Depressive Symptoms and Impaired Physical Function
after Acute Lung Injury
A 2-Year Longitudinal Study
Oscar J. Bienvenu1,2, Elizabeth Colantuoni3,4, Pedro A. Mendez-Tellez3, Victor D. Dinglas5,
Carl Shanholtz6, Nadia Husain4, Cheryl R. Dennison7, Margaret S. Herridge8, Peter J. Pronovost3,9,
and Dale M. Needham5,10
1Department of Psychiatry and Behavioral Sciences,3Department of Anesthesiology and Critical Care Medicine,5Outcomes After Critical Illness
and Surgery (OACIS) Group, Division of Pulmonary and Critical Care Medicine, and10Department of Physical Medicine and Rehabilitation, Johns
Hopkins University School of Medicine, Baltimore, Maryland;2Department of Mental Health,4Department of Biostatistics, and9Department
of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland;6Division of Pulmonary
and Critical Care Medicine, University of Maryland, Baltimore, Maryland;7Johns Hopkins University School of Nursing, Baltimore, Maryland;
and8Inter-Departmental Division of Critical Care, University of Toronto School of Medicine, Toronto, Ontario, Canada
Rationale: Survivors of acute lung injury (ALI) frequently have sub-
stantial depressive symptoms and physical impairment, but the lon-
gitudinal epidemiology of these conditions remains unclear.
sive symptoms and physical impairment after ALI, as well as risk fac-
tors for these conditions.
Methods: This prospective, longitudinal cohort study recruited
patients from 13 intensive care units (ICUs) in four hospitals, with
follow-up 3, 6, 12, and 24 months after ALI. The outcomes were
or equal to 8 (“depressive symptoms”) in patients without a history
of depression before ALI, and two or more dependencies in instru-
mental activities of daily living (“impaired physical function”) in
patients without baseline impairment.
Measurements and Main Results: During 2-year follow-up of 186 ALI
survivors, the cumulative incidences of depressive symptoms and im-
incidence by 3-month follow-up; modal durations were greater than
21 months for each outcome. Risk factors for incident depressive
symptoms were education 12 years or less, baseline disability or un-
employment, higher baseline medical comorbidity, and lower blood
were longer ICU stay and prior depressive symptoms.
Conclusions: Incident depressive symptoms and impaired physical
function are common and long-lasting during the first 2 years after
ALI. Interventions targeting potentially modifiablerisk factors (e.g.,
substantial depressive symptoms in early recovery) should be eval-
uated to improve ALI survivors’ long-term outcomes.
Keywords: depression; recovery of function; critical illness; critical care;
acute lung injury
Survivors of acute lung injury/acute respiratory distress syn-
drome (ALI) and other critical illnesses frequently havesubstan-
associated decrements in quality of life (1–9). At present, there
are gaps in knowledge regarding the incidence and duration of
these conditions in ALI survivors, as well as their risk factors.
Our objective was to longitudinally examine the incidence and
duration of depressive symptoms and impaired physical function-
ing in the first 2 years after ALI. We also sought to determine risk
factors for each of these conditions, to help inform future preven-
tion and treatment efforts. Some of the results of this study have
been reported previously in the form of an abstract (10).
Mechanically ventilated patients with ALI (11) were enrolled consecu-
tively in a prospective cohort study involving 13 intensive care units
(ICUs) at four hospitals in Baltimore, Maryland, between October
2004 and October 2007 (12). To avoid inclusion of patients with primary
neurologic disease or head trauma, neurologic specialty ICUs at the
participating hospitals were excluded. Key exclusion criteria were (1)
preexisting illness with a life expectancy of less than 6 months, (2) pre-
existing cognitive impairment or communication/language barriers, (3)
no fixed address, (4) transfer to a study site ICU with preexisting ALI
of greater than 24 hours’ duration, (5) more than 5 days of mechanical
(Received in original form March 21, 2011; accepted in final form November 29, 2011)
Supported by National Institutes of Health Acute Lung Injury SCCOR Grant P050
HL73994. O.J.B. was supported by a Mentored Patient-Oriented Research Career
Development Award (K23 MH64543). D.M.N. was supported by a Clinician-
Scientist Award from theCanadian Institutes of Health Research. P.J.P. was supported
by a Mid-career Investigator Award in Patient-Oriented Research (K24 HL88551).
The funding bodies had no role in the study design, data collection, analysis, inter-
pretation, writing, or decision to submit the manuscript for publication.
Author Contributions: O.J.B., E.C., P.A.M.T., C.S., C.R.D., M.S.H., P.J.P., and D.M.N.
contributed to the conception and design of this study. P.A.M.T., V.D.D., C.S., C.R.D.,
P.J.P., and D.M.N., contributed to the acquisition of data. O.J.B., E.C., P.A.M.T.,
V.D.D., N.H., M.S.H., P.J.P., and D.M.N. contributed to the analysis and interpreta-
tion of data. O.J.B. and E.C. drafted the manuscript, and all authors critically revised
it for important intellectual content and approved the final version to be submitted.
Correspondence and requests for reprints should be addressed to Oscar J. Bienvenu,
M.D., Ph.D., 600 North Wolfe St., Meyer 115, Baltimore, MD 21287. E-mail:
Am J Respir Crit Care Med
Copyright ª 2012 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201103-0503OC on December 8, 2011
Internet address: www.atsjournals.org
Vol 185, Iss. 5, pp 517–524, Mar 1, 2012
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Survivors of acute lung injury (ALI) frequently have sub-
stantial depressive symptoms and impaired physical function
after hospital discharge, but the longitudinal epidemiology
and risk factors for these conditions have not been fully
What This Study Adds to the Field
This prospective, longitudinal cohort study shows that, in
the first 2 years after ALI, new-onset depressive symptoms
and new-onset physical impairment are common and long
lasting (cumulative incidences were 40 and 66%, respec-
tively, and modal durations were greater than 21 months for
each outcome). Depressive symptoms were a significant and
potentially modifiable risk factor for later-onset physical
ventilation before ALI, and (6) a physician order for no escalation of ICU
care (e.g., no vasopressors or hemodialysis) at the time of study eligibility.
Informed consent was obtained after patients regainedcapacity, typ-
ically around the time of hospital discharge (13). Follow-up occurred at
3, 6, 12, and 24 months after the onset of ALI. The institutional review
boards of Johns Hopkins University and all participating study sites
approved this research.
Definition of Depressive Symptoms Incidence, Remission,
To ascertain patients’ baseline mood status, we reviewed the medical
records related to the ALI hospitalization for evidence of any preexisting
“depression” diagnosis. At each follow-up time point, depressive symp-
toms were measured using the depression subscale of the Hospital Anxiety
and Depression (HAD) Scale (14, 15). “Incident depressive symptoms”
were defined as having an HAD depression score greater than or equal to
8 at any follow-up, in the absence of baseline depression. The HAD de-
pression subscale was designed to evaluate depressive states in patients
with general medical illnesses, as it primarily measures anhedonia rather
than neurovegetative symptoms (e.g., diminished energy) that could be
symptomatic of general medical conditions rather than depressive states.
The HAD depression subscale has been validated as a screening tool for
depressive states in many medical and general population settings, with an
optimal threshold of 8 or more in most studies, corresponding to a sensi-
tivity and specificity of approximately 80% across studies (15); the crite-
rion standards for these studies were depression-related psychiatric
diagnoses—which varied by study but included major depressive disorder
and/or dysthymia or adjustment disorder—measured using structured or
semistructured (clinical) diagnostic interviews (15).
We were also interested in the course of incident depressive symp-
toms after ALI. We defined remission as having an HAD depression
score less than 8 at any follow-up time point after incident depressive
symptoms, along with a statistically reliable decrease in score using
the Reliable Change Index (RCI) (16). To calculate the RCI, we used
standard deviation (SD) and test–retest reliability estimates from pre-
vious studies (17, 18). To have a statistically significant change, patients
had to have a difference in scores of greater than or equal to 4; this
threshold is substantially larger than the minimal clinically important
difference (1.5 points) established for this measure (19). We defined
recurrence as having an HAD depression score greater than or equal to
8 at any follow-up after remission, along with an increase in scores of
greater than or equal to 4.
Definition of Impaired Physical Function Incidence,
Remission, and Recurrence
We chose dependencies in instrumental activities of daily living (IADLs)
(20) as our measure of physical impairment, as IADL dependencies
are reflective of more subtle dysfunction than ADL dependencies (20),
and the former are less prone to ceiling effects in predicting the ability to
live independently (21). IADL dependencies (i.e., difficulty with using the
telephone, shopping, preparing meals, doing housework, laundering
clothes, transportation, taking medications, and managing money) are
strongly associated with other physical performance measures, such as gait
velocity, balance function, grip strength, and chair stand time (22). In the
current study, numbers of IADL dependencies were strongly related to 36-
item Short-Form health survey (SF-36v2) (23) Physical Component scores
at each follow-up, with Spearman rank correlations ranging between 20.64
and 20.71. We chose a threshold of two or more IADL dependencies, as
used elsewhere (24, 25), to help ensure that the measured dysfunction
would be meaningful to patients and caregivers. Patients were considered
to have “incident impaired physical function” if they did not have baseline
(pre-ALI) impairment (assessed retrospectively around hospital discharge,
using the IADL instrument) but had two or more dependencies at any
follow-up. Patients self-reported their IADL dependencies in 86% of the
baseline assessments and in 96% of the follow-up assessments; their closest
available proxies reported on the remainder.
We were also interested in the course of incident impaired physical
function after ALI. We defined remission as having fewer than two
IADL dependencies at any follow-up time point after incident impaired
physical function, along with a statistically reliable decrease in number
of dependencies. To calculate the RCI, we used SD and test–retest
reliability estimates from previous studies (26, 27). To have a statisti-
cally significant change, patients had to have a difference in number of
dependencies of two or more. We defined recurrence as having two or
more IADL dependencies at any follow-up after remission, along with
an increase in number of dependencies of two or more.
Risk Factors for Incident Depressive Symptoms and Incident
Impaired Physical Function
We conducted separate analyses of risk factors for new-onset depressive
symptoms and new-onset physical impairment after ALI. Potential risk
factors were selected in part based on findings from previous studies
of ALI survivors (28, 29); some predictors of depressive symptoms at
3- and 6-month follow-ups were reported previously (30, 31).
status (disabled or unemployed vs. employed), body mass index, and the
Charlson Comorbidity Index (32). Critical illness/ICU variables included
organ failure (maximum Sequential Organ Failure Assessment [SOFA]
 score), low blood glucose (operationalized using the mean daily min-
imum value), medication doses (mean daily benzodiazepine [midazolam-
equivalent] and corticosteroid [prednisone-equivalent] doses), surgical
(vs. medical) ICU admission, length of stay, delirium (proportion of ICU
study days with a positive Confusion Assessment Method for the ICU 
assessment), and deep sedation (proportion of ICU study days with Rich-
mond Agitation-Sedation Scale  score of 24 or 25). We also examined
prior depressive symptoms as a risk factor for new-onset physical impair-
ment and prior impaired physical function as a risk factor for new-onset
Cumulative incidence functions for depressive symptoms and impaired
physical function were generated separately using the Kaplan-Meier es-
timator. These discrete-time survival data were analyzed using logistic
regression models, which allowed for a flexible baseline hazard function
(with indicator variables for the 6-, 12-, and 24-mo follow-ups) to exam-
ine associations with potential risk factors (36). Multivariable models
included all potential risk factors that had a bivariate association (P <
0.10) with the outcome variable.
Our primary analyses involved assumptions about depressive symp-
HAD depression scores were missing, but SF-36v2 (23) Mental Health
domain scores were available, depressive symptoms were deemed pres-
ent if the Mental Health domain score was less than or equal to 69. This
threshold was derived from a receiver operating characteristic analysis
with the HAD depression score threshold (> 8) as the criterion vari-
able, using data from the current study (area under the curve ¼ 0.84).
Using this procedure, we replaced 4, 3, 4, and 1 missing HAD depres-
sion scores at 3-, 6-, 12-, and 24-mo follow-ups, respectively. Otherwise,
when patients had missing values for particular follow-ups, we assumed
that their prior depressive symptoms or physical function status
remained constant. Thus, our incidence estimates may be conservative,
because we assume that subjects remain free of depressive symptoms
or impaired physical function for longer than may be the case. To
evaluate the potential for bias with this missing data strategy, we per-
formed complete case analyses (i.e., only analyzing data from patients
with complete data at all follow-ups) as sensitivity analyses. Results of
the complete case analyses were similar to those of the primary anal-
yses; hence, we only present results of the primary analyses. Statistical
significance was defined as P , 0.05 (two-sided). All analyses were
performed using R statistical software (37).
Of 520 eligible patients with ALI, 274 (53%) survived their acute
hospitalizationandwere eligible forconsent. Additional patients
died, declined, or could not be contacted for consent, leaving 196
consenting survivors at 3 months after ALI (Figure 1). Of these
196 participants, 186 (95%) had at least one follow-up visit with
complete HAD and IADL data. Thirty-nine of these patients
(21%) had baseline (pre-ALI) depression, and 74 (40%) had
baseline impaired physical function. The point prevalences of
518 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1852012
depressive symptoms and impaired physical function at the four
follow-up time points ranged from 24 to 32% and 43 to 64%,
respectively (Figure 1). At each follow-up, depressive symptoms
and impaired physical function were significantly related to each
other cross-sectionally (Figure 1).
Onset and Duration of Incident Depressive Symptoms and
Incident Impaired Physical Function
During 2-year follow-up after ALI, the cumulative incidence of
depressive symptoms in the 147 patients at risk was 40%, and the
cumulative incidence of impaired physical function in the 112
patients at risk was 66% (Figure 2). Incidence was highest by
the 3-month follow-up and declined thereafter.
The modal durations of incident depressive symptoms and in-
cident impaired physical function were each more than 21
months (the maximum duration possible), with remissions dur-
ing the follow-up period in 39 and 54%, respectively, of those
eligible for remission (i.e., those with incidence before 24-mo
follow-up) and recurrences in 20 and 14%, respectively, of those
with remissions. Of those with incident depressive symptoms,
69% had depressive symptoms at 24-month follow-up; of those
with incident impaired physical function, 58% were impaired at
Figure 3 illustrates individual and mean symptom levels for
patients whose incident conditions remitted or did not remit dur-
ing 2-year follow-up after ALI. In patients whose incident de-
pressive symptoms remitted, the mean HAD depression score
remained approximately 5 throughout the follow-up period; this
score corresponds to the 75th percentile in a large nonclinical
sample of adults (17). In patients whose depressive symptoms
did not remit, the mean HAD depression score remained greater
than or equal to 10; this score corresponds to the 96th percentile
in a large nonclinical sample of adults (17). In patients whose
incident impaired physical function remitted, the mean number
of IADL dependencies remained approximately 1 throughout the
follow-up period. In patients whose impaired physical function
did not remit, the mean number of IADL dependencies remained
greater than or equal to four.
Risk Factors for Incident Depressive Symptoms and Incident
Impaired Physical Function
Table 1 shows the distribution of potential risk factors in the
entire sample (n ¼ 186) and in those without baseline depres-
sion (n ¼ 147, 79%) or baseline impaired physical function (n ¼
112, 60%) who were at risk for these incident conditions.
Potential risk factors that had a bivariate association (P <
0.05) with incident depressive symptoms after ALI were educa-
tion 12 or fewer years, baseline disability or unemployment,
higher baseline medical comorbidity, and lower blood glucose
in the ICU (Table 2). In a multivariable model, only education
12 or fewer years was significantly associated with incident de-
pressive symptoms (odds ratio [OR] ¼ 3.1; 95% confidence
interval [CI], 1.5–6.6).
Potential risk factors that had a bivariate association (P <
0.05) with incident impaired physical function were longer ICU
length of stay and depressive symptoms at last follow-up (Table
2). In a multivariable model (Table 2), only depressive symp-
toms at last follow-up were significantly associated with incident
impaired physical function (OR ¼ 2.7; 95% CI, 1.2–6.0).
In addition to reflecting impaired physical function, IADL de-
pendencies could reflect impaired cognitive function. For example,
as “nonphysical” IADLs (22). To determine whether depression-
related cognitive dysfunction could underlie the relationship
Figure 1. Flow diagram of study participants.aSome patients
had a follow-up visit but did not have complete Hospital
Anxiety and Depression Scale depression score (HADd)
or number of dependencies in instrumental activities of
daily living (IADL) data for the following reasons, respec-
tively (cognitively incapable/physically incapable/other):
At 3 months, 22 did not have complete HADd data
(9/5/8), and 13 did not have complete IADL data (4/4/5).
At 6 months, 13 did not have complete HADd data (5/2/6),
and 5 did not have complete IADL data (0/2/3). At 12
months, 14 did not have complete HADd data (5/4/5),
and 4 did not have complete IADL data (1/3/0). At 24
months, 10 did not have complete HADd data (0/6/4),
and 4 did not did not have complete IADL data (0/2/2).
The proportions with HADd > 8 or IADL > 2 reflect point
prevalences, not incidences. Cross-sectionally, depressive
symptoms and impaired physical function were related,
*P , 0.05 or **P , 0.001.
Bienvenu, Colantuoni, Mendez-Tellez, et al.: Depressive Symptoms and Physical Function after ALI 519
between depressive symptoms at last follow-up and incident im-
paired physical function, we repeated the prior analyses to eval-
uate if depressive symptoms at last follow-up were only associated
with individual nonphysical incident IADL dependencies. The
number of patients with incident IADL dependencies/number
at risk were: using the telephone, 34/175; shopping, 80/133; pre-
paring food, 57/132; housekeeping, 85/121; doing laundry, 67/136;
traveling, 73/143; taking medications, 48/159; and managing
Figure 2. Cumulative incidence of depressive
symptoms or impaired physical function in
the first 2 years after acute lung injury. During
2-year follow-up after acute lung injury, the
cumulative incidence of depressive symptoms
was 40%, and the cumulative incidence of im-
paired physical function was 66%. Incidence
was highest by the 3-month follow-up and de-
Figure 3. Recovery from incident depres-
sive symptoms or impaired physical func-
tion in the first 2 years after acute lung
injury. Thin lines and thick lines indicate
individual and mean trajectories, respec-
tively, for patients whose conditions
remitted (A and C) and did not remit
(B and D) during 2-year follow-up after
acute lung injury. Horizontal dashed lines
indicate thresholds for depressive symp-
toms (A and B) and impaired physical
function (C and D). HAD ¼ Hospital
Anxiety and Depression Scale; IADL ¼
instrumental activities of daily living.
520AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 1852012
money, 62/149. Adjusted ORs and 95% CIs relating depressive
symptoms at last follow-up to incident IADL dependencies were:
using the telephone, 1.7 (0.7–4.1); shopping, 2.1 (1.0–4.2); prepar-
ing food, 3.2 (1.5–6.6); housekeeping, 2.0 (1.0–4.0); doing laundry,
2.0 (1.0–3.9); traveling, 1.8 (0.9–3.8); taking medications, 2.2 (1.0–
4.7); and managing money, 1.5 (0.8–3.1). Thus, the results did not
support the hypothesis that depressive symptoms only precede
nonphysical IADL dependencies (taking medications and manag-
ing money), because preceding depressive symptoms were sig-
nificantly associated with incident dependencies in shopping,
preparing food, housekeeping, and doing laundry, as well as taking
medications; the weakest association was with managing money.
This multisite, prospective longitudinal study of 186 ALI survi-
vors demonstrates that incident depressive symptoms and inci-
dent impaired physical function are common and long-lasting
during the first 2 years after ALI. Our analyses indicate that de-
pressive symptoms are not only relatively persistent in ALI sur-
vivors but also an independent risk factor for subsequent
impairment in physical function. Hence, early identification
and treatment of depressive states should be evaluated as a po-
tential intervention to minimize the suffering and impairment
that affect so many of these patients.
The cumulative 2-year incidences of depressive symptoms and
impaired physical function after ALI were high at 40 and 66%,
additional incident cases throughout the 2-year follow-up period
suggests that events after the ALI hospitalization (e.g., further ill-
ness and hospitalization, and financial and other stressors [38, 39])
contribute to ongoing morbidity for ALI survivors. Importantly,
most survivors with post-ALI incidence of depressive symptoms
or impaired physical functioning were affected at the last follow-
up. The most common pattern was to have incidence by 3-month
follow-up and persistence through the last follow-up. Given that
depressive symptoms and impaired physical function are com-
mon and persistent/recurrent in ALI survivors, comprehensive
and ongoing evaluation, treatment, and rehabilitation of these
patients are necessary (40).
The point prevalences of substantial depressive symptoms in
the current report (24–32% during the first 2 yr post-ALI) are
comparable to those in previous studies of ALI survivors (range
17–43%, median 28% during the first 2 yr post-ALI) (1). These
point prevalences are substantially higher than the 8% point
prevalence of an HAD depression score greater than or equal
to 8 in a large nonclinical sample of adults (17).
We identified several risk factors for incident depressive symp-
ployment, baseline comorbid medical conditions, and lower blood
in the follow-up period (i.e., at 3-mo follow-up) (30, 31). Having 12
or fewer years of education was a particularly strong and indepen-
dent risk factor for incident depressive symptoms in this study.
Lower education and other indicators of low socioeconomic status
are well-established risk factors for depressive illness (41).
We also identified two risk factors for incident physical impair-
ment in ALI survivors: longer ICU length of stay and prior de-
pressive symptoms. Having prior depressive symptoms was a
particularly strong and independent risk factor for incident phys-
ical impairment in this study. Importantly, although a history of
depression is often noted in patients admitted to an ICU, antide-
pressants are often stopped in this setting; starting or restarting
antidepressants and/or psychotherapy early during patient recov-
erymight improve long-termphysical and psychiatric outcomes in
ALI survivors (42).
TABLE 1. POTENTIAL RISK FACTORS FOR INCIDENT DEPRESSIVE SYMPTOMS OR INCIDENT IMPAIRED PHYSICAL FUNCTION IN ACUTE
LUNG INJURY SURVIVORS
Incident Depressive Symptoms Incident Impaired Physical Function
Potential Risk Factors All (n ¼ 186) Case (n ¼ 58) Noncase (n ¼ 89) Case (n ¼ 74) Noncase (n ¼ 38)
Age, yr, mean (SD)
Education < 12 yr†
Disability or unemployment
BMI . 30†
Charlson Comorbidity Index, mean (SD)
Critical illness/ICU factors
Maximum daily SOFA score . 10
Mean daily minimum glucose , 100 mg/dl
Mean daily midazolam equivalent dose . 75 mg
Mean daily prednisone equivalent dose > 50 mg†
Surgical ICU admission
Length of stay, d, mean (SD)
Delirium, proportion of d, mean (SD)
Deep sedation, proportion of d, mean (SD)
Impaired physical function at last follow-up†
Depressive symptoms at last follow-up
30 (52%)30 (35%)*
19 (26%) 4 (10%)k
Definition of abbreviations: BMI ¼ body mass index; ICU ¼ intensive care unit; SD ¼ standard deviation; SOFA ¼ Sequential Organ Failure Assessment.
Those at risk for incident depression or incident impaired physical function were those without baseline depression (n ¼ 147) or baseline impaired physical function
(n ¼ 112), respectively, before acute lung injury.
*0.05 , P < 0.1, derived from discrete time survival logistic regression models.
yn ¼ 9 with missing education data; n ¼ 2 with missing BMI data; n ¼ 1 with missing prednisone equivalent data; n ¼ 3 with missing baseline physical function data.
zP , 0.001, derived from discrete time survival logistic regression models.
xP , 0.01, derived from discrete time survival logistic regression models.
kP , 0.05, derived from discrete time survival logistic regression models.
Bienvenu, Colantuoni, Mendez-Tellez, et al.: Depressive Symptoms and Physical Function after ALI521
Several possible mechanisms may explain why depressive
symptoms are a risk factor for impaired physical function in
ALI survivors. First, depressive symptoms may decrease motiva-
tion for, and reward from, physical activities necessary for recov-
ery or maintenance of functioning (43). This is consistent with
our clinical experience that depressed patients are more difficult
to engage in physical therapy, which is often crucial for recovery
of function (28). Second, depressive symptoms can amplify
symptoms of general medical illnesses (44, 45), and an increased
physical symptom load could negatively affect functioning.
Third, depressive symptoms can affect adherence to medication
regimens (46), which could worsen the course of general med-
ical illnesses. Fourth, depressive symptoms could affect func-
tioning through direct neurobiologic pathways, including
neuroendocrine and inflammatory mechanisms (47). Finally, it
is possible that depressive symptoms negatively influence
patients’ perceptions of what they are able to do; nevertheless,
like others (48), we do not doubt that depression-associated
impairments in functioning are real, based on our clinical expe-
rience with these patients.
There are several potential limitations of this study. First, we
measured depressive symptoms using a well-validated self-
report questionnaire (15), rather than psychiatric diagnoses us-
ing expert clinicians with specialized training to perform semi-
structured interviews and incorporate informant and medical
record data (49). We believe that, given the added burden for
participants, the latter method would have pushed the limits of
feasibility and resulted in substantially higher losses to follow-
up and incomplete data, especially during the first 12 months
when patients were still in early recovery and required three
follow-up assessments. Obtaining psychiatric diagnoses also
would have been logistically difficult, given the need for expert
clinicians to be physically present in patients’ homes or long-
term care facilities (58% of participants required at least one
such visit during 2-yr follow-up).
Second, we used medical records to identify baseline (pre-
ALI) depression, likely a relatively specific, but insensitive,
method that could lead to an overestimate of the incidence of
post-ALI depressive symptoms due to nondetection of baseline
depression. On the other hand, chart review may have detected
depression that had remitted well before ALI, thus potentially
underestimating the incidence of post-ALI depressive symp-
toms. Such potential biases are generally unavoidable, given
the infeasibility of directly assessing patients’ mood status im-
mediately before ALI onset. To examine the validity of our
method, we compared retrospectively ascertained pre-ALI
SF-36v2 Mental Health domain scores in patients with and with-
out baseline depression identified via their medical records. Pre-
ALI Mental Health domain scores were substantially lower
in patients with baseline depression (mean ¼ 52, SD ¼ 23) than
in patients without baseline depression (mean ¼ 72, SD ¼ 23)
(P , 0.001).
Third, we did not account for possible effects of treatment of
depression or impaired physical function. Thus, we may have
missed instances of depressive symptoms or impaired physical
function that occurred and resolved before the first follow-up
or in between follow-ups.
Fourth, although we statistically controlled for several poten-
tial confounders in our analyses of risk factors, residual con-
founding could have influenced the associations detected in
this study. However, because it is not possible to randomize
patients to depressive symptoms, physical impairment, or indeed
many of the potential risk factors we examined, observational
studies provide essential information regarding likely relation-
ships. Given the findings of the current study, it is important
to evaluate interventions for early identification and treatment
TABLE 2. ESTIMATED ODDS RATIOS FOR INCIDENT DEPRESSIVE SYMPTOMS OR INCIDENT IMPAIRED PHYSICAL FUNCTION GIVEN
POTENTIAL RISK FACTORS
Incident Depressive Symptoms Incident Impaired Physical Function
Potential Risk Factors OR (95% CI)P Value OR (95% CI)P Value OR (95% CI)P Value OR (95% CI)P Value
Age (per 10 yr)
Education < 12 yr
Disability or unemployment
BMI . 30
Charlson Comorbidity Index (per point)
Critical illness/ICU factors
Maximum daily SOFA score . 10
Mean daily minimum glucose , 100 mg/dl
Mean daily midazolam equivalent
dose . 75 mg
Mean daily prednisone equivalent
dose > 50 mg
Surgical ICU admission
Length of stay (per d)
Delirium, proportion of days (per 10%)
Deep sedation, proportion of days
Impaired physical function at last follow-up
Depressive symptoms at last follow-up
0.65 (0.34–1.23) 0.18
1.10 (0.98–1.23) 0.10
1.42 (0.74–2.70) 0.28
0.81 (0.42–1.55) 0.511.48 (0.76–2.86) 0.24
1.68 (0.94–3.00)0.08 1.29 (0.67–2.47) 0.44
2.40 (1.11–5.17)0.022.66 (1.17–6.01) 0.02
Definition of abbreviations: BMI ¼ body mass index; CI ¼ confidence interval; ICU ¼ intensive care unit; OR ¼ odds ratio; SOFA ¼ Sequential Organ Failure Assessment.
ORs derived from discrete time survival logistic regression models.
522AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 185 2012
of depressive states as part of a comprehensive post-ICU reha-
bilitation program (40), to determine if such an intervention
would improve patients’ mood states and physical functioning,
as demonstrated previously in populations of elderly depressed
persons (48, 50).
Incident depressive symptoms and incident impaired physical
function are common and long-lasting during the first 2 years af-
terALI. Depressive symptoms are an independent risk factor for
impaired physical function in this population. Hence, early iden-
tification and treatment of depressive states should be evaluated
as a potential intervention to improve ALI survivors’ long-term
Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgment: The authors thank all of the patients who participated in the
study and the dedicated research staff who assisted with the study, including
Feild, Ms. Thelma Harrington, Dr. Praveen Kondreddi, Ms. Frances Magliacane,
Ms. Stacey Murray, Dr. Kim Nguyen, Dr. Susanne Prassl, Dr. Abdulla Damluji,
Ms. Arabela Sampaio, Ms. Kristin Sepulveda, Dr. Shabana Shahid, Dr. Faisal Siddiqi,
and Ms. Michelle Silas.
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