The prevention of perioperative neurocognitive disorders is a priority for patients, families, clinicians, and researchers. Given the multiple risk factors present throughout the perioperative period, a multicomponent preventative approach may be most effective. The objectives of this narrative review are to highlight the importance of sleep, pain, and cognition on the risk of perioperative neurocognitive disorders and to discuss the evidence behind interventions targeting these modifiable risk factors. Sleep disruption is associated with postoperative delirium, but the benefit of sleep-related interventions is uncertain. Pain is a risk factor for postoperative delirium, but its impact on other postoperative neurocognitive disorders is unknown. Multimodal analgesia and opioid avoidance are emerging as best practices, but data supporting their efficacy to prevent delirium are limited. Poor preoperative cognitive function is a strong predictor of postoperative neurocognitive disorder, and work is ongoing to determine whether it can be modified to prevent perioperative neurocognitive disorders.

As older persons increasingly rely on surgical treatment, preventing perioperative neurocognitive disorders including postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorder has become a priority for patients, for families, and for perioperative research.1,2  Defined by an acute, fluctuating disturbance in attention and awareness, postoperative delirium occurs in up to 50% of older patients and is associated with excess hospital costs, higher risk of long-term cognitive impairment, and poor functional outcomes.3,4  Characterized by cognitive deficits in memory and executive function, delayed neurocognitive recovery (diagnosed within 30 postoperative days) and postoperative neurocognitive disorder (diagnosed within 3 to 12 months) were once considered mainly as research outcomes with questionable clinical impact. However, they are now recognized as key barriers to optimal functional recovery after surgery.5,6  For decades, strategies to prevent perioperative neurocognitive disorders by targeting isolated perioperative interventions have produced negative or inconclusive results.7–10  Given that there are numerous potential inciting factors for perioperative neurocognitive disorders, it is likely that multicomponent interventions may be more effective. For example, one of the most successful evidence-based multicomponent prevention strategies is the Hospitalized Elder Life Program (HELP), which has been shown in meta-analysis to consistently prevent delirium in hospitalized older persons.11  There are 14 core interventions in HELP, highlighting the complex and myriad precipitating factors that can contribute to delirium and the challenges faced by clinicians seeking to employ a comprehensive program. The objective of this narrative review is to highlight and expand upon three key intervenable targets to consider in any multicomponent intervention designed to optimize perioperative brain health: sleep, pain, and cognition (fig. 1).

Fig. 1.

The impact of sleep, pain, and cognition on perioperative brain health and postoperative recovery. Here depicted is a patient presenting for orthopedic surgery. The scenarios depict how the patient’s sleep, pain, and cognition are well managed throughout the postoperative period (left). The patient then remains delirium-free in the hospital and returns home at their cognitive and functional baseline (left center). Conversely, if sleep, pain, and cognition are poorly managed (right), the same patient may experience delirium and/or the inability to return to their cognitive and functional baseline (right center).

Fig. 1.

The impact of sleep, pain, and cognition on perioperative brain health and postoperative recovery. Here depicted is a patient presenting for orthopedic surgery. The scenarios depict how the patient’s sleep, pain, and cognition are well managed throughout the postoperative period (left). The patient then remains delirium-free in the hospital and returns home at their cognitive and functional baseline (left center). Conversely, if sleep, pain, and cognition are poorly managed (right), the same patient may experience delirium and/or the inability to return to their cognitive and functional baseline (right center).

Close modal

Sleep, Circadian Rhythms, and Brain Health

Sleep is a complex, naturally occurring physiologic state that is critical to survival and health in animals and humans. A fundamental aspect of ensuring optimal physiologic functions, including sleep, is the adherence to ~24-h cycles known as circadian rhythms, which are thought to be ubiquitous to life on earth. If separated from our environmental and lifestyle choices, sleep–wake cycles are governed by our circadian system via the sleep-promoter hormone melatonin, which peaks during darkness.12 

Sleep appears critical to optimal brain health and cognitive function, but only recently has there been increasing attention within the perioperative field.13,14  What is defined as “normal” sleep varies from individual to individual and with age and comorbid disease. Broadly, the following five dimensions of sleep appear the most relevant to definitions and measurements of sleep health: (1) sleep duration: the total amount of sleep obtained per 24 h, with between 7 and 8 h considered optimal for most; (2) sleep continuity or efficiency: the ease of falling asleep and returning to sleep after awakening; (3) timing of the sleep–wake cycle within the 24-h day; (4) alertness/sleepiness: the ability to maintain attentive wakefulness; and (5) satisfaction/quality: the subjective assessment of “good” or “poor” sleep.13  All sleep “disorders” or “disturbances” can be understood via one or commonly multiple dimensions. For example, insomnia is characterized by difficulty initiating or continuing sleep, but this often leads to lower sleep duration, irregular timings, subjective sleepiness and poor satisfaction/quality.

Unfortunately, as many as one in three people will experience some form of sleep and/or circadian disturbances in their lifetimes; these disturbances often go unaddressed, are increasingly common worldwide, and worsen over time.15–19  Despite clinicians’ familiarity with the diurnal nature of our own sleep and behavioral cycles and the physical and psychologic toll associated with its disruption (e.g., after a busy night on-call), there remains relatively few considerations given to the impact of sleep and circadian disruption in our patients and how it may impact their brain health and overall functional recovery during the perioperative period.

Sleep Disturbance and Delirium

There is now increasing recognition for the potential link between sleep disturbances and perioperative neurocognitive disorders including delirium.20  Sleep/circadian disturbances are more common in older persons and are more pronounced after critical illness and in neurodegenerative diseases such as Alzheimer disease, the very groups most vulnerable to perioperative neurocognitive disorders.19,21–23 

Sleep disruption before surgery has been shown to predict postoperative delirium. In an observational study of 50 adults undergoing major noncardiac surgery in which sleep patterns were assessed objectively the night before surgery with a wearable actigraphy device, patients who developed postoperative delirium had significantly higher measures of preoperative sleep fragmentation including both the percentage of time spent wake after sleep onset (mean [SD], 44% [22%] vs. 21% [20%]; P = 0.012) and frequency of nightly awakenings (mean [SD], 17 [9] vs. 9 [6]; P = 0.047) compared to those without delirium.24  This finding has been demonstrated in other studies and in a recent meta-analysis of data from 12 studies and 1,199 patients in which the pooled odds ratio for postoperative delirium for patients with preoperative sleep disturbances was significantly higher than for those without a preoperative sleep disturbance (odds ratio [95% CI], 5.24 [2.28 to 3.69]; P < 0.001; I2 = 0%).20  Possible shared pathophysiological pathways between sleep disturbance and delirium include altered melatonin metabolism, neurotransmitter imbalance, and reduced neuroprotection from key deficiencies such as vitamin D.25–29  Undergoing major surgery with preexisting sleep disruption makes it likely these symptoms will be exacerbated during the postoperative recovery period as pain, nausea, light, noise, and immobility ensue.

However, based on current evidence, one cannot conclude causation. The extent to which sleep disturbances may cause delirium or vice versa is not yet fully understood, but these two conditions may share a common neuropathology. There is some evidence that poor sleep behavior traits and circadian disruption predicts incident Alzheimer disease, but few large prospective studies exist for sleep and delirium.19,30  Sleep disruption and problems with rest–activity cycles are also comorbid with many conditions relevant to brain health and perioperative neurocognitive disorders including heart failure and pain, and therefore these issues could potentially be a manifestation of underlying disease such as preclinical neurodegeneration.31,32  Whether disordered sleep directly increases the risk of delirium or whether it is indicative of an underlying comorbidity that increases risk may be difficult if not impossible to determine. Testing whether treatment of sleep disorders reduces delirium in controlled studies may be the best way to sort out these direct or indirect effects. How this affects the perioperative physician is also evolving. The role of sleep in the preservation of perioperative cognition is an active area of research, and it may be that sleep disruption comes to be seen as a chronic condition in need of optimization rather than reversal.

Sleep-disordered Breathing, Continuous Positive Airway Pressure, and Delirium

Sleep-disordered breathing is a complex, multisystemic disorder that warrants particular mention. In particular, the obstructive variant of sleep apnea (or OSA) is associated with obesity and increased risk for airway difficulties, adverse cardiac events, postoperative respiratory complications, and perioperative neurocognitive disorders.33  In the general population, OSA is associated with reductions in cognitive reserve, increased risk for cognitive impairment and worsening executive function, and amyloid deposition in key brain regions.34–36  Because many of these findings share characteristics of perioperative neurocognitive disorders, a link between OSA and perioperative neurocognitive disorders has also been proposed. Possible mechanisms underlying the association between OSA and delirium include abnormalities in sleep architecture leading to sleep disruption, hypoxia, vascular injury, low-grade systemic inflammation, oxidative stress, and decrease in insulin growth factor-1, as has been seen with neuronal injury and apoptosis.37 

Using objective polysomnography, preoperative sleep-disordered breathing defined by a high apnea–hypopnea index was associated with more than six-fold increased odds for postoperative delirium (odds ratio [95% CI], 6.4 [2.6 to 15.4], P < 0.001), including patients without an existing formal OSA diagnosis.38  In a small cohort of older patients undergoing elective knee replacement, the incidence of delirium was significantly higher in patients with OSA as compared to those without OSA (8 of 15 [53%] vs. 19 of 95 [20%]; P = 0.0123).39  However, a recent retrospective observational cohort study of 7,792 surgical patients did not find a significant association between preoperative OSA and postoperative delirium after adjustment for perioperative confounders.40  Both OSA and postoperative delirium remain greatly underdetected, and on balance of evidence, their relationship still warrants close attention. For example, the Society of Anesthesia and Sleep Medicine currently recommends using preoperative screening tools such as the STOP-Bang preoperative screening for OSA, given the link with increased perioperative complications.41 

Although the use of continuous positive airway pressure slows the deterioration of cognition, brain function, and mood in nonsurgical patients with OSA, thus far data from the surgical population is less conclusive.42–44  When patients who were at risk for sleep apnea were randomized in a continuous positive airway pressure group versus standard care, the perioperative use of continuous positive airway pressure did not change the incidence of postoperative delirium (12 of 58 [21%] vs. 9 of 56 [16%]; odds ratio [95% CI], 1.36 [0.52 to 3.54]; P = 0.53).45  Whereas both preoperative and postoperative residual OSA severity as defined by apnea-hypopnea index were significantly correlated with delirium severity in this sample, continuous positive airway pressure use was not found to be significantly correlated. Further studies with particular attention on continuous positive airway pressure adherence or the use of other respiratory adjuncts such as high-flow nasal oxygen are ongoing and may yield positive results in the future. It remains unclear whether the best strategy to prevent postoperative delirium is to treat the OSA directly using continuous positive airway pressure or to consider OSA patients at high risk and use more general delirium prevention strategies in this group. Currently, it is unknown whether OSA is a risk factor for delayed neurocognitive recovery or postoperative neurocognitive disorder. In the coming years, prospective clinical trials investigating this area will provide much-needed data.46,47 

Other Postoperative Sleep-related Interventions and Delirium

In terms of pharmacologic interventions to prevent delirium, dexmedetomidine and melatonin have been extensively studied. For intensive care unit (ICU) patients who are mechanically ventilated, sedation with dexmedetomidine may be less likely to be associated with delirium compared to benzodiazepines or propofol.48,49  Although there are inconsistent findings between studies, recent meta-analyses suggest that sedation of critically ill patients with dexmedetomidine may reduce the frequency and duration of delirium.50,51  Although these findings may primarily reflect the benefit of avoiding deliriogenic sedatives, the exact mechanism remains unclear. However, unlike all other sedatives and the commonly used anesthetics, dexmedetomidine appears most likely to preserve sleep architecture as currently inferred via electroencephalogram (EEG). In healthy volunteers, dexmedetomidine induced stage N3 non–rapid eye movement sleep in a dose-dependent fashion with an EEG pattern mimicking natural sleep without impairing next-day psychomotor performance.52  A low-dose dexmedetomidine infusion prolonged total sleep time and increased sleep efficiency and time spent in stage N2 non–rapid eye movement sleep in 76 older ICU patients.53  In a randomized, blinded, placebo-controlled trial of 700 older noncardiac surgery patients, a low-dose dexmedetomidine infusion given to both ventilated and extubated patients from the time of ICU admission until 8 am the morning of postoperative day 1 greatly reduced the risk of delirium as compared to placebo (32 of 350 [9%] vs. 79 of 350 [23%]; odds ratio [95% CI], 0.35 [0.22 to 0.54]; P < 0.0001).54  Additionally, patients in the dexmedetomidine group reported significantly better sleep quality (2 [0 to 4] vs. 4 [2 to 6]); 0 to 11 scale, where lower scores indicate better sleep; the values are shown as medians [interquartile range]; P < 0.0001). Finally, oral dexmedetomidine is now a possibility after successful testing in human subjects; however, optimal dosing has yet to be established, and it is not yet approved by the Food and Drug Administration (Silver Spring, Maryland). Subjects taking oral dexmedetomidine displayed both preserved sleep architecture on EEG and next-day psychomotor vigilance.55  This may open new possibilities outside of the ICU for investigation as to whether dexmedetomidine can be effective as a sleep-promoting agent.

Melatonin is commonly used in the general population and in the ICU for the promotion of sleep. Given its increasing use, some understanding of its role in sleep and circadian rhythms is warranted. As previously mentioned, the sleep–wake cycle is perhaps the most obvious and important behavior under intrinsic circadian output control. However, sleep–wake cycles are also affected by external cues. Of these cues, light is by far most important; others are food, sound, and exercise, many of which are disrupted in sickness and hospital settings. Melatonin is the major sleep-promoting hormone under circadian control. Taking its external cue from low light, its concentration peaks just before sleep initiation. Melatonin levels are measured from the saliva or serum, often in serial measurements, and are an accepted surrogate marker for our “internal time.”56  Critical care settings often involve exposure to light, noise, pain, nausea, or clinical care at night, which may explain the evidence for suppressed nocturnal melatonin peak secretion in ICU patients.57 

Recent data suggest that delirious patients may also have reduced serum levels of melatonin.58  For this reason, melatonin supplementation has been investigated as a potential intervention to prevent delirium. In a prospective before–after trial of 500 cardiac surgery patients where prophylactic melatonin was given the night before surgery, the incidence of postoperative delirium was significantly lower in the intervention group (21 of 250 [8.4%] vs. 52 of 250 [20.8%]; P = 0.001).59  Although a randomized trial investigating the prophylactic use of the melatonin receptor agonist ramelteon showed some promise in preventing delirium in older medical patients (1 of 33 [3%] vs. 11 of 34 [32%], ramelteon vs. placebo; P = 0.003), it was not shown to prevent postoperative delirium in elective cardiac surgery patients in another trial (19 of 59 [32%] vs. 22 of 58 [38%], ramelteon vs. placebo; P = 0.516).60,61  Other clinical trials of melatonin or ramelteon have not demonstrated similar success, and a recent meta-analysis of 16 clinical trials concluded that evidence neither supports nor opposes the use of melatonin in the prevention of delirium of hospitalized patients.62  Trials with individually targeted timing and dosing in those who are most at risk for suppression and misalignment of melatonin secretion may yield improved results. However, this may require accounting for sleep and circadian rhythm regulation before the perioperative period.

Aside from postoperative delirium, the impact of melatonin levels and melatonin supplementation on other perioperative neurocognitive disorders has been less extensively studied. In 97 patients aged 65 to 90 undergoing major orthopedic or abdominal surgery, patients with more than two-fold fluctuations in 6-sulfatoxymelatonin, a main metabolite of melatonin, had a significantly higher incidence of delayed neurocognitive recovery as determined by a cognitive battery 1 week postoperatively (22 of 39 [56%] vs. 9 of 56 [16.7%]; P < 0.01).63  In contrast, a study of 36 abdominal surgery patients with a mean age of 70 found no association between abnormal 6-sulfatoxymelatonin levels and the incidence of delayed neurocognitive recovery.64  In a placebo-controlled trial of 139 patients older than 65 undergoing hip arthroplasty, patients given melatonin beginning the night before surgery and then for the next 5 nights had significantly higher Mini Mental State Exam scores on days 1, 3, and 5, but scores between groups were similar on day 7.65  It should be noted that delayed neurocognitive recovery as defined as a predetermined decrease from the baseline Mini Mental Status Exam score was not an outcome in this trial. Significantly worse subjectively rated fatigue and sleep quality were found in the control group. In another placebo-controlled trial of 54 patients undergoing breast surgery, patients administered nightly melatonin for 1 month preoperatively until 3 months after surgery did not have significantly different rates of delayed neurocognitive recovery at 2 weeks or postoperative neurocognitive disorder at 3 months, despite subjective improvements in sleep efficiency and total sleep duration.66  Because of the small sample size and resulting lack of power, as well as the substantial heterogeneity in outcome definition seen in these studies, there is a clear need for further work on the relationship between melatonin and perioperative neurocognitive disorders other than delirium.

Finally, because of the overall paucity of effective sleep-promoting medications, there have now been increased efforts to trial multifaceted nonpharmacologic sleep interventions to prevent ICU delirium. A before–after quality improvement project in 300 medical ICU patients implemented a bundle of environmental changes including ear plugs, eye masks, and soothing music to decrease nighttime sleep disruption and promote daytime wakefulness. In the intervention group, the incidence of delirium was significantly less than in the preintervention group (odds ratio [95% CI], 0.46 [0.23 to 0.89]; P = 0.02).67  Taken as a whole, bundled sleep interventions may reduce the risk of delirium, but more work is needed to confirm these findings in adequately controlled trials and to pinpoint which aspect(s) of the multicomponent sleep bundles are the most effective.

Summary

Sleep and circadian disturbances are important risk factors for the development of neurodegenerative diseases including Alzheimer disease, which in turn are important predisposing factors for postoperative delirium (fig. 2). To what extent sleep disturbances may cause delirium, which sleep disorders are particularly risky, or at which time point in the perioperative course these factors are important are unclear. Certain chronic sleep patterns may predispose to delirium and may in turn make patients more susceptible to acute perioperative sleep disturbances that may precipitate delirium. Additionally, postoperative delirium may cause acute de novo sleep disturbances, adding further complexity. More work is needed to untangle these relationships to derive effective interventions. Although the relationship between sleep and circadian health and delirium is beginning to emerge, further work is also needed to understand the consequences of sleep disturbances and delayed neurocognitive recovery and postoperative neurocognitive disorder. Finally, there is a large degree of overlap between sleep disorders, pain, and cognition. Thus, future trials should aim to incorporate multimodal targets incorporating these components.

Fig. 2.

Sleep and circadian disruption and perioperative neurocognitive disorders. Preexisting sleep disorders and baseline neuropathology may contribute to sleep and circadian rhythm disruption in the perioperative period, which may then be a precipitating factor for perioperative neurocognitive disorders. OSA, obstructive sleep apnea.

Fig. 2.

Sleep and circadian disruption and perioperative neurocognitive disorders. Preexisting sleep disorders and baseline neuropathology may contribute to sleep and circadian rhythm disruption in the perioperative period, which may then be a precipitating factor for perioperative neurocognitive disorders. OSA, obstructive sleep apnea.

Close modal

Pain and Perioperative Neurocognitive Disorders

The relationship between pain and perioperative neurocognitive disorders and the modification of that relationship by the treatment of pain are incredibly complex (fig. 3). Inflammation and pain are closely biochemically linked, and many of the mediators of the body’s response to injury and inflammation in both the peripheral and central nervous system including prostaglandins, bradykinins, interleukins, and tumor necrosis factor-α can be elevated in painful conditions.68,69  This relationship is relevant to perioperative neurocognitive disorders, because one commonly proposed mechanistic framework for both postoperative delirium and delayed neurocognitive recovery is through neuroinflammation.2,5,6,70,71  In this proposed mechanism, either peripheral or central nervous system injury leads to inflammatory cytokine release, endothelial activation, breakdown of the blood–brain barrier, and activation of microglia, potentially culminating in neuronal injury and subsequent brain dysfunction.72–74  Another interesting link between pain and cognitive dysfunction comes from the knowledge that cholinergic neurons modulate pain signals, and cholinergic deficiency and anticholinergic medication use have been implicated in both pain hypersensitivity and delirium.27,75  These biochemical links between inflammation, pain, and neuronal injury or dysfunction are more easily identified in preclinical models than in clinical studies given the difficulties inherent to selecting and sampling the ideal mediators in perioperative patients. Despite this limitation, there are a number of studies supporting an association between pain and subsequent perioperative neurocognitive disorders that are worthy of review.

Fig. 3.

The relationships between pain, inflammation, and analgesia on the risk for perioperative neurocognitive disorders. Red lines and plus signs signify processes that may worsen other conditions. Green arrows and minus signs indicate processes that may ameliorate or improve other conditions.

Fig. 3.

The relationships between pain, inflammation, and analgesia on the risk for perioperative neurocognitive disorders. Red lines and plus signs signify processes that may worsen other conditions. Green arrows and minus signs indicate processes that may ameliorate or improve other conditions.

Close modal

The majority of clinical studies linking pain to perioperative neurocognitive disorders focus on the potential association between postoperative pain and postoperative delirium. Although this focus is reasonable given their temporal association, the presence of preoperative pain may also play a significant role and should not be overlooked. For example, in a cohort of 333 major noncardiac surgery patients 65 and older, the presence of moderate preoperative pain (odds ratio [95% CI], 2.2 [1.2 to 4.0]; P < 0.05) and the presence of severe preoperative pain (3.7 [1.5 to 9.0]; P < 0.05) at rest were independently predictive of postoperative delirium.76  An increase in pain scores from preoperative baseline to postoperative day 1 was also predictive of postoperative delirium (1.1 [1.01 to 1.2]; P < 0.05). In 459 older patients undergoing elective orthopedic surgery, the severity of preoperative pain was significantly associated with an increased risk of subsequent delirium (severe pain vs. no/mild pain; odds ratio [95% CI], 2.0 [1.4 to 3.0]; P = 0.013) for trend between no/mild, moderate, and severe pain).77  The relationship between pain and delirium may be modified by the presence of underlying depression, because subgroup analysis of patients with depression from this cohort revealed that for every 1-point increase on the postoperative visual analog pain scale, the risk of delirium significantly increased. Interestingly, investigations of alterations in synaptic connectivity in the prefrontal cortex suggest that changes may occur in this region for patients with depression, in chronic pain, and in disorders of executive function, suggesting a potential close neuropathological link between these conditions.78 

As previously mentioned, the preponderance of clinical evidence associating pain and perioperative neurocognitive disorders involves acute postoperative pain. In a cohort of 541 older patients with hip fracture, cognitively intact patients with any episode of severe postoperative pain at rest (as defined by a score of 4 or greater on a 5-point scale) through postoperative day 3 had a nine-fold increase in the risk of subsequent delirium (risk ratio [95% CI], 9.0 [1.8 to 45.2]; P = 0.01).79  In 361 patients with a mean age of 66 undergoing major noncardiac surgery, postoperative pain at rest was significantly associated with subsequent postoperative delirium (risk ratio, 1.20 [1.04 to 1.37] per 1-point increase on the visual analog scale; P = 0.015).80  In a similar population, patients with high levels of postoperative pain and receiving high doses of opioids had significantly higher rates of delirium, in both patients at low risk for delirium (17 of 34 [50%] vs. 35 of 174 [20%]; P = 0.0004) and patients at high risk for delirium (23 of 32 [72%] vs. 46 of 93 [49%]; P = 0.031) compared to patients with lower levels of pain.81  In contrast, in 89 older patients undergoing major abdominal surgery, uncontrolled pain as defined by a pain score of greater than 5 without adequate medication administration was not found to be significantly associated with delirium (risk ratio [95% CI], 1.0 [0.7 to 1.4]; P = 0.91).82  It should be noted when discussing the evidence linking pain to perioperative neurocognitive disorders that the assessment of pain can be very challenging in patients with impaired cognition, and therefore current guidelines recommend using a multisource, multidimensional approach to the assessment of pain in older persons.83  Additionally, many of the above-referenced trials do not contain information as to whether chronic pain or opioid use was present preoperatively, limiting the interpretation of these results.

Pain Treatment and Perioperative Neurocognitive Disorders

The adequate diagnosis and management of pain is a core intervention in HELP, as well as multicomponent ICU care guidelines such as the ABCDEF bundle, and is also recommended in consensus guidelines for reducing postoperative delirium from multiple interdisciplinary working groups.11,84–86  As previously mentioned, data from multiple perioperative studies suggest that the presence of preoperative or postoperative pain or worsening severity of pain in the postoperative period is associated with subsequent delirium. In many of these studies, it is difficult to determine based on their results whether adequate treatment of pain can prevent delirium or conversely whether undertreatment of pain can precipitate delirium. Because low pain scores may indicate either absence of pain or effective treatment of pain, evaluation of the impact of pain treatment on the risk of perioperative neurocognitive disorders requires adjustment for either factor. This relationship is confounded even further when considering the specific medication used to treat pain, because many drugs have been implicated as precipitating factors for delirium, especially opioids.

Opioids

Amid the enhanced awareness of perioperative neurocognitive disorders and the opioid epidemic, avoidance or minimization of opioids has become an essential consideration in perioperative care. On one hand, opioids remain some of the most effective analgesics for acute pain, especially for severe painful conditions such as after trauma or surgery. On the other hand, opioid-related side effects such as sedation or hallucination may precipitate, worsen, or mimic symptoms of delirium such as disorientation or hypoactive motor and cognitive function. Given these considerations, current guidelines for best practices to avoid delirium advocate for avoiding opioids, at least as first line agents.70,86  However, data suggest that simply administering fewer opioids may not prevent perioperative neurocognitive disorders. For example, in a retrospective matched cohort study of 86 medical–surgical patients with a mean age of 80 admitted with painful conditions and with an opioid ordered, delirious patients received a significantly lower fraction of the allowed dose ordered than nondelirious patients (11 of 43 [26.14%] vs. 21 of 43 [48.21%]; P < 0.001).87  In the cohort study of hip fracture patients mentioned previously in which pain at rest was associated with a nine-fold increased risk of delirium, investigators found that patients administered less than 10 mg of morphine equivalents per day were at significantly increased risk of delirium compared to patients receiving more than 10 mg (risk ratio [95% CI], 5.4 [2.4 to 12.3]; P < 0.001).79  In 236 patients older than 65 undergoing hip fracture repair, opioid consumption during the first 3 postoperative days was not different between patients with and without delirium (mean [SD], 0.66 [0.82] vs. 0.49 [0.59] mg/kg morphine equivalents; P = 0.176), but patients with delirium did have significantly higher pain scores (mean [SD], 2.6 [1.9] vs. 1.7 [1.8]; P = 0.007).88  Although the higher risk of delirium with lower opioid doses does not directly imply that those patients’ pain was less well treated, data from these cohorts suggest that increased opioid dose is not associated with an increased risk of postoperative delirium, at least in the context of acute pain. Given the clinical and societal importance of limiting opioid use, it is reasonable to employ multimodal efforts to control pain before resorting to opioids.89  Ideally, effective analgesia can be accomplished while limiting opioids, but in the event that opioid-sparing techniques such as use of anti-inflammatory agents and regional, neuraxial, or local analgesia are not successful, residual untreated pain may have more of an effect on delirium than further limiting opioid use.

In terms of specific opioids, tramadol and meperidine have been linked to an increased risk of delirium, but there are limited data on the differential impact of the agents more typically used in the perioperative period such as fentanyl or hydromorphone.90  The mode of opioid administration may be more relevant. In the cohort study of 333 patients undergoing major noncardiac surgery mentioned previously, patients who only received oral opioid analgesics were found to have a significantly reduced risk of postoperative delirium compared to patients treated with intravenous opioids (odds ratio [95% CI], 0.4 [0.2 to 0.7]; P < 0.05).81  Additionally, a prospective cohort study of 225 patients older than 65 yr undergoing noncardiac surgery found that patients who were treated with oral opioids alone had significantly reduced odds of delayed neurocognitive recovery as assessed by a three-test battery as opposed to those treated with intravenous opioids via a patient-controlled system (odds ratio [95% CI], 0.22 [0.06 to 0.80]; P = 0.02). This finding came after controlling for a number of patient- and surgery-specific confounders including pre- and postoperative pain levels.91 

Nonopioid Analgesics

The pathophysiological overlap between inflammation, pain, and neuronal injury makes analgesics with anti-inflammatory effects attractive candidates to prevent delirium in patients with acute postoperative pain. In a randomized trial of 620 older patients undergoing elective total joint arthroplasty, scheduled parecoxib (a selective COX2 inhibitor) for 3 days led to a significant reduction in the incidence of postoperative delirium compared to placebo (19 of 310 [6.2%] vs. 34 of 310 [11%]; P = 0.031).92  The parecoxib group also had significantly less delayed neurocognitive recovery, defined by a decrease of more than 2 points on the Mini Mental Status Exam from baseline, than placebo controls on postoperative days 1, 3, and 5 (day 5: 28 of 310 [8.7%] vs. 53 of 310 [19.4%]; P < 0.001). It should be noted that the Mini Mental Status Exam is limited in its utility as a test for detecting cognitive dysfunction and is not recommended for this purpose by the perioperative neurocognitive disorder nomenclature working group.1  Although acetaminophen is not considered an anti-inflammatory, it shares some characteristics of nonsteroidal anti-inflammatory drugs including action on the cyclooxygenase pathway and putative blockade of central nervous system prostaglandin production.93  A randomized, placebo-controlled factorial trial in 121 cardiac surgery patients older than 60 yr found that scheduled intravenous acetaminophen for the first 48 h postoperatively significantly lowered the incidence of delirium as compared to placebo (6 of 60 [10%] vs. 17 of 60 [28%]; P = 0.01).94  Patients receiving acetaminophen also had significantly reduced delirium duration (median 1 vs. 2 days; P = 0.03). The rates of delayed neurocognitive recovery at discharge were not different between groups.

In both the parecoxib and acetaminophen trials, there were either clinically insignificant differences or no differences found between groups in opioid equivalents administered and in postoperative pain scores, suggesting that neither opioid sparing nor superior pain control were the main drivers of the results. It is possible that this finding was instead related to the prevention of neuroinflammation; however, this hypothesis will have to be confirmed in subsequent studies because neither trial included biomarker analyses. Additionally, the possibility that the effect of these interventions occurred through reducing neuroinflammation should be taken in context with the negative findings of multiple clinical trials investigating the intraoperative use of different drugs with both anti-inflammatory and analgesic properties including intravenous lidocaine, magnesium, and steroids to prevent perioperative neurocognitive disorders after cardiac surgery.95–99 

Gabapentin is another nonopioid analgesic that has been investigated as an intervention to minimize perioperative opioid use. In a large double-blind placebo-controlled trial involving 697 patients with a mean age of 72 yr undergoing noncardiac surgery, the administration of 900 mg of gabapentin preoperatively and for the first 3 postoperative days did result in a small but significant reduction in the amount of morphine equivalents on the first postoperative day (median [interquartile range], 6.7 [1.3 to 20.0] vs. 6.7 [2.7 to 24.8] mg; P = 0.04).100  However, there were no differences between the gabapentin and placebo groups in the primary outcome of postoperative delirium (84 of 350 [24%] vs. 72 of 347 [20.8%]; P = 0.30). Commonly, especially in enhanced recovery pathways, multimodal and opioid-sparing analgesia protocols will combine multiple agents. Data for this approach are limited, but one prospective study of a fast track protocol for 220 older patients undergoing major joint replacement found no cases of postoperative delirium employing a multicomponent strategy including standardized anesthetic and postoperative analgesic protocols utilizing various combinations of paracetamol, gabapentin, tramadol, celecoxib, and ibuprofen across four different centers.101 

Ketamine is another commonly used opioid-sparing analgesic. Like opioids, ketamine has potential psychotropic effects such as hallucinations, nightmares, or psychosis that are undesirable in patients at risk for perioperative neurocognitive disorders.102  These effects may be dose-dependent; therefore trials evaluating ketamine’s effectiveness in reducing opioid consumption and perioperative neurocognitive disorders focus on low-dose interventions. In a three arm randomized active and placebo-controlled trial of 56 adult patients undergoing major open abdominal surgery, the administration of low-dose (0.25 mg/kg bolus and 0.125 mg · kg–1 · h–1 infusion) and minimal-dose (no bolus, 0.015 mg · kg–1 · h–1 infusion) ketamine during the anesthetic and the following 48 h resulted in lower postoperative opioid consumption as compared to placebo (mean [SD], 42.7 [13.4] vs. 40.2 [13.5] vs. 72.7 [15.3] mg piritramide; P < 0.0001).103  However, patients in the low-dose group had significantly higher Intensive Care Delirium Screening Checklist scores than both the minimal-dose and placebo groups (median [interquartile range), 2 [1 to 3] vs. 1 [0 to 1] and 0 [0 to 1], respectively; P = 0.007). In 58 patients older than 55 yr of age undergoing cardiac surgery with cardiopulmonary bypass, patients randomized to receive an intravenous bolus of 0.5 mg of ketamine had significantly lower rates of postoperative delirium than placebo controls (1 of 29 [3%] vs. 9 of 29 [31%]; P = 0.01).104  In a different study in the same population by the same investigators, they found that the same intervention could possibly reduce the incidence of delayed cognitive recovery at 1 week postoperatively, as defined by a 2 SD decrease on assessments of memory and executive functions, as compared to placebo (7 of 26 [27%] vs. 21 of 26 [81%]; P < 0.001) after adjusting for training effects using assessment data from concurrent nonsurgical controls.105 

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) trial sought to more definitively investigate whether the prophylactic intraoperative administration of ketamine could prevent postoperative delirium, also using a three-armed design.9  In the trial, 672 patients older than 60 yr undergoing major cardiac and noncardiac surgery were randomized to either low-dose (0.5 mg/kg) or high-dose (1.0 mg/kg) ketamine boluses or placebo given in the time between induction and surgical incision. There was no difference in the incidence of postoperative delirium during the first 3 postoperative days between patients who received any dose of ketamine as compared to placebo (88 of 450 [19.45%] vs. 44 of 222 [19.82%]; P = 0.92). There was also no significant difference found in delirium rates across all three groups (40 of 227 [17.65%] vs. 47 of 223[21.3%] vs. 44 of 222 [19.82%] in low-dose, high-dose, and placebo groups, respectively; P = 0.80). Furthermore, no significant differences among groups were found with respect to time to delirium onset, severity, or duration of delirium. Postoperative opioid consumption was not significantly different between the three groups at any time point. Last, more patients in the ketamine groups reported experiencing hallucinations (45 of 227 [20%] vs. 62 of 223 [28%] vs. 40 of 222 [18%] in low-dose, high-dose, and placebo groups, respectively; P = 0.01) and nightmares (27 of 227 [12%] vs. 34 of 223 [15%] vs. 18 of 222 [8%]; P = 0.03). Therefore, the results of the PODCAST trial should give providers caution when considering intraoperative ketamine as a means to either reduce the risk of delirium or postoperative opioid consumption, because neither high- nor low-dose regimens were effective for these outcomes, and there was evidence of significant harm from ketamine with regards to its psychotropic effects.

Regional or Neuraxial Analgesia

A successful regional nerve block may be very effective for postoperative pain control when placed in an appropriate candidate. If this effective analgesia can be obtained while also sparing the use of opioids, then it is theoretically possible that regional nerve blocks can prevent delirium in multiple ways. The best available data for this approach come from studies in orthopedic surgery patients. In 207 patients at intermediate- or high-risk of delirium undergoing hip fracture surgery who were randomized to undergo a fascia iliaca or sham block administered on admission and repeated every 24 h until delirium occurrence or discharge, the use of the fascia iliaca block resulted in a significantly reduced incidence of delirium (11 of 102 [10.78%] vs. 25 of 105 [23.8%]; risk ratio [95% CI], 0.45 [0.23 to 0.87]).106  Additionally, patients who received fascia iliaca blocks experienced lower delirium severity (mean [SD], 14.34 [3.6] vs. 18.61 [3.4) DRSR-98 score; P < 0.001) and shorter delirium duration (mean [SD], 5.22 [4.28] vs. 10.97 [7.16] days; P < 0.001). For patients undergoing total knee arthroplasty, a cohort study of 85 patients demonstrated that analgesia via a femoral nerve catheter in addition to patient-controlled analgesia (PCA) was associated with lower rates of postoperative delirium as compared to PCA alone (7 of 28 [25%] vs. 31 of 51 [61%]; P = 0.002).107  After controlling for preoperative cognitive function, the odds of postoperative delirium were significantly higher in the PCA group than patients who received a femoral nerve catheter in addition to their PCA (odds ratio [95% CI], 7.02 [2.06 to 23.97]; P = 0.002). The use of intraoperative spinal anesthesia as an alternative to general anesthesia has been proposed to reduce anesthetic exposure for patients at risk for postoperative delirium. Interestingly, this may not always be the case, because patients under spinal anesthesia with supplemental monitored anesthesia care may still receive high doses of intravenous sedatives.108  This makes the interpretation of trials investigating the benefit of neuraxial anesthetics on postoperative delirium challenging. A large randomized controlled trial is currently underway specifically examining whether spinal anesthesia or general anesthesia is superior for older patients undergoing hip fracture surgery, with postoperative delirium as a secondary outcome.109 

For operations on the thorax or abdomen, analgesia via the use of an epidural catheter can be very effective, albeit with the inherent risk of hypotension.110  In a trial of 70 patients older than 70 yr of age randomized to either combined general and epidural anesthesia followed by epidural PCA with bupivacaine and sufentanil compared to general anesthesia and PCA alone, the use of epidural PCA did not significantly reduce the incidence of delirium (8 of 31 [26%] vs. 8 of 33 [24%]; P > 0.05).111  A higher proportion of patients in the PCA group demonstrated poor scores on the Abbreviated Mental Test than the epidural PCA group on postoperative day 4 (number of patients with scores ≤ 8, 9, and 10 was 5, 11, and 17 vs. 1, 5, and 25; P < 0.05) and postoperative day 5 (5, 13, and 15 vs. 1, 7, and 23; P < 0.05). In a secondary analysis of the PODCAST trial, the investigators found that patients who received postoperative epidural analgesia did not have a significantly reduced odds of postoperative delirium within the first 3 postoperative days compared to those without an epidural after adjusting for several confounders including age and type of procedure (adjusted odds ratio [95% CI], 0.65 [0.32 to 1.35]; P = 0.247).112  A post hoc analysis was performed in which patients treated with an epidural were less likely to experience any episode of delirium during the study follow-up, after adjustment for the same confounders (adjusted odds ratio [95% CI], 0.36 [0.17 to 0.78]; P = 0.009). Because postoperative delirium is often defined by any single episode of delirium, and this analysis was conducted post hoc, it is unclear how impactful this finding is.

Finally, the use of epidural analgesia has been included in studies evaluating the effectiveness of enhanced recovery pathways for colonic surgery. In one trial, 240 open colorectal surgery patients older than 70 yr were randomized to a fast-track protocol (consisting of preoperative dietary, hydration, and bowel preparation interventions, thoracic epidural anesthesia and postoperative epidural PCA with ropivacaine only, and postoperative mobilization and dietary interventions) or traditional care (notably consisting of general anesthesia and postoperative fentanyl).113  Patients in the fast-track group had a significantly lower incidence of postoperative delirium within the first 5 days (4 of 117 [3.4%] vs. 15 of 116 [12.9%]; P = 0.008).

Summary

Severe or uncontrolled preoperative or postoperative pain and increased levels of pain from the preoperative to postoperative period are all associated with postoperative delirium. Proper diagnosis and adequate treatment of pain remains a key component of preventative strategies for postoperative delirium. Although multimodal analgesic strategies including nonopioid analgesics and regional or neuraxial analgesia have demonstrated success in effectively controlling pain and potentially reducing opioid requirements, at this time the quality of evidence underlying any one analgesic approach to prevent delirium is low. Evidence is stronger, however, that undertreatment of pain is more of a significant risk factor for postoperative delirium than treatment with potentially deliriogenic medications. There are few data available on the relationship between pain, pain treatment, and delayed neurocognitive recovery or postoperative neurocognitive disorder.

A disturbance in cognition, either temporarily or longer term, is a defining feature of postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorder.1  An emerging component of perioperative care now consists of perioperative multicomponent strategies to enhance recovery. In this context, preoperative optimization and the goal of the best possible functional recovery for surgical patients increasingly includes measures taken to protect perioperative cognitive function.114  Thus, the detection of perioperative neurocognitive disorders and evaluation of strategies employed to prevent them relies on a thorough understanding of the cognitive areas affected in the perioperative period, the development of validated instruments to measure perioperative cognition, and the current state of evidence for strategies to improve postoperative cognitive function.

Baseline Cognitive Performance and Perioperative Neurocognitive Disorders

The degree of preexisting organ dysfunction is an important risk factor for many types of postoperative complications.115–117  The same can be said for brain function, because poor baseline cognition is a strong predictor of future cognitive dysfunction. Although there is continuing debate as to which cognitive test or battery of tests is best suited for the perioperative period, there is strong evidence that patient performance on a preoperative cognitive test can predict perioperative neurocognitive disorders. Screening tests such as the Mini-Cog and Mini Mental Status Exam, which were originally designed to detect mild cognitive impairment or dementia, have been used to evaluate perioperative cognitive function. In two longitudinal cohort studies of surgical patients older than 65 yr, investigators found that a preoperative Mini-Cog score indicative of moderate cognitive dysfunction (3 or lower or 2 or lower) was associated with a significantly higher risk of postoperative delirium (odds ratio [95% CI], 2.4 [1.2 to 4.9]; P = 0.015; and 4.5 [1.3 to 15.7]; P = 0.017, respectively) and more days with postoperative delirium (mean [SD], 4 [6] vs. 1 [2] days; P = 0.012).118,119  In 425 older hip fracture surgery patients, those with a Mini Mental Status Exam score of less than 24 had a significantly increased incidence of postoperative delirium (76 of 141 [54%] vs. 73 of 284 [26%]; P ≤ 0.001).120  In a similar population, a higher preoperative Mini Mental Status Exam score was associated with a lower incidence of postoperative delirium (odds ratio [95% CI], 0.67 [0.52 to 0.86]; P = 0.002).121 

In addition to tests of global cognitive function, poor performance on targeted tests of executive function can also predict postoperative delirium in older patients undergoing major noncardiac surgery (odds ratio [95% CI], 1.23 [1.06 to 1.43]; P < 0.01 for a three-test composite and log mean ratio [95% CI], 1.27 [1.11 to 1.46]; P < 0.01 for color trial 2).122,123  Preoperative test performance is also associated with persistent cognitive deficits, because older hip arthroplasty patients who performed less than 2 standard deviations on at least two of seven neuropsychological tests had higher incidences of both delayed neurocognitive recovery at 7 days (23 of 91 [25.3%] vs. 26 of 195 [13.3%]; P = 0.012) and of postoperative neurocognitive disorder at 3 months (13 of 87 [14.9%] vs. 14 of 197 [7.1%];, P = 0.039) and 12 months (5 of 83 [9.4%] vs. 2 of 188 [1.1%]; P < 0.001).124  In a cohort of 566 older surgical patients, lower preoperative scores on an 11-test cognitive battery was identified as the dominant risk factor for postoperative delirium after adjustment for other established predictors (risk ratio [95% CI], 2.0 [1.5 to 2.5] for each 0.5 SD decrease; P < 0.05).125  Last, preoperative test performance may also help identify patients at risk for long-term cognitive decline, because a higher preoperative Mini Mental Status Exam score was associated with a lower risk of dementia 5 yr after cardiac surgery (odds ratio [95% CI], 0.68 [0.54 to 0.84]; P < 0.001).126  Based in part on the findings of these studies, the Perioperative Neurotoxicity Working Group recommends evaluating baseline cognition using a screening test in patients older than 65 or who are at otherwise high risk for perioperative neurocognitive disorders.127  They do not recommend one screening test in particular, however, because more work is needed to assess the predictive power and clinical utility of these screening tests in perioperative patients.

Cognitive Reserve

Cognitive reserve can be described as resiliency of an individual’s cognitive processes in the face of injury. In contrast to cognitive performance assessed at one point in time, cognitive reserve is characterized by the accumulation or loss of cognitive abilities over the lifespan. Differences in cognitive reserve have been theorized to explain observed differences between patients in phenotypes or degrees of impairment seen after similar pathologic findings of neurologic injury such as stroke or Alzheimer disease, and the concept can be applied to perioperative neurocognitive disorders (fig. 4).128  Cognitive reserve is typically described in terms of years of education attained, occupational complexity, and cognitive lifestyle behaviors. There is some evidence to suggest that differences in cognitive reserve may predict perioperative neurocognitive disorders. In two cohort studies of hospitalized older patients, each year of education obtained was associated with a significantly decreased risk of delirium (odds ratio [95% CI], 0.91 [0.87 to 0.95]; P < 0.01; and 0.76 [0.62 to 0.95]; P = 0.016, respectively).129,130  Low educational attainment was also found to be a strong predictor of postoperative delirium in older patients after hip fracture surgery or hip replacement (odds ratio [95% CI], 3.59 [1.14 to 11.25]; P < 0.05).131  However, a large cohort study of similar patients did not find an association between years of education or multiple other markers of cognitive reserve and postoperative delirium.132  It should be noted that this cohort exhibited a high median years of education (15 yr), suggesting that this effect may not be as evident in highly educated populations.

Fig. 4.

Cognitive trajectories and perioperative neurocognitive disorders. Depicted are theoretical cognitive trajectories of a patient with high baseline cognitive reserve (blue line) and a patient with low baseline cognitive reserve (red line). Both patients experience an event in the perioperative period leading to a decrease in cognitive function, but only the patient with low baseline reserve may manifest symptoms. The green dashed lines represent the theoretical mechanism through which cognitive interventions in the pre- and postoperative phases may influence cognitive reserve and either prevent or aid recovery from perioperative neurocognitive disorders. Adapted from Stern.128 

Fig. 4.

Cognitive trajectories and perioperative neurocognitive disorders. Depicted are theoretical cognitive trajectories of a patient with high baseline cognitive reserve (blue line) and a patient with low baseline cognitive reserve (red line). Both patients experience an event in the perioperative period leading to a decrease in cognitive function, but only the patient with low baseline reserve may manifest symptoms. The green dashed lines represent the theoretical mechanism through which cognitive interventions in the pre- and postoperative phases may influence cognitive reserve and either prevent or aid recovery from perioperative neurocognitive disorders. Adapted from Stern.128 

Close modal

Educational attainment may also predict long-term postoperative cognitive function. In a large longitudinal cohort of older patients undergoing major noncardiac surgery, educational achievement of high school or higher was associated with a significantly lower risk of delayed neurocognitive recovery at 1 week (odds ratio [95% CI], 0.6 [0.4 to 0.9]; P = 0.002), but not for postoperative neurocognitive disorder at 3 months.133  In another large prospective cohort of major noncardiac surgery patients of which 355 were older than 60, patients with postoperative neurocognitive disorder at 3 months had slightly fewer mean years of education (mean [SD], 13.2 [2.4] or 13.7 [2.8] years; P = 0.013).134  Less well characterized than educational level is the relationship between baseline cognitive lifestyle behaviors and perioperative neurocognitive disorders. In a cohort of 141 patients with a mean age of 71 yr, greater participation in preoperative cognitive lifestyle behaviors including reading books, using email, or playing computer games was found to be protective against delirium after elective orthopedic surgery (increase of one activity per week; odds ratio [95% CI], 0.92 [0.86 to 0.98]; P = 0.006).121 

Prehabilitation to Prevent Perioperative Neurocognitive Disorders

Prehabilitation refers to the attempt to optimize preoperative modifiable risk factors to improve functional outcomes after surgery, often focusing on preoperative physical, nutritional, and psychologic health. Of these three domains, physical prehabilitation has been the most studied. Although there are inconsistent results among trials and uncertainty with regards to whether physical prehabilitation can reduce postoperative complications, multiple clinical trials in abdominal and orthopedic surgery have demonstrated improved postoperative physical capacity in patients who participated in home-based exercise regimens as compared to usual care.135  Nutritional prehabilitation, consisting mainly of nutritional supplements and dietary counseling, may potentially accelerate the return to preoperative functional capacity in colorectal surgery when added to a physical prehabilitation program.136  Both physical deconditioning and poor nutritional status are elements of frailty, which has been shown in retrospective studies to be strongly associated with postoperative delirium and possibly postoperative neurocognitive disorder.137,138  Such elements may be modifiable. In a six-armed randomized trial of 246 older prefrail or frail adults, physical, cognitive, nutritional, or combined intervention training were all shown to reduce future frailty scores to a significantly larger degree than a usual care control.139  If physical and nutritional prehabilitation can improve postoperative functional outcomes and reverse frailty in older persons, it is then possible that these interventions may prevent perioperative neurocognitive disorders. Data from clinical trials evaluating this potential effect are limited, however. In a single center before and after unblinded study of 627 patients undergoing major abdominal surgery, the incidence of postoperative delirium was found to be significantly lower in patients who underwent a multicomponent intervention to improve physical and nutritional health and reduce frailty factors as compared to patients who did not receive this intervention (22 of 267 [8.2%] vs. 42 of 360 [11.7%]; adjusted odds ratio [95% CI], 0.56 [0.32 to 0.98]; P = 0.043).140 

Bolstered by the theory that increasing cognitive reserve can protect against neurologic injury and experimental data suggesting that neurogenesis and neuroplasticity still occur in later life, numerous investigators have evaluated whether cognitive exercise can improve cognitive performance in older persons.141–144  Perhaps the most notable example is the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial, which demonstrated that 10 h of computerized cognitive training led to sustained improvements in processing speed over the following 10 yr.145  In perioperative research, attempts have been made to apply this technique to prevent perioperative neurocognitive disorders. In a randomized trial of 141 abdominal surgery patients older than 60, 3 h of supervised memory exercises 1 to 4 weeks before surgery significantly reduced the incidence of delayed neurocognitive recovery at 1 week compared to usual care (11 of 69 [15.9%] vs. 26 of 72 [36.1%]; P = 0.007).146  In contrast to its success in older adults in the general population, computerized cognitive training appears to be less feasible in older surgical patients.147  Although a small feasibility trial of 45 older cardiac surgery patients noted high degrees of patient interest and enjoyment with a computerized cognitive prehabilitation program, there were low rates of adherence (39% during the preoperative period), and no effect on the incidence of postoperative delirium or delayed cognitive recovery was found.148  In a recent randomized trial of 251 patients older than 60 undergoing major noncardiac nonneurologic surgery, preoperative computerized cognitive exercise did not significantly reduce the risk of postoperative delirium as compared to usual care in the primary analysis. However, a post hoc per-protocol analysis excluding patients who never used the cognitive exercise program revealed a significantly reduced incidence of postoperative delirium favoring the cognitive exercise group (16 of 121 [13.2%] vs. 29 of 126 [23%]; P = 0.04).149  It should be noted that for this trial and the feasibility trial that used the same cognitive exercise platform, the median length of time spent training was ~4.5 h, which falls short of “recommended dose” of 10 h of cognitive exercise in the ACTIVE trial. Further investigation is necessary to determine whether adherence to cognitive prehabilitation can be improved and whether cognitive prehabilitation can reduce delirium and/or other perioperative neurocognitive disorders in an adequately powered trial.

Postoperative Cognitive Training

Postoperative cognitive training may also prevent perioperative neurocognitive disorders. A randomized trial of 47 lung transplant patients with a mean age of 65 yr demonstrated greater score improvements at 12 weeks on the Forward Digit Span (mean [SD], 0.93 [1.09] vs. 0.04 [0.52]; P = 0.004) and Verbal Fluency tests (mean [SD], 1.32 [1.82] vs. 0.1[1.53]; P = 0.033) with the use of a computerized program for 8 weeks after surgery.150  Among 46 lung transplant recipients with a mean age of 66 yr, the use of 8 weeks of computerized cognitive training started 4 weeks after surgery resulted in significantly higher scores on the digit span forward test (mean [SD], 0.93 [1.09] vs. 0.04 [0.52]; P = 0.0044) and verbal fluency (mean [SD], 1.32 [1.82] vs. 0.10 [1.53]; P = 0.0331).150  It should be noted, however, that these mean differences are less than the SD for the group, which is a common benchmark used in previous studies to define perioperative neurocognitive disorders. The best known multicomponential intervention to prevent hospital delirium, HELP, includes the provision of cognitively stimulating activities at least three times daily as a core intervention.151  In a before–after study of 179 consecutive abdominal surgery patients older than 65 in which a modified version of HELP was implemented that focused only on nutrition, mobilization, and cognitively stimulating activities including discussing current events or word games, the delirium rate was significantly reduced in the intervention group (0 of 102 [0%] vs. 13 of 77 [16.7%]; P < 0.001).152  A similar approach employing daily cognitively stimulating conversation and word games was employed in a randomized pilot trial in 50 older hip or knee arthroplasty patients. The investigators found that patients in the intervention group had a significantly lower incidence of delayed neurocognitive recovery as defined by a decrease of 2 points or more from the baseline Mini Mental Status Exam score as compared to usual care controls (3 of 25 [12%] vs. 11 of 25 [44%]; P = 0.012).153 

Summary

Poor baseline cognition, defined by either poor preoperative performance on screening tests of cognitive function or decreased markers of cognitive reserve, is strongly associated with perioperative neurocognitive disorders. As such, the routine use of a validated screening test in the preoperative period has been recommended to help identify at-risk patients. Although physical and nutritional prehabilitation may improve postoperative functional capacity and reverse frailty in nonoperative patients, more investigation is necessary to determine whether these interventions can prevent perioperative neurocognitive disorders. Cognitive prehabilitation has been shown to reduce delirium incidence in one clinical trial, but further studies are needed to replicate this finding, to determine the optimal training regimen, to improve adherence, and to investigate whether the technique can prevent delayed cognitive recovery and/or postoperative neurocognitive disorder. Postoperative cognitive exercise may improve postoperative cognition and prevent postoperative delirium, but high-quality evidence from adequately powered clinical trials is needed to better determine these effects.

Conclusions

The increasing awareness of the long-term negative consequences of perioperative neurocognitive disorders on functional outcomes after surgery has led to the development of multicomponent interventions to optimize postoperative brain health. Decades of perioperative research targeting isolated intraoperative interventions focusing on altering the exposure to anesthesia or surgery have not yet been able to identify a singular intervention to successfully prevent perioperative neurocognitive disorders. Given the multiple predisposing and precipitating risk factors for postoperative delirium and the incomplete overlap with risk factors for delayed neurocognitive recovery and postoperative neurocognitive disorder, it is likely that a multicomponent approach encompassing all phases of the perioperative period (preoperative, intraoperative, and postoperative) may be more effective. Going forward, critically needed perioperative research into three targets for optimal perioperative brain health: sleep, pain and cognition, will enable providers to better identify high-risk patients and confidently employ interventions into well defined care plans (table 1). When this can be achieved, perioperative medicine may reach its goal of an ideal recovery for both the bodies and minds of surgical patients.

Table 1.

Summary of Evidence and Future Directions

Summary of Evidence and Future Directions
Summary of Evidence and Future Directions

Acknowledgments

The authors acknowledge Lisa Graf, B.F.A., from the Beth Israel Deaconess Medical Center Media Services Department, Harvard Medical School, Boston, Massachusetts, for her work on figure 1.

Research Support

Supported by grant No. R01AG06554 from the National Institute on Aging, National Institutes of Health, Bethesda, Maryland (to Drs. O’Gara, Marcantonio, and Subramaniam); by grant No. R03AG067985 from the National Institute on Aging, National Institutes of Health and a mentored research training grant from the Foundation for Anesthesia Education and Research, Schaumburg, Illinois, (to Dr. Gao); by the Binational Industrial Research and Development Foundation, Tel Aviv, Israel (to Dr. O’Gara); and by grant Nos. K24AG035075 and P01AG031720 from the National Institute on Aging (to Dr. Marcantonio).

Competing Interests

Dr. O’Gara receives consulting income from Sedana Medical, Danderyd, Sweden, for work unrelated to this review. The other authors declare no competing interests.

1.
Evered
L
,
Silbert
B
,
Knopman
DS
,
Scott
DA
,
DeKosky
ST
,
Rasmussen
LS
,
Oh
ES
,
Crosby
G
,
Berger
M
,
Eckenhoff
RG
;
Nomenclature Consensus Working Group
:
Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery–2018.
Anesthesiology
.
2018
;
129
:
872
9
2.
Mahanna-Gabrielli
E
,
Schenning
KJ
,
Eriksson
LI
,
Browndyke
JN
,
Wright
CB
,
Culley
DJ
,
Evered
L
,
Scott
DA
,
Wang
NY
,
Brown
CH
, IV
,
Oh
E
,
Purdon
P
,
Inouye
S
,
Berger
M
,
Whittington
RA
,
Price
CC
,
Deiner
S
:
State of the clinical science of perioperative brain health: Report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018.
Br J Anaesth
.
2019
;
123
:
464
78
3.
Sprung
J
,
Roberts
RO
,
Weingarten
TN
,
Nunes Cavalcante
A
,
Knopman
DS
,
Petersen
RC
,
Hanson
AC
,
Schroeder
DR
,
Warner
DO
:
Postoperative delirium in elderly patients is associated with subsequent cognitive impairment.
Br J Anaesth
.
2017
;
119
:
316
23
4.
Marcantonio
ER
:
Delirium in hospitalized older adults.
N Engl J Med
.
2017
;
377
:
1456
66
5.
Evered
LA
,
Silbert
BS
:
Postoperative cognitive dysfunction and noncardiac surgery.
Anesth Analg
.
2018
;
127
:
496
505
6.
Berger
M
,
Terrando
N
,
Smith
SK
,
Browndyke
JN
,
Newman
MF
,
Mathew
JP
:
Neurocognitive function after cardiac surgery: From phenotypes to mechanisms.
Anesthesiology
.
2018
;
129
:
829
51
7.
Rasmussen
LS
,
Johnson
T
,
Kuipers
HM
,
Kristensen
D
,
Siersma
VD
,
Vila
P
,
Jolles
J
,
Papaioannou
A
,
Abildstrom
H
,
Silverstein
JH
,
Bonal
JA
,
Raeder
J
,
Nielsen
IK
,
Korttila
K
,
Munoz
L
,
Dodds
C
,
Hanning
CD
,
Moller
JT
;
ISPOCD2 (International Study of Postoperative Cognitive Dysfunction) Investigators
:
Does anaesthesia cause postoperative cognitive dysfunction?: A randomised study of regional versus general anaesthesia in 438 elderly patients.
Acta Anaesthesiol Scand
.
2003
;
47
:
260
6
8.
Radtke
FM
,
Franck
M
,
Lendner
J
,
Krüger
S
,
Wernecke
KD
,
Spies
CD
:
Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.
Br J Anaesth
.
2013
;
110
:
i98
105
9.
Avidan
MS
,
Maybrier
HR
,
Abdallah
AB
,
Jacobsohn
E
,
Vlisides
PE
,
Pryor
KO
,
Veselis
RA
,
Grocott
HP
,
Emmert
DA
,
Rogers
EM
,
Downey
RJ
,
Yulico
H
,
Noh
GJ
,
Lee
YH
,
Waszynski
CM
,
Arya
VK
,
Pagel
PS
,
Hudetz
JA
,
Muench
MR
,
Fritz
BA
,
Waberski
W
,
Inouye
SK
,
Mashour
GA
;
PODCAST Research Group
:
Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: An international, multicentre, double-blind, randomised clinical trial.
Lancet
.
2017
;
390
:
267
75
10.
Shroyer
AL
,
Grover
FL
,
Hattler
B
,
Collins
JF
,
McDonald
GO
,
Kozora
E
,
Lucke
JC
,
Baltz
JH
,
Novitzky
D
;
Veterans Affairs Randomized On/Off Bypass (ROOBY) Study Group
:
On-pump versus off-pump coronary-artery bypass surgery.
N Engl J Med
.
2009
;
361
:
1827
37
11.
Hshieh
TT
,
Yang
T
,
Gartaganis
SL
,
Yue
J
,
Inouye
SK
:
Hospital elder life program: Systematic review and meta-analysis of effectiveness.
Am J Geriatr Psychiatry
.
2018
;
26
:
1015
33
12.
Czeisler
CA
,
Gooley
JJ
:
Sleep and circadian rhythms in humans.
Cold Spring Harb Symp Quant Biol
.
2007
;
72
:
579
97
13.
Buysse
DJ
:
Sleep health: Can we define it? Does it matter?
Sleep
.
2014
;
37
:
9
17
14.
Yaffe
K
,
Falvey
CM
,
Hoang
T
:
Connections between sleep and cognition in older adults.
Lancet Neurol
.
2014
;
13
:
1017
28
15.
Bhaskar
S
,
Hemavathy
D
,
Prasad
S
:
Prevalence of chronic insomnia in adult patients and its correlation with medical comorbidities.
J Family Med Prim Care
.
2016
;
5
:
780
4
16.
Stranges
S
,
Tigbe
W
,
Gómez-Olivé
FX
,
Thorogood
M
,
Kandala
NB
:
Sleep problems: An emerging global epidemic? Findings from the INDEPTH WHO-SAGE study among more than 40,000 older adults from 8 countries across Africa and Asia.
Sleep
.
2012
;
35
:
1173
81
17.
Ferrie
JE
,
Kumari
M
,
Salo
P
,
Singh-Manoux
A
,
Kivimäki
M
:
Sleep epidemiology: A rapidly growing field.
Int J Epidemiol
.
2011
;
40
:
1431
7
18.
Medic
G
,
Wille
M
,
Hemels
ME
:
Short- and long-term health consequences of sleep disruption.
Nat Sci Sleep
.
2017
;
9
:
151
61
19.
Li
P
,
Gao
L
,
Gaba
A
,
Yu
L
,
Cui
L
,
Fan
W
,
Lim
ASP
,
Bennett
DA
,
Buchman
AS
,
Hu
K
:
Circadian disturbances in Alzheimer’s disease progression: A prospective observational cohort study of community-based older adults.
Lancet Healthy Longev
.
2020
;
1
:
e96
105
20.
Fadayomi
AB
,
Ibala
R
,
Bilotta
F
,
Westover
MB
,
Akeju
O
:
A systematic review and meta-analysis examining the impact of sleep disturbance on postoperative delirium.
Crit Care Med
.
2018
;
46
:
e1204
12
21.
McKenna
H
,
van der Horst
GTJ
,
Reiss
I
,
Martin
D
:
Clinical chronobiology: A timely consideration in critical care medicine.
Crit Care
.
2018
;
22
:
124
22.
Hu
K
,
Li
P
,
Gao
L
:
Sleep, rest–activity rhythms and aging: A complex web in Alzheimer’s disease?
Neurobiol Aging
.
2021
;
104
:
102
3
23.
Leng
Y
,
Musiek
ES
,
Hu
K
,
Cappuccio
FP
,
Yaffe
K
:
Association between circadian rhythms and neurodegenerative diseases.
Lancet Neurol
.
2019
;
18
:
307
18
24.
Leung
JM
,
Sands
LP
,
Newman
S
,
Meckler
G
,
Xie
Y
,
Gay
C
,
Lee
K
:
Preoperative sleep disruption and postoperative delirium.
J Clin Sleep Med
.
2015
;
11
:
907
13
25.
Dessap
AM
,
Roche-Campo
F
,
Launay
JM
,
Charles-Nelson
A
,
Katsahian
S
,
Brun-Buisson
C
,
Brochard
L
:
Delirium and circadian rhythm of melatonin during weaning from mechanical ventilation: An ancillary study of a weaning trial.
Chest
.
2015
;
148
:
1231
41
26.
Campbell
AM
,
Axon
DR
,
Martin
JR
,
Slack
MK
,
Mollon
L
,
Lee
JK
:
Melatonin for the prevention of postoperative delirium in older adults: A systematic review and meta-analysis.
BMC Geriatr
.
2019
;
19
:
272
27.
Hshieh
TT
,
Fong
TG
,
Marcantonio
ER
,
Inouye
SK
:
Cholinergic deficiency hypothesis in delirium: A synthesis of current evidence.
J Gerontol A Biol Sci Med Sci
.
2008
;
63
:
764
72
28.
Bowman
K
,
Jones
L
,
Pilling
LC
,
Delgado
J
,
Kuchel
GA
,
Ferrucci
L
,
Fortinsky
RH
,
Melzer
D
:
Vitamin D levels and risk of delirium: A mendelian randomization study in the UK Biobank.
Neurology
.
2019
;
92
:
e1387
94
29.
Pilling
LC
,
Jones
LC
,
Masoli
JAH
,
Delgado
J
,
Atkins
JL
,
Bowden
J
,
Fortinsky
RH
,
Kuchel
GA
,
Melzer
D
:
Low vitamin D levels and risk of incident delirium in 351,000 older UK Biobank participants.
J Am Geriatr Soc
.
2021
;
69
:
365
72
30.
Gao
L
,
Li
P
,
Cui
L
,
Wong
PM
,
Johnson-Akeju
O
,
Lane
J
,
Saxena
R
,
Scheer
F
,
Hu
K
:
Sleep disturbance and incident Alzheimer’s disease: A UK Biobank study of 502,538 middle-aged to older participants.
Alzheimers Dement
.
2020
;
16
:
e044575
31.
Gao
L
,
Lim
ASP
,
Wong
PM
,
Gaba
A
,
Cui
L
,
Yu
L
,
Buchman
AS
,
Bennett
DA
,
Hu
K
,
Li
P
:
Fragmentation of rest/activity patterns in community-based elderly individuals predicts incident heart failure.
Nat Sci Sleep
.
2020
;
12
:
299
307
32.
Finan
PH
,
Goodin
BR
,
Smith
MT
:
The association of sleep and pain: An update and a path forward.
J Pain
.
2013
;
14
:
1539
52
33.
Practice guidelines for the perioperative management of patients with obstructive sleep apnea: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Obstructive Sleep Apnea.
Anesthesiology
.
2014
;
120
:
268
86
34.
Alchanatis
M
,
Zias
N
,
Deligiorgis
N
,
Amfilochiou
A
,
Dionellis
G
,
Orphanidou
D
:
Sleep apnea-related cognitive deficits and intelligence: An implication of cognitive reserve theory.
J Sleep Res
.
2005
;
14
:
69
75
35.
Leng
Y
,
McEvoy
CT
,
Allen
IE
,
Yaffe
K
:
Association of sleep-disordered breathing with cognitive function and risk of cognitive impairment: A systematic review and meta-analysis.
JAMA Neurol
.
2017
;
74
:
1237
45
36.
André
C
,
Rehel
S
,
Kuhn
E
,
Landeau
B
,
Moulinet
I
,
Touron
E
,
Ourry
V
,
Le Du
G
,
Mézenge
F
,
Tomadesso
C
,
de Flores
R
,
Bejanin
A
,
Sherif
S
,
Delcroix
N
,
Manrique
A
,
Abbas
A
,
Marchant
NL
,
Lutz
A
,
Klimecki
OM
,
Collette
F
,
Arenaza-Urquijo
EM
,
Poisnel
G
,
Vivien
D
,
Bertran
F
,
de la Sayette
V
,
Chételat
G
,
Rauchs
G
;
Medit-Ageing Research Group
:
Association of sleep-disordered breathing with Alzheimer disease biomarkers in community-dwelling older adults: A secondary analysis of a randomized clinical trial.
JAMA Neurol
.
2020
;
77
:
716
24
37.
Mirrakhimov
AE
,
Brewbaker
CL
,
Krystal
AD
,
Kwatra
MM
:
Obstructive sleep apnea and delirium: Exploring possible mechanisms.
Sleep Breath
.
2014
;
18
:
19
29
38.
Roggenbach
J
,
Klamann
M
,
von Haken
R
,
Bruckner
T
,
Karck
M
,
Hofer
S
:
Sleep-disordered breathing is a risk factor for delirium after cardiac surgery: A prospective cohort study.
Crit Care
.
2014
;
18
:
477
39.
Flink
BJ
,
Rivelli
SK
,
Cox
EA
,
White
WD
,
Falcone
G
,
Vail
TP
,
Young
CC
,
Bolognesi
MP
,
Krystal
AD
,
Trzepacz
PT
,
Moon
RE
,
Kwatra
MM
:
Obstructive sleep apnea and incidence of postoperative delirium after elective knee replacement in the nondemented elderly.
Anesthesiology
.
2012
;
116
:
788
96
40.
King
CR
,
Fritz
BA
,
Escallier
K
,
Ju
YS
,
Lin
N
,
McKinnon
S
,
Avidan
MS
,
Palanca
BJ
:
Association between preoperative obstructive sleep apnea and preoperative positive airway pressure with postoperative intensive care unit delirium.
JAMA Netw Open
.
2020
;
3
:
e203125
41.
Chung
F
,
Memtsoudis
SG
,
Ramachandran
SK
,
Nagappa
M
,
Opperer
M
,
Cozowicz
C
,
Patrawala
S
,
Lam
D
,
Kumar
A
,
Joshi
GP
,
Fleetham
J
,
Ayas
N
,
Collop
N
,
Doufas
AG
,
Eikermann
M
,
Englesakis
M
,
Gali
B
,
Gay
P
,
Hernandez
AV
,
Kaw
R
,
Kezirian
EJ
,
Malhotra
A
,
Mokhlesi
B
,
Parthasarathy
S
,
Stierer
T
,
Wappler
F
,
Hillman
DR
,
Auckley
D
:
Society of Anesthesia and Sleep Medicine Guidelines on preoperative screening and assessment of adult patients with obstructive sleep apnea.
Anesth Analg
.
2016
;
123
:
452
73
42.
Cooke
JR
,
Ayalon
L
,
Palmer
BW
,
Loredo
JS
,
Corey-Bloom
J
,
Natarajan
L
,
Liu
L
,
Ancoli-Israel
S
:
Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: A preliminary study.
J Clin Sleep Med
.
2009
;
5
:
305
9
43.
Dalmases
M
,
Solé-Padullés
C
,
Torres
M
,
Embid
C
,
Nuñez
MD
,
Martínez-Garcia
,
Farré
R
,
Bargalló
N
,
Bartrés-Faz
D
,
Montserrat
JM
:
Effect of CPAP on cognition, brain function, and structure among elderly patients with OSA: A randomized pilot study.
Chest
.
2015
;
148
:
1214
23
44.
Crawford-Achour
E
,
Dauphinot
V
,
Martin
MS
,
Tardy
M
,
Gonthier
R
,
Barthelemy
JC
,
Roche
F
:
Protective effect of long-term CPAP therapy on cognitive performance in elderly patients with severe OSA: The PROOF study.
J Clin Sleep Med
.
2015
;
11
:
519
24
45.
Nadler
JW
,
Evans
JL
,
Fang
E
,
Preud’Homme
XA
,
Daughtry
RL
,
Chapman
JB
,
Bolognesi
MP
,
Attarian
DE
,
Wellman
SS
,
Krystal
AD
:
A randomised trial of peri-operative positive airway pressure for postoperative delirium in patients at risk for obstructive sleep apnoea after regional anaesthesia with sedation or general anaesthesia for joint arthroplasty.
Anaesthesia
.
2017
;
72
:
729
36
46.
Berger
M
,
Oyeyemi
D
,
Olurinde
MO
,
Whitson
HE
,
Weinhold
KJ
,
Woldorff
MG
,
Lipsitz
LA
,
Moretti
E
,
Giattino
CM
,
Roberts
KC
,
Zhou
J
,
Bunning
T
,
Ferrandino
M
,
Scheri
RP
,
Cooter
M
,
Chan
C
,
Cabeza
R
,
Browndyke
JN
,
Murdoch
DM
,
Devinney
MJ
,
Shaw
LM
,
Cohen
HJ
,
Mathew
JP
;
INTUIT Investigators
:
The INTUIT study: Investigating neuroinflammation underlying postoperative cognitive dysfunction.
J Am Geriatr Soc
.
2019
;
67
:
794
8
47.
Vacas
S
:
Blood brain barrier dysfunction and postoperative neurocognitive disorders. Clinical Trial Protocol.
September 2020
.
Available at: https://clinicaltrials.gov/ct2/show/NCT04566562. Accessed October 2021
.
48.
Pandharipande
PP
,
Pun
BT
,
Herr
DL
,
Maze
M
,
Girard
TD
,
Miller
RR
,
Shintani
AK
,
Thompson
JL
,
Jackson
JC
,
Deppen
SA
,
Stiles
RA
,
Dittus
RS
,
Bernard
GR
,
Ely
EW
:
Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial.
JAMA
.
2007
;
298
:
2644
53
49.
Jakob
SM
,
Ruokonen
E
,
Grounds
RM
,
Sarapohja
T
,
Garratt
C
,
Pocock
SJ
,
Bratty
JR
,
Takala
J
;
Dexmedetomidine for Long-Term Sedation Investigators
:
Dexmedetomidine vs. midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials.
JAMA
.
2012
;
307
:
1151
60
50.
Zeng
H
,
Li
Z
,
He
J
,
Fu
W
:
Dexmedetomidine for the prevention of postoperative delirium in elderly patients undergoing noncardiac surgery: A meta-analysis of randomized controlled trials.
PLoS One
.
2019
;
14
:
e0218088
51.
Ng
KT
,
Shubash
CJ
,
Chong
JS
:
The effect of dexmedetomidine on delirium and agitation in patients in intensive care: Systematic review and meta-analysis with trial sequential analysis.
Anaesthesia
.
2019
;
74
:
380
92
52.
Akeju
O
,
Hobbs
LE
,
Gao
L
,
Burns
SM
,
Pavone
KJ
,
Plummer
GS
,
Walsh
EC
,
Houle
TT
,
Kim
SE
,
Bianchi
MT
,
Ellenbogen
JM
,
Brown
EN
:
Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study.
Clin Neurophysiol
.
2018
;
129
:
69
78
53.
Wu
XH
,
Cui
F
,
Zhang
C
,
Meng
ZT
,
Wang
DX
,
Ma
J
,
Wang
GF
,
Zhu
SN
,
Ma
D
:
Low-dose dexmedetomidine improves sleep quality pattern in elderly patients after noncardiac surgery in the intensive care unit: A pilot randomized controlled Trial.
Anesthesiology
.
2016
;
125
:
979
91
54.
Su
X
,
Meng
ZT
,
Wu
XH
,
Cui
F
,
Li
HL
,
Wang
DX
,
Zhu
X
,
Zhu
SN
,
Maze
M
,
Ma
D
:
Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: A randomised, double-blind, placebo-controlled trial.
Lancet
.
2016
;
388
:
1893
902
55.
Chamadia
S
,
Hobbs
L
,
Marota
S
,
Ibala
R
,
Hahm
E
,
Gitlin
J
,
Mekonnen
J
,
Ethridge
B
,
Colon
KM
,
Sheppard
KS
,
Manoach
DS
,
DiBiasio
A
,
Nguyen
S
,
Pedemonte
JC
,
Akeju
O
:
Oral dexmedetomidine promotes non-rapid eye movement stage 2 sleep in humans.
Anesthesiology
.
2020
;
133
:
1234
43
56.
Cajochen
C
,
Kräuchi
K
,
Wirz-Justice
A
:
Role of melatonin in the regulation of human circadian rhythms and sleep.
J Neuroendocrinol
.
2003
;
15
:
432
7
57.
Olofsson
K
,
Alling
C
,
Lundberg
D
,
Malmros
C
:
Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients.
Acta Anaesthesiol Scand
.
2004
;
48
:
679
84
58.
Yoshitaka
S
,
Egi
M
,
Morimatsu
H
,
Kanazawa
T
,
Toda
Y
,
Morita
K
:
Perioperative plasma melatonin concentration in postoperative critically ill patients: Its association with delirium.
J Crit Care
.
2013
;
28
:
236
42
59.
Artemiou
P
,
Bily
B
,
Bilecova-Rabajdova
M
,
Sabol
F
,
Torok
P
,
Kolarcik
P
,
Kolesar
A
:
Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients.
Kardiochir Torakochirurgia Pol
.
2015
;
12
:
126
33
60.
Hatta
K
,
Kishi
Y
,
Wada
K
,
Takeuchi
T
,
Odawara
T
,
Usui
C
,
Nakamura
H
;
DELIRIA-J Group
:
Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial.
JAMA Psychiatry
.
2014
;
71
:
397
403
61.
Jaiswal
SJ
,
Vyas
AD
,
Heisel
AJ
,
Ackula
H
,
Aggarwal
A
,
Kim
NH
,
Kerr
KM
,
Madani
M
,
Pretorius
V
,
Auger
WR
,
Fernandes
TM
,
Malhotra
A
,
Owens
RL
:
Ramelteon for prevention of postoperative delirium: A randomized controlled trial in patients undergoing elective pulmonary thromboendarterectomy.
Crit Care Med
.
2019
;
47
:
1751
8
62.
Ng
KT
,
Teoh
WY
,
Khor
AJ
:
The effect of melatonin on delirium in hospitalised patients: A systematic review and meta-analyses with trial sequential analysis.
J Clin Anesth
.
2020
;
59
:
74
81
63.
Wu
Y
,
Wang
J
,
Wu
A
,
Yue
Y
:
Do fluctuations in endogenous melatonin levels predict the occurrence of postoperative cognitive dysfunction (POCD)?
Int J Neurosci
.
2014
;
124
:
787
91
64.
Gögenur
I
,
Middleton
B
,
Burgdorf
S
,
Rasmussen
LS
,
Skene
DJ
,
Rosenberg
J
:
Impact of sleep and circadian disturbances in urinary 6-sulphatoxymelatonin levels, on cognitive function after major surgery.
J Pineal Res
.
2007
;
43
:
179
84
65.
Fan
Y
,
Yuan
L
,
Ji
M
,
Yang
J
,
Gao
D
:
The effect of melatonin on early postoperative cognitive decline in elderly patients undergoing hip arthroplasty: A randomized controlled trial.
J Clin Anesth
.
2017
;
39
:
77
81
66.
Hansen
MV
,
Madsen
MT
,
Andersen
LT
,
Hageman
I
,
Rasmussen
LS
,
Bokmand
S
,
Rosenberg
J
,
Gögenur
I
:
Effect of melatonin on cognitive function and sleep in relation to breast cancer surgery: A randomized, double-blind, placebo-controlled trial.
Int J Breast Cancer
.
2014
;
2014
:
416531
67.
Kamdar
BB
,
King
LM
,
Collop
NA
,
Sakamuri
S
,
Colantuoni
E
,
Neufeld
KJ
,
Bienvenu
OJ
,
Rowden
AM
,
Touradji
P
,
Brower
RG
,
Needham
DM
:
The effect of a quality improvement intervention on perceived sleep quality and cognition in a medical ICU.
Crit Care Med
.
2013
;
41
:
800
9
68.
McMahon
SB
,
Cafferty
WB
,
Marchand
F
:
Immune and glial cell factors as pain mediators and modulators.
Exp Neurol
.
2005
;
192
:
444
62
69.
Campbell
JN
,
Meyer
RA
:
Mechanisms of neuropathic pain.
Neuron
.
2006
;
52
:
77
92
70.
Inouye
SK
,
Westendorp
RG
,
Saczynski
JS
:
Delirium in elderly people.
Lancet
.
2014
;
383
:
911
22
71.
Hughes
CG
,
Patel
MB
,
Pandharipande
PP
:
Pathophysiology of acute brain dysfunction: What’s the cause of all this confusion?
Curr Opin Crit Care
.
2012
;
18
:
518
26
72.
MacLullich
AM
,
Edelshain
BT
,
Hall
RJ
,
de Vries
A
,
Howie
SE
,
Pearson
A
,
Middleton
SD
,
Gillies
F
,
Armstrong
IR
,
White
TO
,
Cunningham
C
,
de Rooij
SE
,
van Munster
BC
:
Cerebrospinal fluid interleukin-8 levels are higher in people with hip fracture with perioperative delirium than in controls.
J Am Geriatr Soc
.
2011
;
59
:
1151
3
73.
Dantzer
R
,
O’Connor
JC
,
Freund
GG
,
Johnson
RW
,
Kelley
KW
:
From inflammation to sickness and depression: When the immune system subjugates the brain.
Nat Rev Neurosci
.
2008
;
9
:
46
56
74.
Jalleh
R
,
Koh
K
,
Choi
B
,
Liu
E
,
Maddison
J
,
Hutchinson
MR
:
Role of microglia and Toll-like receptor 4 in the pathophysiology of delirium.
Med Hypotheses
.
2012
;
79
:
735
9
75.
Naser
PV
,
Kuner
R
:
Molecular, cellular and circuit basis of cholinergic modulation of pain.
Neuroscience
.
2018
;
387
:
135
48
76.
Vaurio
LE
,
Sands
LP
,
Wang
Y
,
Mullen
EA
,
Leung
JM
:
Postoperative delirium: The importance of pain and pain management.
Anesth Analg
.
2006
;
102
:
1267
73
77.
Kosar
CM
,
Tabloski
PA
,
Travison
TG
,
Jones
RN
,
Schmitt
EM
,
Puelle
MR
,
Inloes
JB
,
Saczynski
JS
,
Marcantonio
ER
,
Meagher
D
,
Reid
MC
,
Inouye
SK
:
Effect of preoperative pain and depressive symptoms on the development of postoperative delirium.
Lancet Psychiatry
.
2014
;
1
:
431
6
78.
Ong
WY
,
Stohler
CS
,
Herr
DR
:
Role of the prefrontal cortex in pain processing.
Mol Neurobiol
.
2019
;
56
:
1137
66
79.
Morrison
RS
,
Magaziner
J
,
Gilbert
M
,
Koval
KJ
,
McLaughlin
MA
,
Orosz
G
,
Strauss
E
,
Siu
AL
:
Relationship between pain and opioid analgesics on the development of delirium following hip fracture.
J Gerontol A Biol Sci Med Sci
.
2003
;
58
:
76
81
80.
Lynch
EP
,
Lazor
MA
,
Gellis
JE
,
Orav
J
,
Goldman
L
,
Marcantonio
ER
:
The impact of postoperative pain on the development of postoperative delirium.
Anesth Analg
.
1998
;
86
:
781
5
81.
Leung
JM
,
Sands
LP
,
Lim
E
,
Tsai
TL
,
Kinjo
S
:
Does preoperative risk for delirium moderate the effects of postoperative pain and opiate use on postoperative delirium?
Am J Geriatr Psychiatry
.
2013
;
21
:
946
56
82.
Ganai
S
,
Lee
KF
,
Merrill
A
,
Lee
MH
,
Bellantonio
S
,
Brennan
M
,
Lindenauer
P
:
Adverse outcomes of geriatric patients undergoing abdominal surgery who are at high risk for delirium.
Arch Surg
.
2007
;
142
:
1072
8
83.
Schofield
P
:
The assessment of pain in older people: UK national guidelines.
Age Ageing
.
2018
;
47
:
i1
22
84.
Marra
A
,
Ely
EW
,
Pandharipande
PP
,
Patel
MB
:
The ABCDEF bundle in critical care.
Crit Care Clin
.
2017
;
33
:
225
43
85.
Hughes
CG
,
Boncyk
CS
,
Culley
DJ
,
Fleisher
LA
,
Leung
JM
,
McDonagh
DL
,
Gan
TJ
,
McEvoy
MD
,
Miller
TE
;
Perioperative Quality Initiative (POQI) 6 Workgroup
:
American Society for Enhanced Recovery and Perioperative Quality Initiative joint consensus statement on postoperative delirium prevention.
Anesth Analg
.
2020
;
130
:
1572
90
86.
American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults
:
American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults.
J Am Geriatr Soc
.
2015
;
63
:
142
50
87.
Robinson
S
,
Vollmer
C
:
Undermedication for pain and precipitation of delirium.
Medsurg Nurs
.
2010
;
19
:
79
84
88.
Sieber
FE
,
Mears
S
,
Lee
H
,
Gottschalk
A
:
Postoperative opioid consumption and its relationship to cognitive function in older adults with hip fracture.
J Am Geriatr Soc
.
2011
;
59
:
2256
62
89.
Koepke
EJ
,
Manning
EL
,
Miller
TE
,
Ganesh
A
,
Williams
DGA
,
Manning
MW
:
The rising tide of opioid use and abuse: The role of the anesthesiologist.
Perioper Med (Lond)
.
2018
;
7
:
16
90.
Swart
LM
,
van der Zanden
V
,
Spies
PE
,
de Rooij
SE
,
van Munster
BC
:
The comparative risk of delirium with different opioids: A systematic review.
Drugs Aging
.
2017
;
34
:
437
43
91.
Wang
Y
,
Sands
LP
,
Vaurio
L
,
Mullen
EA
,
Leung
JM
:
The effects of postoperative pain and its management on postoperative cognitive dysfunction.
Am J Geriatr Psychiatry
.
2007
;
15
:
50
9
92.
Mu
DL
,
Zhang
DZ
,
Wang
DX
,
Wang
G
,
Li
CJ
,
Meng
ZT
,
Li
YW
,
Liu
C
,
Li
XY
:
Parecoxib supplementation to morphine analgesia decreases incidence of delirium in elderly patients after hip or knee replacement surgery: A randomized controlled trial.
Anesth Analg
.
2017
;
124
:
1992
2000
93.
Flower
RJ
,
Vane
JR
:
Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol).
Nature
.
1972
;
240
:
410
1
94.
Subramaniam
B
,
Shankar
P
,
Shaefi
S
,
Mueller
A
,
O’Gara
B
,
Banner-Goodspeed
V
,
Gallagher
J
,
Gasangwa
D
,
Patxot
M
,
Packiasabapathy
S
,
Mathur
P
,
Eikermann
M
,
Talmor
D
,
Marcantonio
ER
:
Effect of intravenous acetaminophen vs. placebo combined with propofol or dexmedetomidine on postoperative delirium among older patients following cardiac surgery: The DEXACET randomized clinical trial.
JAMA
.
2019
;
321
:
686
96
95.
Mathew
JP
,
Mackensen
GB
,
Phillips-Bute
B
,
Grocott
HP
,
Glower
DD
,
Laskowitz
DT
,
Blumenthal
JA
,
Newman
MF
;
Neurologic Outcome Research Group (NORG) of the Duke Heart Center
:
Randomized, double-blinded, placebo controlled study of neuroprotection with lidocaine in cardiac surgery.
Stroke
.
2009
;
40
:
880
7
96.
Mathew
JP
,
White
WD
,
Schinderle
DB
,
Podgoreanu
MV
,
Berger
M
,
Milano
CA
,
Laskowitz
DT
,
Stafford-Smith
M
,
Blumenthal
JA
,
Newman
MF
;
Neurologic Outcome Research Group (NORG) of The Duke Heart Center
:
Intraoperative magnesium administration does not improve neurocognitive function after cardiac surgery.
Stroke
.
2013
;
44
:
3407
13
97.
Royse
CF
,
Saager
L
,
Whitlock
R
,
Ou-Young
J
,
Royse
A
,
Vincent
J
,
Devereaux
PJ
,
Kurz
A
,
Awais
A
,
Panjasawatwong
K
,
Sessler
DI
:
Impact of methylprednisolone on postoperative quality of recovery and delirium in the steroids in cardiac surgery trial: A randomized, double-blind, placebo-controlled substudy.
Anesthesiology
.
2017
;
126
:
223
33
98.
Whitlock
RP
,
Devereaux
PJ
,
Teoh
KH
,
Lamy
A
,
Vincent
J
,
Pogue
J
,
Paparella
D
,
Sessler
DI
,
Karthikeyan
G
,
Villar
JC
,
Zuo
Y
,
Avezum
Á
,
Quantz
M
,
Tagarakis
GI
,
Shah
PJ
,
Abbasi
SH
,
Zheng
H
,
Pettit
S
,
Chrolavicius
S
,
Yusuf
S
;
SIRS Investigators
:
Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): A randomised, double-blind, placebo-controlled trial.
Lancet
.
2015
;
386
:
1243
53
99.
Sauër
AM
,
Slooter
AJ
,
Veldhuijzen
DS
,
van Eijk
MM
,
Devlin
JW
,
van Dijk
D
:
Intraoperative dexamethasone and delirium after cardiac surgery: A randomized clinical trial.
Anesth Analg
.
2014
;
119
:
1046
52
100.
Leung
JM
,
Sands
LP
,
Chen
N
,
Ames
C
,
Berven
S
,
Bozic
K
,
Burch
S
,
Chou
D
,
Covinsky
K
,
Deviren
V
,
Kinjo
S
,
Kramer
JH
,
Ries
M
,
Tay
B
,
Vail
T
,
Weinstein
P
,
Chang
S
,
Meckler
G
,
Newman
S
,
Tsai
T
,
Voss
V
,
Youngblom
E
;
Perioperative Medicine Research Group
:
Perioperative gabapentin does not reduce postoperative delirium in older surgical patients: A randomized clinical trial.
Anesthesiology
.
2017
;
127
:
633
44
101.
Krenk
L
,
Rasmussen
LS
,
Hansen
TB
,
Bogø
S
,
Søballe
K
,
Kehlet
H
:
Delirium after fast-track hip and knee arthroplasty.
Br J Anaesth
.
2012
;
108
:
607
11
102.
Krystal
JH
,
Karper
LP
,
Seibyl
JP
,
Freeman
GK
,
Delaney
R
,
Bremner
JD
,
Heninger
GR
,
Bowers
MB
, Jr
,
Charney
DS
:
Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.
Arch Gen Psychiatry
.
1994
;
51
:
199
214
103.
Bornemann-Cimenti
H
,
Wejbora
M
,
Michaeli
K
,
Edler
A
,
Sandner-Kiesling
A
:
The effects of minimal-dose versus low-dose S-ketamine on opioid consumption, hyperalgesia, and postoperative delirium: A triple-blinded, randomized, active- and placebo-controlled clinical trial.
Minerva Anestesiol
.
2016
;
82
:
1069
76
104.
Hudetz
JA
,
Patterson
KM
,
Iqbal
Z
,
Gandhi
SD
,
Byrne
AJ
,
Hudetz
AG
,
Warltier
DC
,
Pagel
PS
:
Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass.
J Cardiothorac Vasc Anesth
.
2009
;
23
:
651
7
105.
Hudetz
JA
,
Iqbal
Z
,
Gandhi
SD
,
Patterson
KM
,
Byrne
AJ
,
Hudetz
AG
,
Pagel
PS
,
Warltier
DC
:
Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery.
Acta Anaesthesiol Scand
.
2009
;
53
:
864
72
106.
Mouzopoulos
G
,
Vasiliadis
G
,
Lasanianos
N
,
Nikolaras
G
,
Morakis
E
,
Kaminaris
M
:
Fascia iliaca block prophylaxis for hip fracture patients at risk for delirium: A randomized placebo-controlled study.
J Orthop Traumatol
.
2009
;
10
:
127
33
107.
Kinjo
S
,
Lim
E
,
Sands
LP
,
Bozic
KJ
,
Leung
JM
:
Does using a femoral nerve block for total knee replacement decrease postoperative delirium?
BMC Anesthesiol
.
2012
;
12
:
4
108.
Sieber
FE
,
Gottshalk
A
,
Zakriya
KJ
,
Mears
SC
,
Lee
H
:
General anesthesia occurs frequently in elderly patients during propofol-based sedation and spinal anesthesia.
J Clin Anesth
.
2010
;
22
:
179
83
109.
Neuman
MD
,
Ellenberg
SS
,
Sieber
FE
,
Magaziner
JS
,
Feng
R
,
Carson
JL
;
REGAIN Investigators
:
REgional versus General Anesthesia for promoting INdependence after hip fracture (REGAIN): Protocol for a pragmatic, international multicentre trial.
BMJ Open
.
2016
;
6
:
e013473
110.
Hughes
MJ
,
Ventham
NT
,
McNally
S
,
Harrison
E
,
Wigmore
S
:
Analgesia after open abdominal surgery in the setting of enhanced recovery surgery: A systematic review and meta-analysis.
JAMA Surg
.
2014
;
149
:
1224
30
111.
Mann
C
,
Pouzeratte
Y
,
Boccara
G
,
Peccoux
C
,
Vergne
C
,
Brunat
G
,
Domergue
J
,
Millat
B
,
Colson
P
:
Comparison of intravenous or epidural patient-controlled analgesia in the elderly after major abdominal surgery.
Anesthesiology
.
2000
;
92
:
433
41
112.
Vlisides
PE
,
Thompson
A
,
Kunkler
BS
,
Maybrier
HR
,
Avidan
MS
,
Mashour
GA
;
PODCAST Research Group
:
Perioperative epidural use and risk of delirium in surgical patients: A secondary analysis of the PODCAST trial.
Anesth Analg
.
2019
;
128
:
944
52
113.
Jia
Y
,
Jin
G
,
Guo
S
,
Gu
B
,
Jin
Z
,
Gao
X
,
Li
Z
:
Fast-track surgery decreases the incidence of postoperative delirium and other complications in elderly patients with colorectal carcinoma.
Langenbecks Arch Surg
.
2014
;
399
:
77
84
114.
Engelman
DT
,
Ben Ali
W
,
Williams
JB
,
Perrault
LP
,
Reddy
VS
,
Arora
RC
,
Roselli
EE
,
Khoynezhad
A
,
Gerdisch
M
,
Levy
JH
,
Lobdell
K
,
Fletcher
N
,
Kirsch
M
,
Nelson
G
,
Engelman
RM
,
Gregory
AJ
,
Boyle
EM
:
Guidelines for perioperative care in cardiac surgery: Enhanced Recovery After Surgery Society recommendations.
JAMA Surg
.
2019
;
154
:
755
66
115.
Sprung
J
,
Abdelmalak
B
,
Gottlieb
A
,
Mayhew
C
,
Hammel
J
,
Levy
PJ
,
O’Hara
P
,
Hertzer
NR
:
Analysis of risk factors for myocardial infarction and cardiac mortality after major vascular surgery.
Anesthesiology
.
2000
;
93
:
129
40
116.
Sharifpour
M
,
Moore
LE
,
Shanks
AM
,
Didier
TJ
,
Kheterpal
S
,
Mashour
GA
:
Incidence, predictors, and outcomes of perioperative stroke in noncarotid major vascular surgery.
Anesth Analg
.
2013
;
116
:
424
34
117.
Bell
S
,
Dekker
FW
,
Vadiveloo
T
,
Marwick
C
,
Deshmukh
H
,
Donnan
PT
,
Van Diepen
M
:
Risk of postoperative acute kidney injury in patients undergoing orthopaedic surgery: Development and validation of a risk score and effect of acute kidney injury on survival: Observational cohort study.
BMJ
.
2015
;
351
:
h5639
118.
Robinson
TN
,
Wu
DS
,
Pointer
LF
,
Dunn
CL
,
Moss
M
:
Preoperative cognitive dysfunction is related to adverse postoperative outcomes in the elderly.
J Am Coll Surg
.
2012
;
215
:
12
8
119.
Culley
DJ
,
Flaherty
D
,
Fahey
MC
,
Rudolph
JL
,
Javedan
H
,
Huang
CC
,
Wright
J
,
Bader
AM
,
Hyman
BT
,
Blacker
D
,
Crosby
G
:
Poor performance on a preoperative cognitive screening test predicts postoperative complications in older orthopedic surgical patients.
Anesthesiology
.
2017
;
127
:
765
74
120.
Lee
HB
,
Mears
SC
,
Rosenberg
PB
,
Leoutsakos
JM
,
Gottschalk
A
,
Sieber
FE
:
Predisposing factors for postoperative delirium after hip fracture repair in individuals with and without dementia.
J Am Geriatr Soc
.
2011
;
59
:
2306
13
121.
Tow
A
,
Holtzer
R
,
Wang
C
,
Sharan
A
,
Kim
SJ
,
Gladstein
A
,
Blum
Y
,
Verghese
J
:
Cognitive reserve and postoperative delirium in older adults.
J Am Geriatr Soc
.
2016
;
64
:
1341
6
122.
Smith
PJ
,
Attix
DK
,
Weldon
BC
,
Greene
NH
,
Monk
TG
:
Executive function and depression as independent risk factors for postoperative delirium.
Anesthesiology
.
2009
;
110
:
781
7
123.
Cunningham
EL
,
Mawhinney
T
,
Beverland
D
,
O’Brien
S
,
McAuley
DF
,
Cairns
R
,
Passmore
P
,
McGuinness
B
:
Observational cohort study examining apolipoprotein E status and preoperative neuropsychological performance as predictors of post-operative delirium in an older elective arthroplasty population.
Age Ageing
.
2017
;
46
:
779
86
124.
Silbert
B
,
Evered
L
,
Scott
DA
,
McMahon
S
,
Choong
P
,
Ames
D
,
Maruff
P
,
Jamrozik
K
:
Preexisting cognitive impairment is associated with postoperative cognitive dysfunction after hip joint replacement surgery.
Anesthesiology
.
2015
;
122
:
1224
34
125.
Jones
RN
,
Marcantonio
ER
,
Saczynski
JS
,
Tommet
D
,
Gross
AL
,
Travison
TG
,
Alsop
DC
,
Schmitt
EM
,
Fong
TG
,
Cizginer
S
,
Shafi
MM
,
Pascual-Leone
A
,
Inouye
SK
:
Preoperative cognitive performance dominates risk for delirium among older adults.
J Geriatr Psychiatry Neurol
.
2016
;
29
:
320
7
126.
Lingehall
HC
,
Smulter
NS
,
Lindahl
E
,
Lindkvist
M
,
Engström
KG
,
Gustafson
YG
,
Olofsson
B
:
Preoperative cognitive performance and postoperative delirium are independently associated with future dementia in older people who have undergone cardiac surgery: A longitudinal cohort study.
Crit Care Med
.
2017
;
45
:
1295
303
127.
Berger
M
,
Schenning
KJ
,
Brown
CH
, IV
,
Deiner
SG
,
Whittington
RA
,
Eckenhoff
RG
,
Angst
MS
,
Avramescu
S
,
Bekker
A
,
Brzezinski
M
,
Crosby
G
,
Culley
DJ
,
Eckenhoff
M
,
Eriksson
LI
,
Evered
L
,
Ibinson
J
,
Kline
RP
,
Kofke
A
,
Ma
D
,
Mathew
JP
,
Maze
M
,
Orser
BA
,
Price
CC
,
Scott
DA
,
Silbert
B
,
Su
D
,
Terrando
N
,
Wang
DS
,
Wei
H
,
Xie
Z
,
Zuo
Z
;
Perioperative Neurotoxicity Working Group
:
Best practices for postoperative brain health: Recommendations from the Fifth International Perioperative Neurotoxicity Working Group.
Anesth Analg
.
2018
;
127
:
1406
13
128.
Stern
Y
:
Cognitive reserve.
Neuropsychologia
.
2009
;
47
:
2015
28
129.
Jones
RN
,
Yang
FM
,
Zhang
Y
,
Kiely
DK
,
Marcantonio
ER
,
Inouye
SK
:
Does educational attainment contribute to risk for delirium?: A potential role for cognitive reserve.
J Gerontol A Biol Sci Med Sci
.
2006
;
61
:
1307
11
130.
Martins
S
,
Paiva
JA
,
Simões
MR
,
Fernandes
L
:
Delirium in elderly patients: Association with educational attainment.
Acta Neuropsychiatr
.
2017
;
29
:
95
101
131.
Galanakis
P
,
Bickel
H
,
Gradinger
R
,
Von Gumppenberg
S
,
Förstl
H
:
Acute confusional state in the elderly following hip surgery: Incidence, risk factors and complications.
Int J Geriatr Psychiatry
.
2001
;
16
:
349
55
132.
Saczynski
JS
,
Inouye
SK
,
Kosar
CM
,
Tommet
D
,
Marcantonio
ER
,
Fong
T
,
Hshieh
T
,
Vasunilashorn
S
,
Metzger
ED
,
Schmitt
E
,
Alsop
DC
,
Jones
RN
;
SAGES Study Group
:
Cognitive and brain reserve and the risk of postoperative delirium in older patients: Analysis of data from a prospective observational study.
Lancet Psychiatry
.
2014
;
1
:
437
43
133.
Moller
JT
,
Cluitmans
P
,
Rasmussen
LS
,
Houx
P
,
Rasmussen
H
,
Canet
J
,
Rabbitt
P
,
Jolles
J
,
Larsen
K
,
Hanning
CD
,
Langeron
O
,
Johnson
T
,
Lauven
PM
,
Kristensen
PA
,
Biedler
A
,
van Beem
H
,
Fraidakis
O
,
Silverstein
JH
,
Beneken
JE
,
Gravenstein
JS
;
ISPOCD Investigators; International Study of Post-Operative Cognitive Dysfunction
:
Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study.
Lancet
.
1998
;
351
:
857
61
134.
Monk
TG
,
Weldon
BC
,
Garvan
CW
,
Dede
DE
,
van der Aa
MT
,
Heilman
KM
,
Gravenstein
JS
:
Predictors of cognitive dysfunction after major noncardiac surgery.
Anesthesiology
.
2008
;
108
:
18
30
135.
Borrell-Vega
J
,
Esparza Gutierrez
AG
,
Humeidan
ML
:
Multimodal prehabilitation programs for older surgical patients.
Anesthesiol Clin
.
2019
;
37
:
437
52
136.
Gillis
C
,
Buhler
K
,
Bresee
L
,
Carli
F
,
Gramlich
L
,
Culos-Reed
N
,
Sajobi
TT
,
Fenton
TR
:
Effects of nutritional prehabilitation, with and without exercise, on outcomes of patients who undergo colorectal surgery: A systematic review and meta-analysis.
Gastroenterology
.
2018
;
155
:
391
410.e4
137.
Mahanna-Gabrielli
E
,
Zhang
K
,
Sieber
FE
,
Lin
HM
,
Liu
X
,
Sewell
M
,
Deiner
SG
,
Boockvar
KS
:
Frailty is associated with postoperative delirium but not with postoperative cognitive decline in older noncardiac surgery patients.
Anesth Analg
.
2020
;
130
:
1516
23
138.
Nomura
Y
,
Nakano
M
,
Bush
B
,
Tian
J
,
Yamaguchi
A
,
Walston
J
,
Hasan
R
,
Zehr
K
,
Mandal
K
,
LaFlam
A
,
Neufeld
KJ
,
Kamath
V
,
Hogue
CW
,
Brown
CH
, IV
:
Observational study examining the association of baseline frailty and postcardiac surgery delirium and cognitive change.
Anesth Analg
.
2019
;
129
:
507
14
139.
Ng
TP
,
Feng
L
,
Nyunt
MS
,
Feng
L
,
Niti
M
,
Tan
BY
,
Chan
G
,
Khoo
SA
,
Chan
SM
,
Yap
P
,
Yap
KB
:
Nutritional, physical, cognitive, and combination interventions and frailty reversal among older adults: A randomized controlled trial.
Am J Med
.
2015
;
128
:
1225
36.e1
140.
Janssen
TL
,
Steyerberg
EW
,
Langenberg
JCM
,
de Lepper
CCHAVH
,
Wielders
D
,
Seerden
TCJ
,
de Lange
DC
,
Wijsman
JH
,
Ho
GH
,
Gobardhan
PD
,
van Alphen
R
,
van der Laan
L
:
Multimodal prehabilitation to reduce the incidence of delirium and other adverse events in elderly patients undergoing elective major abdominal surgery: An uncontrolled before-and-after study.
PLoS One
.
2019
;
14
:
e0218152
141.
Valenzuela
M
,
Sachdev
P
:
Can cognitive exercise prevent the onset of dementia?: Systematic review of randomized clinical trials with longitudinal follow-up.
Am J Geriatr Psychiatry
.
2009
;
17
:
179
87
142.
Ball
K
,
Berch
DB
,
Helmers
KF
,
Jobe
JB
,
Leveck
MD
,
Marsiske
M
,
Morris
JN
,
Rebok
GW
,
Smith
DM
,
Tennstedt
SL
,
Unverzagt
FW
,
Willis
SL
;
Advanced Cognitive Training for Independent and Vital Elderly Study Group
:
Effects of cognitive training interventions with older adults: A randomized controlled trial.
JAMA
.
2002
;
288
:
2271
81
143.
Ngandu
T
,
Lehtisalo
J
,
Solomon
A
,
Levälahti
E
,
Ahtiluoto
S
,
Antikainen
R
,
Bäckman
L
,
Hänninen
T
,
Jula
A
,
Laatikainen
T
,
Lindström
J
,
Mangialasche
F
,
Paajanen
T
,
Pajala
S
,
Peltonen
M
,
Rauramaa
R
,
Stigsdotter-Neely
A
,
Strandberg
T
,
Tuomilehto
J
,
Soininen
H
,
Kivipelto
M
:
A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controlled trial.
Lancet
.
2015
;
385
:
2255
63
144.
Mahncke
HW
,
Connor
BB
,
Appelman
J
,
Ahsanuddin
ON
,
Hardy
JL
,
Wood
RA
,
Joyce
NM
,
Boniske
T
,
Atkins
SM
,
Merzenich
MM
:
Memory enhancement in healthy older adults using a brain plasticity-based training program: A randomized, controlled study.
Proc Natl Acad Sci U S A
.
2006
;
103
:
12523
8
145.
Rebok
GW
,
Ball
K
,
Guey
LT
,
Jones
RN
,
Kim
HY
,
King
JW
,
Marsiske
M
,
Morris
JN
,
Tennstedt
SL
,
Unverzagt
FW
,
Willis
SL
;
ACTIVE Study Group
:
Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults.
J Am Geriatr Soc
.
2014
;
62
:
16
24
146.
Saleh
AJ
,
Tang
GX
,
Hadi
SM
,
Yan
L
,
Chen
MH
,
Duan
KM
,
Tong
J
,
Ouyang
W
:
Preoperative cognitive intervention reduces cognitive dysfunction in elderly patients after gastrointestinal surgery: A randomized controlled trial.
Med Sci Monit
.
2015
;
21
:
798
805
147.
Vlisides
PE
,
Das
AR
,
Thompson
AM
,
Kunkler
B
,
Zierau
M
,
Cantley
MJ
,
McKinney
AM
,
Giordani
B
:
Home-based cognitive prehabilitation in older surgical patients: A feasibility study.
J Neurosurg Anesthesiol
.
2018
;
31
:
212
7
148.
O’Gara
BP
,
Mueller
A
,
Gasangwa
DVI
,
Patxot
M
,
Shaefi
S
,
Khabbaz
K
,
Banner-Goodspeed
V
,
Pascal-Leone
A
,
Marcantonio
ER
,
Subramaniam
B
:
Prevention of early postoperative decline: A randomized, controlled feasibility trial of perioperative cognitive training.
Anesth Analg
.
2019
;
130
:
586
95
149.
Humeidan
ML
,
Reyes
JC
,
Mavarez-Martinez
A
,
Roeth
C
,
Nguyen
CM
,
Sheridan
E
,
Zuleta-Alarcon
A
,
Otey
A
,
Abdel-Rasoul
M
,
Bergese
SD
:
Effect of cognitive prehabilitation on the incidence of postoperative delirium among older adults undergoing major noncardiac surgery: The neurobics randomized clinical trial.
JAMA Surg
.
2021
;
156
:
148
56
150.
Song
Y
,
Cui
X
,
Zhang
Y
,
Gao
H
,
Cai
Q
,
Mu
Z
:
Home-based computerized cognitive training for postoperative cognitive dysfunction after lung transplantation in elderly population: A randomized controlled trial.
J Nerv Ment Dis
.
2019
;
207
:
693
9
151.
Inouye
SK
,
Bogardus
ST
, Jr
,
Baker
DI
,
Leo-Summers
L
,
Cooney
LM
, Jr
;
Hospital Elder Life Program
:
The Hospital Elder Life Program: A model of care to prevent cognitive and functional decline in older hospitalized patients.
J Am Geriatr Soc
.
2000
;
48
:
1697
706
152.
Chen
CC
,
Lin
MT
,
Tien
YW
,
Yen
CJ
,
Huang
GH
,
Inouye
SK
:
Modified hospital elder life program: Effects on abdominal surgery patients.
J Am Coll Surg
.
2011
;
213
:
245
52
153.
Cheng
CM
,
Chiu
MJ
,
Wang
JH
,
Liu
HC
,
Shyu
YI
,
Huang
GH
,
Chen
CC
:
Cognitive stimulation during hospitalization improves global cognition of older Taiwanese undergoing elective total knee and hip replacement surgery.
J Adv Nurs
.
2012
;
68
:
1322
9