Original Article

Functional Disability 5 Years after Acute Respiratory Distress Syndrome

List of authors.
  • Margaret S. Herridge, M.D., M.P.H.,
  • Catherine M. Tansey, M.Sc.,
  • Andrea Matté, B.Sc.,
  • George Tomlinson, Ph.D.,
  • Natalia Diaz-Granados, M.Sc.,
  • Andrew Cooper, M.D.,
  • Cameron B. Guest, M.D.,
  • C. David Mazer, M.D.,
  • Sangeeta Mehta, M.D.,
  • Thomas E. Stewart, M.D.,
  • Paul Kudlow, B.Sc.,
  • Deborah Cook, M.D.,
  • Arthur S. Slutsky, M.D.,
  • and Angela M. Cheung, M.D., Ph.D.
  • for the Canadian Critical Care Trials Group

Abstract

Background

There have been few detailed, in-person interviews and examinations to obtain follow-up data on 5-year outcomes among survivors of the acute respiratory distress syndrome (ARDS).

Methods

We evaluated 109 survivors of ARDS at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit. At each visit, patients were interviewed and examined; underwent pulmonary-function tests, the 6-minute walk test, resting and exercise oximetry, chest imaging, and a quality-of-life evaluation; and reported their use of health care services.

Results

At 5 years, the median 6-minute walk distance was 436 m (76% of predicted distance) and the Physical Component Score on the Medical Outcomes Study 36-Item Short-Form Health Survey was 41 (mean norm score matched for age and sex, 50). With respect to this score, younger patients had a greater rate of recovery than older patients, but neither group returned to normal predicted levels of physical function at 5 years. Pulmonary function was normal to near-normal. A constellation of other physical and psychological problems developed or persisted in patients and family caregivers for up to 5 years. Patients with more coexisting illnesses incurred greater 5-year costs.

Conclusions

Exercise limitation, physical and psychological sequelae, decreased physical quality of life, and increased costs and use of health care services are important legacies of severe lung injury.

Introduction

The acute respiratory distress syndrome (ARDS) represents an important and costly public health problem.1 Prospective systematic evaluation of long-term outcomes among survivors of ARDS has been limited to 2 years of follow-up.2-11 Few comprehensive, longitudinal data have been obtained from survivors of critical illness with regard to 5-year pulmonary, functional, and health-related quality-of-life outcomes or health care utilization and costs. The Toronto ARDS follow-up study began in 1998 and enrolled relatively young patients with very severe lung injury and few coexisting illnesses.10 The primary goal of this 5-year follow-up study was to catalogue, quantify, and describe the extent of physical, mental, and quality-of-life impairments after ARDS and to determine factors associated with poor outcomes and increased health care utilization.

Methods

Study Design

We conducted a prospective, longitudinal cohort study of 109 patients with ARDS who survived until they were discharged from the intensive care unit (ICU). The patients were recruited from four academic medical–surgical ICUs in Toronto between May 1998 and May 2001. Inclusion and exclusion criteria have been described previously.10 At the end of 1 year, written informed consent was obtained from all patients to permit another 4 years of follow-up. The study was approved by the research ethics boards at all participating hospitals.

Characteristics of Patients and ICU Course

Table 1. Table 1. Characteristics of Patients with the Acute Respiratory Distress Syndrome (ARDS) at 1 Year and 5 Years after Discharge from the Intensive Care Unit (ICU).

At the time of the onset of ARDS, the median age of the patients was 44 years (interquartile range, 35 to 57); 83% had no or one coexisting condition, and 83% were working full time. Pneumonia and sepsis were the most common risk factors for ARDS in this cohort. We collected data on baseline demographic characteristics and measures of severity of illness in the ICU daily during the first week and twice weekly thereafter.10 These measures included the Acute Physiology and Chronic Health Evaluation II (APACHE II) (range of scores, 0 to 71, with higher scores indicating greater severity of illness),12 the Multiple Organ Dysfunction Score (range, 0 to 24, with higher scores indicating more severe organ dysfunction),13 and the modified Lung Injury Score (range, 0 to 4, with higher scores indicating more severe lung injury).14 Other characteristics of the patients during their stay in the ICU are listed in Table 1.

Follow-up Protocol

We evaluated survivors of ARDS in an ambulatory clinic or in their homes at 3, 6, 12, and 24 months and then yearly for up to 5 years after they were discharged from the ICU. At each visit, patients underwent a detailed interview, physical examination (including muscle-strength measurements), pulmonary-function testing, chest radiography, and the 6-minute-walk test15 with continuous oximetry. They also completed the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (scores range from 0 to 100, with higher scores indicating better health status).16 Family caregivers were also interviewed. A description of the follow-up visits can be found in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Health Care Utilization and Cost Data

We prospectively collected data on health care utilization from hospital and outpatient clinical records, patients' monthly diaries, and self-reports at scheduled study visits. This approach provided patient-specific and activity-based resource-use data after hospital discharge. For health care costs, we took the perspective of a third-party payer (Ontario Ministry of Health) to estimate direct medical charges, which we equated with costs that included hospitalization, emergency room and outpatient visits, professional fees, drugs, laboratory and radiology tests and procedures, outpatient and inpatient rehabilitation, home care, and services provided in a long-term care facility. We excluded indirect medical costs and direct nonmedical costs. Costs were adjusted for inflation rates with the use of the health care component of the Canadian Consumer Price Index17 and were expressed in 2009 Canadian dollars. Our methods for determining health care use and costs are detailed in the Supplementary Appendix.

Statistical Analysis

Continuous variables were summarized with the use of medians and the 25th and 75th percentiles (the interquartile range). Categorical variables were summarized with the use of proportions and 95% confidence intervals. Reported costs for patients who died before the 5-year period ended are complete costs. To avoid bias in our cost analyses because of incomplete cost data, we used the partitioned estimator of Bang and Tsiatis to estimate mean total costs to 5 years and costs accrued in each year.18 In addition, we used the regression method of Lin to estimate the dependence of total costs on patient-level covariates.19 Details of modeling and further analyses are included in the Supplementary Appendix. All analyses were preplanned.

Results

Baseline Characteristics and Follow-up Assessments

Figure 1. Figure 1. Follow-up Status of Patients with Acute Respiratory Distress Syndrome from 1 Year to 5 Years.

The number of patients designated as lost to follow-up varies between yearly visits because some patients returned after missing one or more visits over the 5-year course of the study.

Of the 109 patients included in the follow-up, 83 reconsented at 1 year to an additional 4 years of follow-up. The proportions of surviving patients who were included in the follow-up during the 1-year to 5-year periods, respectively, were 86%, 85%, 90%, 82%, and 86% (Figure 1).

Global Assessment

At 5 years after ICU discharge, no patient had demonstrable weakness on examination, but all commented on having varying degrees of perceived weakness and stated that their ability to do vigorous exercise was reduced, as compared with their ability before their critical illness. Patients' weight remained stable between 1 and 5 years after ICU discharge.

Figure 2. Figure 2. Survival Rates, 6-Minute Walk Distance, and Quality of Life for 5 Years after Discharge from the Intensive Care Unit.

Exact survival times were used for these analyses. In the top graph, the solid line is the Kaplan–Meier survival curve from 0 to 5 years; dashed lines represent the 95% confidence interval. The middle graph shows the distance walked in 6 minutes in meters (solid line) and the percent of the predicted distance (dashed line). The bottom graph shows the physical-component score (PCS) and the mental-component score (MCS) on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36); scores range from 0 to 100, with higher scores indicating better health status. Vertical bars in the middle and bottom graphs represent half 95% confidence intervals.

At 5 years, the median distance walked in 6 minutes was 436 m (interquartile range, 324 to 512) (76% of the distance in an age-matched and sex-matched control population), which was consistent with a persistent reduction in ability to exercise (Figure 2). Distance walked in 6 minutes was significantly correlated with the physical-component score of the SF-36 at 3, 6, and 12 months and at 2, 3, 4, and 5 years (P<0.01). The patient and ICU characteristics originally evaluated as part of the 1-year ARDS outcomes analyses are shown in Table 1. None of these characteristics were significantly associated with the 6-minute walk distance at 5 years. However, patients for whom the rate of change in the Lung Injury Score was above the median, indicating faster resolution of lung injury during the ICU stay, had a longer median 6-minute walk distance at the 5-year follow-up than did those with a rate of change below the median, indicating slower resolution of lung injury during the ICU stay (454 m vs. 427 m, P=0.09). This was also true for the rate of change in the Multiple Organ Dysfunction Score during the ICU stay (P=0.09).

Thirty-nine percent of patients achieved a 6-minute walk distance of 80% or more of the predicted distance at 5 years. When we looked at whether age, coexisting illness, or rate of resolution in the Lung Injury Score during the ICU stay was associated with a better functional outcome, we found a very small effect of age, with greater odds of a walk distance above 80% of the predicted distance with increasing age (odds ratio, 1.46 per decade [1.04 per year]; P=0.06). Coexisting illness had a greater effect, with a lower chance of being above 80% of the predicted distance with each additional illness (odds ratio, 0.48 per illness; P=0.06). There was no association with the rate of resolution in the Lung Injury Score during the ICU stay (P=0.54).

The mean score on the physical component of the SF-36 at 5 years remained approximately 1 SD below the mean score for an age-matched and sex-matched control population. Age was significantly associated with the slope of the physical-component score over the 5-year period after discharge from the ICU. In post hoc analyses in which patients were divided into thirds according to age (<38, 38 to 52, and >52 years), those in the two younger groups had a significantly steeper slope in improvement in the physical-component score from discharge to 5 years, as compared with those who were older than 52 years of age (P=0.002) (see the Supplementary Appendix). The estimated mean increases in physical-component score were 11.7 and 9.2 points greater in the two younger age groups, respectively, than the corresponding increase in the oldest age group, but none of the three groups had a score as high as the predicted score at 5 years.

Spectrum of Impairments 5 Years after ARDS

The patients with ARDS had new or continued impairments related to a variety of physical and neuropsychological disorders between 2 and 5 years of follow-up. These included new tracheal stenosis requiring surgical resection and dilation and rehospitalizations (in 2 patients) and complicated by a major depressive disorder in 1 patient; ongoing disability from heterotopic ossification involving the knees and elbows (in 4 patients); frozen shoulders (in 2 patients); vocal-cord dysfunction and voice changes (in 1 patient); new or recurrent reactive airways disease (in 4 patients); and dental implants for ICU-acquired tooth damage (in 1 patient). There were ongoing concerns about cosmesis in 10 patients; these were related to procedures (e.g., laparotomy; tracheostomy or tracheostomy revision; insertion of a chest tube, a central line, or an arterial line; and burns, striae, and facial scars from prolonged noninvasive mask ventilation). Patients reported that these concerns contributed to social isolation and sexual dysfunction. Other causes of disability included bilateral forefoot amputations due to necrosis from vasopressor use (in 1 patient) and new sensorineural hearing loss and tinnitus attributed to ototoxic ICU medications (in 2 patients). Fifty-one percent of patients reported at least one episode of physician-diagnosed depression, anxiety, or both between 2 and 5 years of follow-up; several patients had substantial mental health challenges, including an acute psychotic episode due to post-traumatic stress disorder (in 1 patient) and severe agitated depression and agoraphobia (in 2 patients). Family mental health problems, including anxiety, depression, or post-traumatic stress disorder, as reported by patients or family members, occurred in 27% of cases over the same time period. Other problems, such as social isolation, sexual dysfunction, job loss, and disputes over disability and insurance claims, were also qualitatively discussed during the study interviews.

Pulmonary-Function Testing and Chest Radiography

Table 2. Table 2. Clinical Outcomes from 1 Year to 5 Years in Survivors of ARDS.

Patients had normal or near-normal volumetric and spirometric test results between 3 and 5 years (Table 2). Forty percent of the participants were seen at a home visit, during which pulmonary assessment was limited to spirometry. After ICU discharge, 25 patients underwent computed tomography (CT) of the chest at least once between the 2-year and 5-year follow-up visits. The most common finding was minor, nondependent pulmonary fibrotic changes that were consistent with ventilator-induced lung injury. Less common findings included bronchiectasis, bullae, pleural thickening, and pulmonary fibrosis. Only patients with bronchiectasis, pulmonary fibrosis, or both on CT imaging had clinically important pulmonary symptoms, including cough, sputum production, and exertional dyspnea.

Survival and Return to Work

A Kaplan–Meier 5-year survival curve is shown in Figure 2. During the first year of follow-up, 12 patients died,10 and 9 died over the next 4 years (Figure 1). Causes of death in these 9 patients are listed in the Supplementary Appendix.

Eighty-three percent of the patients who were followed up for 5 years were working full time before their critical illness (Table 1); 77% of these patients were working for a salary outside the home, 6% were students attending college or university, and 17% were women doing unpaid work within the home. At the 5-year follow-up, 77% of patients had returned to work, and 94% of these patients returned to their original work. Two patients reached retirement age and did not return to work. The majority of patients who returned to work did so by 2 years after ICU discharge; five patients returned to work between 3 and 5 years after discharge, but not all of the five remained in the work force (Table 2). Patients often required a gradual transition to work, a modified work schedule, or job retraining in collaboration with third-party private insurers, with supporting justification and documentation from our ARDS research group.

Health Care Utilization and Costs over 5 Years

Figure 3. Figure 3. Cumulative Costs to 5 Years after Discharge from the Intensive Care Unit (ICU), Stratified According to Number of Coexisting Illnesses at Time of ICU Admission.

Costs are in 2009 Canadian dollars.

Average costs per patient per year from years 3 through 5 ranged from $5,000 to $6,000 (Table 2). Medication costs increased to year 3 and then remained constant in years 4 and 5. Rehospitalization costs decreased up to 3 years of follow-up and then remained stable in years 4 and 5, and outpatient costs declined each year throughout the 5 years. Rehospitalizations were related to ICU-acquired complications, complications of preexisting illnesses, or the development of new medical problems. Cumulative postdischarge costs per patient were associated with the number of coexisting illnesses at the time of ICU admission (≤1 vs. ≥2 coexisting illnesses) (Figure 3). Only the presence of coexisting disease was significantly associated with costs incurred over the 5-year follow-up period in regression modeling (data not shown).

Discussion

We found that relatively young patients who survived ARDS had persistent exercise limitations and a reduced physical quality of life 5 years after their critical illness. Pulmonary function was near-normal to normal at 5 years. The decrements in quality of life and exercise capacity may have resulted from persistent weakness, as well as a spectrum of physical and neuropsychological impairments that were also documented during follow-up. These patients had modest preexisting illnesses, and most were working before their illness yet they incurred health care costs at a greater rate over time than did age-matched and sex-matched healthy persons.

We also found that the cumulative costs after hospitalization were associated with the burden of coexisting illnesses at the time of ICU admission. This observation is consistent with other reports that link coexisting illness with poor clinical outcomes after ICU discharge and increased costs over time.20-22 The incremental cumulative health care costs of an ARDS episode are difficult to determine without a control group. However, the costs reported for the patients with ARDS in our study are higher than those incurred by healthy workers ($1,100 to $3,200 per year)23,24 and are closer to the low end of the range of costs among patients with chronic disease.24,25 One may view survivors of severe ARDS as having a burden of chronic disease related to a decrement in coexisting organ dysfunction or the development of new disability. The finding that relatively young, previously working persons with modest coexisting disorders do not return to baseline levels of health care utilization after an episode of critical illness may have important public health ramifications.

ICU-acquired weakness may continue to be an important contributor to long-term function and quality-of-life outcomes in survivors of ARDS.23-33 The spectrum of physical and neuropsychological impairments that compound such weakness may also contribute to these outcomes. These data are consistent with other reports of long-term sequelae in survivors of critical illness.7,34-52 However, our study shows that such dysfunction persists over a period of 5 years and that heterogeneous issues contribute to this reported disability over time. Our study also shows that psychological and emotional dysfunction persists in both patients and caregivers for up to 5 years after discharge from the ICU.

The decrements in the 6-minute walk distance and the score on the physical component of the SF-36 at 5 years may suggest that previously working, relatively young patients may have an irreversible decrease in function after critical illness, although this decrease is less marked than the decrements recently described in older patients with more coexisting disorders.22,53 Early mobility and rehabilitation are promising interventions for ameliorating such impairments, but the ability to stratify risks and tailor programs to individual needs requires further study.54-65 Recent work highlights the need to balance the potential risk of ICU-acquired weakness with the potential benefit of neuromuscular blockers and systemic glucocorticoids in severely lung-injured patients.66-68 In addition, ICU-based interventions may play a role in reducing longer-term neuropsychological disorders in ICU survivors (e.g., ICU diaries to help reduce post-traumatic stress disorder69,70). These data underscore both the important effect that the process of ICU treatment may have on longer-term outcomes and the need for ongoing study in this area.66-70

Through in-person follow-up we came to understand the burden on caregivers associated with the recovery of patients with lung injury. There is an emerging literature on morbidity among caregivers and the important psychological impairments sustained by family members for prolonged periods after the initial episode of critical illness.71-76 Dysfunction in these family members may also have an important negative effect on patients' recovery and rehabilitative potential.

The strengths of our study are the well-defined multisite inception cohort, detailed characterization of the patients, and longitudinal design, with high rates of follow-up to 5 years and comprehensive in-person evaluations. Our findings may help to inform patients, family caregivers, primary care physicians, and specialists about patterns of very-long-term outcomes after critical illness. A limitation of the study is the modest sample size. In addition, the patients were relatively young and they had severe lung injury, with few coexisting illnesses and minimal preexisting pulmonary disease. Therefore, these data cannot be generalized to all survivors of critical illness. Subtle impairments may be less evident in younger patients, and reported coexisting illness might be underestimated in this young patient population. We did not record standardized serial strength measurements or conduct a detailed neuromuscular assessment; however, the patients were examined and muscle power was formally evaluated during follow-up visits. The relationship between the study team and the patients and their caregivers helped to ensure excellent follow-up, but it may have had a therapeutic effect, thereby confounding the outcome measurements. Thus, the outcomes we report may be better-than-average outcomes for patients with ARDS, given the active surveillance and care administered. The data on cost and health care utilization consisted of information that was externally validated, either fully (ICU and inhospital data) or partially (hospital readmission [63%]), combined with self-reports (on outpatient care utilization and medication use); the latter may be limited by reporting or recall bias.

In summary, young, previously working patients with ARDS who have few coexisting illnesses may not recover completely and may have ongoing functional limitations after an episode of critical illness. This may be attributed to persistent ICU-acquired weakness, in addition to a variety of other physical and mental health impairments. Family members may also have psychological dysfunction, which may further compromise outcomes. The health burden of critical illness may be likened to that of chronic disease with similar health care utilization. Research priorities include a better understanding of the pathophysiology of ICU-acquired weakness and an evaluation of the effects of a customized, family-centered, rehabilitation program on long-term outcomes after a critical illness.

Funding and Disclosures

Supported by grants from the Canadian Intensive Care Foundation, the Physician's Services Incorporated Foundation, and the Ontario Thoracic Society.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

We thank our patients with ARDS and their families for their perseverance and commitment to the successful completion of the 5-year follow-up.

Author Affiliations

From the Department of Medicine, University Health Network (M.S.H., C.M.T., A.M., G.T., P.K., A.M.C.); the Interdepartmental Division of Critical Care (M.S.H., A.C., C.B.G., C.D.M., S.M., T.E.S., A.S.S.); the Department of Public Health Sciences (N.D.-G., A.M.C.); the Departments of Critical Care Medicine and Anesthesia, Sunnybrook Health Sciences Centre (A.C., C.B.G.); the Departments of Anesthesia (C.D.M.) and Medicine and Critical Care Medicine (A.S.S.) and the Keenan Research Center at the Li Ka Shing Knowledge Institute (C.D.M., A.S.S.), St. Michael's Hospital; the Dalla Lana School of Public Health (G.T., N.D.-G., A.M.C.) and the Departments of Medicine (S.M., T.E.S.) and Anesthesia (T.E.S.), Mount Sinai Hospital — all at the University of Toronto, Toronto; and the Departments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada (D.C.).

Address reprint requests to Dr. Herridge at Toronto General Hospital, NCSB 11C-1180, 585 University Ave., Toronto, ON M5G 2N2, Canada, or at .

Supplementary Material

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    1. Table 1. Characteristics of Patients with the Acute Respiratory Distress Syndrome (ARDS) at 1 Year and 5 Years after Discharge from the Intensive Care Unit (ICU).
      Table 1. Characteristics of Patients with the Acute Respiratory Distress Syndrome (ARDS) at 1 Year and 5 Years after Discharge from the Intensive Care Unit (ICU).
    2. Figure 1. Follow-up Status of Patients with Acute Respiratory Distress Syndrome from 1 Year to 5 Years.
      Figure 1. Follow-up Status of Patients with Acute Respiratory Distress Syndrome from 1 Year to 5 Years.

      The number of patients designated as lost to follow-up varies between yearly visits because some patients returned after missing one or more visits over the 5-year course of the study.

    3. Figure 2. Survival Rates, 6-Minute Walk Distance, and Quality of Life for 5 Years after Discharge from the Intensive Care Unit.
      Figure 2. Survival Rates, 6-Minute Walk Distance, and Quality of Life for 5 Years after Discharge from the Intensive Care Unit.

      Exact survival times were used for these analyses. In the top graph, the solid line is the Kaplan–Meier survival curve from 0 to 5 years; dashed lines represent the 95% confidence interval. The middle graph shows the distance walked in 6 minutes in meters (solid line) and the percent of the predicted distance (dashed line). The bottom graph shows the physical-component score (PCS) and the mental-component score (MCS) on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36); scores range from 0 to 100, with higher scores indicating better health status. Vertical bars in the middle and bottom graphs represent half 95% confidence intervals.

    4. Table 2. Clinical Outcomes from 1 Year to 5 Years in Survivors of ARDS.
      Table 2. Clinical Outcomes from 1 Year to 5 Years in Survivors of ARDS.
    5. Figure 3. Cumulative Costs to 5 Years after Discharge from the Intensive Care Unit (ICU), Stratified According to Number of Coexisting Illnesses at Time of ICU Admission.
      Figure 3. Cumulative Costs to 5 Years after Discharge from the Intensive Care Unit (ICU), Stratified According to Number of Coexisting Illnesses at Time of ICU Admission.

      Costs are in 2009 Canadian dollars.