The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: long-term neuropsychological function in survivors of acute lung injury

Expanded abstract Citation Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, Localio AR, Demissie E, Hopkins RO, Angus DC: The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 2012, 185:1307-1315. Background Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking. Methods Objective The objectives were to determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial and to determine the frequency and risk factors for long-term neuropsychological impairment. Design A prospective, multicenter cohort study of a subset of survivors from the Fluid and Catheter Treatment Trial (FACTT) was conducted. Setting The FACTT enrolled patients from 38 North American hospitals between June 2000 and October 2005. Subjects To be eligible for the ALI Cognitive Outcomes Study (ACOS), subjects had to be enrolled in the FACTT and the EA-PAC (Economic Assessment of the Pulmonary Artery Catheter) trial. The FACTT enrolled mechanically ventilated adults who met the American-European Consensus Conference criteria for ALI. Intervention In an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, neuropsychological function at 2 and 12 months after hospital discharge was assessed. Outcomes The primary outcome was the result of a validated telephone battery of standardized neuropsychological tests administered to consenting, English-speaking subjects at 2 and 12 months after hospital discharge. Results Of 406 eligible survivors, 261 patients were approached to participate and 213 consented. One hundred twenty-two subjects, including 102 subjects at 12 months, were tested at least once. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors, respectively. Long-term cognitive impairment was present in 41 (55%) of the 75 survivors who completed cognitive testing. Depression, post-traumatic stress disorder, and anxiety were present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors, respectively. 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 (P <0.02) impairment. Conclusions Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. A 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.


Background
Cognitive and psychiatric morbidity is common and potentially modifi able after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking.

Methods
Objective: e objectives were to determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial and to determine the frequency and risk factors for long-term neuro psy chological impairment. Design: A prospective, multicenter cohort study of a subset of survivors from the Fluid and Catheter Treatment Trial (FACTT) was conducted. e primary outcome was the result of a validated telephone battery of standardized neuropsychological tests administered to consenting, English-speaking subjects at 2 and 12 months after hospital discharge.

Results
Of 406 eligible survivors, 261 patients were approached to participate and 213 consented. One hundred twenty-two subjects, including 102 subjects at 12 months, were tested at least once. Memory, verbal fl uency, and execu tive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors, respect ively. Long-term cognitive impairment was present in 41 (55%) of the 75 survivors who completed cognitive testing. Depression, post-traumatic stress disorder, and anxiety were present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors, respectively. Enrollment in a conservative fl uid 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 (P <0.02) impairment.

Conclusions
Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. A fl uid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this fi nding requires confi rmation. the critical care setting. Neuropsychiatric morbidities are prevalent and long-lasting in survivors of critical illness [2]. With a growing number of ALI survivors, more eff ort is being directed toward understanding and improving the long-term physical, cognitive, and psychiatric morbidities experienced by these survivors.
e Fluid and Catheter Treatment Trial (FACTT) suggested shortterm physiologic benefi t from a conser vative fl uid management strategy when compared with a liberal fl uid management strategy, as evidenced by improved lung function and shorter duration of mecha nical ventilation [3,4]. In the FACTT, the conservative strategy group had better lung injury scores and oxygenation indices as well as lower plateau pressures and positive end-expiratory pressures. However, there was no diff erence in hospital mortality at 60 days between the two treatment groups.
As a concurrent study to the FACTT, the ALI Cognitive Outcomes Study (ACOS) demonstrated a high incidence of cognitive impairment and psychiatric symptoms in long-term survivors of ALI. Fifty-fi ve percent of patients had cognitive impairment on neuropsychological testing. However, cognitive impairment was signifi cantly more common in the fl uid conservative arm (P = 0.005), particularly in executive dysfunction domains (such as planning a trip or balancing a checkbook). In the ACOS, enrollment in the conservative fl uid management strategy (P = 0.004) and lower partial pressure of arterial oxygen (P = 0.02) were associated with cognitive impairment at 12 months, suggesting that the short-term benefi ts achieved as a result of a conservative fl uid strategy might come at the cost of long-term cognitive dysfunction.
e results of this study illustrate that physiologic outcomes are not necessarily associated with patient-centered outcomes. e ACOS is th e fi rst study to determine whether neuro psychological function can be assessed in a multicenter trial. It is also the fi rst large-scale assessment of a previously validated telephone-administered neuropsycho logical instrument. However, one weakness of the study is its small sample size, a consequence of high patient attrition and low telephone enrollment. Several possible explanations account for this lack of follow-up. For instance, the subject may have been lost to follow-up because of death, known as a competing risk. It is also possible that the subject was lost to follow-up because of neurocognitive defi cits, known as informative censoring. Although bias from pre-study cognitive baseline should have been addressed by randomization, unmeasured diff er ences could have resulted in diff erential attrition between study arms. Non-informative censoring, or random loss to follow-up, is another potential explanation for the high patient attrition in this study.

Recommendation
Consistent with previous studies, the ACOS showed neurocognitive defi cits in a large proportion of subjects recovering from ARDS (55% of patients had cognitive impairment on neuropsychiatric testing). Future studies should incorporate more long-term follow-up, as benefi ts of intensive care unit interventions observed during the early part of recovery from critical illness may not translate into improvement in long-term outcomes.