key: cord-0793401-lysfrat5
authors: Palakshappa, Jessica A.; Krall, Jennifer T.W.; Belfield, Lanazha T.; Files, D. Clark
title: Long-Term Outcomes in Acute Respiratory Distress Syndrome: Epidemiology, Mechanisms, and Patient Evaluation
date: 2021-05-27
journal: Crit Care Clin
DOI: 10.1016/j.ccc.2021.05.010
sha: 6d4bfcb66629fed12b97a05df78384f9f219b00a
doc_id: 793401
cord_uid: lysfrat5

Survivors of ARDS experience challenges that persist well beyond the time of hospital discharge. Impairment in physical function, cognitive function and mental health are common and may last for years. The current COVID-19 pandemic is drastically increasing the incidence of ARDS worldwide, and long-term impairments will remain lasting effects of the pandemic. The evaluation of the ARDS survivor should be comprehensive and systematically evaluate common domains of impairment that have emerged from long-term outcomes research over the past two decades.

J o u r n a l P r e -p r o o f Pulmonary. Patients with ARDS experience severe problems with gas exchange, causing 131 profound hypoxia and necessitating mechanical ventilation. Lung injury resolution is a complex 132 and coordinated response that begins from the onset of injury and has been extensively 133 reviewed by others. 2 When successful, lung injury recovery results in liberation from mechanical 134 ventilation. However, residual pulmonary injuries such as fibrosis and pulmonary diffusion 135 impairments may be present following hospital discharge and may influence a patient's long-136 term physical function. Through the mid-1990s, research in long-term outcomes following ARDS 137 focused primarily on pulmonary recovery. 13, 24, 25 In most survivors of ARDS, pulmonary function 138 returns to normal within 6 to 12 months despite severe initial lung injury. 26 Residual pulmonary 139 function impairments are often asymptomatic and include mild restriction or obstruction or mild 140 reduction in diffusing capacity. 14,27,28 141

Radiographic evidence of ARDS often persists beyond symptomatic and pulmonary 142 function recovery. In 1999, Desai et al. described the acute and late phase computerized 143 tomography (CT) scan patterns following ARDS. While ground glass opacification and 144 consolidation are reported in the early phase, a reticular pattern is more common in the late 145 phase and associated with duration of mechanical ventilation. 29 The Toronto ARDS Outcomes 146 Study Group reported CT imaging findings 5 years after severe ARDS between 1998 and 147 2001. 30 Pulmonary CT imaging abnormalities were found in the majority of patients (75% of 24 148 patients) but were generally minor and in the non-dependent lung regions. In this study, no 149 correlation was found between radiographic findings and symptoms, pulmonary function tests, 150 or health-related quality of life measures, suggesting the long-term impairments patients face 151

following ARDS are complicated and are likely not secondary to structural lung disease in the 152 majority of patients. 153 J o u r n a l P r e -p r o o f

The long-term pulmonary manifestations of COVID-19 ARDS will be realized as more 154 COVID-19 ARDS survivors are studied in follow-up. Emerging data indicate that many patients 155 experience persistent respiratory complaints. 31 Efforts are underway worldwide to enroll COVID-156 19 survivors in long-term follow-up. One such study in the United States, called Blue Coral, is 157 prospectively enrolling patients with severe COVID-19, and includes long term follow-up in a 158 subset of these patients (https://petalnet.org/studies/public/bluecoral). 159 160 Neuromuscular. The skeletal muscle system, a major target in ARDS, has often been 161 overlooked as an organ of injury. The loss of muscle mass and function during critical illness 162 has long been recognized since the time of Osler, but it was not until the 1990s that case series 163 emerged reporting profound neuromuscular weakness in heterogeneous cohorts of critically ill 164 patients. 32-38 A variety of terms, such as acute quadriplegic myopathy, thick filament myopathy, 165 critical illness myopathy, and critical illness polyneuropathy, were used to describe the varied 166 electrical and pathologic patterns of neuromuscular injury seen in these patients, often after 167 receiving prolonged mechanical ventilation. [39] [40] [41] [42] In 2003, a landmark observational study 168 carefully quantified injury to the neuromuscular system in a cohort of critically ill patients on 169 mechanical ventilation for > 7 days, using a clinical exam, electrophysiology and muscle 170 biopsies. 43 This work coined the term "Intensive Care Unit Acquired Paresis", which later 171 became known as "Intensive Care Unit Acquired Weakness (ICUAW)". 44 In the 25% of patients 172 in this cohort that met this criteria for severe muscle weakness, characterized by Medical 173

Research Council (MRC) sum score of <48 of 60, all patients had electrophysiologic or 174 pathologic neuromuscular injury. Importantly, patients who met this clinical diagnosis of ICUAW 175 had increased short-and long-term mortality, a finding confirmed in subsequent studies 45-47 176 Those who remained severely weak following hospital discharge had an increased risk of death 177 in follow up, highlighting ICUAW as a risk factor for subsequent mortality. 178 J o u r n a l P r e -p r o o f

The mechanisms driving muscle wasting in ARDS are complex and incompletely 179 understood. However, patients with ARDS universally experience muscle wasting (loss of 180 muscle mass and function) of the limb and respiratory muscles to variable degrees. 181

Electromyography and nerve conduction studies may reveal predominantly neuropathic (critical 182 illness polyneuropathy), myopathic (critical illness myopathy), or mixed (critical illness 183 neuromyopathy) patters of injury in severe cases. 48 the ROSE randomized controlled trial of cisatracurium versus placebo in early ARDS found no 205 increase in ICUAW incidence through day 28 (47% cisatracurium group vs 39% in placebo 206 group), though missing data for this secondary outcome was common. 63 207

Skeletal muscle wasting that occurs during ARDS is likely a major driver of reduced 208 physical function in ARDS survivors observed during long-term follow-up. Certain risk factors 209 and ICU exposures have been variably implicated in the development of muscle weakness in 210 long-term follow-up. In cohorts of patients with acute respiratory failure requiring mechanical 211 ventilation, increased age, severity of illness, comorbid illness, and ICU length of stay have 212 been associated with long-term physical function impairment. 26, [64] [65] [66] One study suggests that 213 compliance with low tidal volume ventilation reduces long-term mortality, even when adjusting 214 for hospital mortality. 12 Similarly, in a randomized trial of an ICU and hospital based physical 215 therapy intervention in patients with severe acute respiratory failure, patients randomized to the 216 intervention arm had improved physical function in long-term follow-up, despite no measured 217 benefit at hospital discharge. 67 Collectively these data suggest that ICU exposures during 218 hospitalization with ARDS may influence long-term outcomes such as mortality and physical 219 function. 220

One interesting observation is that ARDS survivors follow different physical function 221 recovery trajectories. Risk factors such as age, male sex, longer lengths of stay and hearing or 222 vision loss are more likely to remain functionally impaired. 64, 65, 68 The mechanisms underlying 223 failed versus successful recovery are incompletely understood, though some clues are 224 emerging. Muscle biopsies from humans with long term weakness following critical illness show 225 a transcriptomic signature consistent with failed muscle regeneration. 69 Patients with sustained 226 muscle atrophy have decreased muscle stem (satellite) cell content. 70 Future work is needed to 227 better understand potential mechanisms underlying the muscle recovery of ARDS survivors, 228 and this mechanistic work and trajectory analyses will contribute to tailored approaches to study 229 specific ARDS long-term endotypes. 230

Lastly, it is important to recognize that not all deficits identified following a critical illness 231 are due to critical illness itself. 71 Longitudinal cohorts that measured physical function and deficit 232 accumulation prior to and following critical illness have demonstrated this finding. 72, 73 These 233 studies found that many deficits were accumulating prior to the incident illness. Indeed, these 234 pre critical illness functional deficits influence mortality and long-term functional 235 impairment. 72, 74, 75 Failure to recognize pre critical illness physical function in ARDS survivors 236 results in misattribution and could lead to frustration on the part of both clinicians and patients. 237 238 Cardiovascular. While less well described than pulmonary and muscle injury during ARDS, 239 cardiac injury does occur in a subset of patients and may contribute to long-term morbidity and 240 mortality. Troponin elevation is found in at least 90% of patients hospitalized with ARDS or 241 sepsis and appears to be correlated with severity of illness. 76,77 Elevated cardiac biomarkers 242 during critical illness have been associated with long-term mortality. 78 prevalence of cognitive impairment varies based on subpopulation studied, timing of 264 assessment, and cognitive assessment tool used. In a prospective study by Hopkins and 265 colleagues (n=106; 62 followed for one year), 78% of patients were cognitively impaired on a 266 neuropsychological battery at one-year follow-up. 83 In a subsequent study (n=120), participants 267 underwent comprehensive neuropsychological testing at hospital discharge, one year, and 2 268 years. The majority of participants in this cohort (78%) were impaired at hospital discharge, 46% 269

at 1 year, and 47% at 2 years. 84 In NHLBI ARDNet studies, longitudinal outcome data also 270 supports the conclusion that cognitive impairment following ARDS is common and persistent. In 271 long-term outcome assessments following the EDEN trial, 25% of patients were cognitively 272 impaired on the Mini Mental State Examination Telephone version at 6 months and 21% at 12 273 months. 85 Following the Statins for Acutely Injured Lungs in Sepsis (SAILS) study, cognitive 274 impairment was present in 37% of ARDS survivors at 6 months and 29% at 12 months. 86 In a 275 large multicenter, prospective cohort study of a diverse population of patients in general medical 276 and surgical ICUs, many of whom were intubated and likely had ARDS, one out of four patients 277 had cognitive impairment 12 months after critical illness to the degree seen in patients with mild 278

Alzheimer's disease and one out of three had impairment to the degree seen in patients with 279 moderate traumatic brain injury. 87 In this cohort, impairments were found in broad range of 280 domains, more than just memory, including executive functioning. While we do not yet know the 281 prevalence of cognitive impairment following COVID-19 ARDS, early research suggests that 282 neurologic features are often present during acute COVID-19 infection. 88-90 Also, the population 283 at highest risk for severe COVID-19 infection overlaps significantly with those at risk for 284 cognitive decline (advanced age, obesity, diabetes) and we can expect there may be an There are multiple pathways by which critical illness may lead to new or worsening 297 cognitive impairment. Hypoxemia is common in patients with ARDS and the hippocampus is 298 susceptible to hypoxic insults. 98 Neuroimaging studies of ARDS survivors demonstrate 299 accelerated cerebral and hippocampal atrophy. 99 Autopsy studies of ARDS patients whose 300 critical illness was complicated by delirium have also shown hippocampal hypoxic ischemic 301 lesions. 100 Damage to the endothelial glycocalyx has been linked with long term cognitive 302 impairment in a preclinical model and humans with sepsis. 101 While hippocampal ischemic injury 303 may be an important contributory cause of cognitive impairment, animal studies suggest that 304 cytokine-mediated injury from mechanical ventilation may also play a central role. In a porcine 305 model of ARDS, cytokine-mediated brain damage from lung injury was found to be the major 306 pathophysiological contributor to hippocampal damage, rather than hypoxemia. 102 This was 307 supported by a pig model of mechanical-ventilation induced ARDS that found cognitive 308 impairment was greater in the lung injury group (with evidence of more inflammation) compared 309 to the hypoxia-only group. 103 Mechanical ventilation has also been shown to trigger hippocampal 310 apoptosis in mechanically ventilated mice. 104 311

Damage to the blood-brain barrier and amyloid-β clearance have also been proposed as 312 potential mechanisms for the cognitive impairment seen following ARDS. Similarities between 313 the pathophysiology of Alzheimer's disease (primarily accumulation of amyloid-β) and the acute 314 sequelae of high-tidal volume mechanical ventilation in mice suggest there may be a 315 mechanistic link between delirium, Alzheimer's disease, and the underlying cognitive damage 316 reported following ARDS. 105,106 Chronic accumulation of amyloid-β contributes to baseline blood-317 brain barrier weakening which, in turn, may result in an increased susceptibility to hippocampal 318 exposure to cytokines and cytokine-mediated damage in patients with underlying cognitive 319 impairment and Alzheimer's disease. Finally, emerging data suggest that bacterial translocation 320 to the brain in sepsis may contribute to delirium and cognitive impairment. 107 While the causal 321 mechanisms are likely complex, it is clear there is a link between the lung and brain injury seen 322 in ARDS. 323 324 Mental Health. Mental health symptoms have been described in a significant proportion of 325 ARDS survivors. Among 629 patients enrolled in three ARDNet trials with at least one 326 psychiatric measure, two-thirds had substantial symptoms in one or more domain during one-327

year follow-up. 108 At 6 months, prevalence of substantial symptoms of depression, anxiety, and 328 post-traumatic stress disorder (PTSD) was 36%, 42%, and 24%. The majority of survivors 329 (63%) with any psychiatric morbidity had substantial symptoms in two or more domains 330 suggesting co-occurrence of mental health symptoms is common. In this study, severity of 331 illness, mechanical ventilation duration, and ICU length of stay were not associated with worse 332 psychiatric symptoms; younger age, female sex, baseline unemployment, alcohol misuse, and 333 greater in-ICU opioid use were associated with post-ICU psychiatric symptoms. In a systematic 334 review by Davydow and colleagues, the median point prevalence of depression, PTSD, and 335 nonspecific anxiety were similar at 28%, 28%, and 24% respectively. 109 ARDS influences long-term health domains beyond physical and mental health for both 356 patients and families. A multi-center study in the United States found that nearly half of 357 previously employed ARDS survivors were jobless at 12 months following their illness. 114 Those 358 that return to work often experience job loss, occupation change, or worse employment 359 status. 115 Noted barriers to returning to work include persistent fatigue and weakness, poor 360 functional status, work-related stress, and the need for job retraining. Studies have uncovered 361 significant financial burdens on ARDS survivors. One study of survivors found that average 362 costs per patient from years 3 through 5 ranging from were $5,000 to $6,000, close to costs 363 They also describe a lack of support after hospital discharge and significant strain both 376 emotionally and financially with often a new caregiving role. Emerging data suggests that ARDS 377 has a substantial impact on the long-term outcomes of both patients and their families. 378

One overarching problem with the long-term outcomes field has been a lack of 379 standardization of the assessment tools across different research studies. There has been an 380 attempt to standardize the tools that clinical researchers employ to measure long-term 381

outcomes, to bring uniformity to this issue. 120 Investigators designing studies should employ 382 these core outcome measures, which can also be found on https://www.improvelto.com/coms/ 383

Detailed and comprehensive prospective observational studies have greatly impacted 385 the field of critical care and established the basic epidemiology and many of the risk factors for 386 persistent impairments following ARDS. 121 Through the work of a three-round modified Delphi 387 process, a core set of outcomes now exists for clinical research of acute respiratory failure, 120 388 which will allow even greater comparison across cohort studies and the incorporation of these 389 important outcomes in ICU and post-ICU clinical trials. While there is growing consensus around 390 the recommended evaluation of long-term outcomes following ARDS in clinical research, much 391 less is known about the optimal evaluation of patients post-ARDS as part of routine clinical care. 392

To increase the awareness of long-term consequences of critical illness, the term "post-393 intensive care syndrome" (PICS) has been used to refer to the physical, cognitive, and/or 394 test and/or the EuroQol-5D-5L. 125 The initial assessment is recommended to occur within 2 to 4 402 weeks of hospital discharge and again with important life or health changes. While the impact 403 of screening ARDS survivors with these particular tools on longer-term outcomes (such as 404 subsequent morality or improvements in persistent impairments) has not been studied, we 405 agree that these tools serve as a good place to start in the post-ICU evaluation of ARDS 406 survivors. For those patients with subjective complaints of muscle weakness, a global 407 assessment of muscle strength using the MRC scale or handheld dynamometers can also be 408 useful, particularly if following patients longitudinally. While not included in the SCCM 409 recommendation, the short physical performance battery (SPPB), a tool extensively validated in 410 the geriatric population and with increased use in the post ICU population, may be a useful 411 adjuvant. The SPPB evaluates lower extremity strength, balance and gait speed and can be 412 completed in 5 minutes. 126 It may compliment the 6 minute walk test and provide insight into 413 balance and lower extremity strength, which are key for maintaining functional independence. 414

While the majority of patients will have improvement in physical function in the weeks 415 and months following hospital discharge, there will be some that report a persistent impairment 416 in exercise tolerance. 66 In those patients, pulmonary function testing, chest imaging with 417 computed tomography and echocardiography might be helpful to assess for post-ARDS 418 pulmonary and cardiac injury. Patients who complain of impaired exercise tolerance without a 419 clear etiology from this initial evaluation may benefit from a cardiopulmonary exercise test. 420 through standardized tests such as the SPPB or six-minute walk distance may assist in guiding 431 a tailored approach to assess deficits in balance, strength or endurance. Repeat functional 432 testing over time can be useful to gauge recovery or lack thereof over time. 433

There has been a growing attention to the assessment of long-term outcomes following 434 COVID-19 in patients both with and without ARDS. An International Task Force sponsored by 435 the American Thoracic Society and the European Respiratory Society has suggested that 436 obtaining pulmonary function testing and chest computerized tomography scans as well as a 437 transthoracic echo may be useful in the evaluation of post-COVID ARDS patients and should be 438 obtained for those with persistent symptoms, but there is no evidence at present to support 439 widespread screening with these tests in all patients recovering from COVID-19 or even COVID-440 19 ARDS. 129 In a more recent publication, the International Task Force recommends 441 rehabilitation for those with persistent limitations and suggests pulmonary rehabilitation as a 442 useful framework. 130 Based on what is known regarding long-term outcomes following ARDS, 443 they also recommend a formal assessment of physical and emotional functioning at 6 to 8 444 weeks to identify unmet rehabilitation needs. 130 We anticipate our understanding of the clinical 445 evaluation of ARDS patients will deepen as we learn from patients recovering from COVID-19 in 446 the coming months. 447 448

Long-term impairments in physical function, cognitive function, mental health and other domains 450 are common after ARDS. In the pre-COVID19 era, long-term outcomes from ARDS became 451 apparent as mortality from ARDS decreased. In the post-COVID-19 era, long-term outcomes 452 will become a significant problem due to the massive increase in ARDS associated with the 453 pandemic. This lasting effect of the COVID-19 pandemic will persist long after the acute illness 454 diminishes. Providers should be prepared to care for the myriad of problems that are of 455 significant importance to patients and families experiencing ARDS. in recognition and prevalence of long-term impairments. In the post-COVID-19 era, there is an 484 anticipated exponential increase in long-term impairments following ARDS even as 

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