Health-Related Quality of Life (HRQL)
HRQL can be defined as a set of causally linked dimensions of health, including biologic/physiologic, mental, physical, social function, cognitive, and health perception.12 Measures of HRQL assess how disease and its treatment are related to physical, social, emotional, or cognitive functioning. HRQL has emerged as an important measure of recovery from a variety of disease states, including critical illness, and has been used to evaluate patient-centered outcomes.
Most studies indicate that a significant proportion of ICU survivors experience some impairment in HRQL; however, this can be quite variable.13,14 Case mix may represent one important reason for these differences in reported HRQL. Critically ill patient populations are very diverse. The premorbid functional status of the patient and the etiology of the critical illness and its outcome represent important determinants of reported HRQL. Trauma patients with brain injury but normal cognitive function and intact social and work functioning reported a higher quality of life than trauma patients who were unemployed and had cognitive impairment.15 Critically ill multiple-trauma survivors experience decreased quality of life associated with cognitive impairments and decreased income.16 Elderly patients (>70 years) hospitalized in the ICU more than 30 days reported decreased physical functioning and poorer health and memory, but most were still functionally independent.17 Survivors of sepsis18 and prolonged mechanical ventilatory support (mean of 45 days) had compromised physical function, and the degree of dysfunction was related to premorbid functional status and the underlying disease.19
Although there is clearly some heterogeneity across different populations of ARDS patients, there appears to be less variability in reported HRQL compared with general populations of critically ill patients. In 1994, McHugh and her colleagues,20 using a prospective cohort study, serially evaluated pulmonary function and quality of life to assess the relationship between pulmonary dysfunction and functional disability. These authors found that the Sickness Impact Profile (generic quality-of-life measure of the subject's self-perceived physical and psychological condition) scores were very low at extubation, rose substantially in the first 3 months, and then exhibited only slight improvement to 1 year. When quality of life was assessed using a lung-related Sickness Impact Profile score, only a modest proportion of the patients' overall dysfunction was attributed to residual pulmonary problems. Weinert and coworkers21 identified functional impairment in a cohort of acute lung injury survivors. They administered the Medical Outcomes Study 36-item short-form health survey (SF-36), which yields scores in eight domains including physical and social functioning, role limitations because of emotional or physical problems, mental health, vitality, bodily pain, and general health perceptions.22 While all domains of the SF-36 were reduced, the largest decrements were in physical ability to maintain their roles (role-physical) and physical functioning. While some decreased quality of life was attributed to pulmonary dysfunction, many more patients attributed this to global and generalized disability. Schelling and colleagues23 made similar observations about impaired physical functioning and inferred that disability was due to pulmonary dysfunction; however, they did not assess this in their study. Davidson and colleagues24 designed a study to determine if there were differences in health-related quality of life in ARDS survivors and comparably ill controls. They used the SF-36 and a pulmonary disease–specific measure (St. George's Respiratory Questionnaire [SGRQ]) to determine the degree to which perceived physical disability in ARDS survivors was related to pulmonary dysfunction. Similar to previous reports, all domains of the SF-36 were reduced, and the largest decrement was in the role-physical domain. ARDS survivors had significantly worse scores on the SGRQ compared with critically ill controls. There appeared to be an ARDS-specific degree of physical disability, but it was not clear whether this was solely related to pulmonary dysfunction or there were other important extrapulmonary contributors.
Angus and colleagues25 used the quality-of-well-being (QWB) score in a prospective cohort of ARDS survivors to measure quality-adjusted survival in the first year after hospital discharge. The mean QWB scores for the ARDS cohort at 6 and 12 months were significantly lower than the scores of a control population of patients with cystic fibrosis. When QWB was disaggregated into its component subscores, post hoc analyses showed that the symptom-component scores of the QWB accounted for 70 percent of the decrement in perfect health at 6 and 12 months. Although respiratory symptoms were reported in almost half the patients, the most common complaints were musculoskeletal and constitutional.
In a prospective cohort study of 78 survivors of ARDS, Orme and coworkers26 evaluated HRQL and pulmonary function outcomes in patients treated with higher tidal volume versus lower tidal volume ventilation strategies. Both groups (higher and lower tidal volumes) reported decreased HRQL in physical functioning, role-physical, bodily pain, general health, and vitality (energy) on the SF-36. The pulmonary function abnormalities correlated with decreased HRQL for domains reflecting physical function.
Not only is the observation of impaired physical functioning robust across studies and investigators, but it also appears to persist for long periods of time following ICU or hospital discharge. The paper by Davidson and coworkers24 discussed earlier reported outcomes at 23 months after discharge, and Herridge and colleagues27 also have reported persistent physical dysfunction at 2 years after ICU discharge.
Hopkins and colleagues28 were the first to rigorously evaluate cognitive dysfunction in ARDS survivors and to report the significant impact this had on reported HRQL outcomes. Fifty-five consecutive ARDS survivors completed detailed neuropsychological testing and questionnaires relating to health status and cognitive and psychological function at hospital discharge and 1 year after ARDS onset. These authors reported that decreased HRQL was related to cognitive dysfunction. Impaired cognitive function following ARDS also has been reported by others.29
Decreased HRQL has been associated with posttraumatic stress disorder (PTSD) and is manifest in the emotional domains of the SF-36 (e.g., role-emotional, mental health, and vitality). PTSD may represent yet another important contributor to subsequent disability and loss of employment.30
HRQL in ARDS survivors is affected by physical limitation, cognitive impairment, and emotional dysfunction. The HRQL data have had an enormous impact on the critical care community and have helped to focus attention on long-term morbidity after critical illness. However, these data provide limited insights into the specific determinants of morbidity. Natural history cohort data—evaluating both functional and cognitive long-term outcomes—have helped us to begin to understand the heterogeneous nature of reported morbidity and the complexity of interaction among physical, emotional, and cognitive domains in individual patients (see Fig. 19-1).
Physiologic and Functional Outcomes in ARDS Survivors
Many authors have focused on residual pulmonary function abnormalities as a probable explanation for long-term functional impairment in ARDS patients. While most ARDS follow-up studies report pulmonary dysfunction, the pulmonary function abnormalities tend to be modest and may not fully explain functional limitation. More recently, neuromuscular dysfunction sustained as a result of the inciting critical illness and its attendant ICU care has been associated with ongoing physical impairment in ARDS survivors. These data have been gleaned from in-person prospective natural history cohort data.
Pulmonary Function Abnormalities
The lung was the obvious focus of outcome studies early after the first description of ARDS in 1967. The studies of pulmonary function have suffered from several limitations, including a lack of consecutive patient recruitment and loss to follow-up, limited sample size, limited follow-up times, and studies of pulmonary function in isolation without any concurrent functional evaluation. Evaluation of pulmonary function on its own or coupled with HRQL measures has remained a dominant theme until recently.
Many ARDS survivors have persistent pulmonary function impairments that typically are mild to moderate, with restrictive changes and a reduction in diffusion capacity.31–33 Orme and colleagues26 reported that ARDS survivors had abnormal pulmonary function associated with decreased health-related quality of life 1 year following hospital discharge, and Schelling and colleagues34 recently reported no additional improvement in pulmonary function after the first year following ARDS. In a recent publication, Neff and colleagues35 reviewed 30 studies that evaluated pulmonary function in ARDS survivors. They reported significant variability in obstructive (0% to 33%) and restrictive (0% to 50%) defects, as well as compromised diffusion capacity (33% to 82%). This spectrum of pulmonary dysfunction may relate to population heterogeneity with respect to evolving definitions or severity of ARDS, severity of lung injury, ICU ventilatory strategy, prior history of lung disease or smoking, and the presence of other pulmonary processes that fulfill the ARDS definition but have a very different natural history (e.g., bronchiolitis obliterans organizing pneumonia).
Most outcome studies found that ARDS survivors frequently are unable to resume their prior lifestyle, but the degree of pulmonary dysfunction does not fully explain their functional limitation. This observation has led investigators to explore other possible contributors to physical disability.
Limitation in Physical Functioning
One of the limitations in the ARDS morbidity literature has been an absence of data that objectively quantify functional disability. These data would be most useful in the context of in-person assessment in addition to concurrent physiologic and HRQL outcome measures. Multiple outcome measures may result in a better understanding of the determinants of functional morbidity and how this might be ameliorated. The Toronto ARDS Outcomes group evaluated exercise capacity (distance walked in 6 minutes with continuous oximetry) and pulmonary function and conducted an interview, physical examination, and HRQL measure in 109 ARDS survivors at 3, 6, and 12 months after ICU discharge.36,37 Similar to other pulmonary function studies, the ARDS patients had mild restrictive disease and reduced diffusion capacity at 3 months following ICU discharge. By 6 and 12 months, they had normal to near-normal lung volumes and spirometric measures with a persistent mild reduction in carbon dioxide diffusion capacity—lung impairment similar to that noted by others. The ARDS survivors had profound muscle weakness and wasting and were only able to achieve 66% of their predicted exercise capacity 1 year after ICU discharge. This functional disability was reflected in the HRQL assessment, in which patients reported profound reduction in the physical functioning and role-physical domains of the SF-36. Impaired exercise capacity was related to burden of comorbid disease, exposure to systemic corticosteroid treatment during the ICU period and the rate of resolution of lung injury, and multiple-organ dysfunction during the ICU stay. The precise determinant(s) of the observed muscle wasting and weakness were not clear, but possibilities included critical illness polyneuropathy, ICU-acquired myopathy, and entrapment neuropathies.
Critical Illness Polyneuropathy
An acute polyneuropathy was described in the 1980s in association with multiple-organ dysfunction and sepsis. This was called critical illness polyneuropathy and has been characterized electrically and morphologically by a primary axonal degeneration of motor and sensory fibers.38,39 The prevalence of critical illness polyneuropathy is 70 percent and has been documented in populations with sepsis, multiple-organ dysfunction, and ARDS.40 The precise etiology is unknown, but it may represent ischemic nerve injury secondary to a disturbance in the microcirculation. There has been a recent report that critical illness polyneuropathy may persist for years following ICU discharge and contribute to long-term physical limitation.41
The incidence of an ICU-acquired myopathy and its impact on disability and prolonged rehabilitation in the post-ICU period are uncertain. A recent report described a 25% incidence of ICU-acquired paresis in patients remaining on the mechanical ventilator for 7 or more days.42 Myopathic changes have been documented both in the presence43 and the absence44 of corticosteroid and neuromuscular blockade use. Several patients from the Toronto ARDS Outcomes study underwent open muscle biopsy45 in an attempt to better understand the nature of the observed muscle wasting and weakness. The median time to biopsy was almost 1 year after ICU discharge, and all patients had histopathologic evidence of a chronic myopathic process. Muscle injury is likely multifactorial, and it may represent an important determinant of long-term functional impairment.
The Toronto ARDS Outcomes study observed a 6% prevalence of peroneal and ulnar nerve palsies.37 Although this represents only a small proportion of patients, these nerve palsies complicated rehabilitation therapy and precluded return to original work in some cases. Other studies also have found detrimental long-term consequences resulting from compression neuropathies.46
Heterotopic ossification is the deposition of para-articular ectopic bone and has been associated previously with polytrauma, burns, pancreatitis, and ARDS.47,48 It has been linked with paralysis and prolonged immobilization. There was a 5% prevalence of heterotopic ossification in the Toronto ARDS Outcomes study, with all patients having large joint immobilization, leading to important functional limitation (Fig. 19-2). Natural history cohort studies facilitate unexpected observations—such as heterotopic ossification—and link them to functional disability. Heterotopic ossification is remediable with appropriate surgical intervention, and screening for this might be an important part of a multidisciplinary intervention to improve functional outcomes.
Heterotopic ossification involving the right knee of an ARDS survivor.
Emotional Function after ARDS
The relationship between critical illness and emotional (mood) disorders is being recognized increasingly. Mood disorders represent important contributors to long-term HRQL impairments in survivors of critical illness. However, it is unclear whether these disorders are a psychological reaction to extraordinary emotional and physiologic stress, sequelae of brain injury sustained due to a critical illness and its treatment, or both.
Individuals with critical illness have to cope with a disease or injury that is life threatening as well as very burdensome interventions. The combination of medications, physiologic changes, pain, altered sensory inputs, and an unfamiliar environment may contribute to emotional changes following critical illness.49–51 Recent evidence suggests that mood disorders that occur secondary to medical illness may constitute discrete entities in which symptoms are similar to primary mood disorders, but there is a male predominance and earlier onset.52
The reported prevalence and severity of mood disorders including symptoms of depression, anxiety, and PTSD in survivors of critical illness are quite variable among patients following ICU hospitalization.49,50,53–54 Rincon and colleagues55 noted symptoms of depression and anxiety in 14% and 24%, respectively, of patients following critical illness. Similar prevalence rates of anxiety and depression have been reported by Scragg56 and Orme and coworkers.26 In contrast, Weinert and colleagues21 found that 43% of patients with acute lung injury reported symptoms of depression, and Angus and coworkers25 reported a 50% prevalence of depression and anxiety at 1 year in ARDS patients. The Toronto ARDS Outcomes study found that 58% of ARDS survivors reported depressive symptoms almost 2 years after ICU discharge.57 By contrast, Hopkins and coworkers28 found that ARDS patients reported minimal symptoms of depression or anxiety that were within the normal range in their natural history ARDS cohort study. The observed depression and anxiety after ICU treatment are likely multifactorial, and further study will be needed to better understand patient predisposition, illness, and treatment-specific determinants of affective morbidity.
PTSD is the development of characteristic symptoms that occur following a traumatic event(s) where triggers include a serious personal threat experienced with helplessness and intense fear.58,59 The diagnostic criteria include a history of traumatic event(s) accompanied by symptoms from each of three symptom clusters: hyperarousal symptoms, intrusive recollections, and avoidant/numbing symptoms.60 Schelling and colleagues30 were the first to introduce the concept of PTSD resulting from critical illness and ICU treatment to the critical care community. These authors evaluated HRQL and PTSD in a cohort of 80 ARDS survivors 4 years following discharge from the ICU. Almost a third of the ARDS survivors reported impaired memory, bad dreams, anxiety, and sleeping difficulties after ICU discharge, with a prevalence rate of PTSD of 28%. PTSD was related to the number of adverse ICU-related memories recalled by patients. Other authors61,62 also have noted this relationship. Memory for nightmares or delusions while in the ICU, as well as a complete absence of any ICU memories, also has been perceived as a traumatic event.63 The prevalence of PTSD has been reported to be as high as 38%61 and is a persistent complaint for years after ICU discharge.29,61,63a We are just beginning to fully appreciate how long-standing and debilitating mood disorders are following critical illness and the important contribution they have to decreased HRQL.
Cognitive Impairment in ARDS Survivors
Cognitive impairment represents the major threat to both recovery and quality of life following an acute illness.29 Quality of life is largely determined by the ability to return to baseline level of cognitive performance.24,28,56 Long-term cognitive dysfunction—even when modest—results in vastly increased medical and disability costs. For example, a 3-point decrease on the Mini Mental State Exam was associated with increased overall health care expenditures of $6000 per year.29 The per-patient societal cost burden for even mild cognitive impairments is over $15,000 per year, and it is considerably higher ($34,515) for individuals with moderate to severe cognitive dysfunction.64
Cognitive impairments have been observed in a variety of patient populations with hypoxia.65–73 Hypoxia-related cognitive impairments include memory deficits,74 executive dysfunction,74,75 visual-spatial deficits,77 and intellectual decline.73,77 Critical illness, including ARDS, is associated with significant cognitive dysfunction.28,29,78,79 Approximately 33% of ICU survivors develop cognitive impairments that are similar to the cognitive dysfunction observed in mild dementia.66 Cognitive impairments are a major determinant of the ability to return to work, work productivity, and life satisfaction following cardiac surgery,80,81 traumatic brain injury,82 and ARDS.29 Even mild cognitive dysfunction results in clinically significant difficulties in driving, money management, and activities of daily living.83–87 Data obtained from interviews with seriously ill patients indicate that 90 percent of these patients would rather die than survive with cognitive disability.88
Hopkins and colleagues28 published the seminal long-term cognitive outcome study in ARDS survivors in 1999. In this natural history cohort, they found that 100% of ARDS survivors had cognitive impairments, including memory, attention, concentration, and decreased intellectual function, at the time of hospital discharge. At 1-year follow-up, 30% of the survivors had decreased intellectual function, and 78% had impaired memory, attention, concentration, and/or mental processing speed. ARDS survivors had significantly lower IQ than their estimated premorbid IQ (p ≤0.05) and the measured IQ 1 year later.
Hopkins and colleagues28 hypothesized that hypoxia may be an important contributor to cognitive dysfunction in ARDS survivors, and they undertook a detailed assessment of oximetry during the period of critical illness. The ARDS survivors' oximetry was measured for a total of 31,665 hours, with a mean of 609 ± 423 hours. The patients' mean oxygen saturations and their duration were outlined as follows: <90% = 122 ± 144 hours, <85% = 13 ± 18 hours, and <80% = 1 ± 3 hours. On average, these patients had 25 episodes of oxygen desaturation of less than 90% and 1 episode of desaturation of less than 85% for a duration of more than 2 hours. In this cohort, the degree of hypoxia was significantly correlated with neurocognitive sequelae (r2 = 0.25–0.45, all p <0.01).28
Since the Hopkins and colleagues report of cognitive impairments in ARDS survivors, other groups have confirmed their findings.29,57,78 In a retrospective study of 33 ARDS survivors, Marquis and coworkers78 reported impaired attention, visual processing, psychomotor speed, and cognitive flexibility compared with critically ill control subjects. Rothenhäusler and colleagues29 retrospectively evaluated 46 ARDS survivors and found that 24% had cognitive impairments and 41% were disabled and could not return to work. Limitations of this study were low follow-up rate and the administration of one brief cognitive test that assessed only memory and attention. A study of self-reported memory problems in the Toronto ARDS Outcomes cohort found that 20% of ARDS survivors rated their memory as poor 18 months following their ICU discharge.57
Cognitive impairments occur in a significant number of ARDS survivors at 1 year, with little improvement at 2 years after hospital discharge.89 In their recent prospective 2-year follow-up study, Hopkins and colleagues28 assessed cognitive outcome in 71 consecutive ARDS survivors treated with higher and lower tidal volume strategies. The result was that 59% and 43% of patients had evidence of cognitive dysfunction (>1.5 SD below the mean) in at least two cognitive domains at 1- and 2-year follow-up, respectively. Cognitive performance at hospital discharge was significantly lower than at 1- and 2-year follow-up (p <0.001). There were no significant differences between 1- and 2-year cognitive outcomes except improvement in performance IQ. Cognitive impairments at 1 and 2 years correlated with duration of hypoxemia, but they were not associated with gender, type of ventilator treatment, mean blood pressure, or time on sedative medications.
The recent report entitled, “Surviving Intensive Care: A Report from the 2002 Brussels Roundtable,” indicated that future investigations should prioritize studies of cognitive impairments in survivors of critical illness.90 Cognitive dysfunction in ARDS survivors is prevalent, with impairments reported in up to 78% of patients in some studies.28 It represents significant morbidity and is a major obstacle to recovery in severely ill patients. The etiology of the cognitive impairments is likely multifactorial and the subject of ongoing debate, but the paper by Hopkins and colleagues28 already has demonstrated a relationship to hypoxia, and several recent studies have demonstrated an association between delirium and cognitive impairments in critically ill patients.91,92 For a detailed review of delirium in this book, see Chap. 62. Future investigations are required to further delineate etiology and to identify interventions that may improve or prevent cognitive impairment in ARDS survivors.
Brain Tissue Loss after ARDS
Hypoxia and/or ischemia damage the hippocampus in humans,74,93–95 rats,96 and monkeys.97 Research in humans using quantitative magnetic resonance imaging (MRI) analysis of neural structures shows significant reductions in hippocampus volume associated with hypoxia but not in the nearby areas of the parahippocampal gyrus or the temporal lobe.75,94,95,98 Using quantitative MRI, brain morphologic changes, including ventricular enlargement, cerebral atrophy, and hippocampal atrophy, have been found in patients with pulmonary disorders following anoxia,98 asthma,99 carbon monoxide poisoning,73,100 and obstructive sleep apnea.68,69,101 Carbon monoxide poisoning and its concomitant hypoxia result in acute demyelination, generalized cortical atrophy,73 and discrete lesions in the basal ganglia,102 thalamus,103 substantia nigra,104 and white matter.72 Hopkins and colleagues reported recently generalized atrophy68 and atrophy of both gray and white matter structures, including the corpus callosum,105 fornix,106 and hippocampus,74,94,95 following carbon monoxide poisoning.
In light of their prior work linking hypoxia to morphologic changes in the brain and cognitive dysfunction, Hopkins and colleagues sought to evaluate whether there was a structural correlate for hypoxia and impaired cognition in ARDS survivors. They compared computed tomographic (CT) brain scans of 15 ARDS patients with those of normal age- and gender-matched controls (with normal scans) using quantitative image analysis.107 ARDS survivors exhibited brain atrophy, significantly enlarged ventricles, and an increased ventricle-to-brain ratio (another measure of generalized atrophy and an indirect index of white matter integrity) compared with the matched controls. The generalized brain atrophy, which was similar morphologically to that found in carbon monoxide poisoning, was associated with cognitive dysfunction.