Published ahead of print on November 12, 2004, doi:10.1164/rccm.200406-763OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200406-763OC
Two-Year Cognitive, Emotional, and Quality-of-Life Outcomes in Acute Respiratory Distress SyndromeDepartment of Medicine, Pulmonary and Critical Care Divisions, and Statistical Data Center, LDS Hospital; University of Utah School of Medicine, Salt Lake City; and Psychology Department and Neuroscience Center, Brigham Young University, Provo, Utah; and Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida Correspondence and requests for reprints should be addressed to Ramona O. Hopkins, Ph.D., Critical Care Medicine, LDS Hospital, Eighth Avenue and C Street, Salt Lake City, UT 84602. Email: ldrhopki{at}ihc.com
Acute respiratory distress syndrome (ARDS) has a high mortality and is associated with significant morbidity. Prior outcome studies have focused predominant on short-term outcomes (6–12 months). We assessed longitudinal neurocognitive, emotional, and quality of life in ARDS survivors at hospital discharge, and 1 and 2 years after hospital discharge using neuropsychologic tests and emotional and quality-of-life questionnaires. Neurocognitive sequelae occurred in 73% (54 of 74) of ARDS survivors at hospital discharge, 46% (30 of 66) at 1 year, and 47% (29 of 62) at 2 years. ARDS survivors report moderate to severe depression (16% and 23%) and anxiety (24% and 23%) at 1 and 2 years, respectively. The ARDS survivors had decreased quality of life, with the physical domains improving at 1 year, with no additional change at 2 years. Role emotional, pain, and general health did not change from hospital discharge to 2 years. Mental health improved during the first year and declined at 2 years. ARDS results in significant neurocognitive and emotional morbidity and decreased quality of life that persists at least 2 years after hospital discharge. ARDS can cause significant long-term, brain-related morbidity manifest by neurocognitive impairments and decreased quality of life.
Key Words: ARDS • cognitive outcome • emotional function • quality of life Acute respiratory distress syndrome (ARDS) is a common cause of mortality and morbidity, affecting an estimated 150,000 people per year in the United States (1); however, recent evidence suggests the incidence actually may be higher than first reported (2). Compared with 20 years ago, mortality has decreased from 80% to 30% of ARDS patients (3–5) resulting in approximately 100,000 people who survive ARDS each year in the United States (6). ARDS occurs in response to a variety of physiologic insults, including sepsis, trauma, pneumonia, massive transfusion, and other medical or surgical conditions. Treatment of ARDS requires aggressive supportive care, including positive pressure ventilation (5) and increased oxygen concentrations, which include the risks of barotrauma, oxygen toxicity, and nosocomial infection. ARDS may be a consequence of multiple organ system dysfunction, including the central nervous system (7, 8). Patients who survive ARDS are at risk for physical, emotional, and neurocognitive deficits (9–12) and diminished quality of life (10–15) 6–12 months after hospital discharge. Approximately 33% of general medical intensive care unit (ICU) survivors, some with ARDS, had cognitive impairments (16) 6 months after hospital discharge. In 1999, we reported that a majority of ARDS survivors had neurocognitive impairments, including impaired memory, attention, concentration, mental processing speed, and global intellectual decline 1 year after discharge (10). Since our report of cognitive impairments in ARDS survivors, others have made similar observations (9, 12, 16, 17). The prevalence of neurocognitive impairments varies from 25% (12) to 78% in patients with more severe ARDS (10). Neurocognitive impairments are a major determinant in return to work, work productivity, and life satisfaction after ARDS (12). Even mild cognitive impairments may result in clinically significant problems with driving, money management, and the ability to perform activities of daily living (18–21). Survivors of ARDS have decreased quality of life in the first year after hospital discharge, especially in the physical domains (e.g., physical functioning, bodily pain, role physical) (10, 14, 15). Decreased quality of life has been associated with pulmonary symptoms (15, 21), abnormal pulmonary function (22, 23), muscle wasting and weakness (24), neurocognitive impairments (12), depression (11, 15, 23), anxiety (11), and posttraumatic stress disorder (12). Neurocognitive and emotional function, and quality of life are important because many patients with ARDS survive and exhibit significant morbidity. Prior ARDS outcome studies have focused predominately on short-term outcomes (6–12 months). There are no prospective neurocognitive and emotional outcome studies of ARDS patients beyond 12 months. We previously reported 1-year outcome data in ARDS survivors (11); however, 2-year outcome data have not been reported. The purpose of this longitudinal outcome study was to characterize neurocognitive and emotional function and quality of life 1 year after hospital discharge in a prospectively identified cohort of ARDS survivors. Preliminary data of this study were previously published in abstract form (25).
Patient Selection For this study, patients with ARDS were selected from a randomized clinical trial of higher tidal volume versus lower tidal volume ventilation management (22). Between February 1994 and December 1999, patients were invited to participate in a 2-year outcome study to assess neurocognitive and emotional function and quality of life. A detailed description of the ventilation strategy is available (22). This 2-year outcome study was approved by the LDS Hospital Institutional Review Board and conformed to institutional and federal guidelines for the protection of human subjects. Written informed consent was obtained from subject before hospital discharge, after treatment of ARDS. A total of 120 consecutive patients with ARDS were evaluated for this study; 42 patients died, 3 survivors were excluded (2 with cognitive disability, 1 with Alzheimer's disease), and 1 patient declined the study. Of the 74 ARDS survivors enrolled in the study, 3 died in the first year after hospital discharge from either pulmonary fibrosis/cor pulmonale, liver failure, or diabetic complications. Five survivors declined to return for 1-year follow-up (e.g., busy schedules, not interested), resulting in 66 survivors who completed the 1-year evaluation. Two ARDS survivors died in the second year (bowel obstruction, cardiac failure) and 2 declined to return for the 2-year follow-up, resulting in 62 survivors who completed the 2-year evaluation.
The inclusion criteria for the ventilation study from which our patients were selected were: tracheal intubation, PaO2/FIO2
Assessment of Hypoxemia and Hypotension Continuous mean blood pressure data were automatically collected through the GE-Marquette (Milwaukee, WI) bedside physiologic monitoring system connected to a computer during ventilatory support. Continuous blood pressure was measured from the arterial catheters and were sampled every 2 minutes, and the median value for each 15-minute period was recorded (29). The duration of hypotension events was calculated by adding consecutive measurements (each measurement represents a 15-minute interval) that were more than 60 and less than 50 mm Hg.
Neurocognitive and Emotional Function Neurocognitive sequelae was defined as scores on 2 or more neuropsychologic tests that are greater than 1.5 SD or one test score that is greater than 2 SD below the normative population mean. Our definition of neurocognitive sequelae is similar to previous studies (16, 38, 39). To assess the magnitude of neurocognitive impairment, an overall impairment score was derived using age, sex, and education corrected T scores (mean = 50, SD = 10) (40, 41) by assigning a numeric value of 1 for each SD the T scores were more than 1 SD below the mean and summing the total number of SDs below the mean across all (n = 25) tests. T scores less than or equal to 40 received a score of 0, scores greater than 1 SD (30–39) received a score of 1, scores greater than 2 SD (20–29) received a score of 2, scores greater than 3 SD (10–19) received a score of 3, and scores greater than 4 SD (0–9) received a score of 4, with a range of 0 to 100 (e.g., 4 x 25 = 100). The overall impairment score was used as the primary outcome.
Quality of Life
Statistical Analysis
Primary outcome.
Secondary outcomes. Pearson's correlations between ICU length of stay, Acute Physiologic and Chronic Health Evaluation II scores, duration of intubation, oximetry SaO2 less than 90% and mean blood pressure less than 60 and less than 50 mm Hg, and days on sedative, narcotic, and paralytic medications with neurocognitive scores were performed. Correlations were considered significant at the 0.05 two-sided significance level. Pearson's correlations between 1-year Beck Depression Inventory and Beck Anxiety Inventory scores and neurocognitive scores were performed. Correlations were considered significant at the 0.05 two-sided significance level. Similar to analysis of neurocognitive outcome, the SF-36 data were analyzed using a doubly multivariate RMANOVA to determine if the domain scores of the SF-36 significantly changed over time. Individual domain scores were analyzed using univariate RMANOVA if the overall analysis was significant at the 0.05 two-sided significance level. For individual domain scores that were significant from the univariate RMANOVA at the 0.05 two-sided significance level, pairwise comparisons between hospital discharge and 2-year domain scores and 1-year and 2-year domain scores were performed.
Descriptive statistics and medical data are presented in Table 1. There were 41 females and 33 males, with a mean age of 46 ± 16 years (range 16–81 years), median age (interquartile range) of 46 (35–57) years, and mean education level of 13 ± 2.3 years (range 9–22 years). Excluding patients that died, the follow-up rate was 93% at 1 year and 90% at 2 years. Thirty-one patients (42%) were referred for rehabilitation before hospital discharge: 23 for physical weakness or deconditioning, 4 for limb fractures, and 4 for limb amputations. Nine of these patients (12%) were subsequently identified on the rehabilitation unit as having cognitive impairments and received cognitive rehabilitation. At 2 years, 34% (21 of 62) were working or were full-time students, 34% (21 of 62) were receiving disability payments started after hospital discharge for ARDS, and 32% (20 of 62) were not working or retired. For ARDS survivors who completed the 1-year outcome, 70% (46 of 66) had neurocognitive sequelae at hospital discharge, 46% (30 of 66) at 1 year, and 47% (29 of 62) 2 years after hospital discharge.
At 2 years, intellectual function as measured by the Wechsler Adult Intelligence Test-Revised resulted in a mean Full Scale IQ of 99.7 ± 11.9, suggesting average intellectual functioning in the ARDS survivors. The OPIE premorbid IQ estimate had a mean of 99.3 ± 10.2. The OPIE premorbid IQ was significantly lower than the patients with ARDS measured using the Full Scale IQ at hospital discharge (89.7 versus 99.3; t = 9.75, p  0.001); however, there was no difference between the OPIE and the patients measured Full Scale IQ at 1 year (p = 0.2) or 2 years (p = 0.72). Figure 1 shows the intelligence and memory scores for the ARDS patients.
The Beck Depression Inventory and Beck Anxiety Inventory mean scores at 2 years were 10.4 ± 10.6 (range 0–51) and 10.0 ± 10.1 (range 0–45), respectively, indicating minimal depression and anxiety. However, 23% (n = 14 patients) had scores greater than 16 on the Beck Depression and Beck Anxiety Inventories, indicating moderate to severe symptoms of depression and anxiety.
Primary Outcome
Secondary Outcomes
The duration of hypoxemia measured by the duration of oximetry SaO2 < 90%, correlated with digit span (r = –0.247, p = 0.03), Rey Auditory Verbal Learning Trial 5 (r = –0.197, p = 0.04), and Trail Making Test Part B (r = 0.269, p = 0.01) at hospital discharge, which were in the expected direction. There were no significant correlations between duration of hypoxemia with any neurocognitive scores at 1- and 2-year follow-up. There were no significant correlations between neurocognitive scores and ICU length of stay, Acute Physiologic and Chronic Health Evaluation II scores, duration of intubation, or the number of days the patients received sedative, narcotic, or paralytic medications. Of the 74 subjects, 60% (44 of 74) had at least one 15-minute period with a mean blood pressure less than 60 mm Hg and 12% (9 of 74) less than 50 mm Hg. There were no significant correlations with the mean blood pressure less than 60 mm Hg and any neuropsychologic test score. The mean blood pressure less than 50 mm Hg correlated with memory scores at hospital discharge: Rey-Osterrieth Complex Figure delay recall (r = .375, p = 0.001); Delay Recall Index of the Wechsler Memory Scale-Revised (r = 0.219, p = 0.04); at 1 year with Rey Auditory Verbal Learning Trial 5 (r = 0.258, p = 0.04), and Rey Auditory Verbal Learning Test delay recall (r = 0.320, p = 0.009). There were no significant correlations between neuropsychologic test scores and mean blood pressure less than 50 mm Hg at 2 years. The Beck Depression Inventory correlated with object assembly (r = –0.268, p = 0.04) and the Beck Anxiety Inventory correlated with object assembly (r = –0.354, p = 0.006) at 2 years.
Quality of Life
Our data extend previous findings because we assessed 2-year neurocognitive outcome in a prospectively identified cohort of ARDS survivors. The premorbid estimated IQ of patients with ARDS was significantly lower than their measured IQ at hospital discharge; however, the patients' IQ improved to their premorbid level by 1 year with no additional improvement at 2 years. Seventy percent of our ARDS survivors had neurocognitive sequelae at hospital discharge, 45% at 1 year, and 47% at 2 years. There was no improvement in neurocognitive sequelae from 1 to 2 years. Other studies report neurocognitive impairment prevalence rates of 20 to 35% 1 year after ARDS (9, 12, 16). The neurocognitive impairments at 2 years are similar to those in other ARDS survivors (9, 12, 17) and in medical ICU survivors (16). The 2-year neurocognitive scores of the ARDS survivors with neurocognitive sequelae (  50% of survivors) fell below the 6th percentile of the normal distribution of cognitive function. These ARDS survivors found activities that require executive function, memory, attention, or quick mental processing speed to be very difficult or impossible. The neurocognitive impairments in our patients are similar to those observed in medical ICU survivors (16) after carbon monoxide poisoning (39) and several years after elective coronary artery bypass surgery (38). It is difficult to compare our results with previous findings (9, 12, 16, 17) because our study differs with respect to the definition of sequelae, neuropsychologic tests administered, time to follow-up, patient population, study design (prospective versus retrospective), and ARDS etiology and severity. Differences in the neurocognitive tests may have also contributed to the observed differences. For example, one study used a self-reported questionnaire of memory (9), and another administered only a brief memory and attention test instead of a comprehensive neuropsychologic test battery (12). Although 42% of the ARDS patients received rehabilitation therapy, most of the ARDS patients were not evaluated for cognitive impairments, with only 12% identified as having post-ICU cognitive impairments by the clinical rehabilitation team and subsequently received cognitive rehabilitation therapy. The cognitive impairments in the patients with ARDS appear to be underrecognized by ICU and rehabilitation providers. Studies suggest that many physicians fail to recognize (or assess) cognitive impairment in 35 to 90% of patients in non-ICU clinical practice settings (45, 46). In addition, cognitive impairments are rarely evaluated in ICU patients (16) and may be overlooked in one of every two cases (47). Education regarding cognitive sequelae after ARDS is needed to enhance referral of patients to rehabilitation, not only for physical debilitation and weakness, but also for cognitive impairments. Only two patients had no episodes of hypoxemia, despite attentiveness of respiratory therapists, nurses, and critical care physicians to all patients. The duration of hypoxemia at hospital discharge modestly correlated with attention, verbal memory, and executive function. The correlations between the duration of hypoxemia and neuropsychologic outcome are less robust than we previously reported (10). The duration of hypoxemia did not correlate with any neurocognitive score at 2 years. The duration of hypotension modestly correlated with memory impairments at hospital discharge and 1 year, but not at 2 years. These findings suggest that the effects of hypoxemia and hypotension play a role in neurocognitive sequelae at discharge and 1 year but not at 2 years, which may be due to improvement in cognitive sequelae in some patients over time. We did not find relationships between ICU length of stay, Acute Physiologic and Chronic Health Evaluation II scores, and duration of intubation, tidal volume, gender, or days receiving sedative, narcotic, or paralytic medications with neurocognitive function. Others have reported that the cumulative dose of some sedatives (48) and delirium (49–51) may contribute to neurocognitive and affective sequelae in critically ill patients. One potential mechanism of neurocognitive impairments is hyperglycemia, which exacerbates hypoxic (52) and ischemic brain injury (53, 54). Hyperglycemia is associated with poor neurologic outcome after head injury (55, 56) and stroke (53). Other potential mechanisms for the neurocognitive impairments include elevated cytokines and inflammation from sepsis (57). For example, patients with elevated cytokines from chronic fatigue syndrome have impaired attention, concentration, and memory (58). A study that induced cytokine activation in healthy volunteers found elevated cytokine levels were associated with impaired memory (59). Inflammation has also been implicated in the pathogenesis of cognitive impairments associated with Alzheimer's disease (60). The etiology of the neurocognitive impairments is undoubtedly multifactorial and the subject of ongoing discussion. Future investigations are required to further delineate etiologic determinants and identify interventions to improve or prevent neurocognitive impairments. Our ARDS patients reported depression and anxiety that persisted up to 2 years after hospital discharge. The depression and anxiety observed in our ARDS survivors is similar to that previously reported (22, 61, 62). Critically ill patients who survive their ICU stay frequently report depression and anxiety (9, 13, 15, 22, 24, 63). Approximately 23% of our patients with ARDS reported moderate to severe symptoms of depression and anxiety at 2 years. However, the Beck Depression Inventory and Beck Anxiety Inventory correlated only with one neurocognitive test, object assembly, at 2 years. Because only 1 test of 25 correlated with depression and anxiety, this suggests that symptoms of depression and anxiety did not influence neurocognitive performance. Similarly, at 1 year, there was no association between depression and anxiety and neurocognitive outcome (11). The determinants of depression and anxiety associated with ARDS and critical illness is unknown. Potential mechanisms that may contribute to affective morbidity include organ dysfunction, medications (64), pain, altered sensory inputs, sleep deprivation, elevated cytokines (65), stress related activation of the hypothalamic pituitary axis (66), cerebral atrophy (67), hypoxemia (68), neurotransmitter aberrations from brain injury (69), elevated catecholamine levels from administration of epinephrine or norepinephrine in the ICU, and stress from critical illness and ICU treatment (70–72). The quality of life in our ARDS survivors was significantly lower than the normal population, and was similar to previous reports in other ARDS patients (9, 10, 12–15, 73). We found three distinct patterns for the SF-36 domains in our ARDS patients from hospital discharge to 2 years after discharge. The first pattern showed physical function, social function, role physical, and vitality domains were low at hospital discharge, improved at 1 year with no additional improvement at 2 years, similar to neurocognitive function. A second pattern for role emotional, pain, and general health domains showed higher scores at hospital discharge, albeit lower than normal, with no change over time. Of interest is the lack of change in the general health domain from hospital discharge to 2 years. The lack of change is likely the result of the nature of the items included in the general health domain, because they assess patients' perceptions of their general health (e.g., is your health excellent to poor compared with most people, do you get sick more easily than other people, do you expect your health to get worse) rather than compared with their current health or health post-ARDS. That is, they were asked to assess their general health compared with other individuals, rather than to how their health was before ARDS or the post-ARDS effects on their general health. A third pattern for the mental health domain showed improvement during the first year and then declined to the hospital discharge level at 2 years. These results raise the question as to why the mental health domain declines at 2 years. One possible reason for the decline in mental health at 2 years may be depression, which has been associated with decreased life satisfaction (15) and lower quality of life (11). The strengths of this study include the longitudinal prospective cohort study design, consistent follow-up times, high follow-up rates, automated hypoxemia and hypotension data capture, comprehensive measures of neurocognitive outcome, and a well-defined ARDS population. The limitations of our study and most prior ARDS outcome studies include the inability to measure premorbid cognitive and emotional function, quality of life, and the lack of an appropriate control group. Because we did not follow a control group of ICU survivors who did not have ARDS, the neurocognitive sequelae we observed may not be specific to ARDS but rather may represent morbidity from critical illness. We also did not follow a normal control group; however, it should be noted that we used demographically (i.e., age, sex, and education) corrected neuropsychologic test scores for statistical analyses, which correct for variables known to effect test performance. The use of the automated moving median technique for oximetry and blood pressure measurements minimizes variability (29), and could miss brief periods of hypoxemia or hypotension. The correlations we found between hypoxemia and hypotension with neurocognitive sequelae may underestimate the magnitude of brief decrements. Our findings may not generalize to other ARDS patients with less severe ARDS, patients with acute lung injury, or patients who are not enrolled in randomized clinical trials because such studies often employ stringent inclusion and exclusion criteria. ARDS is a life-threatening illness that results in significant long-term morbidity, including neurocognitive impairments, depression, anxiety, and decreased quality of life. ARDS survivors' neurocognitive impairments were more likely to improve than decline at 1 year with little additional improvement at 2 years. These patients with ARDS had decreased quality of life with the physical domains improving during the first year; little change in role emotional, pain, and general health; and improvement, then subsequent decline, in mental health at 2 years. ARDS is common, and survival appears to be improving, yet physicians need to be mindful of adverse brain-related outcomes in many of these patients. As survival improves, attention to proximal determinants and possible interventions to prevent cognitive and emotional morbidity are warranted and should be an emphasis in ARDS and critical care outcomes research.
This research was sponsored by Deseret Foundation Grant numbers 300, 318, and 359 and NIH ARDS SCOR Grant #HL50513. Conflict of Interest Statement: R.O.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.K.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.B.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.J.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.F.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form June 16, 2004; accepted in final form November 5, 2004
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ABSTRACT
METHODS
16 years, and presence of an ARDS risk factor (e.g., aspiration, multiple trauma, pancreatitis, pneumonia, sepsis). Patients were excluded (n = 193) if they had disease states that were deemed irreversible (e.g., liver failure, malignancy, patients with acquired immune deficiency syndrome), traumatic brain injury, prior neurologic disease, prior cognitive disability, or if they were enrolled in another ARDS study (e.g., ARDSNet studies). Patient demographics and medical data were collected prospectively as part of routine clinical care, including length of stay; Acute Physiologic and Chronic Health Evaluation II (i.e., APACHE II) scores (
