Long-term cognitive impairment after acute respiratory distress syndrome: a review of clinical impact and pathophysiological mechanisms

Abstract

Acute respiratory distress syndrome (ARDS) survivors experience a high prevalence of cognitive impairment with concomitantly impaired functional status and quality of life, often persisting months after hospital discharge. In this review, we explore the pathophysiological mechanisms underlying cognitive impairment following ARDS, the interrelations between mechanisms and risk factors, and interventions that may mitigate the risk of cognitive impairment. Risk factors for cognitive decline following ARDS include pre-existing cognitive impairment, neurological injury, delirium, mechanical ventilation, prolonged exposure to sedating medications, sepsis, systemic inflammation, and environmental factors in the intensive care unit, which can co-occur synergistically in various combinations. Detection and characterization of pre-existing cognitive impairment imparts challenges in clinical management and longitudinal outcome study enrollment. Patients with brain injury who experience ARDS constitute a distinct population with a particular combination of risk factors and pathophysiological mechanisms: considerations raised by brain injury include neurogenic pulmonary edema, differences in sympathetic activation and cholinergic transmission, effects of positive end-expiratory pressure on cerebral microcirculation and intracranial pressure, and sensitivity to vasopressor use and volume status. The blood-brain barrier represents a physiological interface at which multiple mechanisms of cognitive impairment interact, as acute blood-brain barrier weakening from mechanical ventilation and systemic inflammation can compound existing chronic blood-brain barrier dysfunction from Alzheimer's-type pathophysiology, rendering the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated hippocampal damage. Although some contributory elements, such as the presenting brain injury or pre-existing cognitive impairment, may be irreversible, interventions such as minimizing mechanical ventilation tidal volume, minimizing duration of exposure to sedating medications, maintaining hemodynamic stability, optimizing fluid balance, and implementing bundles to enhance patient care help dramatically to reduce duration of delirium and may help prevent acquisition of long-term cognitive impairment.

Keywords: ARDS; Blood-brain barrier; Cognitive impairment; ICU delirium; Inflammation; Mechanical ventilation; Outcomes; Pathophysiological mechanisms.

Fig. 1

Confluence of clinical risk factors and pathophysiological events culminating in cognitive impairment following ARDS and brain injury. Combinations of irreversible clinical risk factors, pathophysiological events, and modifiable clinical risk factors, each occurring to varying extents, produce an aggregate sum of risk for long-term cognitive impairment. Cognitive outcomes reflect a continuum up to a threshold beyond which a patient is likely to experience an adverse outcome, defined as long-term cognitive impairment. The aggregate sum of these factors can bring the patient’s risk for long-term impairment closer toward this threshold (the upward trajectory indicated by the red arrow); however, minimization of modifiable clinical factors can bring the aggregate sum further away from the threshold, promoting a less adverse cognitive outcome (the downward trajectory indicated by the green arrow)