Risk factors for long-term cognitive impairment comprise a combination of irreversible clinical factors, potentially modifiable clinical complications of provider interventions, and pathophysiological events that may occur in the natural history of ARDS in brain injury. Figure 1 illustrates the confluence of these factors and how they may culminate in an adverse long-term cognitive outcome. The heterogeneity of ARDS etiology and severity can expose patients to varying balances of these factors: for instance, ARDS of a pulmonary etiology may expose patients to more severe hypoxemia, whereas ARDS related to sepsis may expose patients to more severe inflammatory activation, while overall disease severity can impact length of stay.

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) Full size image

Pre-existing cognitive impairment and the interface of delirium and dementia

Pre-existing cognitive impairment is a risk factor for cognitive decline after critical illness [25, 26], though data are limited by under-recognition of pre-existing cognitive impairment [14] or exclusion of patients with pre-existing cognitive impairment from longitudinal follow-up studies [1, 6]. Alzheimer’s disease, characterized by cerebral accumulation and deposition of the amyloid-β peptide, is the most common type of cognitive impairment [27, 28]. Although one third of elderly patients admitted to the intensive care unit have pre-existing cognitive impairment, this history is often unknown to their medical teams [14], in turn precluding comparisons of pre-morbid versus longitudinal cognitive performance. Among patients confirmed not to have pre-existing dementia, one study found hospitalization itself significantly associated with a greater likelihood of developing dementia, along a temporal pattern of abrupt, rather than gradual, cognitive decline [29].

Delirium during critical illness predicts long-term cognitive decline after ARDS [1, 4, 26], and longer durations of delirium in critically ill patients predict more severe cognitive impairment at 1-year follow-up [30]. The closely intertwined relationship between delirium and pre-existing cognitive impairment raises a physiological question: does long-term cognitive impairment following ARDS reflect a reduction in the threshold for developing delirium due to underlying Alzheimer’s pathology, or does delirium contribute independently to this end? It is known that pre-existing cognitive impairment is a key underlying risk factor for delirium, which affects as many as 70–87% of critically ill patients [31, 32]. Particularly among the elderly, ICU delirium can persist during hospitalization following transfer from the ICU in 40–50% of patients, commonly with incomplete resolution by discharge [33]. A meta-analysis of long-term sequelae of delirium in elderly patients found increased risk of developing dementia within 3–5 years of discharge, with an odds ratio of 12.52 (95% CI 1.86–84.21) [34]. Patients with Alzheimer’s disease, when hospitalized, are three times as likely as adults without dementia to experience delirium; cognitive deficits can persist up to 5 years after discharge [25]. Clinically, patients with Alzheimer’s disease who experience delirium suffer accelerated cognitive decline beyond the natural course of dementia alone, with twofold increases in the slope of decline [35]. Recent pathology-based studies corroborate delirium-associated acceleration of cognitive decline independent of pre-existing dementia pathology [36].

Delirium subtypes and pathways

Studies of the pathophysiology of short- and long-term cognitive impairment reflect similarities and differences between delirium and dementia pathways, in which pre-existing pathophysiology diminishes the reserve with which to face acute insults. Shared mechanistic features of dementia and delirium include synaptic disconnection resulting from the loss of presynaptic terminals, diminished cholinergic activity leading to impaired arousal and inattention, and microglial activation perpetuating systemic inflammation [37]. Girard et al. classify the phenotypes of delirium in the intensive care unit into five subtypes: sedative-associated, hypoxic, septic/inflammatory, metabolic, and unclassified [30]. Among these, the duration of metabolic delirium is not associated with long-term adverse cognitive outcomes [30]. Pathophysiologically, MacLullich et al. classify the etiologies of delirium into two categories: direct brain insults—primary insults such as hemorrhage, hypoxia, hypoperfusion, or drugs—versus aberrant stress responses—the dysfunction of ordinarily adaptive responses to acute systemic stressors such as infection or trauma [38]. Differences in serum markers between patients with inflammatory versus non-inflammatory delirium suggest activation of multiple possible pathways: a systemic inflammation pathway associated with IL-8 elevation among patients with inflammation, and an alternative pathway characterized by elevation of amyloid-β and IL-10 in patients without inflammation, suggesting activation of existing pathways of underlying cognitive impairment [39]. Individual pathophysiological mechanisms may be associated with multiple delirium subtypes in which a single phenotype dominates, and these relationships remain an active area of investigation.

ARDS and hypoxemia: short-term and long-term effects

Profound hypoxemia is one of the cardinal features of ARDS. While, in the short-term, this can predispose patients to hypoxic delirium phenotypes [30], lower PaO 2 levels are associated with long-term cognitive impairment at 12-month follow-up, particularly in the domains of executive function and psychomotor tasks [1, 40].

Inflammation and septic delirium

The production of cytokines TNF-α, IL-6, IL-1α, and IL-1β can produce a constellation of behaviors termed “sickness behavior,” comprising impaired concentration, malaise, diminished motivation, psychomotor retardation, and depression [41], corresponding with septic delirium. In one study, this state was found to be associated with recruitment of additional brain structures in order to maintain the same level of cognitive performance during systemic inflammation [42]. Existing brain injury enhances vulnerability to inflammation: in mouse models of neurodegenerative disease, lipopolysaccharide in brain-injured versus control mice induces compounded cognitive deficits on maze-learning tasks greater than exaggerated sickness behavior alone [43].

Mechanical ventilation and inflammatory and sedative-associated delirium

Mechanical ventilation is independently associated with persistent cognitive impairment, diminished quality of life, and depression [44]. One third of mechanically ventilated patients perform abnormally on neurocognitive testing at 6 months, comprising deficits in visuo-construction, visual memory, psychomotor speed, and verbal fluency [44]. Accelerated Alzheimer’s disease-type pathophysiology can follow short-term high-tidal-volume mechanical ventilation in mice, including impaired β-amyloid clearance, increased inflammation mediated by TNF-α and IL-6, and altered blood-brain barrier permeability [45]. Prolonged courses of mechanical ventilation in ARDS also expose patients to sedating medications and anesthesia. Among delirium subtypes, sedative-associated delirium is the most common and, with prolonged duration, associated with the greatest degree of long-term cognitive impairment at 12 months following discharge [30]. Among sedative types, benzodiazepines impart the greatest risk for delirium, while dexmedetomidine has been associated with lower risk for delirium [46]; however, data and practice choices are limited, as most intensive care unit patients are treated with multiple sedatives [30]. The effect of paralytic exposure on long-term cognitive outcomes is unknown [3]. Continuous exposure to sedative medications over several days results in impaired sedative clearance, in turn exacerbating delirium [30]. In addition to inducing acute-on-chronic cholinergic transmission dysfunction in elderly patients, transient axonal damage may represent another mechanism by which sedatives can contribute to long-term cognitive decline [47].