1 or 2) at any time during FACTT (E3). Ineffective circulation was defined as a cardiac index of less than 2.5 liters per minute per square meter in the PAC group and as cold, mottled skin with a capillary re-filling time of greater than 2 seconds in the non-PAC group (E4). †

Lowest systolic blood pressure was recorded daily to determine the cardiovascular component of the Brussels organ failure score. ‡

Cardiac index was measured in 39 survivors (20 in the liberal-strategy group and 19 in the conservative-strategy group). §

Using mean PaO2:FiO2 on-study to categorize subjects as ALI or ARDS, 77% met criteria for

ARDS (PaO2:FiO2 ≤ 200), 23% met criteria for ALI, and there was no association with cognitive impairment (p=0.82).

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Table E6. Association between identified candidate risk factors and long-term cognitive impairment, adjusted for each potential covariate, one covariate at-a-time.* Cognitive impairment at the subject level was defined as impairment in memory, verbal fluency, and/or executive function in the 75 subjects who completed tests in each of these domains.

Hypoxemia Logistic Regression Model

Total N in Model

Odds Ratio (95% CI) p-value

PaO2 (base model) † ‡ § 67 1.56 (1.09 – 2.24) 0.015 Adjusted for: Age

67 1.57 (1.08 – 2.28) 0.017

Gender 67 1.53 (1.07 – 2.20) 0.021 Race 67 1.52 (1.05 – 2.19) 0.026 Level of education 67 1.57 (1.09 – 2.25) 0.015 Time to testing 67 1.56 (1.09 – 2.24) 0.015 Psychiatric impairment 67 1.49 (1.03 – 2.16) 0.033 Mean arterial pressure (baseline) 66 1.51 (1.05 – 2.18) 0.028 Vasopressor use (baseline) 67 1.57 (1.06 – 2.32) 0.023 Vasopressor use ‡ 67 1.68 (1.14 – 2.49) 0.009 Central venous pressure ‡ 67 1.60 (1.11 – 2.32) 0.012 Primary lung injury 67 1.51 (1.01 – 2.26) 0.043 Conservative fluid-management 67 1.48 (1.02 – 2.15) 0.037

Fluid-Management Logistic Regression Model

Total N in Model

Odds Ratio (95% CI) p-value

Conservative fluid-management strategy (base model)

75 4.03 (1.53 – 10.59) 0.005

Adjusted for: Age

75 4.15 (1.56 – 11.00) 0.004

Gender 75 4.36 (1.60 – 11.85) 0.004 Race 75 4.47 (1.66 – 12.01) 0.003 History of heavy alcohol use † 72 5.46 (1.92 – 15.53) 0.001 History of cerebrovascular disease † 73 4.78 (1.77 – 12.91) 0.002 Level of education 75 4.45 (1.64 – 12.07) 0.003 Time to testing 75 4.00 (1.52 – 10.53) 0.005 Psychiatric impairment 75 3.84 (1.43 – 10.31) 0.008 Mean arterial pressure (baseline) † 74 4.88 (1.76 – 13.58) 0.002 Vasopressor use (baseline) 75 3.89 (1.47 – 10.28) 0.006 Vasopressor use ‡ 75 4.28 (1.59 – 11.51) 0.004 Central venous pressure ‡ 75 3.40 (1.21 – 9.58) 0.021 Primary lung injury 75 3.51 (1.24 – 9.94) 0.018 PaO2

† ‡ 67 3.35 (1.16 – 9.70) 0.026

* Potential covariates were included in the multivariable logistic regression models if the variable was found to be associated with cognitive impairment in the univariate analyses (p<0.20) and to assess whether inclusion of the potential covariate altered the odds ratio for the candidate risk factor by > 10%. Age, race, level of education, and time from enrollment to testing were forced into the models. See methods for details. † History of heavy alcohol use was missing in 3 survivors; history of cerebrovascular disease was missing in 2 survivors; baseline mean arterial pressure missing in 1 survivor. On-study PaO2 measurements were missing in 8 survivors.

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‡ On-study values. Daily measurements on-study were summarized, at the subject level, as means. § For each 10-unit decrease in partial pressure of oxygen in arterial blood (PaO2), odds ratio for the development of cognitive impairment increases by 1.56 in the base model.

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Figure E1.

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Conservative Fluid-Management Strategy

N=503


N=322


N=333

Tested at 12 months §

N=56 Tested at 12 months

§

N=46

Liberal Fluid-Management Strategy N=498



Deceased: N=13 Incarcerated: N=1 Incapable

†: N=5

Declined: N=9 Missing: N=1 Lost to follow-up

†: N=26

Total: N=55‡

Deceased: N=91 Ineligible

†: N=31

Declined: N=26 Unable to be contacted: N=74 Total: N=222


N=37


N=38

Deceased: N=9 Incarcerated: N=1 Incapable

†: N=4

No contact information: N=1 No telephone service: N=1 Declined: N=16 Lost to follow-up

†: N=24

Total: N=56‡

Deceased: N=103 Ineligible

†: N=24

Declined: N=22 Unable to be contacted: N=71 Total: N=220

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* Of 1001 FACTT subjects who underwent randomization, 227 were ineligible for long-term

follow-up as part of EA-PAC as no regulatory approval was in place and 119 refused consent (21). †

Subjects were categorized as ineligible if the time window to be tested had elapsed due to the regulatory halt, as incapable if self-determined or determined by a surrogate to be physically or mentally incapable of telephone-based neuropsychological testing, and as lost to follow-up if consent was obtained but the subject was not tested. ‡

Reasons for not being testing, in those who consented, are categorized initially as causes outside of investigator control and then as causes which may be potentially remediable by future investigators. §

Of 52 subjects tested at 2 months (20 from liberal arm and 32 from conservative arm), 32 were re-tested at 12 months. Subjects were not required to undergo testing at 2 months to be tested at 12 months.

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