Intensive care medicine has dramatically evolved over the last 15 years, after reports from many landmark trials.1 Updated strategies for mechanical ventilation2 and “bundles” of strategies to optimize hemodynamic therapy3 have reduced the rates of morbidity and death from deadly critical conditions such as the adult respiratory distress syndrome (ARDS) and sepsis.
Despite these important improvements in short-term outcomes, it is increasingly recognized that intensive care unit (ICU) survivors suffer considerable long-term complications that affect their usual functioning.4 Recently, the Society of Critical Care Medicine convened a conference in which these long-term complications were named the “post-intensive care syndrome.”5
Quality of life, particularly its physical component, is considerably lower after a stay in the medical or surgical ICU.6–8 Posttraumatic stress disorder, depression, and sexual dysfunction are consistently reported years after ICU discharge.9–13
Perhaps the most frequently unrecognized complication in ICU survivors is cognitive impairment. Current data suggest that neurocognitive impairment after an ICU stay is common and that it persists 6 years or more after hospital discharge.
Hopkins et al14,15 analyzed 10 cohort studies of long-term cognitive impairment after an ICU stay; 5 of them focused on patients with ARDS. The prevalence of cognitive impairment was as high as 78% at hospital discharge, 46% at 1 year, and 25% 6 years after discharge.15,16 Of the cognitive domains compromised, memory was the most often affected, followed by executive function and attention.14,17
Interestingly, data suggest that cognition may improve somewhat in the first 6 to 12 months after ICU discharge.15 Therefore, if we can detect it early on and promptly refer patients for cognitive therapy, we may eventually improve the prognosis of this disabling complication.
This review will focus on how to evaluate, prevent, and treat cognitive impairment in patients who survive an ICU stay.
COGNITIVE IMPAIRMENT AFTER A STAY IN THE ICU
The association between ICU stay and neurocognitive dysfunction is poorly understood. Potential causes include hypoxemia,18 hypotension, 19 hyperglycemia,14 and—an area of growing interest and evolving research—sedation and delirium.20
Patients on mechanical ventilation are commonly given sedatives and analgesics to prevent anxiety and pain.21 However, these medications are strongly associated with delirium.22 In fact, recent studies found that benzodiazepines have an independent, dose-related, temporal association with delirium, with some reports describing a 20% increase in delirium per milligram of benzodiazepine.23 In another study, which included medical and surgical ICU patients, use of morphine was the strongest predictor of delirium, with a sixfold increase in odds over a period of 5 months.24
Delirium is important to prevent, diagnose, and treat, since it has a direct association with the development of long-term cognitive impairment.22,25 A review of studies that included 1,885 medical and surgical patients found that those who developed delirium during an ICU stay were three times more likely to have cognitive dysfunction when assessed 3 years later.20
Whether delirium is a primary disorder associated with cognitive impairment or if it only represents an underlying process leading to poor cognitive outcomes is unknown. As delirious patients are more likely to be older, to be mechanically ventilated, to require more sedation, and, in particular, to be sicker, the association between delirium and cognitive impairment may reflect the relationship between these risk factors and poor cognitive outcomes.26
Glucose and its relationship with cognitive function is another topic of investigation. A secondary analysis of a study that included ARDS survivors revealed that blood glucose values higher than 153 mg/dL, higher glucose variability, and duration of mechanical ventilation were associated with cognitive sequelae.27,28
Other studies focused on mechanical ventilation. In one study,29 one-third of patients who had been mechanically ventilated showed signs of neurocognitive impairment when they were evaluated 6 months after hospital discharge.
Mild cognitive impairment differs from cognitive impairment after an ICU stay
Cognitive impairment after ICU discharge does not follow the same pattern as mild cognitive impairment, and some authors consider these two types of cognitive impairment to be unrelated.
While mild cognitive impairment is progressive and associated with aging, cognitive impairment in ICU survivors develops rapidly after acute illness and is usually related to numerous pathologic and neurochemical pathways.
For example, the neurotransmitter acetylcholine is thought to be involved in cognitive function as well as neuroplasticity of the motor cortex. In a model of cognitive impairment after stroke, activity of the cholinergic system was reduced.30,31 Further, in a study in rats, Baskerville et al32 showed that experience-dependent plasticity could be completely blocked by damaging the cholinergic neurons in the nucleus basalis of Meynert, thereby affecting memory and other functions supported by this pathway.
Another implicated pathway involves dopamine. Of interest, dopamine augmentation has been shown to enhance simple motor memories and to improve procedural learning. Understanding of these neurochemical alterations opens opportunities for investigation of drug therapies.