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Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies

Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies
Elizabeth Mahanna-Gabrielli, MD
Roderic G Eckenhoff, MD
Section Editors:
Natalie F Holt, MD, MPH
Mario F Mendez, MD, PhD
Deputy Editor:
Nancy A Nussmeier, MD, FAHA
Literature review current through: Nov 2022. | This topic last updated: Dec 15, 2022.

INTRODUCTION AND DEFINITIONS — The term perioperative neurocognitive disorder (PND) is used as an overarching term to describe alterations in behavior, affect, and cognition that occasionally occur after anesthesia and surgery based on Diagnostic and Statistical Manual 5th edition (DSM-V) terminology for neurocognitive disorder (NCD) [1-4]. This term PND includes preexisting cognitive impairment diagnosed in the preoperative period, postoperative persistent or recurrent delirium (beyond the transient "emergence," from general anesthesia), delayed neurocognitive recovery (cognitive decline not due to delirium and diagnosed up to 30 days after a procedure), and major or minor neurocognitive decline that persists or is diagnosed up to 12 months after the procedure (termed NCD [postoperative]). This topic will address anesthetic and perioperative strategies to prevent and mitigate PND.

Diagnosis and management of delirium and other overt cognitive impairment occurring in nonsurgical settings are discussed elsewhere:

(See "Diagnosis of delirium and confusional states".)

(See "Delirium and acute confusional states: Prevention, treatment, and prognosis".)

(See "Evaluation of cognitive impairment and dementia".)


Preexisting cognitive impairment — A significant percentage of patients over the age of 65 have mild or major neurocognitive decline prior to surgery [5-7]. It is most important to recognize these patients as they have a greater likelihood of developing postoperative delirium, persistent neurocognitive impairment [5], or later dementia [8]. (See 'Risk assessment' below and 'Preoperative cognitive screening' below.)

Postoperative delirium — There are two distinct categories of postoperative delirium: transient agitation and delirium occurring during or shortly after emergence from general anesthesia, and persistent or recurrent delirium which may occur later in the postoperative period.

Emergence delirium – Transient occurrences of emergence delirium, agitation, or excessive somnolence that rapidly resolve after initial emergence from general anesthesia may occur. Such transient emergence agitation is a common phenomenon during initial emergence from general anesthesia as a patient transitions through the delirium stage (stage II). This brief phenomenon is sharply distinguished from other types of postoperative agitation or delirium since it is confined to the emergence period as consciousness is being restored [9]. Although an expected transitional phase during emergence from general anesthesia, severe symptoms require specific management, as discussed separately. (See "Emergence from general anesthesia", section on 'Severe agitation'.).

Persistent or recurrent delirium – In some adults and children, agitation or delirium persists or reoccurs after emergence from general anesthesia, or only becomes evident in the post-anesthesia care unit (PACU). Persistent or recurrent postoperative delirium may also occur later in the postoperative period after any type of surgery and anesthetic technique. Evaluation and treatment of these phenomena during the early recovery period are discussed in separate topics. (See "Delayed emergence and emergence delirium in adults", section on 'Emergence delirium' and "Emergence delirium and agitation in children".)

Early postoperative delirium is an acute change in cognition that usually occurs in the first postoperative week. It is characterized by impaired attention and an altered level of consciousness that may manifest as overt agitation, hyperexcitability, disinhibition, crying, restlessness, and confusion (hyperactive subtype), or as excessive somnolence with altered mental status (hypoactive subtype) [10-12]. The hyperactive subtype is overt and more easily detected. Some patients fluctuate between hyper- and hypoactive delirium [13].

Postoperative neurocognitive impairment — The patient, informant, or clinician may note postoperative cognitive impairment that is more subtle than overt delirium. In some cases, there is additional objective evidence of decline in cognition or activities of daily living [1,2,4,14]. (See "Evaluation of cognitive impairment and dementia".)

At least two syndromes, defined by the timing of onset (and resolution) of symptoms and the severity of symptoms, are described [1,2,4]:

Delayed neurocognitive recovery – Delayed neurocognitive recovery persisting up to 30 days after a procedure has been reported in 17 to 43 percent of postoperative adult patients, and is often associated with major surgical procedures and/or a medically complicated postoperative recovery period [15]. In most, neurocognitive recovery is apparently complete within 30 days, although it is unclear if residual subclinical injury or vulnerability may persist in a subset of recovered patients [4].

Neurocognitive disorder (postoperative) – In some cases, objective evidence of cognitive impairment persists beyond 30 days for a year or longer after surgery. Cognitive decline that persists or is diagnosed up to 12 months after a surgical procedure is termed neurocognitive disorder (NCD) with a qualifying term that specifies the setting (postoperative) [1-4]. If symptoms are first reported more than one year after a surgical procedure, the term "postoperative," is dropped in the clinical description.

Persistent NCD (postoperative) is further qualified as being mild (with symptoms roughly equivalent to the National Institute on Aging/Alzheimer's Association [NIA/AA] term mild cognitive impairment) or major (with symptoms roughly equivalent to the NIA/AA definition for dementia) [16,17].

The presence of preoperative neurocognitive impairment, even if mild, and the occurrence of postoperative delirium are associated with the development of dementia within five years of having the surgery [8]. Some retrospective studies have raised the possibility that anesthesia and surgery may lead to onset or worsening of dementia [18-23], although other studies do not support such an association [24-28]. One study used a Medicare database to compare this risk in patients aged 68 to 77 years without Alzheimer disease (AD) including nearly 55,000 who underwent an appendectomy for acute appendicitis versus nearly 275,000 matched controls who did not undergo appendectomy [24]. After 7.5 years of follow-up, the appendectomy group had a lower rate of AD than the control group (7.6 versus 8.6 percent; hazard ratio [HR] 0.89, 95% CI 0.86-0.92). However, these reassuring findings may not be generally applicable to older patients undergoing larger and more invasive procedures than appendectomy.

Another term that has been historically used in research regarding postoperative decline on various neuropsychologic tests (compared with an individual's preoperative performance) is postoperative cognitive dysfunction (POCD) [1-4]. However, definitions for POCD have been inconsistent among different research groups, with variations in the specific neuropsychologic tests administered, methods used to calculate decline, and timing and magnitude of reported decline [1,2,4,29]. Also, POCD definitions have not required documentation that clinical symptoms or complaints of overt cognitive impairment were noted by the patient, family members, or clinicians. Furthermore, many studies of POCD did not include a control group of patients undergoing a hospitalization without any surgical intervention [30,31].

PATHOPHYSIOLOGIC MECHANISMS — The systemic inflammatory response to the surgical procedure itself is thought to be an important cause of all types of PND. Proposed mechanisms include a preexisting neuroinflammation or neurodegeneration (that may not be known or acknowledged by the patient), which primes the brain to react more strongly to an acute systemic inflammatory response [2,32-35]. The result is accelerated progression of neuroinflammation and neurodegeneration, and delay in neurocognitive recovery. Progression or eventual resolution of PND caused by these initial inflammatory responses to surgery may be impacted by patient-specific and perioperative factors. (See 'Role of anesthetic agents and techniques' below and 'Postoperative anesthetic management' below.)


Risk assessment

Patient-related factors – The most consistent preoperative risk factors for delirium and other forms of PND are older age and the presence of preoperative cognitive impairment [5,12,36-41].

Adults >65 years of age have an incidence of persistent postoperative delirium ranging from 4 to 55 percent after surgery and anesthesia, while the incidence is >80 percent in critically ill older patients [12,42-44]. Older adults are also at risk for other forms of postoperative neurocognitive disorder (NCD) [1,4,30,45-47]. In a 2016 systematic review that included 25 studies, approximately 12 percent of older adults developed a mild or major form of NCD after noncardiac surgery [30].  

A preoperative diagnosis of Alzheimer disease (AD) and related dementias is associated with postoperative delirium and PND [17,45,48-53]. Notably, some older adults have preoperative neurodegenerative dementia that has not been diagnosed.

Other risk factors for PND include preoperative sleep disruption, excessive consumption of alcohol, polypharmacy or psychotropic drug use, and medical comorbidities such as severe vascular disease, diabetes, prior neuronal damage (eg, stroke, traumatic brain injury), or frailty [36-38,54-68].

A lower educational level is associated with an increased risk for development of PND, while a higher level of education may be a surrogate for cognitive reserve that protects against PND [49,63,69-72].

Procedure-related factors – Postoperative delirium is more likely after major surgery such as cardiac or major orthopedic surgery. Incidence is highest after major surgical procedures including open cardiac surgery (26 to 52 percent); minimally invasive cardiac surgery (8 to 26 percent); major orthopedic surgery (hip fracture repair or total hip and knee arthroplasty; 17 to 31 percent); major head and neck surgery (12 to 36 percent); and colorectal surgery (8 to 54 percent) [42,73-81].

Similarly, other studies have also noted that prolonged or complex surgical procedures confer risk [12,33,36,73,82,83]. Duration of surgery (and anesthesia) is a risk factor, or may be an indication of a more complex procedure [83,84]. In one retrospective study of more than 68,000 patients undergoing surgery for hip fracture repair, every 30 minute increase in surgical duration increased risk for delirium by 6 percent (odds ratio 1.06, 95% CI 1.03-1.08) [83].

Institution-related factors – One multi-institutional clinical data registry that included >200,000 older adults undergoing cardiac or noncardiac surgical procedures identified some outlier institutions with significantly lower or higher rates of delirium than the average 12 percent, after adjustment for patient risk factors and surgical case mix [73]. Although reasons for institutional variability are unclear, multidisciplinary hospital-level processes to prevent delirium in high-risk surgical patients are likely helpful [12,73,85-91].

Preoperative cognitive screening — A brief preoperative cognitive screen may detect or confirm a diagnosis of preexisting cognitive impairment [65,92-96]. Preoperative cognitive screening is particularly important in older or frail adults and those with other risk factors, and is useful for planning prevention strategies. Such screening also serves as a baseline to assess postoperative development of delirium and other forms of PND [40,41,94,95]. Although most preoperative screening has employed widely used mental status scales, such as the Mini-Mental State Examination (MMSE), shorter scales, such as the Mini-Cog, may be more practical and easily administered [65,92-95]. In addition to cognitive screen, it may be useful to obtain a baseline delirium screen with the Confusion Assessment Method (CAM) or the NEECHAM confusion scale [97,98]. (See "Anesthesia for the older adult", section on 'Assessment of baseline cognitive function' and "Anesthesia for the older adult", section on 'Assessment for frailty' and 'Risk assessment' above.)

Surgeons and anesthesiologists often fail to identify subtle cognitive impairment during routine preoperative evaluations unless cognitive screening is performed [94,99]. Many patients do not mention the presence of previous or current symptoms [3,17,36,37,45,48-53,73,99-103]. For this reason, it is particularly important to question the patient about any previous episodes of cognitive impairment in the postoperative setting [3]. Also, directed questioning of family members regarding symptoms is often helpful. Furthermore, if donepezil and/or memantine are noted on the patient's medication list, cognitive impairment or dementia is suspected.

Some institutions have implemented preoperative risk stratification to identify high-risk patients (eg, patients with pre-existing dementia or frailty) who may benefit from multidisciplinary delirium prevention programs [12,17,85-91,100,104]. Such prevention programs may include cognitive prehabilitation, avoidance of intravenous (IV) agents associated with higher risk; avoidance of excessive anesthetic depth, hypotension, or cerebral desaturation; and planned use of postoperative prevention strategies, including identification of potentially problematic medication interactions. (See 'Cognitive prehabilitation' below and 'Role of anesthetic agents and techniques' below and 'Postoperative prevention strategies' below.)

Cognitive prehabilitation — Cognitive prehabilitation (eg, cognitive exercise or preconditioning) is offered to selected patients in some centers. However, evidence that such efforts can reduce risk for postoperative cognitive dysfunction (POCD) or delirium is scant [5,105].

Cognitive exercise – Small studies of computer-based cognitive exercises targeting memory, speed, attention, flexibility, and problem-solving functions during the preoperative period have reported inconsistent results. One randomized trial in 251 older patients undergoing major noncardiac surgery reported a trend toward a lower incidence of postoperative delirium in patients who participated in a preoperative cognitive exercise program compared with controls (14.4 versus 23.0 percent) [106]. Another randomized trial in 141 older patients undergoing major gastrointestinal surgery noted a lower incidence of POCD on neuropsychological tests administered one week after surgery in those who participated in preoperative cognitive training compared with controls (15.9 versus 36.1 percent) [107]. Other randomized trials have noted difficulties in ensuring patient participation and absence of impact on incidences of POCD or delirium [108,109].

Electroacupuncture cognitive preconditioning – Acupuncture at specified locations on the scalp combined with transcranial electrical stimulation (ith adjustments of timing, frequency, and intensity of the stimulation) has been used for cognitive preconditioning [110,111]. In a randomized trial conducted in 90 patients undergoing spine surgery, higher postoperative Mini-Mental Status Examination scores and lower plasma levels of neuroinflammatory markers (interleukin (IL) 6, IL-10, and S100 bet) were noted in patients who received electroacupuncture applied 30 minutes before anesthesia compared with controls [110].

Considerations for informed consent — Preoperative identification of preexisting cognitive impairment is useful to identify patients who may need assistance to fully understand the informed consent process [5]. In addition, patients and families should be informed about the possibility of postoperative exacerbation of a preexisting cognitive impairment, as well as planned preventive strategies [3,12,41,112].

ROLE OF ANESTHETIC AGENTS AND TECHNIQUES — This section will address the possible role of anesthetic agents and techniques in development of PND. However, it has been challenging to determine whether anesthesia-related factors are clinically significant since multiple other factors may cause neuropathologic changes and impair neurologic function in patients undergoing surgery. These include episodes of hypoxia or hypotension, stress responses to surgery, and hospitalization itself. For example, a Swedish registry study with more than 4000 surgical patients matched with more than 21,000 hospitalized controls noted that nonsurgical hospitalization is associated with greater dementia risk than hospitalization for surgical intervention [31].

Avoid excessive depth during general anesthesia — Although deeper anesthesia has been associated with development of postoperative delirium, a causative relationship has not been established [3,113-122]. The healthy human brain is resilient to even deep anesthesia [123]. However, since increasing age decreases anesthetic requirements, anesthetic dosing should be age-adjusted [5,124-126]. Other patient-related factors that may alter anesthetic requirements should also be considered when titrating anesthetic agents. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Influence of patient-related factors'.)

We employ continuous monitoring of the end-tidal anesthetic concentration (ETAC) to titrate inhalation anesthetic agents, with the goal of avoiding concentrations that are either too low or excessively high. We initially target an ETAC concentration close to the age-adjusted MAC value (ie, the exhaled concentration of the anesthetic agent at which 50 percent of patients do not move in response to a noxious stimulus). However, anesthetic concentrations are continuously titrated according to the individual patient's responses to maintain adequate anesthetic depth. (See "Accidental awareness during general anesthesia", section on 'End-tidal anesthetic concentration'.)

We also employ either raw electroencephalography (EEG) or processed EEG (eg, bispectral index [BIS], patient state index [PSI]), or other neuromonitoring techniques to aid in managing intraoperative dosing of anesthetic agents and avoid excessive anesthetic depth, particularly in older patients and others at risk for development of PND, and particularly when ETAC monitoring is not feasible (ie, inhalation agents are not administered) [127,128]. Our practice is consistent with recommendations of the European Society of Anaesthesiology (ESA) guideline on postoperative delirium, the American Society of Anesthesiologists (ASA) Brain Health Initiative, and the American Society for Enhanced Recovery and Perioperative Quality Initiative joint consensus statement on the role of neuromonitoring [3,5]. (See "Accidental awareness during general anesthesia", section on 'Brain monitoring'.)

When monitoring with EEG, clinicians should avoid low processed EEG values or burst suppression, both of which are associated with high doses of anesthetic agents, particularly if such dosing results in hypotension or blood pressure (BP) significantly lower than baseline values [3,36,127,129,130]. The frequency and duration of burst suppression on EEG has been associated with risk for delirium and/or prolonged emergence in several observational studies [116,117,131,132]. Other EEG patterns have also been associated with risk of delirium [131,133-135]. However, it is not clear whether such patterns identify a vulnerable brain or excessive anesthetic depth in individual patients [136,137]. It is also uncertain whether adjusting anesthetic depth to avoid their occurrence is beneficial. Studies examining outcomes have provided mixed results:

Impact on delirium – Studies have provided mixed results. A 2020 meta-analysis along with a subsequently published trial noted that EEG-based monitoring did not decrease the incidence of postoperative delirium (RR 0.79; 95% CI 0.60-1.05), although intensive care unit (ICU) length of stay was slightly reduced (three studies, weight mean difference [WMD] -0.29 days; 95% CI, -0.53 to -0.05) [138,139]. In contrast, two earlier meta-analyses of trials concluded that the use of processed EEG monitoring to guide anesthesia was associated with a 30 to 38 percent relative reduction in risk of postoperative delirium compared with no neuromonitoring [118,119]. Studies of regional versus general anesthesia also bear on this issue (see 'Choice of anesthetic technique' below), in that whether the EEG is monitored or not, the lack of difference in delirium outcome in large randomized trials makes anesthetic depth per se an unlikely contributor to delirium [140-142].

Impact on other neurocognitive outcomes – Studies examining the impact of EEG monitoring to avoid excessive anesthetic depth on other neurocognitive outcomes are limited and have provided somewhat inconsistent results [114,115,118,119,143-146]. (See 'Postoperative neurocognitive impairment' above.)

Avoid excessive sedation during regional anesthesia — We avoid excessive sedation in older patients undergoing regional anesthesia. However, there are not high quality data to support this recommendation. In a randomized trial, 200 older patients (mean age of 82 years) undergoing hip fracture repair received spinal anesthesia plus intravenous (IV) propofol [120]. The overall incidence of delirium was similar in patients receiving lighter sedation compared with those receiving heavier sedation.

Avoid extremes of blood pressure — We avoid extremes of BP (ie, hypotension or hypertension) and maintain BP within 20 percent of the patient's baseline, keeping mean arterial pressure (MAP) ≥65 mmHg and systolic BP ≥100 mmHg in most patients. (See "Hemodynamic management during anesthesia in adults", section on 'Blood pressure targets'.)

Intraoperative hypotension with possibly decreased cerebral blood flow has been implicated in development of postoperative delirium and other forms of PND [5,55,142,147-151]. A retrospective study noted that postoperative delirium was diagnosed in 2183 of 316,717 noncardiac surgical patients (0.7 percent), and that intraoperative MAP <55 mmHg was associated with delirium with a duration-dependent relationship [151]. The adjusted odds ratio (aOR) was 1.22 (95% CI 1.11-1.33) for duration lasting <15 minutes , with a higher aOR of 1.57 (95% CI 1.27-1.94) if duration lasted ≥15 minutes [151]. However, data are not consistent. Other studies in noncardiac and cardiac surgical patients have not found an association between intraoperative hypotension and postoperative delirium [152-154]. Occurrence and duration of hypotension may reflect pre-existing patient vulnerability due to risk factors such as older age, frailty, or medical comorbidities, and these factors are also associated with postoperative delirium. (See 'Risk assessment' above.)

One prospective cohort study in noncardiac surgical patients found that increased risk for postoperative delirium was associated with BP variability, rather than with absolute or relative hypotension [155]. Similarly, in cardiac surgical patients, episodes of either markedly low or high BP during cardiopulmonary bypass have been associated with increased risk for PND, possibly due to inability to compensate via autoregulation [156-158]. A randomized trial conducted in 199 older patients undergoing cardiac surgery found that risk of postoperative delirium was reduced by maintaining a patient’s MAP target above their individual lower limit of cerebral autoregulation (as predetermined with transcranial Doppler technology), compared with standard management (OR 0.55; 95% CI 0.31-0.97) [159]. However, most centers do not use this technology and employ BP targets rather than this individualized approach. (See "Management of cardiopulmonary bypass", section on 'Mean arterial pressure' and 'Avoid excessive depth during general anesthesia' above.)

Avoid cerebral desaturation — Cerebral oximetry monitoring with near-infrared spectroscopy may be employed for selected cases to maintain regional cerebral oxygen saturation (rSO2) values near the patient's baseline. Studies in cardiac and noncardiac surgery have noted an association between rSO2 <65 percent and delayed postoperative neurocognitive recovery and delirium, as well as other adverse outcomes [158,160-170]. Monitoring cerebral oximetry to maintain optimal cerebral oxygenation may affect outcomes such as PND by detecting abnormalities in autoregulation of cerebral blood flow [158]. (See 'Avoid extremes of blood pressure' above and "Management of cardiopulmonary bypass", section on 'Neuromonitoring modalities'.)

Combinations of cerebral oximetry and processed EEG neuromonitoring have been used to avoid either excessive anesthetic depth or cerebral oxygen desaturation. In one randomized trial conducted in 192 older adults undergoing noncardiac surgery, less postoperative cognitive dysfunction was noted in the group with these concomitant modalities compared with controls with no neuromonitoring [171].

Choice of anesthetic techniques and agents

Choice of anesthetic technique — Evidence is insufficient to recommend specific anesthetic techniques to avoid or minimize PND; thus, we select an appropriate anesthetic technique based on other considerations [3,12,100,140,172-177].

General versus neuraxial or regional anesthesia – Compared with general anesthesia, neuraxial or regional anesthesia with light, deep, or no sedation does not consistently decrease the incidence of delirium or other PND [3,12]. In a randomized trial of 950 older patients undergoing hip fracture surgery, the incidence of postoperative delirium was similar in those who received neuraxial anesthesia (spinal and/or epidural) without any sedation compared with those who received general anesthesia [141]. Another randomized trial in 1600 patients undergoing hip fracture surgery also noted a similar incidence of delirium after spinal anesthesia (with or without sedative agents) compared with general anesthesia [140]. Furthermore, a randomized trial in 217 older patients undergoing lumbar spine fusion noted that spinal anesthesia with targeted BIS-guided sedation did not reduce delirium compared with general anesthesia with masked BIS values [142]. Also, in patients undergoing extracorporeal shock wave lithotripsy, a randomized trial in 100 patients noted a similar incidence of postoperative delirium after spinal anesthesia with no sedatives compared with general anesthesia [174].

Some retrospective studies have noted a lower incidence of postoperative delirium when neuraxial rather than general anesthesia was used [83,172,173,178,179]. However, such observational studies are likely to be limited by confounding variables affecting anesthetic choice (eg, anxiety, agitation, or delirium in the preoperative period) [180]. One randomized trial in 1802 patients aged 60 to 90 years undergoing major noncardiac (thoracic or abdominal) surgery did find that patients receiving combined epidural plus general anesthesia had a lower risk of postoperative delirium (relative risk [RR] 0.35, 95% CI 0.20-0.63) [181]. It is possible that epidural analgesia mitigates delirium risk by reducing postoperative pain and opioid dosing after selected procedures [182]. However, a higher risk of intraoperative hypotension with systolic BP <80 mmHg (RR 1.47, 95% CI 1.31-1.65) was noted in patients receiving combined epidural plus general compared with those receiving only general anesthesia [181].

Evidence also suggests that the incidence of other types of PND is unaffected by selection of neuraxial versus general anesthesia [3,174,183-187]. Scant evidence exists for other types of regional anesthetic techniques such as peripheral nerve blocks or local anesthesia compared with general anesthesia. For example, in older hip fracture patients, delirium incidence was not reduced by use of either femoral nerve blocks nor fascia iliaca nerve blocks even though opioid requirements were reduced in patients receiving these blocks [188,189]. In patients undergoing coronary revascularization, cognitive outcomes are not different after coronary artery bypass grafting (CABG) with general anesthesia compared with percutaneous coronary intervention (PCI) with minimal or no sedation [190].

Inhalation versus intravenous anesthetic techniques – In adults, the likelihood of developing delirium is not affected by selection of a total IV anesthetic (TIVA) technique versus an inhalation-based anesthetic technique for general anesthesia [12,176].

In a 2018 meta-analysis of 28 trials that included more than 4500 older adults undergoing noncardiac surgery with an inhalation-based technique or a propofol-based TIVA technique, the incidence of postoperative delirium was similar [177]. Although low-certainty evidence in that meta-analysis suggested that TIVA may reduce postoperative cognitive dysfunction (POCD; OR 0.52, 95% CI 0.31-0.87; 869 participants), marked heterogeneity between studies in selection of specific neuropsychologic testing methods was noted. One subsequently published randomized trial found a lower incidence of delayed neurocognitive recovery at one week after surgery in patients who received propofol-based TIVA rather than sevoflurane-based anesthesia (OR 0.58, 95% CI 0.34-0.98) [191].

In children, emergence delirium is less likely to occur after TIVA compared with inhalation-based anesthetic techniques, as discussed separately. (See "Emergence delirium and agitation in children", section on 'Anesthetics'.)

Intravenous agents associated with higher risk — We avoid high doses or minimize administration of certain anesthetic agents and other medications in older adults and others at high risk for delirium [12,192,193]. (See "Drug prescribing for older adults", section on 'Beers criteria'.)

Benzodiazepines – Perioperative benzodiazepine administration is associated with increased risk of delirium and is avoided in high-risk patients, particularly older adults [194].

One trial conducted in patients >70 years of age who had regional anesthesia with sedation noted that those receiving midazolam (administered as an initial bolus dose of 0.05 mg/kg followed by 0.5 mcg/kg as needed) had a higher incidence of intraoperative agitation compared with those receiving dexmedetomidine (administered as a loading dose of 1 mcg/kg followed by continuous infusion at 0.2 to 0.8 mcg/kg per hour) [195]. An observational study that included 2,848,897 patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) noted that approximately 75 percent received midazolam in the perioperative period and approximately 25 percent received gabapentinoid concurrently with midazolam [196]. After adjustment for covariates that included age, gender, race, comorbidities, type of anesthesia, year of surgery, hospital location, hospital teaching status, hospital size, and insurance provider, risk for delirium was not associated with midazolam use in either the THA or TKA group. However, concurrent use of midazolam and gabapentinoids was associated with increased risk for postoperative delirium (OR 1.45, 95% CI 1.38-1.52 in THA patients; and OR 1.32, 95% CI 1.23-1.34 in TKA patients), as well as risk for respiratory complications [196]. Other large observational studies have also associated administration of benzodiazepines with the risk of delirium [128,172,173].

However, data are not consistent. A large, post-hoc analysis of three prospective studies in older patients undergoing noncardiac surgery used propensity score matching to determine that the incidence of delirium on the first postoperative day was similar to that in 909 patients who received midazolam premedication compared with 357 patients who had no midazolam [197].

Gabapentinoids – We avoid perioperative administration of gabapentinoids in older patients and other high-risk patients, as these agents may increase likelihood of delirium or POCD, possibly due to side effects that include sedation, confusion, dizziness, lightheadedness, and visual disturbances [172,198-200].

A 2022 large retrospective study used propensity matching to identify 237,872 pairs of patients ≥65 years old who did or did not receive perioperative gabapentin [200]. Compared with nonusers, gabapentin users had increased risk of delirium (3.4 versus 2.6 percent; RR 1.28, 95% CI 1.23-1.34). Similar results were noted in another large retrospective study that included nearly 1.7 million patients, in which perioperative administration of gabapentinoids was associated with increased risk for delirium (OR 1.26, 95% CI 1.16-1.36) [172]. As noted above, delirium is particularly likely if gabapentinoids and midazolam are used concurrently [196].

Opioids – We use age-adjusted doses of opioids based on ideal body weight, and use multimodal opioid-sparing techniques for postoperative pain management to minimize total opioid doses. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'.)

Opioids (particularly meperidine) may precipitate delirium, but uncontrolled pain is also a risk factor for delirium [10,59,173,201]. Thus, intraoperative opioid doses are individualized, based on ideal body weight to avoid overdosing, and are titrated to supplement other anesthetic agents. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Dosing considerations'.)

Although meperidine is sometimes used to treat postoperative shivering [202], it is typically avoided in high-risk patients because its metabolite, normeperidine, is associated with delirium [203,204]. (See "Perioperative temperature management", section on 'Shivering'.)

Ketamine – The psychotomimetic side effects of ketamine may present as emergence delirium (eg, hallucinations, nightmares, vivid dreams) [173,205-208]. We do not avoid ketamine as it has analgesic, opioid-sparing, and antidepressant properties. Ketamine did not prevent (or cause) postoperative delirium in a large multicenter trial [208]. A meta-analysis of other small randomized trials reported similar results [209]. (See "Maintenance of general anesthesia: Overview", section on 'Ketamine'.)

Other medications associated with higher risk – Generally, we avoid diphenhydramine, metoclopramide, anticholinergics (particularly scopolamine), diphenhydramine, metoclopramide, and agents that may cause serotonin syndrome (table 1) in older patients and others at high risk for development of postoperative delirium or other neurocognitive disorder (NCD).

Intravenous agents associated with lower risk — Antiinflammatory agents including acetaminophen, nonselective anti-inflammatory drugs (NSAIDS), and selective COX-2 inhibitors are often used as part of a multimodal anesthetic. Some evidence suggests these agents may decrease risk for PND, perhaps due to opioid-sparing and/or anti-inflammatory properties.

Anti-inflammatory drugs

Acetaminophen – IV acetaminophen (ie, paracetamol) is an antiinflammatory and analgesic agent that reduces pain intensity and has minor opioid-sparing effects after major surgery [210,211]. In a small randomized trial in older adults having cardiac surgery, postoperative scheduled IV acetaminophen combined with IV propofol or IV dexmedetomidine reduced the incidence of in-hospital delirium compared with placebo (10 versus 28 percent; hazard ratio [HR] 2.8, 95% CI 1.1-7.8; 121 patients), and reduced opioid use during the first 48 postoperative hours (median morphine equivalents, 323 versus 405 mcg) [211].

Selective cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory drugs – We routinely use nonsteroidal antiinflammatory agents (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors during the perioperative period in patients who do not have a high risk of bleeding or kidney injury. In a large retrospective study, a lower incidence of delirium was noted in patients who received NSAIDs (OR 0.85, 95% CI 0.79-0.91) or COX-2 inhibitors (OR 0.82, 95% CI 0.77-0.89) [172].

Parecoxib is an IV selective COX-2 inhibitor that is not available in the United States. A 2018 systematic review noted less opioid consumption and a lower incidence of POCD up to one week after noncardiac surgery in small randomized trials of patients who received parecoxib administered during the intraoperative and postoperative periods as a supplemental agent to produce postoperative analgesia [212], with similar results reported in one additional trial [213].

Dexamethasone or methylprednisolone – Although perioperative administration of steroids to reduce inflammatory responses has been studied (eg, dexamethasone [214-220], methylprednisolone [221-223]), results are inconsistent. Concerns regarding adverse side effects have limited use of steroids to prevent PND.

Dexmedetomidine – Although evidence is insufficient to recommend routine use of dexmedetomidine to prevent delirium or other types of PND, it is reasonable to administer an intraoperative infusion (or continue infusion in the postoperative period) in high-risk patients with the aim of reducing the incidence of agitated emergence delirium. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Medications to prevent delirium' and "Maintenance of general anesthesia: Overview", section on 'Dexmedetomidine'.)

Some studies suggest that intraoperative administration of dexmedetomidine ameliorates or reduces the incidence of agitated emergence delirium [224-226]. A 2018 meta-analysis of randomized trials in patients undergoing either cardiac or noncardiac surgery noted a lower incidence of delirium when intraoperative or postoperative dexmedetomidine was administered, compared with no exposure to dexmedetomidine (OR 0.35, 95% CI 0.24-0.51; 18 trials, 3309 patients) [227]. Another 2018 meta-analysis limited to patients undergoing cardiac surgery noted similar results (risk ratio 0.46, 95% CI 0.34-0.62; ten trials, 1387 patients) [228]. A subsequently published trial in 169 patients undergoing cardiac surgery also noted less delirium in the dexmedetomidine group compared with placebo (OR 0.33, 95% CI 0.12-0.90; 169 patients) [229]. However, a 2022 meta-analysis of nine randomized trials (942 patients) in patients undergoing cardiac surgery reported no difference in the incidence of delirium after perioperative administration of dexmedetomidine, although a lower incidence of delayed neurocognitive recovery was noted [230]. Data are most robust for studies investigating postoperative dexmedetomidine infusions in the intensive care unit [12,227,229,231]. However, study results are not consistent for intraoperative dexmedetomidine administration, and some data shows no benefit for delirium reduction [230,232,233].

Evidence supporting use of dexmedetomidine to prevent other types of PND is limited [234-237]. One trial conducted in older patients undergoing laparotomy noted that those receiving intraoperative dexmedetomidine had less cognitive decline on neuropsychiatric tests administered on the third and seventh postoperative days compared with baseline test scores, as well as less cognitive impairment at one postoperative month (assessed only via a telephone interview) compared with patients who did not receive dexmedetomidine [237].

Inhalation anesthetic agents — There is scant evidence to support use of any one inhalation agent to decrease incidence of PND; thus, we select specific inhalation anesthetics based on other considerations. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Specific inhalation anesthetic agents'.).

A trial examining use of nitrous oxide (N2O) noted no association with long-term decline of cognitive function compared with patients who received general anesthesia with no exposure to N2O [238].

Studies of the potent volatile inhalation agent desflurane have mixed results. One small trial in 30 patients found less POCD (ie, delayed neurocognitive recovery) at one week in patients who received desflurane compared with those who received isoflurane [239]. Conversely, a retrospective study of 532 adults ≥60 years of age noted a higher incidence of delirium in patients receiving desflurane rather than sevoflurane or isoflurane [240]. A review of retrospective studies noted no difference in POCD for use of desflurane versus sevoflurane for maintenance of general anesthesia [241].


Postoperative prevention strategies — Postoperative factors that may impact development, worsening, or resolution of PND include pain and other discomfort, certain medications, sensory impairments, immobilization, dehydration, specific laboratory abnormalities (eg, sodium or glucose levels), sleep deprivation, and intensive care unit (ICU) admission [5,12,242].

In the immediate postoperative period, including the patient's stay in the post-anesthesia care unit (PACU), efforts to prevent delirium and later development of other forms of PND include nonpharmacologic measures such as cognitive stimulation with provision of reassurance and reorientation; maintenance of sensory input (glasses, hearing aids); early mobilization; removing lines, drains, and restraints; avoiding dehydration; avoiding hypoxia; and minimizing or avoiding medications associated with risk for delirium while providing control of postoperative pain [243]. In particular, the clinical effect of each opioid dose should be closely monitored. Nonopioid agents and techniques are preferred when feasible. For patients admitted to an ICU, daily awakening and breathing trials may also be useful. Multidisciplinary bundled care guidelines to implement these nonpharmacologic measures reduce the incidence of delirium [12,45,52,85,173,243-245]. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Prevention' and 'Intravenous agents associated with higher risk' above and "Management of acute perioperative pain in adults".)

Postoperative detection — Brief postoperative screening tools for delirium can help rule out delirium or identify patients who require further testing [12,36,246-249]. We typically use the Confusion Assessment Method (CAM) test, specifically a brief version of the CAM termed the 3-Minute Diagnostic Assessment or 3D-CAM [249,250], or the CAM-ICU version. These tests are easily administered in the postoperative period. (See "Diagnosis of delirium and confusional states", section on 'Recognizing the disorder'.)

Postoperative management strategies

Delirium – Known causes of delirium should be investigated and treated as appropriate [12]. These include medication-induced delirium, or delirium caused by other medical conditions. The possibility of substance intoxication or withdrawal (eg, alcohol, amphetamines, cocaine, cannabinoids) should also be considered. If suspected, a toxicology screen may provide useful information. (See "Diagnosis of delirium and confusional states" and "Testing for drugs of abuse (DOAs)".)

For severe agitation in the PACU, treatment with a small dose of haloperidol (eg, 0.5 to 2 mg) is sometimes necessary after treatment of reversable causes. (See "Delayed emergence and emergence delirium in adults", section on 'Evaluation and treatment'.)

In patients with persistent or severe delirium in the postoperative period, a neurology consult is advisable even though an acute intracranial event such as stroke is a rare cause [251].

Other postoperative neurocognitive decline – Most persistent neurocognitive decline can be classified as delayed neurocognitive recovery, typically with symptomatic recovery within 30 days of exposure to surgery and anesthesia [4]. (See 'Incidence and clinical features' above.)

There are no known effective treatments for such delayed recovery. General management is similar to that for hospitalized patients with other forms of PND, including referral to a geriatric neurologist and/or memory clinic after discharge. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Persistent cognitive dysfunction' and "Evaluation of cognitive impairment and dementia".)


Delirium – Delirium at the time of PACU discharge is predictive of persistent delirium later in the postoperative course [252], as well as worse outcomes than patients without delirium (eg, prolonged length of hospital stay, discharge to a nursing home, mortality) [11,42,43,46,117,253-255]. Persistent postoperative delirium also portends greater decline in functional status [256-259], variable degrees of cognitive decline [49,257,260-266], and a greater risk of subsequent dementia [8,19,49,255,264,267-269], although causation is still uncertain.

Older adults experiencing postoperative delirium are particularly likely to have a longer length of hospital stay, discharge to a nursing home, and development of dementia and/or cognitive decline [45,46,255,270-272]. Up to 40 percent of older adults who develop postoperative delirium never return to their preoperative cognitive baseline [45,260]. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Outcomes'.)

Other postoperative neurocognitive decline – Although most patients with delayed neurocognitive recovery are asymptomatic within one month, recovery is slower in a fraction of patients, and some impairments do not resolve [273]. Some data suggest an association between hospitalization and an accelerated trajectory of preexisting cognitive decline or dementia, regardless of whether a surgical intervention was performed [1,32,47]. Long-term cognitive and functional impairments have been demonstrated for five years or longer in some critically ill hospitalized surgical (and medical) patients [31,274]. Factors determining whether an individual patient will recover to baseline cognitive status, or whether subsequent decline would have occurred in the absence of surgery and anesthesia are unknown. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Persistent cognitive dysfunction' and "Mild cognitive impairment: Prognosis and treatment".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Delirium and confusional states in older adults".)


Clinical features – Perioperative neurocognitive disorder (PND) refers to changes in behavior, affect, and cognition after surgery and anesthesia, and includes:

Delirium manifests as overt agitation, hyperexcitability, disinhibition, crying, restlessness, and confusion (hyperactive subtype), or as excessive somnolence with altered mental status (hypoactive subtype). (See 'Postoperative delirium' above.)

Cognitive impairment manifests with objective evidence of decline in cognition or activities of daily living. The timing of onset and resolution are specified as:

-Delayed neurocognitive recovery (up to 30 days after exposure to surgery and anesthesia)

-Neurocognitive disorder (NCD; postoperative) diagnosed up to 12 months post-procedure.

The severity of symptoms may be specified as major (similar to dementia) or minor (mild cognitive impairment). (See 'Postoperative neurocognitive impairment' above.)

Risk factors for PND (See 'Risk assessment' above.)

Patient-related factors include older age, preexisting cognitive impairment (which may be detected by a brief preoperative cognitive screen), preoperative sleep disruption, excessive consumption of alcohol, psychotropic drug use, medical comorbidities (eg, prior neuronal damage such as stroke or traumatic brain injury, severe vascular disease, diabetes), and frailty.

Procedure-related factors include cardiac, major orthopedic, or emergency procedures, or prolonged duration of surgery.

Preoperative management – We discuss individual risk and implications of PND during the informed consent process. (See 'Considerations for informed consent' above.)

Risk mitigation for all patients For all patients we avoid the following:

Excessive anesthetic depth during general anesthesia. We employ continuous monitoring of the end-tidal anesthetic concentration (ETAC) to titrate inhalation anesthetic agents. We also employ either raw or processed electroencephalography (EEG), particularly when ETAC monitoring is not feasible (ie, when inhalation agents are not administered) and in patients at risk for PND. (See 'Avoid excessive depth during general anesthesia' above.)

Excessive sedation during neuraxial or other regional anesthetic techniques. (See 'Avoid excessive sedation during regional anesthesia' above.)

Higher doses of intravenous (IV) anesthetic and adjunct agents that may increase risk for PND in patients at high risk. In particular, we minimize or avoid benzodiazepines, opioids, gabapentinoids, diphenhydramine, metoclopramide, anticholinergics (particularly scopolamine), and agents that can cause serotonin syndrome. (See 'Intravenous agents associated with higher risk' above.)

Extremes of blood pressure (BP; ie, hypotension or hypertension). (See 'Avoid extremes of blood pressure' above.)

Risk mitigation for high-risk patients

We suggest using antiinflammatory agents including acetaminophen, nonselective antiinflammatory drugs (NSAIDS), and selective COX-2 inhibitors as part of a multimodal anesthetic technique, which may decrease PND risk due to opioid-sparing and/or anti-inflammatory properties (Grade 2C).

We suggest administering an intraoperative infusion of dexmedetomidine or continuing infusion in the postoperative period in high-risk patients admitted to an intensive care unit (ICU) may reduce incidence of delirium (Grade 2C). (See 'Intravenous agents associated with lower risk' above.)

Evidence is insufficient to recommend specific anesthetic techniques (eg, neuraxial versus general anesthesia; total IV anesthesia [TIVA] versus inhalation-based anesthesia; or use of any one inhalation agent) to avoid PND; thus, we select an appropriate anesthetic technique based on other considerations. (See 'Choice of anesthetic technique' above and 'Inhalation anesthetic agents' above.)

Postoperative management

Employing nonpharmacologic measures such as cognitive stimulation with provision of reassurance and reorientation; maintenance of sensory input (glasses, hearing aids); early mobilization; avoidance of dehydration; and minimizing or avoiding medications associated with delirium risk while providing excellent control of postoperative pain. (See 'Postoperative prevention strategies' above and 'Intravenous agents associated with higher risk' above.)

Using a brief postoperative screening tool to detect delirium such as a brief version of the Confusion Assessment Method (CAM) test termed the 3-Minute Diagnostic Assessment (3D-CAM), or the CAM-ICU version. (See 'Postoperative detection' above.)

Investigating known causes of delirium and treating as appropriate, including medication-induced delirium, substance intoxication or withdrawal.

Obtaining a neurology consult in patients with severe or persistent delirium. (See 'Postoperative management strategies' above.)

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